INTRODUCTION

 

Did you know that the ketogenic diet was NOT initially created for weight loss? Recently, the “keto” diet has become another fad diet for people trying to lose weight. Since 2000, more researchers have started to study the ketogenic diet, causing an increase in dieters who are employing this diet.¹

 

For decades, various entities have promoted fad diets as a way to lose weight and accrue other health benefits, with no data to back them up. The ketogenic diet began to reach the public’s consciousness in the 1970s, gained popularity in the early 2010s, and by 2017, it was a frequent topic in national news media. Google searches for the ketogenic diet (sometimes called the paleo diet, which is similar but not identical) quadrupled that year; questions about this diet were in the top 10 health questions.² Many people started using the ketogenic diet without understanding how it works or its associated benefits and risks. In 2014, celebrities like Lebron James, Kim Kardashian, and Megan Fox started using the ketogenic diet during its fad weight loss phase. In 2020, around 6% of Americans were consuming a ketogenic, high fat diet.³

 

In the 1920s, researchers noticed that some patients with epilepsy experienced benefits during fasting, so they discovered a way to mimic fasting to treat the disease.¹ Soon, physicians began to use the ketogenic diet for its antiepileptic properties.¹ However, in the next decades, researchers introduced antiepileptic medications and the ketogenic diet’s popularity faded. Treatment for epilepsy still includes some of the first antiepileptic medications: phenobarbital and phenytoin.⁴ Although physicians began using phenobarbital in 1912 for epilepsy, the U.S. Food and Drug Administration did not approve phenytoin for use in epilepsy until 1938.⁵ In the 1940s, clinicians used troxidone, but its toxicity profile was unacceptable. Ethosuximide, approved in 1958, replaced it. Approval of carbamazepine and valproic acid in the 1960s made the ketogenic diet unnecessary and obsolete for the most part.⁵

 

Although pharmacists are the medication experts on the clinical team, they must understand all types of treatment, including nonpharmacologic interventions. During a ketogenic diet, patients eat a limited number of carbohydrates so the body will enter ketosis. Because of the diet’s intensity, pharmacists and technicians need to understand how the diet works to ensure patient safety. When patients start or are on the ketogenic diet, pharmacists need to counsel patients to ensure no drug interactions occur. Pharmacists also need to counsel patients who may have started the diet by themselves about its benefits and the risks. Also, remember interested dieters might embrace a New Year's resolution regarding ketogenic dieting, because National Keto Day is January 5th!

 

This continuing education activity summarizes knowledge of the ketogenic diet, the diet’s mechanism and its positive and negative effects, current medical uses for patients with epilepsy, diabetes, polycystic ovary syndrome (PCOS), and others, and recommendations for patient education and counseling.

 

KETOGENIC DIET

 

The ketogenic diet alters how the body burns energy, from carbohydrates to lipids. The traditional food pyramid places fats in the smallest section at the top, with carbohydrates in the largest bottom section. The ketogenic diet flips the pyramid, so most recommended foods are fats and very few are carbohydrates.

 

According to the Dietary Guidelines for Americans, 25% to 35% of an adult’s diet should come from fats, 45% to 65% from carbohydrates, and 10% to 30% from protein.⁶ In a 2000 calorie day for ketogenic diet patients, fat should account for 70% to 80% or 165 g of daily caloric intake.⁷

 

Although an exact timeframe is unknown, researchers believe that it can take the body up to four weeks to adapt to the ketogenic diet and ketosis.⁸ Patients initiating the diet could try daily exercise to force the body to break down fats, but its efficacy for reducing time to ketosis is unknown.⁸

 

Ketogenesis

 

The ketogenic diet uses ketosis and ketogenesis. When people eat carbohydrates, the body uses cellular respiration to produce energy from breaking down glucose molecules. However, if no carbohydrates are available, which would be the case during extended exercise or fasting periods, the body will naturally enter ketosis. Ketosis is a state of elevated ketone bodies, which include beta-hydroxybutyric acid, acetoacetic acid, and acetone in the blood.⁹ When the body needs energy, ketogenesis occurs to produce these ketone bodies, which can be used as an alternative energy source.

 

In normal cellular respiration, acetyl-CoA is condensed with oxaloacetate to begin the citric acid cycle. Beta-oxidation of fatty acids can produce acetyl-CoA, similar to the production of acetyl-CoA from glycolysis of glucose. In times of reduced glucose (i.e., fasting, extended exercise, ketogenic diet), the body diverts the acetyl-CoA produced from the fatty acids into ketogenesis.

 

Ketosis begins with fatty acid oxidation and the production of acetyl-CoA. Using the enzyme 3-ketothiolase, acetyl-CoA is converted into acetoacetyl-CoA. Then, the enzyme HMG-CoA synthase converts acetoacetyl-CoA to HMG-CoA.⁹ Low glucose levels during starvation or a high fat diet—a signal that the body needs to produce an alternative energy source for the brain—trigger this step of ketogenesis.¹⁰

 

The last step of energy production during ketosis is the conversion of HMG-CoA to the ketone bodies acetoacetate (AcAc) and 3-beta-hydroxybutyrate (3HB). Using HMG-CoA lyase, AcAc and 3HB are cleaved from HMG-CoA.⁹ By being in a constant state of ketogenesis from eating fatty foods, patients on the ketogenic diet change their natural fuel source from glucose to ketone bodies.

 

Ketone Bodies

 

The 3 main types of ketone bodies are AcAc, 3HB, and least commonly, acetone. The liver produces AcAc, 3HB, and acetone in a 78:20:2 ratio, respectively, during fatty acid oxidation.¹¹ Acetone is produced the least because it’s the byproduct of the uncommon and spontaneous decarboxylation of 3HB.¹¹ Ketone bodies are the only non-glucose derived energy source for the brain.¹⁰ The brain cannot process fatty acids, so they must be converted into ketone bodies first. They provide energy to the brain because both AcAc and 3HB can diffuse across blood brain barrier.⁹

 

During a normal day, ketone bodies account for only 2% to 6% of an individual's energy requirements. However, after a three- to four-day fast, ketone bodies account for 30% to 40% of the body's energy source.⁹ The liver can produce 185 grams of ketone bodies daily, which is enough to satisfy a person’s daily energy needs.⁹

 

By using ketone bodies, patients can avoid breaking down carbohydrates as an energy source, similar to how the body naturally functions during fasting. Ketone bodies are thought to have a direct beneficial mechanism, which will be discussed later, in disorders like epilepsy.

 

Effects of Insulin and Glucagon

 

Insulin and glucagon are important in ketosis and ketone bodies. Low insulin levels trigger steps in the ketosis process. Insulin, also called the antiketogenic hormone, decreases 3HB production, whereas glucagon, the ketogenic hormone, increases 3HB production.¹²

 

When humans consume carbohydrates and blood glucose levels rise, the pancreas releases insulin to absorb the blood sugar for energy storage.¹³ Insulin inhibits hormone-sensitive lipase and HMG-CoA synthase, enzymes that take part in fatty acid breakdown. It also stimulates acetyl-CoA carboxylase, causing the conversion of acetyl-CoA to malonyl-CoA, and blocking fatty acid transport into the mitochondria.¹⁰ As a result, insulin decreases the need for fatty acid oxidation and ketone bodies are decreased. The ketogenic diet requires patients to avoid carbohydrates to diminish insulin production and promote these mechanisms.

 

Glucagon does the opposite of insulin. The body uses epinephrine and glucagon to stimulate adipose (fat) tissue to produce more fatty acid.⁹ Glucagon triggers phosphorylation of hormone-sensitive lipase and HMG-CoA synthase, thus promoting ketogenesis.⁹ The body releases fatty acids from triglycerides, so they can be broken down by the newly activated enzymes.

 

A successful ketogenic diet requires a high glucagon/insulin ratio, similar to that experienced during fasting and by patients with diabetes. The high ratio increases fatty acid production and oxidation. Ketogenesis will follow.

 

Foods Consumed

 

Most foods for a ketogenic diet will have moderate amounts of proteins, no carbohydrates, with many fats. To prevent heart disease, physicians and pharmacists can counsel patients to eat healthy fats. Table 1 describes some examples of foods that are common in the ketogenic diet.

 

Table 1. Food Options Commonly Used in the Ketogenic Diet¹⁴

Fish and Seafood	-        Full of protein -        No carbs -        Associated with positive cardiovascular and health benefits
Poultry and Meat (Chicken, beef)	-        Rich in protein -        No carbs -        Limit processed meats
Nuts (Almonds, walnuts, pecans, cashews)	-        High in fiber, protein, and unsaturated fats -        Very low carbs -        Antioxidants
Non-starchy Vegetables (Broccoli, green beans, bell peppers)	-        Include other vitamins and nutrients -        Antioxidants
Cheese	-        No carbohydrates -        High in fats, protein, calcium -        Too many saturated fats
Avocados	-        Potassium, unsaturated fats -        Most carbohydrates in avocados are fiber

 

Patients on the ketogenic diet must understand how to track their nutrition to diet properly, calculating proteins, carbohydrates, and fats daily. Patients must calculate carbohydrates to account for dietary fiber because fiber is not digested with other carbohydrates.¹⁴ When tracking nutrition, patients on the ketogenic diet must track net carbohydrates, which can be found by subtracting the dietary fiber content from the total carbohydrates. The total carbohydrate level reported on nutrition labels does not accurately reflect the carbohydrate content the patient has consumed.

 

Most of the foods mentioned in Table 1 are high in fat. Fish, seafood, meat, poultry, and eggs are main staples. Processed meats, like bacon, should be eaten more sparingly compared to non-processed meats, like chicken and beef.¹⁴ Patients can eat chicken and fish more frequently because they promote cardiovascular health, unlike red meat. Many people believe that berries are not allowed on the ketogenic diet, but strawberries, raspberries, and blackberries have very low net carbohydrates. The total carbohydrates in berries may appear high, but their high fiber content allows berries to have a low net carbohydrate content.

 

A vegetarian ketogenic diet is a possibility, even though options are more limited. Vegetarian options with high protein and low carbohydrates include nuts, tofu, and seitan (a meat substitute made from the gluten in wheat).¹⁵ These dieters can also enjoy peanut butter-based desserts for more proteins. Seeds are high in fat and have high dietary fiber. For higher calorie meals, eggs and dairy (hard cheeses and plain yogurt) are an important fat option. Eggs have many fats, but essentially no carbohydrates.¹⁵

 

Any food that is high in net carbohydrates will disrupt the body's ketosis. These are foods like starchy vegetables, juices, syrup, chips, and crackers.¹⁴ Foods high in carbohydrates will give the body enough energy to not oxidize fatty acids and prevent the production of ketone bodies.¹⁴

 

PAUSE AND PONDER: Would a fasting patient reach ketosis quicker than a patient who is not fasting?

WHO BENEFITS FROM THE KETOGENIC DIET?

Obesity

Obesity, a leading risk factor for many chronic health conditions, continues to rise in the United States. According to the CDC, the prevalence of diabetes has increased to 41.9% from 2017 to 2020.¹⁶ Many have adopted low-carbohydrate, high fat lifestyles to lose weight. A 2016 meta-analysis of 11 randomized control trials assessed the efficacy of the ketogenic diet. Among the 1369 participants, those on the ketogenic diet experienced greater weight loss than those who participated in a low-fat diet.¹⁷ After six months to two years of intervention, patients experienced significant weight loss, HDL cholesterol increase, and triacylglycerol (TAG) reduction. The studies were limited by moderate to high heterogeneity and possible publication bias. A 2021 study evaluated the efficacy of the ketogenic diet using a mobile health application in comparison to a calorie restricted, low-fat application.¹⁸ Of the 155 participants, those using the ketogenic diet app experienced greater weight loss (12.3 pounds) at 12 weeks. Hemoglobin A1c (HbA1c) and liver enzymes also improved for the ketogenic diet group. This study was limited by operating fully remotely via the application. Patients could have benefited from in-person counseling or on-site visits to promote adherence.¹⁸

Another meta-analysis of 13 randomized controlled trials showed that participants on the ketogenic diet benefited from greater weight loss than those on a low-fat diet proving that the ketogenic diet can be used for obese patients. The low-fat diet group consisted of 787 patients while the ketogenic diet group consisted of 790. Patients that were part of the keto group lost approximately 3.6 pounds (1.6 kilograms) more than the low-fat group.¹⁹ Patients saw a greater increase in HDL and a more significant reduction in TAG in the keto group.

Type 2 Diabetes

Patients with type 2 diabetes (T2D) sometimes benefit from the ketogenic diet through improved glycemia and reduced insulin resistance. A study of 28 patients with T2D following a ketogenic diet showed that blood glucose and HbA1c improved. The ketogenic diet could potentially help patients with T2D reduce the number or dose of medications.²⁰ Another comparative study showed that obese patients with T2D had improvement in blood glucose profiles, insulin sensitivity, and HbA1c when adhering to the ketogenic diet for two consecutive weeks.²¹ However, the study was limited by short duration and small sample size.

Polycystic Ovary Syndrome

Similar benefits seem to apply to patients with polycystic ovarian syndrome (PCOS). Patients with PCOS experience hyperandrogenism, insulin resistance, and ovulatory dysfunction.²² Current treatment options include metformin, clomiphene, and letrozole; the ketogenic diet may provide good results for these women through insulin reduction.

In addition to the symptoms listed above, women with PCOS tend to gain weight, develop acne, and experience hirsutism.²³ Physicians recommend lifestyle modifications and hormonal contraceptives as first line interventions, but often, these interventions are insufficient, and symptoms persist.²³

Researchers have conducted many studies to evaluate the benefits of the ketogenic diet for women with PCOS, yet the studies are greatly limited by sample size. For example, a 2019 study consisting of 14 women with PCOS struggling with their weight assessed changes in body weight, BMI, fat body mass, lean body mass, HDL, and several other parameters. At 12 weeks, participants saw a 9.43-kilogram (20.7 pound) reduction in body weight, 3.35 reduction in BMI, and an 8.29-kilogram (18.2 pound) reduction in fat body mass.²³

A pilot study consisting of five women tested the ability of the ketogenic diet to reduce PCOS symptoms. Researchers provided the women with low-carbohydrate diet books and handouts alongside group meetings to test the ketogenic diet’s efficacy for PCOS. Participants consumed fewer than 20 grams of carbohydrates per day for six months. To test participants’ adherence, researchers measured ketones and body weight. Throughout the 24-week period, participants lost weight with a mean BMI decrease of four kilograms (approximately 8.8 pounds) which was a 14.3% total reduction in body weight.²⁴ The study resulted with clear reductions in testosterone, fasting serum insulin, and an overall improvement of PCOS symptoms.

Additionally, an eight-week crossover study involving 30 women with PCOS demonstrated various benefits. On average, weight loss ranged from 1.3 to 1.6 kg (2.8-3.5 pounds). When compared to baseline, the results of this study highlight the relationship between decreases in testosterone and fasting insulin.²⁵ Overall, improvements in insulin resistance, testosterone levels, and weight loss, the ketogenic diet may help patients with PCOS.

Epilepsy

The original use for the ketogenic diet was as an antiepileptic therapy in children.¹ After the discovery of antiepileptic medications, the need for the ketogenic diet diminished. However, researchers are bringing the ketogenic diet back to help treat patients who are refractory to modern antiepileptic medications.

In combination with medications, researchers have seen up to a 50% reduction in the number of seizures patients are having, with 10% to 15% becoming seizure free.²⁶ Co-administration with antiepileptics is possible for some medications. However, most patients are children and maintaining this strict diet is difficult.

During a retrospective study, researchers compared the effects of the ketogenic diet to modern anticonvulsant medications in 150 children. At one year, 55% of patients remained on the diet, and 27% of the patients who remained in the trial had a greater than 90% decrease in seizure frequency.²⁷ The diet allowed children to reduce their medication burden (patients averaged having 6.2 anticonvulsant medications before the trial), and proved to be more effective than many medications. More studies in larger patient populations are needed over longer periods of time to make stronger conclusions.

Research attributes the ketogenic diet’s anticonvulsant properties to an increased seizure threshold. Mitochondria in the brain have healthier biogenesis and density, leading to increased resistance to metabolic stress.²⁸ Another way the diet increases seizure threshold is through decreased glucose consumption and production of glycolytic ATP.²⁸ Subsequently, potassium channels remain open and hyperpolarize the neuronal membrane.²⁸

Researchers have found that ketone bodies produced from fatty acid oxidation have their own anticonvulsant effects. Although different ketone bodies have different effects, researchers have found that they can alter various neuronal membrane transporters to decrease excitability. Ketone bodies can inhibit transporters like the vesicular glutamate transporter and neuronal potassium channels. Inhibition of these transporters prevents signal transmission and causes decreased excitability of neuronal cells.²⁹

Other Neurodegenerative Disorders

In addition to epilepsy, promising evidence shows that the ketogenic diet has favorable effects for other neurodegenerative disorders. As the incidence of Alzheimer’s disease (AD) increases, few treatment options are available. The ketogenic diet may reduce deposition of amyloid beta (Aβ) plaques in patients with AD. With the addition of D-β-hydroxybutyrate (an enantiomer of the ketone body 3HB) to the ketogenic diet, ketones were able to increase neuron survival by reversing Aβ (1-42) toxicity. ³⁰ By increasing ketone production in the liver, the ketogenic diet can reduce the production of reactive oxygen species.³¹ Ketone bodies also work to block histone hyper-acetylation initiated by histone deacetylases (HDACs), increasing antioxidant levels. The ketogenic diet can improve metabolic efficiency which improves ATP concentrations resulting in further protective effects.³¹

Ketones’ neuroprotective effects can potentially help patients with Parkinson’s disease by reducing oxidative stress, maintaining energy supply, and modulating deacetylation and inflammatory responses.^31,32 Because they can reduce inflammation and inhibit the glutamate excitatory synapse, infusions of ketone bodies like 3HB may lead to small improvements in Parkinson’s symptoms.³² The use of the ketogenic diet for Parkinson’s is still controversial, thus further research is necessary.

Glaucoma

Glaucoma is the second leading cause of vision loss in the world.³³ Because ketone bodies are the major source of energy when participating in the ketogenic diet, mitochondrial dysfunction in the retina and optic nerves associated with glaucoma may be decreased.^32,34 A 2020 observational study assessed the benefit of the ketogenic diet in 185,638 adults with glaucoma from three studies between 1976 and 2017. Results showed that following a low carbohydrate diet was associated with 20% lower risk of developing primary open-angle glaucoma with initial paracentral visual field loss.³⁵ However, evidence is still lacking, and researchers need to investigate more to prove the ketogenic diet’s efficacy for glaucoma.

Colorectal Cancer

According to the American Cancer Society, colorectal cancer is the third leading cause of cancer-related deaths in men and women in the United States.³⁶ A 2022 study suggests that the ketone body, 3HB, can suppress colorectal cancer.³⁷ In one experiment, investigators evaluated the ability of the ketogenic diet to prevent tumor growth and development in mice.

They discovered that 3HB could suppress tumor growth by reducing proliferation of colonic crypt cells.³⁷ 3HB induced positive changes in tumor growth through the upregulation of the homeodomain-only protein X (HOPX). The HOPX protein inhibits cancer organoid growth when overexpressed.³⁷ Mice fed the ketogenic diet showed elevated levels of HOPX specific to the colonic tissue.

Overall, mice assigned to the ketogenic diet experienced improved long-term survival rates. To test the efficacy of the ketogenic diet for existing tumors, after two cycles of dextran sodium sulfate, researchers introduced the diet to the mice. After exposure to the diet, tumor growth decreased. When researchers discontinued the ketogenic diet from the mice, tumor development proceeded.³⁷

This discovery led to further testing, this time in human organoids. Organoids are tissue cultures derived from stem cells.³⁸ In the right environment, they are used to replicate organs. They are an essential tool to monitor disease development. Findings mimicked the results from the mice in 41 patients with colorectal cancer. This suggests that the ketogenic diet may be used for the prevention and treatment of colorectal cancer in the future.³⁷

PAUSE AND PONDER: How do you think patients would feel using the ketogenic diet as a primary treatment for neurodegenerative diseases in the future?

Contraindications to the Ketogenic Diet

Some patients should not follow the ketogenic diet. It is contraindicated in patients with liver failure, pancreatitis, inborn disorders of fat metabolism, primary carnitine deficiency, carnitine palmitoyl transferase deficiency, carnitine translocase deficiency, porphyria, and pyruvate kinase deficiency.^39,40

Because of the high risk of developing diabetic ketoacidosis (DKA), patients with type 1 diabetes on SGLT2 inhibitors should not participate in the ketogenic diet.⁴¹ DKA occurs when the body produces a dangerously high level of ketones at a rapid pace. Feeling extremely thirsty and frequent urination are early symptoms of DKA. Later symptoms of DKA include dry skin and mouth, flushing, fatigue, stomach upset, and pain. Another notable warning sign of DKA is a fruity odor on the patient’s breath. Acetone is responsible for the sweet scent and indicates high levels of ketones in the body.⁴² If left untreated, DKA can further develop, ultimately leading to death.

Pregnancy is also a contraindication. The CDC recommends 340 additional calories per day during the second trimester of pregnancy and 450 additional calories per day during the third trimester.⁴³ The CDC also recommends a well-balanced diet for women who are expecting. Losing weight during pregnancy is not safe and can be harmful to a patient’s baby.⁴³ Folic acid and iron supplementation is pivotal in a fetus’ development. The World Health Organization recommends daily iron and folic acid supplements to reduce the risk of low birth weight.⁴⁴ If a pregnant woman were to go on the ketogenic diet, she would need to ensure she consumes the suggested dose of 120 mg elemental iron and 2800 µg (2.8 mg) folic acid daily.⁴⁴ Overall, no evidence indicates that the ketogenic diet is safe for pregnant women.

KETOGENIC DIET SAFETY AND COUNSELING

Although several studies suggest the ketogenic diet can be effective for weight loss, limited literature is available concerning its long-term effects. Long-term effects include hepatic steatosis, hypoproteinemia, kidney stones, and vitamin and mineral deficiencies.⁴⁰

Currently, no guidelines address the ketogenic diet specifically, and other guidelines do not include the ketogenic diet for the treatment of the previously mentioned diseases. Researchers must complete longer term studies with larger patient populations to prove the ketogenic diet’s benefits and elucidate any long-term risks. Pharmacists and other healthcare providers should keep this in mind when recommending the diet to patients.

The Keto-Flu

A common adverse effect of the ketogenic diet is the “keto-flu.” The symptoms are indicative of carbohydrate withdrawal that can create symptoms like brain fog, fatigue, nausea, vomiting, constipation, and muscle soreness.^{40, 39} Symptoms usually begin within one to two days and resolve within a week or less. Pharmacists can counsel patients on proper hydration, light exercise, rest, and starting the diet slowly to try to prevent the keto-flu.

Cardiovascular Effects

As research has previously shown, the ketogenic diet shows short-term benefits for obesity and cholesterol. Due to the overconsumption of fats, researchers wondered about the longer-term effects. In rodent studies, the ketogenic diet led to the development of hepatic inflammation and nonalcoholic fatty liver disease.⁴⁵ Limited research has been done for nonalcoholic fatty liver disease in humans and more study is needed.

Other Adverse Effects

While on the ketogenic diet, patients may experience constipation. The healthcare team should implement a bowel regimen for the patient including an agent like polyethylene glycol 3350 (MiraLAX^®) that’s sugar-free, meaning it adds no additional carbs. Other notable side effects are kidney stones and a decrease in bone density. To prevent kidney stone occurrence, pharmacists can counsel patients on drinking large amounts of liquids.. Patients can reach out to their providers to ensure they check bone health routinely. Several advisory groups recommend bone mineral density screening for women aged 65 and older and men aged 70 and older, and for other patients who are at high risk. Patients participating in the ketogenic diet are no exception, and could be considered high-risk if they do not consume enough calcium and vitamin D. Pharmacists can counsel patients to monitor their calcium and vitamin D intake and supplement it if necessary. Upon screening, providers may also recommend calcium and vitamin D supplementation for patients who experience a decline in bone mineral density.⁴⁶

What Can Health Professionals Do?

Pharmacists can counsel patients on ketone testing to prevent occurrences of DKA. When a patient’s blood glucose exceeds 240 mg/dL, testing ketone levels every four to six hours is warranted.⁴⁷ Ketones can be monitored through the urine and blood. A urine stick test is the most common and changes color depending on the ketone level. Although urine tests are convenient, blood ketone tests from finger sticks are more accurate because they measure 3HB and/or AcAc in the blood.⁴⁸ If ketone tests indicate high levels, the patient is at moderate or high risk for ketoacidosis and patients should seek medical attention. Table 2 shows normal ketone levels, the optimal state of nutritional ketosis, and the level for ketoacidosis.

Table 2. Ketone Levels48
Normal Ketone	≤ 0.5 mmol/L
Nutritional Ketosis	1 - 3 mmol/L
Ketoacidosis	≥ 20 mmol/L

Patient adherence to long-term regimens always becomes challenging. Counseling patients on the importance of sticking to their diet and other medications will increase the likelihood of desired results.

PAUSE AND PONDER: On average, how long do you think a patient can remain adherent to the ketogenic diet lifestyle?

Medication management is a vital component of patient safety. To ensure that starting the ketogenic diet is safe, a healthcare professional should perform a complete medication reconciliation. Pharmacists, with an interdisciplinary team, should then develop a plan for medication adjustments (including OTCs) and carbohydrate intake. The use of medication package inserts, institutional databases, and manufacturer helplines can assist the team in determining carbohydrate content of drugs to make the process more seamless.⁴⁶ The following oral suspensions contain high carbohydrate contents:⁴⁹    

• Amoxicillin
• Nystatin
• Levetiracetam
• Midazolam
• Phenobarbital
• Phenytoin
• Baclofen
• Ibuprofen

Making patients aware that they must inform the healthcare team of any new medications is equally as important.

Some medications are of concern with the ketogenic diet.

• Patients taking SGLT2 inhibitors should not participate in nutritional ketosis due to the increased risk of diabetic ketoacidosis.
• Clinicians need to monitor patients taking the anticonvulsant valproate (a fatty acid) and might need to adjust their doses since the ketogenic diet increases metabolic efficiency and valproate can be burned by cells for energy.⁵⁰ Patients may feel as though valproate is not as effective after starting the ketogenic The dose, in this case, may need to be increased temporarily.
• A case study showed that topiramate can increase blood pH, inducing metabolic acidosis and kidney stones.⁵¹ This may become hazardous if patients are already in nutritional ketosis.
• Patients may experience hypotension while taking antihypertensive agents and following the ketogenic They should monitor blood pressure frequently.

Pharmacists and other health professionals should inform patients to stay hydrated to reduce the risk for kidney stones and eat low salt food items.

MYTHS AND FACTS

The ketogenic diet has become increasingly popular over the years. Halle Berry, Vanessa Hudgens, Kourtney and Kim Kardashian are a few of many celebrities that have tried the ketogenic diet and have seen incredible results. MTV’s Jersey Shore star, Vinny Guadagnino, also known as the Keto Guido, is no stranger to the diet and has even written a keto cookbook. Seeing such drastic transformations all over tabloids and social media, without a doubt leaves people wondering “Why not? If they can do it, so can I,” while others think, “This can’t be real.”

 

Many misconceptions create skepticism among patients from the abundance of information available on the internet. Pharmacists can alleviate patient worries by staying informed and referring patients to reliable resources. Table 3 below dispels common myths.

 

Table 3. Myths and Facts About the Ketogenic Diet52
MYTH	FACT
The ketogenic diet is bad for your health.	The ketogenic diet has several health benefits including: ●      Weight loss ●      Improved brain function ●      Reduction of seizures ●      Blood sugar management ●      Improvement of PCOS symptoms Side effects may include nausea, vomiting, constipation, or other common side effects.
All I have to do is consume any type of fat while going keto.	Patients should eat healthy fats like avocados, nuts, seeds, and fish. Healthy fats lower LDL levels and raise HDL levels. Unhealthy fats saturated and trans fatty acids (e.g., fried foods, pastries, butter, and cream) raise LDL levels.
If I go keto, I will get ketoacidosis.	Ketosis and ketoacidosis are different conditions. The ketogenic diet induces ketosis. ●      In ketosis, the body burns fat since carbohydrates are unavailable. Nutritional ketosis is a normal response. ●      Ketoacidosis is a complication seen primarily in patients with T2D where the blood becomes acidic. It can be life-threatening.
I will have no energy if I start a ketogenic diet.	Some people may experience an adjustment period while beginning the ketogenic diet. They may experience temporary fatigue, brain fog, or the “keto-flu.” Eventual ketone production fuels the brain with energy and resolves symptoms.
The ketogenic diet is only useful for weight management.	The ketogenic diet has proven effective in patients with diabetes, PCOS, metabolic syndromes, Alzheimer’s disease, and obesity.
I can’t drink any alcohol while on the ketogenic diet.	Various low-carb alcoholic beverages can be substituted. Light beer, vodka, gin, and rum are a few examples, but patients should keep intake low-moderate. Patients should avoid sweet drinks and cocktails to prevent high sugar intake.

 

Another common misinterpretation is that any low-carbohydrate food is considered keto. No food item has the same benefit as the other. The healthcare team must work with patients to create dietary plans that are more feasible for them. With a tailored diet plan, patients are more likely to feel structured and reach their goals. Overall, providers should conclude that patient education is necessary to certify patient trust and safety.

 

PATIENT RESOURCES

 

Reliable resources for patients are hard to find. Table 4 describes some resources that pharmacists can provide to patients for more information.

 

Table 4. Resources About the Ketogenic Diet for Patients

Cleveland Health Clinic	-        Discusses what patients eat on the ketogenic diet -        Small tidbits on benefits and risks -        Includes information on populations that could benefit from the diet -        https://health.clevelandclinic.org/what-is-the-keto-diet-and-should-you-try-it/
Harvard University Health	-        Discusses key-takeaways from a ketogenic diet review -        Gives food examples -        Easy-to-understand -        Discusses health implications for certain patient populations -        https://www.health.harvard.edu/blog/ketogenic-diet-is-the-ultimate-low-carb-diet-good-for-you-2017072712089
Academy of Nutrition and Dietetics	-        Popular nutrition website that presents findings on various health topics -        Discusses populations that the ketogenic diet would not be safe in -        Gives background on the diet -        https://www.eatright.org/health/wellness/fad-diets/what-is-the-ketogenic-diet
Everyday Health	-        Discusses risks and benefits of the diet -        Provides food substitutions and daily meal plans -        Discussion potential supplements and vitamins that may be beneficial to dieters -        Discusses other nutrition techniques for other topics -        Articles are peer-reviewed -        https://www.everydayhealth.com/diet-nutrition/ketogenic-diet/comprehensive-ketogenic-diet-food-list-follow/
EatingWell	-        Brief explanation about the ketogenic diet -        Provides variety of food options for dieters -        Easy-to-understand and discusses other nutrition techniques -        Peer reviewed and gives background on all authors/editors -        https://www.eatingwell.com/article/290697/ketogenic-diet-101-a-beginners-guide/

 

 

CONCLUSION

Following a low-carbohydrate, high fat diet that uses ketone production to fuel the body requires a large selection of foods if patients are to maintain this diet. This is the challenge of the ketogenic diet. Pharmacists and technicians need a good understanding of what this diet is—and what it is not—so they know when prescribers are likely to use it for diseases. Pharmacists, as they screen for contraindications, should identify the signs of ketosis and counsel patients on managing safe ketone levels.

Patient education is the key to reaching patient goals. Pharmacists must be ready to address patient questions and concerns regarding the ketogenic diet in conjunction with current medications. When pharmacists are a part of the care process, outcomes improve.

 

Download CE Activity

INTRODUCTION

This continuing education (CE) activity aims to guide safe insulin dose adjustments when adding glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1-RAs), and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs (GIP/GLP-1 RAs) in those with type 2 diabetes (T2D). Clinical utilization of GLP-1 RAs and GIP/GLP-1 RAs in combination with insulin has been lagging despite their benefits.¹ This is due to a lack of clinician comfort with insulin adjustment despite Food and Drug Administration (FDA) approval and improved insurance coverage. Pharmacists can optimize a patient’s regimen by reducing the risk of hyperglycemia or hypoglycemia, adverse drug reactions (ADRs), and medication/injection burden.

 

Diabetes Basics

Diabetes is an endocrinological disorder characterized by metabolic imbalance (glucose utilization and insulin effect).² In patients who have diabetes, hyperglycemia occurs and could lead to long-term complications such as myocardial infarction, cerebrovascular accident, peripheral artery disease, retinopathy, nephropathy, and neuropathy.²

 

A glycated hemoglobin level (A1c) greater than or equal to 6.5% indicates a person has diabetes.³ When discussing how an A1c correlates to a patient’s self-monitored blood glucose (SMBG; home blood glucose testing using a glucometer or a continuous glucose monitor [CGM]), it can be helpful to consider an estimated average glucose (eAG).³ The complete equation and calculator can be found at https://professional.diabetes.org/glucose_calc. A simplification is remembering that an A1c of 7% equals an eAG of 154 mg/dL and that each A1c percentage represents about 30 mg/dL. Generally, for an A1c goal of less than 7%, fasting blood sugars (FBGs) should be between 80 and 130 mg/dL, and 2-hour post-prandial glucose (PPGs) values should be less than 180 mg/dL.³

 

Previously, mainstay treatment options for glycemic control included metformin, sulfonylureas (glimepiride, glipizide, and glyburide), thiazolidinediones (pioglitazone), and dipeptidyl peptidase-4 inhibitors (alogliptin (Nesina), linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). Newer treatment options that are focused on cardiorenal benefits, weight management, and glycemic control include⁴

• Sodium-glucose cotransporter 2 (SGLT-2) inhibitors: canagliflozin (Invokana), bexagliflozin (Brenzavvy), dapagliflozin (Farxiga), empagliflozin (Jardiance), and ertugliflozin (Steglatro)
• GLP-1-RAs: dulaglutide (Trulicity), exenatide ER (Bydureon), exenatide IR (Byetta), liraglutide (Victoza), lixisenatide (Adlyxin), and semaglutide (Ozempic)
• GIP/GLP-1 RA (tirzepatide [Mounjaro])

 

The diabetes management landscape is changing. Even if patients have appropriate glycemic control, their medication regimen may not be optimal based on co-morbidities. Please see the following link to the American Diabetes Association’s recommendations on medication selection: https://diabetesjournals.org/view-large/figure/5311673/dc25S009f3.tif.

 

Insulin

Insulin has been a cornerstone of diabetes management for decades. With the advent of newer medication classes, it can appear as though insulin’s importance in current practice is diminishing. Many individuals still benefit from the use of insulin, including those with type 1 diabetes (T1D), patients with newly diagnosed T2D with an elevated A1c, and those with access/cost concerns regarding branded medications.

 

Although treatment options for diabetes have advanced and include SGLT-2 inhibitors, GLP-1-RAs, and GIP/GLP-1 RAs, these drugs can be cost prohibitive depending on the situation.⁴ Insulin itself can also be cost-prohibitive depending on insurance coverage (or lack thereof) and patient-specific dosing needs. In certain situations where patients pay out-of-pocket, reducing the daily insulin dose can help reduce the cost.

 

Insulin’s onset of action, duration of action, and concentration help to categorize it.

• Patients use bolus insulins such as ultra rapid, short, or regular insulin prior to meals to manage blood glucose spikes. These insulin types generally help lower PPGs. Checking SMBGs two hours after a meal helps to understand the effect while checking prior to mealtimes ensures safety.
• Patients use basal insulins, injected once or twice daily, to provide constant insulin action throughout the day and night. Options include intermediate, long-acting, and ultra-long-acting. These insulin types generally help lower FBGs and patients who use these insulins should check their SMBGs when in a fasting state as well.
• Examples of concentrated insulins include insulin lispro U-200 (insulin lispro U-200), insulin degludec (Tresiba U-200), insulin glargine U-300 (Tuojeo U-300), and insulin regular U-500. Testing for insulin degludec U200 and insulin glargine U-300 would match basal insulin testing. Testing for insulin lispro U-200 and insulin regular U-500 would match bolus insulin testing.
• Mixed insulins contain a mix of a bolus/regular insulin and an intermediate insulin in pre-fixed percentages to reduce the injection burden. Examples include insulin aspart protamine/insulin aspart (Novolog 70/30), insulin lispro protamine/insulin lispro (Humalog 75/25 or Humalog 50/50), and insulin isophone (NPH)/insulin regular (Humulin 70/30 or Novolin 70/30). For safety, these require fixed meal timings and portions and thus testing is recommended two hours before and after breakfast and dinner.

 

Insulin Dosing

In practice, clinicians usually start patients on a basal insulin rather than a bolus insulin as it involves fewer injections and provides steadier coverage throughout the day. Generally, a starting basal insulin dose is calculated using 0.1 to 0.2 units/kg/day or 10 units daily.⁵ When insulin needs increase beyond 0.5 units/kg/day of basal insulin, providers (such as clinical pharmacists) can consider the addition of bolus insulin.⁶ Using greater than 0.5 units/kg/day of basal insulin is referred to as overbasalization (see SIDEBAR).

 

 

SIDEBAR: Overbasalization^6,7

Overbasalization describes the situation in which the patient’s bedtime glucose readings are significantly higher (greater than 50 points) than their fasting values. Ideally, bedtime and fasting readings should be in equilibrium. Overbasalization is common in patients whose basal insulins are titrated to a fasting goal without considering the patient’s end-of-day blood sugars. It also occurs if prescribers think adding a medication would increase the patient’s injection/medication burden. This generally occurs when the patient’s basal insulin dosing exceeds 0.5 units/kg/day. Ideally, the provider should consider a medication that helps lower PPGs.

 

Using GLP-1 RAs and GIP/GLP-1 RAs has increased the ability to minimize the need for bolus insulin, reduce the risk of hypoglycemia, and lower PPG. Using a collaborative practice agreement within an interprofessional collaborative team has significantly reduced overbasalization and A1c.

 

 

The total amount of insulin a patient takes in a day is their total daily dose (TDD). This TDD is a helpful starting point when making insulin adjustments. For example, if a patient is taking 100 units of insulin per day (this could be basal or basal + bolus) then generally 10% to 15% is a reasonable adjustment.⁵ This equates to an increase or decrease of 10 to 15 units. For a smaller TDD of 20 units the adjustment would be 2 to 3 units. Alternately, patients can self-adjust the dosing within specified parameters such as increasing a basal insulin by 2 units (up to a pre-specified maximum) every three days that the FBGs are above goal.⁵

 

Patient/situation specific parameters that additionally need to be considered are the patient specific glycemic goal, glycemic trends (variability vs. stability), planned lifestyle changes, hypo/hyperglycemia, and ADRs. The prior recommendations only account for medication changes while everything else remains constant. Realistically, dosing changes will likely need to be made at larger percentages to accommodate multiple changing factors.

 

If PPGs indicate a need for improvement of glycemic control, clinicians can consider either a GLP-1 RA (for T2D) or bolus insulin (T1D or T2D). Adding a GLP-1 RA can be more complex for those on a multiple daily injection (MDI) insulin regimen (basal + bolus). Guidance regarding basal + bolus insulin dose deprescribing varies.

 

Insulin Dose Adjustment with GLP-1 RAs and GIP/GLP-1 RAs

Three studies have reviewed the efficacy of adding liraglutide to an MDI insulin regimen in patients with T2D.^8-10 They documented a significant reduction in A1c from baseline in the GLP-1 RA group compared to the MDI control groups. Two studies—one conducted by researchers at the Mountain Diabetes and Endocrine Center, Asheville, North Carolina and a second conducted in Europe and Saudi Arabia called the MDI Liraglutide Trial—showed significantly reduced insulin dosing in the liraglutide groups.^8,9 In contrast, the third study (N = 71), conducted at the University of Texas Southwestern Medical Center (UTSMC), Dallas, did not show a significant reduction in insulin dosing.¹⁰

 

The Mountain Diabetes and Endocrine Center study made insulin dose adjustments based on A1c but included only 37 participants. The study protocol indicated that researchers should reduce the basal dose by 20% for those with an A1c less than or equal to 8%.⁸

 

In the MDI Liraglutide Trial (N = 124), the insulin adjustments were based on FBGs and PPGs . When fasting values were less than 90 mg/dL or participants had nocturnal hypoglycemia, the researchers reduced the basal dose by 20% to 40%. If the fasting values were 90 to 126 mg/dL, the researchers reduced the basal doses by 20% to 30%. The researchers did not adjust the basal insulin dose if fasting glucose levels were above 126 mg/dL. If they found the patient’s pre-meal glucose value to be less than 126 mg/dL, they reduced the bolus dose of the prior meal by 10% to 20%. If participants experienced daytime hypoglycemia, the researchers reduced the bolus dose of the preceding meal by more than 20%.⁹

 

The UTSMC study protocol reduced insulin doses by 20% if the A1c was less than or equal to 8%. The investigators did not adjust the insulin dose if the A1c was greater than 8%. They did not define the specific bolus and basal insulin dose adjustments.¹⁰

 

The TRANSITION2D study (N = 60) reviewed insulin deintensification with once weekly semaglutide.¹¹ These researchers transitioned patients who were reasonably well controlled (A1c 7.5% or less) from bolus insulin to a GLP-1 RA (semaglutide) in a one-step approach. They discontinued bolus insulin upon initiating semaglutide, then titrated the semaglutide dose.¹¹ A limitation to real-world applicability was that less than 25% of the participants were on 80 to 120 units of insulin per day.¹¹ Concerns in the real world would be a lack of tolerance to semaglutide or lack of follow-up on the patients’ behalf, as this would lead to hyperglycemia. Also, shared decision making between the patient/provider would first need to optimize glycemic control using insulin dose adjustments to reduce the risk of hyperglycemia/diabetic ketoacidosis (DKA)/hyperosmolar hyperglycemic state (HHS).

 

Traditional insulin dosing guidance and these studies show that insulin dose adjustments can vary widely from 10% to 40%. One path isn’t necessarily correct as adjusting insulin doses is an art of sorts.

 

HYPOGLYCEMIA TREATMENT

Accounting for and incorporating historical patient-specific parameters helps minimize the risk of hypoglycemia. Patient education regarding appropriate identification, treatment, and prevention of recurrence is paramount for safety. Common hypoglycemia symptoms are hunger, difficulty concentrating, headache, shakiness, sweating, and irritability. The 15-15 Rule advises patients with low blood sugar, defined as less than 70 mg/dL, to consume 15 g of carbohydrates and then wait 15 minutes to recheck the SMBG. Options to increase the blood sugar are 4 ounces of regular juice or non-diet soda, 1 tablespoon of sugar, honey, or syrup, 3 to 4 glucose tablets, or 1 dose glucose gel.¹² It is important to know that glucose tablets and gel are available without a prescription. Most patients know that if they experience hypoglycemia, they should eat something sweet. However, without following the treatment/prevention steps, patients may experience additional concerns. Table 1 describes appropriate action steps.

 

Table 1. Action Steps to Address Hypoglycemia¹³

Appropriate step	Assessment questions
Patients must check initial and subsequent glucose values to have objective data	What values did you see when you checked your blood sugar?
Initial treatment should consist of 15 grams of simple carbohydrates for the quickest improvement of hypoglycemia symptoms. Of note, treatment with complex carbohydrates or carbohydrates + protein/fat* will delay the improvement of hypoglycemia symptoms.	What food/drink/treatment option did you initially use to address the low blood sugar?
Overtreatment with more than 15 grams of carbohydrates leads to overcorrection (hyperglycemia)	How much of the food/drink/treatment option did you initially use to address the low blood sugar?
After consuming a simple carbohydrate, the patient should consume a complex carbohydrate + protein pairing, to prevent hypoglycemia from recurring within two hours	Once the blood sugar returned to a safe range, what did you eat to keep the blood sugar steady?

^*Examples of complex carbohydrates (wheat/corn/peas/potatoes/fruit) and carbohydrates + protein/fat (apple + peanut butter/pizza/candy bar)

 

NEWER THERAPIES

As this activity discusses newer therapies, new information is consistently being learned. To provide comprehensive and current or guideline-directed care, these must be a part of the patient assistance process. Some patients have strong feelings for or against newer therapies, so it is helpful to be able to provide the information in a non-biased manner.

 

SGLT-2 Inhibitors    

SGLT-2 inhibitors increase urinary excretion of excess glucose and thus can increase the risk of genitourinary infections such as yeast infections and urinary tract infections. This class of medications also has significant long-term cardiorenal benefits.¹⁴ Optimization of these medications would also be ideal, especially when affordable, to reduce the need for insulin.

 

Although this CE activity’s focus is to review insulin dosing adjustments when introducing concurrent GLP-1 RA and GIP/GLP-1 RA dose adjustments, clinicians can apply some of the same practices when adjusting other medications, such as SGLT2-inhibitors.

 

GLP-1 RAs

The FDA approved the first GLP-1 RA, exenatide, in 2005, and patients needed to inject it twice daily.¹⁵ Now, patients can inject GLP-1 RAs daily or weekly. In 2019, the FDA approved the first non-injectable GLP-1 RA, oral semaglutide (Rybelsus).¹⁵ Additionally, this group of medications provides cardiorenal protective effects and weight loss.¹⁶ Common ADRs are gastrointestinal intolerances such as nausea, upset stomach, constipation, and vomiting.¹⁶

 

Semaglutide is the most effective medication in this class from a glycemic management perspective.¹⁶ Dulaglutide, liraglutide, and exenatide are the most tolerated in this class; however, of these options dulaglutide is the most effective.¹⁶ Before these newer DM medications were available, the commonly utilized PPG-lowering options were metformin, sulfonylureas, bolus insulin, and mixed insulin. Of those, metformin is the only one that does not increase risk of hypoglycemia.

 

GIP/GLP-1 RAs

GIP/GLP-1 RAs have a dual hormonal activation that promotes satiety, slows digestion, and reduces hunger. Common ADRs are similar to that of GLP1-RAs but even though tirzepatide is more potent at improving glycemic control than semaglutide, it is also better tolerated.¹⁶ Currently, the FDA has approved tirzepatide as the only medication in this class. Additionally, despite the dual activation, patients tend to tolerate tirzepatide better than some GLP-1 RAs based on anecdotal experience. Tirzepatide also provides cardiorenal protective effects.¹⁷

 

Combination basal insulin + GLP-1 RA medications

Currently, the FDA has approved two fixed-ratio combinations (FRC) of basal insulin/GLP-1 RA: insulin degludec/liraglutide, also known as iDeglira (Xultophy), and insulin glargine/lixisenatide, also known as iGlarlixi (Suliqua).¹⁸ These medications have a fixed level of a basal insulin and a once daily GLP-1 RA combined into a single pre-filled pen. Insulin has no maximum daily limit but the GLP-1 RAs do. Thus (because these products are fixed ratios combinations) the maximum daily GLP-1 RA dose limits the daily insulin dose in FRCs.¹⁹ The dosing is based on units of the insulin component.

 

For example, each unit of iDeglira contains 1 unit of insulin and 0.036 units of liraglutide.²⁰ The maximum dose is 50 units, which contains 50 units of insulin degludec and 1.8 mg of liraglutide (liraglutide's maximum daily dose). The manufacturer advises patients who are insulin and GLP-1 RA naïve to start at 10 units daily, whereas those that are currently on basal insulin can start at 16 units daily.¹²

 

IGlarlixi is available in the United States as Soliqua 100/33, indicating that there is 0.33 mg of lixisenatide for every unit of insulin glargine. The maximum dosage of iGlarlixi is 60 units; however, this is based on the lixisenatide daily maximum of 20 mcg. Those transitioning from less than 30 units of basal insulin would be started on 15 units of iGlarlixi. For those between 30 to 60 units of basal insulin, the starting dose would be 30 units of iGlarlixi.²¹

 

A study completed at the Diabetes Center of the Békés County Central Hospital in Hungary (N = 62) sought to review the safety and efficacy of switching well-managed patients with T2DM (A1c less than 7.5%) from basal/bolus insulin (low TDD) to insulin degludec/liraglutide combination.²⁰ The study defined low TDD as less than or equal to 70 units of insulin per day. The transition method was to stop the prior basal/bolus insulin regimen and to start 16 units of iDeglira. Then the FBGs were titrated to 90 to 108 mg/dL by increasing the iDeglira dose by 2 units every 3 days. The study continued or initiated metformin and titrated it up to 3000 mg (the maximum daily dose of metformin is higher in Hungary than in the United States). The intervention reduced the TDD from 43.3 units to 22.55 units, which was significant.²⁰

 

Theoretically, this is a wonderful way to reduce injection burden and optimize adherence.⁶ These medications’ clinical utility depends on the patient’s lifestyle patterns, insurance coverage, medication availability, and out-of-pocket cost. Depending on the patient, the fixed ratio dosing and once-daily dosing could be a benefit or a drawback. Patients who would like to minimize injection burden and can safely delay insulin may prefer a once weekly GLP-1 RA or GIP/GLP-1 RA injection. Having the ability to titrate basal insulin and a GLP-1 RA separately allows more dosing individualization, which leads to more patients achieving goal FBGs.²²

 

INTRODUCTION TO THE CASES

The rest of this activity focuses on case-based learning. For these cases, learners should assume that any information not provided is within normal limits, there is no change from baseline, or any change has been addressed. These cases derive from patients in a primary care setting, but this information can help in various settings. Also, due to the focus on insulin dose adjustments, the healthcare provider does not discuss the use of GLP-1 RAs or GIP/GLP-1 RAs for an indication of obesity. As obesity can co-exist with T2D, healthcare providers should monitor weight during initiation and titration of GLP-1 RAs or GIP/GLP-1 RAs.

 

CGMs have been more accessible in recent years, and they provide excellent graphic review of glycemic control. This learning experience uses glycemic charts. The charts depicted here would be gathered from a patient’s glucometer or SMBG log and commonly depict the last 14 days of glycemic control. Clinicians should crosscheck values from a SMBG log with the patient’s glucometer if they have concerns about inaccuracy. Each column that lists a glucose value specifies the timing with regard to meals; acB is before breakfast, acL is before lunch, acD is before dinner, and HS is at bedtime. During the initial pharmacist visit, pharmacists need to manage patients expectations and urge frequent testing because it allows for the safest insulin dose adjustments. It also ideally decreases the testing needs moving forward by limiting the patient’s insulin doses and frequency.

 

PAUSE AND PONDER: Thought Questions

Safety:

• Is the patient tolerating the current regimen?
• Is the patient experiencing any hypoglycemia?

Efficacy:

• Is the current regimen helping the patient achieve glycemic goals?
• What medication adjustments would help move the current glycemic patterns towards the goal?

 

CASE 1: Arya Brown–pronouns: he/him/his

Arya is a patient who presents for his first pharmacist visit. First, the pharmacist reviews the electronic medical record for Arya’s recent history.

 

Visit 1

Arya reported that he was doing well with dulaglutide 0.75 mg weekly and his current insulin glargine dose of 18 units daily. He reported that his appetite was more controlled, and he felt more energetic since starting dulaglutide. The patient was excited to increase the dose of dulaglutide.

 

The patient’s current SMBG log shows he checks his FBGs only sporadically, and they fall between 128 and 154 (average = 143), no hypoglycemia, and consistent values above goal. Based on the anticipated improvement of glycemic control throughout the day by increasing the dulaglutide dose to 1.5 mg weekly, the pharmacist started shared decision making to continue the current insulin glargine for now. The pharmacist asked the patient to check his blood sugars in the evening, either before dinner or at bedtime, to allow for further assessment of glycemic trends throughout the day. Arya verbalized understanding of this request, but reports that he will likely only check blood sugars once a day and therefore asked to alternate testing times.

 

Visit 2

Arya presented for his second pharmacist visit after his third dose of dulaglutide 1.5 mg. He said that his blood sugars were at goal and that he had slight but tolerable nausea with the current dulaglutide dose. He reported that the nausea improved since the first injection at this dose. The pharmacist and Arya discussed the option of maintaining the dulaglutide dose for the next prescription to allow additional time for tolerance. However, Arya prefers to increase it to dulaglutide 3 mg weekly with the next prescription after four doses of 1.5 mg have been taken. He indicates the symptoms have improved over time and are barely noticeable.

 

His current SMBGs show FBGs ranging from 128 to 141 (average = 135). Since his glycemic control is now closer to goal than previously, he will need to adjust insulin glargine dosing to minimize the risk of hypoglycemia. The risk of causing temporary hypoglycemia is higher than that of causing temporary hyperglycemia. Thus, the pharmacist decides to reduce the insulin dose by 6 units. This is a 33% insulin reduction.

 

Visit 3

At Arya’s third visit, he reports feeling nauseous and vomiting after injecting the second dose of dulaglutide 3 mg weekly. He says he vomited after the first dose and thought it may have been related to a food choice at that time. The vomiting improved after a couple of days, but it recurred after the second dose of dulaglutide 3 mg. The patient shows his glucometer for SMBGs as noted in Table 3.

 

Table 3. Arya Visit 3

Date	AcB	HS	HS dose (insulin glargine)	comment
			12 units
	134		12 units
		147	12 units
	136		12 units
			12 units
	124	149	12 units
			12 units	Dulaglutide 3 mg (dose 1)
			12 units
	117	146	12 units
			12 units
		137	12 units
	120		12 units
		131	12 units
	116		12 units	Dulaglutide 3 mg (dose 2)
		127	12 units
Visit 3			12 units
Average	125	140

 

The SMBGs indicate improved glycemic control. The pharmacist suggested that Arya’s ADRs seem intolerable. Arya agrees. He was amenable to stopping the dulaglutide 3 mg weekly and resuming the lower 1.5 mg weekly dose when his symptoms abate (at least a week after the last dose). Now the discussion turned to what insulin dose the patient should take with the lower dose of dulaglutide.

 

The patient’s prior glycemic control is a blueprint for patient specific response to insulin dose adjustments. Since Arya is returning to the 1.5 mg of dulaglutide weekly, and he has taken that dose before, the glycemic control information presented during visit 2 is helpful. The general takeaway is that his glycemic control was close to goal while on dulaglutide 1.5 mg weekly and insulin glargine 18 units daily. The pharmacist and the patient make a shared decision to adjust the insulin glargine to 20 units daily to move the patient’s glycemic control closer to goal.

 

They agree to re-try dulaglutide 3 mg weekly in the future if he tolerates the 1.5 mg weekly dose better over time. They also discuss the possibility of using a different GLP-1 RA or a GIP/GLP-1 RA, as tolerance between medications can vary.

 

CASE 2: Alex Devi–pronouns: they/them/theirs

Visit 1

Alex presented to their first pharmacist visit and reports that their insurance now covers tirzepatide for diabetes at a reasonable cost, so they would like to minimize MDI insulin regimen. The patient denies any contraindications to GIP/GLP-1 RA. The pharmacist tells Alex that they can adjust their insulin doses based on tolerance to tirzepatide, but there is no guarantee that insulin can be stopped.

 

Based on the current optimized glycemic control (Table 4), starting and titrating tirzepatide will necessitate insulin dose adjustments. They are currently injecting insulin degludec 36 units daily and insulin lispro 8 units with breakfast, 10 units with lunch, and 14 units with dinner. To limit the risk of hypoglycemia, the pharmacist and Alex planned to decrease doses and assess this specific patient’s response. As tirzepatide will primarily impact post-prandial glycemic control, and the patient is on a medication (insulin lispro) that can cause post-prandial hypoglycemia, the goal was to focus on bolus insulin reduction. In this case, glycemic control appears steady throughout the day. The pharmacist planned to reduce all prandial doses equally to allow blood sugars to rise throughout the day and let the full effect of tirzepatide occur while limiting hypoglycemia due to insulin. Due to tirzepatide’s potency as a dual GIP/GLP-1 RA and Alex’s current glycemic control, they will reduce the insulin lispro dose by 4 units per meal. Thus, the patient’s total daily insulin dose was reduced by 12 units per day, an 18% reduction in TDD of insulin.

 

Table 4. Alex Visit 1

Date	acB	acB dose (insulin lispro)	acL	acL dose (insulin lispro)	acD	acD dose (insulin lispro)	HS	HS dose (insulin degludec U100)	Notes
	117	8	109	10	137	14	171	36 units
	93	8	129	10	128	14	161	36 units
	107	8	91	10	145	14	127	36 units
	126	8	79	10	141	14	152	36 units
	93	8	133	10	147	14	131	36 units
	82	8	121	10	124	14	170	36 units
	107	8	132	10	128	14	160	36 units
	112	8	125	10	111	14	165	36 units
	105	8	89	10	147	14	170	36 units
	77	8	96	10	133	14	130	36 units
	108	8	111	10	91	14	146	36 units
	92	8	103	10	113	14	164	36 units
	97	8	110	10	118	14	151	36 units
	101	8	89	10	97	14	132	36 units
	122	8	131	10	121	14	130	36 units
Visit 1	104	8	125	10				36 units	Start tirzepatide 2.5 mg
Average	103		111		125		151

 

Visit 2

Table 5 summarizes Alex’s glycemic control when they returned for their second appointment. The pharmacist looks for trends and sees that the blood sugar averages appear to be lowest pre-dinner and then highest at bedtime. A potential concern is that Alex may overeat at dinnertime as a response to rapidly decreasing blood sugars between lunch and dinner. Alex denies any hypoglycemia symptoms or adverse effects from tirzepatide. They just finished the fourth dose of tirzepatide 2.5 mg and are interested in increasing the dose. To increase tirzepatide, the pharmacist used the information gathered to minimize the patient’s insulin intake. Based on the response and current SMBGs, roughly 4 units is an appropriate dose reduction per meal. Logistically, this would eliminate the breakfast insulin, reduce the lunchtime dose to 2 units, and reduce the dinnertime insulin dose to 6 units. The pharmacist needs to evaluate the lunchtime dose of 2 units further. For someone with T2D, 2 units is a minimal dose of insulin. The actual effect is questionable, especially in this individual, where another medication is being titrated up.

 

Table 5. Alex Visit 2

Date	acB	acB dose (insulin lispro)	acL	acL dose (insulin lispro)	acD	acD dose (insulin lispro)	HS	HS dose (insulin degludec U-100)	Notes
	113	4	95	6	79	10	150	36 units
	79	4	122	6	91	10	139	36 units
	107	4	107	6	113	10	162	36 units
	102	4	125	6	91	10	172	36 units
	104	4	118	6	99	10	164	36 units	tirzepatide 2.5 mg (Dose 3)
	81	4	118	6	81	10	156	36 units
	120	4	102	6	101	10	158	36 units
	85	4	123	6	75	10	169	36 units
	77	4	127	6	79	10	168	36 units
	84	4	108	6	103	10	126	36 units
	111	4	89	6	79	10	139	36 units
	112	4	115	6	92	10	140	36 units	tirzepatide 2.5 mg (Dose 4)
	87	4	87	6	101	10	174	36 units
	73	4	102	6	76	10	139	36 units
	85	4	127	6	98	10	163	36 units
Visit 2	107	4						36 units
Average	95		111		91		155

 

Reviewing the pre-dinner glycemic values (the lowest throughout the day) and eliminating the lunchtime insulin dose would help reduce the risk of hypoglycemia. Thus, the consensus was to eliminate the breakfast and lunchtime insulin doses while reducing the dinner time dose to 6 units. Therefore, they decided to reduce the patient’s total daily insulin dose by 14 units, a 25% reduction in TDD of insulin. The pharmacist advised the patient that he can skip testing his SMBG before lunch as he is not injecting a bolus insulin at that time.

 

Visit 3

Alex presented for their third appointment and denies any adverse effects with tirzepatide 5 mg weekly. Alex was happy with reducing injection burden from four times a day to twice a day! They reported they have lost some weight. They have also increased activity slightly and are planning to make that a priority in the upcoming month. They would like to continue titrating tirzepatide when able. Looking at current glycemic values (Table 6), the adjustments made at the last visit stabilized control again.

 

Table 6. Alex Visit 3

Date	acB	acB dose (insulin lispro)	acD	acD dose (insulin lispro)	HS	HS dose (insulin degludec U100)	Notes
	110	0	111	6	115	36 units
	119	0	106	6	132	36 units
	133	0	129	6	96	36 units
	126	0	100	6	99	36 units
	126	0	99	6	151	36 units	tirzepatide  5 mg (Dose 2)
	118	0	111	6	97	36 units
	130	0	110	6	124	36 units
	112	0	131	6	149	36 units
	134	0	106	6	144	36 units
	99	0	105	6	103	36 units
	97	0	117	6	154	36 units
	98	0	111	6	153	36 units	tirzepatide 5 mg (Dose 3)
	115	0	121	6	141	36 units
	119	0	96	6	129	36 units
	122	0	98	6	154	36 units
Visit 3	102	0				36 units
Average	116		110		129

 

Based on this patient’s previous responses, it seems that the insulin dose should be reduced by about 12 to 14 units of insulin to accommodate the tirzepatide dose increase. Additionally, due to Alex’s anticipated activity change, they may need to reduce the total daily insulin dose further. The pharmacist can help reduce the injection burden by eliminating the dinnertime dose of insulin lispro. Next, the basal dose needs to be adjusted. There is room for discussion, based on the factors noted (current glycemic control, planned activity changes, and dose increase of tirzepatide). To limit the risk of hypoglycemia, they decide to reduce insulin degludec from 36 units to 26 units. This is a reduction of 16 units of insulin. They could have reduced the patient’s basal dose to accommodate everything except the activity change if it was unclear that they were planning to make a change soon.

 

All plans must be patient-specific, and with this discussion, the patient is reliable and was waiting to change their activity once this discussion occurred. For other patients who are not as clear that they are planning a change, the pharmacist could advise reducing the basal insulin dose to approximately 30 units daily for now and then communicate with the clinic when they make the change for review of SMBGs to allow for additional adjustments.

 

CASE 3: Zephyr Hernandez–pronouns: she/her/hers

Visit 1

Zephyr’s provider referred her to the pharmacist because her A1c was above goal and she was experiencing hypoglycemic episodes. From a complete assessment of the patient’s medication and lifestyle routine, it appeared that the patient’s mealtimes were inconsistent. Zephyr indicated her schedule dictates whether she can eat breakfast and/or lunch, but that she tries to eat dinner consistently. She injects insulin aspart protamine/insulin aspart 70/30 mix, 24 units in the morning and 30 units in the evening. Based on Zephyr’s readings (Table 7), she has hypoglycemia before dinner when she skips lunch. She treats the hypoglycemia with soda or candy. The patient says she skips her breakfast mixed insulin dose when she skips breakfast but then ends up with hyperglycemia pre-dinner.

 

Table 7. Zephyr Visit 1

Date	acB	acB dose (insulin aspart protamine/insulin aspart 70/30 mix)	acL	acD	acD dose (insulin aspart protamine/insulin aspart 70/30 mix)	HS	Notes
	123	24	122	113	30	137
	134	24	106	78	30	257	skipped lunch
	88	24	114	112	30	118
	159	24	109	76	30	188	skipped lunch
	76	24	121	111	30	123
	118	0	156	187	30	187	skipped breakfast
	123	0	164	190	30	128	skipped breakfast
	139	24	116	106	30	164
	95	24	96	68	30	196	skipped lunch
	113	24	107	102	30	141
	117	24	120	109	30	186
	159	0	145	189	30	145	skipped breakfast
	149	24	132	72	30	179	skipped lunch
	117	24	127	109	30	125
	107	24	114	79	30	212	skipped lunch
Visit 1	96	0	163				skipped breakfast
Average	120		126	113		166

 

During the visit, the pharmacist and Zephyr reviewed the 15-15 Rule for identifying and treating hypoglycemia. They also discussed the fact that mixed insulin, unfortunately, does not allow mealtime flexibility due to the fixed ratio. The patient says she will try to maintain steady mealtimes and portions. She also asked to try a medication like semaglutide and has no contraindications.

 

The pharmacist explained that the first dose of semaglutide is a tolerance dose and is not expected to have a significant clinical impact. Transitioning to an MDI insulin regimen would help stabilize blood sugars, minimize hypoglycemia, and provide insulin dosing flexibility. However, Zephyr preferred not to switch insulin to MDI insulin at this time. She stated she will focus on having consistent meals instead. Based on her preference, they adjusted the current insulin regimen to reduce the risk of hypoglycemia. The pharmacist advised her to reduce the insulin aspart protamine/insulin aspart 70/30 morning dose to 20 units, the evening dose to 26 units, and to start semaglutide 0.25 mg weekly.

 

Visit 2

At the second visit, Zephyr reported that she could not maintain steady meal times despite her efforts. She initially reduced her insulin doses as requested, but once she realized she couldn’t maintain steady mealtimes, she resumed her previous dosing. Therefore, her current SMBG values closely resemble her last visits' values (Table 7). The pharmacist advised Zephyr to communicate questions, concerns, and changes to the clinic in between appointments moving forward. As Zephyr was unable to maintain steady meal choices, she couldn’t safely remain on mixed insulin due to safety concerns.

 

Consequently, the pharmacist talked with Zephyr about two options based on her goal to increase the semaglutide dose to 0.5 mg weekly. One option would be to transition to basal/bolus insulin (administered TID or QID), but the patient previously rejected this option. An alternative option (dependent on the patient’s prandial insulin dose) would be to transition the patient to basal-only insulin and eliminate prandial insulin. This option creates a risk of hyperglycemia until the semaglutide doses can be titrated. Thus, periodic clinical assessment of hyperglycemia would be critical. DKA and HHS are a concern with significantly elevated blood sugars. Still, temporary elevations in the high 100s to low 200s may be acceptable if the patient is not safe or willing to take alternate recommended options.

 

After this review, Zephyr stated she cannot tolerate more than two insulin injections a day. They decided to transition Zephyr to once daily basal insulin and then a bolus insulin with dinner, as that is her largest and most consistent meal of the day. Based on her current regimen, she was injecting 37.8 units of basal insulin and 16.2 units of prandial insulin per day. She could transition to a bolus insulin dose of 4 to 8 units and a basal dose of 34 to 38 units with a goal of a total insulin dose of 42 units per day (~22% reduction from the prior TDD). Eliminating the prandial insulin would be risky. Dependent on Zephyr’s motivation, ability to tolerate semaglutide, and attention to portion sizes and SMBGs, she may do well without any prandial insulin.

 

Semaglutide does not require set mealtimes or portions for safety. The pharmacist believed that with time, the patient would do well on basal insulin + semaglutide at higher doses, if tolerated. Sometimes, this interim period is the toughest for clinical decision-making.

 

CASE 4: Sahar Kim–pronouns: they/them/theirs

Visit 1

Sahar presented for their first visit, reporting that despite their FBGs being at goal, their A1c has been above goal. The insurance company did not cover their CGM so the pharmacist asked Sahar to test SMBGs more frequently. They sporadically checked, when possible, at the day's beginning or end (Table 8).

 

They were currently prescribed insulin glargine-yfgn (Semglee), which is a biosimilar to insulin glargine (Lantus), and inject 52 units once daily. The SMBG chart indicates FBGs of 80 to 100 mg/dL, and bedtime values are in the high 100s to low 200s.

 

Table 8. Sahar Visit 1

Date	acB	HS	HS insulin (insulin glargine-yfgn)
	78	198	52
	89		52
		201	52
	123	188	52
	111		52
			52
	97	187	52
	79		52
		210	52
	83	218	52
	98		52
		189	52
	109		52
		186	52
	87	199	52
Visit 1	98		52
Average	96	197

 

PAUSE AND PONDER: What would be the appropriate term for this situation regarding glycemic control/treatment?

 

Sahar declined an oral medication, as they have trouble swallowing them. They were amenable to an alternate once daily injection, as they would prefer not to have more than one injection daily. Sahar and the pharmacist deemed that an FRC would be the preferred option due to overbasalization and the patient’s preference to minimize injections. After some investigation into insurance coverage and discussion, they determined that iGlarlixi would be reasonable.

 

The pharmacist started Sahar on 30 units of iGlarlixi daily, which equates to 30 units of insulin glargine and 10 mcg of lixisenatide. Additionally, they were previously injecting at bedtime, but the FDA-approved labeling recommends morning dosing of iGlarlixi.²¹ Sahar reported that they will not be able to attend the next appointment (intended to be in approximately 2 weeks) or speak on the phone for the next 6 weeks. As they have been reliable and this was a transitional period in their treatment, the pharmacist developed a self-adjustment dosing plan. The pharmacist advised Sahar to increase iGlarlixi by 2 units once a week (up to 42 units daily) for each week that all their FBGS are greater than 130 mg/dL.

 

Visit 2

Sahar returned 6 weeks later and indicates that they increased iGlarlixi to 42 units over time based on the guidance the pharmacist provided at the last visit. They denied any ADRs (including hypoglycemia) associated with the FRC. A review of SMBGs shows stabilization between morning and bedtime values, indicating that the bedtime values have come down and the FBGs have increased. Although the FBG average is above 136, the trend shows decreasing FBGs over the last week or so. Through shared decision-making, Sahar and the pharmacist decided to maintain the current dose. The pharmacist expects to see an improvement in the A1c based on this improved PPG control. This is because although FBG and HS readings are being tested for ease, the improvement in HS readings indicates an improvement in PPGs.

 

TAKEAWAYS

We’ve reviewed many situations where insulin still plays a significant role in diabetes care. The advent of newer medications and greater coverage and affordability require a balance between new and old therapies to maximize the benefits and minimize the risks of both. Many medications for diabetes or coexisting obesity and diabetes (diabesity) are in the pipeline. This balance of optimal medication management will continue to change as the FDA approves new medications for diabetes.

 

Patient safety, especially prevention of hypoglycemia, is paramount in insulin dose adjustments, but monitoring and education regarding side effects is a close second. The pharmacist will need to adjust the dose or medication if there is a safety risk. Especially with the positive benefits associated with GLP-1 RAs, some patients may want to tolerate the adverse effects or hope they improve.

 

While these cases are extrapolated from the ambulatory care perspective, this knowledge can be helpful in a variety of settings. For example, pharmacists can use the principles discussed here for people obtaining their medications in the retail setting or those in the process of being titrated who are then hospitalized.

Download CE Activity

INTRODUCTION

The increasing prevalence of dietary supplement use among individuals who engage in regular physical activity has raised a variety of important health concerns.¹ Manufacturers often market commonly used products—including creatine, protein powder, and pre-workout supplements—as products that enhance athletic performance, promote muscle growth, and reduce recovery time. Recovery time refers to the period of time the body needs to repair and restore itself after physical activity, in particular after intense exercise or strength training (see SIDEBAR).² These features attract many customers in pursuit of their fitness goals; however, the increase in consumption of these supplements is not always accompanied by accurate knowledge or professional guidance. This raises an array of concerns regarding the efficacy, safety, and long-term health implications of creatine, protein powder, and pre-workout supplements.¹ Given the increasing number of patients who use dietary supplements, it is imperative that pharmacy teams understand this topic to provide guidance and counseling and care.³

 

SIDEBAR: Recovery Time and Physical Activity⁴

• To stay healthy and avoid injury, the body needs time to rest and recover after physical activity.
• Muscle fatigue depends on how much and how hard an individual exercises, and it varies from person to person.
• Physical activity puts stress on the muscles to build strength and improve performance.

 

Supplements can help the body recover faster by supporting muscle repair and reducing the risk of overuse injuries.

 

OVERVIEW OF DIETARY SUPPLEMENTS

The Dietary Supplement Health and Education Act (DSHEA) of 1994 defines a dietary supplement as a product intended for oral consumption that contains one or more dietary ingredients intended to supplement the diet. These dietary ingredients may include vitamins, minerals, herbs, botanicals, amino acids, or other substances found in the food supply, such as enzymes and live microorganisms.⁵ As the use of dietary supplements continues to grow, individuals turn to them for various reasons, most commonly to address nutrient or vitamin deficiencies, boost energy levels, and/or meet specific nutritional needs that may be difficult to achieve through a regular diet.⁶

 

A widely used supplement, creatine, supports the rapid regeneration of adenosine triphosphate (ATP) during high-intensity, anaerobic exercise, contributing to improved strength, sprinting performance, and muscle mass.⁷ Protein powders are also commonly used particularly for their role in supporting and maintaining skeletal muscle mass.⁸ Pre-workout supplements—multi-nutrient products designed to enhance physical performance—have gained popularity for their potential to improve training capacity, accelerate recovery, and increase energy during workouts.⁹ Overall, creatine, protein powders, and pre-workout supplements are dietary supplements commonly used to boost physical performance, promote muscle growth, and support recovery. However, their effectiveness can vary based on the specific ingredients and formulations of each product.

 

How Dietary Supplements are Regulated

The Food and Drug Administration’s (FDA) Center for Food Safety and Applied Nutrition (CFSAN) is the division responsible for overseeing dietary supplements, as these products are regulated as food under United States (U.S.) law.⁵ The FDA’s role includes⁵

• Inspecting manufacturing facilities
• Reviewing new dietary ingredient (NDI) notifications and related submissions
• Investigating consumer complaints
• Monitoring adverse event reports related to supplements on the market

While the FDA has specific and critical regulatory responsibilities, it does not approve dietary supplements or their labeling before they reach the market.⁵

 

Over the past few decades, hundreds of dietary supplements have entered the market. This has limited the FDA’s ability to fulfill its responsibilities in comprehensively monitoring the supplement market.¹⁰ Because the FDA’s resources and capacity are limited, they have primarily acted only when significant quality concerns have emerged, including microbial and/or heavy metal contamination, adulteration with synthetic drugs, and inaccurate or incomplete ingredient labeling.¹⁰ When evaluating dietary supplements such as creatine, protein powder, and pre-workout supplements, pharmacy team members can be essential consultants. They should recommend products that have been verified by third-party laboratories, such as the U.S. Pharmacopeia (USP), NSF International, or ConsumerLab.com. In addition, they should educate patients about potential quality and safety concerns.¹⁰

 

Common Misconceptions About Dietary Supplements

Numerous misconceptions surround dietary supplements, and the growing influence of social media has accelerated their spread. One common belief is that the FDA tests and approves all dietary supplements before they reach consumers. However, the FDA does not have the capacity to evaluate these products for safety and efficacy prior to their sale.⁵ Another widespread misconception is that dietary supplements are safe for everyone; however, just because a product is classified as a supplement does not mean it is harmless. For example, even commonly used supplements, like creatine, are not suitable for everyone and may pose risks for certain populations who should avoid their use.

 

CREATINE

Creatine is an endogenous substance made in the liver, pancreas, and kidney from L-arginine, glycine, and methionine by L-glycine-arginine aminotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) enzymes.¹¹ Once it has been synthesized, creatine travels through the bloodstream via sodium- and chloride-dependent creatine transporters to reach its target tissues, like skeletal muscle and brain.¹² Inside the cell, creatine kinase converts 65% of creatine into phosphocreatine.¹² Phosphocreatine stores high-energy phosphate groups that can be used quickly by skeletal muscle to make ATP, the main energy source for cells, by donating phosphate groups to turn adenosine diphosphate (ADP) back into ATP.¹¹ Muscles rely on this conversion into ATP for energy during short-duration and high-intensity exercise.¹²

 

Creatine supplementation increases the rate of phosphocreatine synthesis during recovery periods. This enhances muscle performance, recovery, and overall training outcomes, which is why many individuals are inclined to use creatine.¹² Creatine also helps increase muscle mass and reduce body fat percentage, and it has been shown to enhance performance in short, high-intensity exercise.^11,13

 

Dose

Individuals can begin using creatine with a total of 20 grams daily for up to seven days; this is described as a loading phase.¹⁴ Most creatine powder products contain 3 to 5 grams per scoop (it is important to read the product’s label), so achieving this dose typically requires using four to five scoops per day, consumed throughout the day. Mixing one scoop into a beverage of choice with each meal or snack can make it easier to incorporate into one’s routine.

 

After the loading phase, individuals continue with the maintenance phase of 2.25 to 10 grams daily for up to 16 weeks.¹⁴ This typically equates to 1 to 2 scoops per day. While individuals may choose to continue supplementation beyond this 16-week period, most studies have been limited to around 16 weeks. Long-term data is limited, but the available studies have not reported any serious adverse effects.

 

Of note, a loading or induction phase is not strictly necessary; alternatively, research shows that smaller, consistent daily doses are also effective if the loading phase is not desired.¹⁵ Some individuals prefer to skip the loading phase because consuming 20 grams per day (approximately four to five scoops) can be difficult to incorporate into their routine. Also, patients who experience mild adverse effects (described below) should divide their creatine consumption into smaller doses taken throughout the day.¹⁶

 

PAUSE AND PONDER: How might a patient’s daily routine influence the recommendation between a creatine loading phase and a lower daily dose?

 

Selecting a Product

Creatine is available in a wide range of commercial products (see Table 1), most commonly as a powder formulation.¹³ It can be found in both solid and liquid dosage forms. The liquid formulation is thought to improve creatine solubility, which may allow patients to consume less. However, it has limitations in shelf life, as creatine is not stable in liquid form over extended periods.¹⁷ The solid dosage form includes powders and capsules.¹⁶

 

The most popular form is creatine monohydrate.¹⁴ Creatine monohydrate has been used extensively without resulting in major adverse events.¹⁷ While researchers have conducted studies to evaluate different forms of creatine, creatine monohydrate remains the most researched and superior available form.^11,14,17

 

Table 1. Available Creatine Products^11,14

Type of Creatine	Description	Clinical Pearls
Creatine monohydrate	The most common form of creatine.   Stored in muscle for quick energy.	·       Widely studied ·       Proven safe and effective ·       Affordable
Creatine nitrate	Creatine bound to nitrate	Claims of better absorption, but this is not strongly supported by studies.
Di-creatine malate	Creatine bound to malate	Claims to have increased water solubility, but research is limited.
Creatine ethyl ester	Creatine bound to esterified ethanol	Claims better absorption due to increased uptake across the membrane, but evidence does not support superior efficacy over creatine monohydrate.
Creatine gluconate	Creatine bound to a glucose molecule	Claims improved absorption and transport of creatine into muscle cells, but the research is limited.   Should be avoided with diabetes because it could impact blood sugar levels.
Creatine citrate	Creatine bound to citric acid	Claims to improve creatine solubility and absorption but has not proven superior over monohydrate
Creatine magnesium chelate	Creatine bound to magnesium	Claims to enhance stability, absorption, and overall effectiveness of creatine supplementation, but further research is necessary to support these claims.

 

Based on currently available data, creatine monohydrate is recommended when helping a patient select a creatine product. Creatine monohydrate has the strongest evidence supporting its use, primarily due to its high bioavailability and well-documented effectiveness in enhancing muscle strength and power. While formulation type is generally not a critical factor, powder is the most commonly used and widely available form.¹¹ As mentioned earlier, when recommending dietary supplements like creatine, choosing a product that has undergone third-party testing is the safest option. For example, a creatine monohydrate supplement which has a USP or NSF seal is a reliable choice.¹⁴

 

Safety

Creatine is overall well tolerated with minimal adverse effects.¹⁴ The most common adverse effects associated with oral creatine include^14,16

• Dehydration
• Diarrhea
• Gastrointestinal upset
• Muscle cramps
• Water retention leading to weight gain

 

It is rare to experience severe adverse effects when taking creatine, however, the following may occur¹⁴

• Interstitial nephritis
• Renal insufficiency
• Rhabdomyolysis
• Venous thrombosis

 

Prior to beginning creatine supplementation, individuals with the following conditions should avoid its use until first discussed with their physician:¹⁶

• Bipolar disease (may increase mania)
• Diabetes
• Kidney disease
• Liver disease
• Parkinson’s disease, especially in combination with caffeine (may accelerate progression of disease)
• Pregnant or breastfeeding

 

A pharmacy technician should refer to the pharmacist if the patient^14,16

• Has a disease state or condition listed above
• Asks for a recommendation on which creatine supplement to use
• Has questions or concerns regarding possible drug interactions or adverse effects
• Has specific questions about dosing based on their condition, disease state, or current medications or use of other supplements

 

Common Misconceptions

People share a considerable amount of information about dietary supplements like creatine online and on other platforms, but some of this information can be inaccurate or misleading. Misinformation may discourage individuals from using a supplement that could offer benefit. Therefore, it is essential for pharmacy team members to understand key facts about creatine in order to provide accurate information and help prevent the spread of false claims. Table 2 describes many common misperceptions and provide the evidence needed to respond.

 

Table 2. Common Misconceptions and Evidence-based Facts^11,15,18

Common Misconceptions	Evidence-Based Facts
Creatine supplementation results in weight gain.	Creatine supplementation may sometimes cause water retention, particularly during the initial stages of use. However, this effect is not universal, and creatine can actually offer benefits, such as improved intracellular hydration, which may enhance muscular strength and reduce fatigue.
Creatine is safe for everyone.	Some studies have reported potential liver or kidney complications, which is why individuals with these conditions, as well as the other exclusion groups mentioned in the text, are advised to avoid creatine supplementation or need to consult with a physician prior to use.
A loading phase is required for creatine supplementation to be effective.	Creatine supplementation at lower daily doses has also been shown to be effective, making the loading phase optional.
Creatine has the same effects as anabolic steroids.	Creatine supplementation does not stimulate muscle growth via hormonal mechanisms, as anabolic steroids do.
Creatine causes hair loss.	No direct evidence indicates creatine supplementation causes hair loss or baldness. Most research attributes hair loss in individuals taking creatine to genetics and hormonal factors rather than the supplement itself.
Creatine causes dehydration and cramping.	Creatine does not increase the risk of dehydration or muscle cramping. Maintaining proper hydration during exercise is important whether or not an individual is using creatine.
Creatine only improves lower body strength.	A 2021 meta-analysis demonstrated that creatine supplementation significantly improves upper limb strength performance during short-duration exercises. These effects were observed regardless of age, sex, training protocol, or dosage.

 

PROTEIN POWDER

Protein is a fundamental component of a balanced diet and plays a critical role in a healthy lifestyle. It is found in both animal- and plant-based sources and is essential for biological functions, such as tissue-building and maintaining optimal health.¹⁹ However, many individuals struggle to meet their daily protein requirements, particularly when the goal is to enhance their physical appearance or athletic performance. Protein powder offers a convenient solution to help individuals reach these goals.²⁰ Medically, it can also benefit patients who have difficulty consuming adequate daily protein intake due to chewing or swallowing limitations.²¹

 

Dose

The recommended dietary protein intake in healthy adults is based on their body mass, lean body mass, and level of physical activity.²² The Recommended Dietary Allowance (RDA) and Acceptable Macronutrient Distribution Range (AMDR) are both used as guidance on the recommended amount of protein to consume each day.²² The RDA for protein is a minimum of 0.8 grams per kilogram per day (g/kg/day) to support healthy individuals’ nutritional needs.²² It should be noted that the RDA is the minimum requirement; therefore, individuals should aim to intake 1.2 to 1.7 g/kg/day to benefit from the effects of efficient protein intake.²³ When this range is achieved, older adults are at less risk of muscle loss and frailty, and athletes can see significant changes in muscle and performance.²³ This can be incorporated as 0.4 g/kg/meal or about 20 g per meal depending on weight.²⁰ In addition, the AMDR states that 10% to 35% of an individual’s energy intake (calories) should be from protein.²²

 

For active individuals who want to maximize their muscle support, the Academy of Nutrition and Dietetics, Dieticians of Canada, and the American College of Sports Medicine recommend doubling the RDA of protein.²⁴ For example, individuals who are in resistance training may wish to consume 1.2 to 2 g/kg/day.²² In addition, to aid in recovery, active individuals may wish to consume 15 to 20 gs of protein within one to two hours after exercising. Older adults, who want to reduce their risk of muscle loss, may also consume a higher amount of protein per day.²³

 

Insufficient amounts of protein can result in adverse consequences for one’s health, including decreased protein synthesis.²² When protein synthesis is affected, it negatively influences other processes in the body including²²

• Muscle mass density and function
• Bone and calcium homeostasis
• The immune system
• Fluid and electrolyte balance
• Enzyme production and activity

 

By consuming protein above the RDA and within the AMDR, individuals can improve muscle preservation, reduce age-related muscle loss, maintain body composition and metabolic health, and increase muscle mass and strength.²²

 

Selecting a Product

Meeting daily protein intake goals is important for overall health and performance; however, it can be challenging through diet alone. In such cases, protein supplements, such as protein powder, can help to achieve those goals effectively.²⁰ Selecting the appropriate type of protein powder is essential to optimize the benefits of adequate protein intake. Protein powder should be tailored to the individual’s specific needs and goals.

 

For example, a study involving 18 women with bulimia nervosa or binge eating disorder found that consuming high-protein supplements three times daily significantly reduced the frequency of binge eating episodes. The participants reported feeling less hungry and fuller, which led to a reduction in overall food intake. This study suggests that protein supplementation may help manage disordered eating patterns in individuals with bulimia nervosa or binge eating disorder.²⁵

 

In contrast, protein supplements are also used in the treatment of anorexia nervosa, but to promote healthy weight gain. Registered dietitians recognize that the use of dietary supplements, including protein powders, which are often part of the standard of care in treating patients who struggle to meet their nutritional needs through food alone due to psychological or physical barriers.²⁶ A case study reported protein supplementation helped to increase caloric intake, preserve lean body mass, and support gradual weight restoration.²⁷

 

Table 3 provides guidance to tailor protein powder selection.²⁰

 

Table 3. Types of Protein Powders²⁰

Whey	Concentrate	·       Vary in lactose and fat content ·       In many protein drinks, bars, and nutritional products ·       Used in infant formula ·       Do not use if allergic to milk
	Hydrolysate	·       Hydrolyzed whey protein ·       Easiest to digest because its long protein chains are pre-broken down ·       Used in specialized infant formulas and in medical supplements for nutritional deficiencies ·       Do not use if allergic to milk
	Isolate	·       High in protein, low in fat or lactose ·       In protein bars and drinks ·       Suitable for lactose intolerance ·       Do not use if allergic to milk
Milk protein	·       Supports immune system ·       Enhances muscle growth ·       Do not use if allergic to milk
Egg protein	·       Released more slowly than whey ·       Taken throughout the day ·       Do not use if allergic to eggs
Plant-based	Brown rice protein	·       Suitable for vegetarians or individuals who do not consume dairy ·       Gluten-free
	Pea protein	·       Highly digestible ·       Hypo-allergenic (not likely to cause an allergy)
	Hemp protein	·       Good source of omega-3 fatty acids

 

As described in Table 3, protein powders are available in different formulations and can be selected based on an individual’s dietary needs, allergies, or fitness goals. Milk-derived proteins, such as whey (including concentrate, isolate, or hydrolysate forms) are commonly recommended for those aiming to promote muscle growth due to their rapid absorption and high biological value.

 

However, it is important to note that whey protein is produced during the cheese-making process. Enzymes are added to milk to separate the solid curds from the liquid whey. The liquid whey is then pasteurized and dried to create protein powder.²⁰ Because whey is derived from milk, it should not be used in individuals with a milk allergy.²⁰ Similarly, milk protein powders, which contain both whey and casein (milk protein), may also enhance muscle growth but should not be used in those with milk allergies. These are important factors to consider when selecting a protein, as milk allergy is one of the most common allergies in the U.S., affecting over 4.7 million adults.²⁸

 

For those with lactose intolerance or dietary restrictions, whey protein isolate (which is low in lactose) or plant-based proteins (including brown rice, pea, and hemp protein) may be tolerated better.²⁰

 

PAUSE AND PONDER: When choosing a protein powder, how might an individual’s health conditions, allergies, or fitness goals influence the type of protein powder suitable for them?

 

Safety

Protein is classified as a dietary supplement, and it is essential for patients to inform their healthcare providers about any supplements they are taking. Factors such as food intake, meal timing, and nutritional status can influence the pharmacokinetics of medications. The drug’s ability to be properly absorbed can be influenced by a high consumption of protein from meals and supplements. Medications such as levodopa, used in Parkinson’s disease, and beta-lactam antibiotics (such as penicillin, amoxicillin, and cephalexin) rely on transporter proteins for absorption, and their uptake may be reduced with a high protein intake. Additionally, a high-protein, low-carbohydrate diet can significantly increase the clearance of the beta-blocker propranolol and moderately increase the clearance of theophylline, potentially impacting the therapeutic efficacy of both medications. A high-protein meal can also increase the absorption of certain drugs, such as the immunosuppressant tacrolimus.²⁹

 

Protein supplementation for patients on anticoagulation is also a major concern because of vitamin K concentrations in protein supplements. It is important that patients, especially those on warfarin, notify their anticoagulation healthcare team about protein supplement use. Plant-based protein powders, such as those containing soy, may contain vitamin K; thus, decreasing the effect of warfarin.³⁰ It is important to check the ingredient list in the Nutrition Facts labeled on protein supplements and look for Vitamin K. For example, protein supplement drinks such as Boost High Protein Nutritional Drink contains Vitamin K1 as an ingredient. In this situation, it is critical to select another protein powder formulation.

 

Protein powder supplements may contain ingredients that can contribute to gastrointestinal discomfort, weight gain, or elevated blood glucose levels. Patients should review product ingredients carefully when experiencing adverse reactions. Since protein powder is a dietary supplement, the FDA does not evaluate it for safety or efficacy prior to marketing. Therefore, consumers cannot be certain that the product contains what is claimed on the label.³¹

 

Furthermore, some products may contain added sugars or dextrin, maltodextrin, or sweeteners that can contribute to weight gain, which may not be ideal for individuals who want to lose or maintain weight.²⁰ Patients with diabetes should also pay close attention to protein powders with sugar listed as one of the first three ingredients and verify that the product is low in carbohydrates.²⁰ Patients with kidney disease may not be able to tolerate more than the recommended daily allowance of protein at one time because they can’t efficiently remove waste products during the metabolism of protein. These patients may need a product that is lower than average in protein. For example, they should select a protein powder with a lower-range protein content such as 10 to 15 g per serving.²⁰ If patients have irritable bowel syndrome or are lactose intolerant, a protein powder without lactose sugars, artificial sweeteners, dextrin, or maltodextrin is recommended.²⁰ It is also important to check and avoid ingredients containing gluten in patients with a gluten allergy or sensitivity.²⁰

 

The pharmacy technician should refer the patient to the pharmacist if the patient

• has diabetes, kidney, or liver disease, gastrointestinal problems, or any chronic illness that require dietary oversight
• takes prescription medications because timing of supplements may be considered
• is a child, teen, pregnant, or breastfeeding
• complains about adverse effects from a protein supplement
• takes multiple protein supplements, as they are at risk of overconsumption

 

Common Misconceptions

Similar to other dietary supplements, information about protein used as a supplement may be inaccurate or misleading. Protein is a commonly used supplement, and it is important to address misconceptions about usage, concerns, and key information related to its use. Misinformation may come from peer influence, social media, and seemingly credible sources. It is essential for pharmacy team members to understand the uses of protein supplementation to provide accurate information and help prevent the spread of false claims.

 

Protein powder can be used in those that need to meet their nutritional requirements and in those looking to build muscle. While it is commonly believed that only athletes require protein supplementation, individuals of all activity levels may benefit depending on their dietary needs. The RDA reflects the minimum daily protein intake needed, but it is mistaken as the target for everyone to follow.²² In contrast, the AMDR recommends that protein intake accounts for 10% to 35% of daily energy intake, measured in kilocalories.³² For example, people who consume 1,300 calories per day should aim to consume 33 to 114 grams of protein daily, based on individual needs and health goals.

 

Some individuals may be hesitant to increase their protein intake due to concerns about its potential impact on comorbid conditions, although current evidence does not support their concerns. Table 4 clarifies misleading information to encourage individuals to use protein supplements knowledgeably and confidently as part of a healthy lifestyle.²²

 

Table 4. Common Misconceptions and Evidence-based Facts^33-35

Common Misconceptions	Evidence-Based Facts
High-protein diets weaken bones and increase the risk of osteoporosis.	A high protein diet along with eating more dairy, calcium, and exercising daily can help protect the bones.
Consuming high amounts of protein will damage kidneys, even if the individual is healthy.	The National Health and Nutrition Examination Survey found that even with very high protein intake from all sources, blood urea nitrogen levels remained within the normal range, indicating that there is no risk of developing chronic kidney disease or harming the kidneys.
High protein diets, especially from animal sources, increase the risk of heart disease and type 2 diabetes.	An analysis of the Framingham Heart Study Offspring Cohort showed an inverse relationship between inflammation and dietary protein intake, showing that there was a beneficial effect for higher animal- and plant-based protein intake. No data demonstrates a relationship between dietary protein and cardiovascular disease or type 2 diabetes mellitus.

 

PRE-WORKOUT

“Pre-workout” is a term used to describe supplements composed of multiple ingredients, intended to be taken before a workout.³⁶ Manufacturers of these supplements propose pre-workout supplements enhance performance, energy, endurance, and focus during a workout; however, limited research supports these claims.³⁷

 

Common Ingredients

Pre-workout supplements can include countless combinations of ingredients, but most multi-nutrient formulas feature a core set of commonly used components, including^9,36

• Caffeine
• Beta-alanine
• Creatine
• Citrulline
• Taurine
• Tyrosine
• B vitamins (B-6, B-12)

 

While many pre-workout supplements share a core group of commonly used ingredients, their formulations can vary significantly.³⁶ Unfortunately, many companies do not list all included ingredients and their specific quantities on the label; this variability makes it difficult for pharmacists to recommend or evaluate products.² Much of the existing research on pre-workout supplements focuses on caffeine as the primary stimulant.³⁷ It has been found that many products containing caffeine do not have accurate amounts listed on their label.² Use of products with unreliable labeling can put patients at risk for adverse effects.²

 

Selecting a Product

Since pre-workout supplements contain ingredients similar to those found in energy drinks, it is important to distinguish between the two. Pre-workout supplements are designed to enhance both short-term exercise performance and long-term training outcomes.³⁷ In contrast, energy drinks and shots typically consist of caffeine along with a few vitamins or amino acids, aiming primarily to increase energy and alertness. They are intended for use at any time throughout the day.³⁷ Because of the variability in composition and unreliability of the labeling on pre-workout supplement products, it is recommended to avoid their use and rather focus on eating a balanced diet to support energy needs.²

 

Safety

Caffeine and beta-alanine are the most widely used ingredients included in pre-workout supplements found in 86% and 87% of products, respectively.³⁶

 

Beta-alanine is included because it enhances exercise capacity and performance by elevating muscle carnosine levels, which buffer the accumulation of lactic acid in muscles.³⁸ This buffering effect helps delay fatigue during high-intensity exercise, making it especially beneficial for short bursts of activity such as weightlifting or sprinting.³⁸ While both are generally well tolerated, long-term doses of beta-alanine that exceed 6.4 g per day or caffeine use beyond several weeks at doses above 400 mg/day may increase the risk of adverse events (see Table 5) and dependence.^39,40

 

Table 5. Potential Adverse Events of Beta-Alanine and Caffeine^2,36,39-41

Ingredient	Potential Adverse Events
Beta-Alanine	·       Mild: o   Flushing o   Paresthesia o   Pruritus
Caffeine	·       Mild to Moderate (> 400 mg per day): o   Vomiting o   Tachycardia o   Hypokalemia o   Hypoglycemia o   Anxiety and restlessness o   Gastrointestinal upset (including diarrhea and nausea) o   Diuresis o   Headache o   Insomnia o   Palpitations o   Muscle tremors ·       Severe (10 to 14 g per day): o   Agitation o   Seizures o   Ventricular dysrhythmias o   Hypotension o   Shock

 

Patients should be aware of their total daily caffeine intake, which includes not only coffee and energy drinks but also caffeinated beverages, medications, and multivitamins that may also contain caffeine.³⁷ To determine if a medication contains caffeine, patients can read their medications’ list of ingredients or ask their pharmacist.

 

Caffeine is rapidly absorbed from the stomach and small intestine, reaching peak serum concentrations within 30 to 60 minutes following oral intake. Although food may slow the absorption rate, it does not reduce the total amount that will eventually be absorbed.⁴¹ Studies have found that individuals with lower CYP1A2 activity have increased reports of symptoms of toxicity, as caffeine is hepatically metabolized by CYP1A2 which causes caffeine to be absorbed more slowly.^41-43 The plasma elimination half-life ranges from 3 to 7 hours in healthy adults and 3 to 4 hours in children. This range is shortened in smokers, due to the activation of the CYP1A2 enzyme by cigarette smoke, and prolonged in the last trimester of pregnancy, in patients with cirrhosis, and in infants.⁴¹

 

In terms of safety, most adults can consume a maximum of 400 mg of caffeine per day, while children are typically safe when ingesting up to 2.5 mg/kg of caffeine per day.⁴¹

 

Table 6. Approximate Caffeine Content in Select Beverages
Coffee	100 mg
Tea	20-90 mg
Celsius Energy Drink	200 mg
Monster Energy Drink	160 mg

 

Toxicity and lethality risks increase with higher doses. Life-threatening events are seen when greater than 150 to 200 mg/kg of caffeine is consumed, and fatalities have been reported when 5 to 50 g of caffeine was ingested.⁴¹ However, recovery after ingestion of 50 g has also been reported.⁴¹

 

Pharmacists should counsel patients who are taking caffeine-containing products while concomitantly using pre-workout supplements because they are consuming high levels of caffeine.³⁷ This increased level of caffeine can increase the risk of adverse events described above.³⁷

 

Regarding pre-workout supplement use, the pharmacy technician should refer to the pharmacist if the patient

• Has pre-existing medical conditions, including high blood pressure, anxiety, seizure history, kidney or liver impairment, and heart disease or arrhythmias
• Is pregnant or breastfeeding
• Is asking for a recommendation on which pre-workout supplement to use
• Is experiencing or has questions regarding possible drug interactions and adverse effects
• Has specific questions about dosing based on their condition, disease state, or current medications/supplements

 

For example, Jenny, a 58-year-old woman, is interested in using a pre-workout supplement to help motivate her to be active after a long day at work. When the technician asks about her current caffeine intake, she mentions that she drinks two cups of coffee each day and also has a Sparkling Fuji Apple Pear (her favorite flavor) Celsius. The technician explains that each cup of coffee contains approximately 100 mg of caffeine, and the Celsius drink contains about 200 mg. Most pre-workout supplements contain between 150 to 300 mg of caffeine. If Jenny were to add a pre-workout supplement to her routine, her total caffeine intake could exceed 500 mg per day, increasing her risk of experiencing adverse events.

 

PAUSE AND PONDER: With the growing popularity of stimulant-containing products, how can you further assess patients’ consumption of caffeine? (Hint: Remember hidden sources of caffeine.)

 

CONCLUSION

With the growing popularity of supplement use in the fitness industry, products such as creatine, protein powders, and pre-workout supplements continue to be widely used. Pre-workout supplements are typically taken before exercising to enhance performance and focus, while creatine and protein powders are commonly used to support muscle growth and recovery. When used appropriately, these supplements may improve physical performance, promote muscle development, and reduce recovery time.⁶

 

As pharmacists and pharmacy technicians, it is part of our professional responsibility to educate the public about the potential risks and benefits of these products and to provide evidence-based recommendations. Our role also includes advocating for patients and staying informed about the latest developments, which are becoming increasingly prominent in the wellness market. Gaining a deeper understanding of these products is essential to recognize when we can confidently make recommendations or when to refer individuals to a physician or registered dietitian for more individualized guidance.

 

It is also important to acknowledge that these products still require more research to establish their full safety and efficacy, standards that are already well established for prescription medications.¹⁰ Additionally, current research often overlooks key individual factors such as genetics, the gut microbiome, and habitual diet, all of which can significantly influence exercise performance, recovery, and muscle growth.⁶

 

Download CE Activity

INTRODUCTION

The number of older adults (aged 65 years and older) is expected to exceed 1.5 billion by 2050.¹ Multimorbidity is expected to affect 65% of older adults aged 65 to 84 years and up to 82% of those aged 85 years or older.¹ With multimorbidity, the number of medications taken by the vulnerable older adult population increases. Along with drug-disease and drug-drug interactions, age-related physiological changes that alter pharmacokinetics and pharmacodynamics increase the risk of adverse drug events (ADEs).²

 

Throughout this continuing education activity, consider a hypothetical patient, Ms. Polly, who is an 85-year-old female. Enrolled in a Program of All-Inclusive Care for the Elderly (PACE), she has been able to live safely at home. Table 1 lists her current medication regimen.

 

Table 1. Medication Regimen

Acetaminophen/diphenhydramine PM 25/500 mg, 2 tablets nightly PRN for insomnia Alendronate 70 mg weekly for osteoporosis Amlodipine 10 mg daily for hypertension Aspirin 81 mg daily for heart attack prevention Cetirizine 10 mg daily for allergies Donepezil 10 mg daily for Alzheimer’s disease Fluticasone nasal spray 2 sprays in each nostril daily for allergies Furosemide 20 mg daily for peripheral edema Gabapentin 300 mg twice daily for neuropathic pain Glipizide ER 5 mg daily for pre-diabetes Ibuprofen 200 mg three times daily for pain Omega-3 Fish Oil 1000 mg twice daily for hyperlipidemia Oxybutynin 5 mg twice daily for overactive bladder Pantoprazole 40 mg daily for GERD Paroxetine 30 mg daily for depression Potassium chloride 10 mEq daily for potassium deficiency Pravastatin 40 mg daily for hyperlipidemia Propranolol 40 mg twice daily for hypertension Senna-docusate 8.6-50 mg, 2 tablets daily for constipation

ABBREVIATIONS: GERD = gastroesophageal reflux disease; mEq = milliequivalent; mg = milligrams; PRN = as needed

 

Ms. Polly’s healthcare needs have become more complex with her increasing confusion, declining ability to perform activities of daily living, and a recent fall. Her daughter continues to be her main caregiver and has requested more help from PACE; thus, the prescriber has reached out to the clinical pharmacist for assistance. This CE activity will review best practices for deprescribing with a focus on why, who, when, what, and how to safely deprescribe medications in the vulnerable older adult population.

 

WHY, WHO, AND WHEN TO DEPRESCRIBE

 

WHY: Older Adults Have Specific Needs

Since older adults have differing health and functional statuses, prescribers must individualize medication selection for these patients. Prescribing the right medication and dose for the right indication at the right time while providing benefit and avoiding ADEs is challenging. Comorbidities and complexity of medication regimens may result in suboptimal medication use. Suboptimal medication use comprises (1) underprescribing, (2) polypharmacy or overuse, and (3) high-risk prescribing, such as potentially inappropriate medications (PIMs), prescribing cascades, and anticholinergic and sedative effects.²

 

Estimates suggest that as many as 65% of older adults in the United States are exposed to polypharmacy and 29% to PIMs.^3,4 Polypharmacy is generally defined as the use of five or more medications and often occurs because of a prescribing cascade, which means the culprit medication causes an ADE that is mistaken for a new medical condition for which a subsequent medication is initiated as treatment. “Hyperpolypharmacy” or “excessive polypharmacy” is generally considered the use of 10 or more medications.⁵ Polypharmacy is associated with undesirable outcomes: frailty, cognitive decline, functional decline, falls, fractures, emergency department (ED) visits, hospitalizations, and mortality.^3,5,6

 

Evidence suggests that older age and indicators of poor health (i.e., multiple chronic conditions, cognitive decline, frailty) are risk factors for polypharmacy. The number of medications in a patient’s regimen may be the single most important predictor of ADEs.⁶ The likelihood of taking inappropriate medication increases with the number of drugs prescribed. Experts consider medications inappropriate in older adults when they pose individual or cumulative adverse event risk.

 

The Choosing Wisely Campaign brought awareness and encouraged conversations between healthcare providers and patients about medication overuse and potentially doing more harm than good within healthcare. This partnership between the American Board of Internal Medicine (ABIM) Foundation and specialty societies was formed in 2012. At the time, the healthcare field and society generally thought that more care was better, and patients tended to perceive prescribers as ignoring their patients’ interests if they did not prescribe certain medications.⁷

 

Understanding suboptimal prescribing allows healthcare providers to mitigate the risk of poor health outcomes in vulnerable older adults. Deprescribing is the process of healthcare professional-supervised medication withdrawal with the goal of managing polypharmacy and improving outcomes.⁸ Pharmacists review medication regimens comprehensively to identify and consider discontinuation of high-risk medications and those that cause more harm than benefit. Deprescribing encourages a proactive and systematic approach to mitigate potential medication-related problems (MRPs). This approach is preferable over a reactive approach (i.e., discontinuing an offending medication after an ADE occurs).

 

PAUSE AND PONDER: Why should healthcare providers re-evaluate medications periodically?

 

According to the World Health Organization, the global ADE-related mortality rate increased approximately 3.3-fold from 2001 to 2019, with the highest rates occurring in those aged 75 years and older.⁹ A systematic review of 14 hospital-based observational studies in older adults found an ADE to occur more often with an increased number of medications.¹⁰ More than 50% of ADEs could be prevented with safe prescribing practices.⁵ Safe medication use requires that healthcare providers ensure regimen appropriateness, considering treatment initiation, treatment optimization, and cessation of unnecessary or inappropriate medications.

 

WHO: The Age-Friendly Movement

The Institute for Healthcare Improvement in partnership with The John A. Hartford Foundation, American Hospital Association, and the Catholic Health Association developed the Age-Friendly Health Systems initiative to improve the care of older adults and the lives of caregivers. This framework—the Age-Friendly 4Ms, depicted in Figure 1—is a patient-centered approach to medication optimization that addresses polypharmacy and deprescribing. Conversations with healthcare providers can be re-framed to discuss “What Matters” to the patients and caregivers. Medications impact all the “M” domains: What Matters, Mentation and Mobility.^11,12

 

Figure 1. Age-Friendly Health Systems 4Ms Framework¹¹

 

Reasons for deprescribing may vary from patient to patient. When reviewing common goals for deprescribing, consider the perspectives of the patient, the caregiver, and the healthcare team. Identify which reasons for deprescribing may be most relevant or meaningful to each party involved in the patient’s care. Examples include

• reducing medication regimen complexity and pill burden to improve adherence
• reducing anticholinergic burden to improve and/or preserve cognitive function
• reducing fall and fracture risk
• reducing hospitalizations
• reducing mortality
• reducing costs

 

These deprescribing goals improve patients’ quality of life. Deprescribing considers not only single medications but also the aggregate interaction risk from multiple medications.¹³

 

Deprescribing often presents challenges due to barriers faced by healthcare providers and patients. Healthcare providers’ may have limited time and lack of training which serves as the most significant barriers. Patient-related barriers to deprescribing include satisfaction with medications, reluctance, resistance to change, and opposition to alternative treatments. Despite these challenges, many barriers can be addressed through education, communication, and shared decision-making.

 

Although many patients express not wanting to take medications, their beliefs and acceptance of polypharmacy and discontinuing medications is poorly understood. To further understand patients’ views, preferences and willingness, researchers from the University of South Australia and University of Sydney developed the Patients’ Attitudes Towards Deprescribing (PATD) questionnaires, including the revised PATD for older adults and caregivers and the revised PATD for cognitively impaired individuals (rPATDcog).^14-16

 

A population-based survey of Medicare beneficiaries 65 years and older using PATD questions found most older adults are open to having one or more medications deprescribed and two-thirds want to reduce the number of medications taken.¹⁷ A multi-center cross-sectional survey found older adults and caregivers are open to deprescribing, with more than 90% willing to discontinue a medication if a healthcare provider initiates the conversation.¹⁸

 

While primarily used for research, providers may use the revised PATD questionnaire clinically to target patients and caregivers who are willing to discontinue medications. The original work is available here: https://www.australiandeprescribingnetwork.com.au/925-2/.¹⁶ Understanding attitudes and willingness may enhance shared decision-making conversations about deprescribing.

 

PAUSE AND PONDER: How do you determine which medications to deprescribe?

 

WHEN TO DEPRESCRIBE

Older adults are often high-risk for potential MRPs due to pharmacokinetic (the body’s effect on a medication) and pharmacodynamic (a medication’s effect on the body) changes. However, advanced age is not an independent risk factor for MRPs. Elements of high-risk patients who may benefit from deprescribing include the following¹⁹:

• Polypharmacy: Use of multiple medications is the strongest risk factor for MRPs. Table 2 lists common types of potential MRPs.
• Multimorbidity: Having multiple chronic conditions increases the risk of drug-disease interactions.
• Renal impairment: Reduced renal function increases ADE risk.
• Transitions of care: Medication management by multiple prescribers can result in miscommunication and medication discrepancies, such as inadvertent continuation.
• Nonadherence: Patients may be nonadherent to their medication regimens due to experiencing real or perceived adverse effects and/or lack of benefit, complexity, burden, and cost.
• Limited life expectancy/end of life care: Goals of care change from slowing disease progression and prolonging life to improving quality of life. Patients may no longer benefit from preventive medications and use certain medications for symptomatic management.
• Frailty and dementia: Frailty—an age-related syndrome of physiologic decline—is associated with increased adverse events and risk of harm, such as falls, which can be detrimental. ADEs may worsen or exacerbate these syndromes (i.e., fatigue or cognitive impairment).

 

Table 2. Types of Potential Medication-Related Problems

Adverse Drug Events Adverse Drug Interactions Excessive Duration Inappropriate/Unnecessary Medications Ineffective Therapy No Indication Nonadherence Suboptimal Dosing Supratherapeutic Dosing

 

 

Aging is not an identical experience for every person, so frailty—declining mental and physical resilience, or the ability to bounce back and recover from events like illness and injury—is a more appropriate measure of health status than age alone. Frailty has been associated with poor patient outcomes. The Edmonton Frail Scale is a validated, reliable, and multidimensional screening tool for all healthcare settings. The free tool with a training course is available here: https://edmontonfrailscale.org/. It assesses nine domains: cognition, general health status, functional independence, social support, medication use, nutrition, mood, continence, and functional performance. The highest level of frailty is a score of 17.²⁰ Assessing frailty severity can help with shared decision-making and determining goals of care.

 

PAUSE AND PONDER: How can you use prescribing clinical tools for deprescribing?

 

WHAT TO DEPRESCRIBE

While few studies have measured the clinical implications of underprescribing, evidence has shown an association between polypharmacy and PIMs. A systematic review of 38 clinical trials found that deprescribing interventions in community-dwelling older adults (aged 65 years and older) may provide small reductions in use of PIMs and mortality.⁶ Prescribers and pharmacists should periodically reevaluate any medication initially prescribed for a clinical indication since benefits, risks, conditions, and comorbidities change over time, which may result in inappropriate use. Medication review should consider the following factors: goals of care, remaining life expectancy, treatment targets, time until benefit, number needed to treat (NNT, a statistical measure that indicates how many patients need to be treated with a specific intervention to prevent one additional adverse outcome), number needed to harm, and ADEs.²¹

 

Collaborative approaches and numerous clinical application tools highlighted below are available for safe prescribing and to reduce medication overuse. Focusing on medications and potential ADE risk, healthcare providers can employ these clinical tools to identify medications for potential deprescribing.

 

Risk-Benefit Analysis

Older adults are vulnerable to ADEs associated with “high-risk” single medications and medication classes, including anticoagulants, benzodiazepines, cardiovascular agents, digoxin, hypoglycemics, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, psychotropics, and those with anticholinergic effects. “High-risk” medication combinations—for example, angiotensin-converting enzyme inhibitors, diuretics, and NSAIDs in patients with chronic kidney disease (known as the “triple whammy”)—augment ADE risk.¹³

 

In a “Less is More” special communication about polypharmacy and deprescribing, experts proposed grouping medications into two categories for older adults to determine if the likely benefit outweighs potential risk/harm, while noting that medications may fall into both categories.¹³

 

“Disease and/or symptom control medications” are used to manage active disease and symptoms and help maintain quality of life.¹³ Discontinuing these medications could result in symptom return or functional decline due to disease worsening. Examples include analgesics, anti-anginals, anti-heart failure medications, and levothyroxine. Dose reduction of disease/symptom control drugs may be appropriate if symptoms are mild or intermittent, but these should be discontinued if altogether ineffective. Notably, aggressive treatment may be inappropriate for hypertension or diabetes management in some older adults, as this could increase the risks of hypotension or hypoglycemia, respectively.¹³

 

Preventive medications are intended to prevent future morbid events.¹³ Their use should be guided by assessment of absolute risks and benefits of treatment for individual patients, taking into consideration the time required for benefit (known as "time to benefit"), patient preferences, and estimated life expectancy. For example, osteoporosis guidelines recommend a “drug holiday” (temporary discontinuation of therapy) from bisphosphonates depending on fracture risk after five years of treatment to mitigate risk of atypical femoral fractures and osteonecrosis of the jaw. Despite discontinuation, bisphosphonates’ anti-fracture effects persist because this medication class has long half-lives and remain stored in bone for up to 10 years. Another example is statins, which are commonly used for primary prevention of cardiovascular events. Evidence suggests that statin discontinuation after eight years does not increase cardiovascular event risk.¹³

 

Choosing Wisely Campaign

The American Board of Internal Medicine’s global Choosing Wisely (CW) Campaign encourages patient engagement and healthcare provider conversation to choose care that is evidence-based, necessary, and free from harm. Since 2012, a compilation of more than 600 evidence-based statements from approximately 80 healthcare organizations advise healthcare providers, patients, and caregivers about optimization, appropriateness, and avoidance of unnecessary medical testing and treatments, available at https://www.choosingwisely.org/.^7,22,23,24

 

The American Society of Consultant Pharmacists (ASCP) convened a task force in 2018 under the CW campaign to further help pharmacists initiate and implement deprescribing. The task force reinforced deprescribing in older adults by reviewing and providing evidence-based references. ASCP’s guidance provides ten statements focused on avoiding DDIs and prescribing cascades and encouraged medication reviews to mitigate potential ADEs²⁵:

1. DO NOT initiate medications to treat new and emerging symptoms without first ascertaining that the new symptom is not an ADE related to an already prescribed medication.
2. DO NOT continue medications at care transitions without reviewing and reconciling to verify accurate and complete medication lists in concert with current medical problems.
3. DO NOT recommend highly anticholinergic medications in older adults without first considering safer alternatives or non-pharmacologic measures.
4. DO NOT use anticholinergics concomitantly with cholinesterase inhibitors for dementia.
5. DO NOT use two or more medications known to increase bleeding risk (e.g., antiplatelets, direct oral anticoagulants [DOACs], warfarin, aspirin, NSAIDs, corticosteroids, selective serotonin reuptake inhibitors), without evaluating the potential risks and benefits.
6. DO NOT prescribe or routinely continue medications for older adults with limited life expectancy without consideration to individual goals of care, presence of comorbidities, and time to benefit for preventive medications.
7. DO NOT use three or more central nervous system-active medications (e.g., antidepressants, antipsychotics, benzodiazepines, antiepileptics, Z-drugs, opioids, gabapentinoids).
8. DO NOT combine opioids with benzodiazepines or gabapentinoids to treat pain and DO re-evaluate routinely for deprescribing during chronic use.
9. DO NOT prescribe tramadol without consideration of the potential risks and harms related to serotonergic excess, seizures, falls, and drug-drug interactions (DDIs).
10. DO NOT use strong CYP3A4 and P-glycoprotein inhibitors or inducers with DOACs and DO periodically assess for such DDIs.

 

The American Geriatrics Society (AGS) also worked on the CW campaign to identify treatments that potentially have more risks than benefits in older adults, concluding the following²⁶:

• DO NOT use antipsychotics first-line to treat behavioral and psychological symptoms of dementia.
• DO NOT use benzodiazepines or sedative-hypnotics first-line for insomnia, agitation, or delirium.
• DO NOT use cholinesterase inhibitors for dementia without periodic assessment for perceived cognitive benefits and adverse gastrointestinal effects.
• DO NOT use antidiabetics to achieve hemoglobin A1c less than 7.5% in most older adults; moderate control is generally better.
• DO NOT use antimicrobials to treat bacteriuria in older adults unless they experience specific urinary tract symptoms.
• DO NOT maintain long-term proton pump inhibitor (PPI) therapy for gastrointestinal symptoms without an attempt to stop or reduce PPI at least once per year in most patients.
• DO NOT use NSAIDs for patients with hypertension, heart failure, or chronic kidney disease.
• DO NOT use prescription appetite stimulants or high-calorie supplements for treatment of anorexia or cachexia (unexplained wasting) in older adults.
• DO NOT prescribe medication without conducting a medication regimen review.

 

Prescribing Cascades

It bears repeating that providers should not initiate medications—prescription or over-the-counter (OTC)—or use a new medical device to treat new and emerging symptoms without first ascertaining that the new symptom is not an ADE of an already prescribed medication.²⁴ This is the first CW statement endorsed by ASCP and it describes a prescribing cascade. Prescribing cascades are preventable, yet often unrecognized, even though researchers in the geriatric field first introduced the concept in the 1990s and then revisited and expanded upon it in 2017.^27,28 They emphasized that “the identification and interruption of prescribing cascades is an important, actionable, and underappreciated opportunity to improve medication safety in older people.”^27,28

 

Prescribing cascades contribute to polypharmacy and adverse outcomes in vulnerable older adults. By becoming familiar with the common prescribing cascades, outlined in Table 3, pharmacists and pharmacy technicians can identify culprit and cascade medications. If culprit medications remain clinically indicated, prescribers should use the lowest possible dose, a safer alternative with fewer adverse effects, or non-pharmacologic therapy, rather than initiating a cascade medication to address the ADE.

Table 3. Prescribing Cascades to Avoid or Amend29
CULPRIT MEDICATION	ADVERSE DRUG EVENT	CASCADE MEDICATION
ACE inhibitors	Cough	Cough suppressants
Alpha-1 blockers	Orthostatic hypotension	Meclizine
Amiodarone	Tremor	Lithium
	Hypothyroidism	Thyroid hormones
Amitriptyline	Cognitive impairment	Cholinesterase inhibitors
Antipsychotics	Cognitive impairment	Cholinesterase inhibitors
	Extrapyramidal symptoms	Benztropine
Benzodiazepines	Cognitive impairment	Cholinesterase inhibitors
Beta blockers	Depression	Antidepressants
Bisphosphonates	GERD	PPIs/H2RAs
Bupropion	Insomnia	Sedatives-hypnotics
Calcium channel blockers	Constipation	Laxatives
	Peripheral edema	Diuretics
Cholinesterase inhibitors	Insomnia	Sedatives-hypnotics
	Urinary incontinence	OAB anticholinergics
Corticosteroids	Insomnia	Sedatives-hypnotics
Diuretics	Urinary incontinence	OAB anticholinergics
Dopaminergics	Psychotic symptoms	Antipsychotics
Gabapentinoids	Peripheral edema	Diuretics
Lithium	Extrapyramidal symptoms	Antiparkinsonians
	Tremor	Propranolol
Metoclopramide	Extrapyramidal symptoms	Antiparkinsonians
NSAIDs	GI bleeding or heartburn	PPIs/H2RAs
	Hypertension	Antihypertensives
OAB anticholinergics	Cognitive impairment	Cholinesterase inhibitors
SGLT2 inhibitors	Urinary tract infections	Antibiotics
SSRIs/SNRIs	Insomnia	Sedatives-hypnotics
Statins	Myalgia	NSAIDs/opioids
Thiazide diuretics	Hyperuricemia or gout	Allopurinol/colchicine

ABBREVIATIONS: GERD = Gastroesophageal reflux disease; GI = Gastrointestinal; H2RAs = Histamine-2 receptor antagonists; NSAIDs = Non-steroidal anti-inflammatory drugs; OAB = Overactive bladder; PPIs = Proton pump inhibitors; SGLT2 = Sodium glucose cotransporter-2; SNRIs = Serotonin norepinephrine reuptake inhibitors; SSRIs = Selective serotonin reuptake inhibitors

 

Anticholinergic Medications

Older adults are more sensitive to anticholinergic adverse effects, including confusion, dry mouth, blurry vision, constipation, and urinary retention. A large case-control observational study of 58,769 patients diagnosed with dementia and 225,574 matched controls found statistically significant associations of dementia risk with exposure to anticholinergic medications, such as antidepressants, antipsychotics, antiparkinsonians, antiepileptics, and bladder anticholinergics.³⁰ Participants who took a single strong anticholinergic medication daily for three years had almost 50% increased odds of dementia within a 10-year period. Dementia risk was increased in patients taking more than one anticholinergic medication due to the cumulative impact.³⁰ Pharmacists can use one or a combination of multiple validated expert anticholinergic scales to calculate aggregate anticholinergic scores. An anticholinergic burden score of three or higher is associated with increased cognitive impairment and mortality. The most frequently validated scale is the Anticholinergic Cognitive Burden (ACB) scale.^31,32 An Anticholinergic Burden Calculator is available at no cost for use here: https://www.acbcalc.com/.

 

A small longitudinal study of 69 participants found those who took an anticholinergic medication in combination with the cholinesterase inhibitor donepezil over a two year period declined by seven points on the Mini-Mental State Examination as compared with a three point decline in those taking donepezil alone.³³ Thus, concomitant therapy with anticholinergics may counteract efficacy of cholinesterase therapy, resulting in a more rapid cognitive and functional decline.

 

Revisiting the case, Ms. Polly is taking donepezil for Alzheimer’s disease. Her prescriber consults with the pharmacist to initiate memantine for her progressive dementia due to increasing confusion and declining function. Medication review identifies several medications with anticholinergic effects that may be worsening Ms. Polly’s cognitive function, including cetirizine, diphenhydramine, furosemide, oxybutynin, and paroxetine. The pharmacist recommends deprescribing anticholinergic medications for which risk outweighs benefit. With reducing aggregate anticholinergic burden, donepezil may be more effective. This avoids added polypharmacy by initiating memantine, effectively preventing a prescribing cascade. Following discontinuation of these medications, the pharmacy technician can follow up with Ms. Polly and her caregiver to assess if there has been improvement.

 

Resources are available to assess polypharmacy and identify PIMs in vulnerable, older adults. The following section provides an overview, applicability, and utility in practice for the most common clinical tools: Beers Criteria, STOPP/START Criteria, STOPPFall Criteria, STOPPFrail Criteria, and the Medication Appropriateness Index.

 

Beers Criteria

The late Mark Beers, MD and his colleagues developed the Beers Criteria in 1991 with a mission to identify medications for which potential harm outweighed expected benefit and that should be avoided in long-term facilities. Since then, several updates have expanded the criteria to apply to older adults aged 65 years and older in ambulatory, acute, and institutionalized care settings, except end-of-life and hospice. Upon Dr. Beers’s death, AGS assumed responsibility for maintaining the criteria.

 

The 2023 AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults is a well-known, widely available clinical tool to support shared clinical decision-making. It is available for free in the Journal of the American Geriatrics Society.³⁴ For ease of clinical practice application, the AGS provides a pocket card and an app, for a fee, available at https://geriatricscareonline.org/. To encourage engagement and conversation, AGS provides patient and caregiver educational resources that are available for free at https://www.healthinaging.org/.

 

The AGS Beers Criteria lists medications and medication classes that the society and its geriatric expert panel consider potentially inappropriate for use in older adults. The criteria are structured by category with each section including a clear rationale and recommendation:

1. Medications considered potentially inappropriate
2. Medications potentially inappropriate in patients with certain diseases or syndromes
3. Medications to use with caution
4. Potentially inappropriate drug-drug interactions
5. Medications to avoid or adjust dosages based on renal function
6. Medications with strong anticholinergic effects

 

Importantly, the identified medications are “potentially inappropriate” rather than “definitely inappropriate.” The key word is “potentially,” as the prescribing and deprescribing processes are to be patient centric. The AGS panel recognizes that harm is typically more pronounced in the “old-old” than in the “young-old” and in patients with complex multi-morbidity and frailty.³⁴ The indicators are categorized based on whether they involve avoiding the initiation of a PIM or discontinuing one that is already prescribed. To apply the AGS Beers Criteria, prescribers and pharmacists must identify the PIMs and, when clinically appropriate, consider safer pharmacologic or nonpharmacologic alternatives.

 

STOPP/START Criteria

The Screening Tool of Older Person's Prescriptions (STOPP) and Screening Tool to Alert doctors to Right Treatment (START) criteria are additional resources for identifying potentially inappropriate prescribing in older adults. These aim to identify PIMs and potential prescribing omissions, respectively.³⁵ The STOPP criteria are most helpful in the context of polypharmacy. The original version, published in 2008, included 65 STOPP criteria, which more than doubled in the third version, updated in 2023, with 133 STOPP criteria. These more expansive criteria assist pharmacists and pharmacy technicians in identifying and preventing more DDIs, drug-disease interactions, and potential ADEs during medication reviews.

 

The STOPP criteria is divided into sections by organ systems—including cardiovascular, coagulation, central nervous, renal, gastrointestinal, respiratory, musculoskeletal, urogenital, and endocrine—with separate sections for drugs that increase fall risk, analgesics, and antimuscarinic or anticholinergic drugs.³⁵ The criteria also address the need to clarify an indication for each medication, labeling the following as PIMs:

• Any medication prescribed without a clinical indication
• Any medication prescribed beyond recommended duration
• Any duplicate medication class

 

Additional variations of the STOPP criteria help healthcare providers to identify PIMs in older adults with a high risk of falls (STOPPFall) and in those with limited life expectancy (STOPPFrail).^36,37 STOPPFall identifies medication classes considered to be fall-risk-increasing-drugs (FRIDs). To further assist in shared-decision making of deprescribing, practical decision trees based on the STOPPFall guidance are available online (https://kik.amc.nl/falls/decision-tree/).³⁶

 

While most prescribing tools are designed to identify and prevent PIMs in the general older population, STOPPFrail consists of 27 potentially inappropriate prescribing indicators to assist healthcare providers in deprescribing in frail older adults.³⁷ Deprescribing in frail older adults may improve their quality of life through a reduction in adverse events, hospitalizations, and mortality. Medication review in this population should focus on deprescribing and symptom management, rather than preventive and intensive treatment. STOPPFrail is applicable in adults aged 65 or older who meet all the following criteria³⁷:

• End-stage irreversible pathology
• Poor one year survival prognosis
• Severe functional or cognitive impairment or both
• Symptom control is priority rather than preventing disease progression

 

Example criteria include³⁷

• Avoid antiplatelets for primary cardiovascular prevention due to lack of evidence
• Bisphosphonates are unlikely to be beneficial for short-term osteoporosis treatment
• Aim for antidiabetic monotherapy with less stringent glycemic control (i.e., hemoglobin A1c goal of less than 8%)

 

End-of-Life Care

Prescribers and pharmacists should re-evaluate medications and minimize the pill burden for patients receiving palliative care, particularly at end-of-life (i.e., life expectancy of less than three months). Prevention of long-term complications is no longer indicated.²¹ Rather, the goal is comfort care through symptom-specific medications (SSMs) to treat pain, dyspnea (shortness of breath), nausea, cognitive disturbances, anxiety, and depression. The number of SSMs increases while the number of medications intended to treat comorbidities decreases. Therefore, the definition of polypharmacy shifts for end-of-life care, focusing on inappropriate medication use.

 

The shared decision-making process must still consider patient and caregiver preferences. While some patients may prefer only symptomatic treatment without life-prolonging measures, other patients may feel neglected following discontinuation of certain long-term medications.²¹ A literature review of 67 articles established preliminary recommendations for long-term medication classes shown in Table 4.²¹

 

Table 4. Deprescribing at End-of-Life21
MEDICATION CLASS	RECOMMENDED ACTION PLAN	GDR
Anticoagulants	Discontinue for deep vein thrombosis primary prevention	No
Antihyperglycemics	Reduced dosages to prevent hypoglycemia	Variable
Antihypertensives	Discontinue for hypertension	Yes
Antimicrobials	Variable: goal is symptom control	No
Statins	Discontinue	No

ABBREVIATIONS: GDR = gradual dose reduction

 

Medication Appropriateness Index

Unlike the previously mentioned clinical tools that are PIMs and medication class lists developed by expert consensus; the Medication Appropriateness Index (MAI) is patient centric. The MAI, developed more than 30 years ago, is a patient screening tool that measures potentially inappropriate prescribing in older adults. The 10 simple questions focus on indication, effectiveness, dosing, duration, and potential for interactions to ultimately rate medications as appropriate, marginally appropriate, or inappropriate.^38,39 A MAI Calculator is available at no cost for use here: https://globalrph.com/medcalcs/medication-appropriateness-index-calculator/.

 

HOW TO SAFELY DEPRESCRIBE

 

Deprescribing Tools

Once polypharmacy and PIMs are identified, many clinical tools are available to analyze benefit versus risk and guide pharmacy teams on how to safely discontinue specific medications and medication classes.

 

Deprescribing.org

https://deprescribing.org/resources/

Canadian Medication Appropriateness and Deprescribing Network

https://www.deprescribingnetwork.ca/professionals

 

Deprescribing.org is a website developed by Canadian pharmacists that provides guidance, tools, and approaches for deprescribing.⁴⁰ Included within these resources are evidence-based guidelines and easy to use algorithms to determine when and how to stop specific medication classes: antihyperglycemics, antipsychotics, benzodiazepines, cholinesterase inhibitors, memantine, and PPIs.⁴⁰ The companion site, Canadian Medication Appropriateness and Deprescribing Network, provides additional guidance on commonly inappropriate medications for healthcare providers and patients, including a Deprescribing Educational Program and brochures.⁴¹

 

US Deprescribing Research Network https://deprescribingresearch.org/resources-2/resources-for-clinicians/

The US Deprescribing Research Network is a tool funded by the National Institute of Aging to develop and provide information on deprescribing for older adults.⁴² The network’s efforts center around four “cores” addressing the needs of different stakeholders (e.g., researchers, patients) and a series of working groups focusing on research and standardized outcome measures. Resources for healthcare providers promote education by providing guides for specific medication classes and reference the deprescribing tools described above.⁴²

 

Primary Health Tasmania https://www.primaryhealthtas.com.au/resources/deprescribing-resources/

Primary Health Tasmania is a not-for-profit organization in Australia that provides a comprehensive guide to personalized deprescribing, including principles, assessment of benefit versus harm, and patient and healthcare provider perceptions. These in-depth guidelines recommend deprescribing strategies for an extensive list of common medication classes: allopurinol, anticholinergics, anticoagulants, antiepileptics, antihyperglycemics, antihypertensives, antiplatelets, antipsychotics, benzodiazepines, bisphosphonates, cholinesterase inhibitors, gabapentinoids, glaucoma ophthalmics, inhaled corticosteroids, long-acting nitrates, NSAIDs, opioids, PPIs, statins, and calcium and vitamin D.⁴³

 

MedStopper https://medstopper.com/

MedStopper is an online clinical tool for polypharmacy that assists healthcare providers, patients, and caregivers in the shared decision-making process and prioritization of deprescribing.⁴⁴ Upon entering a patient’s regimen, MedStopper arranges the medications from “more likely to stop” to “less likely to stop,” based on the criteria in Table 5. A team of clinicians and researchers affiliated with Canadian healthcare institutions, including the University of British Columbia and the Centre for Effective Practice developed this site and is grounded in evidence-based resources such as the Beers and STOPP/START Criteria. However, it remains in the Beta testing phase, so pharmacy teams should still use it with caution.⁴⁴

 

Table 5. Deprescribing Opportunities and Prioritization44
Medication	Conversation
Potential to improve symptoms	Is the medication helping symptoms?
Potential to reduce the risk of future illness	Does the effectiveness justify the potential adverse effects, inconvenience, and cost?
Likelihood to cause harm	Are symptoms caused by medications?

 

Using the Edmonton Frail Scale, healthcare providers can identify patients as frail to adjust MedStopper’s “may cause harm” ranking. The specific indication for each medication affects the ranking categories for “may improve symptoms” or “may reduce future illness.” Categories are based on the rating levels of an unhappy, neutral, or happy face, with a color-coded discontinuation priority. Medications and indications also include links for resources, such as calculators for risk/benefit assessment, NNT, Beers Criteria, or STOPP Criteria. Healthcare providers can reference the tapering suggestions and symptom monitoring, as appropriate.⁴⁴

 

Go back and review Ms. Polly’s medication regimen in Table 1. Which medications may be inappropriate based on the numerous prescribing and deprescribing tools that are readily available? Figure 2 shows a snapshot of a suggested plan for deprescribing utilizing the MedStopper clinical tool.

 

Figure 2. Deprescribing Plan Based on Stopping Priority by MedStopper

NOTE: Incomplete medication regimen

 

PAUSE AND PONDER: When do medications need a gradual dose reduction for discontinuation?

 

Pharmacist-Led Deprescribing

Research shows that comprehensive medication reviews may reduce PIM use and mortality in community-dwelling older adults aged 65 years and older.⁶ A narrative review of 25 global randomized controlled trials found that pharmacist-led deprescribing interventions had a beneficial effect on 69% of medication outcomes—including discontinuation, dose reductions, and medication changes—for patients with a mean age of 60 years or older residing in the community and nursing facilities.⁴⁵

 

Pharmacists must follow a stepwise, patient-centric approach to deprescribing, while performing a comprehensive medication review of prescription and OTC medications as depicted in Figure 3. Since prescribing and deprescribing clinical tools do not consider preferences, life expectancy, and goals of care, it is essential to understand “what matters” to the patient and/or caregiver.

 

Figure 3. Stepwise Approach to Deprescribing

ABBREVIATIONS: MRPs = medication-related problems

 

Prescribers, pharmacists, and pharmacy technicians should assess if patients are not adhering to prescribed medications and, if not, why. Opportunities to deprescribe may be identified by asking just one question to a patient and/or caregiver. Pharmacy technicians are typically trained to ask, “do you have any questions for the pharmacist about your medication?” Instead, open-ended questions, such as “how do you feel about the number and types of medication you take?” or “how did your new medication help with your symptoms?” could gather more useful information. It is also important to ask if patients experience any adverse effects from their medications.

 

What Matters and Shared Goals

Deprescribing conversations ought to involve shared decision-making. Research shows older adults’ priorities are typically maintaining cognition, function, and independence over life extension.^46,47 Patient preferences and health status change over time. Knowing a patient’s priorities and preferences about medication use helps align treatment decisions and guide deprescribing.

 

To determine a patient’s health priorities and preferences, healthcare providers can use the universal health Outcome Prioritization Tool (OPT) which is nonspecific to diseases and treatments. This simple tool elicits the preferences of older adults by having them consider trade-offs and rank the relative importance of four health outcomes^46,47:

1. extending life (regardless of health)
2. preserving independence/maintaining function and activities of daily living
3. reducing or eliminating pain
4. reducing or eliminating symptoms (e.g., dizziness, fatigue, nausea, shortness of breath)

 

Several studies found that preserving independence and reducing pain were the most important health outcomes, whereas life extension was the least important.^18,48,49 In the Older Patients’ Perceptions of Medicines and Willingness to Deprescribe survey, of the 50 participants, 76% wanted to keep their symptomatic medications and 61% wanted to keep their preventive medications.¹⁸

 

The “What Matters to You?” study of 350 patients used the OPT to assess the most important health outcome for older adults.⁵⁰ Patients with cognitive impairment more often prioritized life extension. Importantly, cognitively impaired patients may struggle to understand health outcomes and the “trade-off principle”—prioritizing one health outcome while accepting potential deterioration in other health outcomes—which makes patients weigh and prioritize health goals. Patients with declining health status are generally more accepting of further decline. A secondary outcome found that the OPT is feasible for intensive treatment decision-making. For those patients who are unable to prioritize the four health outcomes, the OPT is still useful to facilitate a conversation about patient preferences and trade-offs to align decision-making.⁵⁰

 

Considering Ms. Polly: how can the 4Ms aid in recommending oxybutynin discontinuation to her prescriber? “What matters to the patient is being able to continue to live in her home. Oxybutynin is anticholinergic and is negatively affecting her mentation and mobility as she has recent falls. Please consider a discontinuation trial of oxybutynin and non-pharmacologic options for overactive bladder.”

 

Identifying Medications for Discontinuation

Upon establishing goals of care, the next step is to engage the patient or caregiver and decide whether to deprescribe any medications. Common reasons for deprescribing include

1. No active indication (e.g., health condition resolved)
2. New or worsening condition
3. Potential risks outweigh anticipated benefits
4. Preventive indication with life-limiting conditions
5. Lack of benefit or ineffectiveness
6. Result of a prescribing cascade
7. Nonadherence
8. Interactions or ADEs

 

Prescribers and pharmacists can use the available prescribing and deprescribing clinical tools, but they must also review all medications and assess the benefit versus risk for individualized patients.

 

Developing an Action Plan

Upon identifying medications to deprescribe, prescribers and pharmacists must collaborate to develop an action plan to implement, monitor, and follow-up. When deprescribing, withdraw medications one-by-one by prioritizing those that are inappropriate and/or increase the risk of harm. It is critical to continuously consider “what matters” to the patient. Multiple medications can be withdrawn simultaneously if patients are experiencing ADEs, medications are easy to discontinue, or if they have minimal withdrawal effects.

 

If deprescribing is justified, prescribers, pharmacists, and pharmacy technicians need a plan of action for each medication (i.e., whether to abruptly stop or if gradual dose reduction (GDR) is necessary). Healthcare providers need to educate patients or caregivers on withdrawal symptoms to look for and emphasize the need to promptly report them.

 

Certain medications require a GDR or taper to prevent an adverse drug withdrawal event—meaning discontinuation results in clinically significant symptoms or signs—or worsened conditions.⁵¹ GDRs can identify the lowest effective dose, minimize symptom re-occurrence, and encourage patient willingness. For example, discontinuing benzodiazepines may cause agitation. If this withdrawal symptom is unfamiliar to healthcare providers, then a prescribing cascade may occur with initiation of an antipsychotic.⁴³

 

Most medications have limited evidence and few guidelines for deprescribing. If no guidance is available, it is safer to attempt a GDR over weeks to months to discontinue rather than abruptly discontinuing. If a deprescribing guideline is unavailable, taper and discontinue medications in reverse of guideline recommended treatment. For example, the prescribing information for donepezil recommends initiation of therapy at 5 mg daily for four to six weeks, then increase the dose to 10 mg daily. To taper donepezil, decrease the 10 mg daily dose to 5 mg daily for four to six weeks and then discontinue therapy. Pharmacists can recommend a GDR plan in consideration of pharmacokinetics (e.g., half-lives), pharmacodynamics, dose, and duration of medications.⁵¹

 

To achieve successful deprescribing, a trusting relationship, ongoing communication, and adequate documentation is essential between prescribers, pharmacists, pharmacy technicians, patients, and caregivers. Using the word “trial” is reassuring to patients and caregivers since it implies patients can restart the medication if needed.

 

Returning to Ms. Polly, the pharmacist can initiate the conversation with her daughter by saying, “I understand you feel overwhelmed. It seems now would be a good time to take another look at your mother’s medications. We can ease the burden of her medication regimen and simplify it for her. This trial of stopping a couple of her medications may help with her confusion and lower her fall risk.”

 

CONCLUSION

Deprescribing is an essential part of good prescribing and an important strategy. It ensure older adults are not taking suboptimal medications. Effective and safe deprescribing requires a patient-centered, shared decision-making approach with evaluation of preferences, level of functioning, life expectancy, and goals of care. Numerous clinical resources are available to reduce polypharmacy, assess benefit versus risk, and provide guidance and approaches for how to discontinue specific medications. Deprescribing inappropriate or unnecessary medications impacts clinical outcomes—such as reduction in hospitalizations, ED visits, falls and overall healthcare costs—mitigates ADEs, and improves quality of life. Simplifying more complex medication regimens may also improve patient adherence to essential medications.

 

With a strong foundation in deprescribing principles and tools, it’s time to reevaluate Ms. Polly’s medication regimen one last time. What other medications should be considered for deprescribing to reduce polypharmacy, mitigate ADEs, and improve quality of life for both Ms. Polly and her daughter?

 

Download CE Activity

INTRODUCTION

Ray and Kai are pharmacists that work together in a very busy outpatient clinic pharmacy. On a typical day, they fill around 800 prescriptions, and they usually have help from three technicians. Unfortunately, if anyone calls out sick or with an emergency, they don't have backup coverage.

 

Several times a week, patients return to the pharmacy and indicate that the prescriptions they received don't seem to be correct. Occasionally, Ray and Kai discover a medication error when patients indicate that their tablets or capsules don't look the same as a previous refill. Just yesterday, a mother returned to the pharmacy because her child’s liquid amoxicillin/clavulanate ran out before it should have. When Kai examined the label, she found a typographical error; it said, “take 5 mL three times a day” when it should have said, “take 2.5 mL three times a day.”

 

When staff members in this pharmacy identify medication errors, they usually discuss the problem quietly with the involved staff and make a mental note to implement corrective action or pay closer attention. Their pharmacy’s workload, staffing, error rate, and method of dealing with medication errors is not much different than many pharmacies across our nation. Throughout this continuing education activity, this example and others will help learners apply the lessons that experts have learned from analyzing medication errors.

 

Patient safety is a cornerstone of quality healthcare, and pharmacy professionals have an obligation to ensure patients receive safe and effective medications. Medication errors often stem from communication gaps, system complexities, or improper medication use. These errors not only compromise patient outcomes but also contribute to increased healthcare costs and increase risks of medication-related adverse effects.¹

 

The National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) tallies and analyzes medication error reports from the National Medication Errors Reporting Program, which is administered by the Institute for Safe Medication Practices (ISMP). NCC MERP defines a medication error as “any preventable event that may cause or lead to inappropriate medication use or patient harm.” Medication errors occur at various stages of the medication-use process, from prescribing and dispensing to administration and monitoring.² Recognizing these errors and implementing prevention strategies are essential to improving patient safety and advancing pharmacy practice.

 

OVERVIEW OF MEDICATION ERRORS

To truly appreciate medication errors’ impact on patients, pharmacy team members must recognize common terms and types of errors.

 

Medication Error Terminology

Several medication errors can arise in clinical and retail settings. To actively prevent patient injury through medication errors, it is important to know what to look for in practice. Terms to be familiar with in all pharmacy practice settings include^3,4:

• Adverse drug event (ADE): An injury resulting from medical intervention related to a drug
• Adverse drug reaction (ADR): An unintended reaction occurring at the intended drug dose
• High-alert medications: Drugs that bear a heightened risk of causing significant patient harm when used in error
• Look-alike/sound-alike (LASA) medications: Medications with similar-looking or similar-sounding names and/or shared features of products or packaging, leading to potential confusion
• Medication reconciliation: The process of creating the most accurate list possible of all medications a patient is taking—including drug name, dosage, frequency, and route—and comparing that list against the physician's admission, transfer, and/or discharge orders, with the goal of providing correct medications to the patient at all transition points

 

PAUSE AND PONDER: When an error is identified, how does your pharmacy respond?

 

Defining and Classifying Medication Errors

Table 1 lists common medication errors that may occur throughout the stages of medication use.⁴

Table 1. Common Medication Errors⁴

Error Type	Description	Examples
Prescribing	Errors occurring when ordering medication	Wrong drug selection, incorrect dose/frequency, illegible handwriting, incomplete prescription, drug interactions
Dispensing	Errors occurring during medication preparation and distribution	Wrong medication, wrong strength, wrong dosage form, incorrect labeling, look-alike/sound-alike drug confusion
Administration	Errors occurring during drug administration to the patient	Wrong route, wrong dose, wrong rate, omission, administering to the wrong patient
Monitoring	Errors occurring due to lack of proper patient monitoring	Failure to monitor for adverse effects, inadequate lab test follow-up, failure to adjust dose for renal/hepatic function

 

Most medication errors are preventable and can also be classified by the severity of their impact on the affected patient. Leading organizations, such as NCC MERP, have developed taxonomies to classify medication errors in more detail, including nine categories labeled A through I. These categories range from circumstances that have the capacity to cause error (Category A) to errors that result in patient death (Category I). While categories E through I describe varying degrees of harm to the patient, categories A through D involve situations with no patient harm. These classifications help institutions analyze trends and implement targeted interventions.⁵

 

Figure 1 displays NCC MERP’s medication error classifications with severity levels increasing from top to bottom.⁵

 

Figure 1. Medication Error Classification⁵

 

A patient comes in to pick up a prescription at Ray and Kai’s pharmacy and the line is out the door. As Kai retrieves the medication, she quickly confirms the patient’s last name and date of birth. Ray knows the patient and greets him; “Hey Charlie, how are the kids?” Kai then realized the prescription in hand was meant for a different patient by the name of Billy and was in the same bin. The correct medication is retrieved, and the patient safely receives what was actually prescribed, resulting in a near miss, rather than a full medication error.

 

Later, Ray and Kai sit down to reflect on what could have happened if the mistake hadn’t been caught in time. If the pharmacy dispensed the wrong medication and the patient noticed and brought it back before taking it, this would be an error, no harm situation. However, if the patient took the incorrect medication and experienced harmful adverse effects, it would result in an error, harm situation. In a more severe scenario, if the patient took the wrong medication and had an allergic reaction or other fatal outcome, it would be considered error, death. After discussion, Ray and Kai decide to speak to the staff about the importance of verifying patient information in full at every encounter. They relay a PRO TIP: employees can place prescriptions for patients with similar names in separate bins to avoid confusion.

 

Even the smallest and most routine tasks, such as verifying a patient’s identity, carry immense responsibility. Every action performed in a pharmacy setting has a direct impact on patient health. A moment of inattention or a skipped step can be the difference between preventing harm and causing irreversible consequences. That’s why it is crucial to approach every task, no matter how routine, with full attention and diligence

 

Beyond preventing individual mistakes, classifying and analyzing medication errors is a key to improving patient care on a larger scale. Recognizing and labeling these errors—whether they are near misses, errors with no harm, or more serious mistakes—provides valuable insight into when and where they happen. By identifying patterns, pharmacies can implement targeted safety measures to minimize risks.^4,5

 

ANALYSE, DOCUMENT, PREVENT

Medication Error Rates

To identify and reduce medication errors effectively, individuals and institutions must track their occurrences systemically. One of the most effective ways to achieve this is by calculating the medication error rate, which provides valuable insight into areas requiring improvement.⁶ The formula for calculating the medication error rate is as follows:

<<ADD IMAGE>>

 

The numerator represents the total number of medication errors recorded during a given period, with each error event counted as one. The denominator consists of all medication orders or doses that were dispensed and administered.⁶ This formula applies across all pharmacy settings, including both community and hospital environments.

 

 

For example, a hospital pharmacy dispenses 100,000 doses in a month and identifies 50 medication errors in that month. What is the medication error rate?

 

Once calculated, error rates are a crucial tool for identifying trends and implementing targeted interventions. By analyzing the data, healthcare teams can pinpoint high-risk areas, set measurable goals, and put corrective measures into action to minimize errors. This proactive approach not only enhances patient safety; it also optimizes pharmacy workflow and overall efficiency.

 

The pharmacy where Ray and Kai work is accredited. During an accreditation audit, one of the surveyors asks Ray about their medication error rate. Ray is unable to answer. The surveyor pushes a little and asks Ray to provide copies of all incident reports regarding medication errors. Ray finds two or three in which the medication error was serious enough to attract attention from the clinical staff or the clinic's risk manager. When the surveyor explains how to calculate a medication error rate, Ray listens carefully. Needless to say, the surveyor noted the lack of documentation about medication errors as a deficit in the survey and indicated that she did not believe that they only had three medication errors in the past year. When Ray and Kai meet to plan corrective action, they realize that without good documentation, they cannot make this calculation.

 

To ensure accuracy and reliability, all pharmacy and healthcare organizations must foster a culture of transparency and promote non-punitive error reporting.^6,7 Management must encourage staff to report errors without fear of retribution, allowing institutions to collect comprehensive data and develop effective mitigation strategies. Hospitals and community pharmacies can gain valuable insight into their performance by benchmarking their calculated error rates against institutions of similar size and complexity. Comparing rates with national standards or similar organizations helps ensure adherence to best practices and provides insight into additional potential interventions.⁷

 

Documenting Medication Errors

Pharmacists and technicians should know how to document and report incidents that occur in their pharmacy properly, usually following policies or procedures put in place by their institution and legal regulations. Unusual incident reports (UIRs) are a formal mechanism for documenting clinically significant medication errors and near misses.

 

Following identification of an incident and corrective patient measures, all relevant personnel should be notified and asked to record their recall of events. These reports should include key details such as who was involved, when and where the incident occurred, type of error, contributing factors, and corrective actions taken.⁸ To prevent recurrence of an incident or find a systemic issue leading to incidents, errors should regularly be recorded regardless of severity or whether it reached the patient or not. A PRO TIP is to maintain a list of errors that should be documented and keep unused UIRs in an accessible place (e.g., pinned on all desktops or stored in designated folders), encouraging staff to fill them out. These forms should be completed in full and a PRO TIP is to include instructions on what steps to take following the incident (i.e., read over and include any forgotten details, ensure all relevant staff is notified). Investigative staff should thoroughly gather data pertaining to the incident, including records, UIRs, patient notes, and physical items used in the event.⁹ Staff should establish a clear chronology of events to determine the root cause and prevent future occurrences.

 

Pharmacists and technicians should be well-versed in properly documenting and reporting incidents in their pharmacy, usually following institutional policies and legal regulations. UIRs serve as a formal mechanism for recording clinically significant errors and near misses. The following steps are necessary for proper documentation and reporting^8-10:

1. Identify and respond to the incident
   • When an error or near miss occurs, prioritize patient safety by taking corrective actions and notify all relevant personnel, including leadership.
2. Thoroughly document the incident
   • UIRs should capture key details such as
     1. who was involved
     2. when and where the incident occurred
     3. type of error and contributing factors
     4. corrective actions taken and follow-up measures
   • All involved personnel should document their recollection of events promptly to ensure accuracy.
3.  Encourage consistent reporting
   • To prevent recurrences and identify systemic issues, all errors—regardless of patient impact severity—should be recorded.
   • PROTIP: Maintain a list of errors that must be documented and keep unused UIRs easily accessible (i.e., pinned on desktops or stored in a designated folder) to encourage completion.
   • Forms should be fully completed, and staff should review their entries for accuracy before submission.
4.  Investigate and analyze the incident
   • Investigative staff should collect all relevant data, including UIRs, records, forms, and any physical items used in the event.
   • Establish a clear chronology of events to determine the root cause and prevent future occurrences.

 

UIRs are considered Quality Improvement data in healthcare organizations, making them confidential and generally protected from disclosure under laws like the Patient Safety and Quality Improvement Act.¹¹ Organizations use these reports internally to enhance patient safety and do not share them with patients or lawyers. However, protection can vary based on state laws and institutional policies, so a PRO TIP for organizations would be to highlight their specific policies and require additional training and separate filings to ensure proper procedures to maintain confidentiality.

 

Individuals must report serious medication errors resulting in patients harm or regulatory violations to state boards of pharmacy and should also report them to accreditation agencies (e.g., Joint Commission) and the FDA through the MedWatch program.⁸ Pharmacy personnel is expected to know how and when to use institution-specific forms and to revise these to simplify and encourage the error reporting process.

 

Ray and Kai are motivated to track medication errors better. When they dust off their stack of unused UIR forms, they realize that their forms are skeletal and their organization would benefit from a better tool. One of their technicians, Tara, volunteers to look at a number of different forms and identifies four. The staff chooses to “pilot” two, meaning they will document all medication errors that occur over the next three weeks on both forms, and then analyze the results. At the end of the pilot, they choose one form but realize that they need to tailor it to their practice. Tara also notes that they could automate the form and include a picture of the dosage forms that were involved.

 

Within three months, Ray and Kai realize from the pictures that a full 25% of their errors involve tablets that are white. Ray and Kai can share a PRO TIP with other organizations now. They create a whiteboard that lists most of their white tablets and the tablet markings. The technicians who handle inventory update the whiteboard when they change generics. Additionally, whenever Ray or Kai visually verify a prescription for a white tablet, they note the tablet marking on the prescription. In this way, they eliminate a good number of errors.

 

Institutions may have different methods for documenting unusual incidents, so it is essential that pharmacy staff know how to access and properly complete these forms. Keeping UIR forms up to date ensures they remain effective and relevant. Attached are three different incident report forms; review them carefully and identify their similarities and differences (see Appendix).^12-14

 

Accurate medication error reporting is the underpinning of identifying risks and improving patient safety. However, traditional error-reporting systems often capture only a portion of actual incidents and do not usually account for adverse effects. This could be attributed to limitations in error-reporting, including but not limited to underreporting due to fear of punishment, time-consuming processes, and a lack of feedback and follow-up.¹⁵ Research suggests that the use of observation, when appropriate and feasible, could lead to more accurate detection of medication errors in practice.^16,17 When applicable, institutions can use observation in combination with tracking error reports and greatly reduce the frequency of medication errors.

 

A strong culture of safety in pharmacy practice encourages transparent error reporting and non-punitive responses. Employees should feel comfortable reporting mistakes without fear of disciplinary action, as this fosters a learning environment rather than a blame culture. Encouraging reporting allows institutions to^7,18

• identify error trends and implement preventative measures
• provide additional training where needed
• improve medication safety policies and procedures

 

All people in positions of authority should encourage pharmacy personnel to report medication errors to their institutions and to the FDA, ISMP, or NCC MERP if appropriate.¹⁹

 

System-Based Prevention Approaches

Healthcare institutions implement structured systems to enhance workflow efficiency and minimize medication errors. These systems provide standardized protocols, technological advancements, and communications strategies that help pharmacy personnel ensure safe and accurate medication dispensing and administration.

 

With advancements in technology, healthcare professionals frequently rely on automated systems to assist with medication safety. While these tools greatly reduce the potential for human error, they should be used to complement, not replace, pharmacist and technician expertise. Proper training and implementation of these tools are essential to their effectiveness. Key technologies that reduce medication errors include the following^18,20,21:

• Barcode scanning as an additional verification step in the dispensing and administration process ensures that the correct drug, dose, and patient matches the prescription and manufacturer specifications.
• Computerized provider order entry (CPOE) and e-prescribing reduce errors by eliminating the risk of misinterpreting handwritten prescriptions. CPOE also alerts prescribers about potential drug interactions, allergies, and dosing errors before orders are processed.
• Automated dispensing cabinets, commonly used in hospitals, help regulate medication storage, access, and tracking to prevent unauthorized or incorrect dispensing.

 

To maximize these systems’ effectiveness, pharmacy staff must remain vigilant, ensuring that they do not blindly trust automation. As recommended by the ISMP, conducting manual double-checks judiciously, selective to certain high-risk tasks or medications, can further enhance patient safety.²²

 

Familiarizing all staff with institutional standard operating procedures (SOPs) is essential for ensuring consistent and safe practice. These guidelines outline step-by-step procedures for specific pharmacy operations, reducing deviations that could lead to medication errors.²³ When adhered to properly, SOPs standardize processes (minimizing variability and human error), provide clear instructions for handling high-alert medications, and outline best practices for prescription verification, dispensing, and patient counseling.^21,23 For example, a hospital SOP may require two licensed healthcare professionals to verify chemotherapy doses independently before administration. In a community pharmacy, an SOP may require mandatory counseling for first-time prescriptions of high-risk medications, such as opioids or anticoagulants. Having SOPs and checklists readily accessible ensures that pharmacy personnel can reference best practices quickly when dealing with complex or high-risk situations.

 

SIDEBAR: A Word About CHECKLISTS

When checklists are numerous in quantity and poor in design, pharmacy staff may experience a sense of checklist fatigue, becoming overwhelmed and disengaged with completing them. This could lead to rushed or skipped steps, negatively impacting performance and patient safety. The following lists some strategies to avoid feeling desensitized to the repetitive nature of checklists^22,24,25:

• Use checklists selectively by focusing on the most important or highest-risk tasks
• Improve the design to be clear, concise, and easy to follow
• Avoid unnecessary or redundant steps
• Regularly ensure the checklists are up-to-date and effective
• Address fatigue with staff and provide training and feedback on the importance of each step

 

PAUSE AND PONDER: When reviewing a prescription, what red flags should prompt you to double check with a prescriber, pharmacist, or colleague?

 

PHARMACY PRACTICE CONSIDERATIONS

Each pharmacy practice type has its own unique concerns and considerations with regard to medication error reporting.

 

Community Pharmacy

In a retail or clinic pharmacy setting, like the one in which Ray and Kai work, pharmacists and pharmacy technicians must exercise caution throughout the prescription filling process to prevent errors. These errors can be minor and initially go unnoticed, but can lead to serious adverse events, hospitalizations, or even fatalities if not promptly identified and addressed.²⁶

 

The first stage of medication processing—receiving a prescription—creates a significant risk for errors. Whether prescriptions are transmitted electronically, by phone, or handwritten, pharmacy personnel may misread, misinterpret, or fail to recognize important details.²⁷ Especially in high-volume settings, healthcare professionals should prioritize accuracy by seeking prescriber clarification when needed, rather than making assumptions or rushing through interpretation.  Errors can also originate from prescribers, and pharmacy personnel should have a high index of suspicion that every prescription is incorrect. Calling to clarify questionable doses or frequencies ensures patient safety and may also prompt prescribers to recognize and correct unintended mistakes.²⁶ All three errors that Ray and Kai documented had been serious enough to result in an ADE or ADR. When they looked back at these errors, they realized that for two of them, if they had questioned the patients or called the prescribers, the errors may have been avoided entirely.

 

Common errors that pharmacists and technicians should be vigilant about in community pharmacy include^1,3,27,28

• Misinterpreting abbreviations and symbols: Sloppy abbreviations and symbols can lead to dangerous dosing errors. Table 2 summarizes the Joint Commission’s “DO NOT USE” list of abbreviations that should be displayed in pharmacies.
• LASA medications: Medications with similar names can be easily confused if not carefully verified.
• Incorrect dosing and strength selection: Errors can occur by selecting the wrong strength of a medication or miscalculating pediatric or weight-based doses.

 

Table 2. The Joint Commission’s “DO NOT USE” List²⁸

Do Not Use	Potential Problem	Use Instead
U, u	Mistaken for “0” (zero), the number “4” (four) or “cc”	Write “unit
IU	Mistaken for IV (intravenous) or the number 10 (ten)	Write “International Unit”
Q.D., QD, q.d., qd   Q.O.D., QOD, q.o.d., qod	Mistaken for each other   Period after the Q mistaken for “I” and the “O” mistaken for “I”	Write “daily”   Write “every other day”
Trailing zero (X.0 mg) * Lack of leading zero (.X mg)	Decimal point is missed	Write X mg Write 0.X mg
MS   MSO4 and MgSO4	Can mean morphine sulfate or magnesium sulfate   Confused for one another	Write “morphine sulfate”   Write “magnesium sulfate”

*Exception: A trailing zero is only allowed when necessary to indicate the exact level of precision, such as in laboratory results, imaging studies that report lesion sizes, or catheter/tube sizes. It may not be used in medication orders or other medication-related documentation.

 

Maintaining readily accessible reference lists can help pharmacy personnel cross-check potential medication errors before contacting prescribers. The ISMP has identified numerous LASA pairs that contribute to medication errors and has created lists of commonly confused abbreviations and symbols.²⁹ Additionally, using TALL Man lettering (e.g., capitalizing part of a drug's name in upper case letters to differentiate similar drug names like hydrALAzine vs hydrOXYzine) when documenting or labeling LASA medications can minimize confusion.²⁹

 

In the hypothetical pharmacy, Ray notes that one of the technicians consistently fills prescriptions for dipyridamole with diphenhydramine. He has pointed this problem out to the technician several times and asked the technician to find the correct medication, but the problem continues. After learning about TALL Man lettering, he realizes that their computer system does not use this simple but useful intervention. He contacts the programmers and asks if they can make the changes, providing the ISMP's list of drugs for which this intervention could prevent many errors. A PRO TIP here is to ask the technician to use a highlighter to highlight the part of the drug name that follows "DIP-" on all drugs that begin with these three letters before filling prescriptions.

 

Errors often arise during the later stages of prescription processing, including data entry, assembly, and pharmacist verification. Pharmacy personnel may rely too heavily on the auto-populated fields in electronic prescribing systems (e.g., McKesson, PioneerRx), assuming the information is correct without double-checking key details. This could lead to incorrect medication strengths, frequency, or refill quantities, ultimately causing billing issues or improper medication dispensing.^27,20

 

Dispensing the wrong formulation can occur if pharmacy staff select similar-looking bottles. Barcode scanning technology can help reduce assembly errors by ensuring use of the correct product. Pharmacists must physically inspect medications rather than relying solely on electronic systems. Pharmacy staff should attach medication guides, auxiliary labels, and other patient education materials as necessary. Pharmacy professionals must recognize that technology is a tool, not a replacement for human oversight. Systems may have glitches or auto-fill errors, and staff should remain vigilant to manually verify accuracy when needed. ²⁰

 

Over the few weeks after the accreditation survey, Ray and Kai see a number of minor medication errors in the pharmacy. During a counseling session, Kai learns that one patient has been taking a diuretic but has not been increasing the amount of potassium in her diet. The patient reports cramping and nausea. Kai realizes that the pharmacy staff stopped using colorful auxiliary labels, assuming that the key counseling points are covered in the multi-page handout that the computer prints with each prescription. Unfortunately, many patients simply throw that multi-page handout into the recycle bin (as did this patient). Kai realizes that using auxiliary labels is an opportunity to improve counseling and to increase the likelihood that patients will take medications correctly.

 

The final step in the prescription process—dispensing the medication to the patient—requires uninterrupted attention to detail. Staff often overlook or rush this step in busy retail pharmacies, especially under pressure from patients who may be in a hurry. Patients who are eager to leave or have pressing time constraints may create an environment where staff feel rushed to complete the transaction quickly, potentially compromising safety. The Joint Commission requires two patient identifiers before dispensing a medication (e.g., full name and date of birth) to prevent mix-ups.²⁶ Failing to confirm the patient’s identity may result in a patient receiving the wrong prescription, leading to serious consequences.

 

While not all patients will ask for counseling, it is the pharmacy staff’s responsibility to offer counseling proactively, especially in critical situations. Pharmacy staff must remain alert to identify potential medication errors and recognize when pharmacist intervention is necessary. Pharmacy technicians are essential to this process. In our hypothetical pharmacy, Ray and Kai realize that the way that they've been dealing with medication errors isn't conducive to ideal teamwork. Further, they realize that they need to engage their technician support team so the pharmacist becomes involved in the process earlier when technicians see red flags.

 

Common errors that require technician awareness and referral to the pharmacist include^2,4,20

• misuse or incorrect administration
• first-time prescriptions, dose changes, or class switches
• high-risk medications or drug interactions
• duplicate therapy or overlapping prescriptions

 

By actively engaging in patient education and ensuring clear communication at the point of dispensing, pharmacy professionals can significantly reduce medication errors and enhance patient safety. A PRO TIP comes from the Indian Health Service where pharmacy staff take a few minutes to remove medication from the bag, read the drug name, open the bottle, shake a few dosage units into the cap, and show it to the patient. Patients may identify medications that look different than they remember, which may signal a change in generic supplier or may identify an error. Although this process sounds time consuming, it actually takes just a few seconds for each bottle, and it prevents adverse outcomes in many cases.

 

Hospital Pharmacy

Hospital pharmacists and pharmacy technicians have serious responsibilities in ensuring safe medication use among high-risk patient populations. Like patients seen in the community, hospitalized patients often have complex conditions, multiple comorbidities, and require high-alert medications. But any event that precipitates hospitalization increases vulnerability to medication-related adverse events.²¹ Learners should note that many of these interventions apply in community centers as well.

 

Similar to retail or clinic pharmacy, miscommunication between prescribers and pharmacy personnel remains a leading cause of medication errors in hospitals. Healthcare providers can reduce errors through effective communication, verification, and collaboration. Regularly confirming prescription details and clarifying discrepancies helps prevent errors before they reach patients. Pharmacy staff need to establish trust and employ open communication with prescribers to ensure patient safety in hospitals. A breakdown in interprofessional relationships can lead to medication errors, such as^18,21

• incorrect medication selection due to misinterpreted verbal or written orders
• dosing errors, particularly in pediatric or renally impaired patients, when key patient information is not communicated
• failure to adjust medications in response to changing renal or hepatic function, leading to toxicity or subtherapeutic dosing
• missed allergy documentation, resulting in patients receiving medications that trigger adverse reactions

By fostering a culture of open dialogue and verification, hospital pharmacy teams can minimize preventable errors and ensure optimal patient care.

 

Consider a hospital pharmacy that employs nine pharmacists on three shifts, with a staffing ratio of one pharmacist to two technicians throughout the entire 24 hours. This pharmacy does a better job of documenting medication errors on unusual incident reports, but considerable room for improvement remains. Lisa is the pharmacist who works closely with the Performance and Quality Improvement (QPI) Department. Her liaison in QPI notifies Lisa that of the 46 medication errors reported in the last quarter, eight were associated with orders from a hospitalist, Dr. Backoff, who rotates shifts. The underlying cause seems to be miscommunication. Dr. Backoff is well known for his offensive behaviors; he humiliates people who ask questions, intimidates coworkers using insults or repeatedly bringing up past errors, excludes staff from opportunities to participate, and is generally so critical that people avoid him.³⁰

 

When staff call Dr. Backoff, he often fails to return the call. Over time, the situation has escalated to the point where staff are afraid to pick up the phone and call him when problems occur. As Lisa works with her QPI liaison, they realize that their workplace has no comprehensive policies and procedures targeting workplace bullying. Without clear guidelines and protocols, people who are targeted by bullies may feel powerless and unwilling to work with their bully.³¹ A PRO TIP is that this organization needs to develop training to address bullying, and Lisa and the QPI liaison need to speak to Dr. Backoff's supervisor immediately. The supervisor can refer Dr. Backoff to employee assistance program or implement corrective and disciplinary action.

 

Certain medications require heightened safety precautions due to their potential for severe patient harm if misused. The ISMP has a list of high-alert medications that require extra safeguards in hospital settings. An example of these are anticoagulants; even small dosing mistakes could lead to severe bleeding or thrombosis (clotting).³² Due to the serious risks associated with high-alert medications, pharmacy staff pharmacists and pharmacy technicians should double-check and arrange independent verification consistently.²¹

 

Medication errors frequently occur during transitions of care, including hospital admission, transfers to other facilities (e.g., long-term care, rehabilitation), and discharge to home. These errors can result in unintentional medication discontinuation, dose and frequency errors, or discharge medication miscommunication, significantly increasing patients’ risk of harm.³³  One of the most significant risks during transitions of care is unintentional medication discontinuation (mistakenly stopping an essential chronic medication). Dose and frequency discrepancies and miscommunications about discharge medications further increase the risk of ADEs post-hospitalization.³⁴

 

To prevent these errors proactively, hospital pharmacists and pharmacy technicians should^21,33

• conduct a thorough medication reconciliation at the time of admission, ensuring all home medications are accurately documented
• maintain clear, updated medication lists through each stage of hospitalization
• collaborate to ensure patients and caregivers receive comprehensive discharge counseling, with the technician reminding or prompting pharmacists if this step is missed, and reinforcing medication changes adherence instructions

 

Lisa’s hospital has a structured transitions of care program. They hire pharmacy students to conduct medication reconciliation under a pharmacist’s supervision. Before pharmacy students can conduct medication reconciliation, they complete a comprehensive training program. Regardless, errors on the medication list still slip through.

 

Lisa's hospital is not alone with this problem. Many hospitals find that errors occur even after medication reconciliation. A 2024 study of the medication reconciliation process and related medication errors indicates that these processes are “very heterogeneous,” meaning that in some areas, medication reconciliation was very good and in others, not so much.³⁵ They found that error rates were unexpectedly high in some areas. This study looked at 929 prescriptions written for 182 patients. In 91% of cases, the reconciler had not specified the drug form. About 72% of medication administration errors pursuant to a faulty medication reconciliation exercise resulted in patients receiving the wrong release dose formulation (i.e., immediate release as opposed to extended release). The researchers indicated that medication error rates did not improve significantly over the period before they conducted routine medication reconciliation.³⁵

 

Lisa has heard coworkers talk about medication reconciliation as a useless process and seeing them roll their eyes when they look at a medication reconciliation report that has obvious errors. In the past, pharmacy staff did not consider a mistake on a medication reconciliation list to be a medication error. However, when a serious error slips through, Lisa’s QPI liaison suggests that they began tracking such errors on unusual incident reports. A PRO TIP here is to track errors in medication reconciliation and try to identify the areas where errors are most likely to occur in the medication reconciliation process. At this hospital, Lisa and the QPI liaison were able to confirm that they also had a problem with identification of the correct formulation. Over the following months, they were able to improve by using additional training and revising their medication reconciliation form to force technicians to ask about the formulation or to see the bottle.

 

PAUSE AND PONDER: Can you think of any processes or policies in your workplace that can be improved to enhance patient safety?

 

Pharmacist and Technician Responsibilities

Pharmacy professionals have a responsibility to actively communicate with their colleagues and other healthcare providers to prevent errors. Effective collaboration within the healthcare team ensures safe medication practices by¹⁸

• clarifying unclear or incomplete prescriptions before dispensing
• confirming appropriate dosing adjustments for renal or hepatic impairment
• coordinating medication reconciliation during transitions of care to prevent omissions or duplications

 

Management needs to empower pharmacists and pharmacy technicians to voice concerns regarding potential medication errors. Addressing these concerns professionally and respectfully fosters a culture of teamwork and patient safety.

 

A key responsibility of pharmacy professionals is to provide clear, understandable medication counseling to patients. However, it is unrealistic to expect that staff can counsel all patients on every detail of their prescription. Instead, pharmacists should prioritize the most critical points, especially on new prescriptions, including³⁶

• dosing instructions and adherence importance
• common and serious adverse effects
• drug interactions and contraindications
• proper storage and administration techniques

 

One effective counseling strategy is the teach-back method, where patients repeat the pharmacist’s instructions back in their own words. This ensures patients fully understand how to use their medication correctly. For example, when dispensing doxycycline, instead of simply stating “Take this with a full glass of water,” a pharmacist using the teach-back method would ask one simple question after explaining how to take the doxycycline: “Can you explain to me how you will take this medication to avoid stomach irritation? I need to be sure I covered everything.”^18,21,26 

 

When a serious medication error occurs, it is crucial to investigate the underlying causes to prevent future occurrences. Root-cause analysis (RCA) is a structured problem-solving method used to analyze errors after they have happened—including what, how, and why it happened—and can help determine what lessons could be learned and how to reduce the risk of recurrence and make care safer.^3,21 For example, if a retail pharmacy dispenses the wrong insulin type and a patient is subsequently hospitalized, an RCA might reveal that the error stemmed from look-alike packaging and a lack of independent verification.

 

Failure mode and effects analysis (FMEA) is a proactive approach to medication safety, identifying potential failures before they occur. By evaluating processes and pinpointing high-risk areas, institutions can implement safeguards to prevent errors before they reach patients.²¹ For instance, before introducing a new automated dispensing cabinet, an FMEA could help identify potential failure points, such as medication selection due to user interface design, allowing for preventive modifications.

 

CONCLUSION

Patient safety is a fundamental pillar in pharmacy practice, and reducing medication errors requires a proactive, systematic approach. Errors can occur at any stage of the medication use process, from receiving and interpreting prescriptions to dispensing and patient counseling. Recognizing common errors—such as abbreviations, LASA drugs, incorrect dosing, and transcription mistakes—helps pharmacy professionals to implement safeguards that prevent harm.

 

 

 

 

 

 

 

 

Download CE Activity

Due to this being a REACCREDITED CE (from 2021), an HTML version is not available.

Download CE Activity