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

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.

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.

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

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

^*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

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

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

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

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

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

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.

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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

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

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

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