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.

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INTRODUCTION

Fad diets have always existed but have been on the rise in recent years due to the explosion of social media in the 21^st Century. A fad diet is a popular diet followed to achieve fast results or fix long-term problems associated with eating, specifically weight.¹ Fad diets are labeled as fads for a reason. These short-lived trends with wide popularity disregard for the rationale behind or quality of the approach itself.^3,4

People who choose fad diets are often trying to fix ongoing problems including overweight or obesity, inadequate nutrition, sedentary behaviors, and failure to maintain overall healthy habits.² Individuals who follow fad diets adhere to a mainstream concept of dieting without acknowledging individual health needs and restrictions. Health consequences may arise as a result of adhering to a diet ill-suited to an individual's nutritional needs and ability to sustain the associated effort. In addition, certain diets may influence medication interactions and disease outcomes. For this reason, fad diets can undermine patient safety.

This continuing education activity summarizes popular fad diets to inform pharmacy teams of their benefits and risks. It will allow teams to make recommendations for patients, understand how medications interact with the diets, and help prevent health complications.

The History of Fad Diets

Fad diets have existed throughout history in different forms. For example, in the 1920s, the Cigarette Diet was popular. Lucky Strike, a cigarette company, promoted the cigarette diet. They claimed that cigarettes would suppress appetite to boost sales using the tagline “Reach for a Lucky instead of a sweet.” Promoters advertised that people would lose weight successfully while following the diet.⁶ The 1940s saw the rise of the Master Cleanse. This juice cleanse consisted of a meal replacement drink consisting of hot water, lemon juice, maple syrup, and cayenne pepper. Its popularity stemmed from promises of cleansing the body of toxins while providing very few calories. It reached new levels of popularity in 2006, when superstar Beyoncé claimed to lose 20 pounds in two weeks using this method ⁶ In the 1960s, The Drinking Man’s Diet made an appearance. The recommendation was to consume high-protein and low-carbohydrate foods while drinking as much alcohol as desired. An example meal may have included a large serving of steak, salad or vegetables, and several alcoholic beverages. The Drinking Man’s Diet’s supporters considered alcohol a good carbohydrate and allowed indulgence. This diet was marketed toward the male population.⁶

People have always been interested in quick fixes for weight loss and appearance without considering how they will feel or how to keep the weight off indefinitely.¹ This approach to choosing a diet or making nutrition decisions ignores tactics that sustain weight loss. Fad diets are inherently unsustainable options that often lead to weight regain. These outcomes prove many fad diets are unreliable (if not dangerous).

With the creation and explosion of modern social media in the early 2000s, fad diets surged in popularity. Social media often fosters a community of misinformation regarding fad diet composition, how to follow the specific diet, and the diet’s benefits.⁵ Much of the information on social media regarding fad diets lacks reputable, verifiable sources. Fad diet promoters use scientific jargon loosely and inappropriately to make information convincing when describing seemingly miraculous diets. However, the information could just be the opinion of an individual or a promotional company sponsorship.⁵ Unless diet information is published by a credible source, it should be regarded as untrustworthy.

Pause and Ponder: How many times a week do you see diet-related content on social media?

Fad Diet Prevalence

Approximately 45 million Americans (about 14% of the total population) go on a diet each year.⁷ Of these diets, 50% are fad diets.⁷ According to the United States (U.S.) Weight Loss & Diet Control Market, the weight loss industry is one of the most advertised with investors spending $66 billion annually.⁷ More people than ever are overweight or obese and using diets as a solution. Table 1 summarizes obesity’s prevalence, which is rising each year in the U.S.

Table 1. Obesity Prevalence in the U.S. Population⁸

According to the Centers for Disease Control and Prevention (CDC), individuals who are overweight or have obesity are at elevated risk for many health issues. These include elevated cholesterol, stroke, heart disease, hypertension, cancer, type 2 diabetes, mental illness, low quality of life, and mortality, among others.⁹ While many factors can influence weight, individuals can adapt their diets to meet nutritional needs and make long-term differences to improve health outcomes.

TYPES OF FAD DIETS

As the definition implies, fad diets’ popularity increases and decreases with current trends. This section discusses some of the most popular current fad diets.

Intermittent Fasting

Individuals following an intermittent fasting diet alternate eating and fasting (not eating or drinking anything) on a cyclic schedule. This diet focuses more on eating during specific periods of time than restricting meal components. Various intermittent fasting schedules exist, but popular versions include alternate-day and time-restricted fasting.^10,11 Alternate-day fasting means fasting every other day, while time-restricted fasting involves eating within set time windows during the day. Individuals should consult a doctor and choose the type of intermittent fasting that best fits their health needs (but most do not). Studies show following intermittent fasting schedules leads to decreased body weight, body mass index (BMI), and waist circumference.¹¹ Studies also show improved blood glucose and triglyceride levels following this diet.¹⁰

The body uses ingested calories—specifically carbohydrates, sugars, and nutrients—as fuel.¹⁰ If people eat continuously throughout the day, the body uses ingested calories as fuel to perform necessary bodily functions. The body stores unused ingested calories in the form of fat where they become an energy reserve.^10,12

When the period between meals lengthens and the body lacks a constant supply of calories for fuel, it turns to the fat reserve to burn fat stored in the body. The theory is that the longer a person goes without eating, the more the body will use its fuel reserve. The more reserve is used, the more fat is burned.¹⁰ As more of the reserve is used for energy while intermittent fasting, more weight is lost through fat burn.

Intermittent fasting regulates eating times without restricting foods or food groups. Dieters must make conscious choices to include foods beneficial to health. This includes fruits, vegetables, plant proteins or lean meats, whole grains, superfoods (see Sidebar: Superfoods), and low-fat dairy options.¹² Healthy choices also include limiting processed foods and sugars.

Sidebar: Superfoods¹³

Superfoods are nutrient-rich and high in important dietary components including antioxidants, vitamins, minerals, fiber, and healthy fats. These help keep the body functioning, reduce disease risk, and improve well-being. Some examples of superfoods are

• Avocados → These include potassium and healthy fats to lower the risk of heart disease.
• Chia seeds → These include fiber, protein, antioxidants, vitamins, and minerals. They are also easy to add to recipes.
• Dark and leafy greens → All greens are good greens, but these are especially nutrient dense, including vitamins A, C, and E. They also contain vitamin K, which promotes bone health.
• Ginger → This includes vitamin C, magnesium, and potassium. It also helps reduce pain and aid nausea.
• Salmon → Fish is high in omega-3 fatty acids, which can help reduce heart disease.
• Yogurt → This includes calcium and protein to help with bone health, cancer prevention, and immune health. It is also a good source of probiotics to support gut health.

Pause and Ponder: Do patients ask about superfoods when discussing dietary information or supplements? Do you know which to recommend?

Pros and Cons

Like most diets, intermittent fasting has benefits and drawbacks. Following intermittent fasting correctly boosts memory, improves blood pressure, induces fat loss while maintaining muscle mass, helps prevent obesity, improves type 2 diabetes by reducing insulin resistance, and improves tissue health.^12,14 Intermittent fasting also regulates the body’s 24-hour cycle to improve physiological functioning and metabolic health. As a result, gastrointestinal (GI) microbiomes, energy levels, and sleep may improve.¹⁵

Drawbacks of this diet include issues with long-term maintenance/adherence, leading to regaining weight.¹⁰ It is difficult and tiring for individuals to maintain fasting for extended periods. In addition, until the body is accustomed to fasting periods, symptoms such as headaches, nausea, or dizziness may occur. Some individuals may feel an initial decrease in energy levels when starting this diet.¹⁰

Keto Diet

The keto diet, also known as the ketogenic diet, is centered around depriving the body of carbohydrates.¹⁶ Researchers originally developed the ketogenic or keto diet in the 1920s as an epilepsy treatment, especially for resistant pediatric cases.¹⁷ The rise of effective antiepileptic drugs and treatments decreased use of the ketogenic diet for this purpose. As originally designed, total daily calories were composed of high fat intake (70% to 80%), moderate amounts of protein (10% to 20%), and low carbohydrate intake (5% to 10%).¹⁶ An iteration of this diet has gained more traction since the 1990s, as people realized its effectiveness for quick weight loss.¹⁶

The keto diet helps with weight loss through the processes of gluconeogenesis and ketogenesis. Under normal circumstances, carbohydrates produce energy for the body.¹⁶ When insufficient carbohydrates are available, insulin secretion is reduced and glucose is less available. The body then exploits gluconeogenesis, using lactic acid, glycerol, and amino acids to produce glucose as an energy source.¹⁶

If carbohydrate levels drop further, the body enters ketogenesis and secretes ketone bodies as an alternative energy source.¹⁶ As insulin secretion levels remain low and ketone bodies are used for energy, fat and glucose storage falls significantly. This can cause other fats to break down, leading to bodily fat loss.¹⁶

To remain in ketogenesis, the body needs constant carbohydrate deprivation.¹⁶ The longer it is deprived of carbohydrates, the more fat is burned in the ketotic state. This is known as nutritional ketosis and is considered safe, as opposed to the metabolic state of ketoacidosis (an accumulation of ketones that increases the blood’s acidity), which can be life-threatening.¹⁶

During ketoacidosis, ketone bodies are produced in large amounts and can acidify the blood pH.¹⁶ Acidic blood pH reduces the amount of oxygen blood delivers to cells leading to cell death and life-threatening complications. Insulin keeps the production of ketone bodies at bay, so sometimes people with type 1 diabetes develop ketoacidosis due to decreased insulin production. Taking diabetes-related medication correctly reduces the risk of ketoacidosis in people with diabetes. Following a low carbohydrate diet for a prolonged amount of time can also lead to ketoacidosis.¹⁷ To reiterate, ketogenesis is the production of ketone bodies in response to carbohydrate and glucose depletion. Low concentrations of ketone bodies are generally regarded as a safe, as opposed to high concentrations caused by ketoacidosis (which is a medical emergency).¹⁶

What to Eat and Avoid

Given the strong emphasis on high-fat foods, healthy fats comprise the largest part of this diet.¹⁶ Foods such as seeds and nuts, coconut, avocados, poultry fat, and plant fats (e.g., olive or coconut oils) are encouraged. In addition, some dairy products—including butter, hard cheese, and yogurt—are allowed, but people on a ketogenic diet should avoid cream, ice cream, and full-fat milk given their natural sugar content.¹⁷ Individuals following this diet should consume a moderate amount of protein, ideally meats high in omega-3 fats.¹⁶ This includes grass-fed beef, free-range poultry, wild-caught fish, and pork. Nuts, seeds, tofu, and eggs are also acceptable protein sources.¹⁷

Adhering to a diet with less than 10% of calories from carbohydrates can be challenging, especially since this diet requires individuals to calculate “net carbs” (See Sidebar: What are “Net Carbs”?).¹⁶ Vegetables lacking high starch contents (e.g., cauliflower, broccoli, onions, leafy greens, bell peppers, garlic, mushrooms, cucumber, summer squash) are encouraged. Small portions of fruit are also allowed, and fruits with a lower net carb content (e.g., berries) are preferred. Other acceptable carbohydrates include dark chocolate, herbs, spices, unsweetened tea, coffee, vinegars, and mustards.¹⁷

Sidebar: What are “Net Carbs”? ¹⁷

The body cannot digest or metabolize some carbohydrates because of their molecular structures. For example, fruits, vegetables, whole grains, and sugar alcohols contain insoluble fibers that are indigestible. Insoluble carbs have no energy value or blood sugar impact, so they are allowed when following the keto diet. The keto diet requires dieters to calculate “net carbs,” the amount of carbohydrates taken in by the body that are digested and metabolized and thus contribute to calories. However, it is important to note that the total calorie level does not change even when “net carbs” are calculated.

Individuals calculate net carbs by subtracting the number of ingestible carbohydrates from the food’s total amount of carbohydrates. For example, food containing 24 total carbohydrates and 21 ingestible carbohydrates equals 3 net carbs. Ingestible carbohydrates can typically be found by subtracting the amount of fiber from the amount of carbohydrates in the food item, but it can be more complicated. A number on online net carb calculators are available to help.

Net carbs are also known as “impact carbs.” Food manufacturers use both terms as marketing strategies, but governing bodies do not regulate use of these phrases.

Foods containing added sugar, whole or refined grains, and flour products are restricted.¹⁷ Starchy foods are also not allowed, including some high-starch vegetables such as corn, potatoes, and winter squash. Fruits with a high net carb content and fruit juices are restricted. Most keto programs also advise against alcoholic beverages due to their carbohydrate content and added sweeteners.¹⁷

Pros and Cons

The keto diet may be beneficial for weight loss, as it uses ketone bodies for energy to deplete glucose and fat storage abilities. Decreasing sugar intake lowers the risk of developing diabetes, obesity, and metabolic syndrome.¹⁶ Following this diet may reduce cholesterol, blood sugar, and blood pressure, and decrease insulin resistance.¹⁷

Diet restrictions may cause short-term adverse effects such as nausea and vomiting, fatigue, headaches, dizziness, and insomnia.¹⁶ This is known as the “keto flu.” Symptoms usually resolve once the body adjusts to the diet after a few weeks. Fluids and electrolyte replenishment can help alleviate discomfort during this period.¹⁶

Documented long-term adverse effects include increased uric acid levels in the blood, increased risk of kidney stones, and osteoporosis.¹⁷ This is due to the diet’s restrictive nature and omission of necessary components to sustain a healthy diet. Nutrient deficiencies can occur as a result of following this diet.¹⁷

People struggle to adhere to the ketogenic diet due to strict regulation of fat, protein, and carbohydrates.¹⁷ Dieters must carefully monitor their adherence to intake limits and meet target levels. This can be difficult for individuals to maintain long-term and lead to low adherence to the diet.¹⁷

Pay-for-Food Systems

Pay-for-food diets are meal prep services or meal delivery services with pre-portioned ingredients, pre-cooked meals, or meal replacement options. Diets focus on weight loss and are designed for convenience. These options take the guesswork out of planning meals and make it easier to track eating.

Nutrisystem

The Nutrisystem meal service claims its diets help with weight loss through a high-protein and low glycemic approach.¹⁸ Nutrisystem expects users to lose one to two pounds a week by managing blood sugar and controlling hunger to avoid overindulgence. Dietitians design meals to include healthy options and relieve the stress of planning.¹⁸

Meals are pre-portioned to fit an individual’s needs and tastes.¹⁸ The meals’ composition of lean protein, healthy fat, and smart carbohydrate ingredients is supposed to curb hunger. Protein shakes and bars are options to supplement plans. Nutrisystem claims deprivation is too restrictive and allows for some deviation from the plan or healthy alternatives to “bad foods.” In addition, dieters can track their progress and calories using Nutrisystem’s app. This system promotes prizes and special offers to keep individuals motivated.¹⁸

Prices vary by plan type but can range from $9.99 to $15.18 a day. Nutrisystem has plans designed specifically for men, women, partners, and people with diabetes.¹⁸

SlimFast

When SlimFast originated, the system promoted meal replacement shakes to lose weight.¹⁹ The company has since expanded to include drink mixes, snacks, and meal replacement bars. The products are grouped into categories such as calorie control, high protein, keto, and intermittent fasting. The website also contains a recipe section for dieters to use in their meal planning.¹⁹

SlimFast plans are based on individuals’ goals and preferences, including the Favorite Foods Plan, Keto Plan, High Protein/Low Carb Plan, Original Plan, and Intermittent Fasting.¹⁹ Dieters purchase SlimFast products to supplement or replace parts of their current diet. Plans themselves are not priced because individuals buy their own groceries and supplement with SlimFast products associated with the plan of their choice. The company also has an app to use for weight management tracking and a private Facebook group to communicate with other individuals on the diet to offer support or guidance.¹⁹ SlimFast claims their plans and products promote and maintain weight loss and encourage people to make better food choices.¹⁹

Jenny Craig

The Jenny Craig company has recently gone out of business after 40 years in the industry. Some experts indicates that one reason has been the availability of weight loss medications and increased competition in this market space. This system emphasized one-on-one coaching mixed with healthy foods to lose weight quickly.²⁰ The company claimed dieters could lose up to 18 pounds in the first four weeks. Coaches designed meal plans to be unrestrictive and included an individual’s favorite foods. Meals focused on low-fat foods with high fiber and protein. This program also emphasized physical activity and occasional intermittent fasting to aid the weight loss process.²⁰

Plans consisted of meals from the program, two snacks, and supplemental grocery items daily to promote weight loss and increase metabolism.²⁰ One snack included Jenny Craig’s Recharge Bar, used when intermittent fasting. The program claimed the Recharge Bar helped dieters lose weight faster, feel less hungry, and maintain fasting. Jenny Craig coaches designed plans and provided guidance for the duration of the program.²⁰

Food was delivered weekly or biweekly. Depending on the type of plan, individuals paid $13.99 to $21.99 per day. Prices were based on the number of meals, membership length, and amount of coaching support included. Promotional offers and meal bundles were available.²⁰

Pros and Cons

Pay-for-food diets can be intriguing as they promote healthy choices, weight loss, and convenience.^18-20  They reduce mental load and stress surrounding dieting by making the choices easier or eliminating the need to choose altogether. Some services also provide support groups or coaches for accountability and guidance. In addition, if dieters can adhere to these plans, meal kits promote portion control and reduce overeating.^18-20

A major con associated with these diets and meal kits is adherence. As people lose weight on these diets, they may stop using them, gain weight back, and become discouraged about trying again. This can reverse improved health outcomes.^18-20 Another con is cost. Individuals may be discouraged by the prices associated with pay-for-food systems. The cost may not be viable or sustainable options for all individuals.^18-20  

Studies have shown these diets to be ineffective. Attrition rates (percentages of people leaving a program) are 30% or greater, and 37% of dieters who complete programs lose less than 5% of their initial body weight.²¹ Other studies failed to produce significant results for how these pay-for-food diets affect weight loss when compared to educating or counseling individuals on weight.²² High attrition rates and insignificant weight loss results suggest these diets are unsustainable and unreliable.²¹

Paleo Diet

The paleo diet goes by many names, including the Paleolithic, caveman, or Stone-Age diet. It consists of (allegedly) eating like humans of the Paleolithic era did, mixed with modern components to supplement the diet. The Paleolithic era occurred from roughly 2.5 million years ago to 1,200 B.C. Diet supporters believe current body function is similar to how it functioned during this era and eating foods available or comparable to this time will improve health.²³ Introduced in 2002 by Dr. Loren Cordain, a scientist specializing in nutrition, this diet has surged in popularity in recent years due to weight loss claims.²⁴

Due to disagreements about which foods were available in the Paleolithic era compared with today, many diet plans are dubbed “paleo.” They differ in specific foods allowed. All plans emphasize high protein, healthy fats, low or moderate carbohydrates, low sugar and sodium, and high fiber to meet weight loss goals.²³ The term “paleo” will be used to describe this model. The paleo diet consists of consuming mostly lean meats, fruits, vegetables, nuts, seeds, and fish, in line with what researchers believe was consumed during the Paleolithic age.²³ It also emphasizes reducing intake of dairy, grains, and carbohydrates.²⁵

Weight loss can occur through several pathways using the paleo diet. ²³ Like the keto diet, ingesting fewer carbohydrates forces the body to use fat for fuel. In addition, replacing highly processed foods, added sugars, and large amounts of carbohydrates with healthier options can aid weight loss. Eating more protein and less calorically dense food (i.e., few calories in a large volume of food) also helps curb hunger and leave individuals more satisfied.²³

Less calorically dense foods—including vegetables, fruits, low-fat or fat-free dairy, and egg whites—can be eaten in larger quantities. These foods help with weight loss as they allow individuals to eat a larger volume and feel full, without ingesting large numbers of calories.²⁶ This reduces snacking and overall food intake.²³

Conversely, calorically dense foods are high in calories and eaten in small amounts. These contribute weight gain as individuals who eat a small volume consume high numbers of calories.²⁷ Examples of calorically dense foods include²⁷

• Proteins: fish, beans, eggs, cheese, yogurt, fats including nuts, avocados, nut butters
• Carbohydrates: potatoes, brown rice, whole grains

Overall, the paleo diet works by breaking down the diet into basic components and making healthier choices. Cutting out foods leading to high glucose or carbohydrate storage also aids in eating healthier and inducing weight loss.²⁸

What to Eat and Avoid

Allowed foods emphasize fresh and healthy choices to remain consistent with foods found in the Paleolithic age.²³ This includes lean meats, fish or shellfish, fruit, vegetables, honey, nuts or seeds, and olive or coconut oils. Frozen fruits and vegetables are allowed as they contain the same nutrients as the fresh variety and may be more convenient. Omega-3 fats are important for the body and can be found in fish, grass-fed beef, avocado, olive oil, some nuts (e.g., walnuts, almonds, pistachios), and seeds. Root vegetables such as cassava and sweet potatoes are highly nutritious and are allowed in moderation.²³

Restricted foods have little nutritional value or a high glycemic index unsuitable for the paleo diet.²³ For example, white potatoes and processed foods are off limits. Other restricted foods include whole or refined grains, cereals, refined sugar, refined vegetable oil, legumes, dairy products, alcohol, coffee, and salt. Canola is a refined vegetable oil and is not allowed. Restricted legumes include peanuts, beans, and lentils.²³

This diet emphasizes eating healthy and portioning fats, proteins, and carbohydrates to enhance health.²³ Calorie counting and general portion control are deemphasized in this diet. Some plans also allow for “cheat meals” (those consisting of food not beneficial to health) in the early stages of the diet to increase adherence.²³

Pros and Cons

Components of this diet including fiber, potassium, and antioxidants aid bodily functions and reduce disease risk. Reducing the intake of highly processed foods with little nutritional value also helps improve overall health.²⁵ Short-term benefits may include weight loss, improved blood pressure and cholesterol levels, and increased insulin sensitivity.²³ One study documented improvements in metabolic levels, specifically glucose control and lipids, in people with diabetes.²⁸

Unfortunately, restricting or excluding foods altogether for long periods of time can lead to nutritional deficiencies and health complications. For example, limiting dairy intake leads to deficiencies of calcium, vitamin D, and B vitamins.²³ These deficiencies can increase risk of osteoporosis and bone injuries.²⁴ Dairy-related nutrient deficiencies are not specific to the paleo diet, but can occur due to its food restrictions. Restricting grains in the diet also deprives the body of nutrients, which increases risks of diabetes and heart disease. In addition, increased meat consumption (especially red meat) contributes to saturated fat intake and increases risks of cardiovascular problems and diabetes.²³ It may also be difficult for people to adhere to a diet that restricts certain categories of foods.

Atkins Diet

The Atkins diet promotes low carbohydrate intake while allowing as much protein and fat as desired. Robert C. Atkins, a heart specialist, developed this diet in the 1960s as a method for weight loss and maintenance.³⁰ Although it is a low-carb diet, the Atkins program acknowledges that eating right is always better than eating less.³¹ This diet is ever evolving to be current with updated nutritional expertise.³⁰

Like the keto diet, Atkins emphasizes low carbohydrate intake of less than 20 g per day to start.³⁰ Unlike the keto diet, consumption of fat and protein is less restricted. Carbohydrates are claimed as the problem without regulating the intake of other food groups. Diet supporters believe the sugars found in carbohydrates cause health issues such as blood sugar imbalances and weight gain.³⁰

Hypothetically, eating fewer carbohydrates lowers dietary sugar leading to greater satiety, increased energy, less stored fat, and higher metabolism.³¹ When the body lacks glucose and carbohydrates to use as energy, it turns to fat to keep the body functioning through ketogenesis. The more fat a person burns, the more weight they lose.

Fat and protein comprise the remainder of the diet. As carbohydrates are viewed as the source of health issues, intake levels of fat and protein are less restricted. Calorie counting and portion control are unnecessary, besides keeping track of carbohydrate intake to stay below the allowable limit.³⁰

The Atkins diet is split into phases with specific allowable limits of carbohydrates (see Table 2). The diet’s phases adjust to reflect changes in body function and weight. As carbohydrate levels fluctuate in each phase, protein and fat levels change to achieve satiety.

Table 2. Atkins Diet Phases³¹

While phases differ in carbohydrate intake levels, they include similar food groups overall.³⁰ Allowed foods include vegetables, oils, fats, and protein (e.g., eggs, cheese, fish, meat and poultry). Dieters can introduce berries, nuts, seeds, starchy vegetables, and whole grains in the third phase, provided they are still losing weight. Dieters can also eat Atkins’ commercial selection of products during and after phase two. Most fruits, alcohol, baked goods high in sugar, bread, pasta, and nuts are restricted in phase one. Some fruits and grains are added by phase three.³⁰

Pros and Cons

Benefits of the Atkins diet include weight loss; decreased blood pressure; and lower incidence of heart disease, metabolic syndrome, and diabetes.³⁰ This diet can also improve blood sugar and cholesterol levels. These benefits are attributed to low carbohydrate intake and subsequent weight loss.³⁰

Reducing carbohydrate intake may initially cause symptoms such as headache, weakness, fatigue, and dizziness.³⁰ Unrestricted fat intake can be unhealthy. In addition, using fat as the body’s energy source for too long may lead to ketoacidosis if dieters misuse the plan.²⁹ Nutrient deficiency can also occur on this diet as a result of restrictions.³⁰

Weight loss pursuant to this diet is difficult to maintain due to its deficiencies and restrictive nature. Following the carbohydrate limit for long periods of time is difficult and unsustainable for some people.³⁰ Cardiologists warn this diet puts oxidative stress (disproportionate levels of oxygen reactive species overwhelming the ability of body systems to detoxify them) on organs and can cause serious heart problems or fatal complications.²⁹ Some long-term studies have shown the Atkins diet is no more effective than other fad diets. In addition, these studies show that most people who lost weight while following the Atkins diet regained it.³⁰

IMPLICATIONS FOR PHARMACY TEAM

Fad dieting can compromise patient safety, and certain patients are at elevated risk for problems. Pharmacy teams are responsible for advising patients about drug-diet interactions and concerns. Table 3 describes conditions and their associated medications that impact the use of fad diets.

Table 3. Implications for Pharmacy Teams^{10,16,23,30,32-40}

Nutritional Myths

As mentioned, misinformation surrounding diets has always existed, and social media has magnified the problem. Some myths are more harmful than others, but knowing the facts is essential to correctly informing others.³² Examples of nutritional myths that pharmacy teams can debunk for their patients are found in Figure 1.

Dieting is not a one-size-fits-all solution. When pharmacy teams advise patients, they must work with patients to consider health factors . Factors to consider include a patient’s medications, lifestyle choices, and known health issues.³³ Pharmacy teams should advise individuals that fad diets are not necessary and following a generally healthy diet is usually sufficient to lose weight. They should make healthy swaps and find strategies that work best for them as individuals. For example, they can cut back on processed foods, consume more fruits and vegetables, and be conscious of fat or carbohydrate intake to ensure healthy sources. These choices are effective ways to achieve the long-term goals without employing fad diets that promote quick fixes.³³

CONCLUSION

Fad diets are undeserving of the positive hype they receive. They are short-term solutions that sometimes work for people looking to lose weight or make changes quickly. However, benefits are outweighed by their unsustainability and poor post-diet maintenance planning. Fad dieting also starts a cycle of yoyo dieting (see Sidebar: Yoyo Dieting). The best option for health is to find strategies that work individually and stick with them. Ditch the fad diets and make long-term healthy choices for better, lasting results.³³

Sidebar: Yoyo Dieting

Yoyo dieting, or weight cycling, occurs when people achieve their goal weight through dieting, stop dieting and return to unhealthy habits, gain the weight back, diet again for a period, gain the weight back, and repeat the cycle. Yoyo dieting is not only a conscious choice. Physiological mechanisms related to energy intake and expenditure, genetics affecting weight control processes, and the interaction between genes and the environment also affect the cycle.³⁴

Yoyo dieting lacks substantial or sustainable changes to lifestyle or nutrition to keep weight off and instead focuses on quick fixes.³⁴ These quick fixes ultimately fail when weight is regained, and the cycle continues. Most weight lost is gained back within the first two to three years after dieting ceases. However, if dieters keep weight off for two years, the likelihood of gaining it back decreases.³⁵

Pause and Ponder: Do you think fad diets are helpful or harmful?

Resources for Pharmacists and Pharmacy Technicians

• CDC Resources - Healthy Weight, Nutrition, and Physical Activity ³⁶
  • https://www.cdc.gov/healthyweight/tools/index.html
• USDA - Healthy Living and Weight ³⁷
  • https://www.nutrition.gov/topics/healthy-living-and-weight

Download CE Activity

INTRODUCTION

Lifestyle modifications have been the mainstay of weight management for years. We’ve all heard the advice: Exercise more, eat less, limit fried foods and sugary drinks, and the weight should slowly disappear. As the weight comes off, you might have some setbacks but just keep tracking your foods and your success is right around the corner.

If only it was that easy!

Scroll any social media platform today and search the term, “#ozempicweightloss” and a plethora of joyful testimonials appear. Some videos have reports of people losing 17 pounds in 3 months or 64 pounds in a year with no cravings for food. “I can eat whatever I want!!” cried a satisfied user. It is as if the golden ticket has been found in all the candy bars ever produced and everyone is going to the candy factory!

Although the recent media emphasis has been on semaglutide, and the Ozempic product primarily, other glucagon-like peptide-1 (GLP-1) receptor agonists have also been associated with weight loss to varying degrees. This continuing education activity’s primary focus is to clarify misinformation, highlight specific GLP-1s’ risks and benefits when used for weight loss, and answer frequently asked questions.

WHAT ARE GLP-1 RECEPTOR AGONISTS?

Major breakthroughs in the physiology of the pancreas occurred in the early 1900s.¹ At that time, physiologists thought the nervous system had exclusive control of all bodily functions. That idea changed when two scientists, William Bayliss and Ernest Starling, discovered a chemical compound they named secretin. Released from intestinal mucosa, secretin stimulated the pancreas.² Shortly after the discovery of the hormone insulin in 1921, research being conducted at the time primarily stimulated the pancreas to produce insulin by administering glucose via the intravenous route. However, when glucose was administered orally (allowing nutrients to travel to gastrointestinal areas), insulin levels improved substantially. This observation was known as the incretin effect. As a result, two insulinotropic hormones were later identified as incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) discovered in 1971 and glucagon-like peptide-1 (GLP-1) discovered in 1985.^1,2

Analyzing the venom of the Gila monster (Heloderma suspectum) in 1990, endocrinologist Dr. John Eng discovered a peptide that stimulated insulin release from the pancreas.³ Named exendin-4, this peptide was similar in structure and function to GLP-1 found in humans. One problem with GLP-1 was that when it is released into the body, dipeptidyl peptidase-4 (DPP-4). quickly inactivated it. Researchers then developed the DPP-4 inhibitors to allow GLP-1 to remain active for a longer period of time. However, synthetically producing GLP-1 receptor agonists (GLP-1RA) directly has extended the peptide’s life. Initial development resulted in twice daily and then daily administration (half-life of 13 hours) of GLP-1RAs. However, when researchers combined semaglutide with a free fatty acid side chain that was tightly bound to albumin, its half-life was increased substantially. The resultant half-life of 165 hours led to an advantageous injection administration schedule for semaglutide: once weekly.^3,4,5

Mechanism of Action

As a class of medications, all GLP-1RAs share common mechanisms of action in the treatment of diabetes: stimulate the pancreas to secrete insulin, suppress the action of glucagon, and decrease gastric emptying.⁴ Scientists previously studied the effects of GLP-1 and noticed that the protein, when injected in rats, decreased appetite quickly.⁵ Once clinicians began using GLP-1RAs to treat diabetes in humans, they also observed weight loss due to decreased appetite, increased feelings of fullness, and reduced caloric consumption.⁴

Researchers determined that the brain contained GLP-1 receptors. Weight loss was due to GLP-1RAs ability to travel to these receptors and influence specific areas of the hypothalamus that are key to controlling appetite, calorie consumption, satiety, and body weight.⁴ Among GLP-1RAs, semaglutide and liraglutide stimulate the highest amount of weight loss success.

Comparison of GLP-1 drugs

Table 1. GLP-1RAs for Weight Loss

Adverse Drug Reactions and Boxed Warning

GLP-1 agonists all have similar and common gastrointestinal adverse effects (nausea [~15–30%], vomiting [~10-15%], diarrhea [~5-10%], abdominal pain, constipation).^6,7,8 Patients can use some strategies to possibly mitigate these adverse effects^6,7,8:

• Increasing the GLP-1 agonist dose slowly
• Staying hydrated and increasing fiber
• Avoiding high-fat foods and alcohol
• Stopping eating when full (and eating only when hungry)
• Spacing meals appropriately
• Using short-term proton pump inhibitors or H₂ blockers if needed

Patients may also experience headache, fatigue, dyspepsia (gastrointestinal upset), dizziness, abdominal distension, eructation  (burping), hypoglycemia in patients with type 2 diabetes, flatulence, gastroenteritis, and gastroesophageal reflux disease.⁷ Clinicians should evaluate patients for gallbladder disease if cholelithiasis (gallstones) or cholecystitis (an inflamed gall bladder) is suspected.

Reports of patients experiencing hair loss have surfaced recently from news and social media. Listed as an adverse reaction for Wegovy, but not for Ozempic, the Wegovy dose is much higher for treatment of weight loss.⁹ Some clinicians think that the rapid loss of weight triggers the body to conserve calories consumed for essential functions.⁹ Since patients eat less while taking the medications, their diet may consist of lower amounts of protein and minerals important for hair growth. Clinicians have seen hair growth resume once the body reaches a plateau in weight loss, therefore the loss of hair is not permanent.⁹

These drugs also share a boxed warning for risks of pancreatitis and medullary thyroid carcinoma (cancer in the thyroid gland in its medulla, the calcitonin-producing area), which is rare.⁶ Patients with a personal history of pancreatitis or a personal or family history of medullary thyroid carcinoma must avoid these drugs.⁶

These drugs also required an FDA approved Medication Guide whenever GLP-1RAs are dispensed. Pharmacy technicians can be very helpful to pharmacists if they check the patient’s bag and make sure that the Medication Guide is in it.

Recent Shortages of GLP-1 Receptor Agonists

The sensation of weight loss success for some has caused serious problems for other patients who have diabetes and are struggling to find medication at local pharmacies. Staff in community-based pharmacy practice are well aware of the semaglutide shortages that have occurred in the past year. Pharmacists and technicians should be able to explain the current drug shortages, adverse reactions, and FDA approved or off-label use to patients and other healthcare providers.

“Ozempic face”

As social media and now news media have reported the success of dramatic weight loss, some users bemoan weight loss woes associated with use of GLP-1 agonists. The term, “Ozempic face,” introduced by a dermatologist in New York, describes the typical female patient who has lost a significant amount of weight on semaglutide but now needs (or wants) dermal fillers for her sagging facial structures.¹⁰ Patients complain about sagging skin and a gaunt appearance, two problems that follow the loss of facial fat after any harsh weight loss.

Facial fat loss is common when patients lose weight, and when the weight loss is significant, patients will look older. Skin wrinkles and loosens—hallmarks of aging. Similar to weight loss from old-fashioned dieting, fat loss while taking GLP-1 agonists affects the entire body (not just the face). But patients on GLP-1 agonists for cosmetic weight loss fail to understand that they can’t just lose weight where they’d like to lose weight. The facial fat loss is distressing to them.¹⁰ Pharmacy teams need to know that “Ozempic face” is a slang term, and GLP-1 agonists don’t specifically target the face.¹¹

Weight Loss Blockbuster or Fad

Over the past two years, celebrities and social media influencers have posted successful weight loss stories while using semaglutide and as a result, catapulted its popularity as a weight loss miracle.¹² Questions remain as to how long the weight loss effect will last and if patients will gain the weight back once stopping the treatment. Novo Nordisk, semaglutide’s manufacturer, indicates weight loss can be sustained with long-term use. However, the data collected is limited by a time span of two to three years. Since people who pay out-of-pocket for semaglutide will pay around $1200 per month and some insurance companies may not cover the medication, pharmacists should counsel patients that once the medication is discontinued, weight gain is likely to occur and the weight gain might exceed the original amount lost.¹²

FDA APPROVED AND OFF-LABEL USE

In December of 2017, the FDA approved semaglutide (Ozempic) for the treatment of diabetes. As significant weight loss was observed, the Semaglutide Treatment Effect in People with obesity (STEP) studies produced promising weight loss data.¹³ As a result, the FDA approved semaglutide for an additional indication, weight loss, in June 2021 under the brand name Wegovy.

Diabetes

In patients with type 2 diabetes mellitus (T2DM), semaglutide is used in combination with diet and exercise to reduce blood sugar levels.¹⁴ In patients with T2DM who additionally have established cardiovascular disease, liraglutide and semaglutide are indicated to help lessen the risk of major cardiovascular incidents. Dulaglutide, liraglutide, and semaglutide also have beneficial effects on chronic and diabetic kidney disease.⁶ Patients who have a history of pancreatitis should avoid any member of the GLP-1RA class and they are not to be used as treatment for patients who have type 1 diabetes.

Dosing semaglutide for the treatment of diabetes requires a period of time for dosage escalation to minimize adverse effects. The FDA has approved both subcutaneous and oral semaglutide (Rybelsus) dosage forms, but only the injectable version is approved for weight loss. Subcutaneously, semaglutide is initially dosed at 0.25 mg once weekly, and after four weeks the patient should increase to 0.5 mg weekly for four weeks. Doses of 1 mg and 2 mg are optional if glycemic control has not been achieved, however the 1 mg dose should also be used for a minimum of four weeks before increasing to the maximum 2 mg strength.⁶ Dosed on the same day of the week, injections can be dosed at any time of the day with or without regard to meals. Patients sometimes miss or forget their scheduled dosing day. If this occurs, patients should inject the dose within 5 days of the missed dose.⁶

Patients who have diabetes and currently use metformin, sulfonylureas, thiazolidinediones, or insulin can use semaglutide in combination.  However, patients can administer semaglutide and insulin injections at the same time and in the same areas of the body, but not close together; they must never mix them together in the same syringe.¹⁴ Hypoglycemic episodes are possible when using a sulfonylurea and/or insulin with semaglutide. Pharmacists therefore should remind patients of the signs and symptoms of hypoglycemia when these drugs are used together. Prescribers may need to adjust the dose of insulin and/or a sulfonylurea when starting semaglutide.⁶

Obesity and Weight Management

Affecting 70% of American adults, obesity and being overweight contribute to a variety of complications and have reduced quality of life.¹⁵ Debilitating and expensive disease states associated with obesity include: T2DM, cardiovascular disease, osteoarthritis, sleep apnea and cancer.^13,15 Since obesity has roughly tripled worldwide from 1975 to 2016, investigating the reasons for the rise in prevalence and finding solutions is of utmost importance to prevent and treat obesity.¹⁶

The access and ease of inexpensive prepared high caloric foods, limited physical activity, and sedentary life styles are factors that have contributed to the rise of obesity.¹⁷ As mentioned, treatment typically has concentrated around the modification of these lifestyle habits.¹⁸ Although the weight reduction is usually moderate in magnitude, it is recovered over time (yes, that means that people gain the weight back!).¹³

Anti-obesity medications have been added to lifestyle modifications. Discouraged by adverse drug reactions, contraindications, cost, and moderate weight loss results with weight that is regained over time, many patients and prescribers are hesitant to consider these treatment options.¹⁶

Maintaining weight loss has proved equally difficult due to the regulatory centers in the brain that control appetite. Increased hunger and abnormal satiety signals controlled by neuroendocrine pathways have been discovered in the hypothalamus.¹⁶ Researchers have also identified levels of hormones that regulate weight in the hypothalamus. These hormones (leptin, ghrelin, peptide YY, and GIP) play a role in counteracting weight loss after dieting and lead to regain of weight.^{17, 16}

Once semaglutide was approved for the treatment of diabetes, clinical trials focused on weight loss. The STEP trials were phase 3 studies implemented to evaluate the safety and efficacy of semaglutide 2.4 mg subcutaneously once weekly injections for 68 weeks. Patients enrolled in the studies were adults with obesity or overweight, a mean age of 46.2 to 55.3 years, mean BMI of 35.7 to 38.5 kg/m², and were mostly female (mean: 74.1% to 81.0%) for five of the trials.¹³All studies included lifestyle interventions at varied intensities.^{13, 18} In one of the larger studies that compared semaglutide with placebo, semaglutide was associated with a 12.4% loss of body weight.¹⁵As a result of the  ≥ 5% in weight loss exhibited in the studies, the FDA approved semaglutide for chronic weight management.^18,15 The approval came in June of 2021, and the manufacturer marketed semaglutide as Wegovy.

The STEP 8 trial compared once-weekly semaglutide to once-daily liraglutide and enrolled 338 adult patients with 126 receiving semaglutide 2.4 mg, and 127 participants receiving liraglutide 3 mg. Participants were overweight or obese, without diabetes, had a mean BMI of 37.5, and most had 0-2 comorbidities with dyslipidemia and hypertension being the most frequent.^{19, 18} The primary results at 68 weeks reported an estimated mean change in body weight at -15.8% with semaglutide, and -6.8% with liraglutide.¹⁹ Based on data from this STEP study, the researchers concluded semaglutide is far superior to liraglutide when used for weight loss and had significantly improved cardiometabolic risk factors.^{19, 18}

The most frequent adverse side effects reported in the STEP studies were gastrointestinal disorders. Most gastrointestinal side effects were considered mild or moderate in severity and usually were most prominent during the dose titration phase.¹⁹ In the STEP 8 study, semaglutide (84.1%) reported a higher occurrence of gastrointestinal events than liraglutide (82.7%).¹⁹  Other side effects reported were hypoglycemia, acute pancreatitis, gallbladder disorders that generally resulted in cholelithiasis (gall stones), malignant neoplasms (cancer), change in pulse and injection site reactions.^{18, 19}

SIDEBAR: Alcohol use disorder potential

As patient use of semaglutide has expanded over the past several years, a side effect has emerged that is surprising many clinicians. Patients have reported an abrupt loss in the desire to drink alcohol, almost to the point of repulsion for some patients. GLP-1RAs are known to decrease the desire, enjoyment, and consumption of fatty foods in humans, but observations that patients began to decrease alcohol consumption was unexpected. Although studies to date have observed a reduction of alcohol in rats, mice, and monkeys when receiving GLP-1RAs, reliable researchers avoid extrapolating results from animal studies directly to humans, especially since humans tend to consume more alcohol than animals.²⁰ Since several patients have reported decreased intake of alcohol and data from animal models reflect these results, researchers are starting to investigate GLP-1RAs effect on patients who have alcohol use disorder (AUD).

Existing studies on GLP-1RAs effect on AUD in humans are minimal. A recent study published from Denmark compared the use of a different GLP-1RA, exenatide 2 mg versus placebo in patients with AUD. Researchers were looking to determine if exenatide reduced the amount of heavy drinking days. At the same time, functional MRI brain scans were also completed during the study that focused on areas involved in addiction and reward centers of the brain. Administered once weekly to 127 patients along with cognitive behavior therapy for 26 weeks, exenatide failed to show a decrease in heavy drinking days.²¹  However, in a subgroup of obese patients (BMI > 30 kg/m²) heavy drinking days and total alcohol intake was reduced.²¹ Brain scans revealed weakened alcohol cue reactivity and lower dopamine transporter availability for those patients in the exenatide group.²¹

Ongoing phase two clinical trials are studying the effects of semaglutide on patients with AUD.²² Since semaglutide usage and availability have increased with approved indications for diabetes and obesity, researchers are continuing to investigate this drug class for potential promising new therapies.

Product information

When used for chronic weight management, semaglutide (Wegovy) is approved in addition to a reduced calorie diet and increased physical activity.^{7, 15} Semaglutide is indicated for patients who meet one of the following criteria: BMI of 30 kg/m² or greater, or patients who have a BMI of 27 kg/m² with at least one comorbid weight related condition (cancer, cardiac disease, diabetes, dyslipidemia, obstructive sleep apnea).^{7, 15} Available in a prefilled pen that contains one dose, semaglutide is a clear and colorless liquid that can be injected into the upper arm, lower stomach or upper thigh.⁷ Semaglutide should be stored in the refrigerator between 36°F to 46°F (2°C to 8°C).⁷ If the pen has been frozen, exposed to light, or heat above 86°F (30°C), the pen should be discarded. The pen remains stable and active for 28 days once removed from refrigeration. Each pen contains the exact dose to be delivered with the needle located inside each pen, therefore each pen should be disposed of in a sharps container.⁷

Drug shortages, alternatives for therapy

Shortly after marketing Wegovy, the facility hired by Novo Nordisk to fill syringes was cited by the FDA for issues with current good manufacturing processes.^{23, 24} As a result, deliveries and manufacturing of Wegovy was halted in December of 2021.²⁴ At the same time, staggering demand for the drug was reported by the manufacturer mainly due to news and social media platforms announcing the success of several celebrity weight loss stories. As a result of the Wegovy shortage, prescribers started to write for Ozempic off label in an effort to treat obesity and therefore depleted the supplies of Ozempic.²⁴ At the end of 2022 and early 2023, Novo Nordisk announced that supply issue resolution for Wegovy was on the horizon and that production of the drug was being increased. Due to residual and increasing demand though, some supply issues might continue sporadically but over time distribution centers and pharmacies should receive more drug product in the months ahead.²⁵

CONCLUSION

Probably the first drug to be considered a social media sensation, semaglutide’s entrance into the realm of prescription weight loss treatments has been filled with anticipation, fame, demand, intrigue, and acceptance. Lifestyle management will continue to play a role in losing and maintaining weight loss, with or without a GLP-1RA used in treatment for weight management. Long term use of semaglutide seems to be necessary to maintain a healthy weight but more research is necessary. Gastrointestinal side effects are seen as the most prevalent adverse effect, leading some patients to discontinue the drug. As availability of semaglutide increases due to resolution of the issues that halted production, price, and lack of coverage by insurance plans continues to be problematic for some patients. This is an area where pharmacy technicians can help by looking for coupons or patient assistance programs.

Researchers continue to investigate the various effects seen as a result of usage of semaglutide. Investigators are hopeful of finding new treatments for patients that are struggling with alcohol use disorder and addictive behaviors. GLP-1RAs will continue to be in the headlines for years to come. Pharmacists and technicians hold the golden ticket of information by helping patients and providers understand this unique class of medication’s history, mechanism of action, dosing, side effects, storage requirements, pricing and potential treatments being investigated.

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