Understanding GLP-1 Receptor Agonists (Ozempic, Wegovy, and Others)

GLP-1 receptor agonists (GLP1-RAs) have gained popularity due to their effectiveness in managing type 2 diabetes and promoting weight loss. Originally developed to reduce blood glucose in type 2 diabetes only, research published in the New England Journal of Medicine documenting the powerful weight loss effects of the active ingredient semaglutide began the movement to prescribe GLP-1 receptor antagonists as an off-label weight-loss drug.

This class of medications function by mimicking the hormone GLP-1, a peptide hormone secreted by the L cells in the small intestine. In response to food intake, GLP-1 crosses the blood brain barrier and signals directly to the hypothalamus to reduce hunger signals to slow the ingestion of calories. 

In addition, GLP-1 activates stretch receptors in the small intestine, which in turn signal to the hypothalamus to reduce appetite and increase energy expenditure. Additionally, GLP-1 helps reduce blood glucose concentrations by stimulating pancreatic insulin secretion. 

GLP-1 RA Research

In 2021, researchers from Northwestern University published the landmark STEP-1 trial in the New England journal of Medicine (1). The study investigated the effect of once-weekly 2.4mg semaglutide injection in 1961 non-diabetic patients with either (a) a BMI of 30 or higher, or (b) a BMI of 27 along with weight-related comorbidities. 

Researchers discovered that after 68-weeks, those who received semaglutide experienced an average weight loss of 14.9%, while those who received a placebo injection experienced a weight change of only 2.4%. In total, 86.4% of the semaglutide group lost a minimum of 5% of their bodyweight, with minimal adverse effects.

The STEP 2 trial, published in The Lancet, investigated the effect of a standard 1.0 mg dose of semaglutide vs. a higher 2.4 mg dose in comparison with matched placebos over 68 weeks in 1210 participants (2). A 2.4 mg weekly injection resulted in 9.64% weight loss, a 1.0 mg weekly injection resulted in 6.99% weight loss, and a placebo injection resulted in 3.42% weight loss. The higher dose also achieved slightly better glycemic control, reductions in cardiometabolic risk, and improved physical function relative to the standard dose.

In the STEP 3 trial, 611 participants were randomly assigned to receive either semaglutide 2.4 mg or placebo in addition to intensive behavioral therapy to support a healthier lifestyle (3). Their results demonstrated that those who received semaglutide experienced an average weight reduction of 16.0% after 68 weeks, compared to 5.7% for those receiving placebo. Additionally, 86.6% of those treated with semaglutide achieved a 5% reduction in bodyweight, compared with 47.6% of those receiving placebo.

In the STEP-4 trial, 902 participants received semaglutide 2.4 mg for the initial 20 weeks, and were then randomly assigned to receive either (a) semaglutide or (b) a placebo for the remaining 48 weeks (4). Those who continued taking semaglutide lost an additional 7.9% body weight, resulting in a total weight loss of 17.4% over the entire trial. Those who switched to the placebo regained an average of 6.9% of their initial weight, resulting in a total weight loss of 5.0%.

The STEP-5 trial, published in Nature Medicine, evaluated the long-term efficacy of semaglutide 2.4 mg versus placebo in maintaining weight loss over a 2-year period in 304 participants (5). The study found that semaglutide resulted in significant weight loss until week 60, with the effects maintained through week 104. At the end of the 2-year period, there was an average placebo-corrected weight loss of 12.6%.

These investigations provided strong evidence that semaglutide is an effective therapy for both weight loss and type 2 diabetes, and the combined benefits have led to a surge in prescriptions, reaching approximately 40 million in the U.S. in 2022.

GLP1-RA Side Effects

While weight loss can bring about significant health benefits, it’s important to note that rapid weight loss can have negative consequences, including a decrease in muscle mass, lower bone density, a decrease in resting metabolic rate (RMR). The combined effects can increase the risk for sarcopenia – the gradual loss of muscle mass, strength, and function.

Physiologists have discovered that when people lose weight, about 25-30% of their weight loss is lean muscle mass, and the remainder is a reduction in fat mass. In the STEP-1 study, patients treated with semaglutide lost nearly 14 kg in total, with 8.5 kg (60%) being fat loss and 5 kg (38%) being lean mass loss, which exceeds normal physiological expectations.

However, it’s important to note that the DEXA scans used to measure body composition may not be perfect in distinguishing between lean mass and adipose tissue, and the placebo group in the study lost more lean mass (-1.83kg) than fat mass (1.37kg), which could indicate potential error.

An analysis of 18 randomized control trials comparing the effects of GLP-1 RAs, SGLT-2 inhibitors, and Metformin demonstrated that semaglutide, dapagliflozin, ipragliflozin, and canagliflozin showed a significant weight loss in comparison with placebo treated controls (6). 

In addition to lean body mass loss, other gastrointestinal side effects have also been observed including constipation, diarrhea, nausea, vomiting, and abdominal pain, feeling excessively full, excessive bloating and belching, and heartburn. 

Researchers from British Columbia analyzed a random sample of 16 million patients from the PharMetrics Plus for Academics database (IQVIA), a large health claims database that captures 93% of all outpatient prescriptions and physician diagnoses in the US between the years 2006-2020. They included patients with a recent history of obesity, and excluded those with diabetes or who had been prescribed another antidiabetic drug.

They found that the administration of GLP-1 agonists is associated with a:

• 9.09 times higher risk of pancreatitis (inflammation of the pancreas)
• 4.22 times higher risk of bowel obstruction (a condition characterized by the obstruction of food passage through the small or large intestine, leading to symptoms such as abdominal cramping, bloating, nausea, and vomiting)
• 3.67 times higher risk of gastroparesis (stomach paralysis, a condition that restricts the passage of food from the stomach to the small intestine, resulting in symptoms such as vomiting, nausea, and abdominal pain)

These results are similar to those of a study investigating the long-acting GLP-1 RA liraglutide. A 16-week randomized study demonstrated that liraglutide significantly delayed the gastric emptying of solids over a 16 week period (7).

Take Home Message

While the weight loss effects of GLP-1 RAs are powerful, caution should be exercised when prescribing this class of medications to those trying to lose weight or reduce their blood glucose, due to their extensive list of unwanted side effects.

Research has demonstrated that the most effective way to lose weight and keep it off in the long-term is via lifestyle modification, including a low-fat, low-energy diet containing between 1,300-1,700 kcal per day (8). Interestingly, another study identified that in a population that lost an average of 30 kg for 5.5 years, only 4.3% reported using medication as part of their weight loss strategy (9).

A systematic review published in 2019 demonstrated that the most frequently reported habits of those successful at long-term weight loss and maintenance included having healthy foods available at home, regular breakfast intake, increasing vegetable consumption, decreasing sugary and fatty foods, limiting certain foods, and reducing fat in meals. They also found that increased physical activity was the most accurate predictor of weight loss maintenance (10). 

In conclusion, while GLP-1 RAs have shown promise in improving glycemic control and weight loss in individuals with type 2 diabetes, lifestyle modification is likely to be a more effective long-term solution. The benefits of lifestyle modification, such as improved insulin sensitivity, weight loss, and reduced risk of cardiovascular disease, are not limited to the short-term and can have a lasting impact on overall health. Additionally, lifestyle modification can be more cost-effective and has fewer side effects compared to GLP-1 RAs.

While GLP-1 RAs may be a useful tool in the short-term, they should always be used in conjunction with lifestyle modification to achieve optimal results. By combining the benefits of both approaches, overweight individuals or those living with type 2 diabetes can achieve better glycemic control, weight loss, and improved overall health. 

Ultimately, a comprehensive approach to managing type 2 diabetes that includes lifestyle modification and GLP-1 RAs, if necessary, is likely to be more effective in the long-term.

Author Bio:

Cyrus Khambatta, PhD is the New York Times bestselling co-author of Mastering Diabetes, and has helped more than 10,000 people reverse the underlying cause of insulin resistance. He earned a Bachelor of Science in Mechanical Engineering from Stanford University in 2003, as well as a PhD in Nutritional Biochemistry from the University of California at Berkeley in 2012.

He is the co-founder of Mastering Diabetes and Amla Green, and is an internationally recognized nutrition and fitness coach who has been living with type 1 diabetes since 2002. In 2022, Mastering Diabetes was acquired by the health and wellness company Love.Life, to complement its medically supervised offerings with coaching services that combat various chronic health conditions.

References

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2. Davies M, Færch L, Jeppesen OK, Pakseresht A, Pedersen SD, Perreault L, et al. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. The Lancet. 2021 Mar 13;397(10278):971–84. 
3. Wadden TA, Bailey TS, Billings LK, Davies M, Frias JP, Koroleva A, et al. Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial. JAMA. 2021 Apr 13;325(14):1403–13. 
4. Rubino D, Abrahamsson N, Davies M, Hesse D, Greenway FL, Jensen C, et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA. 2021 Apr 13;325(14):1414–25. 
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8. 1. Shick SM, Wing RR, Klem ML, McGuire MT, Hill JO, Seagle H. Persons successful at long-term weight loss and maintenance continue to consume a low-energy, low-fat diet. J Am Diet Assoc. 1998 Apr;98(4):408–13. 
9. 1. Klem ML, Wing RR, McGuire MT, Seagle HM, Hill JO. A descriptive study of individuals successful at long-term maintenance of substantial weight loss. Am J Clin Nutr. 1997 Aug 1;66(2):239–46. 
10. 1. Paixão C, Dias CM, Jorge R, Carraça EV, Yannakoulia M, de Zwaan M, et al. Successful weight loss maintenance: A systematic review of weight control registries. Obesity Reviews. 2020;21(5):e13003.