Semaglutide, the Magic Pill Against Obesity: Truth or Fallacy?

• Pharmacological treatments for adults with a body mass index (BMI) ≥ 30kg/m² or ≥ 27kg/m² in those with an obesity-related comorbidity can provide a valuable adjunct to diet and exercise.
• Semaglutide is a GLP-1 agonist recently approved for obesity treatment and is the most effective among the other FDA-approved anti-obesity medications.
• The main side effects of semaglutide administration are transient and mild-to-moderate gastrointestinal (GI) symptoms.
• Semaglutide administration can lead to significant losses of muscle mass and considerable loss of total and visceral fat mass.

Obesity is a highly prevalent, multifactorial, chronic, relapsing disease that affects 650 million adults globally, translating into approximately 30% of men and 35% of women. Obesity requires long-term management and is associated with several physical and mental health complications. Specifically, it can lead to insulin resistance and type-2 diabetes, hypertension, dyslipidemia, cardiovascular disease, obstructive sleep apnea, and nonalcoholic fatty liver disease (NAFLD). It is also associated with reduced life expectancy, mainly due to cardiovascular morbidity and mortality.

Although lifestyle intervention (diet and exercise) represents the cornerstone of obesity management, sustaining weight loss over the long term is challenging. Most overweight or obese people typically achieve only modest weight loss that is often regained, thus going through countless weight loss failures. Notably, it has been demonstrated that weight loss through lifestyle modification usually plateaus at a level of 5%-10% and is associated with a high risk of relapse, which may be related to metabolic adaptation. Although weight loss of 5%-10% is linked to improvements in cardiovascular risk factors, type-2 diabetes, and quality of life, weight losses beyond 10% produce even greater health benefits, including remission of type-2 diabetes and reductions in cardiovascular (CVD) events. As such, weight loss of ≥ 10%-15% is recommended in people with complications of overweight and obesity, such as cardiovascular disease, osteoarthritis, obstructive sleep apnea, NAFLD, and type-2 diabetes.

Therefore, pharmacological treatments for people unable to achieve such weight loss goals only with a comprehensive weight loss program provide a valuable adjunct to lifestyle interventions. Clinical guidelines suggest adjunctive pharmacotherapy (anti-obesity medications) with a reduced calorie diet and increased physical activity for adults with a body mass index (BMI) ≥ 30kg/m² or ≥ 27kg/m² in those with an obesity-related comorbidity such as type-2 diabetes, hypertension, or dyslipidemia.

The current medications approved for chronic weight management in the US or Europe are orlistat, phentermine-topiramate, naltrexone-bupropion, liraglutide 3.0 mg, and semaglutide 2.4 mg. While the first four generally produce an average of 4%-8% greater weight loss than lifestyle interventions alone (2.6 kg to 8.8 kg in one year), semaglutide appears to increase this value to 15%, translating into a mean weight loss of 12.5kg from baseline weight after 68 weeks. Semaglutide given for two years resulted in substantial and sustained changes in body weight versus lifestyle interventions alone (-15.2% vs. -2.6%), encouraging long-term weight loss maintenance. Taken together, results show semaglutide to be the most effective currently approved for weight loss in adults with overweight or obesity.

Both liraglutide and semaglutide are glucagon-like peptide-1 (GLP-1) agonists. GLP-1 is a gut hormone released in response to food intake, acting as a satiety signal in the brain, thus regulating energy homeostasis. Moreover, it controls glucose metabolism by stimulating insulin release and inhibiting glucagon secretion. For chronic weight management, liraglutide is administered subcutaneously at a dose of 3.0 mg daily. In comparison, semaglutide has a more long-acting effect and is administered subcutaneously at a dose of 2.4 mg weekly. Although both have been shown to reduce energy intake, decrease hunger and food cravings as well as increase feelings of satiety, semaglutide has the most potent effect.

Liraglutide was the first GLP-1 agonist approved by the Food and Drug Administration (FDA) for chronic weight management after demonstrating weight losses of 4%-6% over that achieved with lifestyle intervention alone after 20-56 weeks. Semaglutide, on the other hand, was initially approved by the FDA in 2017 under the brand name Ozempic for the treatment of type-2 diabetes and for reducing classical cardiovascular risk factors (e.g., blood pressure, lipid levels), thus the risk of cardiovascular events in persons with type-2 diabetes and cardiovascular disease. Moreover, a once-daily oral version of the medication, at a maximum dose of 14 mg, was approved for treating type-2 diabetes in the US in 2019 and in Europe in 2020. Semaglutide lowers blood glucose and improves HbA1c via stimulating insulin and suppressing glucagon secretion in a glucose-dependent manner, leading to lower blood glucose levels with a low risk for hypoglycemia.

In June 2021, the FDA approved semaglutide as an adjunct to reduced calorie intake and increased physical activity for chronic weight management since scientific evidence demonstrated an extra 12.4% weight loss compared with other anti-obesity medications. Weight loss with semaglutide was also accompanied by greater improvements with respect to cardiometabolic risk factors, including reductions in waist circumference, blood pressure, glycated hemoglobin levels (HbA1c), and lipid levels as well as a greater decrease in C-reactive protein (CRP), a marker of inflammation. Therefore, it is becoming evident that semaglutide can be very useful for people with overweight and obesity complications (e.g., prediabetes, hypertension, and obstructive sleep apnea) who require weight losses of 10% to 15% or more to alleviate these complications.

Currently, once-weekly subcutaneous semaglutide 2.4 mg is approved for use in Canada, Europe, the UK, and the USA under the brand name Wigovy as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adults with obesity (BMI ≥30kg/m²) or overweight (initial BMI ≥27kg/m²) with at least one weight-related comorbidity.

Growing data has demonstrated the efficacy and tolerability of once-weekly subcutaneous semaglutide 2.4 mg in individuals who are overweight or obese. The main side effect is the possibility of GI symptoms, which are typically transient and mild-to-moderate in severity. The chief safety issues with drugs of this class are the rare occurrence of pancreatitis and a prohibition of use in patients with a personal or family history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma.

Another safety issue that has emerged and deserves discussion is the quality of weight loss with semaglutide. The usual proportion of lean mass loss in total weight loss is 25%. In the semaglutide-treated participants, a mean loss of 8.36 kg of total body fat mass and 5.26 kg of total body lean mass was observed, meaning that lean mass accounted for approximately 39% of total weight, substantially higher than ideal. Intriguingly, this average proportion was also applicable to even less total weight loss, meaning that in cases of <15% weight loss, muscle mass loss may be even equal to fat mass loss. This is concerning since a decrease in muscle mass is associated with an increased risk of sarcopenia and frailty, especially in older patients, with a higher likelihood of weight regain after weight loss as well as with an increased risk for elevated blood glucose levels, thus type-2 diabetes. Therefore, it is preferable to predominantly reduce body fat without significant loss of muscle mass when losing weight. The fact that semaglutide results in increased losses in muscle mass also does not take away the significant decreases in total fat mass (-19.3% from baseline) and visceral fat mass (-27.4% from baseline). It just highlights the importance of diet and physical activity, which should always be the first line of treatment for obesity, and even in cases where the criteria of pharmacological interventions are met, to complement the medical prescription closely.

Overall, semaglutide and other anti-obesity medications are not a panacea and should only be used by obese adults with a body mass index (BMI) ≥ 30kg/m² or overweight adults with a BMI ≥ 27kg/m² with at least one obesity-related comorbidity. Moreover, the importance of combining lifestyle modifications such as dietary and physical activity should not be ignored in obesity treatment. Dietary modification and physical activity of at least 150-250 minutes/week are fundamental for the long-term management of obesity and should always be prioritized or at least be utilized adjunctively to pharmacotherapy.

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