Introduction

Semaglutide has been developed based on the vast body of research behind the development of liraglutide. Compared to liraglutide, which is administered once daily, semaglutide has an even longer half-life, allowing for once weekly administration. While a significant improvement over once or twice daily subcutaneous administration, the injecting route could be a barrier for some potential users.[1] Semaglutide 2.4 mg administered subcutaneously once weekly, was approved by the FDA in 2021 as an adjunct to reduced calorie intake and increased physical activity for chronic weight management in adults with obesity (initial BMI ≥30 kg/m 2 ) or overweight (initial BMI ≥27 kg/m 2 ) with at least one weight-related comorbidity. [2] Once-weekly subcutaneous semaglutide 1.0 mg was approved by the US FD FDA in 2017 and the E EMA in 2018 for the treatment of type 2 diabetes. 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.[3] The dose of semaglutide for weight management is 2.4 mg injected subcutaneously once weekly (on the same day each week, with or without meals). This dose was selected based on a phase 2 clinical trial in which greater weight loss was achieved with once-daily semaglutide, 0.4 mg (equal to 2.8 mg weekly), than with placebo or liraglutide 3.0 mg/day.[4] It is available in single-use, prefilled pens. The initial dose is 0.25 mg, administered by subcutaneous injection in the abdomen, thigh, or upper arm once weekly for 4 weeks. The dose is increased in 4-week intervals (over a total of 16 weeks) until a dose of 2.4 mg per week is reached.[5]

Mechanisms of action for weight loss

Semaglutide is a long-acting GLP-1 receptor agonist with 94 percent homology with native human GLP-1. It has structural modifications to allow for reversible albumin binding, reducing renal clearance and decreasing degradation by DPP-4, while also allowing for sufficiently high GLP-1R affinity. This formulation results in slower degradation and a half-life 155 to 184 hours, allowing for once-weekly subcutaneous dosing without compromising weight loss e?cacy. [6-7] Figure. 1 shows theoretical and empirically supported mechanisms of action of semaglutide. Semaglutide promotes insulin secretion from beta cells in the pancreas and decreases glucagon secretion in a glucose-dependent manner. Semaglutide results in weight loss via reduced energy intake with minimal effects on energy expenditure.Compared to placebo, semaglutide 2.4 mg (i.e., once-weekly for 20 weeks) reduced ad libitum energy intake by 35%, as shown with a laboratory meal paradigm.Semaglutide, relative to placebo, also resulted in larger reductions in hunger and food cravings, increased fullness and satiety, and better control of eating. Studies in rodents have also shown that semaglutide has direct and indirect effects on neutral pathways involved in hedonic and homeostatic appetite control. Gastrointestinal effects have been hypothesized to mediate the effects of GLP-1 receptor agonists on weight loss. However, only a very small proportion (<1 percentage point) of weight loss is explained by nausea or vomiting. Delayed gastric emptying could hypothetically contribute to the weight loss effects. However, studies have shown that semaglutide tends to have minimal effects on gastric emptying.  Weight-loss and cardiometabolic efficacy Semaglutide Treatment Effect in People with obesity (STEP) was a pivotal, global phase 3 clinical development program that evaluated semaglutide 2.4 mg once weekly for weight management. [5]

Safety

As with other GLP-1 receptor agonists, the most common side effects with semaglutide are gastrointestinal. In STEP trials 1-3, the percent of participants in the semaglutide 2.4 mg vs placebo groups who experienced nausea was 33.7-58.2% versus 9.2-22.1%; diarrhea was 21.3-36.1% vs 11.9-22.1%; vomiting was 21.8-27.3% vs 2.7-10.8%; and constipation was 17.4-36.9% vs 5.5-24.5%. Most gastrointestinal events were mild-to-moderate in severity, transient, and occurred during the first 20 weeks of treatment during dose escalation. For example, in STEP 3, the median event duration of nausea was 5 days in both groups, vomiting was 2 days in both groups, diarrhea was 3 days in both groups, and constipation was 27 days with semaglutide vs 16 days with placebo. [8] The proportion of patients with premature discontinuation because of adverse events was 5.9-7.0% in the semaglutide groups and 2.9-3.5% in the placebo groups. Gastrointestinal effects were the main adverse-event-related cause of drug discontinuation, accounting for 3.4 to 4.5% of discontinuations in the semaglutide group versus 0 to 1% in the placebo group. Gallbladder-related disorders (primarily cholelithiasis) were reported in 2.6% vs 1.2% of participants on semaglutide vs placebo in STEP 1, 0.2% vs 0.7% of participants in STEP 2, and 4.9% vs 1.5% in STEP 3. Semaglutide is contraindicated in pregnancy and in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2, or known hypersensitivity to semaglutide or any of the components. Rare cases of acute pancreatitis, hypoglycemia, acute kidney injury, diabetic retinopathy in patients with type 2 diabetes, angioedema and anaphylaxis have been reported with semaglutide.

Cardiovascular safety

As with other GLP-1 receptor agonists, semaglutide is associated with increases in heart rate of 1 to 4 beats per minute. Pulse rate should be monitored routinely in patients taking semaglutide, and the medication should be stopped in those with sustained increases. The small mean increase in pulse rate does not appear to adversely affect cardiovascular outcomes, as revealed by results of the Trial to Evaluate Cardiovascular and Other Longterm Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6). In this multicenter, double-blind, cardiovascular outcomes study, 3297 adults with type 2 diabetes and established cardiovascular disease were randomized to receive semaglutide (0.5 mg or 1.0 mg) daily or volume-matched placebo for 104 weeks. The median observation time was 2.1 years. The primary composite outcome – death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – occurred in significantly fewer participants treated by semaglutide (6.6%) than by placebo (8.9%) (HR, 0.74; 95% CI, 0.58 to 0.95; p < 0.001 for noninferiority; p = 0.02 for superiority). Cardiovascular outcomes currently are being investigated in people with obesity with established cardiovascular disease (but not diabetes) in the Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) trial. Participants are randomized to semaglutide 2.4 mg or placebo for 31 to 59 months of treatment. The trial’s primary outcome is time to ?rst occurrence of a composite endpoint consisting of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. An observational, non-interventional survey study, called SELECT-LIFE, will examine the long-term effects of participants taking part in the SELECT trial. SELECT-LIFE will last up to 10 years after the SELECT trial ends.[5,9]

Conclusion

Semaglutide has demonstrated the highest percent weight loss of any obesity medication to date. Several trials of injectable semaglutide are in process, which may expand the global reach of obesity pharmacotherapies, as well as the options for weight management in youth. Over the years, the use of GLP-1RAs has first been associated with several adverse events, which were later mostly nuanced or refuted. As one of the newer agents within the class, the safety of semaglutide—both the subcutaneous and oral formulation— has been scrutinized in the phase 3 programs and CVOTs. Compared with placebo and active comparator, semaglutide induces mostly mild and transient gastrointestinal disturbances, and increases the risk of cholelithiasis.semaglutide, like other GLP-1 RAs, is associated with GI adverse effects, namely nausea and vomiting. More serious adverse effects include pancreatitis and medullary thyroid carcinoma, although thyroid cancers have not been reported in human trials.[10]

References

[1] Smits MM, Van Raalte DH. Safety of Semaglutide. Front Endocrinol (Lausanne). 2021;12:645563. 

[2] Food and Drug Administration. FDA approves new drug treatment for chronic weight management, First Since 2014 2021.

[3] Food and Drug Administration. Victoza? (liraglutide [rDNA origin] injection), solution for subcutaneous use 2010. 

[4] O'Neil PM , Birkenfeld AL , McGowan B , Mosenzon O , Pedersen SD , Wharton S , et al. E?cacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet 2018;392(10148):637–49 .

[5] Chao AM, Tronieri JS, Amaro A, Wadden TA. Semaglutide for the treatment of obesity. Trends Cardiovasc Med. 2023;33(3):159-166. 

[6]  Lau J , Bloch P , Sch?ffer L , Pettersson I , Spetzler J , Kofoed J , et al. Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J Med Chem 2015;58(18):7370–80 .

[7] Knudsen LB , Lau J . The discovery and development of liraglutide and semaglutide. Front Endocrinol (Lausanne) 2019;10:155.

[8] 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;325(14):1403–13 .

[9] Tan HC, Dampil OA, Marquez MM. Efficacy and Safety of Semaglutide for Weight Loss in Obesity Without Diabetes: A Systematic Review and Meta-Analysis. J ASEAN Fed Endocr Soc. 2022;37(2):65-72.

[10] Singh G, Krauthamer M, Bjalme-Evans M. Wegovy (semaglutide): a new weight loss drug for chronic weight management. J Investig Med. 2022;70(1):5-13.