Semaglutide in obesity

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist targeting areas of the brain that regulate appetite and food intake (1)

NICE has recommended semaglutide as an option for weight management - weight loss and weight maintenance. This is alongside a reduced-calorie diet and increased physical activity in adults. The criteria for use are (2):

• Must be used in a specialist weight management service.
• Must have BMI of >35 kg/m².
• Must have BMI 30-30.4 kg/m² and a condition that can be improved with weight management, such as diabetes.
• Lower BMI thresholds (lower by 2.5 kg/m²) for those in at-risk groups such as people from South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean family backgrounds. These groups have a higher risk of diabetes and heart disease at lower thresholds of obesity.
• the company provides semaglutide according to the commercial arrangement
• a maximum of 2 years use
• Consider stopping semaglutide if less than 5% of the initial weight has been lost after 6 months of treatment

In the OASIS 1 study (3):

• in adults with overweight or obesity without type 2 diabetes, oral semaglutide 50 mg once per day led to a superior and clinically meaningful decrease in bodyweight compared with placebo
  • estimated mean bodyweight change from baseline to week 68 was -15.1% with oral semaglutide 50 mg versus -2.4% with placebo
  • gastrointestinal adverse events (mostly mild to moderate) were reported in 268 (80%) participants with oral semaglutide 50 mg and 154 (46%) with placebo

Use of glucagon like peptide-1 (GLP-1) receptor agonists for weight loss has been linked to an increased risk of pancreatitis, gastroparesis, and bowel obstruction (4)

• study evidence showed that GLP-1 agonists are associated with increased risk of pancreatitis (HR 9.1), bowel obstruction (HR 4.2) and gastroparesis (HR 3.7) when compared with bupropion-naltrexone for weight loss
  • based on a comparison of outcomes in 4144 non-diabetic patients using liraglutide, 613 using semaglutide and 654 using bupropion-naltrexone, it was calculated that the incidence of biliary disease was 18.6 per 1000 person-years for liraglutide, 11.7 for semaglutide and 12.6 for bupropion. For pancreatitis the incidence rates were 7.9, 4.6 and 1.0 respectively

The STEP7 study (n=375) (5):

• investigated the use of once weekly GLP-1 receptor agonist semaglutide 2.4 mg for weight management in people from east Asia
  • found semaglutide 2.4mg/week resulted in greater weight loss at 44 weeks vs placebo (estimated mean percentage weight change −12.1% [SE 0.5] vs −3.6% [0.7]) and greater proportion of patients with loss of ≥5% bodyweight (85% vs 31% placebo)
  • study authors noted that results of this study support the use of semaglutide 2·4 mg for weight management in people of east Asian ethnicity with overweight or obesity and with or without type 2 diabetes

Note:

• Semaglutide has also demonstrated cardiovascular benefits; RCT data showed that in adults aged 45 and older with overweight or obesity who have concurrent cardiovascular disease (but no history of diabetes), semaglutide reduces the overall risk of major cardiac events (heart attack, stroke, or cardiovascular death) by 20% at a mean follow-up of 40 months (6).
• Some evidence suggests that overall weight loss with semaglutide may include both a reduction in adiposity as well as a reduction in fat-free mass (a surrogate marker for muscle mass); however, the long-term implications of this are currently unclear (7).

References

1. Bergmann NC, Davies MJ, Lingvay I, et al. Semaglutide for the treatment of overweight and obesity: a review. Diabetes Obes Metab. 2023 Jan;25(1):18-35.
2. NICE. Semaglutide for managing overweight and obesity. Technology appraisal guidance TA875. Published: 08 March 2023. Last updated: 04 September 2023
3. Knop FK et al. Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet June 25, 2023
4. Mahase E. GLP-1 agonists linked to adverse gastrointestinal events in weight loss patients BMJ 2023; 383 :p2330 doi:10.1136/bmj.p2330
5. Mu Y et al. Efficacy and safety of once weekly semaglutide 2·4 mg for weight management in a predominantly east Asian population with overweight or obesity (STEP 7): a double-blind, multicentre, randomised controlled trial. Lancet Diabetes and Endocrinology February 05, 2024
6. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023 Dec 14;389(24):2221-32.
7. Ida S, Kaneko R, Imataka K, et al. Effects of antidiabetic drugs on muscle mass in type 2 diabetes mellitus. Curr Diabetes Rev. 2021;17(3):293-303.