What's behind the variable responses to semaglutide for weight loss?

If you or someone you know has tried semaglutide for weight loss, it's possible you've encountered stories or experienced first-hand the powerful effect of this drug on efforts to achieve weight loss goals. A portion of patients, however, do not experience their desired outcomes despite titrating up to the highest dose. What do we know about why semaglutide is remarkably effective for some patients and has a minimal impact for others?

While clinical trials evaluating the safety and efficacy of semaglutide for weight loss report unprecedented positive results compared to alternative anti-obesity medications, there is also a percentage of trial participants who have a lower response or no response to therapy. To date, nine Semaglutide Treatment Effect in People with Obesity (STEP) trials have been performed. Per a review published in June 2024 in the medical journal Frontiers in Endocrinology, the STEP trials consistently show patient populations have a wide variability in response to semaglutide for weight loss, with 32-40% being “super-responders” and losing in excess of 20% body weight, and about 10-17% being “non-responders,” losing less than 5% body weight from baseline.1

The cause(s) of different degrees of response to semaglutide for weight loss have not been studied. It is speculated that genetics, metabolic parameters, and demographics play a role in the variability of responses. Some individuals inherit a genetic characteristic known as the “hungry gut” phenotype, resulting in reduced levels of satiety after eating and faster gastric emptying compared to the general population.1 These individuals tend to respond more favorably when treated with glucagon-like peptide 1 (GLP-1) agonists and experience higher levels of weight loss with semaglutide, a GLP-1 agonist. Pre-diabetes and type 2 diabetes are metabolic characteristics that may be predictive of a lower response to semaglutide therapy. The mean body weight decrease in patients without diabetes was 14.9% versus 9.6% in patients with diabetes treated with semaglutide.1 Lastly, the STEP trials reveal gender may be a factor in predicting a patient's response. Men have lower degrees of weight loss on semaglutide (average 8-9.3% weight loss in men versus 14-16.2% in females).1 Future trials are needed to create tools for identifying super-responders and non-responders to guide personalized treatment decisions.

Tirzepatide (a dual GLP-1 and gastric inhibitory polypeptide (GIP) agonist) may be an option for semaglutide non-responders, although more research is necessary for tirzepatide to gain an FDA indication for this purpose. The SURMOUNT-1 trial demonstrated tirzepatide therapy resulted in clinically-meaningful weight loss (at least 5%) in 89-91% participants on the 10 or 15 mg dose.2 This trial excluded patients with diabetes. In the subsequent SURMOUNT-2 trial, tirzepatide was studied in patients with diabetes and 79-83% patients achieved 5% weight loss or more on the 10 or 15 mg dose.3 Comparatively, patients receiving semaglutide 2.4 mg (the highest dose studied) achieved 5% weight loss or more in 86.4% patients without diabetes4 and in only 68.8% patients with diabetes.5 It is tempting to conclude that male patients with type 2 diabetes may have a better chance of achieving weight loss goals with tirzepatide rather than semaglutide based on these data. However, the authors of the SURMOUNT-1 trial emphasize a direct comparison between semaglutide and tirzepatide based on the available data is not possible due to differences in study populations and design.

Do you have additional questions about semaglutide, tirzepatide, or the compounded products available at our pharmacy? You can fill out our interest form here and one of our pharmacists will reach out with more information.

Citations

1. Tzoulis P, Baldeweg SE. Semaglutide for weight loss: unanswered questions. Front Endocrinol (Lausanne). 2024 Jun 5;15:1382814. DOI: 10.3389/fendo.2024.1382814. PMID: 38904050; PMCID: PMC11188346.

2. Jastreboff A, et al. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). N Engl J Med. 2022 June 4; 387:205-216. DOI: 10.1056/NEJMoa2206038.

3. Garvey WT, et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2023 Aug 19;402(10402):613-626. doi: 10.1016/S0140-6736(23)01200-X. Epub 2023 Jun 26. PMID: 37385275.

4. Wilding J, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP-1). N Engl J Med 2021 Feb 10; 384:989-1002. DOI: 10.1056/NEJMoa203218.

5. 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. Davies, Melanie et al. The Lancet, Volume 397, Issue 10278, 971 - 984