W. Marshall Fettig

Background: Type 2 Diabetes Mellitus (T2DM) is a major health problem worldwide, characterized by persistent hyperglycemia, and associated with both long and short-term complications. T2DM affects approximately 374 million adults aged 20-79 worldwide,¹ and its impact on the US economy was estimated at $327 billion in 2017.² Semaglutide, a glucagon-like peptide-1 receptor agonist, has been approved as a treatment for T2DM, as well as for weight management in obesity. SGLP-1 receptor agonists have been shown to significantly reduce overall body mass and improve lipid profiles. In fact, High-dose Semaglutide has demonstrated efficacy in increasing total % weight loss over placebo and low-dose Semaglutide. Weight reductions were accompanied by improved HbA1c and improved comorbidity risk factors.^2,6

Objective: The literature at present is unclear on the mechanisms at play producing the ancillary benefits of semaglutide and similar agents. Specifically the pathogenesis and disease progression of the significant comorbidities associated with diabetes mellitus. Additionally, durability of the effect of GLP-1 receptor agonists and the effects of similar agents on body composition should be seriously considered while weighing the worth of these agents.

Search Methods: MeSH searches were conducted using the PubMed database for “diabetes mellitus” and “weight loss”, “diabetes mellitus” and “weight loss”, and “diabetes mellitus” with “pharmacologic therapies.” Sources were further assessed for impact factor and study design independently during the selection process.

Results: Genome wide association studies were used to identify correlations between genomic variations and the development of either form of DM. The role of Endoplasmic Reticulum (ER) stress in the progression of both forms of DM is being explored, and studies suggest that targeting ER stress may be a novel common pathway for the protection β-cell mass in T1DM and T2DM.³ Pancreatic β-cells are susceptible to ferroptosis, and low expression of antioxidant enzymes renders these cells particularly vulnerable to oxidative stress.⁴ Semaglutide administration was also found to be effective in reducing hepatic steatosis in mice.⁵

Conclusions: While the pathologic progression of DM and the pathogenesis of hepatic steatosis are not yet fully understood, Semaglutide has been shown to be a promising therapy for both conditions. The remarkable effects of these agents certainly bear the weight of further investigation, however, great caution is still necessary. The durability of effect, changes in body composition, and cost must be considered on a case-by-case basis as these agents are not necessarily the panacea that they have been portrayed to be.

Work Cited:

1. Goyal R, Jialal I. Diabetes Mellitus Type 2. [Updated 2022 Jun 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK513253/
2. Davies M, Færch L, Jeppesen OK, et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomized, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet.
3. Eizirik DL, Pasquali L, Cnop M. Pancreatic β-cells in type 1 and type 2 diabetes mellitus: different pathways to failure. Nat Rev Endocrinol. 2020;16(7):349-362. doi:10.1038/s41574-020-0355-7
4. Sha W, Hu F, Xi Y, Chu Y, Bu S. Mechanism of Ferroptosis and Its Role in Type 2 Diabetes Mellitus. J Diabetes Res. 2021;2021:9999612. Published 2021 Jun 28. doi:10.1155/2021/9999612
5. Li R, Ye Z, She D, et al. Semaglutide May Alleviate Hepatic Steatosis in T2DM Combined with NFALD Mice via miR-5120/ABHD6. Drug Des Devel Ther. 2022;16:3557-3572. Published 2022 Oct 12. doi:10.2147/DDDT.S384884
6. Tsapas A, Avgerinos I, Karagiannis T, et al. Comparative Effectiveness of Glucose-Lowering Drugs for Type 2 Diabetes: A Systematic Review and Network Meta-analysis. Ann Intern Med. 2020;173(4):278-286. doi:10.7326/M20-0864