Semaglutide Mechanism of Action and Benefits in Type 2 Diabetes and Obesity
Semaglutide is a GLP-1 receptor agonist that significantly improves outcomes in type 2 diabetes and obesity through multiple mechanisms including glucose-dependent insulin stimulation, glucagon suppression, delayed gastric emptying, and appetite suppression, with demonstrated cardiovascular benefits and substantial weight loss effects. 1
Mechanism of Action
- Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1 that selectively binds to and activates the GLP-1 receptor, which is the target for native GLP-1 1
- The principal mechanism of protraction resulting in semaglutide's long half-life (approximately 1 week) is albumin binding, which decreases renal clearance and protects against metabolic degradation 1
- Semaglutide is modified in position 8 to provide stabilization against degradation by the dipeptidyl peptidase-4 (DPP-4) enzyme 1
- GLP-1 receptors are expressed in multiple organs, including pancreas, gastrointestinal tract, heart, brain, kidney, lung, and thyroid, explaining the pleiotropic benefits of semaglutide 2, 3
Glycemic Control Mechanisms
- Semaglutide reduces blood glucose through multiple mechanisms: 1
- Stimulates insulin secretion in a glucose-dependent manner
- Lowers glucagon secretion in a glucose-dependent manner
- Delays gastric emptying in the early postprandial phase
- Both first- and second-phase insulin secretion are increased in patients with type 2 diabetes treated with semaglutide compared with placebo 1
- Semaglutide lowers fasting glucagon by 8%, postprandial glucagon response by 14-15%, and mean 24-hour glucagon concentration by 12% compared to placebo 1
- The glucose-dependent nature of insulin stimulation and glucagon suppression explains the low likelihood of hypoglycemia with GLP-1 receptor agonists 2
Benefits in Type 2 Diabetes
- Semaglutide significantly reduces HbA1c in patients with type 2 diabetes 3
- In patients with type 2 diabetes, treatment with semaglutide 1 mg resulted in reductions of 29 mg/dL (22%) for fasting glucose, 74 mg/dL (36%) for 2-hour postprandial glucose, and 30 mg/dL (22%) for mean 24-hour glucose concentration compared to placebo 1
- Semaglutide may promote β-cell proliferation and protect against apoptosis, potentially preserving pancreatic function 2
- GLP-1 receptor agonists are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment 4
Weight Loss Benefits
- Semaglutide produces substantial weight loss in both diabetic and non-diabetic populations 2
- In the STEP trial, weekly semaglutide (2.4 mg) reduced mean body weight from baseline by 14.9% in patients who were non-diabetic, overweight or obese 2
- Weight loss with semaglutide is greater in those without diabetes (mean weight loss 6.1–17.4%) compared with patients with diabetes (4–6.2%) 2
- Prior to semaglutide, this degree of weight loss had only been reported with bariatric surgery 2
Cardiovascular Benefits
- The cardioprotective effects of GLP-1 receptor agonists are mediated by several mechanisms: 2
- Improved myocardial substrate utilization
- Anti-inflammatory and anti-atherosclerotic effects
- Reduced myocardial ischemia injury
- Lower systemic and pulmonary vascular resistance
- Improved lipid profiles
- In the SUSTAIN 6 trial, the primary outcome of cardiovascular death, non-fatal myocardial infarction or stroke occurred in 6.6% of patients in the semaglutide group compared with 8.9% of patients in the placebo group (RR 0.74,95% CI 0.58–0.95) 2
- In a randomized double-blind study of non-diabetic patients with pre-existing cardiovascular disease and BMI > 27, the primary cardiovascular endpoint occurred in 6.5% of patients allocated to semaglutide compared with 8.2% of patients in the placebo group (p = 0.001) 2
Administration and Pharmacokinetics
- Semaglutide is administered as a subcutaneous injection once weekly 3
- Absolute bioavailability of semaglutide is 89%, with maximum concentration reached 1 to 3 days post dose 1
- Similar exposure is achieved with subcutaneous administration in the abdomen, thigh, or upper arm 1
- With an elimination half-life of approximately 1 week, semaglutide remains in the circulation for about 5 weeks after the last dose 1
Adverse Effects and Safety Considerations
- Nausea, vomiting, and diarrhea are the most frequently reported adverse effects of GLP-1 receptor agonists 2
- These gastrointestinal side effects are dose-dependent and more frequent with short-acting than long-acting drugs 2
- Slow titration is helpful in increasing gastrointestinal tolerability 2
- Acute pancreatitis, a rare adverse effect, has been linked to GLP-1 receptor agonists 2
- Current guidelines recommend using GLP-1 receptor agonists with caution in patients with a history of pancreatitis 2
- Semaglutide is contraindicated in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 based on animal studies 2
Clinical Implications
- Semaglutide offers multiple benefits beyond glycemic control, including substantial weight loss and cardiovascular protection, making it an excellent choice for patients with type 2 diabetes, especially those with obesity or cardiovascular risk factors 3, 5
- The once-weekly administration improves convenience and potentially adherence compared to medications requiring more frequent dosing 4
- When initiating semaglutide, gradual dose titration is essential to mitigate gastrointestinal side effects 2
- Weight regain occurs after cessation of treatment, highlighting the need for long-term use 3