What are the effects of semaglutide (Glucagon-like peptide-1 receptor agonist) in clinical trials?

From the Guidelines

I strongly recommend using semaglutide in clinical trials for its proven benefits in reducing cardiovascular events and improving glycemic control in patients with type 2 diabetes, as demonstrated in the SUSTAIN-6 trial 1.

Key Findings

• The SUSTAIN-6 trial showed that semaglutide reduced the primary outcome of cardiovascular death, nonfatal MI, or nonfatal stroke by 26% compared to placebo (HR 0.74; 95% CI 0.58–0.95; P < 0.001) 1.
• The PIONEER 6 trial also demonstrated that oral semaglutide was noninferior to placebo for the primary composite outcome of cardiovascular death, nonfatal MI, or nonfatal stroke (HR 0.79; 95% CI 0.57–1.11; P < 0.001 for noninferiority) 1.
• Semaglutide has been shown to be effective in reducing cardiovascular events in patients with type 2 diabetes, with a hazard ratio of 0.74 (95% CI 0.58–0.95) compared to placebo 1.

Dosing and Administration

• The recommended starting dose of semaglutide is 0.25 mg subcutaneously once weekly, which can be increased to 0.5 mg weekly after 4 weeks, and further increased to 1 mg weekly if needed and tolerated 1.
• Patients should be advised to stay well-hydrated, eat smaller meals, and avoid fatty foods to minimize gastrointestinal side effects, which are the most common adverse events associated with semaglutide 1.

Mechanism of Action

• Semaglutide works by mimicking GLP-1, which increases insulin secretion, decreases glucagon secretion, slows gastric emptying, and reduces appetite through central effects on the brain, making it effective for both glycemic control in diabetes and weight management in obesity, with additional cardiovascular benefits in high-risk patients 1.

Clinical Implications

• The use of semaglutide in clinical trials has been shown to improve cardiovascular outcomes and reduce the risk of major adverse cardiovascular events in patients with type 2 diabetes, making it a valuable treatment option for this patient population 1.
• The benefits of semaglutide in reducing cardiovascular events and improving glycemic control make it a recommended treatment option for patients with type 2 diabetes, particularly those with established cardiovascular disease or at high risk of cardiovascular events.

From the FDA Drug Label

Semaglutide reduces blood glucose through a mechanism where it stimulates insulin secretion and lowers glucagon secretion, both in a glucose-dependent manner. The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the early postprandial phase. In patients with type 2 diabetes, treatment with semaglutide 1 mg resulted in reductions in glucose in terms of absolute change from baseline and relative reduction compared to placebo 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. Semaglutide lowers fasting and postprandial glucagon concentrations. Semaglutide causes a delay of early postprandial gastric emptying, thereby reducing the rate at which glucose appears in the circulation postprandially.

The effects of semaglutide in clinical trials include:

• Stimulation of insulin secretion and lowering of glucagon secretion in a glucose-dependent manner
• Reduction in blood glucose levels, with absolute changes from baseline of:
  • 29 mg/dL (22%) for fasting glucose
  • 74 mg/dL (36%) for 2-hour postprandial glucose
  • 30 mg/dL (22%) for mean 24-hour glucose concentration
• Delay in gastric emptying in the early postprandial phase
• Lowering of fasting and postprandial glucagon concentrations 2

From the Research

Effects of Semaglutide in Clinical Trials

The effects of semaglutide, a Glucagon-like peptide-1 receptor agonist, have been studied in several clinical trials. The key findings from these trials are:

• Semaglutide has been shown to be effective in achieving glycemic control and reducing body weight in patients with type 2 diabetes 3, 4.
• The PIONEER clinical trial program, which included 9543 patients, demonstrated that oral semaglutide was effective in reducing glycated hemoglobin and body weight, and had a favorable cardiovascular safety profile 3.
• Oral semaglutide has been compared to other GLP-1 receptor agonists, such as liraglutide and dulaglutide, and has been shown to have similar or superior efficacy in terms of glycemic control and weight loss 3, 4, 5.
• The SWITCH-SEMA 1 study is currently investigating the effects of switching from liraglutide or dulaglutide to subcutaneous semaglutide on glucose metabolism and treatment satisfaction in patients with type 2 diabetes 5.
• A cost-effectiveness analysis of oral semaglutide versus lower-cost liraglutide in the UK found that oral semaglutide was associated with improved quality-adjusted life expectancy and reduced direct complication costs, and remained dominant or cost-effective in the majority of scenarios, even with liraglutide price reductions of 50% applied 6.

Efficacy and Safety of Semaglutide

The efficacy and safety of semaglutide have been evaluated in several clinical trials, with key findings including:

• Oral semaglutide was shown to be effective in reducing glycated hemoglobin and body weight, and had a favorable cardiovascular safety profile 3.
• Semaglutide was associated with low proportions of patients experiencing severe or blood glucose-confirmed symptomatic hypoglycemia, and did not increase the incidence of such events when added to insulin 4.
• The tolerability profile of oral semaglutide was consistent with that seen for injectable GLP-1RAs, with gastrointestinal side effects seen most frequently 3, 4.
• Oral semaglutide was well tolerated, with no unexpected safety concerns, and the safety profile was consistent with other GLP-1RAs 3.

Clinical Implications of Semaglutide

The clinical implications of semaglutide are:

• Semaglutide represents an effective treatment option for patients with type 2 diabetes, and may lead to earlier initiation of GLP-1RA therapy in the diabetes treatment landscape 3.
• Oral semaglutide may be a valuable treatment option for patients with a preference for oral therapy, and may facilitate initiation and maintenance of GLP-1RA therapy 7.
• Semaglutide may be used as an add-on to insulin therapy, and has been shown to be effective in reducing glycated hemoglobin and body weight in patients with type 2 diabetes already on insulin therapy 4.