Key Semaglutide Studies in Type 2 Diabetes

Cardiovascular Outcome Trials

SUSTAIN-6 enrolled 3,297 patients with type 2 diabetes at high cardiovascular risk, randomized to once-weekly subcutaneous semaglutide (0.5 mg or 1.0 mg) or placebo for 2 years 1, 2
The primary composite outcome (cardiovascular death, nonfatal MI, or nonfatal stroke) occurred in 6.6% of semaglutide patients versus 8.9% of placebo patients (HR 0.74 [95% CI 0.58–0.95]; P < 0.001 for superiority) 1, 2
This represents a 26% reduction in major adverse cardiovascular events 2, 3
Cardiovascular deaths were significantly reduced: 4.7% with semaglutide versus 6.0% with placebo 1
Mean patient age was 65 years with baseline HbA1c of 8.7% and mean body weight of 92 kg 4
More patients discontinued treatment due to adverse events, mainly gastrointestinal 1
Important caveat: Increased rates of diabetic retinopathy complications were observed, requiring careful monitoring in patients with existing retinopathy 4, 5

PIONEER-6 enrolled 3,183 patients with type 2 diabetes and high cardiovascular risk, followed for a median of 15.9 months 1
Oral semaglutide demonstrated non-inferiority only to placebo for the primary composite outcome (HR 0.79 [95% CI 0.57–1.11]; P < 0.001 for noninferiority) 1, 2
Critical distinction: Oral semaglutide did NOT demonstrate cardiovascular superiority, unlike injectable semaglutide 2

Semaglutide has been evaluated in more than 8,000 patients across the spectrum of type 2 diabetes 6
Trials demonstrated superiority with sustained improved glycemic control and weight loss compared to oral antidiabetic agents, other GLP-1 receptor agonists, and basal insulin 6
HbA1c reduction: 1.5-1.9% after 30-56 weeks of treatment 7
Weight reduction: 5-10% from baseline in clinical efficacy studies 7
Injectable semaglutide produces significantly greater weight loss than oral semaglutide 2

Semaglutide 1 mg resulted in the following reductions compared to placebo: 8
- Fasting glucose: 29 mg/dL (22% reduction)
- 2-hour postprandial glucose: 74 mg/dL (36% reduction)
- Mean 24-hour glucose concentration: 30 mg/dL (22% reduction)
Both first- and second-phase insulin secretion are increased compared with placebo 8
Fasting glucagon reduced by 8%, postprandial glucagon by 14-15%, and mean 24-hour glucagon by 12% 8

Absolute bioavailability of subcutaneous semaglutide is 89% 8
Half-life of approximately 7 days, reaching steady state in 4-5 weeks 8, 7
Steady-state concentrations: approximately 65.0 ng/mL for 0.5 mg and 123.0 ng/mL for 1 mg once-weekly dosing 8
Semaglutide is extensively bound to plasma albumin (>99%) 8
Age, sex, race, ethnicity, and renal impairment do not have clinically meaningful effects on pharmacokinetics 8

Most common adverse reactions (≥5%): nausea, vomiting, diarrhea, abdominal pain, and constipation 8
Gastrointestinal side effects are mostly mild-to-moderate and transient 5
Increased risk of biliary disease (cholelithiasis) 5
No unexpected safety issues have arisen, with a safety profile similar to other GLP-1 receptor agonists 5
Low risk of hypoglycemia when used as monotherapy 5, 7, 9
Semaglutide does not prolong QTc intervals to any clinically relevant extent at 1.5 times the maximum recommended dose 8

Semaglutide is well tolerated in adults and elderly patients with renal or hepatic disorders, demanding no dose modification 9
Patients at risk for deterioration of existing diabetic retinopathy should be carefully monitored, particularly if also treated with insulin 5

Semaglutide has been compared with placebo, sitagliptin, exenatide extended release, and insulin glargine as monotherapy or add-on therapy 7
Demonstrated superiority over these comparators for glycemic control and weight loss 6, 7

The American Diabetes Association recommends injectable semaglutide as a first-line therapy for patients with or at high risk for atherosclerotic cardiovascular disease, heart failure, or kidney disease 2
The American College of Cardiology and American Heart Association support the use of GLP-1 receptor agonists with proven cardiovascular benefits, such as injectable semaglutide, for patients with established cardiovascular disease or high cardiovascular risk 2
Injectable semaglutide has demonstrated mortality reduction and cardiovascular benefits, while oral semaglutide only showed non-inferiority 2