Clinical Trials on Semaglutide
Major Cardiovascular Outcomes Trials
The SUSTAIN-6 trial is the pivotal cardiovascular outcomes study for subcutaneous semaglutide, demonstrating a 26% reduction in major adverse cardiovascular events (MACE) in patients with type 2 diabetes and established cardiovascular disease. 1
SUSTAIN-6 Trial Design and Results
- Study population: 3,297 patients with type 2 diabetes randomized to once-weekly subcutaneous semaglutide (0.5 mg or 1.0 mg) or placebo for 2 years 1
- Primary outcome: First occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke occurred in 6.6% of the semaglutide group versus 8.9% in the placebo group (HR 0.74; 95% CI 0.58–0.95; P < 0.001) 1, 2
- Key limitation: This was a moderate-sized trial powered for noninferiority testing for regulatory approval, not specifically designed as a cardiovascular outcomes trial 1
- Discontinuations: More patients stopped treatment in the semaglutide group due to adverse events, predominantly gastrointestinal 1
PIONEER-6 Trial (Oral Semaglutide)
- Study design: 3,183 patients with type 2 diabetes and high cardiovascular risk followed for a median of 15.9 months 1
- Primary outcome: Oral semaglutide was noninferior to placebo for the 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
- Purpose: Preapproval trial designed to rule out unacceptable cardiovascular risk, not to demonstrate superiority 1
- Future studies: The cardiovascular effects of oral semaglutide will be further evaluated in larger, longer-term outcomes trials 1
SUSTAIN Glycemic Control Trials (SUSTAIN 1-7)
The SUSTAIN clinical trial program evaluated semaglutide in over 8,000 patients across the spectrum of type 2 diabetes, consistently demonstrating superior glycemic control and weight loss versus all comparators. 3, 4
Key Efficacy Findings Across SUSTAIN Trials
- HbA1c reduction: Semaglutide produced 1.5-1.9% HbA1c reduction after 30-56 weeks of treatment 5
- Weight loss: Resulted in 5-10% weight reduction from baseline in clinical efficacy studies 5
- Comparators evaluated: Placebo, sitagliptin, exenatide extended-release, and insulin glargine as monotherapy or add-on therapy 4, 5
- Mechanism: Works via the incretin pathway, stimulating insulin and inhibiting glucagon secretion, while also decreasing energy intake by reducing appetite and food cravings 4
Pharmacokinetic Studies
Dosing and Administration Characteristics
- Half-life: 7 days at doses of 0.5 or 1 mg, reaching steady state in 4-5 weeks 5, 6
- Bioavailability: 89% absolute bioavailability with subcutaneous administration 6
- Peak concentration: Reached 1-3 days post-dose 6
- Steady-state concentrations: Approximately 65.0 ng/mL for 0.5 mg and 123.0 ng/mL for 1 mg once-weekly dosing 6
- Elimination: Approximately 1-week half-life means semaglutide remains in circulation for about 5 weeks after the last dose 6
Special Populations
- Renal impairment: Does not impact pharmacokinetics in a clinically relevant manner across all degrees of renal impairment (mild, moderate, severe, ESRD) 6
- Hepatic impairment: No impact on semaglutide exposure across all degrees of hepatic impairment 6
- No dose adjustments needed: Based on age, sex, race, ethnicity, or renal function 6
High-Dose Semaglutide Trial
A phase 2 trial evaluated semaglutide doses up to 16 mg weekly in 245 individuals with type 2 diabetes and BMI ≥27 kg/m², showing modest additional glucose-lowering with more weight loss but increased adverse events. 7
High-Dose Trial Results (40 weeks)
- HbA1c change: Estimated treatment difference between 16 mg and 2 mg was -0.5 percentage points (95% CI -1.0 to -0.1; P = 0.015) for the hypothetical estimand 7
- Weight change: -4.5 kg difference (95% CI -7.6 to -1.4; P = 0.004) favoring the 16 mg dose 7
- Safety trade-off: Treatment-emergent adverse events and discontinuations due to adverse events (primarily gastrointestinal) were more frequent in the 8 mg and 16 mg groups compared to 2 mg 7
- Hypoglycemia: No severe hypoglycemic episodes reported 7
Drug Interaction Studies
Semaglutide has minimal clinically relevant drug interactions, with no dose adjustments required for co-administered oral medications. 6
Evaluated Co-Medications
- No significant interactions with metformin, oral contraceptives (ethinylestradiol/levonorgestrel), warfarin, digoxin, or atorvastatin 6
- Gastric emptying delay: May influence absorption of concomitantly administered oral medications, though clinical studies showed no clinically relevant impact 6
- CYP enzymes: Very low potential to inhibit or induce CYP enzymes or inhibit drug transporters 6
Safety Profile Across Trials
Common Adverse Events
- Gastrointestinal effects: Most common reason for treatment discontinuation across all trials 1, 4
- Hypoglycemia risk: Increased when combined with sulfonylureas (documented symptomatic hypoglycemia in 17.3-24.4% with semaglutide plus sulfonylurea) or insulin 6
- Injection site reactions: Reported in 0.2% of semaglutide-treated patients 6
- Pancreatic enzymes: Mean increase from baseline in amylase of 13% and lipase of 22% 6
- Cholelithiasis: Reported in 1.5% (0.5 mg) and 0.4% (1 mg) of patients versus 0% with placebo 6
- Heart rate: Mean increase of 2-3 beats per minute 6
Cardiovascular Safety
- QTc interval: Does not prolong QTc intervals to any clinically relevant extent at 1.5 times the maximum recommended dose 6
- Thyroid C-cell tumors: Carcinogenicity studies in mice and rats showed statistically significant increases in thyroid C-cell adenomas and carcinomas at all dose levels tested 6
Clinical Positioning Based on Guidelines
The American Diabetes Association and European Society of Cardiology strongly recommend semaglutide as part of the glucose-lowering regimen for patients with type 2 diabetes who have established atherosclerotic cardiovascular disease or are at high cardiovascular risk. 2