What was the SUSTAIN Study?
The SUSTAIN clinical trial program was a comprehensive series of phase 3 trials (SUSTAIN 1-11) evaluating the efficacy and safety of once-weekly subcutaneous semaglutide (a GLP-1 receptor agonist) for the treatment of type 2 diabetes, with SUSTAIN-6 specifically designed as a cardiovascular outcomes trial to assess cardiovascular safety and benefits. 1, 2
Primary Purpose of the SUSTAIN Program
The SUSTAIN trials evaluated semaglutide across the full spectrum of type 2 diabetes management, enrolling over 8,000 patients in various clinical scenarios 3:
- Glycemic control assessment: Comparing semaglutide to placebo, other GLP-1 receptor agonists, SGLT2 inhibitors, and insulin regimens 4, 5, 6, 7
- Weight reduction outcomes: Demonstrating consistent weight loss across all trials 3
- Cardiovascular safety evaluation: Meeting regulatory requirements for new diabetes medications 1, 2
SUSTAIN-6: The Cardiovascular Outcomes Trial
SUSTAIN-6 (NCT01720446) was specifically designed as a multi-center, multi-national, placebo-controlled, double-blind cardiovascular outcomes trial that demonstrated semaglutide reduced major adverse cardiovascular events (MACE) by 26% compared to placebo (HR 0.74; 95% CI 0.58-0.95; P<0.001). 1, 2
Key Trial Design Features 2:
- Population: 3,297 patients with inadequately controlled type 2 diabetes and established atherosclerotic cardiovascular disease
- Duration: Minimum observation time of 2 years (median 2.1 years)
- Primary endpoint: Time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke
- Eligibility criteria: Patients ≥50 years with established cardiovascular disease, cerebrovascular disease, peripheral artery disease, chronic kidney disease, or NYHA class II-III heart failure; OR patients ≥60 years with specified cardiovascular risk factors
SUSTAIN-6 Results 1, 2:
- MACE reduction: 6.6% in semaglutide group vs. 8.9% in placebo group
- Non-fatal stroke reduction: Significant benefit (HR 0.61; 95% CI 0.38-0.99)
- Cardiovascular death: No significant difference (HR 0.98)
- Non-fatal MI: Trend toward benefit but not statistically significant (HR 0.74; 95% CI 0.51-1.08)
Clinical Impact and Guideline Recognition
Based on SUSTAIN-6 results, major cardiovascular and diabetes guidelines now strongly recommend semaglutide specifically for patients with type 2 diabetes and established atherosclerotic cardiovascular disease or high cardiovascular risk. 1, 8
The American College of Cardiology and American Heart Association recommend initiating semaglutide 1:
- At the time of diagnosis of clinical atherosclerotic cardiovascular disease
- At the time of type 2 diabetes diagnosis in patients with established cardiovascular disease
- At hospital discharge after admission for an atherosclerotic cardiovascular event
- In patients determined to be at high risk of atherosclerotic cardiovascular disease
Important Context from Other SUSTAIN Trials
SUSTAIN 10 compared the most frequently prescribed doses in clinical practice: semaglutide 1.0 mg weekly versus liraglutide 1.2 mg daily, demonstrating superior HbA1c reduction (-1.7% vs -1.0%, P<0.0001) and greater weight loss (-5.8 kg vs -1.9 kg, P<0.0001) with semaglutide. 4
SUSTAIN FORTE evaluated a higher 2.0 mg dose for patients needing additional glycemic control, showing superior HbA1c reduction compared to the standard 1.0 mg dose (ETD -0.23 percentage points, P=0.0003). 6
SUSTAIN China confirmed efficacy and safety in Asian populations, with semaglutide superior to sitagliptin for both glycemic control and weight reduction. 5
Safety Profile Across SUSTAIN Trials
The most common adverse events were gastrointestinal (nausea, vomiting, diarrhea), occurring in 15-20% of patients, typically transient and dose-dependent 8, 3. Higher rates of gastrointestinal adverse events and treatment discontinuation occurred with semaglutide compared to active comparators (43.9% vs 38.3% for GI disorders in SUSTAIN 10). 4