The SUSTAIN Trial Program: Semaglutide for Type 2 Diabetes

The SUSTAIN program comprises 13 Phase 3 trials (SUSTAIN 1–6 and SUSTAIN Plus 1–7, excluding SUSTAIN 7 which was discontinued) designed to evaluate semaglutide across diverse type 2 diabetes populations and treatment contexts. The program enrolled over 13,000 participants globally, with trials ranging from 30 to 104 weeks in duration. The program employed a modular design strategy: early trials (SUSTAIN 1–3) evaluated semaglutide monotherapy and as add-on to individual classes of diabetes medications; SUSTAIN 4–6 focused on populations with established cardiovascular disease or high cardiovascular risk; SUSTAIN Plus trials evaluated specific combinations and dosing regimens.

A unifying theme across SUSTAIN trials was the evaluation of both glycaemic efficacy and cardiovascular/renal outcomes. SUSTAIN-6, the largest and longest trial, was specifically powered to assess cardiovascular outcomes—a rigorous regulatory expectation for modern diabetes medications introduced following cardiovascular outcome trial programs for other drug classes.

SUSTAIN 1 enrolled participants inadequately controlled on diet and exercise alone; SUSTAIN 2 enrolled those on metformin monotherapy; SUSTAIN 3 evaluated semaglutide as add-on to thiazolidinediones; SUSTAIN 4 enrolled participants with established cardiovascular disease; SUSTAIN 5 assessed semaglutide in patients with moderate renal impairment; and SUSTAIN 6 enrolled high-risk participants with type 2 diabetes and either established cardiovascular disease or multiple cardiovascular risk factors (mean age 64 years). This cascade design ensured comprehensive evaluation across treatment-naïve to heavily pre-treated populations and across renal function categories.

Most SUSTAIN trials used once-weekly subcutaneous semaglutide at doses of 0.5 mg, 1.0 mg, or 1.4 mg (distinct from the 2.4 mg used in STEP obesity trials), escalated over 4–8 weeks. Treatment duration ranged from 30 weeks (SUSTAIN 1) to 104 weeks (SUSTAIN 6). Comparators included placebo, sitagliptin (a DPP-4 inhibitor), dulaglutide (another GLP-1 agonist), and open-label insulin. This varied comparator approach enabled assessment of semaglutide's efficacy relative to established diabetes treatments.

Across the SUSTAIN program, semaglutide consistently reduced HbA1c by 1.0–1.8 percentage points depending on baseline HbA1c, dose, and concomitant medications. SUSTAIN 1 (monotherapy) showed HbA1c reduction of 1.5–1.8 percentage points with semaglutide 1.0 mg and 1.4 mg, respectively, compared to minimal change with placebo. SUSTAIN 2 (add-on to metformin) showed comparable efficacy. These HbA1c reductions are substantial and among the largest achieved with any single diabetes medication. Additionally, 50–70% of participants achieved HbA1c targets (<7% or 53 mmol/mol, per current guidelines) with semaglutide, compared to 20–35% with comparators.

Fasting plasma glucose reductions of 20–30 mg/dL (1.1–1.7 mmol/L) were observed, and postprandial glucose excursions were substantially reduced. The consistency of glycaemic control across diverse patient populations (treatment-naïve, on metformin, on thiazolidinediones, with renal impairment) demonstrates semaglutide's broad therapeutic utility in type 2 diabetes.

Secondary endpoints included weight loss, blood pressure, lipid parameters, and markers of renal function. Semaglutide produced weight loss of 2–4 kg across the SUSTAIN trials—modest compared to the STEP program but meaningful given the lower doses used (0.5–1.4 mg in SUSTAIN versus 2.4 mg in STEP). Systolic blood pressure reductions of 2–4 mmHg and improvements in LDL cholesterol and triglycerides were consistently observed. These cardiometabolic improvements contribute to overall cardiovascular risk reduction beyond glycaemic control.

Regarding renal outcomes, SUSTAIN 5 (in participants with renal impairment) showed that semaglutide did not worsen renal function and provided efficacy for glycaemic control even in moderate renal disease. Additionally, markers of albuminuria improved with semaglutide, suggesting renoprotective effects. These findings supported use of semaglutide even in populations with comorbid renal disease, though dose adjustments may be considered in severe renal impairment.

SUSTAIN-6, the cardiovascular outcomes trial, enrolled 3,297 participants with type 2 diabetes and established cardiovascular disease or high cardiovascular risk and randomised them to semaglutide 1.0 mg or placebo. The trial demonstrated a 26% relative risk reduction in the primary composite endpoint (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke; hazard ratio 0.74, 95% CI 0.58–0.95). This cardiovascular benefit was achieved without increased adverse events and paralleled findings from LEADER (liraglutide) and LEADER-like outcomes trials in other GLP-1 agonists. The mechanism underlying cardiovascular benefit likely involves both glycaemic control and direct cardioprotective effects of GLP-1 signaling.

Regarding safety in SUSTAIN-6, gastrointestinal events (nausea, vomiting, diarrhoea) were more common with semaglutide (approximately 25–35%) than placebo (~10%), but were generally transient. Acute pancreatitis occurred in 0.4% of semaglutide recipients versus 0.3% with placebo—not statistically significantly different. No increased risk of thyroid cancer or malignancy was observed. Notably, heart rate increased by approximately 2–3 bpm with semaglutide, though clinically significant arrhythmias were rare.

The SUSTAIN program established semaglutide's efficacy for diabetes control and demonstrated cardiovascular benefits in high-risk populations; however, the trials enrolled predominantly white, middle-income populations with relatively good medical care access, potentially limiting generalisability to more diverse populations. Additionally, the lower semaglutide doses in SUSTAIN (0.5–1.4 mg) compared to STEP (2.4 mg) mean that the full weight loss potential of the drug was not realised in these diabetes trials. Some participants may have tolerated and benefited from dose escalation beyond 1.4 mg, but this was not systematically explored.

Finally, while the SUSTAIN program demonstrated cardiovascular benefits in high-risk diabetes populations, extrapolation to primary prevention (cardiovascular benefit in low-risk individuals) remains uncertain, though emerging data from SELECT (non-diabetic obesity) suggest benefits may extend beyond high-risk diabetes populations.