The SUSTAIN Program: Injectable Semaglutide in Type 2 Diabetes

What the SUSTAIN program set out to answer

Semaglutide is a modified GLP-1 receptor agonist designed for once-weekly dosing through structural changes that extend its half-life to approximately one week. Before it could be approved as Ozempic, Novo Nordisk needed to demonstrate that it improved glycemic control across the typical treatment algorithm for type 2 diabetes: as monotherapy in drug-naive patients, as add-on to widely used oral agents, head-to-head against the leading injectable comparators, and in a dedicated cardiovascular outcomes trial required by FDA guidance introduced after the rosiglitazone controversy.

The SUSTAIN program (SUSTAIN-1 through SUSTAIN-10) addressed all of those questions across roughly 10,000 participants. The cardiovascular outcomes trial, SUSTAIN-6, was particularly consequential: it not only satisfied the non-inferiority requirement but showed a statistically significant reduction in MACE, establishing semaglutide as a GLP-1 receptor agonist with demonstrated heart-protective benefit.

Constituent trials

Approximate results from primary publications. OADs = oral antidiabetic drugs; SU = sulfonylurea; TZD = thiazolidinedione; HR = hazard ratio; MACE = major adverse cardiovascular events.

Glycemic and weight efficacy across the program

Taken together, the ten SUSTAIN trials demonstrated that semaglutide 1.0 mg consistently reduced HbA1c by approximately 1.5 to 1.8 percentage points across diverse treatment backgrounds, making it one of the most efficacious agents in the T2DM armamentarium at the time of its approval. The 0.5 mg dose provided meaningful but somewhat smaller reductions, offering a starting dose for patients at risk of GI side effects.

Body-weight reductions of 3 to 6 kg at 1.0 mg were reproducible across the program. While smaller than the weight losses subsequently demonstrated with tirzepatide or with semaglutide 2.4 mg in the STEP program, they were substantially larger than those seen with comparators such as sitagliptin, exenatide ER, or insulin, and without the weight-gain risk associated with sulfonylureas or insulin.

In head-to-head trials (SUSTAIN-3, -7, -10), semaglutide was superior to exenatide extended-release, dulaglutide, and liraglutide 1.2 mg on both HbA1c and weight, positioning it as the leading once-weekly GLP-1 receptor agonist before tirzepatide's approval.^[3]

SUSTAIN-6: The cardiovascular outcomes trial

SUSTAIN-6 (NCT01720446) enrolled 3,297 patients with T2DM who had either established cardiovascular disease or multiple CV risk factors, randomizing them to semaglutide 0.5 mg, semaglutide 1.0 mg, or matching placebo for a minimum of 104 weeks.^[2] The primary endpoint was time to first occurrence of a three-component MACE: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke.

The trial met its non-inferiority criterion. More importantly, the data crossed the superiority boundary: the primary MACE endpoint occurred in 6.6% of semaglutide-treated patients versus 8.9% in the placebo group, a hazard ratio of 0.74 (95% confidence interval 0.58 to 0.95), representing a 26% relative risk reduction. The effect was largely driven by a reduction in non-fatal stroke (HR 0.61), with a non-fatal MI reduction that trended positive but did not individually achieve statistical significance.

A striking finding in SUSTAIN-6 was a numeric increase in retinopathy complications in the semaglutide group (HR approximately 1.76). This finding, likely attributable to rapid HbA1c normalization in patients with pre-existing retinal disease, was added to the semaglutide label. It created a note of caution for patients with proliferative diabetic retinopathy requiring close monitoring during initiation of therapy.

SUSTAIN-6 was subsequently used to add a cardiovascular risk-reduction indication to the Ozempic label, though the FDA's label language references the MACE finding without claiming the mechanism is independent of glycemic improvement.

Regulatory outcome

The FDA approved Ozempic (semaglutide 0.5 mg and 1.0 mg injection) for type 2 diabetes in December 2017, supported principally by SUSTAIN-1 through SUSTAIN-5 as efficacy trials and SUSTAIN-6 as the required CVOT. The EMA and MHRA followed with approvals in 2018.

A 2.0 mg dose of Ozempic was subsequently approved by the FDA in 2022 based on additional data, providing an option for patients requiring more intensive HbA1c lowering. The 2.0 mg dose was not part of the original SUSTAIN program.

The SUSTAIN program established semaglutide as the reference GLP-1 receptor agonist against which subsequent agents, including tirzepatide and oral semaglutide (the subject of the PIONEER program), have been measured. The SUSTAIN-6 CV outcome data became central to the medical case for treating T2DM with semaglutide in high-risk cardiovascular populations.