SUSTAIN 4 shows semaglutide beats insulin glargine on A1c and weight

A phase 3 trial called SUSTAIN 4 compared once-weekly semaglutide injections with once-daily insulin glargine in adults with type 2 diabetes who were not reaching their blood sugar goals on metformin alone or metformin plus a sulfonylurea. The study, funded by Novo Nordisk and published in The Lancet Diabetes & Endocrinology, followed 1,089 people across 196 sites in 14 countries for 30 weeks.^[1]

Participants were randomly assigned to 0.5 mg semaglutide, 1.0 mg semaglutide, or insulin glargine, all added to their existing metformin regimen. At the end of the study, average A1c had dropped from a starting point of 8.17% by 1.21 percentage points with the lower semaglutide dose and 1.64 points with the higher dose, compared with a 0.83-point drop with insulin glargine. Both semaglutide doses beat insulin glargine by a statistically significant margin.^[1]

Weight changes told a similar story. Starting from an average body weight of 93.45 kg, people on 0.5 mg semaglutide lost 3.47 kg and those on 1.0 mg lost 5.17 kg over 30 weeks. People on insulin glargine gained 1.15 kg on average. The difference between semaglutide and insulin glargine ranged from about 4.6 kg to 6.3 kg, depending on dose.^[1]

Semaglutide also caused less low blood sugar. Severe or blood-glucose-confirmed hypoglycemia occurred in 4% of people on the lower semaglutide dose and 6% on the higher dose, compared with 11% on insulin glargine. Severe hypoglycemia specifically was rare across all groups, affecting fewer than 1% to 1% of participants.^[1]

Side effects differed by drug type. Nausea was the most common complaint with semaglutide, reported by 21% of people on the lower dose and 22% on the higher dose. Nasopharyngitis, a mild upper-respiratory infection, was most common with insulin glargine, affecting 12% of that group. More people stopped semaglutide early because of side effects — 14% and 15% for the two doses — compared with 7% for insulin glargine, mostly due to gastrointestinal issues with semaglutide and skin reactions like rash or itching with insulin glargine. Six deaths occurred during the trial: four among semaglutide patients, including one pancreatic cancer case judged possibly related to the drug, and two among insulin glargine patients, both cardiovascular.^[1]

Why it matters for patients

For people with type 2 diabetes choosing between an injectable GLP-1 drug like semaglutide and long-acting insulin, this trial offers a direct head-to-head comparison rather than separate studies against placebo. The results show semaglutide can lower blood sugar more and cause weight loss instead of weight gain, a meaningful difference for many patients managing diabetes alongside excess weight. The lower rate of hypoglycemia with semaglutide also matters because low blood sugar episodes can be dangerous and disruptive to daily life.

At the same time, semaglutide is not free of downsides. Gastrointestinal side effects like nausea led more people to quit the drug early than those on insulin. The trial's authors describe semaglutide's safety profile as similar to that of other drugs in its class, which are already known for stomach-related side effects. Patients weighing these two treatment options might consider both the metabolic benefits and the tolerability trade-offs described here, though only a clinician can weigh individual health circumstances.

The trial was open-label, meaning participants and doctors knew which drug they were taking, which can influence some reported outcomes even when objective measures like A1c and weight are used.^[1]