Semaglutide: SUSTAIN-6, STEP 1, SELECT and FLOW Explained

Semaglutide came before tirzepatide and has the longer record. Its history shows how a medicine's label grows: glucose control first, then heart outcomes, weight management, and kidney outcomes, each added only after a trial designed to answer that one question.

A hormone redesigned to last a week

The active form of human GLP-1, called GLP-1(7-37), is a chain of 31 amino acids. It was characterised in the mid 1980s by the peptide chemist Svetlana Mojsov, the endocrinologist Joel Habener and their colleagues, who showed in 1987 that this form stimulates insulin release at tiny concentrations. Their discovery, together with the work of Lotte Bjerre Knudsen at Novo Nordisk on turning it into long-acting medicines, received the 2024 Lasker Clinical Medical Research Award.

The natural hormone cannot be used as a medicine because the body breaks it down so quickly. Novo Nordisk's first answer was liraglutide, which carries a fatty acid so that it binds to albumin in the blood and lasts long enough to be given once a day. Liraglutide was approved for type 2 diabetes in Europe in 2009 and in the United States in 2010, and for weight management in 2014 and 2015 under the name Saxenda.

Semaglutide was designed from the start for once-weekly use. The design paper, published in 2015, sets out two goals: stronger binding to albumin, and full stability against the enzymes that break GLP-1 down. The chosen molecule differs from human GLP-1 at two positions, aminoisobutyric acid at position 8 and arginine at position 34, and carries a fatty acid chain on the lysine at position 26. Its affinity for the GLP-1 receptor was about three times lower than liraglutide's, while its binding to albumin was stronger. In minipigs its plasma half-life after an intravenous dose was 46.1 hours. In people, the SUSTAIN-6 investigators describe a half-life of approximately one week.

How the label grew

Semaglutide is sold by Novo Nordisk as Ozempic, a weekly injection for type 2 diabetes, and as Wegovy for weight management and cardiovascular risk. Each new use on the US label followed a trial built to answer that specific question.

SUSTAIN-6: the first heart safety test

Regulators require a new diabetes medicine to show that it does not increase cardiovascular risk. SUSTAIN-6 was designed for that purpose. It randomised 3,297 adults with type 2 diabetes to one of two semaglutide dose levels or placebo for 104 weeks, on top of their usual care. Most were at high risk: 83 percent already had cardiovascular disease, chronic kidney disease or both.

The primary outcome was a first cardiovascular death, non-fatal heart attack or non-fatal stroke. It occurred in 6.6 percent of the semaglutide group and 8.9 percent of the placebo group, a hazard ratio of 0.74 with a 95 percent confidence interval of 0.58 to 0.95. That confirmed non-inferiority, which was the question the trial was built for. Non-fatal stroke was less frequent, 1.6 against 2.7 percent, and so was new or worsening kidney disease. Deaths from cardiovascular causes were similar in the two groups.

One safety signal went the other way. Complications of diabetic retinopathy, meaning bleeding inside the eye, blindness, or conditions needing laser or injection treatment in the eye, were significantly more frequent with semaglutide, with a hazard ratio of 1.76 and a 95 percent confidence interval of 1.11 to 2.78. More participants stopped treatment because of adverse events, mainly gastrointestinal, although there were fewer serious adverse events overall.

STEP 1: weight management

STEP 1 enrolled 1,961 adults with a BMI of 30 or more, or 27 or more with at least one weight-related condition, and without diabetes. Two in three were randomised to semaglutide at the dose level used for weight management and one in three to placebo, for 68 weeks. Both groups also received a lifestyle intervention, so the placebo group shows what that intervention achieved on its own.

Average body weight fell by 14.9 percent with semaglutide and by 2.4 percent with placebo, an estimated difference of 12.4 percentage points with a 95 percent confidence interval of 11.5 to 13.4. In kilograms, the average change was 15.3 against 2.6.

Nausea and diarrhoea were the most common adverse events. They were typically transient and mild to moderate, and they eased with time. Gastrointestinal events led 4.5 percent of the semaglutide group to stop treatment, against 0.8 percent of the placebo group.

SELECT: heart outcomes without diabetes

SELECT asked whether semaglutide reduces cardiovascular events in people with overweight or obesity who do not have diabetes. It enrolled 17,604 adults aged 45 or older with established cardiovascular disease and a BMI of 27 or more, split evenly between semaglutide and placebo. The average time on treatment was 34.2 months and the average follow-up 39.8 months.

A primary event occurred in 569 of the 8,803 people on semaglutide and 701 of the 8,801 on placebo. This is the result behind the March 2024 decision to add cardiovascular risk reduction to the Wegovy label.

Relative and absolute risk

A hazard ratio of 0.80 is usually reported as a 20 percent lower risk. That is a relative figure. The absolute difference in SELECT was 1.5 percentage points over a little more than three years: 8.0 percent of the placebo group against 6.5 percent of the semaglutide group. Another way to express the same result is that about 67 people would need to be treated for that period for one of them to avoid a primary event. All three numbers are correct, and the size of an effect only becomes clear when you see them together.

FLOW: kidney outcomes

FLOW enrolled 3,533 adults with type 2 diabetes and chronic kidney disease, split evenly between semaglutide and placebo. The trial was stopped early after the monitoring committee recommended it at a pre-specified interim analysis, and the median follow-up was 3.4 years.

The primary outcome combined kidney failure, a fall of at least 50 percent in kidney function measured as eGFR, and death from kidney or cardiovascular causes. It occurred in 331 people on semaglutide and 410 on placebo, a 24 percent lower risk with a hazard ratio of 0.76 and a 95 percent confidence interval of 0.66 to 0.88. The kidney-specific part of the outcome gave a similar result, with a hazard ratio of 0.79, and so did cardiovascular death, with 0.71. Kidney function also declined more slowly on semaglutide, by 1.16 mL per minute per 1.73 m² each year.

Safety: what the label warns about

Semaglutide carries the same boxed warning as the rest of its class. Thyroid C-cell tumours were seen in rodents, their relevance to humans is unknown, and it must not be used by anyone with a personal or family history of medullary thyroid carcinoma or with multiple endocrine neoplasia syndrome type 2.

In its March 2024 announcement, the FDA also listed these warnings: pancreatitis, gallbladder problems, kidney injury, serious allergic reactions, eye complications in people with type 2 diabetes, increased heart rate, and suicidal thoughts. The common side effects it listed were nausea, diarrhoea, vomiting, constipation, abdominal pain, headache, fatigue, indigestion, dizziness, bloating, belching, gas and heartburn, and low blood glucose in people with type 2 diabetes.

The retinopathy finding from SUSTAIN-6 is a good example of how safety knowledge accumulates. It was a signal in a trial designed for a different question, and it became a specific warning that shapes how people with existing eye disease are monitored.

Two numbers from one trial

When the Wegovy tablet was approved in December 2025, the company reported its phase 3 trial, OASIS 4, in two ways. The trial enrolled 307 adults without diabetes and ran for 64 weeks. Counting everyone randomised, including people who stopped, average weight fell by about 14 percent against 2 percent on placebo. Estimating what would have happened if everyone had stayed on treatment, the figures were about 17 percent against 3 percent.

Both pairs describe the same trial. The first answers what happens to people who are prescribed the medicine; the second estimates the effect in people who keep taking it. Headlines tend to quote the larger number, so it is worth checking which one you are reading. The same distinction applies to every trial in this article.

What these trials do not tell you

• They describe one manufacturer's product. The results belong to semaglutide made by Novo Nordisk, prescribed and monitored by doctors. The FDA reports 990 adverse event reports linked to compounded semaglutide and has warned about salt forms, semaglutide sodium and semaglutide acetate, saying it has no information on whether they share the properties of the ingredient in the approved medicine.
• Most follow-up is measured in years, not decades. The longest of these trials followed people for a little over three years on average. Longer-term knowledge comes from monitoring after approval.
• They were funded by the manufacturer. All four trials were sponsored by Novo Nordisk, which is standard for trials submitted to regulators.
• They studied defined groups. SELECT only enrolled people who already had cardiovascular disease, and FLOW only people with both type 2 diabetes and chronic kidney disease.