STEP 1 (Semaglutide for Obesity)

For most of the 2010s, the pharmacologic options for obesity were modest. Orlistat, phentermine-topiramate, and naltrexone-bupropion produced average weight losses in the range of 5 to 9% in phase 3 trials, enough to improve metabolic parameters but short of the 10 to 15% threshold that most obesity specialists considered clinically meaningful for severe disease. GLP-1 receptor agonists had been developed for type 2 diabetes and produced incidental weight loss in that setting, but no GLP-1 drug had been tested at the doses needed to evaluate its full anti-obesity potential. Novo Nordisk developed a weekly subcutaneous formulation of semaglutide at 2.4 mg, substantially higher than the 1 mg dose approved for diabetes, and designed the STEP program to test it specifically in people with obesity.

STEP 1 enrolled 1,961 adults with a BMI of 30 or above, or 27 or above with a weight-related complication, who did not have diabetes. Participants received weekly subcutaneous semaglutide 2.4 mg or placebo for 68 weeks alongside structured lifestyle intervention. Mean weight loss reached 14.9% in the semaglutide group versus 2.4% on placebo. Eighty-six percent of semaglutide participants lost at least 5% of body weight; a third lost 20% or more. Robert Kushner was the trial's principal investigator, and John Wilding was lead author of the New England Journal of Medicine publication in 2021.

At the time of publication, no pharmacologic treatment had come close to 15% mean weight loss in a phase 3 trial. The magnitude overlapped with outcomes from Roux-en-Y gastric bypass at the lower end of that procedure's range, which prompted genuine reassessment of whether bariatric surgery retained a sufficiently large efficacy advantage to justify its perioperative risks for all eligible patients. That conversation was not settled by one trial, but the reference point had shifted. The FDA approved semaglutide 2.4 mg as Wegovy in June 2021.

The drug's clinical reach extended further when the SELECT trial, published in 2023, enrolled obese adults without diabetes and demonstrated a 20% reduction in major cardiovascular events with semaglutide 2.4 mg over a mean of 34 months of treatment exposure. That result moved semaglutide from an obesity medication with metabolic benefits into a drug with a dedicated cardiovascular indication, qualitatively similar to the position statins occupy in lipid management. Supply shortages followed the launch and persisted for years, limiting access despite formal approval and insurance coverage expansion.