Semaglutide promises ‘new era’ in medical therapy for obesity


Kaplan LM, et al. 3-CT-SY27. Presented at: American Diabetes Association Scientific Sessions, June 25-29, 2021 (virtual meeting).

Kaplan reports he has received consultant fees from Eli Lilly, Gelesis, GI Dynamics, Intellihealth, Johnson & Johnson, Novo Nordisk, Pfizer, Rhythm Pharmaceuticals, the NIH and the Obesity and Nutrition Institute. Kushner reports he serves on an advisory board for and received research grants from Novo Nordisk.

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Superior weight-loss efficacy with the GLP-1 receptor agonist semaglutide demonstrated in the phase 3 STEP studies suggests clinicians have a new opportunity to control obesity and its medical complications, including type 2 diabetes.

Lee M. Kaplan

In an overview of the Semaglutide Treatment Effect in People with Obesity (STEP) clinical trial program, researchers said semaglutide 2.4 mg (Wegovy, Novo Nordisk) is likely to “usher in a new era” in the medical treatment of obesity — one where specific weight-loss targets are achievable, where efficacy can have a major impact on complications, and where clinically important risk factors for cardiovascular disease may be reduced.

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“But to be effective, semaglutide has to be used,” Lee M. Kaplan, MD, PhD, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital, said during a virtual presentation at the virtual American Diabetes Association Scientific Sessions. “Obesity needs to be recognized as a disease in its own right, as well as a risk factor for numerous other diseases. Equitable access to obesity treatment needs to be broadened, and health care providers need to take more responsibility for control of this serious problem.”

Assessing the STEPs

As Healio previous reported, the FDA approved once-weekly injectable semaglutide 2.4 mg injection in June for chronic weight management in adults with obesity or with overweight and at least one weight-related condition. The agency’s decision made it the first-approved drug for chronic weight management in adults with general obesity or overweight since 2014.

The approval comes after the publication of the four phase 3 STEP trials, each of which had the same coprimary endpoints of percentage change in body weight and weight reduction of at least 5% from baseline to 68 weeks compared with placebo. Researchers used the primary estimand to assess effects regardless of treatment discontinuation or rescue interventions.

The pivotal STEP 1 trial, published in The New England Journal of Medicine in February, included 1,961 adults without diabetes with obesity or overweight with a with a weight-related comorbid condition. Researchers randomly assigned participants semaglutide 2.4 mg or placebo; both groups received lifestyle intervention. Researchers found that mean change in body weight from baseline to week 68 was –14.9% for the semaglutide group and –2.4% for the placebo group, for an estimated treatment difference of –12.4 percentage points (95% CI, –13.4 to –11.5). Participants assigned semaglutide lost a mean –15.3 kg vs. –2.6 kg in the placebo group, for an estimated treatment difference of –12.7 kg (95% CI, –13.7 to –11.7).

Robert Kushner

“Weight did not plateau until about 68 weeks; this is the first time we have ever seen that type of long-term weight loss in obesity trials,” Robert Kushner, MD, professor of medicine and medical education at Northwestern University Feinberg School of Medicine, said during an overview of the four studies.

STEP 2, published in March in The Lancet, included 1,210 adults diagnosed with type 2 diabetes with overweight or obesity. At 68 weeks, estimated change in mean body weight from baseline was 9.6% with semaglutide 2.4 mg vs. 3.4% with placebo, for an estimated treatment difference of 6.2 percentage points (95% CI, 7.3 to 5.2). At week 68, more patients on semaglutide 2.4 mg achieved weight reductions of at least 5% vs. placebo (68.8% vs. 28.5%), for an OR of 4.88 (95% CI, 3.58-6.64).

“One-third of individuals in this trial achieved at least 20% weight loss or more,” Kushner said. “That is phenomenal for weight-loss trials.”

STEP 3, published in JAMA in February, assessed the effect of semaglutide 2.4 mg on body weight in 611 adults with obesity but without diabetes when added to intensive behavioral therapy (30 counseling visits) with an initial low-calorie diet for 8 weeks. At 68 weeks, semaglutide plus intensive behavioral therapy and a low-calorie diet resulted in reductions in body weight of 16% vs. 5.7% for placebo (P < .001).

“Weight loss on average at 68 weeks was about 1% higher than in the STEP 1 trial, which did not receive intensive behavioral therapy,” Kushner said. “If you look at categorical weight loss, you do not see much difference. To summarize, data suggests that semaglutide with monthly, brief lifestyle counseling alone is sufficient to produce mean weight loss of 15%. That has profound implications for the practical use of this drug in primary care.”

STEP 4, published in JAMA in March, assessed continued weight loss or weight maintenance among 535 adults with obesity who continued semaglutide therapy beyond 20 weeks vs. 268 participants who were switched to placebo at 20 weeks. After randomization, the estimated mean weight change from week 20 to week 68 was –7.9% with continued semaglutide vs. a mean increase of 6.9% among participants switched to placebo, for a difference of –14.8 percentage points (95% CI, –16 to –13.5).

“That reminds us of the biology of obesity and the effect of drug treatment,” Kushner said. “If you remove the drug, the disease starts to come back.”

Variability in response

Kaplan said upward of one-third of participants who received semaglutide 2.4 mg experienced at least 20% weight loss and 11% of participants experienced at least 30% weight loss, approaching the efficacy of bariatric surgery.

However, nearly 10% of participants without diabetes, and more than 30% of participants with type 2 diabetes experienced less than 5% weight loss.

“While the average and overall weight-loss response is superb for this drug, this distribution tells us that some people … will exbibit less than 5% weight loss,” Kaplan said. “We should not be dissuaded by the fact that some patients are not going to lose as much weight on this medication from treating other patients who will.”

Kaplan said as better therapies emerge for treating obesity, including semaglutide, clinicians can expect even greater benefits in terms of comorbidities and even reduced mortality risk.

“Like other anti-obesity therapies, there is large patient-to-patient variability in its effects,” Kaplan said. “Failure in one patient does not predict response in another, and we should always remember that as we treat different patients with these medications.”

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