Medical therapy

Semaglutide promises a ‘new era’ in the medical treatment of obesity



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

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

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Superior weight loss efficacy with the GLP-1 receptor agonist semaglutide demonstrated in 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 clinical trial program on the treatment effect of semaglutide in people with obesity (STEP), the researchers stated that semaglutide 2.4 mg (Wegovy, Novo Nordisk) is likely to “ ushering in a new era” in the medical treatment of obesity – one where weight loss goals are achievable, where efficacy can have a major impact on complications, and where clinically important risk factors for disease cardiovascular can be reduced.

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

Assessment of stages

As Healio previously reported, the FDA approved a weekly injection of 2.4 mg of semaglutide in June for chronic weight management in obese or overweight adults and at least one weight-related condition. The agency’s decision made it the first drug approved 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 primary endpoints of percent change in body weight and weight reduction of at least 5% from baseline to 68 weeks per compared to placebo. The researchers used the primary estimate to assess effects independent of stopping treatment or rescue interventions.

The pivotal STEP 1 trial, published in The New England Journal of Medicine in February included 1,961 obese or overweight non-diabetic adults with a comorbid weight-related condition. The researchers randomly assigned participants semaglutide 2.4 mg or placebo; both groups received a lifestyle intervention. The researchers found that the 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 to semaglutide lost an average of –15.3 kg versus –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

“The weight didn’t plateau until about 68 weeks; this is the first time we’ve seen this kind 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, the 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 (CI 95 %, 3.58-6.64).

“One-third of people in this trial achieved weight loss of at least 20 percent or more,” Kushner said. “It’s 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 obese but non-diabetic adults when added to intensive behavioral therapy (30 consultations) with an initial low-calorie diet for 8 weeks. At 68 weeks, semaglutide plus intensive behavioral therapy and a calorie-restricted diet resulted in a 16% reduction in body weight compared to 5.7% for placebo (P .001).

“The average weight loss at 68 weeks was about 1% greater than in the STEP 1 trial, which did not receive intensive behavioral therapy,” Kushner said. “If you look at categorical weight loss, you don’t see much difference. To sum up, the data suggests that semaglutide along with brief monthly lifestyle advice alone is enough to produce an average weight loss of 15 This 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 in 535 obese adults who continued treatment with semaglutide beyond 20 weeks versus 268 participants who switched to placebo at 20 weeks. After randomization, the estimated mean weight change from week 20 to week 68 was -7.9% with continuation of semaglutide versus a mean increase of 6.9% in participants who switched to placebo, for a difference of – 14.8 percentage points (95% CI, -16 to –13.5).

“It 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.”

Response variability

Kaplan said more than a third of participants who received semaglutide 2.4 mg experienced weight loss of at least 20% and 11% of participants experienced weight loss of at least 30%, which which approximates the effectiveness 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.

“Although the average and overall weight loss response is excellent for this drug, this distribution tells us that some people … will experience less than 5% weight loss,” Kaplan said. “We shouldn’t be deterred by the fact that some patients won’t lose as much weight with this drug as treating other patients who will.”

Kaplan said that as better therapies emerge to treat 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 great patient-to-patient variability in its effects,” Kaplan said. “One patient’s failure does not predict another’s response, and we should always remember that when treating different patients with these drugs.”