Semaglutide for Weight Loss? A Good First STEP, With Caveats

Marlene Busko

February 10, 2021

The phase 3a STEP 1 trial that investigated the use of semaglutide (Novo Nordisk), a glucagon-like peptide-1 (GLP-1) agonist, for weight loss is aptly named, some say.

"In sum, we have a long way to go to control the obesity epidemic...but on the face of it, the STEP 1 trial (like its name) is a good beginning," write coeditorialists Julie R. Ingelfinger, MD, from Harvard Medical School, Boston, Massachusetts and a deputy editor of the New England Journal of Medicine, and Clifford J. Rosen, MD, from Tufts University School of Medicine, also in Boston.

The trial findings by John P.H. Wilding, DM, University of Liverpool, UK, and colleagues and an accompanying editorial were published online February 10 in the New England Journal of Medicine.

"The results are encouraging, with significantly more patients in the semaglutide group having clinically important weight loss," Ingelfinger and Rosen stress.

However, they also caution that "despite the positive results of this trial, the present study has some important limitations" and "there are concerns, including adverse events (mostly gastrointestinal — nausea, sometimes vomiting, and diarrhea) related primarily to the class of the agent."

Two UK experts drew similar takeaways, speaking to the UK Science Media Centre.

"This was a well-designed study with unequivocal findings," which showed that semaglutide "is indeed likely to be a game changer in the fight against obesity," according to Baptiste Leurent, PhD, London School of Hygiene and Tropical Medicine.

However, if the drug is approved at this dose for this use, patients would need close monitoring for gastrointestinal disorders, and "we also need to better understand what is happening once the treatment is stopped, and whether it could be taken for a shorter period of time."

Sir Stephen O'Rahilly, MD, MRC Metabolic Diseases Unit, University of Cambridge, pointed out that "GLP-1 is made by cells in the intestine and levels increase in the blood after a meal, providing some of the signal to the brain that tells us we are 'full,'" so GLP-1 agonists have been studied as appetite suppressants, in addition to their approved use to treat type 2 diabetes.

Only about 4.5% of participants in STEP 1 stopped taking semaglutide because of gastrointestinal issues, he noted, although more participants in that group reported problems with gallstones, which can follow rapid weight loss. 

And "unlike some previous appetite suppressant drugs which caused significant psychological and psychiatric side effects, there is no evidence that semaglutide has any adverse effects of that nature," O'Rahilly noted.

In sum, he said, "this is the start of a new era for obesity drug development with the future direction being to achieve levels of weight loss comparable to semaglutide, while having fewer side effects."

"Pressing Need" to Address Obesity; Semaglutide Filed for Obesity

There is a "pressing need" to address the worldwide increase in obesity and weight-related coexisting conditions, Ingelfinger and Rosen note.

Sustained long-term weight loss with diet and exercise is challenging; behavioral weight-loss strategies "fail more often than not," bariatric surgery is invasive and often followed by eventual weight regain, they write.

In addition, say Wilding and colleagues, the "use of available [weight-loss] medications remains limited by modest efficacy, safety concerns, and cost."

Subcutaneous semaglutide, approved for treating type 2 diabetes (as Ozempic) in adults at doses of up to 1 mg/week, induced weight loss at higher doses. The current study is part of the global Semaglutide Treatment Effect in People With Obesity program of four trials (STEP 1, 2, 3, and 4) that aimed to test the safety and efficacy of subcutaneous semaglutide 2.4 mg/week for weight loss.

Topline results from STEP 1 were presented June 4, 2020.

And as reported earlier, results from STEP 3 — a 68-week trial of semaglutide versus placebo in 611 participants who all received very intensive diet and exercise counseling — were presented at the virtual ObesityWeek® 2020 meeting.

The four trials of semaglutide for weight loss have been completed and the data were submitted to the US Food and Drug Administration on December 4, 2020 (with a decision expected within 6 months) and to the European Medicines Agency on December 18, 2020.

Most Patients Had 5% Weight Loss With Semaglutide

The STEP 1 trial enrolled 1961 adults with a body mass index (BMI) ≥ 30 kg/m2 or ≥ 27 kg/m2 with at least one weight-related coexisting condition, but without type 2 diabetes, at 129 sites in 16 countries in Asia, Europe, North America, and South America.

Participants were a mean age of 47 and three quarters were women.

Most participants were White (76%), followed by Asian (13%), Black or African American (6%), or other (5%).

On average, they had a BMI of 38 kg/m2 and weighed 105 kg (231 lb). Three quarters had one or more coexisting conditions.

Participants were randomized to receive semaglutide (1306 patients) or placebo (655 patients), added to lifestyle intervention.

Everyone received 17 monthly individual counseling sessions during which they learned about adhering to a diet with a 500-calorie/day deficit, were encouraged to build up to walking 150 minutes each week, and recorded their daily diet and exercise (in a diary or using an app).

Semaglutide was administered with a prefilled pen injector at a dose of 0.25 mg/week for the first 4 weeks, escalated to 2.4 mg/week by week 16 (or lower if the patient had unacceptable side effects).

At 68 weeks, participants in the semaglutide versus placebo group had greater mean weight loss (14.9% vs 2.4%, or 15.3 kg vs 2.6 kg).

Participants in the semaglutide versus placebo group were much more likely to have lost at least 5% of their initial weight (86% vs 31.5%) or at least 10% of their initial weight (69.1% vs 12.0%), or at least 15% of their initial weight (50.5% vs 4.9%; P < .001 for all three comparisons).

Some on Semaglutide Had Weight Loss Equivalent to Bariatric Surgery

About 80% of participants adhered to the study treatment. A third of participants in the semaglutide group who completed the study lost at least 20% of their initial weight, which approaches the 20% to 30% reported weight loss 1 to 3 years after sleeve gastrectomy, the researchers note.

Study coauthor Rachel Batterham, MBBS, PhD, of the Centre for Obesity Research at University College London, said: "The findings of this study represent a major breakthrough for improving the health of people with obesity. No other drug has come close to producing this level of weight loss — this really is a game changer. For the first time, people can achieve through drugs what was only possible through weight-loss surgery."

"The impact of obesity on health has been brought into sharp focus by COVID-19, where obesity markedly increases the risk of dying from the virus, as well as increasing the risk of many life-limiting serious diseases...This drug could have major implications for...health policy for years to come," she noted in a statement from her institution.

Participants in the semaglutide group also had greater improvements in waist circumference and levels of A1c, C-reactive protein (a marker of inflammation), and fasting lipids, as well as in physical function scores on SF-36 and IWQOL-Lite-CT questionnaires.

In their editorial, Ingelfinger and Rosen note that "daily oral semaglutide [already approved in 7-mg and 14-mg doses for the treatment of type 2 diabetes as Rybelsus] might be more appealing to many people," as a weight loss medication than a once-weekly subcutaneous dose. Semaglutide is the first GLP-1 agonist available as an oral agent.

The ongoing Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial (with expected completion in 2023) will shed light on cardiovascular outcomes after 2.5 to 5 years.

GI Disorders and "Important Limitations"

More participants in the semaglutide than the placebo group reported gastrointestinal disorders (typically nausea, diarrhea, vomiting, and constipation; 74.2% vs 47.9%), which were mostly transient and mild to moderate in severity, but also led to more treatment discontinuation (7.0% vs 3.1%).

More patients in the semaglutide versus placebo group had a gall bladder-related disorder (2.6% vs 1.2%, mostly cholelithiasis) and mild acute pancreatitis (3 versus 0 participants), but there were no between-group differences in neoplasms.  

Wilding and colleagues acknowledge the limitations of the study, including the fact that it enrolled mainly women, mainly non-White participants, was relatively short, and excluded patients with type 2 diabetes.

Mean placebo-corrected weight loss with 2.4 mg/weekly subcutaneous semaglutide was greater than with 3.0 mg once-daily subcutaneous liraglutide (Saxenda, Novo Nordisk) — the only GLP-1 agonist approved for weight management — in the 56-week SCALE trial (12.4% vs 4.5%); however, the two studies had different populations.

The study was supported by Novo Nordisk. Author disclosures are available with the article. Ingelfinger is a deputy editor and Rosen is an associate editor of the New England Journal of Medicine. Ingelfinger, Rosen, and Leurent have reported no relevant financial relationships. O'Rahilly has a current research collaboration with Novo Nordisk scientists in an unrelated area and has been a consultant for the company.

N Engl J Med. Published online February 10, 2021. Article, Editorial

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