Weekly semaglutide injection associated with substantial weight loss in obesity
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Adults with obesity assigned the GLP-1 receptor agonist semaglutide experienced substantial weight loss compared with placebo, with more than half of participants losing 15% of body weight, according to data from the STEP 1 study.
“Semaglutide [Ozempic, Novo Nordisk] is the most impactful medication for the treatment of obesity, with 32% of participants losing at least 20% of their initial weight,” Robert Kushner, MD, professor of medicine and medical education at Northwestern University Feinberg School of Medicine, Chicago, told Healio. “It could be a game changer for those who struggle with obesity, which affects over 40% of American adults.”
For the Semaglutide Treatment Effect in People with Obesity (STEP) 1 trial, Kushner and colleagues analyzed data from 1,961 adults without diabetes with a BMI of at last 30 kg/m² or at least 27 kg/m² with a weight-related comorbid condition. Researchers randomly assigned participants in a 2:1 ratio to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 68 weeks. Both groups received lifestyle intervention. Coprimary endpoints were percentage change in body weight and weight reduction of at least 5%. Researchers used the primary estimand to assess effects regardless of treatment discontinuation or rescue interventions.
Significant weight loss observed
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).
Consistent with the GLP-1 receptor agonist class, nausea and diarrhea were the most common adverse events reported with semaglutide; these were typically transient and mild to moderate in severity, according to researchers. Within the cohort, 4.5% of participants in the semaglutide group and 0.8% of participants in the placebo group discontinued treatment due to gastrointestinal events.
Weight loss of at least 5% was significantly greater among participants in the semaglutide group at week 68 vs. placebo (86.4% vs. 31.5%), as was weight loss of 10% or more (69.1% vs. 12%) and weight loss of 15% or more (50.5% vs. 4.9%; P < .001 for all comparisons).
“We know that a lot of the health concerns we see in people who struggle with their weight, such as type 2 diabetes, hypertension, GERD and arthritis of the weight-bearing joints, are improved by losing at least 10% of body weight,” Kushner said. “In this study, nearly 70% of participants were able to achieve this 10% weight loss threshold by taking semaglutide.”
Kushner said future work must involve a more diverse patient population, including more men and people from underrepresented backgrounds.
“Other research questions include long-term use of the medication, how to use it effectively in primary care offices, and benefits in reducing cardiovascular disease,” Kushner said. “The SELECT trial is already underway.”
‘A long way to go’
In commentary accompanying the study, Julie R. Ingelfinger, MD, professor pediatrics at Harvard Medical School and senior consultant in pediatric nephrology at Massachusetts General Hospital for Children, and Clifford J. Rosen, MD, director of the Center for Clinical and Translational Research at the Maine Medical Center Research Institute in Scarborough, called the data encouraging and “a good beginning,” but noted the trial excluded several populations, including men and Black and other nonwhite adults, raising questions about efficacy of semaglutide among those groups. Additionally, more than 40% of the cohort had prediabetes; questions remain about the efficacy of the drug for adults with obesity and normal glucose tolerance. The authors also wrote that subcutaneous administration may not be “palatable or cost-effective in the long run.”
“Similarly, given the effectiveness of bariatric surgery in regard to both weight loss and glucose tolerance, studies comparing these two distinct forms of therapy (surgery and pharmacologic therapy) will be required,” the researchers wrote. “In sum, we have a long way to go to control the obesity epidemic, but STEP 1 serves its name well.”
For more information:
Robert F. Kushner, MD, can be reached at rkushner@northwestern.edu; Twitter: @DrRobertKushner.
Perspective
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This is a long-awaited paper. The findings are notable because of the sheer magnitude of the weight loss, which is 14.9%. Even if you subtract the 2.4% weight loss in the placebo group, you still end up with over 12% weight loss for those assigned semaglutide. The difference compared against other available obesity drugs is basically doubled.
Additionally, with weight loss after undergoing sleeve gastrectomy typically around 25%, we are narrowing the gap between drugs and surgery for obesity treatment. The adverse effect profile of semaglutide is also very good, and this agent has the advantage of being a once-weekly drug.
Perspective
Back to TopDavid A. Cohen MD, FACE, ECNU; Priya Jaisinghani, MD
In the United States, from 1999-2000 through 2017-2018, the prevalence of obesity increased from 30.5% to 42.4%, and the prevalence of severe obesity increased from 4.7% to 9.2% (CDC. Adult Obesity Facts. https://www.cdc.gov/obesity/data/adult.html). The worldwide prevalence of obesity has nearly tripled between 1975 and 2016, with more than 1.9 billion adults aged 18 years or older carrying the diagnosis of overweight, and over 650 million of obese (WHO. Obesity and Overweight. www.who.int/news-room/fact-sheets/detail/obesity-and-overweight).
A clinically relevant reduction in body weight is often recommended in obesity-related conditions such as type 2 diabetes, hypertension, gastroesophageal reflux disease, obstructive sleep apnea and nonalcoholic fatty liver disease. According to the Pharmacological Management of Obesity: An Endocrine Society Clinical Practice Guideline, care of all patients with a BMI greater than 25 kg/m2 should include diet, exercise and behavioral modification. Other therapeutic modalities such as pharmacotherapy (if BMI > 27 kg/m2 with comorbidity or BMI > 30 kg/m2) and bariatric surgery (BMI > 35 kg/m2 with comorbidity or BMI > 40 kg/m2) may be used as an adjunct to behavioral modification. However, sustaining weight loss over the long term is challenging.
Weight management requires an individualized approach to care with lifestyle intervention with diet and exercise as the foundation and pharmacological and surgical interventions reserved for selected patients. Currently, there are five approved weight management medications; however, all are administered at least once daily and have varying side effect profiles, leading to concerns about patients' ability to adhere to the regimen. A medication with less frequent dosing and fewer side effects could potentially improve a patient’s ability to adhere to the regimen.
Wilding et al conducted a double-blind trial to ascertain if once-weekly 2.4 mg semaglutide, when taken as an adjunct to lifestyle intervention, can reduce weight. The study enrolled 1,961 participants with a BMI of 30 kg/m2 or greater (or ≥27 kg/m2 in persons with one or more weight-related coexisting conditions) who did not have diabetes and were randomly assigned to once-weekly 2.4 mg subcutaneous semaglutide or placebo plus lifestyle intervention for 68 weeks. Looking at the participants, the majority were white (75.1%) and female (74.1%) with a mean age of 46 years.
Findings revealed that adults in the semaglutide group had a mean change in body weight of –16.9% compared with –2.4% among the control group. More than 86% of the semaglutide recipients also achieved weight reductions of at least 5% vs. only 31.5% of the controls. Seventy-four percent of the semaglutide group reported at least one gastrointestinal side effect, including nausea, vomiting, diarrhea or constipation, compared with 48% of those in the placebo group. However, most symptoms were mild to moderate in severity and transient in duration. About 4.5% of those on semaglutide discontinued treatment due to GI events compared with 0.8% on placebo.
There are a few limitations to this study. First, given that the highest age-adjusted prevalence of obesity in the United States is among non-Hispanic Black adults (49.6%), followed by Hispanic adults (44.8%), non-Hispanic white adults (42.2%) and non-Hispanic Asian adults (17.4%), the study population questions the external validity when applicable to minority populations (Apovian CM, et al. J Clin Endocrinol Metab. 2015;doi:10.1210/jc.2014-3415). Second, it is unknown if the results are generalizable to long-term treatment effects beyond the 68 weeks or after discontinuation of the medication. Finally, the study also did not take into account cost, quality of life or patient preference, which should be investigated further.
Obesity is becoming an increasingly common condition, which is not only costly but has serious implications leading to premature death. The study with once-weekly semaglutide produces clinically significant weight loss, which will provide another effective option beyond lifestyle changes for people to combat this epidemic.
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