One third (35%) of patients who received semaglutide for treating obesity lost more than one-fifth (greater than or equal to 20%) of their total body weight, according to the outcomes from the ‘Research Study Investigating How Well Semaglutide Works in People Suffering From Overweight or Obesity’ (STEP 1) randomised clinical trial. The findings reported in the paper, ‘Once-Weekly Semaglutide in Adults with Overweight or Obesity’, from the large-scale international trial were published in the New England Journal for Medicine.
"The findings of this study represent a major breakthrough for improving the health of people with obesity. Three quarters (75%) of people who received semaglutide 2.4mg lost more than 10% of their body weight and more than one-third lost more than 20%,” said Professor Rachel Batterham, Professor of Obesity, Diabetes and Endocrinology who leads the Centre for Obesity Research at University College London (UCL) and the UCLH Centre for Weight Management, and one of the principal authors on the paper which involved almost 2,000 people in 16 countries. “No other drug has come close to producing this level of weight loss - this really is a gamechanger. For the first time, people can achieve through drugs what was only possible through weight-loss surgery."
The Phase III 'STEP' randomised controlled trial involved 1,961 adults who were either overweight or had obesity (average weight 105kg/16.5 stone; body mass index 38kg/m2) and took place at 129 sites in 16 countries across Asia, Europe, North America, and South America.
Participants took a 2.4mg dose of semaglutide (or matching placebo) weekly via subcutaneously injection. Overall, 94.3% of participants completed the 68-week study, which started in autumn 2018. Those taking part also received individual face-to-face or phone counselling sessions from registered dietitians every four weeks to help them adhere to the reduced-calorie diet and increased physical activity, providing guidance, behavioural strategies and motivation. Additionally, participants received incentives such as kettle bells or food scales to mark progress and milestones.
In this double-blind trial, patients who did not have diabetes, were randomly assigned in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.
Semaglutide is clinically approved to be used for patients with type 2 diabetes, though is typically prescribed in much lower doses of 1mg. The drug possesses a compound structurally similar to (and mimics) the human glucagon-like peptide-1 (GLP-1) hormone, which is released into the blood from the gut after meals. GLP-1 induces weight loss by reducing hunger, increasing feelings of fullness and thereby helping people eat less and reduce their calorie intake.
The mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group vs. −2.4% with placebo, for an estimated treatment difference of −12.4 percentage points (95% confidence interval [CI], −13.4 to −11.5; p<0.001). More participants in the semaglutide group achieved weight reductions of 5% or more (1,047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]) and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (p<0.001 for all three comparisons of odds).
"This is a significant advance in the treatment of obesity. Semaglutide is already approved and used clinically at a lower dose for treatment of diabetes, so as doctors we are already familiar with its use,” commented Professor John Wilding from the University of Liverpool and the trial's UK Chief Investigator. “For me this is particularly exciting as I was involved in very early studies of GLP1 - when I worked at the Hammersmith Hospital in the 1990s and we were the first to show in laboratory studies that GLP1 affected appetite - so it is good to see this translated into an effective treatment for people with obesity."
The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as vs. −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7). The researchers also reported participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhoea were the most common adverse events with semaglutide, although they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).
"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 including heart disease, type 2 diabetes, liver disease and certain types of cancers<” added Batterham. “This drug could have major implications for UK health policy for years to come."
With evidence from this trial, semaglutide has been submitted for regulatory approval as a treatment for obesity to the National Institute of Clinical Excellence (NICE), the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA).
The STEP 1 study was funded by Novo Nordisk. For more information, please click here