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Regulatory approval sought for 'gamechanger' obesity drug

More than a third (35%) of people who took a new drug for treating obesity lost more than one-fifth (≥20%) of their total body weight, according to a large international trial, writes MedicalBrief. Semaglutide, already approved and used for treatment of diabetes, has been submitted for regulatory approval in the US, EU and UK.

In the Semaglutide Treatment Effect in People with Obesity (STEP)1 study, a total of 86.4% of adults on semaglutide were able to cut at least 5% of their baseline body weight during the trial compared with only 31.5% of those adhering to lifestyle intervention alone, the researchers wrote in the study online in the New England Journal of Medicine. Beyond that, almost 70% of those on semaglutide plus lifestyle intervention achieved a 10% or more weight loss, and more than half were able to lose 15% of their baseline body weight.

In addition to weight loss, semaglutide also improved cardiovascular risk factors including greater reductions in waist circumference, BMI, systolic and diastolic blood pressures, HbA1c, fasting plasma glucose, C-reactive protein, and fasting lipid levels, as well as physical functioning scores and quality of life.

The findings from the large-scale international trial are being hailed as a "gamechanger" for improving the health of people with obesity and could play a major part in helping to reduce the impact of diseases, such as COVID-19.

The drug, semaglutide, works by hijacking the body's own appetite regulating system in the brain leading to reduced hunger and calorie intake.

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, is one of the principal authors on the paper which involved almost 2,000 people in 16 countries.

Batterham (UCL Medicine) said: "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%. 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."

Batterham added: "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. This drug could have major implications for UK health policy for years to come."

The average participant in the trial lost 15.3kg (nearly 3 stone); this was accompanied by reductions in risk factors for heart disease and diabetes, such as waist circumference, blood fats, blood sugar and blood pressure and reported improvements in their overall quality of life.

The trial's UK chief investigator, Professor John Wilding (University of Liverpool) said: "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. 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 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."

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 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 (under the skin) injection; similar to the way people with diabetes inject insulin. 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 those taking semaglutide, the average weight loss was 15.3kg (nearly three stone), with a reduction in BMI of -5.54. The placebo group observed an average weight loss of 2.6kg (0.4 stone) with a reduction in BMI of -0.92.

Those who had taken semaglutide also saw reductions in risk factors for heart disease and diabetes, such as waist circumference, blood fats, blood sugar and blood pressure and reported improvements in their overall quality of life.

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.

While the STEP study has been through Phase I and II trials, assessing the 2.4mg doses for safety, in the Phase III trial some participants reported side effects from the drug including mild-to-moderate nausea and diarrhoea that were transient and generally resolved without permanent discontinuation from the study.

However, an accompanying NEJM editorial, described the gastrointestinal side effects as "concerning" and noted that oral semaglutide has been associated with pancreatitis and with thyroid C-cell tumours in rodents.

"In the real world, it seems unlikely that once-weekly subcutaneous administration would be a palatable or cost-effective solution in the long run."  Instead, daily oral semaglutide might be a more "appealing" option to patients. They suggested that future head-to-head trials compare oral GLP-1 agonists with SGLT-2 antagonists, and also compare these pharmacologic therapies with bariatric surgery to assess long-term outcomes.

 

Study details
Once-Weekly Semaglutide in Adults with Overweight or Obesity

John PH Wilding, Rachel L Batterham, Salvatore Calanna, Melanie Davies, Luc F Van Gaal, Ildiko Lingvay, Barbara M McGowan, Julio Rosenstock, Marie TD Tran, Thomas A Wadden, Sean Wharton, Koutaro Yokote, Niels Zeuthen, Robert F Kushner for the STEP 1 Study Group

Published in the New England Journal of Medicine on 10n February 2021

Abstract
Background
Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.
Methods
In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) 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.
Results
The mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group as compared with −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 than in the placebo group achieved weight reductions of 5% or more (1047 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). The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7). 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 diarrhea were the most common adverse events with semaglutide; 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%]).
Conclusions
In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight.

Funded by Novo Nordisk

 

[link url="https://www.nejm.org/doi/pdf/10.1056/NEJMoa2032183"]New England Journal of Medicine study (Restricted access)[/link]

 

[link url="https://www.nejm.org/doi/full/10.1056/NEJMe2101705"]New England Journal of Medicine editorial (Restricted access)[/link]

 

 

See also MedicalBrief archives:

 

[link url="https://www.medicalbrief.co.za/archives/more-years-of-obesity-means-higher-risk-of-cardiometabolic-disease/"]More years of obesity means higher risk of cardiometabolic disease[/link]

 

[link url="https://www.medicalbrief.co.za/archives/obesity-increases-type-2-diabetes-risk-six-fold-regardless-of-genetics/"]Obesity increases type 2 diabetes risk six-fold, regardless of genetics[/link]

 

[link url="https://www.medicalbrief.co.za/archives/report-breakthrough-slimming-pill-european-congress-obesity/"]Report on ‘breakthrough’ slimming pill — European Congress on Obesity[/link]

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