Fighting the obesity challenge: Lancet study says higher doses of weight loss drugs can safely reduce body weight faster

The STEP UP and STEP UP diabetes clinical trials are the first to investigate whether increasing the dose of semaglutide from the currently approved dose of 2.4 mg to 7.2 mg is safe and leads to additional weight reduction.

What is semaglutide?

Semaglutide is an anti-diabetic and an anti-obesity medication used for long-term weight management. It mimics the hormone glucagon-like peptide-1, which regulates insulin secretion. It can be administered by subcutaneous injection or taken orally.

Why is the study significant?

According to Sean Wharton from the Faculty of Medicine, University of Toronto, and other researchers of the STEP UP Trial, the “greater magnitude of bodyweight change with semaglutide 7.2 mg, compared with lower doses, could help with managing obesity-related complications, which had not been addressed with previous treatments.”

Mumbai-based Dr Aparna Govil Bhasker, bariatric and laparoscopic surgeon (not part of the trial), said such trials help us understand that obesity is a disease and not a self-implicated problem which does not deserve to be treated. “Obesity is a disease and needs to be treated as per its stage and severity. Diet and lifestyle modification, weight loss medications and bariatric surgery are different prongs of treatment. These may be needed in isolation or in combination depending on the severity of the disease,” she said.

Is the study relevant for India?

Dr R M Anjana of Dr Mohan’s Diabetes Specialities Centre, Chennai, says a higher dose may not work uniformly across the Indian population. “We typically see four distinct subtypes — severely insulin-deficient individuals, obese, insulin-resistant individuals, a mixed phenotype with features of both insulin resistance and deficiency and mild age-related diabetes, often seen in older adults. Unlike Western populations, where obesity is a dominant factor, the percentage of individuals with obesity in India is relatively lower. In our context, insulin deficiency is one of the primary drivers of diabetes. Many of our patients are lean, with low body mass index (BMI), and for them, weight loss therapies may offer limited benefit. However, in those with significant intra-abdominal (visceral) fat — a phenotype that is also common in our setting — we can expect more promising results with weight loss strategies such as this higher-dose regimen,” she says.

Since the drug has been available in the market for the past three months and the early signals are encouraging, Dr Anjana believes in a wait and watch approach to fully understand its long-term impact across different patient groups.

What was the trial all about?

STEP UP was a Phase 3, randomised, controlled with a treatment duration of 72 weeks and a 9-week off-treatment follow-up. The trial funded by Novo Nordisk was conducted across 95 hospitals, specialist clinics, and medical centres in 11 countries. Between January 1, 2023, and November 26, 2024, 1,407 trial participants were randomly assigned to receive either the higher 7.2 mg dose of semaglutide, the currently approved 2.4 mg dose or placebo over 72 weeks. All participants—regardless of treatment group—received lifestyle interventions such as dietary counselling and increased physical activity recommendations.

In adults without diabetes, a 7.2 mg dose of semaglutide led to an average weight loss of nearly 19%, surpassing the 16% loss seen with 2.4 mg and 4% with placebo. Nearly half of the participants on the higher dose lost 20 per cent or more of their body weight, with about one-third losing at least 25%. Participants also experienced improvements in waist circumference, blood pressure, blood sugar and cholesterol levels, all key factors in reducing obesity-related health risks.

Similarly, in adults with obesity and diabetes, the 7.2 mg dose resulted in an average 13% weight loss compared to 10% with 2.4 mg and 3.9% with placebo, along with significant reductions in blood sugar levels and waist size.

Are higher doses safe?

Both trials reported that the higher dose of semaglutide was safe and generally well-tolerated. Gastrointestinal side effects like nausea and diarrhoea and some sensory symptoms like tingling were the most common. However, most side effects were manageable, resolved over time and did not lead to participants dropping out of the trial. No increase in serious adverse events or severe hypoglycaemia was observed with the higher dose. However, further research is needed to fully understand long-term benefits and risks.

Why obesity management is not just about diet and lifestyle

As per the National Family Health Survey-5, one in every four Indians is said to be overweight or obese. As per the ICMR-INDIA B study, 101 million people are living with diabetes in India. Both conditions are now affecting younger people leading to early onset of complications. Obesity is no longer an urban phenomenon, it has spread to rural areas as well. “This also means that millions of people are at risk of developing related complications like blindness, heart attacks, kidney failure and amputations when it comes to diabetes. Obesity adds to this burden by further increasing the cardio-vascular risk. It also leads to increased risk of hypertension, dyslipidemia, metabolic dysfunction-associated steatotic liver disease (MASLD) or non-alcoholic fatty liver, joint related issues and obstructive sleep apnoea,” Dr Bhasker explained.

Diet and lifestyle modification alone are not effective in all cases to control weight gain and obesity, she argues. “In the long term, most people are able to maintain less than 5% of their lost weight with diet and exercise alone. There is a need for better medications that can effectively control weight gain and diabetes so that in future, related complications can be avoided. That will not only better the quality of life but bring down long-term healthcare costs related to complications,” Dr Bhasker said.

She however observed that misuse of the drugs must be avoided. “Self-administration and over the counter use must be strictly avoided. They must be reserved for those who need them and not used for cosmetic makeovers,” Dr Bhasker added.