Four-year data on the GLP-1 RA shows obesity and cardiovascular benefits are widespread and long term.
Semaglutide reduced weight by an average of 10% and waste circumference by 7cm for at least four years in overweight or obese people with established cardiovascular disease without diabetes, according to newly released data.
The drug also had significant cardiovascular benefits, independent of weight loss.
“We now have a class of drugs that could … transform many chronic diseases of ageing,” said cardiologist Professor John Deanfield, lead author of one of the two studies presented at the European Congress on Obesity in Venice, Italy last month based on the Semaglutide and Cardiovascular Outcomes (SELECT) trial.
“What we’re starting to see now is a drug class … producing a benefit not only in [patients’] weight, [and] in their glycaemic control, but most importantly in the outcome of this very important disease, cardiovascular disease. And that’s the excitement in this trial, that it is going to potentially change clinical practice,” he said.
The Select trial involved 17,604 people with established cardiovascular disease, but not diabetes, from 41 countries. They were aged 45 or older with a mean of 61 years of age, and had a BMI of 27 or higher, with a mean of 33 kg/m². The group was 72% male. Half were assigned to take semaglutide in addition to standard-of-care recommendations for CVD reduction (without a focus on weight loss), and the other half placebo plus standard care, for an average of 40 months.
Earlier results from the trial showed a 20% lower risk of stroke, heart attack or death from cardiovascular disease, and an average weight loss of 9.4%.
The weight came off and stayed off
One of the new studies, published in Nature Medicine, looked at the weight effects on the study population at four years. It showed patients taking 2.4mg of semaglutide once a week lost an average of 10% of their body weight, 7.7cm from their waistline, and waist circumference-to-height ratio fell 6.9%. This was compared to 1.5%, 1.3cm, and 1% in the placebo group. The semaglutide group continued losing weight until week 65 and kept it off for the four years they were followed up. These results were irrespective of starting blood sugar status or metabolically unhealthy body fat.
After two years, 52% of the semaglutide group had moved to a lower BMI category, compared with 16% of the placebo group, and 12% achieved a BMI of 25kg/m² or less with semaglutide compared to 1.2% in the placebo group.
“What this says is that patients on semaglutide had a much greater chance of no longer having obesity after treatment with this medication,” says lead author and past president of the World Obesity Federation, Professor Donna Ryan from the Pennington Biomedical Research Centre in New Orleans.
Individual weight loss variation was “striking”, the authors wrote. However, 68% lost 5% or more of their body weight, compared to 21% of those on placebo, and 44% achieved 10% weight loss at two years compared with 7% on placebo. Those in lower BMI categories lost a smaller percentage of weight.
Almost all participants, 97%, stayed on the trial until the end. About 77% of those on semaglutide were on the recommended dose by the end of the study. Others were on lower doses or had paused treatment. Individual weight loss was associated with dose.
More of the semaglutide group quit the trial (17% vs 8% in the placebo group) because of gastrointestinal symptoms such as nausea and diarrhoea during the 20-week dose escalation period.
The rates of discontinuation were higher in the lower BMI groups “probably reflecting exposure to a higher level of drug in lower BMI categories,” the authors write “… although other explanations, including differences in motivation and cultural mores regarding body size, cannot be excluded.”
There were more serious adverse events in the placebo group (36% vs 33%) because of the greater number of cardiovascular events in the former. Pancreatitis rates were not higher in the semaglutide group, but gallbladder stones were.
“This degree of weight loss in such a large and diverse population suggests that it may be possible to impact the public health burden of multiple obesity-related illnesses. While our trial focused on cardiovascular events, many other chronic diseases including several types of cancer, osteoarthritis, and anxiety and depression would benefit from effective weight management,” says Professor Ryan.
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Heart attack prevention not tied to weight loss
The second study, led by Professor Deanfield from the University College London, showed that at six months the semaglutide group had a consistent reduction in major adverse cardiovascular events, no matter what weight they started at, and regardless of how much weight they lost.
“That’s a key question for clinicians. You don’t have to look for people with a particularly high level of adiposity and obesity measures to recommend this treatment,” says Professor Deanfield.
Perhaps surprisingly, the magnitude of CV benefit was not related to the amount of weight lost.
Those on semaglutide had a 32% reduction in major adverse cardiovascular events while the placebo group had a 15% reduction. In the semaglutide group, those who lost 5% or more of their body weight had similar rates to those who lost less than 5% or gained weight, whereas greater weight loss in the placebo group was related to a better hazard reduction rate.
“That’s an important question for patients, they ask … does the cardiovascular benefit that I’m hoping to achieve depend on the amount of weight that I lose? And in fact, that’s not the case. You can get no weight loss or very little weight loss and still get the same cardiovascular benefit,” says Professor Deanfield.
It suggests there is another mechanism involved beyond weight loss acting on the cardiovascular system, he says.
“We’ve been a little bit coy about what it actually is because we don’t know yet.”
Semaglutide has a lot of “subtle” effects, such as a change in what people eat as well as how much, and possible impacts on arterial and vascular walls.
“So it is not just an obesity drug, although that’s very upfront and important for the patients, for lots of reasons. It’s a drug that actually targets perhaps the underlying biology of important chronic diseases and benefits. So that’s the excitement.”
‘Practice changing’
A revision of guidelines involving the use of semaglutide is imminent, according to Professor Deanfield, who says the discoveries about semaglutide will have impacts akin to the magnitude of change brought about by statins in his field of cardiology.
The patients in the study were already well looked after in terms of existing therapies, he points out, and semaglutide was still able to add a significant benefit.
“All the big societies are talking about the use of GLP-1s in patients with [pre-existing cardiovascular] disease, to alter their future trajectory to clinical events. … There’s no doubt that patients will benefit … from adding this on to previous existing therapy,” he says.
The researchers say their results apply across gender, age, ethnicity, body size, and country of residence, but cautioned that they could not yet be applied to a population that does not have pre-existing cardiovascular disease.
The Select trial was about secondary, not primary prevention, says Professor Ryan.
“The drug was efficacious in reducing risk for subsequent cardiovascular events. Extrapolating that to a population that has lesser risk was not done in this study and we shouldn’t really do that unless we have evidence.”
The US has announced that the use of semaglutide for secondary cardiovascular event prevention will be publicly funded, in addition to the existing indication for weight loss for people with a BMI of 27 with a comorbidity or a BMI of 30 and above.
“They haven’t laid out what their criteria are for established cardiovascular disease. How far they’ll go with that, we don’t know yet,” says Professor Ryan.
In Australia, the PBS only subsidises semaglutide under specific conditions for people with diabetes mellitus type 2 and supplies are limited. In 2022 it was approved by the TGA for weight loss in adults “as an adjunct to a reduced-energy diet and increased physical activity for chronic weight management (including weight loss and weight maintenance) in adults with an initial Body Mass Index (BMI) of: 30 kg/m2 (obesity), or 27 kg/m2 to <30 kg/m2 (overweight) in the presence of at least one weight-related comorbidity” and in adolescents aged 12 and over with obesity and body weight above 60kg. However, it is not yet available here.
