Semaglutide (CSPC Zhongqi)

The cardiovascular (CV) benefits associated with Novo Nordisk's GLP-1 obesity drug Wegovy (semaglutide) may be due to more than just weight loss alone, the company said. Detailed findings from the Phase III SELECT trial, which Novo Nordisk reported in August as having shown a significant 20% risk reduction in major adverse cardiovascular events (MACE) over a period of up to five years versus placebo, were shared Saturday at the American Heart Association (AHA) annual Scientific Sessions.The SELECT study, which ran from October 2018 through to June of this year, involved just over 17,600 adults aged 45-plus with a body mass index (BMI) of at least 27 and no history of diabetes. Over 70% had a BMI of 30 or more. The primary CV endpoint was a composite of death from CV causes, non-fatal myocardial infarction, or non-fatal stroke in a time-to-first-event analysis.According to the latest findings, which were also published in the NEJM, risk reductions in MACE were achieved regardless of age, gender, ethnicity and starting BMI, and were seen soon after patients started treatment. "This suggests that weight loss alone may not fully explain the benefits of [Wegovy] in reducing the risk of MACE," the company said.Michael Lincoff, who led the trial, said "the differences in rates between the two treatment groups began to emerge very early after initiation of treatment, within the first months."Risk of death cut by 19%A primary CV endpoint event occurred in 6.5% of patients who were given Wegovy, versus 8% of those in the placebo group, for a hazard ratio of 0.8 in favour of Novo Nordisk's drug. Analyses of the three components in MACE showed that the risk of non-fatal myocardial infarction was cut by 28% compared to placebo. Wegovy also reduced the risk of cardiovascular death and non-fatal stroke versus placebo by 15% and 7%, respectively, although neither of these was statistically significant over the length of the trial.Confirmatory secondary endpoints showed that the risk of composite heart failure events, comprising CV death, urgent heart failure visits and hospitalisations, was reduced by 18% with Wegovy compared to placebo, while there was a 19% lower risk of death from any cause.Multiple pathways underlying benefitSupportive secondary endpoints also suggested that Wegovy had "beneficial effects" on other CV risk factors, such hypertension, cholesterol and glucose levels, Novo Nordisk said. Wegovy-treated participants lost an average of 9.4% of total body weight, sustained throughout the trial, although SELECT was not designed to evaluate weight loss. They also saw their waist circumference shrink by about 6.5 cm, relative to placebo. Patients on Wegovy experienced a decrease in C-reactive proteins of 37.8% as well, compared with placebo.Researchers noted that while the mechanisms of the CV protection from Wegovy "remain speculative," there was a consistent effect on associated risk factors that support the idea that multiple pathways are behind the drug's effects. "The CV benefit (of Wegovy) is a combination of many factors, but I would call out glycaemic control, weight loss and inflammation," commented Martin Lange, Novo Nordisk's head of development.Regulators in the US and UK last week approved Eli Lilly's rival weight-loss treatment Zepbound (tirzepatide). The dual GIP and GLP-1 agonist had previously been approved and marketed as Mounjaro for type 2 diabetes. A recent survey of US physicians conducted by FirstWord found that nearly 70% are currently using the drug off-label to treat obesity.More to follow.