Weight loss alone does not explain the lower incidence of heart disease in people taking semaglutide

The SELECT trial provided the first evidence of the benefit of 2.4 mg semaglutide in overweight and obese people without diabetes, showing a reduction of more than 20 per cent in cardiovascular events. This was not surprising, as numerous studies in type 2 diabetes had already demonstrated the benefits of GLP-1, but this was the first large-scale study, involving over 17,000 patients followed for four years, in which Spain played a very active role. Here, in the absence of diabetes, a reduction in these events has been achieved for the first time.

It is a high-quality study because it involves a large number of patients over a very long period, and, naturally, data continue to be published; in this case, the findings are truly interesting. We are already aware of the beneficial effects it has on risk factors such as weight, waist circumference, inflammation, glycated haemoglobin levels, systolic blood pressure and renal function. However, all these improved variables would only account for 31 per cent of this cardiovascular benefit.

There remains a statistically significant proportion—69 per cent—of this cardiovascular benefit that requires further investigation. It is hypothesised that this may be due to the direct anti-inflammatory effect of GLP-1, improvements in vascular health and, naturally, renal and lipid protection.

We now know, thanks to major studies such as SELECT, that the benefit of this new class of drugs goes far beyond weight loss or waist circumference reduction. It has a proven cardiovascular benefit, with a 20 per cent reduction in events. For many reasons, we must stop thinking of it as a drug for losing weight; it is a drug for gaining health and, indeed, cardiovascular health.

The study is of very high quality and its conclusions are clear: the observed benefits of semaglutide in relation to serious cardiovascular problems cannot be explained solely by the improvements seen in the main risk factors identified and assessed in this study.

In the SELECT trial, treatment with semaglutide was associated, compared with placebo, with improvements in various risk factors or markers, such as body weight, waist circumference, glycated haemoglobin, C-reactive protein, blood pressure and certain indicators of kidney function. However, the most interesting finding is that the analyses carried out did not allow the reduction in serious cardiovascular events to be attributed with certainty to the combination of these improvements. Weight loss appears to contribute to this benefit, but would only account for part of it.

The study highlights that we still do not understand a significant proportion of the mechanisms responsible for semaglutide’s cardioprotective effect. The parameters analysed primarily relate to well-known risk factors and biomarkers; therefore, further mechanistic research will be necessary to identify other possible mediators of its cardiovascular effects.

As for the implications of the study, probably the most relevant is that we must move beyond interpreting semaglutide simply as a weight-loss drug. Weight loss is undoubtedly one of its important effects, but it does not appear to explain the observed cardiovascular protection on its own. Understanding the additional mechanisms involved will allow us to better interpret its effects and, eventually, define more precisely which patients may benefit from them.