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Last weekend, results from a much-anticipated clinical trial were published in the New England Journal of Medicine, and in the days since then, variations of the headline “Weight Loss Drug Reduces Risk of Heart Attacks” have been scattered across mainstream news outlets. The blockbuster drug semaglutide (trade names Wegovy and Ozempic) – which has demonstrated impressive efficacy in reducing body weight and improving glycemic control – had reportedly been found to have a third clinical benefit in lowering risk of cardiovascular (CV) events. With semaglutide already considered a game-changing treatment for obesity and type 2 diabetes, these new findings have further added to its aura as a “miracle drug.” But when it comes to cardiovascular benefits, the results of this trial fall far short of miraculous.
Motivation for the Study
Semaglutide is a member of the class of drugs known as GLP-1 receptor agonists, which we have covered in depth in previous podcasts (see AMAs #29 and #45) and newsletters. Briefly, these medications have been shown through numerous clinical trials to be effective in improving metabolic health through weight reduction and improvement of glucose regulation. The mechanisms by which these drugs act are not fully understood but likely involve numerous biochemical pathways related to metabolism, appetite, and inflammation, raising the possibility of a variety of effects beyond (and independent of) reduction of energy intake and blood glucose levels.
Particular interest for potential “bonus” effects of semaglutide has focused on possible improvements to cardiovascular health, given the complex interactions of metabolism and inflammation in the pathogenesis of atherosclerosis. Fueling this interest, a 2021 meta-analysis of GLP-1 receptor agonist trials reported that use of these medications was associated with a 14% reduction in risk of major adverse cardiac events (MACE) relative to placebo among diabetic patients. But no individual trial had been designed specifically to investigate the impact of these drugs on CV endpoints, and in such cases, heterogeneity in study design across trials or anomalous results in particular cohorts can easily undermine the reliability of results from meta-analyses. Further, the analysis had looked only at patients with pre-existing type 2 diabetes, and it remained unclear whether GLP-1 receptor agonists would have similar CV effects in individuals without this inflammatory disease.
About the Study
To address these unknowns, researchers Lincoff et al. conducted the “Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity” (SELECT) trial with the specific aim of evaluating the effects of semaglutide on cardiovascular risk in non-diabetic patients with overweight or obesity. For this double-blind, multi-site, placebo-controlled trial, the investigators enrolled 17,604 patients aged ≥45 (mean age: 61.6±8.9 years) with overweight or obesity (mean BMI: 33.3±5.0) and established cardiovascular disease. Participants were randomized in a 1:1 ratio to receive either placebo or semaglutide (2.4 mg maximal dose, achieved over a 16-weeks ramp from a starting dose of 0.24 mg) once weekly by subcutaneous injection for a mean duration of 34.2±13.7 months.
As a primary endpoint, the authors assessed MACE, a composite of cardiovascular-related death and non-fatal heart attacks or strokes. These events occurred in a reported 6.5% of participants in the semaglutide group (569 of 8,803 patients) and 8.0% of participants in the placebo group (701 of 8,801 patients), corresponding to a relative risk reduction of 20% (HR: 0.80; 95% CI: 0.72-0.90; P<0.001). Secondary efficacy endpoints for heart failure and all-cause mortality likewise favored the semaglutide group, with hazard ratios of 0.82 (95% CI: 0.71-0.96) and 0.81 (95% CI: 0.71-0.93), respectively. An additional secondary endpoint for death from cardiovascular causes followed a similar trend but did not achieve statistical significance between groups (2.5% of patients on semaglutide versus 3.0% on placebo; HR: 0.85; 95% CI: 0.71-1.01; P=0.07).
As with earlier semaglutide clinical trials, the intervention group also experienced greater weight loss and a higher incidence of treatment-related gastrointestinal symptoms than the placebo group. While patients in the placebo arm had lost an average of 0.88±0.08% of their baseline body weight by 104 weeks post-randomization, patients in the semaglutide arm had lost an average of 9.39±0.09%. Notably, this percentage in the intervention group is substantially less than has been observed in previous trials using semaglutide at the same dose over shorter or equivalent treatment durations, but the finding is consistent with other studies showing that real-world results with semaglutide are not as dramatic as the results from clinical trials. Additionally, more participants in the semaglutide group (16.6%) experienced adverse events leading to permanent treatment cessation than in the placebo group (8.2%, P<0.001), and the vast majority of these events were gastrointestinal disorders.
A Weighty Question
The 15-20% relative risk reductions for MACE observed in this trial are considerable, on par with or approaching risk reductions that have previously been reported in high-risk patients on other CV medications, such as statins and PCSK9 inhibitors. So it is certainly true that Lincoff et al.’s results support the idea that semaglutide reduces CV event risk, but this is not the question we ought to be asking.
For individuals with obesity or overweight at baseline, any intervention that reduces fat mass and improves metabolic health would be expected to cause a reduction in CV risk as well, as weight reduction typically results in a reduction in blood pressure, circulating lipid levels, inflammation, and other CVD risk factors. The million-dollar question is instead whether semaglutide reduces CV risk independently of its effects on body weight – for if so, it would have two powerful implications for clinical practice: (1) relative to other anti-obesity treatments, semaglutide would have an advantage of providing bonus CV protection, making it a preferred option for treating obesity among patients with relatively high risk of CVD; and (2) semaglutide would hold promise as a medication indicated for cardiovascular disease, meaning that it might be prescribed specifically for this purpose even among patients without obesity or diabetes.
Addressing this critical question requires a strategy for separating the effects of semaglutide on body weight from its potential effects on CVD risk. This might be accomplished by utilizing an alternative weight reduction strategy in the placebo group (e.g., bariatric surgery, calorie restriction, etc) to ensure that both groups lose comparable weight, such that any additional reduction in MACE risk in the semaglutide group could be clearly distinguished from effects on body weight. Another option would be to stratify all participants into subgroups by percentage of weight lost and evaluate how well the stratification correlates with MACE.
Where SELECT Fell Short
Disappointingly, the SELECT trial employed no such strategies to control for body weight changes, leaving us without any reason to believe that the apparent CV benefits are independent of weight loss or are unique to semaglutide.
Indeed, previous research on bariatric surgery provides strong evidence against the interpretation of additional, semaglutide-specific cardioprotective effects. Several studies have demonstrated reductions in MACE risk of as much as 60% following bariatric surgery (reviewed here), underscoring that weight loss interventions other than GLP-1 receptor agonists also lead to considerable improvements in CV health. Further, although bariatric surgery is associated with much greater reductions in weight than observed in the SELECT trial (typically 20-30%), some evidence has suggested that the CV benefits of surgery correlate with the amount of weight lost.
The authors argue that because the two groups diverged in MACE risk early in the trial, the impact on CV health was too fast to be a secondary effect of weight reduction. Yet their data show that semaglutide-associated body weight reductions also occurred rapidly after the start of the intervention, with roughly half of the weight loss in semaglutide-treated patients taking place within the first 12 weeks on the study drug. Meanwhile, the researchers offer no quantitative information on the point at which the groups diverged significantly in CVD risk – in terms of statistics, we only know that the difference in MACE between the semaglutide and placebo arms had achieved significance by 104 weeks post-randomization (long after body weights had stabilized). In other words, Lincoff et al. are asking us simply to take their word for it.
The Miracle with a Mundane Explanation
The popular press might try to hype the novelty of a weight loss drug that improves cardiovascular health, but if we stop and think for even the briefest of moments, would we really have expected anything different? CV health is arguably the primary reason why weight loss is recommended for those with obesity. Excess fat mass drastically increases the likelihood of high lipid levels, inflammation, hypertension, liver dysfunction, and virtually countless other risk factors for CVD. Elimination of the excess fat has repeatedly been shown to improve these variables and reduce risk of cardiovascular events, so why wouldn’t we expect that semaglutide – a medication with well-established efficacy in promoting weight loss – would do the same?
Whether this drug has a future as a CVD medication depends instead upon whether or not it provides unique benefits to CV health beyond effects on body weight and fat mass. This remains a possibility, though the SELECT trial unfortunately was not designed in such a way that it might test that possibility. In place of a rigorous evaluation of the relevant research question, the authors have substituted a vague rationalization without any supporting data, leaving us with little more knowledge than we had prior to the study’s publication.
Still, the question remains a critical one that deserves rigorous evaluation. If semaglutide is cardioprotective independently of weight loss effects, it would likely emerge as a preferred weight loss treatment for those with high risk of MACE. However, with regard to its use in combating CVD outside the context of obesity, semaglutide still faces the obstacle of cost. While its hefty price tag of $1,349 per month might be justifiable for treating the most recalcitrant cases of obesity, it’s a more difficult sell in treating CVD, for which we have many effective and inexpensive alternatives already on the market. Thus, if physicians begin prescribing semaglutide for CVD, we risk undue financial burden on the healthcare system.
So in summary, yes, a once-weekly injection that can independently improve glycemic control, reduce body weight, and lower cardiovascular risk would indeed be a miracle drug. But as is often the case with anything billed as a “miracle,” the true explanation behind semaglutide’s apparent triple action is likely more mundane – we’ve simply counted one effect twice.
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