Sometimes, the simplest explanation is not the one that turns out to be correct.
Two years ago, published results from the “SELECT” trial demonstrated that the GLP-1 receptor agonist drug semaglutide (trade names Wegovy and Ozempic)—already known for its remarkable efficacy in combating obesity and type II diabetes—was also effective in reducing incidence of major adverse cardiovascular events (MACE, defined as heart attack, stroke, or cardiovascular death) among non-diabetic patients with overweight or obesity.1 The findings fueled even greater excitement over the seemingly limitless therapeutic uses of GLP-1 drugs—not only could they promote weight loss and glycemic control, but they also appeared to have the additional effect of cardiovascular protection.
But in our subsequent commentary, we proposed a simpler (and less exciting) explanation for the results: the reduction in MACE risk with semaglutide was likely due to the weight loss elicited by the medication—not to other, unique benefits for cardiovascular health. After all, study participants had BMIs in the overweight or obese categories at baseline, and excess fat mass is a significant risk factor for cardiovascular events. And since the original publication offered no indication that the investigators had attempted to control for body weight changes or employed other strategies to address their potential influence on cardiovascular results, we arrived at our conclusion by applying an intuitive principle of problem-solving commonly known as Occam’s razor or the “principle of parsimony”: “of two competing theories, the simpler explanation of an entity is to be preferred.”2
Yet a new analysis of SELECT trial results refutes our alternative explanation—reminding us that biology is often anything but simple.3
A refresher on the SELECT trial
As a refresher, the SELECT trial represented the first efforts to specifically investigate cardiovascular (CV) endpoints with GLP-1 receptor agonist medications. To better isolate potential CV effects from the more established effects of these drugs on diabetes management, the researchers chose to study overweight or obese patients without diabetes (mean BMI: 33.3±5.0). A total of 17,604 participants were enrolled and randomized to receive either placebo or semaglutide (2.4 mg maximal dose) once weekly for a mean duration of 34.2±13.7 months. Results showed that a greater proportion of subjects in the placebo group experienced MACE over the follow-up period (701 of 8,801 patients, or 8.0%) than in the semaglutide group (569 of 8,803 patients, or 6.5%). This corresponded to a relative risk reduction of 20% with semaglutide (HR: 0.80; 95% CI: 0.72-0.90; P<0.001) relative to placebo—a considerable effect on par with the protection afforded by other classes of CV medications such as statins or PCSK9 inhibitors.
However, it’s important to note that individuals in the semaglutide also experienced significantly greater weight loss than the placebo group. Compared to an average loss of just 0.88±0.08% of baseline body weight in the placebo group by 104 weeks post-randomization, patients in the semaglutide arm had lost an average of 9.39±0.09%.
Applying Occam’s razor to these results
Data from the SELECT trial clearly demonstrated that semaglutide could reduce risk of MACE among patients with overweight or obesity, but the fact that participants on this drug also lost more weight raised a critical question as to whether we could truly interpret these results as evidence of an independent effect on CV health. As we pointed out in our commentary two years ago, 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 risk factors for cardiovascular disease. The investigators didn’t attempt to control for weight loss effects by imposing calorie restriction or other weight-matching strategies on the placebo group, nor did they perform any analyses on their data that might correct for the weight loss discrepancy.
Thus, we were left with two possibilities that were equally capable of explaining the results reported two years ago. Either the reduction in MACE among participants in the semaglutide group represented a distinct physiological effect of the drug that was independent of its effects on appetite and glycemic control, or the apparent CV protection was a secondary effect of weight loss and improved metabolic health.
The latter explanation, though less desirable and exciting from the perspective of therapeutic implications, is the simpler of the two, as it fits with what we already know about how these drugs impact metabolic health and how metabolic health impacts cardiovascular disease. By contrast, the former explanation would require that we make assumptions beyond what we already know to be true—i.e., that semaglutide has previously unknown impacts on CV health that are independent of its metabolic effects. Thus, in alignment with Occam’s razor, we concluded that, “of two competing theories, the simpler explanation of an entity is to be preferred.”
But Occam’s razor isn’t an inviolable law—indeed, it’s only useful even as a heuristic when presented with two theories that are otherwise equivalent in their ability to explain a given phenomenon or dataset. That means that when new data arise, we must re-examine whether those theories indeed remain equivalent. And with the recent publication of such new data on semaglutide and MACE reduction, our re-examination has led us to revise our earlier conclusions.
What did the new analysis show?
The recent publication shared results of an additional analysis of SELECT trial data in which the authors evaluated the correlation between weight loss from baseline and MACE risk reduction. (Of note, this analysis was prespecified—meaning that the authors had planned on performing this analysis even before collecting data from the original trial.) The logic is straightforward: if the degree of weight loss correlates inversely with MACE rates, then we can conclude that apparent CV benefits are likely secondary to weight loss rather than an independent effect.
But that wasn’t what the investigators found in their analysis. Examining the proportion of weight loss at week 20 of the intervention period, the authors observed no correlation between weight loss and subsequent MACE incidence in the semaglutide group over the remainder of the trial using either linear or non-linear models. However, examination of waist circumference changes by week 20 revealed that greater decreases in waist circumference were modestly associated with greater decreases in subsequent MACE risk (HR=0.91; 95% CI: 0.84–0.98; P=0.02), such that changes in waist circumference were estimated to account for 33% of the effect of semaglutide on MACE risk reduction. Total weight loss by week 104 was also modestly associated with MACE risk reduction over the course of the intervention period (HR=0.93; 95% CI: 0.88–0.98; P=0.003). Together, these results indicate that body composition changes on semaglutide may enhance CV benefits of the drug among overweight or obese patients, but they do not fully account for effects on MACE risk reduction, especially early in the course of treatment.
The implications of these findings are significant, as they indicate that a lack of substantial weight loss with semaglutide does not preclude the opportunity for improved cardiovascular outcomes. Indeed, the fact that semaglutide can offer cardiovascular benefits across a broad range of adiposity levels and independently of weight loss suggests that this medication might be specifically indicated for cardiovascular disease—that is, outside the context of obesity and diabetes—as opposed to current restrictions based on BMI thresholds.
Biology is anything but simple
Occam’s razor is a useful heuristic for problem-solving across many disciplines, but biology and medicine are rife with instances where this principle has failed. (Indeed, there’s a principle that specifically opposes Occam’s razor in the context of medicine—Hickam’s dictum, which is typically presented as the observation that “a patient can have as many diseases as they damn well please.”) So although defaulting to the simplest explanation may make sense when all else is equal, biology is often far more complex than we predict, and therefore, we need to be ready to abandon or revise the simpler theory when presented with new information. Such is the case, it would seem, with GLP-1 drugs and cardiovascular benefits.
The recent analysis of data from the SELECT trial provides evidence of a cardioprotective benefit of semaglutide that is at least partially independent of weight loss, demonstrating that the physiological effects of this medication may be more complex and multifaceted than previously thought. This opens the door for rethinking current restrictions on the uses of GLP-1 drugs and reassessing existing treatment protocols for cardiovascular disease both within the context of obesity and diabetes and outside of these other conditions. So although Occam’s razor might have failed us in our earlier critiques, in this instance, we couldn’t be more pleased to be proven wrong.
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References
- Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563
- Duignan B. Occam’s razor. In: Encyclopedia Britannica. https://www.britannica.com/topic/Occams-razor
- Deanfield J, Lincoff AM, Kahn SE, et al. Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial. Lancet. 2025;406(10516):2257-2268. doi:10.1016/S0140-6736(25)01375-3
