Greater Weight Loss, Greater Cardiometabolic Benefit: Findings from SURMOUNT-1

The SURMOUNT-1 trial previously demonstrated that tirzepatide can achieve significant weight reduction in people with obesity or overweight who do not have diabetes. A new post hoc analysis, published in Annals of Internal Medicine, explores how the magnitude of weight reduction relates to changes in cardiometabolic risk factors.

This analysis included 1,605 adults treated with tirzepatide for 72 weeks. Participants were grouped by the percentage of body weight lost, ranging from less than 5 percent to 35 percent or more. The goal was to evaluate changes in blood pressure, waist circumference, glucose metabolism, and lipid levels by degree of weight reduction.

Several important findings emerged:

1. Reductions in blood pressure and waist circumference occurred across all weight loss categories, with a linear pattern observed. Participants who lost 35 percent or more of their body weight experienced an average reduction of 14.2 millimeters of mercury in systolic blood pressure and 32.4 centimeters in waist circumference.

2. Improvements in insulin resistance and hemoglobin A1c were seen even in participants with modest weight loss, and in some cases even among those who gained weight. These findings suggest that tirzepatide may exert weight-independent effects on glycemic control.

3. Lipid improvements were more threshold-dependent. Meaningful reductions in triglycerides, low-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol were observed only in participants who lost at least 10 percent of their body weight. In contrast, increases in high-density lipoprotein cholesterol also followed a dose-response pattern, with the greatest increases at 35 percent weight loss or more.

4. The proportion of participants with metabolic syndrome declined sharply with higher weight loss. Among those who lost 35 percent or more of their body weight, only 1 percent met criteria for metabolic syndrome at 72 weeks, compared to 43 percent at baseline.

These findings support existing guideline targets of 5 to 15 percent weight loss for metabolic improvement, but they also suggest that larger reductions in body weight may yield even greater health benefits. There was no observed plateau effect in cardiometabolic improvements, even at the highest levels of weight reduction achieved in the study.

Importantly, the analysis was exploratory and not designed to assess long-term cardiovascular outcomes. Nonetheless, it adds valuable context to the potential role of incretin-based therapies in reducing cardiometabolic risk in people with obesity, particularly when higher levels of weight loss are achieved and sustained.

As more long-term data become available from ongoing trials, such as SURMOUNT-MMO, we will gain a clearer understanding of whether these risk factor improvements translate into fewer cardiovascular events. For now, these results provide compelling evidence that the magnitude of weight loss matters—and that tirzepatide may help achieve both metabolic and clinical goals for many patients.