The SUMMIT trial has demonstrated promising results for the GLP-1 agonist tirzepatide in reducing the risk of cardiovascular (CV) events in patients suffering from obesity and heart failure with preserved ejection fraction (HFpEF). Conducted recently, this pivotal study revealed a significant reduction in mortality from CV causes or worsening heart failure by nearly 40% (P = .026) among those treated with tirzepatide. The primary mechanism driving these benefits is attributed to weight loss facilitated by the drug. The findings suggest a potential shift in clinical focus towards central adiposity rather than general obesity as a means of assessing and treating HFpEF.
Central adiposity, measured by the waist-to-height ratio, emerged as a more reliable predictor of heart failure events than the traditional body mass index (BMI) measurement, with P values less than .001. An overwhelming 96% of the HFpEF patients enrolled in the trial met the criteria for central adiposity, defined as a waist-to-height ratio of ≥ 0.5. This data underscores the role of visceral fat, which is biologically active and proinflammatory, as a crucial driver of risk in HFpEF, contrasting with the biologically dormant subcutaneous fat measured by BMI.
The trial further explored tirzepatide's effects on walking distance and quality of life across different tertiles of waist-to-height ratio. The relative benefit was consistent across these tertiles but was notably greater for patients in the highest tertile of BMI. Incremental increases in C-reactive protein were observed with each greater tertile of obesity, whether measured by waist-to-height ratio (P = .004) or BMI (P less than .006). This indicates a nuanced interaction between inflammation markers and various obesity metrics.
Moreover, a considerable number of patients who had a BMI of less than 30 were identified as obese when assessed through the waist-to-height ratio. This highlights the limitations of BMI as a sole measure of obesity in HFpEF, as fewer patients meet obesity criteria when using BMI compared to waist-to-height ratio.
The SUMMIT trial underscored that tirzepatide effectively reduced CV risk in HFpEF patients regardless of their general adiposity (measured by BMI) or central adiposity (measured by waist-to-height ratio). The analysis revealed differential effects of tirzepatide on patients with general obesity compared to those with central obesity. The findings argue for a paradigm shift in clinical practices, urging clinicians to prioritize assessments based on central adiposity.
Barry A. Borlaug, MD, highlighted the practical implications of these findings, stating:
"I think there is utility" – Barry A. Borlaug, MD
Similarly, Milton Packer, MD, advocated for a shift in focus away from traditional measures of obesity:
"forget about obesity. We need to talk about central adiposity" – Milton Packer, MD
The evidence from this trial suggests that visceral fat plays a pivotal role in HFpEF and should be a focal point in therapeutic strategies. The traditional reliance on BMI may overlook critical aspects of fat distribution that influence patient outcomes. The differential impact of tirzepatide on walking distance and quality of life across various fat distribution metrics further emphasizes the need for refined assessment tools.
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