GLP-1 Agonist Tirzepatide Reduces Cardiovascular Risk in Heart Failure with Preserved Ejection Fraction Patients

A recent analysis from the SUMMIT trial has shown that tirzepatide, a glucagon-like peptide 1 (GLP-1) agonist, effectively lowers the risk of cardiovascular (CV) events in patients with heart failure with preserved ejection fraction (HFpEF). This includes patients with both general and central obesity, measured using the body mass index (BMI) and waist-to-height ratio, respectively.

This finding is significant because central adiposity—a form of fat around the waist—is being scrutinized more closely as a critical factor in CV risk in patients with HFpEF. Experts, including Barry A. Borlaug, MD, from the Mayo Clinic, are calling for a shift from BMI to waist-to-height ratio in patient assessments due to its predictive power for CV risk.

The SUMMIT Trial Results

The SUMMIT trial, a placebo-controlled study, demonstrated that tirzepatide was linked to a nearly 40% reduction in CV-related death or worsening heart failure (P = .026). The new analysis further examined if the outcomes were different between patients with general obesity, determined by BMI, and central obesity, measured by waist-to-height ratio.

Interestingly, the reduction in risk for cardiovascular events with tirzepatide was consistent across categories of BMI and waist-to-height ratio tertiles. This consistency reassures clinicians that treating obesity with GLP-1 agonists can benefit all HFpEF patients.

Differences in Obesity Types

While the effects of tirzepatide were similar in both general and central obesity, several distinctions were observed. Exercise capacity, measured by the 6-minute walk distance, declined progressively in patients with central adiposity across different waist-to-height ratio levels (less than 0.69; 0.69-0.76; and > 0.76). Furthermore, kidney function, as indicated by estimated glomerular filtration rate, also diminished in a stepwise pattern with increasing central adiposity (P = .006).

Conversely, there were no significant correlations between BMI levels (less than 34.3; 34.3-39.9; > 39.9) and exercise capacity or kidney function.

The analysis also showed that incremental increases in C-reactive protein concentrations occurred with each higher tertile of obesity, whether determined by waist-to-height ratio (P = .004) or BMI (P < .006).

The Relevance of Waist-to-Height Ratio

While BMI was the standard for measuring obesity in the SUMMIT trial, the analysis identifies waist-to-height ratio as a more reliable measure of visceral adiposity. This shift in emphasis is crucial as visceral fat, captured by waist-to-height ratio, is both biologically active and inflammatory, unlike subcutaneous fat measured by BMI, which is largely dormant.

Milton Packer, MD, a leading researcher in CV science, underscores that HFpEF is primarily driven by cardiovascular, kidney, and metabolic dysfunctions. Central adiposity, rather than overall body fat, is the fundamental driver of this condition, according to Packer. He notes that the waist-to-height ratio more accurately identifies patients at risk of progressive HFpEF.

In a relook at the PARAGON-HF trial data, it was found that 96% of HFpEF patients met the criteria for central adiposity (waist-to-height ratio ≥ 0.5), compared to only 63% when using BMI criteria. This suggests that waist-to-height ratio might be a superior predictor of heart failure events than BMI.

The Biological Role of Visceral Fat

The SUMMIT analysis supports Packer’s explanation of the biological impact of visceral adipocytes. These fat cells are the source of multiple pathways that contribute to myocardial hypertrophy, inflammation, and fibrosis. While weight loss drugs like tirzepatide help by reducing adipocytes, treatments like SGLT2 inhibitors act by altering adipocyte biology.

Borlaug agrees with Packer, advocating for the use of waist-to-height ratio in CV risk assessment for HFpEF. However, the transition from BMI to waist-to-height ratio in clinical practice might require some time due to practical considerations and the need for accurate measurement.

Practical Implications for Clinicians

Clinicians treating HFpEF patients may need to reassess their approach to obesity assessment. While BMI remains a valuable tool, the new findings suggest that waist-to-height ratio should be considered alongside it to better evaluate CV risk.

Clyde W. Yancy, MD, chief of Cardiology at the Northwestern Feinberg School of Medicine, questions the immediacy of switching from BMI to waist-to-height ratio in clinical practice. He acknowledges the utility of waist-to-height ratio but also highlights the need for accurate measurement and standardized protocols.

Ultimately, the shift towards waist-to-height ratio in assessments is supported by the data, and further research may reinforce its adoption in clinical practice.

Conclusion

The SUMMIT trial analysis strongly suggests that tirzepatide is effective in reducing CV risk in HFpEF patients, regardless of the type of obesity. This study also emphasizes the critical role of central adiposity in CV risk and the need for more accurate diagnostic tools like waist-to-height ratio.

As researchers continue to refine these assessments, clinicians can play a crucial role in identifying at-risk patients and implementing effective strategies to reduce CV risk in HFpEF.

We invite you to share your thoughts and experiences in the comments section below. Don’t forget to subscribe to Archynetys for more insights and updates on the latest in cardiovascular research.