New GLP-1 Data Reinforce CV Benefit

The glucagon-like peptide 1 (GLP-1) agonist tirzepatide lowers the risk for cardiovascular (CV) events in patients with obesity and heart failure with preserved ejection fraction (HFpEF), whether they have general adiposity, measured with the body mass index (BMI), or central adiposity, measured with the waist-to-height ratio, showed a new analysis from the SUMMIT trial.

This is important because central adiposity, relative to general obesity, appears to be so critical to CV risk in patients with HFpEF that some experts are now calling for BMI to be completely replaced by waist-to-height ratio in patient assessments, according to Barry A. Borlaug, MD, a consultant in the Division of Interventional Cardiology at the Mayo Clinic in Rochester, Minnesota.

With the growing epidemic of heart failure, particularly HFpEF, obesity has long been recognized as a key risk factor and a major driver of the underlying pathology. Most patients with HFpEF have obesity, but not all obesity is the same, Borlaug explained.

The recently published placebo-controlled SUMMIT trial showed that tirzepatide was associated with a nearly 4src% reduction (P =.src26) in death from CV causes or worsening heart failure. In the new analysis of those data, the goals were to explore whether the effects of the GLP-1 agonist were different in people with general obesity, measured by BMI, than in those with central obesity, measured with waist-to-height ratio.

Differences in Obesity Types

The analysis assessed whether there are differences between these phenotypes, Borlaug explained during a late-breaker session at the Cardiovascular Research Foundation Technology and Heart Failure Therapeutics (THT) meeting in Boston.

The reduction in risk for CV death or worsening heart failure with tirzepatide was similar across tertiles of obesity for BMI and waist-to-height ratio. Given that major mechanism of benefit is weight loss, it is reassuring to know that treating obesity has benefits in all patients with HFpEF, Borlaug pointed out.

Yet, the study did show differences between types of obesity. Although both obesity phenotypes had a predominance of women and both were generally associated with volume overloaded, exercise capacity, measured with the 6-minute walk distance, incrementally diminished (P less than .srcsrc1) in patients with central adiposity in three levels of waist-to-height ratio (less than src.69; src.69-src.76; and> src.76).

Similarly, there were incrementally greater reductions (P=.srcsrc6) in kidney function, measured with the estimated glomerular filtration rate, for each higher tertile of central adiposity.

There was no relation between obesity and exercise capacity or kidney function in patients who fell into one of the levels of BMI (less than 34.3; 34.3-39.9;> 39.9).

Interestingly, the relative benefit of tirzepatide on walking distance and quality of life, measured with the Kansas City Cardiomyopathy Questionnaire at the end of follow-up, was similar for patients in the three tertiles of waist-to-height ratio, but was greater for patients in the highest tertile of BMI.

Incremental increases in C-reactive protein were seen with each greater tertile of obesity, whether measured with waist-to-height ratio (P =.srcsrc4) or BMI (P less than .srcsrc6).

Waist-to-Height Ratio Predicts Risk Better Than BMI

BMI — not waist-to-height ratio — was the standard baseline measurement of obesity in the SUMMIT trial, but the authors ultimately considered this measure to be “an important limitation.” In the discussion, they call waist-to-height ratio “a more reliable indicator of excess visceral adiposity.” Many patients with a BMI of less than 3src in SUMMIT would have been identified obese by waist-to-height ratio, pointed out Borlaug, a co-author of that trial.

This was the main point of another talk at the THT meeting by Milton Packer, MD, a distinguished scholar in CV science at Baylor University Medical Center in Dallas.

HFpEF is “the ultimate consequence of cardiovascular-kidney-metabolic disease,” but it is not general body fat, overall, that is a fundamental driver of risk, said Packer, the principal investigator of the SUMMIT trial.

When evaluating the risk of developing progressive HFpEF disease, “forget about obesity. We need to talk about central adiposity,” he said.

The subcutaneous fat that is mainly measured by BMI is biologically dormant, he said, whereas the visceral fat captured by waist-to-height ratio is both biologically active and proinflammatory.

This explains why the proportion of HFpEF patients who meet the criteria for obesity is lower when measured with BMI than with waist-to-height ratio, according to Packer. In a recently published relook at the PARAGON-HF trial data, 96% of patients with HFpEF met the criteria for central adiposity, defined as a waist-to-height ratio of ≥ src.5.

Conversely, 37% of HFpEF patients who did not meet the BMI criteria for obesity (less than 3src) met the central adiposity criteria, a waist-to-height ratio of ≥ src.6. Packer, a co-author of the reanalysis of the PARAGON-HF data, said these findings “challenge the current reliance on BMI as an appropriate metric of adiposity.” He reported that the PARAGON-HF reanalysis proved central adiposity to be a much better predictor of heart failure events than BMI (P less than .srcsrc1).

‘Angry’ Destructive Fat

This is consistent with the signaling of what Packer described as “angry” visceral adipocytes. Multiple pathways lead from the visceral adipocyte to myocardial hypertrophy, inflammation, and fibrosis. Although weight loss drugs such as tirzepatide combat these effects by reducing adipocytes, many of the HFpEF treatments, such as sodium-glucose cotransporter 2 inhibitors, induce the same effect by altering adipocyte biology, he explained.

The new SUMMIT analysis makes many of the same points, according to Borlaug. He said he agrees that waist-to-height ratio is more relevant than BMI when assessing and monitoring CV risk in patients with HFpEF. Although it is unclear whether these data will persuade clinicians to select waist-to-height ratio over BMI for the risk assessment of HFpEF, he noted that the SUMMIT data argue for such a change.

Should clinicians treating patients with HFpEF be buying tape measures to calculate waist-to-height ratio, asked Clyde W. Yancy, MD, chief of Cardiology at the Northwestern Feinberg School of Medicine in Chicago, who moderated the late-breaking session during which the new SUMMIT data were presented.

Borlaug expressed some practical concerns, particularly when it comes to ensuring that clinicians calculate waist-to-height ratio accurately and said that clinicians “get very different answers” when they use waist-to-height ratio rather than BMI to identify obesity. Without advocating an immediate switch to waist-to-height ratio as a sole tool for verifying obesity in HFpEF patients, he said, “I think there is utility” in obtaining this metric.

Borlaug reported financial relationship with Amgen, Aria, Axon, AstraZeneca, Boehringer Ingelheim, Corvia, Edwards Lifesciences, Janssen Pharmaceuticals, Medtronic, Novo Nordisk, NGM Bio, Rivus Pharmaceuticals, ShouTi, Tenax Therapeutics,