Heart Failure’s Obesity Paradox Falls Apart on Further Inspection

For the heart failure population, BMI obesity no longer appeared to hold counterintuitive protective effects after comprehensive adjustment for natriuretic peptides and other prognostic variables in a post hoc analysis of PARADIGM.

Eliminating this so-called “obesity paradox,” researchers found that study participants with the highest BMIs actually had excess combined heart failure hospitalizations and cardiovascular deaths, according to John McMurray, MD, of British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Scotland, and colleagues.

Both increased BMI and waist-to-height ratio, another index of adiposity, were associated with a higher risk of heart failure hospitalization specifically in this trial of people with heart failure with reduced ejection fraction (HFrEF). “Greater adiposity was associated with worse symptoms and health-related quality of life, irrespective of the anthropometric index used,” study authors reported in the European Heart Journal.

Researchers have spent years trying to figure out how obesity could be an independent risk factor for the development of heart failure but somehow linked to improved survival among heart failure patients.

“We knew this could not be correct and that obesity must be bad rather than good. We reckoned that part of the problem was that BMI was a weak indicator of how much fatty tissue a patient has,” McMurray said in a press release.

BMI, a blanket index derived from a person’s weight and height, is known to ignore the location or amount of body fat relative to muscle, bone, and retained fluid.

Alternative anthropometric indices proposed include waist circumference, waist-to-hip ratio, weight-adjusted-weight index, body shape index, body roundness index, and relative fat mass. The waist-to-height ratio in particular may be helpful for capturing, to some extent, sex- and race-based differences in stature and the distribution of body fat, according to McMurray and colleagues.

Indeed, the U.K.’s National Institute for Health and Care Excellence last year suggested that waist-to-height ratio should replace BMI in the evaluation of adiposity. The recommendation is that a person’s waist size should be less than half of height in the general population.

This should be extended to patients with heart failure as well, McMurray asserted in a press release.

Current guidelines do not provide any recommendation regarding weight management in HFrEF.

“Unfortunately, few randomized controlled trials using dietary and exercise intervention, bariatric surgery, or novel pharmacological therapies have been conducted in patients with HFrEF, although the latter are being investigated in individuals with HFpEF [heart failure with preserved ejection fraction],” McMurray and colleagues wrote.

Their present analysis was based on PARADIGM, a large multinational trial of over 8,000 people with HFrEF.

Reported in 2014, the study’s main finding was that angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan (Entresto) significantly reduced events compared with angiotensin-converting enzyme inhibitor enalapril.

Benefits of ARNI therapy did not vary by BMI or waist-to-height ratio in the latest report.

No index of adiposity significantly predicted all-cause mortality or cardiovascular death, either.

Study participants had a median BMI of 27.5 kg/m² and 27.6 kg/m² between men and women, and a median waist-to-height ratio of 0.58 and 0.59, respectively.

McMurray’s team acknowledged the possibility of unmeasured confounding remains in their analysis. The investigators lacked information on patients’ cardiorespiratory fitness, for example. The number of people with a low BMI or waist-to-height ratio was also very small.

“Of further interest, therefore, is whether similar results could be obtained in other populations with lower levels of BMI such as Asians,” commented Ryosuke Sato, MD, PhD, and Stephan von Haehling, MD, PhD, both of University of Göttingen Medical Center, Germany.

Even the waist-to-height ratio favored by McMurray’s group has its limitations, the duo noted in an accompanying editorial.

“[Waist-to-height ratio] is an anthropometric index that reflects central obesity well but is not an adequate measure of skeletal muscle mass. As such, this index cannot specify ‘sarcopenic obesity’, [sic] a serious pathological condition that involves both fat accumulation and reduced skeletal muscle mass,” Sato and von Haehling cautioned.

“Combining [waist-to-height ratio] with skeletal muscle mass evaluation, e.g., by bioelectrical impedance analysis (BIA) or dual-energy X-ray absorptiometry (DEXA), may lead to even better risk stratification of HFrEF patients,” they suggested.