Obesity paradox — two for one

Paradox is a funny word to use in medical science. It means something true that defies intuition or contradicts what people believe to be correct. Concerning our bodies, one viewpoint dominates today: it’s better to be thin than fat. The scientific evidence that keeps showing the fallacies of this belief has been relegated to what’s euphemistically called, the obesity paradox. Changing beliefs, even in medical science, comes slowly.

Researchers, led by epidemiologist Antigone Oreopoulos, MSc, at the University of Alberta in Edmonton,* have been delving into the obesity paradox [see sidebar] surrounding the most popularly believed risks associated with obesity: heart disease. Their study, examining mortality risks among heart failure patients associated with obesity, was published in the July issue of the American Heart Journal. This study followed an equally myth-busting one earlier this spring examining coronary artery bypass patients.

Both remind us, once again, that risk factors are not the same as actual risks, nor are they predictive of clinical outcomes.

Failing hearts

In the introduction of this latest study, the authors note that the Canadian Cardiovascular Society Census Conference guidelines “continue to recommend weight loss for obese patients with heart failure, even though this recommendation is not supported by evidence from clinical trials.” So, they did a systematic review of the medical evidence to examine the relationship between BMI and mortality among these patients.

They searched five databases for all the randomized controlled clinical trials and observational studies completed from 1966 through June 2007 that had reported mortality rates and BMI categories. As they noted, the “lower cut point for normal is controversial and is sometimes cited as 22.5 kg/m².” Not all researchers follow the World Health Organization classification scheme, as our Health and Human Services Department does. As they anticipated, some studies used BMIs less than 23 kg/m² as ‘underweight’ or ‘low-normal’ weight. For this analysis, they used the lower WHO cut-offs for “normal,” as BMIs of 18.5-24.9 kg/m². To include as many quality studies possible, for consistency, they accepted BMI levels within 2 kg/m² for standard categories, collapsing data when necessary to match WHO categories. They identified nine studies, five studies were from randomized controlled clinical trials (with clinically confirmed diagnoses), of 28,209 heart failure patients. The patients had been followed for one to six years.

Among the studies excluded because BMIs were unstable or too different from WHO ranges to be usable, all were of high methodological quality (as assessed by Ottawa-Newcastle criteria) and the authors reported that none had found obesity or overweight to be a predictor of increased mortality.

Their primary analysis calculated relative risks for all-cause and cardiovascular mortality associated with weight status. “Because underweight, malnutrition and cachexia are associated with increased mortality in CHF” and could create a false appearance of a benefit of higher weights, they repeated their analysis excluding those studies that had grouped underweight and normal weight patients into one category. To attempt to explain the obesity paradox, which some have suggested as being possibly associated with younger age, higher left ventricular ejection fraction and higher systolic blood pressure, they also did risk-adjusted analyses, comparing each BMI group to confirm their main results were robust.

They found that being overweight, and even more so being obese, was associated with a lower all-cause mortality, and with lower cardiovascular mortality, compared to ‘normal’ weight BMIs; whereas being underweight or low-normal weight was associated with a 20% higher mortality. [Image shows relative risks of all-cause mortality associated with ‘obesity’ compared to ‘normal’ BMIs in heart failure.]

Overweight was associated with a 16% lower all-cause mortality and 19% lower cardiovascular mortality.

Obesity was associated with a 33% lower all-cause mortality and 40% lower cardiovascular mortality.

These, of course, are all small relationships, but the studies consistently suggest a lower risk associated with obesity and do not support fears that obesity is associated with higher risks. Sensitivity analysis and excluding the three studies that had included underweight people in with the ‘normal’ weight group, did not affect the findings. As they said, “the results were nearly identical.”

Their findings, they said, concur with the body of evidence on heart failure patients. Among five studies that had examined BMI as a continuous variable, all had reported “a significant inverse relationship between increasing BMI and mortality,” even controlling for confounding variables. They added:

Our findings are consistent with evidence in other chronic disease populations demonstrating improved mortality with higher BMI levels. In survivors of myocardial infarction, overweight and obese patients are at lower risk for recurrent events compared with patients of normal BMI. A recent meta-analysis examining the effect of BMI on mortality on patients post coronary revascularization showed that obese patients have similar or lower short- and long-term mortality rates compared to nonelevated BMI patients. Similarly, a low baseline fat percentage and reduction in fat mass over time in are independently associated with higher mortality in chronic hemodialysis patients. Although the specific mechanisms may differ, the identification of an obesity paradox in such diverse clinical situations suggests a commonality that merits further investigation.

They then addressed potential explanations that others have proposed for this obesity paradox, such as selection bias and that maybe the obese patients were diagnosed with heart failure earlier at younger ages, had less severe disease or were more aggressively treated; that only the healthiest obese patients had survived long enough to get heart failure; and that smoking status, unrecognized illnesses, or weight loss may account for higher mortalities among thinner people. They also considered a range of comorbidities, including previous heart attacks, hypertension, diabetes, chronic obstructive pulmonary disease, ischemic heart disease, ejection fraction, functional status (NYHA class), and use of a wide range of medications. “There are both favorable and unfavorable risk factors present in obese patients” with heart disease, they said, but “our risk-adjusted analysis suggests a protective effect of overweight and obesity in heart failure.”

It is also possible that excess body weight truly confers a protective effect on HF mortality. Chronic HF is a catabolic state, and the development of wasting, characterized by loss of muscle, bone, and fat, is a marker of more severe disease. Studies have demonstrated that many patients with advanced HF are malnourished, with an energy and protein intake that is inadequate to meet their energy requirements. It has been suggested that moderately obese individuals with CHF may have a higher metabolic reserve and may tolerate the metabolic stresses better than lean individuals with CHF.

The authors also presented a number of additional possible explanations for the benefits seen in obesity. Because these are virtually never mentioned to the public, you deserve to hear them. A few were:

Tumor necrosis factor-a (TNF-α) is elevated in CHF and may contribute to cardiac injury and muscle wasting through its proapoptotic and negative inotropic effects. Adipose tissue produces soluble TNF-α receptors and may play a cardioprotective role in obese patients by neutralizing the biologic effects of TNF-α.

Higher B-type natriuretic peptide (BNP) and N-terminal proBNP levels are also associated with increasing severity of HF and poorer outcomes. Compared with normal BMI counterparts, overweight and obese patients with acute and chronic HF have lower levels of circulating BNP and NT pro-BNP.

Moreover, while increased sympathetic and reninangiotensin activity are negative prognostic factors in HF, a recent study reported attenuated sympathetic nervous system and renin-angiotensin responses to exercise in obese versus lean subjects. Alternatively, as obese patients have higher systolic blood pressure...previous reports have suggested that higher blood pressure confers better prognosis in patients with CHF.

Finally, the interaction between obesity and higher serum lipid levels may also potentially explain the obesity paradox. There is a significant positive correlation between higher cholesterol levels and improved survival in HF...

The concluded: “This systematic review suggests that obese and overweight individuals with CHF are at lower risk for death than CHF patients with normal body weight.”

The bonus study

These researchers from the Division of Cardiothoracic Surgery at the University of Alberta conducted a very similar study examining the obesity paradox among coronary artery bypass and coronary balloon angioplasty (percutaneous coronary intervention) patients. It was published in the February issue of the journal Obesity, but received very little media attention. The methodology was the same and they identified 22 cohort studies in the medical literature for their systematic analysis.

Compared to ‘normal’-weight angioplasty patients, the ‘obese’ patients had at 37% lower chance of dying in the first month after the procedure and 35% lower risk of long-term mortality. Among the post-coronary bypass patients, the obese patients were associated with a 37% lower risk of dying in the first month and 12% lower risk for long-term mortality compared to ‘normal’ weight patients. There were no differences in risks among overweight people associated with either procedure.

The authors concluded that, compared to non-obese people, overweight patients have similar mortality rates after coronary revascularization, and obese patients have lower mortality rates.

© 2008 Sandy Szwarc. All rights reserved.

* Disclosure: There was no project specific funding, but A.O. is supported by a CIHR Strategic Training Fellowship in Tomorrow's Research Cardiovascular Health Professionals; C.M.N. is supported by career salary awards from the Alberta Heritage Foundation for Medical Research; C.M.N. is also supported by New Investigator Awards from the Canadian Institutes of Health Research; G.C.F. is supported by a grant from the National Heart Lung and Blood Institute and the Eliot Corday Foundation; K.K. is supported by a grant from the National Institute of Diabetes, Digestive and Kidney Disease from the NIH and by a Grantin-Aid from the American Heart Association; and F.A.M. is supported by career salary awards from AHFMR and CIHR as well as the Patient Health Management Chair at the University of Alberta.

Sidebar: But don’t fat people have more heart failure to begin with?

Oreopoulos and colleagues noted that obesity has been said to be “an independent risk factor for heart failure,” citing a 2002 study published in the New England Journal of Medicine. Examining that observational study, which had looked for correlations between BMI and heart failure, reveals that it hadn’t been able to find a tenable link.

This epidemiological study had been based on 496 people (258 women and 238 men) in the Framingham Heart Study (during 1976-9 and 1979-83) who had been defined among the cohort as having heart failure, (after excluding those with heart failure at the beginning of the study period and all underweight and young adults). The authors’ determination of heart failure was based on reviewing medical records and information from outside doctors, rather than direct physical, laboratory and radiological exams.

To establish the diagnosis, the authors used the presence of at least two main criteria, or one main and two minor criteria, in the medical records. Their major criteria included nighttime dyspnea or orthopnea (also due to a number of noncardiac or pulmonary factors), jugular venous distention, pulmonary rales (“crackly lungs”, also a common benign finding among elderly), radiographic cardiomegaly, acute pulmonary edema, a third heart sound, central venous pressure above 16 cm of water, hepatojugular reflux, and weight loss of at least 4.5 kg in five days in response to treatment for heart failure. Minor criteria included bilateral ankle edema (with a range of noncardiac causes), nocturnal cough, dyspnea on ordinary exertion, hepatomegaly, pleural effusion, and a heart rate of at least 120 beats per minute; as long as there was no liver cirrhosis, nephrotic (kidney) syndrome or chronic lung disease noted in their charts. Already, readers can see that a number of these symptoms can be mistaken for nonmedical or noncardiac conditions.

In fact, the authors noted that a number of symptoms “may be misconstrued as indicating heart failure more often in obese persons.” This is a precautionary note that any correlations identified must be especially significant to outweigh the weakness in the data going into their modeling.

Their multivariable cox proportional hazard ratio models adjusted for age, alcohol consumption, total serum cholesterol level, current cigarette smoking, valve disease, hypertension, diabetes mellitus, electrocardiographic left ventricular hypertrophy, and myocardial infarction, but hadn’t included factors such as socioeconomic status, physical activity, healthcare or insurance status. It showed that, compared to “normal” BMIs, the association between heart failure and overweight and obesity were odds ratios of 1.30 (CL=1.12–1.72) for overweight and 1.98 (CL=1.54–2.56) for obese — untenable odds and within random chance or statistical error.