Obesity Paradox in Heart Disease Challenged by New Analysis


A new analysis of data of long-term follow-up from 10 population-based cohorts challenges the so-called obesity paradox  — previous counterintuitive findings suggesting that patients with heart disease may live longer if they are overweight or obese.

“Our research differs from previous studies in that we have included a lifespan perspective — we started to follow people before they developed heart disease,” lead author, Sadiya Khan, MD, Northwestern University Feinberg School of Medicine, Chicago, Illinois, told Medscape Medical News.

“We found that obese people live shorter lives, and while overweight people had similar length of life to those of a normal weight, they developed cardiovascular disease earlier than people with normal BMI.”

She explained that previous studies have suggested that obesity may in some way be associated with lower mortality in cardiovascular disease (CVD), known as the obesity paradox. But these studies included patients who already had CVD at the time of the study, and this can introduce many biases, particularly the issue that obese patients may be diagnosed with heart disease earlier and so may appear to live with heart disease for a longer time.

“Our results provide a different context by following people before the onset of cardiovascular disease, which should therefore eliminate this ‘lead time bias’,” Khan said. “We found that obese people develop cardiovascular disease at a younger age and so they have more years with heart disease but in the context of a shorter lifespan.”

The paper was published online in JAMA Cardiology on February 28.

In the paper, the researchers state: “Taking a life course perspective, we observe that the obesity paradox…appears largely to be caused by earlier diagnosis of CVD. Study of inception cohorts of people at the time of cardiovascular diagnosis would not detect this finding, leading to unclear messaging about the true risks of being overweight.”

They say this “false reassurance” is akin to the phenomenon of lead-time bias observed in other situations, such as with cancer screening.

Commenting on the paper for Medscape Medical News, Naveed Satter, MD, professor of cardiovascular and medical sciences at the University of Glasgow, United Kingdom, said that the problem with previous studies is that “not all heart disease is equal.”

“You can be a thin smoker or an obese nonsmoker,” Satter said. “There are many different confounders. When you take a population with any chronic condition you see a different picture which may not tell the truth. We also have to consider when the patient developed heart disease. By starting to follow people before they developed heart disease, these researchers have removed one of the biggest confounders.”

Other strengths of these data are a large population, a wide age range, a long follow-up, and robust statistical methods to overcome other confounders, he added. “And when looking at this cleaner picture, we see clearly than lower BMI is better.”

“Better-quality studies such as this, which have longer-term follow-up and do not include people with disease at baseline, tend to find that lowest risks for bad outcomes are in the leaner people,” Satter said. “We are understanding the complexities of these studies better now and there is more evidence that lowest risks for heart disease or death are in normal weight folk, not those who are overweight or obese.”

The study analyzed individual-level data from 190,672 in-person examinations across 10 large prospective cohorts with an aggregate of 3.2 million years of follow-up. All of the participants were free of CVD at baseline and had objectively measured height and weight to assess BMI.

Results showed that compared with individuals with a normal BMI (defined as a BMI of 18.5 to 24.9), lifetime risks for incident CVD were higher in people in the overweight (BMI, 25.0 to 29.9) and obese (BMI, 30.0 to 39.9) groups.

Compared with normal weight, overweight middle-aged men had a hazard ratio for incident CVD of 1.21; for overweight women, the hazard ratio was 1.32.

Obese men had a hazard ratio for CVD of 1.67, and the corresponding figure for obese women was 1.85.

The hazard ratios for the morbidly obese (BMI, 40.0) were 3.14 for men and 2.53 for women. All these results were statistically significant.

The researchers found the strongest association between BMI categories and heart failure (HF) compared with other subtypes of CVD, with a fivefold increase in incident HF in middle-aged men with morbid obesity, which they say “has particularly important implications for focusing on weight management strategies for HF prevention.”

In terms of lifespan, normal weight middle-aged men lived 1.9 years longer than obese men and 6 years longer than those who were morbidly obese. Normal-weight men had longevity similar to that of overweight men.

Normal-weight middle-aged women lived 1.4 years longer than overweight women, 3.4 years longer than obese women, and 6 years longer than morbidly obese women.

The researchers point out that “our findings suggest that earlier occurrence of CVD in those with obesity is most strongly associated with a greater proportion of life lived with CVD and shorter overall survival in adults aged 20 to 59 years at baseline.”

However, they note that the association of obesity with mortality may change at older ages, which may explain why some earlier studies in older individuals showed no difference in total life expectancy in older men and women with obesity.

“Our results provide critical perspective on the cardiovascular disease burden associated with overweight, highlight unhealthy years lived with increased cardiovascular morbidity, and challenge the prevalent view that overweight is associated with greater longevity compared with normal BMI,” they conclude.

The obesity paradox: Scientists now think that being overweight can protect your health


Around a dozen years ago, researchers noticed that some patients with chronic conditions such as heart disease fared better than others. This should have been encouraging news, perhaps a clue to future treatments. Instead, researchers were baffled. Because the factor that seemed to be protecting these patients was fat: They were all overweight or mildly obese.
“When health-care professionals get their first nutrition books, there’s a chapter on obesity,” says Glenn Gaesser, director of the Healthy Lifestyles Research Center at Arizona State University. “And it generally says that fat people are unhealthy and thin people are healthy.”
Researchers immediately began trying to explain this “obesity paradox”—or, more often, to explain it away. Carl Lavie, a cardiologist in Jefferson, Louisiana, was one of the first clinicians to describe the paradox. It took him over a year to find a journal that would publish his findings. “People thought, ‘This can’t be true. There’s got to be something wrong with their data’,” he told Quartz.

“People thought, ‘This can’t be true. There’s got to be something wrong with their data.’”
Since then, dozens of studies have confirmed the existence of the paradox. Being overweight is now believed to help protect patients with an increasingly long list of medical problems, including pneumonia, burns, stroke, cancer, hypertension, and heart disease. Researchers who have tried to show that the paradox is based on faulty data or reasoning have largely come up short. And while scientists do not yet agree on what the paradox means for health, most accept the evidence behind it. “It’s been shown consistently enough in different disease states,” says Gregg Fonarow, a cardiology researcher at the University of California, Los Angeles.
The researcher who did most to kick off the debate, and in the process became the object of much of the pushback it generated, is an epidemiologist at the US Centers for Disease Control and Prevention named Katherine Flegal. Together with colleagues, she looked at hundreds of mortality studies that included data on body mass index (BMI), which is calculated by dividing a person’s weight in kilograms by the square of their height in meters. People with BMIs of more than 25 are classed as overweight, and those with a BMI over 30 as obese.

Researchers immediately began trying to explain this “obesity paradox”—or, more often, to explain it away.

Flegal found the lowest mortality rates among people in the overweight to mildly obese categories. It’s true that these groups are slightly more likely to suffer from heart disease and some other life-threatening conditions in the first place. But many factors influence the likelihood of a person getting heart disease. And a strong link between weight and disease only emerges among people with severe obesity. So taken at face value, the results seemed to be showing that a little extra weight is genuinely beneficial.
Flegal is a meticulous researcher: her most recent analysis incorporated data from almost 100 studies and close to three million people. It was published by the prestigious Journal of the American Medical Association. Yet Flegal’s work has made her a target for those who scoff at the paradox. Walter Willett, a researcher at the Harvard School of Public Health who has taken a high-profile stance against obesity, told NPR that one recent Flegal study was “really a pile of rubbish” and that “no one should waste their time reading it.” (He was later admonished by the editors at Nature. In recent comments to Quartz, he reiterated his view that the study was “rubbish.”)

Being overweight is now believed to help protect patients with an increasingly long list of medical problems.

Willett’s complaints are starting to look less credible, however, because no one has been able to make the paradox go away. One of the most popular explanations is that fat people get more aggressive treatment than thin people, because their weight raises red flags at the doctor’s office. This seems questionable: studies show that overweight and obese people tend to avoid doctors, get fewer preventive screenings, and receive worse treatment because they’re often misdiagnosed as “fat” rather than with a specific medical condition.

What’s more, at least one team has examined and dismissed the better-treatment explanation. The researchers, led by a French endocrinologist named Boris Hansel, analyzed data on 54,000 patients who were at risk of stroke and heart attack. The optimal treatment for these patients is well known: protective drugs like statins and beta-blockers. But mild obesity seemed to protect at-risk patients whether or not they were taking the drugs.
Another potential explanation is that the data on people of normal weight are skewed. Researchers know that people tend to lose weight toward the end of life, but don’t always realize that they are sick. Smoking also makes people thinner and sicker. So, goes the theory, maybe researchers have inadvertently lumped mortally ill people and smokers in with healthy folk of normal weight, thus making the normal weight group look less healthy than it really is.

No matter how many ways Carnethon sliced and diced the data, the obesity paradox persisted.

There’s some evidence to back up this argument, but the studies on the issue are far from clear. The argument certainly does not seem to make the obesity paradox go away, at least according to Mercedes Carnethon, an epidemiologist at Northwestern University who has analyzed data on diabetes patients. Carnethon began by excluding patients who died within two years of diagnosis, to account for people who were already sick but didn’t know it; she still found higher mortality rates among thin people. Then she ran the data separately for smokers and non-smokers; still no difference. No matter how many ways she sliced and diced the data, the obesity paradox persisted. (Flegal also ran her data with and without smokers, and found no difference.)

If the paradox is real, and extra weight can bring benefits, what constitutes a healthy life? Is there any point trying to diet to lose weight, for example?
Researchers are divided on the public health implications of the paradox, but the approach that makes most sense to me is Health at Every Size. This is based on the idea that healthy behaviors, including nutrition and physical activity, matter more than weight.

Healthy behaviors, including nutrition and physical activity, matter more than weight.

Take exercise. Paul McAuley, a health education researcher at Winston-Salem State University in North Carolina, has been studying fitness for close to 20 years. He says most studies on weight and health fail to take it into account. “Or they ask one question about it,” he says, and don’t bother to go further. When McAuley collects data on fitness, he finds that it predicts health and longevity much more strongly than fatness.

Other researchers have found that Health at Every Size, when compared with a weight-loss approach, leads to lower cholesterol, blood pressure, and other metabolic markers. “We’re so stuck on the fact that the only way to mediate health is through weight,” says Linda Bacon, a nutrition professor at University of California, San Francisco and author of a book on the approach.
If Health at Every Size is taken up more widely and continues to deliver results, we may look back and conclude that the most disturbing element of this controversy is that it was a controversy at all. We don’t know as much as we would like about the complex relationship between weight and health. We don’t know for sure what the obesity paradox means and how to interpret it. Why does it inspire so much pushback?

“We’re so stuck on the fact that the only way to mediate health is through weight.”

“People are furiously looking for some way to make this not the case,” says Deb Burgard, a clinical psychologist in Los Altos, California who treats eating disorders. “And I think that bears some comment. Theoretically we should be very happy to find out that people aren’t dying the way we thought they were going to, that there’s not going to be this terrible outcome. That people at higher weights are going to be OK.”
Even scientists whose own research has identified the paradox often seem ambivalent about the possibility that it might hold true. Carnethon has published several studies documenting the link between overweight or obese and better survival rates among people with type two diabetes. Yet like nearly every researcher I’ve interviewed on the subject, she resists the idea that fat might not always be unhealthy. “We’d never want to back away from weight-loss recommendations,” she says.
Lavie, who recently wrote a book on the paradox, also seems to buy in to the idea that everyone should aim for a BMI in the normal range. “People who are lean develop heart disease despite having a perfect body composition,” he told Quartz.
But where did this definition of “perfect body composition” come from? People of all sizes develop heart disease, and fat people with heart disease tend to do better overall than thin people with heart disease. Maybe the real paradox here lies in our assumptions about what constitutes normal weight.

The Obesity Paradox: Sometimes Being Overweight Is Actually Healthier For You


Ever since Americans started plumping to record rates of obesity, doctors have been crusading against fatty drinks and foods to tame an epidemic in the making. But there’s something cardiologists seldom talk about that has baffled research doctors for years: In the face of illness, being fatter adds years to people’s lives.

On Wednesday, scientists published two reports in the Mayo Clinic Proceedings announcing new clues in the mystery known as the obesity paradox. Being fat can cause all kinds of nasty problems, from heart disease to diabetes. But study after study has found that being overweight is like a shield against death when those diseases set in. As one study author put it, obesity is like a bad friend who gets you sentenced to jail, “but once imprisoned the friend remains loyal and protects you against poor prison conditions and other inmates.”

In a first paper, researchers conducted a meta-analysis of 36 studies, searching for instances of patients undergoing surgery to open up blocked arteries. Obesity frequently leads to coronary artery disease, but thin people can be at risk, too. They reviewed “tens of thousands” of cases and discovered obese and severely obese people had higher survival rates post-surgery than normal weight people. (They were around 25 percent less likely to die.)

It wasn’t the first major review of the literature. One study published last year analyzed three million sick people around the world. Their results were bewildering: “For people with a medical condition, survival is slightly better for people who are slightly heavier.” Yet the cause still eludes scientists.

“At this stage we can only speculate on the reasons for this paradox,” said lead author Abhishek Sharma, of the State University of New York Downstate Medical Center in Brooklyn, in a press release. Maybe doctors are more likely to give overweight patients more drugs, he says. Or maybe they have a higher metabolic reserve. Or maybe skinny people have bad genes. Who knows?

The second paper, however, offers more insight. It attempts to chip away at a nagging question among the people studying the obesity paradox: Is body mass index, or BMI, the right way to measure obesity? Many believe other measures, like the ratio of fat to lean mass, may have more to do with the phenomenon than BMI, which is based on height and weight.

“Body composition plays a critical role in the obesity paradox,” said Carl Lavie, a cardiologist at the University of Queensland School of Medicine in New Orleans and a co-author of both papers. He and his colleagues examined something called the lean mass index — the proportion of human stuff, like muscle and bone, that isn’t body fat — among 48,000 patients.

Their findings yield more evidence for what many have suspected. “At higher BMI, body fat is associated with an increase in mortality,” Lavie said. In other words, the fat isn’t the elixir; being big is. “Whenever examining a potential protective effect of body fat, lean mass index — which likely represents larger skeletal muscle mass — should be considered,” Lavie said.

This is a good lesson. With nearly one in 14 Americans now considered extremely obese, the authors of the two studies were quick to caution that being overweight in the first place is still dangerous. In fact, these papers came on the heels of another that found extreme obesity kills about as effectively as smoking does.

Sources: A. Sharma, A. Vallakati, A. J. Einstein, C. J. Lavie, et al. Relationship of Body Mass Index With Total Mortality, Cardiovascular Mortality, and Myocardial Infarction After Coronary Revascularization: Evidence From a Meta-analysis. Mayo Clinic Proceedings. 2014.

A. De Schutter, C. J. Lavie, et al. Body Composition and Mortality in a Large Cohort With Preserved Ejection Fraction: Untangling the Obesity Paradox. Mayo Clinic Proceedings. 2014.

The Obesity Paradox: Sometimes Being Overweight Is Actually Healthier For You.


Ever since Americans started plumping to record rates of obesity, doctors have been crusading against fatty drinks and foods to tame an epidemic in the making. But there’s something cardiologists seldom talk about that has baffled research doctors for years: In the face of illness, being fatter adds years to people’s lives.

On Wednesday, scientists published two reports in the Mayo Clinic Proceedings announcing new clues in the mystery known as the obesity paradox. Being fat can cause all kinds of nasty problems, from heart disease to diabetes. But study after study has found that being overweight is like a shield against death when those diseases set in. As one study author put it, obesity is like a bad friend who gets you sentenced to jail, “but once imprisoned the friend remains loyal and protects you against poor prison conditions and other inmates.”

In a first paper, researchers conducted a meta-analysis of 36 studies, searching for instances of patients undergoing surgery to open up blocked arteries. Obesity frequently leads to coronary artery disease, but thin people can be at risk, too. They reviewed “tens of thousands” of cases and discovered obese and severely obese people had higher survival rates post-surgery than normal weight people. (They were around 25 percent less likely to die.)

It wasn’t the first major review of the literature. One study published last year analyzed three million sick people around the world. Their results were bewildering: “For people with a medical condition, survival is slightly better for people who are slightly heavier.” Yet the cause still eludes scientists.

“At this stage we can only speculate on the reasons for this paradox,” said lead author Abhishek Sharma, of the State University of New York Downstate Medical Center in Brooklyn, in a press release. Maybe doctors are more likely to give overweight patients more drugs, he says. Or maybe they have a higher metabolic reserve. Or maybe skinny people have bad genes. Who knows?

The second paper, however, offers more insight. It attempts to chip away at a nagging question among the people studying the obesity paradox: Is body mass index, or BMI, the right way to measure obesity? Many believe other measures, like the ratio of fat to lean mass, may have more to do with the phenomenon than BMI, which is based on height and weight.

“Body composition plays a critical role in the obesity paradox,” said Carl Lavie, a cardiologist at the University of Queensland School of Medicine in New Orleans and a co-author of both papers. He and his colleagues examined something called the lean mass index — the proportion of human stuff, like muscle and bone, that isn’t body fat — among 48,000 patients.

Their findings yield more evidence for what many have suspected. “At higher BMI, body fat is associated with an increase in mortality,” Lavie said. In other words, the fat isn’t the elixir; being big is. “Whenever examining a potential protective effect of body fat, lean mass index — which likely represents larger skeletal muscle mass — should be considered,” Lavie said.

This is a good lesson. With nearly one in 14 Americans now considered extremely obese, the authors of the two studies were quick to caution that being overweight in the first place is still dangerous. In fact, these papers came on the heels of another that found extreme obesity kills about as effectively as smoking does.

Sources: A. Sharma, A. Vallakati, A. J. Einstein, C. J. Lavie, et al. Relationship of Body Mass Index With Total Mortality, Cardiovascular Mortality, and Myocardial Infarction After Coronary Revascularization: Evidence From a Meta-analysis. Mayo Clinic Proceedings. 2014.

A. De Schutter, C. J. Lavie, et al. Body Composition and Mortality in a Large Cohort With Preserved Ejection Fraction: Untangling the Obesity Paradox. Mayo Clinic Proceedings. 2014.

Study Offers Insight into “Obesity Paradox” in Kidney Cancer.


Kidney cancer affects more than 55,000 people in the United States each year.
Kidney cancer affects more than 55,000 people in the United States each year.

For years, kidney cancer specialists have puzzled over two seemingly contradictory research findings: Obesity is associated with an increased risk of kidney cancer, yet obese and overweight people have better odds of surviving kidney cancer than normal-weight people.

A new study by a team from Memorial Sloan Kettering has uncovered a possible biological explanation for the phenomenon known as the “obesity paradox.”

A genetic analysis of tumor samples from patients with renal cell carcinoma, a common form of kidney cancer, found normal-weight patients had higher expression of a gene associated with faster-growing tumors than obese patients. Previous studies have shown that the gene, FASN, is overexpressed in aggressive tumors in several types of cancer.

The activity of FASN may help to explain why obese kidney cancer patients tend to fare better than normal-weight patients, says epidemiologist Helena Furberg, a coauthor of the study. With less activity in a cancer-promoting gene, tumors in obese people may grow more slowly than in normal-weight people.

By understanding what drives the progression of these tumors, the research, published online in December in the Journal of the National Cancer Institute, could ultimately lead to better therapeutic strategies.

Metastatic Disease More Likely in Slim Patients

The study included 2,119 kidney cancer patients who underwent surgery at Memorial Sloan Kettering between 1995 and 2012. As had been noted in previous research, this study found that normal-weight people are more likely to have their cancer discovered at advanced stages than obese people.

Obese patients also had a 25 percent lower risk of cancer-related death than normal-weight patients. (Obesity is defined as a body mass index, or BMI, of 30 or greater; normal weight is a BMI of under 25. BMI is an estimate of body fat based on a person’s height and weight.)

But the team’s analysis showed that obesity alone didn’t explain the difference in the risk of death, Dr. Furberg notes. Instead, the risk of death was associated with the stage at which the cancer was detected — and normal-weight people were more likely to have metastatic disease at the time of diagnosis.

These findings led researchers to wonder if there was something different about the tumors themselves in obese patients versus normal-weight patients influencing the cancer’s growth.

Honing In on the Tumor Genome

For answers, Dr. Furberg and her colleagues turned to The Cancer Genome Atlas (TCGA), a project funded by the National Institutes of Health to map the genetic mutations and alterations that occur in cancer cells.

The team’s analysis of genetic data available through TCGA revealed an overexpression of the FASN gene in the tumors of normal-weight patients. “FASN is an oncogene, which are genes that are the gas pedal driving cancer progression,” Dr. Furberg says.

In a normal cell, FASN is involved in the regulation of fatty acids, or fat production and breakdown, explains urologic oncology fellow Ari Hakimi, a coauthor of the study. “Cancer cells hijack that mechanism, and use it to fuel growth,” Dr. Hakimi says.

Their findings suggest that obesity interferes with cancer cells’ ability to hijack the mechanism, which may help prevent tumors from spreading quickly, Dr. Hakimi adds.

Yet researchers cautioned that their findings come with caveats. First, the team didn’t prove that obesity causes decreased expression of FASN. Second, the findings shouldn’t be interpreted as advice about weight management in kidney cancer patients, or how weight gain or loss might influence survival during the course of the disease.

Insights for Future Research

Instead, the findings will guide future research on the role of obesity and FASN in tumor growth. “Our study provides mechanistic insights into the obesity paradox,” Dr. Furberg says. “It gives researchers a different place to start in terms of understanding how body size influences patients’ survival.”

Finally, even though obesity is associated with a lower risk of death from kidney cancer, the statistics don’t speak to any individual’s odds of survival, which are impacted by many factors.

“What this study indicates is a new granularity, or knowledge of cancer, and how the genetics of tumors impact the way in which tumors behave,” says kidney surgeon Paul Russo, the senior author of the study. “We are on the precipice of a better understanding of the things that power tumors, which could eventually lead to tailored treatments and novel strategies to stop tumors from spreading.”