Obesity Itself Increases Risk of Diabetes and Heart Disease

Obesity per se is associated with an increased risk of developing both type 2 diabetes and coronary artery disease (CAD), say US researchers in a large-scale meta-analysis combining genetic and epidemiological data, thus underlining the importance of weight loss.

Haris Riaz, MD, Department of Cardiovascular Medicine, Cleveland Clinic, Ohio, and colleagues, examined data on almost 900,000 individuals from five non-overlapping studies and used Mendelian randomization to reduce the impact of potential confounding factors.

They found that, for each unit increase in body mass index (BMI), the risk of type 2 diabetes increased by 67%, while the risk of CAD increased by 20%. There was no association between obesity and stroke risk.

"This study is important because we can conclude that it is not solely factors [associated with obesity] like high blood pressure, high cholesterol, or lack of exercise that tend to come with obesity that are harmful — the excess fat itself is harmful," commented senior author Haitham Ahmed, MD, also from the Cleveland Clinic, in a press release from the institution.

He warned, "Patients may think their cardiovascular risk is mitigated if their other risk factors are normal or being treated, but this study suggests you cannot ignore the extra weight."

"Physicians should take heed and make sure they are counseling their patients about weight loss in a comprehensive and collaborative manner."

Ahmed added that it's "very important to recognize” that obesity is "not simply a lifestyle choice," despite the contribution of lifestyle factors.

He continued, "It is a disease, and there is a large genetic influence on your weight," noting that "nearly 100 genetic variations" are associated with the development of obesity and subsequent heart disease risk.

The study was published online on November 16 in JAMA Network Open.

In an accompanying editorial, Kaitlin H. Wade, PhD, and George Davey Smith, MD, DSc, from the University of Bristol, UK, say that the authors present "compelling evidence" that obesity itself is associated with both the risk of type 2 diabetes and CAD.

"These results support a global effort to lower the increasing population trends for excess weight and suggest that in most cases any reduction in BMI is likely beneficial," they write.

These results were published at the same time another study, published in the same journal, showed that a person's maximum BMI over decades indicates that obesity, but not stable overweight or normal weight, is linked to premature death, also reported by Medscape Medical News.

Obesity Paradox Debunked by Mendelian Randomization Study

Although the association between dyslipidemia and cardiovascular disease is well characterized, the link between obesity per se and cardiovascular disease remains a matter of debate.

This is especially the case given the so-called "obesity paradox" of apparently improved outcomes with a higher BMI.

Understanding how obesity relates to cardiovascular disease is particularly important, Riaz and colleagues point out, as the benefits gained from the improved treatment of CAD may be offset by the rising prevalence of obesity and metabolic disease.

To avoid some of the potential biases and confounding factors inherent to observational studies, they used Mendelian randomization, which combines genetic and epidemiological data to minimize confounding by mimicking the techniques of a randomized controlled trial.

They conducted a systematic search of the MEDLINE and Scopus databases to identify studies that assessed the association between measures of obesity and the incidence of type 2 diabetes, CAD, and stroke, and reported odds ratios.

Looking at all publications from database inception to January 2018, the team identified 4660 potentially relevant articles, of which seven from a total of 2511 screened studies were included in the systematic review.

After excluding studies with overlapping data, the team arrived at a total of five studies involving 881,692 individuals with an average age of 60 years for inclusion in the meta-analysis.

Four studies reported on type 2 diabetes in 461,871 individuals, of whom 66,341 were obese. This showed that there was a significant association between each standard deviation increase in BMI and type 2 diabetes, at an odds ratio of 1.67 (P < .001).

All five studies reported on CAD in a total of 570,261 participants, of whom 100,103 were obese. This revealed that increases in BMI were again associated with an increased risk, at an odds ratio of 1.20 (P = .03).

For all-cause stroke, three studies looked at the association in a total of 228,816 individuals, including 9774 who were obese. There was, however, no significant association between obesity and stroke, at an odds ratio of 1.02 (P = .65).

This finding was replicated when the researchers looked specifically at ischemic stroke, in 180,795 participants, again at an odds ratio with obesity of 1.02 (P = .65).

The team writes: “Obesity was associated with an increased risk of type 2 diabetes and coronary artery disease and should remain a major focus of public health initiatives.”

Acknowledging, however, the potential limitations of their study, they add, "The present analysis of Mendelian randomization studies was supportive of a causal association; however, it did not prove causality."

"Mendelian randomization assumptions were often not verified in individual studies, and this could have contributed bias to the present meta-analysis."

With Obesity, Is it the Chicken or the Egg?

Wade and Davey Smith say in their editorial that, despite the authors' best efforts, there was some degree of overlay between the cohorts.

"While there was no explicit overlap in the studies that contributed to the current meta-analysis, it is worth noting that, as Mendelian randomization studies become larger, the likelihood of contributory articles including overlapping individuals becomes greater and will lead to over-precise estimates."

They suggest that future studies include data from low- to middle-income countries, as cardiovascular disease is increasingly a cause of morbidity and mortality in the developing world, and look at the risk factors for disease progression as well as those related to onset.

Wade and Davey Smith also question whether dichotomizing body mass index (BMI) into obese and non-obese affects the researchers' ability "to directly infer whether obesity itself causes variation in the risk of cardiovascular events or merely that the underlying liability to obesity influences this risk."

No funding for the study was declared. Sadiya S. Khan reported receiving grants from the National Institutes of Health, and Haitham Ahmed reported receiving grants from Akcea Therapeutics, both outside the submitted work.

JAMA Network Open. November 16, 2018. Full text, Editorial

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