Best evidence to date of an obesity/cardiovascular disease linkage

Despite perceptions otherwise, an association between obesity and cardiovascular disease outcomes has not been clearly established. Such an association is even controversial, with some investigators positing an “obesity paradox” whereby a higher body mass index (BMI) has been associated with improved clinical outcomes.

But a new analysis by a Cleveland Clinic-led research team yields the best evidence to date that obesity is indeed associated with type 2 diabetes and coronary artery disease. The investigation, published in JAMA Network Open on November 16, relies on a relatively new epidemiological study design, Mendelian randomization, that incorporates genetic information to assess associations without many of the biases typical of traditional epidemiologic methods.

“This study is important because we can conclude that it is not solely factors that tend to accompany obesity — such as hypertension, dyslipidemia or lack of exercise — that are harmful but that the excess weight itself is independently harmful,” says the study’s senior author, Cleveland Clinic preventive cardiologist Haitham Ahmed, MD.

“Patients who are obese may believe their cardiovascular risk is mitigated if their other risk factors are normal or being treated, but this study suggests we cannot ignore the extra weight,” Dr. Ahmed continues. “Clinicians must take heed and counsel patients about weight loss in a comprehensive, collaborative manner.”

Methodology to mimic a randomized trial

Dr. Ahmed and colleagues screened more than 2,500 articles from the published literature in search of studies that used Mendelian randomization methods to evaluate associations between measures of obesity and rates of cardiovascular events. They included only studies that reported odd ratios (ORs) with 95 percent confidence intervals (CIs) estimated with an instrumental variable method. Five observational studies comprising a total of 881,692 participants were identified that met the inclusion criteria.

Study characteristics were extracted and data pooled using a random-effects model according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines.

An accompanying editorial in JAMA Network Open notes that Mendelian randomization can help offset limitations of observational studies, such as confounding, reverse causation and selection bias. “The Mendelian randomization methodology exploits the properties of genetic inheritance to mimic a randomized clinical trial to improve causal inference,” the editorialists write.

The editorial adds that analyses like the one by the Cleveland Clinic team are particularly needed because studies of interventions to lower BMI “are inherently difficult, and many have proven unsuccessful in achieving sustained weight loss of a magnitude and duration that could be expected to reduce cardiovascular events or mortality.”

Results: Links with T2DM and CAD, but not stroke

The primary outcomes of interest in Dr. Ahmed’s analysis were the presence or absence of associations between obesity and type 2 diabetes, coronary artery disease (CAD) and stroke.

Pooled estimates from the meta-analysis of the 881,269 patients in the five studies showed the following:

  • For every 1 standard deviation (SD) increase in BMI, the risk of type 2 diabetes rose by 67 percent (OR = 1.67; 95% CI, 1.30-2.14; P < .001).
  • For every 1 SD increase in BMI, the risk of CAD rose by 20 percent (OR = 1.20; 95% CI, 1.02-1.41; P= .03).
  • Obesity was not associated with stroke risk (OR = 1.02; 95% CI, 0.95-1.09; P = .65).

“Although this analysis of Mendelian randomization studies does not prove causality, its findings are supportive of a causal association,” Dr. Ahmed observes. “The associations of obesity with type 2 diabetes and CAD are believed to be independent of traditional risk factors, in light of the Mendelian randomization.”

Big public health implications

He notes that the findings are important because the increasing prevalence of obesity and metabolic syndrome may ultimately offset the public health gains achieved by recent improvements in the treatment of CAD. “Clinicians should continue to emphasize weight reduction as a means to combat CAD,” he advises.

The authors of the accompanying editorial concur, concluding: “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.”