Insulin Resistance May Mediate Obesity-Related Risk for Cardiovascular Disease

Researchers in China published study results demonstrating that insulin resistance mediates the effects of obesity on the risk for cardiovascular disease (CVD) in Cardiovascular Diabetology.

Investigators reviewed data from a previous large-scale prospective cohort study conducted in the Kailuan community in Tangshan, China, from 2006 until the death of participants or December 31, 2019. Participants completed surveys and health exams biennially during the study period.

The researchers in this analysis excluded participants with a history of stroke or myocardial infarction (MI), as well as those who had incomplete baseline data on anthropometric parameters, fasting blood glucose, or fasting triglyceride. The final cohort for this review included 94,136 participants with a mean age of 51.24±12.37.

The study team modeled the outcome, defined as first incident of CVD (including fatal and nonfatal stroke and MI), using Cox proportional hazards regression models, and the mediator, defined as triglyceride-glucose (TyG) index, using linear regression.

Models were adjusted for variables including age, sex, education, income, smoking status, drinking status, history of hypertension, diabetes, and dyslipidemia, as well as use of antihypertensive agents, antidiabetic agents, lipid-lowering agents, plus levels of systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and high sensitivity C reactive protein (hs CRP).

Researchers identified 7327 (7.78%) cases of incident CVD among participants, including 5898 (6.27%) stroke and 1622 (1.72%) MI, during a median follow-up of 13.01 years. Data showed significant differences between the incident CVD and non-CVD groups in age, sex, education, income, smoking, drinking, hypertension, diabetes, dyslipidemia, medications, SBP, DBP, fasting blood glucose, TC, fasting triglyceride, HDL-C, low-density lipoprotein cholesterol, and hsCRP. They found that BMI, waist circumference (WC), waist-to-hip ratio (WHR), and waist-height ratio (WHTR), the proportion of obesity, and TyG index were higher in participants with CVD than those without CVD.

Using mediation analysis, study authors demonstrated an 18% increased risk for CVD (hazard ratio [HR] total association, 1.18; 95% CI, 1.12-1.24) for overweight vs the reference normal weight. CVD risk increased to 45% (HR 1.45; 95% CI, 1.36-1.54) among the obesity group, of which 47.81% and 37.94% were mediated through the TyG index. HR for the indirect association was 1.07 (95% CI, 1.07-1.09) and 1.13 (95% CI, 1.11-1.15) for overweight and obesity, respectively.

Investigators identified a relationship between central obesity and CVD, with a total association HR of 1.35 (95% CI, 1.29-1.41) for WC greater than or equal to 90 cm in men or greater than or equal to 85 cm in women, 1.24 (95% CI, 1.19-1.30) for WHR greater than or equal to 0.90 in men or greater than or equal to 0.80 in women, and 1.30 (95% CI, 1.22-1.40) for WHTR greater than or equal to 0.60, compared with participants of normal weight. The proportion mediated was 32.01%, 35.02%, and 31.06%, respectively. Similar results were identified in the analysis regarding the incidence of stroke and MI.

In sensitivity and subgroup analysis, investigators found similar patterns of mediation. Most notably, they found substantial attenuation of HRs for BMI (44.84% for overweight and 32.54% for obesity), WC (28.04%), WHR (30.44%), and WHTR (27.49%). In addition, incident CVD was observed after adjusting for the TyG index, suggesting that excess risk was attributable to the TyG index.

Study limitations included exclusions of incidents of heart failure and coronary artery disease, which may have caused an underestimation of CVD incident rates. Second, the population from which the study drew participant data had higher rates of general and central obesity than the general Chinese population. The findings of this study may not be generalizable to other populations due to region-specific lifestyle factors. Finally, data on insulin resistance and glycosylated hemoglobin were not collected, so investigators could not use the homeostasis model assessment of insulin resistance or glycosylated hemoglobin to reflect insulin resistance.

The study authors concluded, “Our findings suggested that the association of general and central obesity with risk of CVD was mediated through the TyG index.” They further added that controlling insulin resistance properly may help to significantly reduce the effects that general and central obesity have on CVD.