Insulin Resistance May Increase Risk for Cardiovascular and Metabolic Diseases

Insulin resistance may increase risk of developing cardiovascular and metabolic diseases, according to study findings published in The Lancet Healthy Longevity.

Researchers aimed to evaluate the association among insulin resistance and mortality and cardiovascular diseases in individuals living in urban and rural areas at various levels of economic development on 5 continents. The primary outcome was the composite of mortality or major cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, stroke). Secondary outcomes included cardiovascular mortality, noncardiovascular mortality, stroke, myocardial infarction, and incident diabetes.

The researchers conducted a prospective cohort study that included 141,243 individuals (35-70 years of age; 59% women; 56.4% from urban areas) from 22 countries (Prospective Urban Rural Epidemiology [PURE] study) from January 2003 through February 2019. They used the triglyceride glucose (TyG) index  as a surrogate measure for insulin resistance. Associations between the TyG index and risk for cardiovascular diseases and mortality was assessed with a multivariable Cox frailty model with random effects. Data were from 4 high-income countries (n=16,294), 13 middle-income countries (MICs; n=104,194), and 5 low-income countries (LICs; n=20,755).

Overall, 64.9% of participants never smoked, 60.2% never drank alcoholic beverages, 42.5% had hypertension, 7.9% had diabetes, and 1.9% had history of stroke. Baseline blood samples were analyzed at the Population Health Research Institute, Hamilton, ON, Canada. Samples from China, India, and Turkey were analyzed in a central laboratory in each country following standardization with the Hamilton laboratory. During follow-up, participants were contacted at least once every 3 years by in-person visits or by telephone. Participants with a higher TyG index (tertile 3) had a higher prevalence of stroke, coronary heart disease, diabetes, and hypertension. They also had higher systolic blood pressure, diastolic blood pressure, body mass index, fasting glucose, low-density lipoprotein cholesterol, total cholesterol, and triglyceride levels.

In a median follow-up of 13.2 years (IQR, 11.9-14.6), there were 6345 composite cardiovascular disease events. Additionally, there were 2030 cardiovascular deaths, 3291 cases of stroke, 3038 cases of myocardial infarction, and 5191 incident cases of type 2 diabetes. The highest tertile of the baseline TyG index was associated with a greater incidence of the composite outcome (hazard ratio [HR], 1.21; 95% CI, 1.13-1.30), stroke (HR, 1.16; 95% CI, 1.05-1.28), myocardial infarction (HR, 1.24; 95% CI, 1.12-1.38), and incident type 2 diabetes (HR, 1.99; 95% CI, 1.82-2.16). There was no significant association between the TyG index and noncardiovascular mortality.

The TyG index was associated with increased risk for the composite outcome in MICs (HR, 1.20; 95% CI, 1.11-1.31) and LICs (HR, 1.31; 95% CI, 1.12-1.54; P_interaction =.01), as well as increased risk of the following:

• Cardiovascular mortality (LICs: HR, 1.44; 95% CI, 1.15-1.80; P_interaction =.01)
• Stroke (MICs: HR, 1.17; 95% CI, 1.05-1.30; LICs: HR, 1.35; 95% CI, 1.02-1.78; P_interaction =.19)
• Myocardial infarction (MICs: HR, 1.26; 95% CI, 1.10-1.45; LICs: HR, 1.29; 95% CI, 1.06-1.56; P_interaction =.08)
• Incident diabetes (MICs: HR, 2.68; 95% CI, 2.40-2.99; LICs: HR, 1.64; 95% CI, 1.38-1.94; P_interaction <.0001)

In high-income countries, higher TyG index tertiles were only associated with increased risk for incident diabetes (HR, 2.95; 95% CI, 2.25-3.87; P_interaction <.0001).

Study limitations include the study design and there being no measurement of the fasting insulin level. There are also unaccounted for changes over time and possible underreporting of previous cardiovascular diseases and events, particularly in LIC and MIC countries.

“The TyG index is significantly associated with future cardiovascular mortality, myocardial infarction, stroke, and type 2 diabetes, suggesting that insulin resistance plays a key role in the pathogenesis of cardiovascular and metabolic diseases,” the researchers wrote. “…the TyG index might help in the early identification of people at high risk of developing cardiovascular events or type 2 diabetes.”   

Disclosure: This research was supported by AstraZeneca [Canada], Sanofi-Aventis [France and Canada], Boehringer Ingelheim [Germany and Canada], Servier, and GlaxoSmithKline, with additional contributions from Novartis and King Pharma.