Insulin Resistance, Diabetes Strongly Linked With Premature CHD Among Women

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A prospective cohort study found that diabetes and insulin resistance were the strongest risk factors for premature onset of coronary heart disease (CHD) among American women. Results were published in JAMA Cardiology.

A prospective cohort study found diabetes and insulin resistance were the strongest risk factors for premature onset of coronary heart disease (CHD) among American women. Results were published in JAMA Cardiology.

Premature CHD generally refers to CHD onset prior to age 65 in women and before age 55 in men, and while advances in CHD prevention have been made, outcomes among younger adults have been suboptimal, according to the researchers.

This could be due to temporal trends in age- or sex-based differences in risk factors, clinical presentation, or use of preventive therapies. “There is also scarce information on determinants of premature CHD, particularly in women,” the authors wrote, noting that characterization of biomarker profiles that identify premature CHD has been inadequate.

“We're going to see, unfortunately, younger and younger people having heart attacks,” said study author Samia Mora, MD, MHS. “When a younger individual has a cardiovascular event, it will affect their quality of life going forward, their productivity, and their contribution to society.”


As most studies on biomarkers of premature CHD have reported differences in the levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides, researchers investigated the relative risk of more than 50 clinical risk factors and lipid, lipoprotein, inflammatory, and metabolic biomarkers with incident CHD using data from the Women’s Health Study.

A total of 28,024 women were followed up with for a median of 21.4 years. At the study’s inception, between 1993 and 1996, all participants were 45 years or older, did not have cardiovascular disease or cancer, and received aspirin, vitamin E, β-carotene, or matching placebo until 2004. Participants have since been followed up with on an observational basis, and current data were collected through 2016.

Participants were divided into 4 age groups (<55, 55-<65, 65-<75, and ≥75 years) and were analyzed until occurrence of incident CHD, death, or last follow-up. Incident CHD was defined as “a composite of first myocardial infarction (MI), percutaneous coronary intervention, coronary artery bypass grafting, or CHD death. Coronary heart disease events were confirmed using medical records by a blinded end points committee of physicians.”

Overall, CHD occurred in 1548 individuals (5.5%). Analyses revealed:

  • CHD incidence rates per 100 person-years ranged from 0.07 (95% CI, 0.06-0.09) for CHD onset at less than 55 years to 0.62 (95% CI, 0.57-0.68) for CHD onset at 75 years or older.
  • Diabetes had the highest adjusted hazard ratio (aHR) for CHD onset at any age, ranging from 10.71 (95% CI, 5.57-20.60) at CHD onset in those younger than 55 years to 3.47 (95% CI, 2.47-4.87) at CHD onset in those 75 years or older.
  • Additional risks for CHD onset in participants younger than 55 years included metabolic syndrome (aHR, 6.09; 95% CI, 3.60-10.29), hypertension (aHR, 4.58; 95% CI, 2.76-7.60), obesity (aHR, 4.33; 95% CI, 2.31-8.11), and smoking (aHR, 3.92; 95% CI, 2.32-6.63).
  • MI in a parent before age 60 years was associated with 1.5- to 2-fold risk of CHD in participants up to age 75 years.
  • Lipoprotein insulin resistance had the highest standardized aHR, 6.40 (95% CI, 3.14-13.06), for CHD onset in women younger than 55 years, attenuating with age.

LDL cholesterol, non-HDL cholesterol, apolipoprotein, triglycerides, and inflammatory biomarkers were also significantly associated with CHD in women younger than 55 years. Although the associations were weaker than that of lipoprotein insulin resistance, all factors also attenuated with age.

“The study findings underscore the importance of diabetes and insulin resistance as major determinants of premature CHD, as well as other modifiable major risk factors that can be addressed with lifestyle or preventive interventions,” the researchers wrote.

Limited data on pregnancy complications or vasomotor symptoms mark limitations to the study, and authors caution that results may not be generalizable to women younger than 45 years, men, or non-White racial/ethnic groups, as over 95% of study participants were White. In addition, self-reported lifestyle and medical history are subject to recall bias.

“Prevention is better than cure, and many risk factors for heart disease are preventable,” said study author Sagar Dugani, MD, PhD. “This study shows the impact that lifestyle has on heart health in women of all ages, and younger women in particular.”

“Diabetes is mostly preventable, but it’s a systems-wide problem, and we urgently need further research into new strategies to address it,” Mora added. “These could be innovative lifestyle-based strategies, like community efforts, greater public health efforts, ways to medically target metabolic pathways, or new surgical approaches. We need new strategies to improve outcomes in these younger individuals and address the risk of diabetes, because we’re only seeing the beginning of this epidemic now.”


Dugani SB, Moorthy MV, Li C, et al. Association of lipid, inflammatory, and metabolic biomarkers with age at onset for incident coronary heart disease in women. JAMA Cardiol. Published online January 20, 2021. doi:10.1001/jamacardio.2020.7073