Diabetes, Insulin Resistance Among Best Predictors of Premature Coronary Heart Disease in Women

Sagar Dugani, MD, PhD

An analysis data and blood samples from more than 28,000 women are providing clinicians with an overview of the prognostic value of more than 50 lipid, inflammatory, and metabolic biomarkers for predicting risk of premature coronary heart disease in aging women.

A collaborative effort between clinicians from Brigham and Women’s Hospital and the Mayo Clinic, results of the multivariable-adjusted analysis indicate women with type 2 diabetes were at a tenfold greater risk of developing coronary heart disease over the next 20 years.

"Prevention is better than cure, and many risk factors for heart disease are preventable. This study shows the impact that lifestyle has on heart health in women of all ages, and younger women in particular," said Sagar Dugani, MD, PhD, a hospital internal medicine practitioner at Mayo Clinic in Rochester, MN, in a statement.

With an interest in identifying determinants of premature coronary heart disease in aging women, Dugani and colleagues designed a cohort study with the aim of assessing more than 50 clinical and biomarker risk factors across multiple age groups of women. Using data from the Women’s Health Study, investigators identified 28,024 women aged 45 years or older without cardiovascular disease at baseline for inclusion in their analysis.

Specific biomarkers and risk factors evaluated in the analysis included apolipoproteins, lipids, triglycerides, lipoprotein, inflammatory markers such as fibrinogen, glycan biomarker of N-acetyl side chains of acute-phase proteins, and C-reactive protein), intercellular adhesion molecule, and metabolic markers such as creatinine, HbA1c, homocysteine, and branched-chain amino acids. Of note, a lipoprotein insulin resistance score was calculated using a weighted combination of 6 lipoprotein measures related to the concentration and size of HDL, LDL, and TRL particles.

As part of their analysis, investigators created 4 age groups for assessing risk of coronary heart disease onset. Adjusted hazard ratios were calculated using stratified Cox proportional hazard regression models with age as the time scale and adjusted for clinical factors. The age groups created by investigators were defined as being younger than 55 years old, 55 to less than 65 years old, 65 to less than 75 years old, and 75 years or older.

The median follow-up time of the 28,024 individuals included in the analysis was 21.4 years. During this period, 1548 (5.5%) of patients developed coronary heart disease while the remaining 26,476 (94.5%) did not. Investigators pointed out coronary heart disease incidence rates per 100 person-years ranged from 0.07 (95% CI, 0.06-0.09) for onset at less than 55 years to 0.62 (95% CI, 0.57-0.68) for onset at 75 years or older.

Upon analysis, investigators found diabetes had the highest adjusted hazard ratio for coronary heart disease onset at any of the study age groups. The adjusted hazard ratio for coronary heart disease onset ranged from 10.71 (95% CI, 5.57-20.60) among those younger than 55 years of age to 3.47 (95% CI, 2.47-4.87) among those 75 years or older.

Further analysis of risk factors among women younger than 55 years of age indicated 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) were associated with onset of coronary heart disease.

Among the more than 50 biomarkers examined as part of the study, lipoprotein insulin resistance had the highest standardized risk (aHR, 6.40; 95% CI, 3.14-13.06) for coronary heart disease onset in women younger than 55 years, attenuating with age. Investigators also noted weaker, but significant associations between coronary heart disease onset and low-density lipoprotein cholesterol (aHR, 1.38; 95% CI, 1.10-1.74), non–high-density lipoprotein cholesterol (aHR, 1.67; 95% CI, 1.36-2.04), apolipoprotein B (aHR, 1.89; 95% CI, 1.52-2.35), triglycerides (aHR, 2.14; 95% CI, 1.72-2.67), and inflammatory biomarkers (1.2- to 1.8-fold), all attenuating with age, among those younger than 55.

"In otherwise healthy women, insulin resistance, type-2 diabetes, and its sister diagnosis, metabolic syndrome, were major contributors to premature coronary events," said Samia Mora, MD, MHS, of the Brigham's Center for Lipid Metabolomics in the Division of Preventive Medicine and an associate professor at Harvard Medical School, in the aforementioned statement. "Women under 55 who have obesity had about a fourfold-increased risk for coronary events, as did women in that age group who smoked or had hypertension. Physical inactivity and family history are all part of the picture as well."

This study, “Association of Lipid, Inflammatory, and Metabolic Biomarkers With Age at Onset for Incident Coronary Heart Disease in Women,” was published in JAMA Cardiology.