Diabetes powerfully associated with CHD in women – Women's Health Study

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Diabetes and insulin resistance, in addition to hypertension, obesity, and smoking, appeared to be the strongest risk factors for premature onset of coronary heart disease (CHD), found an analysis from the large, decades-long Womens Health Study.

While deaths related to heart disease have declined among older people, studies suggest that death rates among younger patients have remained stagnant or increased slightly. To understand what factors put younger individuals at higher risk of premature coronary heart disease (CHD), researchers from Brigham and Womens Hospital and the Mayo Clinic analysed more than 50 risk factors in 28,024 women who participated in the study.

Notably, women under 55 with type-2 diabetes had a tenfold greater risk of having CHD over the next two decades, with lipoprotein insulin resistance (LPIR) proving to be a strong, predictive biomarker as well.

“We’re going to see, unfortunately, younger and younger people having heart attacks,” said corresponding author Dr Samia Mora, of the Brigham’s Centre for Lipid Metabolomics in the division of preventive medicine and an associate professor at Harvard Medical School. “When a younger individual has a cardiovascular event, it will affect their quality of life going forward, their productivity, and their contribution to society.”

"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 Dr Sagar Dugani, a hospital internal medicine practitioner at Mayo Clinic in Rochester, Minnesota. Dugani is a co-first author of the study.

The researchers analysed approximately 50 biomarkers associated with cardiovascular health. Commonly used metrics like low-density lipoprotein (LDL) cholesterol (or “bad” cholesterol) and haemoglobin A1C (a measure of blood sugar levels) had much weaker associations with CHD onset in women younger than 55 years than LPIR, a newer metric for insulin resistance. LPIR uses a weighted combination of six lipoprotein measures and is analysed through specialised laboratory testing. Whereas LDL cholesterol was only associated with a 40% increase in risk of CHD onset in women under 55, LPIR demonstrated a six-fold (600%) increase.

“In otherwise healthy women, insulin resistance, type-2 diabetes, and its sister diagnosis, metabolic syndrome, were major contributors to premature coronary events,” said Mora. “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.”

The researchers acknowledged the study is limited in its generalisability – beyond its focus on women, who have been shown to have worse outcomes after premature cardiac events than men, its participants were over 95% white. According to Mora, findings could be even more dramatic in ethnic and racial groups that have a greater prevalence of metabolic syndrome, insulin resistance and diabetes, among other risk factors.

“Diabetes is mostly preventable, but it’s a systems-wide problem, and we urgently need further research into new strategies to address it,” Mora said. “These could be innovative lifestyle-based strategies, like community efforts, greater public health efforts, ways to medically target metabolic pathways, or new surgical approaches.”

With the prevalence of diabetes and its associated risk factors increasing dramatically, and affecting more women than men, the researchers emphasise the urgency of developing effective interventions.

“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,” said Mora.

 

Study details
Association of Lipid, Inflammatory, and Metabolic Biomarkers With Age at Onset for Incident Coronary Heart Disease in Women

Sagar B Dugani; M Vinayaga Moorthy; Chunying Li; Olga V Demler; Alawi A Alsheikh-Ali; Paul M Ridker; Robert J Glynn; Samia Mora

Published in JAMA Cardiology on 20 January 2021

Abstract
Importance
Risk profiles for premature coronary heart disease (CHD) are unclear.
Objective
To examine baseline risk profiles for incident CHD in women by age at onset.
Design, Setting, and Participants
A prospective cohort of US female health professionals participating in the Women’s Health Study was conducted; median follow-up was 21.4 years. Participants included 28 024 women aged 45 years or older without known cardiovascular disease. Baseline profiles were obtained from April 30, 1993, to January 24, 1996, and analyses were conducted from October 1, 2017, to October 1, 2020.
Exposures
More than 50 clinical, lipid, inflammatory, and metabolic risk factors and biomarkers.
Main Outcomes and Measures
Four age groups were examined (<55, 55 to <65, 65 to <75, and ≥75 years) for CHD onset, and adjusted hazard ratios (aHRs) were calculated using stratified Cox proportional hazard regression models with age as the time scale and adjusting for clinical factors. Women contributed to different age groups over time.
Results
Of the clinical factors in the women, diabetes had the highest 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. Risks that were also noted 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). Myocardial infarction 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. From approximately 50 biomarkers, 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. In comparison, weaker but significant associations with CHD in women younger than 55 years were noted (per SD increment) for 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. Some biomarkers had similar CHD age associations (eg, physical inactivity, lipoprotein[a], total high-density lipoprotein particles), while a few had no association with CHD onset at any age. Most risk factors and biomarkers had associations that attenuated with increasing age at onset.
Conclusions and Relevance
In this cohort study, diabetes and insulin resistance, in addition to hypertension, obesity, and smoking, appeared to be the strongest risk factors for premature onset of CHD. Most risk factors had attenuated relative rates at older ages.

 

Brigham and Women’s Hospital material

 

JAMA Cardiology study (Open access)

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