Diabetes and insulin resistance associated with highest relative risk for premature CHD in women

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

Literature - Dugani SB, Moorthy MV, Li C et al., - JAMA Cardiol. 2021 Jan 20;e207073. doi: 10.1001/jamacardio.2020.7073.

Introduction and methods

Identifying individuals at increased risk of premature coronary heart disease (CHD) is important to reduce premature morbidity and mortality rates. Premature CHD is generally defined as CHD occurring in women before age 65 years and in men before age 55 years [1-3]. This study evaluated the associations of more than 50 clinical risk factors and biomarkers with incident CHD in women.

The study was conducted among 28024 US female health professionals participating in the Women’s Health Study [4-7]. All participants were women (aged ≥45 years) without known CVD at baseline. Baseline risk factors were determined and blood samples for biomarker measurements (including lipid, lipoprotein, inflammatory and metabolic biomarkers) were obtained at baseline (April 30, 1993, to January 24, 1996). Median follow-up was 21.4 years and analyses were conducted from October 1, 2017, to October 1, 2020. The primary outcome was incident CHD, defined as the composite of first MI, PCI, CABG, or CHD death. CHD incidence rates were determined in 4 age groups:<55, 55 to <65, 65 to <75, and ≥75 years. Adjusted hazard ratios (aHRs) were estimated for incident CHD per SD increment of each biomarker and for clinical risk factors.

Main results

  • Of the clinical factors, diabetes had the highest relative risk for incident CHD in women (aHR in women >55 years: 10.71, 95%CI 5.57-20.60; aHR in women 55 to 65 years: 10.92, 95%CI 8.44-14.13; aHR in women 65 to <75 years: 4.49, 95%CI 3.46-5.83; aHR in women ≥75 years: 3.47, 95%CI 2.47-4.87).
  • Clinical risk factors that were also associated with increased risk of incident CHD in women younger than 55 years include 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). Relative risks attenuated with age. MI in a parent before age 60 years was associated with 1.5- to 2-fold higher risk of CHD in participants up to age 75 years.
  • The biomarker that was associated with the highest relative risk for incident CHD in women younger than 55 years was LPIR score reflecting lipoprotein insulin resistance (aHR: 6.40, 95%CI 3.14-13.06). Relative risks attenuated with age.
  • Hemaglobin A1c level was associated with incident CHD (aHR in women >55 years: 1.38, 95%CI 1.26-1.50, aHR’s attenuated with age). Other metabolic biomarkers showed no association with incident CHD across age groups.
  • All examined inflammatory biomarkers (CRP, Fibrinogen, ICAM-1, and GlycA) were significantly associated with incident CHD in all age groups (aHR ranged from 1.2 to 1.84). aHR’s attenuated with age.
  • Lipids and lipoproteins that were significantly associated with increased risk of CHD onset in women younger than 55 years include total cholesterol (aHR:1.39, 95%CI 1.12-1.73), LDL-c (aHR: 1.38, 95%CI 1.10-1.74), non-HDL-c (aHR: 1.67, 95%CI 1.36-2.04), apoB (aHR: 1.89, 95%CI 1.52-2.35), and triglycerides (aHR: 2.14, 95%CI 1.72-2.67). Relative risks attenuated with age.
  • Significant risk associations with CHD were also found for small LDL particles, total LDL particles, total TRL particles, TRL triglyceride, TRL cholesterol, TRL large particles, TRL medium particles and TRL very small particles. Most HDL particles had an inverse association with CHD, except small HDL particles.


This study identified diabetes and insulin resistance as major determinants of premature CHD in women. Other clinical factors associated with premature CHD in women include metabolic syndrome, hypertension, obesity, and smoking.


1. De Sutter J, De Bacquer D, Kotseva K, et al; EUROpean Action on Secondary Prevention through Intervention to Reduce Events II study group. Screening of family members of patients with premature coronary heart disease; results from the EUROASPIRE II family survey. Eur Heart J. 2003;24(3):249-257. doi:10.1016/S0195-668X(02)00386-X

2. Kotseva K,Wood D, De Backer G, De Bacquer D, Pyörälä K, Keil U; EUROASPIRE Study Group. EUROASPIRE III: a survey on the lifestyle, risk factors and use of cardioprotective drug therapies in coronary patients from 22 European countries. Eur J Cardiovasc Prev Rehabil. 2009;16(2):121-137. doi:10.1097/HJR.0b013e3283294b1d

3. Lloyd-Jones DM, Nam B-H, D’Agostino RB Sr, et al. Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: a prospective study of parents and offspring. JAMA. 2004;291(18):2204-2211. doi:10.1001/jama.291.18.2204

4. Mora S, Otvos JD, Rifai N, Rosenson RS, Buring JE, Ridker PM. Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease inwomen. Circulation. 2009;119(7):931-939. doi:10.1161/CIRCULATIONAHA.108.816181

5. Ridker PM, Cook NR, Lee I-M, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005;352(13):1293-1304. doi:10.1056/NEJMoa050613

6. Lee I-M, Cook NR, Gaziano JM, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: theWomen’s Health Study: a randomized controlled trial. JAMA. 2005;294(1):56-65. doi:10.1001/jama.294.1.56

7. Cook NR, Lee I-M, Gaziano JM, et al. Low-dose aspirin in the primary prevention of cancer: the Women’s Health Study: a randomized controlled trial. JAMA. 2005;294(1):47-55. doi:10.1001/jama.294.1.47

Find this article online at JAMA Cardiology

Facebook Comments


We’re glad to see you’re enjoying PACE-CME…
but how about a more personalized experience?

Register for free