Premature coronary heart disease in women is often linked to diabetes

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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 Women’s Hospital and the Mayo Clinic analyzed more than 50 risk factors in 28,024 women who participated in the decades-long Women’s Health 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. Findings are published in JAMA Cardiology.

“We’re going to see, unfortunately, younger and younger people having heart attacks,” said corresponding author 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.

“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 Sagar Dugani, MD, Ph.D., a hospital internal medicine practitioner at Mayo Clinic in Rochester, MN. Dr. Dugani is a co-first author of the study.

The researchers analyzed approximately 50 biomarkers associated with cardiovascular health. Commonly used metrics like low-density lipoprotein (LDL) cholesterol (or “bad” cholesterol) and hemoglobin 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 analyzed through specialized laboratory testing. Whereas LDL cholesterol was only associated with a 40 percent increase in risk of CHD onset in women under 55, LPIR demonstrated a sixfold (600 percent) 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 generalizability – beyond its focus on women, who have been shown to have worse outcomes after premature cardiac events than men, its participants were over 95 percent 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 emphasize 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.


In the general population, women die at an older age than men in nearly all parts of the world such that life expectancy is on average 4 years higher among women than men [1]. These differences have been attributed to biological, socioeconomic, environmental, and behavioral factors [2–4].

Although women live longer, this advantage frequently fails to translate into increased healthy life years [5]. Cardiovascular disease (CVD) is the leading cause of death among both men and women [6]. Diabetes is a well-known CVD risk factor and thus patients with diabetes mellitus have a high need for approaches that will reduce premature mortality from CVD.

The number of people with diabetes worldwide is predicted to increase from the current 463 million to 700 million by 2045 [7], and with it, the number of people developing CVD associated with diabetes. While there are only small gender differences in the age-specific prevalence of diabetes in adulthood [8••], there are sex and gender differences in the relationship between diabetes and CVD mortality.

Since the Framingham study is nearly five decades ago, it has been clear that the usual “female protection” is lost among women with insulin-treated diabetes, and that this is based on their higher CVD risk [9]. Several other studies subsequently demonstrated the increased relative risk for CVD in women with diabetes compared with men, in both type 1 (T1DM) and type 2 (T2DM) diabetes [10•, 11, 12•, 13••].

An excess CVD risk has also been shown among women with prior gestational diabetes mellitus (GDM) [14••]. The exact pathophysiological explanations remain under-investigated and need further research, but the higher risk seems to be driven by biological, environmental, and behavioral factors [8••].

Biological causes discussed include a loss of the protective hormonal effect by female sex hormones and sex hormone imbalance in hyperglycemic conditions leading to higher oxidative stress and endothelial dysfunction, a proinflammatory environment acting on estrogen receptor actions, a modulation of vascular response to nitric oxide, and impaired vessel relaxation properties [8••].

Further proposed explanations for the excess CVD mortality reported in women with diabetes compared with those without diabetes include pregnancy-related conditions and sex and gender differences in diabetes management and the management of other CVD risk factors [15] including hypertension [16].

In view of this sex and gender difference in excess CVD risk, our narrative review poses the question, whether all or, at least some women with diabetes, are in need of increased and more aggressive cardiovascular risk reduction than men. This includes the need for any further advances in diabetes prevention, treatment, CVD risk reduction, or management. We further attempt to shed light on the biological and socio-cultural aspects that are potentially responsible for these sex- and gender-related disparities.

Why Do Women Live longer?
In general, in high-income populations, life expectancy is 4–7 years higher in women than in men [17], whereas in low-income countries, a smaller gap was reported as women have less access to health care services [1]. Between the poorest and richest countries, the life expectancy gap opens up to more than 18 years as reported in a 2018 WHO report [1].

There are some data to suggest that this survival difference is mainly due to modifiable risk factors with biological causes only playing a minor role. Key evidence comes from a study comparing 11,000 German male and female cloister inhabitants from Catholic communities with the general population.

A maximum survival disadvantage of about 1 year of life expectancy from a young adult age (25 years) was found in the male cloister inhabitants compared with women from the cloister communities and the general population [18].

Men from the general population had a lower life expectancy from a young adult age compared with the cloister inhabitants. It was also proposed that these males were unable to decrease their mortality risk, in contrast to the female general population, nuns, and monks [18].

The protected environment of the cloister seemed to have positive effects on life expectancy on male inhabitants. Modifiable risk factors, such as smoking, alcohol, unhealthy food choices, excess body weight, and lack of physical inactivity, were more prevalent in the male general population [18].

While women have longer life expectancy, there is evidence to suggest that the balance between healthy and unhealthy live years includes a sex-specific imbalance, the so-called health survival paradox [5]. While women and men spend comparable time in a “good health” state, the longer life expectancy in women results in women accumulating more unhealthy life years compared with men.

Increased Mortality Risk in Women with Diabetes?
In general, the absolute risk for T2DM and CVD mortality is higher in men; however, the relative risk of all-cause and CVD mortality in women with T2DM has consistently been reported to be significantly higher and was also reported in women with T1DM (Table ​(Table1)1) [12•, 19, 20, 21•, 22, 23]. Higher risks were observed in younger groups with diabetes compared with older groups with the highest risk found in women with diabetes between 35 and 59 years of age [22].

Some studies observed higher CVD risk in both sexes, with a non-significant higher relative risk in women [23]. Key findings pertinent to sex differences in CVD outcomes were the reported higher obesity, hypertension, and dyslipidemia, as well as lower prescription of medication among women [23]. Furthermore, the risk of heart failure was reportedly higher in women with T1DM and T2DM (Table ​(Table1)1) [24•, 25•]. There was a narrowing sex ratio within older age categories, indicating that relative risk is higher in women of younger age [24•].

Table 1

Studies reporting sex and gender differences in the effect of diabetes mellitus on all cause and cardiovascular disease mortality and heart failure

AuthorPopulationDesignOutcome
Cardiovascular mortality
  Xu et al. [19]2,314,292 individuals, among whom 254,038 all-cause deaths occurredSystematic review and meta-analysis including prospective cohort 35 studiesPooled women vs. men ratio of the HRs 1.17 (95% CI: 1.12–1.23) and 1.97 (1.49–2.61) respectively for all cause and coronary heart disease (CHD) mortality.increased all-cause mortality in men (HR 1.91 (1.72–2.12)) and women (2.33 (2.02–2.69)) with T2DM vs. healthy population
  Wang et al. [20]5,162,654 participantsSystematic review and meta-analysis including 49 studiesHigher relative all-cause mortality (RRR 1.13, 95% CI 1.07–1.19; p < 0.001) and CVD mortality (1.30, 1.13–1.49; p < 0.001) in women with diabetes vs. men with diabetes.Women with diabetes vs. men with diabetes: CHD mortality RRR 1.58, 95% CI 1.32–1.90; p < 0.001 and stroke mortality 1.08, 1.01–1.15; p < 0.001
  Huxley et al. [21•]447,064 participantsMeta-analysis of 37 prospective cohort studiesHigher risk of fatal CHD in women with diabetes vs. men, pooled ratio of the RR 1.46 (1.14–1.88).Fatal CHD in patients with diabetes vs. no diabetes significantly higher in women than men: 3.50 (2.70–4.53) vs. 2.06 (1.81–2.34).
  Huxley et al. [12•]214,000 participants and 15,273 eventsMeta-analysis of 26 studiespooled women-to-men ratio in patients with T1DM: SMR 1.37 (95% CI 1.21–1.56) for all-cause mortality, 1.44 (1.02–2.05) increased risk for renal disease mortality, 1.37 (1.03–1.81) for stroke mortality, CVD mortality 1.86 (1.62–2.15), 2.54 (1.80–3.60) for incident coronary heart disease
  Prospective Studies Collaboration and Asia Pacific Cohort Studies Collaboration [22]980,793 participants and 76,965 fatalities different ethnicities and age categories, age 35–89 yearsMeta-analysis of 68 prospective studiesDoubling of occlusive vascular mortality risk in men with diabetes RR 2.10, 95% CI 1.97–2.24), tripling in women with diabetes (3.00, 2.71–3.33) after stratification for age, total cholesterol, blood pressure, smoking status and BMI.Higher risks in younger groups with diabetes aged 35–59 years (2.60, 2.30–2.94) vs. older groups aged 70–89 years (2.01, 1.85–2.19), highest risk in women with diabetes and age 35 and 59 years (5.55, 4.15–7.44). in absolute numbers, adjusted diabetes associated excess occlusive vascular mortality comparable in men and women across all age categories
  Wright et al. [23]79,985 patients with incident T2DM between 2006 and 2013 matched to 386,547 patients without T2DMRetrospective cohort studyHigher CVD event risk in both men and women, with a non-significant higher relative risk in women (RR 1.07 (0.98–1.17)
  Clemens et al. [13••]46,606 participants of trials examining the effect of diabetes medications on major adverse cardiovascular events in people ≥18 years of age with T2DMMeta-analysis of 5 CVOTs on 3- or 4-point MACE (i.e., CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, hospitalization for unstable angina for 4-point MACE)Higher risk for women for stroke (RR 1.28; 1.09–1.50), heart failure (1.30; 1.21–1.40), and CKD (1.33; 1.17–1.51), similar risk for PAD (1.12; 0.97–1.30) and lower risk for myocardial infarction (0.71; 0.59–0.86), consistently fewer female participants (28.5–35.8%) in the trials.
Heart failure
  Malmborg et al. [24•]218,549 (46% women) participants, age 40–89 yearsPopulation based studyHigher absolute risk of MACE-HF in men, but in relative terms 15% higher women to men ratio (95% Cl 1.11–1.19, p < 0.001) at the age of 50–60 years. The risk of recurrent CVD events or HF within 30 days irrespective of diabetes or sex, more often with increasing age.
  Ohkuma et al. [25•].12,142,998 individuals and 253,260 heart failure eventsSystematic review and meta-analysis of 47 cohortsWomen with diabetes have increased relative risk of heart failure vs. men:T1DM (RRR 1.47 (1.44, 1.90)), T2DM (RRR 1.09 (1.05, 1.13))
  Kannel et al. [26].5209 men and women, age 30–62 years,Framingham study, 18 year follow upFive- and two-fold increased risk of heart failure in women and men with diabetes respectively vs. healthy population
HR, hazard ratios; RRR, relative risk reduction, defined as the relative decrease in the risk of an event in a cohort exposed compared with a cohort unexposed to a disease/risk; SMR, standardized mortality ratio, defined as an age and sex matched comparison of mortality in a cohort with a specific illness to controls; RR, relative risk, defined as the ratio of the likelihood of an event in an exposed compared to an unexposed cohort; CVOT, cardiovascular outcome trial

Other studies also hypothesize a reduction in sex-related protection in women with diabetes, which is, in turn, associated with higher mortality risk [8••, 27, 28]. Potential risk factors explaining these differences are shown in Fig. 1. In view of this substantial effect of diabetes on CVD risk, there have been discussions over the need for more intensive CVD reduction activities, and individualization of risk reduction approaches [8••, 29, 30•]. It is obvious from the presented data that an individualized risk reduction approach needs to take into account both sex and age (e.g., the use of CVD risk reduction agents in women of reproductive age), but there also needs to be a focus on modifiable risk factors.

Sex Differences in CVD Management Among People with Diabetes
In women with T1DM, adherence to pharmacological intervention and cardio-protective measures was lower in women with guideline recommendations significantly less likely to be achieved by women for the target LDL-C levels, blood pressure, or aspirin prescription [47]. Intensive lifestyle interventions appear to be equally effective in men and women with diabetes in reducing weight, improving fitness, and maintaining healthy functioning.

Similarly, prevention of progression from impaired glucose tolerance to diabetes is equally effective in men and women with a 37% lower progression rate to T2DM reported in a systematic review including 12 RCTs [57•]. Meanwhile, the DaQing study in China reported lower CVD mortality in female than male participants with prediabetes in the 23-year follow-up after lifestyle intervention [58]. These results demonstrate the effectiveness of intensive lifestyle modification in women with prediabetes and suggest that these approaches might also help to reduce CVD mortality in women with diabetes.

However, this strategy needs to be verified in other cohorts. Sociocultural aspects cannot be translated easily to other cohorts and there was a substantial difference in smoking behavior—a serious CVD risk factor—between men and women within the DaQing study.

referece link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544714/


More information: jamanetwork.com/journals/jamac … jamacardio.2020.7073 Dugani, SB, et al. “Association of Lipid, Inflammatory, and Metabolic Biomarkers With Age at Onset for Incident Coronary Heart Disease in Women” JAMA Cardiology DOI: 10.1001/jamacardio.2020.7073

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