Mediating effect of vascular risk factors underlying the link between gestational diabetes and cardiovascular disease

Abstract

Background Women with gestational diabetes (GDM) have an elevated lifetime incidence of cardiovascular disease (CVD), but the basis of this excess risk remains to be established. In this context, we hypothesized that chronic exposure to adverse cardiovascular risk factors may contribute to their elevated risk of CVD. We thus sought to quantify the determinants of CVD risk in women with a history of GDM by performing mediation analyses. Methods Women in Ontario, Canada, with a live-birth pregnancy between Jan 1998 and Dec 2017 (n=757,541) were followed for a median of 13.2 years and stratified into the following 4 groups: women with GDM who developed CVD (GDM+/CVD+); women without GDM who developed CVD (GDM−/CVD+); those with GDM but no CVD (GDM+/CVD−); and those with neither GDM nor CVD (GDM−/CVD−). Lipids (total cholesterol, LDL, HDL, triglycerides) and glycemic variables (A1c, fasting glucose) were measured between 4.3±3.0 and 4.8±3.4 times over follow-up. Results On successive measurements at a median of 4.8, 7.1, and 8.7 years postpartum, respectively, each lipid and glycemic measure progressively worsened from GDM−/CVD− to GDM+/CVD− to GDM−/CVD+ to GDM+/CVD+ (all p<0.0001). At each point in time, each of the lipid and glycemic measures was significantly worse in GDM+/CVD+ compared to GDM+/CVD− (all p<0.001). Moreover, among women who did not develop CVD, all lipid and glycemic measures were significantly worse in those with previous GDM (all p<0.001 for GDM+/CVD− vs GDM−/CVD−). Mediation analyses revealed that the dominant determinants of CVD risk in women with GDM were A1c (56.0% mediation, 95%CI 47.4–67.8) and fasting glucose (47.4%, 38.8–60.8), followed by HDL (25.2%, 21.3–30.7) and triglycerides (12.1%, 9.7–15.6). Upon exclusion of those who developed diabetes during follow-up, the key determinants were HDL (40.8%), fasting glucose (37.7%), A1c (28.6%), triglycerides (21.0%), and LDL (9.9%). Conclusions Adverse glycemic and lipid measures mediate the elevated risk of CVD in women with previous GDM, with the impact of lipids particularly evident in those who do not develop diabetes. These findings thus identify potential targets for risk factor monitoring and ultimately early intervention towards the goal of primary prevention of CVD in this at-risk patient population.

Pregnancy as an Early Cardiovascular Moment: Peripartum Cardiovascular Health

“…147 Data from the Women’s Health Initiative also suggest that hypertension and BMI at the time of study enrollment mediated 24% and 20% of the association between HDP and incident heart failure, respectively. 148 Among those with a history of GDM, risk of CVD was significantly mediated by HbA1c (56%), fasting glucose (46%), HDL cholesterol (25%), and triglyceride levels (12.1%) measured at approximately 4 to 9 years post-partum. 149 Risk factor levels following an APO may signal those who are most likely to develop chronic risk factors.…”

Health impacts of new‐onset diabetes in women post‐gestational diabetes mellitus: Insights from Hong Kong's territory‐wide data

“…On the other hand, Yu et al quantified the impact of type 2 diabetes after GDM using mediation analysis in a Danish nationwide cohort of 1 million parous women observed over 16 years and reported that one-fifth of the increased relative risk of CVD among women with GDM compared with those without could be explained by subsequent type 2 diabetes 8 . Retnakaran et al 6 conducted a retrospective analysis of a cohort of 0.7 million women with a live-birth pregnancy in followed for 13 years and found that the HbA1c and fasting glucose were major determinants (56 and 47%, respectively) for excess CVD risk in women with GDM compared with those without GDM. These proportion estimates were based on measures of relative risk and we supplemented these estimates by firstly reporting the proportion of absolute health burden that could be attributable to subsequent diabetes in women with GDM.…”

“…A few studies have reported the contribution of incident diabetes or hyperglycemia to excess relative risk of cardiovascular disease (CVD), renal dialysis, and hospitalization for foot infection in women with compared with those without GDM 6 , 7 , 8 . However, the proportion in absolute terms is still unknown, specifically, the population attributable fraction (PAF), which is commonly defined as the proportion of cases that would have been prevented over a specified time interval had the exposure of interest been eliminated from the population while distributions of other risk factors in the population remain unchanged 9 .…”

Adverse pregnancy outcomes and future risk of heart failure

“…The mechanisms linking GDM to HF are currently unclear. Women with history of GDM have greater exposure to increased glycemia and dyslipidemia independent of subsequent diabetes development [79]. This hyperglycemia may lead to myocardial fibrosis and remodeling similar to the processes related to diabetic cardiomyopathy [80].…”