Early-Onset Hypertension and Sex-Specific Residual Risk for Cardiovascular Disease in Type 2 Diabetes

In the setting of type 2 diabetes, women consistently experience greater relative cardiovascular disease (CVD) risk than men (1). Blood pressure (BP) lowering with antihypertensive therapy is known to reduce CVD risk in type 2 diabetes, with apparently similar effects by sex (2). Accumulating evidence now indicates that physiologic BP levels are lower in women and that age-related BP elevation in women tends to begin earlier in life and rise faster than in men—particularly in the setting of cardiometabolic stressors such as type 2 diabetes (3,4). Thus, women with early-onset hypertension in the context of type 2 diabetes may represent a population especially likely to derive benefit from more- rather than less-intensive BP control.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial randomized 4,733 adults with type 2 diabetes to intensive (<120 mmHg) or standard (<140 mmHg) antihypertensive treatment targets (5); of all randomized adults who completed the study, a total of 3,792 participants (49% women) provided data on age at hypertension diagnosis (Supplementary Fig. 1). We categorized these participants based on sex and age of hypertension diagnosis: early (<50 years) versus late (≥50 years). We used Poisson regression to assess incidence of CVD events (coronary heart disease, stroke, heart failure, or cardiovascular death) across participant groups. We then used multivariable-adjusted Cox regression analyses to assess whether earlier age of hypertension diagnosis is related to incident CVD risk, by treatment arm (intensive versus standard antihypertensive targets) and by sex. Finally, we used restricted cubic splines to display the hazards of incident CVD in relation to intensive versus standard antihypertensive treatment across the range of age at hypertension diagnosis by sex. All models adjusted for age, BMI, systolic BP (SBP), diastolic BP (DBP), HbA_1c, LDL cholesterol, HDL cholesterol, triglycerides, and smoking status. All analyses were conducted using R v4.2.1, and a two-tailed P value was considered statistically significant.

The ACCORD trial data were acquired from and are available to the scientific community through the National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center.

The ACCORD protocol was approved by the institutional review board or ethics committee at each center of the 77 clinical centers (aggregated within seven networks) across the U.S. and Canada, and by an independent protocol review committee appointed by the National Heart, Lung, and Blood Institute. All participants provided written informed consent.

Study group characteristics are shown in Table 1, in addition to rates of incident CVD events over 4.5 ± 1.6 follow-up years. Event rates were higher for participants with early-diagnosed compared with late-diagnosed hypertension in women (P = 0.005) but not men (P = 0.15), and this excess event risk in women was attenuated in the presence of intensive compared with standard antihypertensive therapy (hazard ratio [HR] 0.65 [95% CI 0.43–0.97], P = 0.036) (Table 2). Accordingly, in multivariable-adjusted survival analyses, early-diagnosed compared with late-diagnosed hypertension was overall associated with a 31% increased hazard for CVD (HR 1.31 [95% CI 1.09–1.57], P = 0.003), and this association was particularly evident in women with early-diagnosed hypertension who received standard as opposed to intensive antihypertensive therapy (Table 3).

Similarly, for every decade earlier in age at hypertension diagnosis, the hazard for incident CVD risk was 11% increased overall (1.11 [1.03–1.21], P = 0.006) and predominantly in women who received standard but not intensive antihypertensive treatment. In restricted cubic splines, the effect of intensive versus standard antihypertensive treatment varied across the range of age at hypertension, with the benefit being especially evident for women with age at hypertension diagnosis less than 50 years (Fig. 1).

In secondary analyses, we found that intensive antihypertensive treatment was associated with rare but significant relative risk for serious adverse events (<4%); notably, this association did not reach statistical significance for women with early-diagnosed hypertension (Supplementary Table 1). We also assessed for any interaction between age at hypertension diagnosis and age at diabetes diagnosis, and observed no significant interactions (Supplementary Table 2). Further, we repeated analyses additionally adjusting for age at diabetes diagnosis and excluding individuals with baseline CVD and found results similar to those in the main analyses (Supplementary Fig. 2).

The cause of excess diabetes-related CVD risk in women remains unclear but has been attributed to sex differences in cardiometabolic risk burden (1). Accordingly, there have been calls for more-intensive CVD risk factor control for women with diabetes, yet without clearly supportive evidence. To our knowledge, the current study is the first analysis of clinical trial data to suggest efficacy of more-intensive antihypertensive therapy for women with type 2 diabetes—namely, those with early-diagnosed hypertension.

Prior studies indicate that early-onset hypertension not only confers greater CVD risk but also appears more heritable than later-onset hypertension (6). In this context, our findings suggest that this higher-risk BP phenotype in women with type 2 diabetes could represent a more genetically determined source of residual CVD risk that may benefit from targeted treatment. Importantly, individuals presenting with hypertension at an earlier age may also have secondary causes of hypertension such as primary aldosteronism or intrinsic kidney disease (7). These secondary causes were not completely assessed in our study and, given they are independent risk factors for CVD, should be considered in the broader context of CVD risk reduction with intensive antihypertensive treatment. Our study limitations also included the open-label trial design and relatively limited sample size that was partly dependent on availability of detailed medical data.

Our findings suggest that women with type 2 diabetes whose hypertension was diagnosed earlier in life could substantially benefit from intensive over standard antihypertensive treatment. Given the potential clinical implications of our findings, additional work is needed to validate our results in separate prospective studies as well as examine underlying mechanisms that could be further targeted as part of efforts to reduce the residual excess CVD risk in women with type 2 diabetes.

Funding. This study was funded in part by National Natural Science Foundation of China (82103908), the Natural Science Foundation of Shandong Province (ZR2021QH014), Shuimu Scholar Program of Tsinghua University, National Postdoctoral Innovative Talent Support Program (BX20230189), and National Institutes of Health grants U54-AG065141, U54-HL170326, and U54-HL169191.

The funding sources had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. H.J. participated in conceptualization, methodology, formal analysis, investigation, resources, data curation, and writing of the original draft. J.E.E. and A.C.K. participated in methodology and review and editing of the writing. K.R., J.C.S., and J.S. participated in resources, review and editing of the writing, and funding acquisition. S.C. participated in methodology, resources, writing of the original draft, supervision, and funding acquisition. H.J. and S.C. are the guarantors of this work and, as such, had full access to all the study data and take responsibility for the integrity of the data and the accuracy of the data analysis.

Handling Editors. The journal editors responsible for overseeing the review of the manuscript were Cheryl A.M. Anderson and Kristen J. Nadeau.