High‐density lipoprotein cholesterol levels are associated with major adverse cardiovascular events in male but not female patients with hypertension

Abstract Background The relationship between high‐density lipoprotein cholesterol (HDL‐C) levels and major adverse cardiovascular events (MACEs) in hypertensive patients of different sexes is unclear. Hypothesis Sex differences in the relationship between HDL‐C levels and the risk of MACEs among hypertensive patients. Methods We performed a post‐hoc analysis of data obtained from the Systolic Blood Pressure Intervention Trial (SPRINT) and explored sex‐based differences in the relationship between HDL‐C levels and MACEs among hypertensive patients using Cox proportional hazards regression. Results A total of 9323 hypertensive patients (6016 [64.53%] men and 3307 [35.47%] women) were assessed using SPRINT data. MACEs occurred in 395 (6.57%) men and 166 (5.02%) women after a mean follow‐up of 3.26 years. When HDL‐C levels were used as a continuous covariate, each 10 mg/dl increase in HDL‐C levels decreased the risk of MACEs in men (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.70–0.88; p < .0001). However, HDL‐C levels were not associated with MACEs in female hypertensive patients (HR, 1.02; 95% CI, 0.89–1.16; p = .7869). Compared with those in the first quartile, MACEs in the fourth quartile had the lowest risk among male patients (HR, 0.58; 95% CI, 0.41–0.82; p = .0023). Female patients in the fourth quartile of HDL‐C levels had an HR of 1.09 for MACEs (95% CI, 0.62–1.93; p = .7678). HDL‐C levels were not associated with the risk of MACEs among females. Conclusion Among elderly hypertensive patients, higher HDL‐C levels were associated with a lower MACE incidence in men but not in women. Unique identifier: NCT01206062.


| INTRODUCTION
Dyslipidemia is an important risk factor for the development and progression of cardiovascular diseases (CVD). Increased levels of low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol have been reported to be significantly correlated with an increased risk of cardiovascular mortality. [1][2][3] Nevertheless, even after intensive statin therapy, patients whose LDL-C levels have reached the target are still at risk for persistent atherosclerosis and cardiovascular events. 1 In recent years, more attention has been paid to the role of highdensity lipoprotein cholesterol (HDL-C), and several studies have shown that HDL-C levels are inversely associated with the risk of cardiovascular events. [4][5][6] Saito et al. reported that HDL-C levels are inversely associated with the risk of ischemic stroke. 7,8 However, recent studies have revealed that high-density lipoprotein (HDL) may lose its protective effects, leading to atherosclerosis or adverse outcomes. [9][10][11] In some cases, high HDL-C levels do not show protection in postmenopausal or older women. [12][13][14] The relationship between HDL-C levels and adverse cardiovascular events in hypertensive patients of different sexes is unclear.
Hence, we used data from the Systolic Blood Pressure Intervention Trial (SPRINT) to assess sex differences in the relationship between HDL-C levels and the risk of adverse cardiovascular events among hypertensive patients.

| MATERIALS AND METHODS
We performed a secondary analysis of SPRINT data. We obtained the limited dataset from the National Institutes of Health Biologic Specimen and Data Repository Information Coordinating Center.

| Study population
The protocol and main results of the SPRINT have been published. 15 Briefly, 9361 patients aged 50 years and older with a screening systolic blood pressure (SBP) of 130-180 mmHg were randomized in the SPRINT, which was a two-arm, multicenter, open-label, controlled trial. The recruited participants were between 50 and 75 years of age and had at least one of the following: presence of clinical or subclinical CVD other than stroke; chronic kidney disease (CKD; defined as estimated glomerular filtration rate of 20-59 ml/ min/1.73 m 2 ); Framingham risk score for 10-year CVD risk ≥15% based on laboratory work conducted in the last 12 months; or patient age of 75 years or older. Eligible participants for the trial were randomized into one of two goals: SBP <120 mmHg for the more intensive goal (intensive arm) and SBP <140 mmHg for the less intensive goal (standard arm). The SPRINT showed that compared with standard management, intensive blood pressure management significantly reduced cardiovascular mortality and all-cause mortality.

| Exposure variables
This study was a post-hoc analysis of SPRINT data. Data on HDL-C and LDL-C levels were collected at baseline. We excluded 38 patients whose data on HDL-C levels were not available. HDL-C levels were separated as sex-specific quartiles because of the nonlinear relationship between HDL-C levels and adverse outcomes. The primary endpoint of our study was major adverse cardiovascular events (MACEs), defined as a composite of myocardial infarction, stroke, heart failure, and/or death from cardiovascular causes. The definitions of MI, stroke, heart failure, and outcomes were the same as those in the SPRINT and presented elsewhere. The outcomes were adjudicated.

| Statistical analysis
The baseline characteristics and outcomes of patients were expressed as frequencies and percentages for categorical variables. Means and SDs or median and interquartile ranges were used for continuous variables, depending on whether datasets were normally distributed (assessed using normal Q-Q plots). We used chi-square analysis to compare categorical variables. We used analysis of variance or the Mann-Whitney U test to compare continuous variables in accordance with the distribution type.
The adjusted variables in this study were selected based on their clinical importance, statistical significance in the univariable analysis, and potential confounding, indicated by estimates that individually changed by at least 10%. We evaluated the relationship between HDL-C and LDL-C levels and MACEs using HDL-C and LDL-C levels as either continuous or categorical variables. A total of three models were used: (1) model 1, unadjusted; (2) Model 2, adjusted for age, treatment arm, and ethnicity; and (3) Model 3, fully adjusted for age, treatment arm, ethnicity, baseline SBP and diastolic blood pressure, baseline body mass index (BMI), smoking status, CKD subgroup, CVD subgroup, baseline total cholesterol, baseline triglycerides, baseline urine albumin/creatinine ratio, number of antihypertensive agents, aspirin use, and statin use. Using HDL-C and LDL-C levels as categorical variables, we used a Cox proportional hazards regression model to calculate the hazard ratios (HR) among categories. The first quartile was used as the reference. We subsequently treated the BMI categories as continuous variables to test the linear trend.
To account for BMI as a continuous variable, we constructed a Cox proportional hazards regression model adjusted for Model 3, in which HDL-C and LDL-C levels were used to calculate the HR for outcomes. We further used restricted cubic splines with four knots at the 5th, 35th, 65th, and 95th percentiles to flexibly model the association of HDL-C and LDL-C levels with the logarithm of the relative risk of outcomes, in which the mean BMI value served as the reference. Subsequently, a two-stage linear regression model was used to calculate the threshold effect of the relationship between HDL-C and LDL-C levels and MACEs. We used a trial method to determine the threshold value by moving the trial turning point along a predefined interval and selecting the value that provided the maximum model likelihood.
Next, we performed log-likelihood ratio analysis comparing the one-T A B L E 1 Baseline characteristics and crude end points of the study participants

| Quartiles of HDL-C levels and MACEs
The association between HDL-C levels and MACEs in hypertensive patients is presented in

| HDL-C levels as a continuous variable and MACEs
As shown in Table 3 Restricted cubic splines were used to flexibly model and visualize the relationship between HDL-C levels and MACEs in both male and female patients. In male patients, elevated HDL-C levels significantly reduced the risk of MACEs. However, the risk of MACEs in women did not change with BMI ( Figure 1).
Next, we used the two-stage linear regression model to calculate the threshold effect. Table 3

| LDL-C levels and MACEs
The association between LDL-C levels and MACEs in hypertensive patients is shown in  Figure S1). When the LDL-C levels were greater than 110 mg/dl, the risk of MACEs did not show statistical correlation with LDL-C levels.

| Interaction and sensitivity analyses
The results of the interaction and stratified analyses are presented in

| DISCUSSION
In this post-hoc analysis involving 9323 hypertensive patients from the SPRINT, we found a significant sex difference in the relationship between HDL-C levels and adverse cardiovascular events. In male patients, high HDL-C levels predicted a lower incidence of cardiovascular outcomes, whereas in female patients, HDL-C levels were not associated with the incidence of adverse cardiovascular events.
Several previous studies have shown that HDL-C levels are inversely associated with both CVD and mortality across a wide range high HDL-C levels in older women may be a marker of HDL dysfunction. This may be one of the reasons why HDL-C loses its cardioprotective effect in older women. 12 As for LDL-C, through meta-analysis, the CTT study has shown since 2010 that a decrease in the absolute value of LDL-C will lead to a significant decrease in atherosclerotic CVD (ASCVD) endpoint events. Subsequent studies, including the IMPROVE-IT, FOURIER, and ODYSSEY OUTCOMES trials, have confirmed that a decrease in the absolute value of LDL-C will result in a decrease in ASCVD endpoint events. [30][31][32] In a study involving 27 533 women with an average follow-up period of 17.2 years, Mora et al. revealed that relying on LDL-C alone might overestimate or underestimate the risk in a subgroup in which LDL-C was inconsistent with another LDL-related measurement method (up to a quarter of the total population). Therefore, in our study, no statistically significant correlation between LDL-C levels and the risk of MACEs was identified among female patients. 33 This may be attributable to the short follow-up period or to the fact that the LDL-C level itself is not a good predictor of MACEs.
This post-hoc analysis has some limitations. First, this was a retrospective study, and the original study was not designed to examine the relationship between HDL-C levels and adverse cardiovascular events. Second, we did not obtain data on HDL function in patients.
Finally, we analyzed the patients' baseline HDL-C levels; although we adjusted the LDL-C levels in the analysis, we were still unable to control for all variables that might have influenced the results.

| CONCLUSION
In elderly hypertensive patients, HDL-C levels were associated with MACEs in male but not female patients. Higher HDL-C levels were associated with a lower MACE incidence in men. In contrast, HDL-C levels were not associated with MACE incidence in women.