Abstract
Background and purpose
Rare comparative studies investigated the relationship between combination therapy of antihypertensive drugs and the incidence of new-onset diabetes mellitus (NODM). The aim of this study was to evaluate which combination therapy, calcium channel blocker (CCB) with angiotensin converting enzyme inhibitor (ACEI) or CCB with angiotensin II type 1 receptor blocker (ARB), is best in reducing/preventing the development of NODM during 4-year follow-up periods in non-diabetic hypertensive Korean patients.
Materials and methods
Finally, a total of 1221 consecutive hypertensive patients without a history of diabetes mellitus who had been prescribed CCB were retrospectively enrolled and divided into the two groups, an ACEI group (combination CCB with ACEI, n = 251) and an ARB group (combination CCB with ARB, n = 970). The primary endpoint was NODM, defined as a fasting blood glucose ≥126 mg/dL or hemoglobin A1c ≥ 6.5%. Secondary endpoint was major adverse cardiac events (MACE) defined as total death, non-fatal myocardial infarction (MI) and percutaneous coronary intervention (PCI).
Results
After propensity-score matched (PSM) analysis, two propensity-matched groups (243 pairs, n = 486, C-statistic = 0.696) were generated. During 4-year follow-up periods, there were similar incidence of NODM (Hazard ratio [HR]; 1.198, 95% confidence interval [CI]; 0.591–2.431, P = 0.616), MACE (HR; 1.324, 95% CI; 0.714–2.453, P = 0.373), total death, MI and PCI between the two groups after PSM analysis.
Conclusion
CCB with ACE or CCB with ARB combination strategies are equally acceptable in hypertensive Korean patients regarding the occurrence of NODM.
Keywords: Angiotensin converting enzyme inhibitor, Angiotensin II type 1 receptor blocker, Calcium channel blocker, Diabetes mellitus
Introduction
Although antihypertensive therapies can reduce cardiovascular morbidity and mortality in a variety of disease [1], they can cause increased incidences of new-onset diabetes mellitus (NODM), unfortunately [2]. Previous prospective studies reported the positive relationship between antihypertensive drugs and NODM [3–6]. These effects of these antihypertensive drugs on blood glucose level are different according to the class of antihypertensive drugs [7, 8]. The incidence of diabetes mellitus (DM) is unchanged or increased by thiazide diuretics and beta-blockers (BB) and unchanged or decreased by calcium channel blockers (CCB), angiotensin converting enzyme inhibitor (ACEI), and angiotensin II type 1 receptor blocker (ARB) in hypertensive patients [9–11]. Because, most of the previous studies investigated the cause-effect relationship only between a single class of antihypertensive agent and NODM [9, 12, 13], the results between combination therapy of antihypertensive drugs and the incidence of NODM is scarce [14]. In addition, whether many previous results could be extended to Asian patients, especially, Korean patients were questioned. Therefore, the aims of this study was to investigate which combination therapy, CCB with ACEI or CCB with ARB, is best to prevent the development of NODM in Korean population during 4-year follow-up periods in non-diabetic hypertensive Korean patients.
Materials and methods
Study population
This study was a non-randomized, single center, observational and retrospective study. From January 2004 to December 2012, a total of 3208 consecutive hypertensive patients without a history of diabetes mellitus (DM) who had been prescribed CCB were retrospectively selected and enrolled using the electronic database of Korea University Guro Hospital. All enrolled patients had undergone glucose tolerance test. Inclusion criteria were both hemoglobin (Hb) A1c < 5.7% and a fasting glucose level < 100 mg/dL and the exclusion criteria were the patients who had been prediabetes, such as impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). Prediabetes was defined as an HbA1c of 5.7–6.4% and an FPG of 100–125 mg/dL (5.6–6.9 mmol/L) according to the criteria of the American Diabetes Association [15]. The first prescription day within the study period was defined as the start day of the study. Finally, a total of 1221 consecutive hypertensive patients who had been prescribed CCB were enrolled and divided into the two groups, an ACEI group (combination CCB with ACEI, n = 251) and an ARB group (combination CCB with ARB, n = 970). A propensity score-matched (PSM) analysis was performed using the logistic regression model (Table 1). The study protocol was approved by the Institutional Review Board at Korea University Guro Hospital (#KUGH 13017).
Table 1.
Baseline clinical characteristics and laboratory results
| Variables | Entire Patients | Propensity score-matched patients | ||||
|---|---|---|---|---|---|---|
| ACEI group (n = 251) |
ARB group (n = 970) |
P value | ACEI group (n = 243) |
ARB group (n = 243) |
P value | |
| Gender (men, %) | 170 (67.7) | 490 (50.5) | <0.001 | 163 (67.1) | 168 (69.1) | 0.627 |
| Age (years) | 57.9 ± 12.5 | 59.3 ± 11.8 | 0.111 | 57.8 ± 12.5 | 59.2 ± 11.8 | 0.204 |
| Body mass index (kg/m2) | 24.8 ± 3.5 | 24.9 ± 3.1 | 0.578 | 24.8 ± 3.6 | 25.0 ± 3.3 | 0.521 |
| Systolic blood pressure (mmHg) | 139.3 ± 20.3 | 137.4 ± 21.4 | 0.355 | 139.6 ± 20.5 | 134.8 ± 19.6 | 0.055 |
| Diastolic blood pressure (mmHg) | 85.9 ± 14.4 | 84.4 ± 13.8 | 0.264 | 86.3 ± 14.4 | 83.2 ± 13.0 | 0.075 |
| Heart rate (beats/min) | 74.2 ± 10.2 | 75.4 ± 9.3 | 0.087 | 74.4 ± 10.4 | 74.6 ± 9.2 | 0.791 |
| Dyslipidemia (%) | 26 (10.4) | 91 (9.4) | 0.693 | 25 (10.3) | 20 (8.2) | 0.434 |
| Previous myocardial infarction (%) | 24 (9.6) | 28 (2.9) | <0.001 | 20 (8.2) | 17 (7.0) | 0.608 |
| Previous PCI (%) | 49 (19.5) | 102 (10.5) | <0.001 | 47 (19.3) | 49 (20.2) | 0.820 |
| Previous cerebrovascular accident (%) | 24 (9.6) | 162 (16.7) | 0.005 | 18 (7.4) | 19 (7.8) | 0.863 |
| Heart failure (%) | 15 (6.0) | 60 (6.2) | 0.902 | 14 (5.8) | 14 (5.8) | 1.000 |
| Coronary artery spasm (%) | 7 (2.8) | 28 (2.9) | 0.934 | 7 (2.9) | 10 (4.1) | 0.459 |
| Atrial fibrillation & arrhythmia | 10 (4.0) | 58 (6.0) | 0.219 | 9 (3.7) | 13 (5.3) | 0.383 |
| Current smokers (%) | 57 (22.7) | 220 (22.7) | 0.937 | 55 (22.6) | 59 (24.3) | 0.862 |
| Current alcoholics (%) | 87 (34.7) | 341 (35.8) | 0.142 | 84 (34.6) | 91 (37.4) | 0.300 |
| Fasting blood glucose (mg/dL) | 95.0 ± 8.7 | 95.4 ± 7.7 | 0.513 | 95.0 ± 8.7 | 94.8 ± 7.1 | 0.735 |
| Hemoglobin A1c (%) | 5.57 ± 0.31 | 5.63 ± 0.28 | 0.005 | 5.58 ± 0.30 | 5.56 ± 0.31 | 0.514 |
| Dyslipidemia (%) | 26 (10.4) | 91 (9.4) | 0.639 | 25 (10.3) | 20 (8.2) | 0.434 |
| Total cholesterol (mg/dL) | 177.8 ± 38.4 | 179.8 ± 36.2 | 0.451 | 178.0 ± 38.2 | 175.7 ± 38.9 | 0.517 |
| Triglyceride (mg/dL) | 143.7 ± 92.5 | 145.1 ± 93.8 | 0.824 | 143.9 ± 93.0 | 140.1 ± 78.9 | 0.632 |
| HDL cholesterol (mg/dL) | 49.7 ± 13.0 | 50.5 ± 12.9 | 0.368 | 49.8 ± 13.2 | 48.8 ± 12.3 | 0.410 |
| LDL cholesterol (mg/dL) | 111.4 ± 33.1 | 113.9 ± 33.6 | 0.355 | 111.6 ± 32.8 | 110.1 ± 32.6 | 0.664 |
| High sensitivity CRP (mg/L) | 3.5 ± 9.2 | 3.0 ± 10.3 | 0.513 | 3.5 ± 9.2 | 4.5 ± 18.1 | 0.468 |
| Hemoglobin (mg/dL) | 14.0 ± 1.7 | 13.8 ± 1.6 | 0.077 | 14.0 ± 1.6 | 14.1 ± 1.6 | 0.599 |
| Serum creatinine (mg/dL) | 1.0 ± 0.6 | 0.9 ± 0.5 | 0.008 | 1.0 ± 0.5 | 0.9 ± 0.3 | 0.132 |
| Medications | ||||||
| Beta blockers (%) | 93 (37.1) | 246 (25.4) | <0.001 | 87 (35.8) | 84 (34.6) | 0.776 |
| Diuretic (%) | 73 (29.1) | 499 (51.4) | <0.001 | 73 (30.0) | 75 (30.9) | 0.844 |
| Nitrate (%)) | 96 (38.2) | 242 (24.9) | <0.001 | 93 (38.3) | 83 (34.2) | 0.345 |
| Lipid lowering agents (%) | 113 (45.0) | 349 (36.0) | 0.157 | 110 (45.3) | 105 (43.2) | 0.648 |
| Aspirin (%) | 8 (3.2) | 20 (2.1) | 0.288 | 8 (3.3) | 6 (2.5) | 0.588 |
| Clopidogrel (%) | 78 (31.1) | 182 (18.8) | <0.001 | 75 (30.9) | 74 (30.5) | 0.922 |
| Cilostazole (%) | 18 (7.2) | 48 (4.9) | 0.165 | 18 (7.4) | 20 (8.2) | 0.735 |
| ACEI (%) | 251 (100.0) | 243 (100.0) | ||||
| Ramipril (%) | 131 (52.2) | 126 (51.8) | ||||
| Perindopril (%) | 54 (21.5) | 52 (21.4) | ||||
| Cilazapril (%) | 22 (8.7) | 22 (9.1) | ||||
| Imidapril (%) | 19 (7.6) | 19 (7.8) | ||||
| Moexipril (%) | 10 (4.0) | 10 (4.1) | ||||
| Enalapril (%) | 9 (3.6) | 9 (3.7) | ||||
| Captopril (%) | 6 (2.4) | 5 (2.1) | ||||
| ARB (%) | 970 (100.0) | 243 (100.0) | ||||
| Losartan (%) | 227 (23.5) | 61 (25.1) | ||||
| Irbesartan (%) | 167 (17.2) | 39 (16.0) | ||||
| Valsartan (%) | 159 (16.4) | 41 (16.9) | ||||
| Telmisartan (%) | 107 (11.0) | 18 (7.5) | ||||
| Olmesartan (%) | 107 (11.0) | 28 (11.5) | ||||
| Candesartan (%) | 104 (10.7) | 26 (10.7) | ||||
| Eprosartan (%) | 94 (9.7) | 28 (11.5) | ||||
| Fimasartan (%) | 5 (0.5) | 2 (0.8) | ||||
| Prescription duration (days) | 1651 ± 1088 | 1802 ± 1008 | 0.302 | 1639 ± 1007 | 1763 ± 986 | 0.259 |
Values are mean ± SD or n (%). The P values for continuous data were obtained from analysis of the unpaired t-test. The P values for categorical data were obtained from the chi-square test. PCI: percutaneous coronary intervention; HDL, high-density lipoprotein; LDL, low-density lipoprotein; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin II type 1 receptor blocker
Study definitions and study end-points
NODM was defined as fasting blood glucose (FBG) ≥ 126 mg/dL or HbA1c ≥ 6.5% [15]. The primary study endpoint was the cumulative incidence of NODM during a 4-year clinical follow-up periods. The secondary endpoint was major adverse cardiac events (MACE) defined as total death, non-fatal myocardial infarction (MI) and percutaneous coronary intervention (PCI). The mean prescription duration of the ACEI group was 1651 ± 1088 days and the ARB group was 1802 ± 1008 days in all patients. After PSM, the mean prescription duration of the ACEI group was 1639 ± 1007 days and the ARB group was 1736 ± 986 days. We followed up on the clinical data of all enrolled patients through face-to-face interviews at outpatient clinics, medical chart reviews and telephone calls.
Statistical analysis
For continuous variables, differences between the two groups were evaluated with the unpaired t-test or Mann-Whitney rank test. Data were expressed as mean ± standard deviations. For discrete variables, differences were expressed as counts and percentages and analyzed with χ2 or Fisher’s exact test between the groups as appropriate. To adjust for potential confounders, PSM analysis was performed using the logistic regression model. All data were processed with Statistical Package for the Social Sciences version 20.0 (IBM; Armonk, NY, USA). We tested all available variables that could be of potential relevance: gender, age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, dyslipidemia, previous MI, previous PCI, previous cerebrovascular accident (CVA), previous heart failure (HF), coronary artery spasm, atrial fibrillation and arrhythmia, current smokers, current alcoholics, laboratory findings (fasting blood glucose, HbA1c, total cholesterol, triglyceride, high-density lipoprotein [HDL]-cholesterol, low-density lipoprotein [LDL]-cholesterol, high-sensitivity C-reactive protein [hs-CRP], Hb, serum creatinine), medications (BBs, diuretics, nitrate, lipid lowering agents, aspirin, clopidogrel, cilostazole). The C-statistics for PSM was 0.696 in this study. Patients with the ACEI group was then one-to-one matched to the patients with the ARB group according to propensity scores with the nearest available pair matching method. Subjects were matched with a caliper width equal to 0.01. The procedure yielded 243 matched pairs. For all analyses, a two-tailed p value of <0.05 was considered to be statistically significant. Various clinical outcomes at 4-year were estimated with the Kaplan-Meier method, and differences between groups were compared with the log-rank test. In addition, multivariate Cox-regression analysis adjusted with variables was performed to determine the different impact on the incidence of NODM between the two groups. The following factors were co-analyzed in multivariate Cox-regression analysis: ACEI group vs. ARB group, age (≥ 65 years), gender (men), BMI (≥ 24 kg/m2), SBP, DBP, dyslipidemia, previous MI, previous PCI, previous CVA, previous HF, current smokers, current alcoholics, BBs, diuretics, nitrates, lipid lowering agent, and clopidogrel.
Results
Baseline, laboratory, and procedural characteristics of this study population are summarized in Table 1. In the total study population, men, previous MI, previous PCI and the use of BBs, nitrates and clopidogrel variables were significantly higher in the ACEI group compared to the ARB group. In contrast, previous CVA, HbA1c and the use of diuretic variables were significantly higher in the ARB group. In PSM patients, the baseline characteristics of the two groups were well-balanced; Table 2 and Fig. 1 show the clinical outcomes by Kaplan-Meier curved analysis and Cox-proportional hazard analysis at 4 years. In the total study population, the cumulative incidence of NODM (7.0% vs. 9.2%, Log rank P = 0.471) was not statistically different between the two groups. However, the incidence of MACE (10.9% vs. 5.9%, Log rank P = 0.003) and PCI (9.2% vs. 3.4%, Log rank P < 0.001) were significantly higher in the ACEI group. After PSM, the incidences of NODM (7.3% vs. 9.0%, Log rank P = 0.615, hazard ratio [HR]; 1.198, 95% confidence interval [CI]; 0.591–2.431, P = 0.616) and MACE (11.3% vs. 10.0%, Log rank P = 0.371, HR; 1.324, 95% CI; 0.714–2.453, P = 0.373) were similar between the two groups. In addition, total death, MI, PCI were not significantly different. Table 3 shows univariate and multivariate Cox-regression analysis for predictors of NODM before and after PSM analysis. Dyslipidemia was a common significant predictor of NODM in the total study population before (HR, 2.039; 95% CI, 1.147–3.625; P = 0.015) and after adjustment (HR, 2.895; 95% CI, 1.139–7.356; P = 0.026). The results of subgroup analysis using Cox regression model in the total study population (Fig. 2) showed that all parameters including age, sex, previous PCI, previous CVA, current smoker, current alcoholics, BB, diuretics, nitrate and lipid lowering agents were comparable between the two groups.
Table 2.
Clinical outcomes by Kaplan-Meier Curved Analysis and Cox-proportional Hazard Ratio Analysis at 4-year
| Outcomes | Cumulative Events up to 4 years (%) | Hazard Ratio (95% CI) | P value | ||
|---|---|---|---|---|---|
| ACEI group | ARB group | Log Rank | |||
| Total study population | |||||
| New-onset diabetes mellitus | 14 (7.0) | 68 (9.2) | 0.471 | 1.235 (0.695–2.195) | 0.472 |
| MACEs | 23 (10.9) | 44 (5.9) | 0.003 | 2.117 (1.278–3.505) | 0.004 |
| Total death | 3 (1.4) | 10 (1.4) | 0.806 | 1.176 (0.324–4.272) | 0.806 |
| Cardiac | 0 (0.0) | 5 (0.7) | 0.259 | – | – |
| Non-fatal myocardial infarction | 4 (1.9) | 5 (0.7) | 0.072 | 3.142 (0.844–11.70) | 0.088 |
| Percutaneous coronary intervention | 19 (9.2) | 26 (3.4) | <0.001 | 2.940 (1.627–5.312) | <0.001 |
| Propensity score-matched Patients | |||||
| New-onset diabetes mellitus | 14 (7.3) | 17 (9.0) | 0.615 | 1.198 (0.591–2.431) | 0.616 |
| MACEs | 23 (11.3) | 18 (10.0) | 0.371 | 1.324 (0.714–2.453) | 0.373 |
| Total death | 3 (1.5) | 6 (3.3) | 0.322 | 1.987 (0.497–7.946) | 0.332 |
| Cardiac | 0 (0.0) | 2 (1.1) | 0.155 | – | – |
| Non-fatal myocardial infarction | 4 (2.0) | 1 (0.6) | 0.177 | 4.032 (0.451–36.07) | 0.212 |
| Percutaneous coronary intervention | 19 (9.5) | 12 (6.4) | 0.180 | 1.632 (0.792–3.361) | 0.184 |
Values are represented as n (%). MACE, major adverse cardiac events; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin II type 1 receptor blocker
Fig. 1.
Kaplan-Meier curved analysis for NODM and MACE in total study patients (a, b) and PSM patients (c, d) at 4 years. PSM: propensity score-matched; NODM: new-onset diabetes mellitus; MACE: major adverse cardiac events; ACEI group: angiotensin converting enzyme inhibitors group (calcium channel blockers + ACEI); ARB group: angiotensin II type 1 receptor blockers group (calcium channel blockers + ARB)
Table 3.
Independent predictors of NODM in the total population
| Variables | Unadjusted | Adjusted | ||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| ACEI group vs. ARB group | 1.235 (0.695–2.195) | 0.472 | 2.099 (0.566–7.781) | 0.267 |
| Age ≥ 65 years | 1.278 (0.818–1.998) | 0.281 | 2.577 (0.811–8.189) | 0.109 |
| Gender (men) | 1.034 (0.670–1.595) | 0.879 | 1.083 (0.429–2.731) | 0.866 |
| BMI ≥ 24 kg/m2 | 1.090 (0.635–1.869) | 0.755 | 1.069 (0.942–1.214) | 0.301 |
| Systolic blood pressure | 0.986 (0.970–1.003) | 0.108 | 0.985 (0.952–1.020) | 0.391 |
| Diastolic blood pressure | 0.981 (0.957–1.005) | 0.120 | 0.999 (0.950–1.051) | 0.973 |
| Dyslipidemia | 2.039 (1.147–3.625) | 0.015 | 2.895 (1.139–7.356) | 0.026 |
| Previous MI | 3.518 (0.490–25.28) | 0.211 | 2.339 (0.244–22.41) | 0.461 |
| Previous PCI | 1.193 (0.646–2.200) | 0.573 | 1.540 (0.322–7.366) | 0.589 |
| Previous CVA | 2.101 (1.289–3.425) | 0.003 | 1.057 (0.241–4.645) | 0.941 |
| Previous heart failure | 1.196 (0.438–3.268) | 0.727 | 1.045 (0.214–5.109) | 0.957 |
| Current smokers | 1.215 (0.751–1.968) | 0.518 | 1.097 (0.402–2.992) | 0.856 |
| Current alcoholics | 1.082 (0.670–1.748) | 0.747 | 1.208 (0.447–3.266) | 0.709 |
| Beta blocker | 1.035 (0.639–1.675) | 0.890 | 1.462 (0.549–3.894) | 0.447 |
| Diuretics | 1.139 (0.738–1.758) | 0.556 | 1.110 (0.451–2.731) | 0.820 |
| Nitrates | 1.229 (0.776–1.949) | 0.379 | 1.476 (0.551–3.950) | 0.439 |
| Lipid lowering agent | 1.761 (1.141–2.716) | 0.011 | 1.307 (0.453–3.777) | 0.620 |
| Clopidogrel | 2.011 (1.274–3.174) | 0.003 | 1.668 (0.465–5.990) | 0.433 |
NODM, new-onset diabetes mellitus; HR, hazard ratio; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin II type I receptor blocker; BMI, body mass index; MI, myocardial infarction; PCI, percutaneous coronary intervention; CVA, cerebrovascular accidents
Fig. 2.
Subgroup analysis for NODM in PSM patients. NODM: new-onset diabetes mellitus; PSM: propensity score-matched; PCI: percutaneous coronary intervention; CVA: cerebrovascular accidents; ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin II type 1 receptor blocker
Discussion
The main findings of this study are as follows: 1) the development of NODM was not significantly different between the two groups and 2) the incidences of MACE, total death, MI, and PCI were also similar between the two groups during the 4-year follow-up periods.
Previous guidelines recommended CCB as one of the first-line drugs suitable for the beginning and maintaining their antihypertensive role in hypertensive patients [16, 17]. Compared with diuretics and BB, CCB has relatively low risk of NODM incidence [9]. The comparative beneficial effect on NODM between the ACEI and ARB is open to dispute [18]. Because in real practice, two or more antihypertensive drugs are needed to achieve target blood pressure and recent guidelines recommend the combination therapy to control blood pressure level [16, 19–21], the authors focused on the effect of these antihypertensive drug combinations on the incidence of NODM. As a result, those patients who were treated with CCB were considered as the baseline study population and the two combination groups (ACEI group vs. ARB group) were compared in aspects with the comparative superiority of beneficial effects on the incidence of NODM.
CCB cause impaired glucose tolerance and borderline increased incidence of DM, but CCB can improve peripheral glucose uptake [22]. ACEI increases insulin sensitivity by inhibition of angiotensin II and/or increase bradykinin, and this increased bradykinin production leads to increased production of prostaglandins and nitric oxide which improve exercise induced glucose metabolism and muscle sensitivity to insulin [23, 24]. ARB suppresses angiotensin II by selectively binding to the corresponding receptor site. Other ARB’s anti-diabetic actions include activation of peroxisome proliferator-activated receptor-γ (PPARγ), suppression of oxidative stress, inhibition of fibrosis, and enhancement of insulin signaling [25, 26]. This means ACEI and ARB have different mechanisms regards to prevent insulin resistance. A meta-analysis reported that ARB showed relatively low rates of type 2 DM compared with ACEI [27]. Another study demonstrated ACEI and ARB had comparable effects on the development of NODM [28]. Burke et al. demonstrated that antihypertensive drug combination which included ACEI had a significantly lower risk of NODM than without ACEI [14]. Yang et al. [29] reported CCB combined with ARB had metabolically neutral effects. The main problem of these diverse results is absence directly compared randomized control trials between ACEI and ARB in long-term follow-up periods. Additionally, there may be significant heterogeneity in meta-analyses for drug classes versus all other antihypertensive agents. This heterogeneity may be a bias across all classes of antihypertensive drugs instead of restricted comparisons of one class versus all other classes [11, 27].
The results of this study were similar with Scheen’s report [30]. Their report said that ACEI in hypertensive nondiabetic individuals showed a mild but significant increase in insulin sensitivity while the other half failed to reveal significant change and the effects of ARB on insulin sensitivity are neutral in most studies. Grimm et al. [31] reported the incidence of NODM during treatment with CCB varies from 0.9% to 2.0% per year and from 1.1% to 1.7% per year by ACEI and regardless of its’ class, the incidence was about 1.7% annually. The incidence of NODM in our study was similar compared with another previous study [32].
Which treatment modality is best between ACEI and ARB in cardioprotective activity is a long-standing debated issue. Although both classes of drugs act on renin-angiotensin system, they have some differences in blood pressure-independent effects such as the reduction of oxidative stress, endothelial dysfunction, inhibition and stabilization of atherosclerotic plaque [33]. However, most renin-angiotensin system inhibitors have common molecular structures and they have “class effects”. In our study, the higher rates of PCI and MACE in ACEI group before PSM may be caused by higher baseline risk factors such as, previous MI and previous PCI compared with ARB group. However, after PSM the rates of PCI and MACE were similar between the two groups. The secondary outcome such as MACE, incidences of total death, MI, PCI were not significantly different between the two groups in this study. This result may be similar with Ricci et al. report [34]. Their report said that in patients at high-risk without heart failure, ARB was similar to ACEI in preventing incident risk of all-cause death, MI, NODM.
Although in our study CCB with ACEI combination therapy did not show significant differences on the development of NODM compared to CCB with ARB combination therapy up to 4-year follow-up periods, our results are meaningful because our study appears to be the first study comparing the effect of antihypertensive drug combinations on the incidence of NODM in hypertensive Korean patients.
This study has some limitations. First, because this study included relative low risk patients, these results could be different in high-risk patients. Second, though the first antihypertensive prescription for nearly all patients was monotherapy, the decision to add a second antihypertensive drug was depended on physician’s discretion. This could affect the end results and maybe a bias of this study. Third, the ACEI group and ARB group were composed with diverse kinds and numbers of drugs and this factor also may be bias. Fourth, the data regarding “family history of DM” in all patients and “history of gestational DM (GDM)” in female patients are important factors for developing NODM. According to the Korea National Health Insurance family tree database, among the population born in the 2010s, 99.6% are matched with a parent or a grandparent [35]. It is estimated that GDM affects around 7% to 10% of all pregnancies worldwide [36]. In Korea, the frequency of GDM diagnosed by Carpenter-Coustan criteria and new International Association of Diabetes and Pregnancy Study Group criteria was 2.6% and 7.5% [37]. However, those two parameters were not included in our registry data. Therefore, we think that which may constitute an important bias and which might have influenced the cumulative incidence of NODM. Finally, because this study was single center retrospective study, large, randomized, controlled clinical trials will be required for a more definitive conclusion.
Conclusion
In conclusion, CCB with ACEI combination therapy did not show significant differences on the development of NODM and individual and composite MACE compared with CCB with ARB combination therapy up to 4-year follow-up periods in Korean patients. Therefore, these two treatment strategies are considered to be equally acceptable in hypertensive Korean patients in the aspect of the occurrence of NODM.
Abbreviations
- ACE
Angiotensin converting enzyme inhibitors
- ARB
Angiotensin II type 1 receptor blockers.
- CCB
Calcium channel blockers
- NODM
New-onset diabetes mellitus
- MACE
Major adverse cardiac events
- PSM
Propensity-score matched
Compliance with ethical standards
Conflict of interest
The authors state that there is no conflict of interests in the present research study.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Yong Hoon Kim and Ae-Young Her contributed equally to this work.
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