Chronic Kidney Disease Progression Risk in Patients With Diabetes Mellitus Using Dihydropyridine Calcium Channel Blockers: A Nationwide, Population-Based, Propensity Score Matching Cohort Study

Background: Whether diabetes mellitus (DM) patients with chronic kidney disease (CKD) can glean individual renal benefit from dihydropyridine calcium channel blockers (DCCBs) remains to be determined. We conducted a nationwide, population-based, propensity score matching cohort study to examine the effect of DCCBs on CKD progression in DM patients with CKD. Methods: One million individuals were randomly sampled from Taiwan’s National Health Insurance Research Database. The study cohort consisted of DM patients with CKD who used DCCBs. The comparison cohort was propensity-matched for demographic characteristics and comorbidities. The endpoint was advanced CKD or end-stage renal disease (ESRD). The Cox proportional hazards model was used to calculate the risks. Results: In total, 9,761 DCCB users were compared with DCCB nonusers at a ratio of 1:1. DCCB users had lower risk of advanced CKD and ESRD than nonusers—with adjusted hazard ratio [aHR; 95% confidence interval (CI)] of 0.64 (0.53–0.78) and 0.59 (95% CI, 0.50–0.71) for advanced CKD and ESRD, respectively. DCCB users aged ≥65 years had the lowest incidence rates of advanced CKD and ESRD—with aHR (95% CI) of 0.47 (0.34–0.65) and 0.48 (0.35–0.65) for advanced CKD and ESRD, respectively. Finally, cumulative DCCB use for >1,100 days was associated with the lowest advanced CKD and ESRD risks [(aHR, 0.29 (95% CI, 0.19–0.44)]. Conclusion: DM patients with CKD who used DCCBs had lower risk of progression to advanced CKD and ESRD than nonusers did.


INTRODUCTION
Dihydropyridine calcium channel blockers (DCCBs), which bind to calcium channels located on vascular smooth muscles to interrupt calcium entry, are widely used in clinical practice to reduce blood pressure (Braunwald, 1982;Eisenberg et al., 2004). In addition, DCCBs can provide many cardiovascular (CV) benefits (Staessen et al., 1997;Nissen et al., 2004;Hasebe and Kikuchi, 2005;Haller, 2008). A meta-analysis of 175,634 patients demonstrated that DCCBs could reduce all-cause mortality and stroke risk and prevent heart failure (Costanzo et al., 2009). Systematic reviews have shown that DCCBs could reduce the risk of Parkinson disease (Lang et al., 2015), incidental dementia (Hussain et al., 2018), and sequelae of traumatic brain injury (Gurkoff et al., 2017). However, because of their vasodilatory effect, DCCBs have also been reported in association with increased gastrointestinal tract bleeding (Kaplan et al., 2000) and proischemic complication (Waters, 1991) risks.

Data Source
In 1995, Taiwan launched a single-payer healthcare system from which the National Health Insurance (NHI) Research Database (NHIRD) was established. Data used in the present study were obtained from the Longitudinal Health Insurance Database, which contains information on 1 million individuals randomly sampled from NHIRD. The data were deidentified to protect privacy. The medical claims data contained information on diagnosis, outpatient visits, hospital admissions, drug prescriptions, and surgical procedures. The diagnostic classification was based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM).

Study Population
We enrolled DM patients who had subsequent new diagnosis of CKD (ICD-9 codes 585.xx). In this study, those who had the record of DM (ICD-9 codes 250.x0 or 250.x2) more than two times within 1 year were defined as DM patients. CKD was defined on the basis of ICD-9 codes 585.xx recorded in NHIRD for more than three times. The date of initial DCCB use was defined as the index date. Patients were followed up until date of first erythropoietin (EPO) prescription, onset of ESRD, withdrawal, death, or December 31, 2013. Diagnosis of ESRD was confirmed by ICD-9-CM codes and inclusion in the Registry for Catastrophic Illness Patient Database, a sub-classification of the NHIRD. Although NHIRD lacks information on CKD staging, the NHI program has stated that patients with estimated glomerular filtration rate (eGFR) < 15 ml/min/1.73 m 2 and hemoglobin level <10 gm/dL may receive the official EPO prescription benefit package. Thus, in the present study, we defined patients with advanced CKD as those with CKD who started EPO prescriptions.
We excluded patients diagnosed as having advanced CKD or ESRD before the index date. A total of 9,761 DCCB users were compared with DCCB nonusers at a ratio of 1:1 using propensity scores after matching for demographic characteristics and baseline comorbidities. Baseline comorbidities included cancer, hyperlipidemia, stroke, chronic obstructive pulmonary disease, cirrhosis, arrhythmia, congestive heart failure, fibromyalgia, coronary artery disease, alcohol-related diseases, peripheral arterial occlusive disease, renal stone, and peptic ulcer disease (list of codes were presented in Supplementary Table S1). The covariates of baseline medications comprised statins, ACEIs/ ARBs, loop diuretics, thiazides, potassium-sparing diuretics, non-DCCBs, alpha-blockers, beta-blockers, insulins, sulfonylureas, biguanides, miglitol, acarbose, thiazolidinedione, dipeptidyl peptidase-4 inhibitors, and other antidiabetics.

Statistical Analysis
Descriptive analyses of demographics, comorbidities, and medications of the cohorts are presented as frequencies and percentages for the categorical variables and as means and standard deviations for the continuous variables. The 1:N Case-Control Matching Macro (Parsons LS et al. SUGI 29) was used to match cases with controls (Parsons, 2012). DM patients with CKD who used DCCB were matched (1:1 ratio) with those who did not use DCCB according to their propensity score through nearest neighbor matching, initially to the eighth digit and then as required to the first digit. Therefore, matches were first made within a caliper width of 0.0000001, and then the caliper width was increased for unmatched cases to 0.1. We reconsidered the matching criteria and performed a rematch (greedy algorithm). For each DM patient on DCCB use, the corresponding comparisons were selected based on the nearest propensity score. A standardized mean difference of ≤0.1 indicates a negligible difference between the two cohorts. Absolute standardized mean difference per covariate before and after PSM was presented in Table 1 and Supplementary Table S2. Cumulative incidence rates of advanced CKD and ESRD were calculated based on the Kaplan-Meier method, and the between-cohort comparisons of the cumulative incidence curves were assessed by log-rank tests.
To consider the effect of the frequency variation in the use of DCCBs, DCCB use was considered as a time-dependent covariate in the Cox proportional hazards model. Hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) for advanced CKD and ESRD were estimated using the Cox proportional hazards models. A two-tailed p value <0.05 was considered statistically significant. The data analysis was generated using SAS (version 9.4) of the SAS System for [Unix] (SAS Institute Inc., Cary, NC, United States), and the figures were created using R. Table 1 lists the demographic characteristics and comorbidities in the propensity score-matched cohorts. The average age of DCCB nonusers and DCCB users was 58.5 ± 13.3 and 58.4 ± 12.6 years, respectively; 44.5 and 44.9% of the DCCB nonusers and users were women, respectively. In the profiles of baseline comorbidities and medications, they did not significantly differ between the two cohorts according to standardized mean differences after PS matching in Table 1. Table 2 presents the incidence values and HRs for advanced CKD or ESRD in the cohorts from Cox proportional hazards models with time-dependent exposure covariates. The incidence rates of advanced CKD and ESRD in DCCB nonusers were 3.27 and 3.64 per 1,000 person-years, respectively. The incidence rates of advanced CKD and ESRD in DCCB users were 2.28 and 2.59 per 1,000 person-year, respectively. The DCCB users had lower advanced CKD and ESRD risk than did nonusers [with HR (95% CI) of 0.71 (0.59-0.85) for advanced CKD and 0.72 (0.61-0.86) for ESRD]. Table 3 lists the incidence and HRs of advanced CKD or ESRD in the cohorts by age and sex from Cox proportional hazards models with time-dependent exposure covariates. Reduced incidence rates of advanced CKD and ESRD in DCCB users were observed in the ≥65-year age group compared with those in DCCB nonusers [with HR (95% CI) of 0.49 (0.36-0.68) in the ≥65-year age group for advanced CKD, respectively, and 0.76 (0.59-1.00) and 0.50 (0.38-0.67) in the 50-64-and ≥65-year age group for ESRD, respectively). Women using DCCBs were at lower advanced CKD and ESRD risks compared with women not using DCCBs [with HR (95% CI) of 0.67 (0.51-0.88) and 0.61 (0.47-0.78) for advanced CKD and ESRD, respectively]. Table 4 shows incidence values and HRs for advanced CKD or ESRD stratified by duration of DCCB therapy. Compared with nonuse, cumulative DCCB use for >300 days reduced CKD risk   Figure 1 depicts cumulative incidence curves of advanced CKD or ESRD for DCCB users and DCCB nonusers by propensity score matching. The p values from the log-rank tests for both cohorts were <0.001, and DCCB users were more likely to have lower advanced CKD and ESRD risks than were DCCB nonusers.

DISCUSSION
DM patients with CKD who used DCCBs had a lower risk of progression to advanced CKD or ESRD compared with those who did not use DCCBs. We suggested several mechanisms of DCCBs that could account for this finding: improved blood pressure  reduction, improved maintenance of renal perfusion, and DCCBs' antiatherosclerotic properties. Although the optimal blood pressure target for improving renal outcomes in patients with CKD remains unclear, the evidence supports blood pressure control through antihypertensives for patients with systolic blood pressure <130 mmHg (Chang et al., 2019). The Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hyperintensive Patients and the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation trial revealed that improved blood pressure control could lead to reduction in the risk of doubling of creatinine levels and progression to advanced CKD compared with the absence of blood pressure control (JATOS, 2005;Heerspink et al., 2010). By contrast, other studies have found that intensive blood pressure control does not improve renal outcomes (Ruggenenti et al., 2005;Appel et al., 2010;Ku et al., 2017). These findings suggest that improved renal outcomes require both improved blood pressure control and improved renal perfusion (Palmer, 2002;Ravera et al., 2006). DCCBs have been effective in lowering systolic blood pressure to <130 mmHg in different patient populations in combination with other antihypertensives (Haller, 2008;Matsui et al., 2009;Association, 2019). DCCBs have a beneficial effect on central systolic blood pressure and arterial stiffness (Matsui et al., 2009). In the past, a concern was raised regarding the effects of DCCBs on kidney function; DCCBs may cause vasodilatation of afferent renal arterioles, increase intraglomerular pressure, and promote proteinuria (Nosadini and Tonolo, 2002). In the present study, because individual information on baseline blood pressure, proteinuria, and eGFR were unavailable, the effects of DCCB on optimal blood pressure control, proteinuria, and eGFR were unknown for both cohorts. However, through propensity matching by antihypertensive classes and comorbidities, we demonstrated that compared with nonuse, DCCB use reduced the risk of progression to advanced CKD and ESRD, consistent with previous findings (Bakris et al., 1996;JATOS, 2005). DCCBs could both improve blood pressure control and preserve renal perfusion through the vasodilatory effect of systemic arterioles and renal arterioles, thus resulting in improved renal outcomes-reduced advanced CKD and ESRD risks. Further, Orekhov et al. have found DCCB could decrease the incorporation of [3H] thymidine, lower the intracellular cholesterol level, and inhibit proliferative activity of cultured cells, which exhibited antiatherosclerotic and atherogenic ability of DCCB in their in vitro models (Orekhov et al., 1988). A multicenter study found that DCCBs slow the progression of plaque volume in patients with hypertension (Kojima et al., 2011). Another study revealed that DCCBs could help slow the progression of minimal atherosclerotic lesions of coronary arteries (Waters et al., 1990). Because atherosclerosis and atherogenic factors could lead to early renal injuries and promote CKD progression (Chade et al., 2005;Kalra et al., 2005), DCCBs, with their antiatherosclerotic properties, would help reduce the risk of progression from early CKD to advanced CKD and ESRD.
Notably, in the present study, the DCCB users aged ≥65 years had the lowest advanced CKD and ESRD risks, suggesting DCCB safety and effectiveness in elderly DM patients with CKD. Elderly patients, particularly those with DM and CKD, may glean more benefits from DCCB use because advanced age is associated with greater arterial stiffness (Scuteri et al., 2018;Galvão et al., 2020). Future studies investigating the renal benefits of DCCBs for elderly patients with DM are warranted. Our study also found a dose-response relationship with DCCB use: of all patients, patients with the longest duration of DCCB use (i.e., >1,100 days) had the lowest advanced CKD and ESRD risks, which further strengthens the evidence of the benefits of DCCBs on renal outcomes.
This study has several limitations. First, participant information on systolic and diastolic blood pressure, pulse pressure, glycated hemoglobin level, glucose level, body mass index, low density lipoprotein level, triglyceride level, family history of kidney disease (including immunoglobulin A nephropathy or autosomal dominant polycystic kidney disease), and exercise habits was unavailable in NHIRD. Second, information on serum creatinine, eGFR, urine albumin-to-creatinine ratio, and urine protein-to-creatinine ratio was also lacking in NHIRD. The NHI program has stated that patients whose eGFR is < 15 ml/min/1.73 m 2 and whose hemoglobin levels is < 10 gm/dL may receive the official EPO prescription benefit package. Because anemia is common in DM patients with CKD, using EPO prescription as a proxy for advanced CKD was reasonable. Third, medication compliance and blood pressure and glucose control among the patients could not be ensured. Also, those individuals on DCCBs may be inherently different from those not on the prescription hence the observed difference rather than the drug effect as the observed difference would be potential confounding by indication. Fourth, the dosage of the antihypertensives, as well as T-type or L-type DCCBs, was not considered. Fifth, ACEIs or ARBs were not completely matched; thus, their effects might not have been eliminated completely. We have used time-dependent model in this study, thus potential immortal time bias in studies for evaluating the effect of drug would be eliminated. Sixth, residual confounding might exist, and we did not run negative control outcome analysis to assess residual confounding should be announced here. Finally, response to antihypertensive treatment involves gene polymorphisms (Stavroulakis et al., 2000;Schelleman et al., 2004). Therefore, the results of this nationwide, population-based cohort study may not be directly applicable to other racial or ethnic populations.
In conclusion, DM patients with CKD who used DCCBs had lower risk of progression to advanced CKD and ESRD compared with those who did not use DCCBs. This study demonstrated the individual renal benefits of DCCBs in DM patients with CKD. Additional randomized controlled trials to confirm these findings are required.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by The NHIRD encrypts personal information of the patients to protect privacy and provides researchers with anonymous identification numbers associated with relevant claims information, including sex, date of birth, medical services received, and prescriptions. Therefore, patient's consent is not required to access the NHIRD. This study was approved to fulfill the condition for exemption by the Institutional Review Board (IRB) of China Medical University (CMUH104-REC2-115-AR4). The IRB also specifically waived the consent requirement. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.