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.

Currently, whether DCCBs have individual benefits or harms on kidney function, particularly in diabetes mellitus (DM) patients with chronic kidney disease (CKD), who are at the highest risk for end-stage renal disease (ESRD), remains unclear (de Leeuw et al., 2004). This is partly because CKD and CV events share multiple risk factors and medications (Cai et al., 2013) and the other part due to intrinsic characteristic of DCCBs of vasodilatation of afferent arterioles and increased intraglomerular pressure (Carmines and Navar, 1989; Kimura et al., 1994). Although numerous randomized controlled trials have investigated the effects of DCCBs on renal function, most have compared angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs) with DCCBs (Chan et al., 1992; Bakris et al., 1996; Velussi et al., 1996; Campo et al., 1997; Estacio et al., 1998; Lewis et al., 2001; Rahman et al., 2012), combined DCCB–ACEI/ARB therapy with noncombination therapy (Hasebe and Kikuchi, 2005), DCCBs with diuretics (de Leeuw et al., 2004), or combined ACEIs/ARB–DCCB therapy with combined ACEI/ARB–diuretics therapy (Kaneshiro et al., 2009; Kohlmann et al., 2009; Bakris et al., 2010; Doi et al., 2010; Ishimitsu et al., 2011; Lee et al., 2012; Ogihara et al., 2014; Oshikawa et al., 2014). However, most of the aforementioned studies had a short follow-up duration (Campo et al., 1997; Doi et al., 2010; Ishimitsu et al., 2011; Lee et al., 2012), small sample size (Chan et al., 1992; Bakris et al., 1996; Campo et al., 1997; Doi et al., 2010; Ishimitsu et al., 2011), intrinsic heterogeneous population (CKD, DM, diabetic CKD, or diabetic non-CKD) (Fernández et al., 2001; Bakris et al., 2010; Ishimitsu et al., 2011), or did not consider possible effects of hypoglycemic agents on renal function in patients with DM (Chan et al., 1992; Bakris et al., 1996; Velussi et al., 1996; Fernández et al., 2001). Whether DCCBs have long-term “individual” effects on renal function remain to be determined. In their study involving patients with type 2 DM, Bakis et al. reported comparable effects of DCCBs and ACEIs in slowing renal disease progression; however, the sample size was only 52 patients (Bakris et al., 1996). We hypothesized that DCCBs have individual effects on delaying CKD progression, particularly in DM patients with CKD. We conducted a nationwide, population-based, propensity score matching study to examine the effects of DCCBs on CKD progression in DM patients with CKD.

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 (with HR [95% CI] of 0.63 [0.46–0.87] and 0.32 [0.21–0.48] for cumulative DCCB use for 301–1,100 and >1,100 days, respectively). Compared with nonuse, cumulative DCCB use for >300 days reduced ESRD risk [with aHR (95% CI) of 0.66 (0.49–0.89), and 0.28 (0.19–0.42) for cumulative DCCB use for 301–1,100, and >1,100 days, respectively].

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.

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 m² 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.