Dihydropyridine Calcium Channel Blocker Therapy and Risk of CKD Progression in Type 2 Diabetes Treated With Renin Angiotensin System Inhibitors and SGLT2 Inhibitors: A Real-World Retrospective Cohort Study

Rationale & Objective: Optimal antihypertensive therapy with renoprotective effects is essential to slow diabetic kidney disease progression. We evaluated the impact of dihydropyridine calcium channel blockers on kidney outcomes in patients with type 2 diabetes receiving guideline-directed renin angiotensin system inhibitors and sodium/glucose cotransporter 2 inhibitors. Study Design, Participants, & Settings: A retrospective cohort study using Clalit Health Services (2016-2021). Exposure: Adults with type 2 diabetes treated with both renin angiotensin system inhibitors and sodium/glucose cotransporter 2 inhibitors were categorized into dihydropyridine calcium channel blockers group (renin angiotensin system inhibitors + dihydropyridine calcium channel blockers, with or without other agents) or a dihydropyridine calcium channel blocker–free group (renin angiotensin system inhibitors ± other antihypertensives excluding dihydropyridine calcium channel blockers). Outcomes: The primary outcome was a major adverse kidney event (MAKE; defined as ≥40% estimated glomerular filtration rate decline or progression to kidney failure). Secondary outcomes included initiation of renal replacement therapy and all-cause mortality. Safety outcomes included hospitalizations and acute kidney injury. Analytical Approach: Inverse probability of treatment weighting was applied to balance baseline characteristics. Results: We included 31,031 patients with type 2 diabetes treated with both sodium/glucose cotransporter 2 inhibitors and renin angiotensin system inhibitors. A total of 12,172 (60.8%) received dihydropyridine calcium channel blockers, and 18,859 (39.2%) received dihydropyridine calcium channel blocker–free therapy. Median follow-up was 1,260 days. Overall, 482 patients experienced MAKE, and 2,064 patients died. Dihydropyridine calcium channel blocker use was associated with a higher risk of MAKE compared with dihydropyridine calcium channel blocker-free therapy (weighted HR, 1.33; 95% CI, 1.03-1.73; P = 0.03), which remained significant after accounting for competing risk of death (HR, 1.39; 95% CI, 1.13-1.7; P = 0.002). Dihydropyridine calcium channel blocker use was not significantly associated with all-cause mortality or safety outcomes. Limitations: The observational design is subject to residual confounding and did not allow for full characterization of medication exposure. Conclusions: In patients with type 2 diabetes treated with renin angiotensin system inhibitors and sodium/glucose cotransporter 2 inhibitors, concomitant therapy with dihydropyridine calcium channel blockers was associated with a higher risk of adverse kidney outcomes. These findings may help inform clinicians when weighing the potential risks and benefits of second-line antihypertensive therapy in this population. Plain-Language Summary: We studied 31,031 adults with type 2 diabetes taking both renin angiotensin system inhibitors and sodium/glucose cotransporter 2 inhibitors. We compared those also using dihydropyridine calcium channel blockers with those using other blood pressure medicines. Over a median follow-up of 3.5 years, major adverse kidney events (kidney failure or a sustained ≥40% drop in estimated glomerular filtration rate) were uncommon but occurred more often in the dihydropyridine calcium channel blockers group. After adjusting for baseline differences, dihydropyridine calcium channel blocker use was associated with a 33% higher risk of major adverse kidney events but not with a higher risk of overall mortality. In conclusion, adding a dihydropyridine calcium channel blocker to renin angiotensin system inhibitor and sodium/glucose cotransporter 2 inhibitor therapy may be associated with worse kidney outcomes, and these findings may help clinicians weigh the risks and benefits of second-line blood pressure treatment in this population.