Dihydropyridine Calcium Channel Blocker Therapy and Risk of Chronic Kidney Disease Progression in Type 2 Diabetes Treated With Renin–Angiotensin System Inhibitors and Sodium–Glucose Cotransporter-2 Inhibitors: A Real-World Retrospective Cohort Study

Rationale & Objective: Optimal anti-hypertensive therapy with reno-protective 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 inhibitors and sodium-glucose cotransporter-2 inhibitors Study Design, Participants & Settings: A retrospective cohort study using Clalit HealthServices (2016-2021).Exposure: Adults with type-2 diabetes treated with both renin-angiotensin inhibitors and sodium-glucose cotransporter-2 inhibitors were categorized into dihydropyridine calciumchannel-blockers group (renin-angiotensin inhibitors + dihydropyridine calcium-channelblockers, with or without other agents) or a dihydropyridine calcium-channel-blockers-free group, (renin-angiotensin inhibitors other antihypertensives excluding dihydropyridine calcium-channel-blockers).Outcomes: The primary outcome was a major adverse kidney event (MAKE; 40% eGFR 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 inhibitors 12,172 (60.8%) received dihydropyridine calcium-channel-blockers, and 18,859 (39.2 %) received dihydropyridine J o u r n a l P r e -p r o o f calcium-channel-blockers -free therapy.Median follow-up was 1,260 days.Overall, 482 patients experienced major adverse kidney event, and 2064 patients died.dihydropyridine calciumchannel-blockers use was associated with a higher risk of major adverse kidney event 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 secondline antihypertensive therapy in this population.