In a prespecified analysis of DAPA-CKD among patients with CKD and albuminuria, dapagliflozin resulted in a placebo-adjusted reduction in systolic blood pressure (BP) reduction of ~3 mmHg. Treatment benefits were apparent across a range of baseline BP levels.

This summary is based on the publication of Heerspink HJL, Provenzano M, Vart P, et al. - Dapagliflozin and Blood Pressure in Patients with Chronic Kidney Disease and Albuminuria. Am Heart J. 2024 Feb 15:S0002-8703(24)00033-4 [Online ahead of print]. doi: 10.1016/j.ahj.2024.02.006

Introduction and methods

Background

SGLT2 inhibitors have consistently been associated with blood pressure (BP) reduction in patients with T2D, most of whom had preserved renal function [1]. However, the consistency and magnitude of BP lowering effects of this drug class have not been well established in a broad population of patients with CKD, with and with no T2D.

Aim of the study

In a prespecified analysis of the DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial, the authors examined the effect of dapagliflozin on systolic BP (SBP) and diastolic BP (DBP) in patients with CKD and albuminuria, with or with no T2D, and whether baseline BP influenced the effects of dapagliflozin on renal, CV, and safety outcomes.

Methods

The DAPA-CKD trial was an international, multicenter, double-blind, placebo-controlled, phase 3 RCT in which 4304 patients with baseline eGFR 25–75 mL/min/1.73 m² and urine albumin-to-creatinine ratio (UACR) 200–5000 mg/g—with or with no T2D—were randomized to dapagliflozin 10 mg or placebo once daily [2]. Study participants were required to be on a stable, maximally tolerated RAASi dose for ≥4 weeks unless there was a medical contraindication. The pharmacological and/or nonpharmacological approach to hypertension management was left to the investigators’ discretion. Median follow-up duration was 2.4 years (IQR: 2.0–2.7).

Outcomes

The primary endpoint was a composite outcome of time to sustained eGFR decline ≥50%, end-stage kidney disease, or death from a renal or CV cause. Secondary endpoints were time to: (1) a composite kidney outcome of ≥50% sustained eGFR decline ≥50%, kidney failure, or death from kidney disease; (2) a composite CV outcome of HF hospitalization or CV death; and (3) all-cause mortality. Change in SBP was a prespecified outcome. Safety assessments included serious adverse events, adverse events resulting in discontinuation of study drug, and adverse events of special interest (such as symptoms of volume depletion, kidney disease events, and potential diabetic ketoacidosis).

Main results

Effect of dapagliflozin on blood pressure

• At 2 weeks, the mean SBP was 3.6 mmHg (95%CI: 2.8–4.4) lower in patients treated with dapagliflozin compared with placebo-treated patients. This effect was largely maintained during the remainder of the trial (mean SBP reduction: 2.9 mmHg; 95%CI: 2.3–3.6).
• The time-averaged reduction in SBP with dapagliflozin versus placebo was 3.2 mmHg (95%CI: 2.5–4.0) in patients with T2D and 2.3 mmHg (95%CI: 1.2–3.4) in patients with no T2D (P for interaction=0.50).
• Analysis of the overall effect of dapagliflozin on mean SBP across several prespecified subgroups showed significant interaction only by baseline SBP (P for interaction=0.01), not by baseline eGFR, baseline UACR, or the presence or absence of resistant hypertension at baseline (all P for interaction>0.05).
• At 2 weeks, the mean DBP was 1.5 mmHg (95%CI: 1.1−2.0) lower in the dapagliflozin group compared with the placebo group. This effect was partially maintained during the duration of the trial (mean SBP reduction: 1.0 mmHg; 95%CI: 0.6−1.4).
• The time-averaged reduction in DBP with dapagliflozin versus placebo was 0.8 mmHg (95%CI: 0.4–1.3) in patients with T2D and 1.4 mmHg (95%CI: 0.7–2.1) in patients with no T2D (P for interaction=0.36).

Effects of dapagliflozin on endpoints by baseline blood pressure

• The effects of dapagliflozin on the primary and secondary endpoints were generally consistent across the 5 baseline SBP categories and were independent of the presence or absence of resistant hypertension at baseline.
• There was no additional effect modification of the primary endpoint by baseline eGFR (P for interaction=0.96) or baseline UACR ( P for interaction=0.29).
• Dapagliflozin’s effect on the primary endpoint was also not influenced by baseline DBP.

Safety

• The frequencies of any serious adverse events, adverse events resulting in discontinuation of study drug, and acute kidney injury were similar for the dapagliflozin and placebo groups and did not vary across baseline SBP categories (all P for interaction>0.05).
• Among patients with baseline SBP <120 mmHg, the number of adverse events related to volume depletion was higher in those treated with dapagliflozin compared with those receiving placebo (8.7% vs. 3.9%; OR: 2.36; 95%CI: 1.2–4.9 ).

Conclusion

In this prespecified analysis of the DAPA-CKD trial among patients with CKD and albuminuria, with or with no T2D, treatment with dapagliflozin resulted in a modest but clinically meaningful reduction in SBP of ~3 mmHg compared with placebo. This reduction was visible at 2 weeks and was maintained during the remainder of the trial. Comparable but smaller DBP reductions were also observed. The beneficial effects of dapagliflozin on the renal and CV outcomes were evident across the spectrum of baseline SBP and DBP. The authors argue that “[s]ince randomized clinical trials have demonstrated substantial benefits of SGLT2 inhibitors in patients with CKD and albuminuria, these agents should be prescribed for reasons other than lowering blood pressure. However, use of dapagliflozin in addition to, or in place of, antihypertensive agents other than ACE inhibitors or ARBs could improve control of hypertension and provide incremental benefits, while ameliorating potential [adverse events], avoiding less well-tolerated antihypertensive agents or using them at lower doses than might otherwise be required.”

References

1. Oliva RV, Bakris GL. Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. J Am Soc Hypertens 2014;8:330-339. doi: 10.1016/j.jash.2014.02.003

2. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med 2020;383:1436-1446. doi: 10.1056/NEJMoa2024816

Find this article online at Am Heart J.