Background and Aim

Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce plasma glucose and hemoglobin A1c (HbA1c) in patients with type 2 diabetes mellitus by increasing urinary glucose excretion in a non-insulin-dependent manner. Three large cardiovascular outcome trials have established that the beneficial effects of these agents go beyond glycemic control.

The Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) trial is aimed at evaluating the hypothesis that treatment with dapagliflozin is superior to placebo in lowering the risk of renal and cardiovascular events in patients with CKD (with or without concomitant type 2 diabetes) already receiving an optimized dose of either an angiotensin-converting enzyme (ACE)inhibitor or an angiotensin receptor blocker (ARB) as background renoprotective therapy.

Methods

Multinational, multicenter, event-driven, randomized, double-blind, parallel-group, placebo-controlled trial that will recruit~4,300 patients at nearly 400 sites in 21 countries.

Interventions

• Dapagliflozin 10 mg OD (added to current background therapy).
• Placebo OD (added to current background therapy).

Outcomes

The primary outcome for the evaluation of the effect of dapagliflozin on delaying the progression of renal disease is the time to the first occurrence of any of the following components of the composite renal endpoint: ≥50%eGFR (estimated glomerular filtration rate) decline (confirmed by a second serum creatinine measurement at least 28 days later), the onset of <15mL/min/1.73m² (which will be ascertained from central laboratory measurements).

Selected adverse event data will also be collected, in view of the extensive experience with dapagliflozin.

Conclusion

In recent times, SGLT2 inhibitors have emerged as powerful oral hypoglycemic agents to reduce the occurrence of renal diseases, as well as cardiovascular disorders in patients with type 2 diabetes. This renal protective effect is possibly connected to several non-glycemic effects such as natriuretic/osmotic diuresis, restoration of tubuloglomerular feedback leading to glomerular afferent vasoconstriction with the reduction in single-nephron hyperfiltration, amelioration of renal tissue hypoxia and attenuation of inflammation and fibrosis. The DAPA-CKD study will test the hypothesis by assessing whether dapagliflozin safely reduces the risk of a composite renal and cardiovascular death endpoint in a broad-spectrum of patients with CKD, with and without diabetes, whoare already on optimized standard of care renoprotective therapy.

Resource:

Heerspink HJL, Stefansson BV, Chertow GM, et al. Rationale and protocol of the Dapagliflozin andPrevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial. Nephrol Dial Transplant. 2020;35(2):274-82.