DAPA-CKD study: Convincing results with dapagliflozin once again

Dapagliflozin reduced kidney failure risk in patients with CKD, the risk of cardiovascular death or hospitalization due to heart failure, and the SGLT2 inhibitor prolonged survival.

Favorable effects on cardiovascular and renal endpoints

The results were presented by study director Hiddo Heerspink (Universiteit Groningen, Netherlands). Dapagliflozin reduced the risk of kidney failure in patients with chronic kidney disease (CKD), the risk of cardiovascular death or hospitalization due to heart failure, and the SGLT2 inhibitor prolonged survival.

"The DAPA-CKD study is a well-done study that shows renal protection in patients with chronic kidney disease, whether or not they have type 2 diabetes mellitus at the same time," said Chantal Mathieu (Catholic University of Leuven, Belgium) commenting on the study at the virtual annual meeting of the European Association for the Study of Diabetes in September 2020. 

Chronic kidney disease (CKD) can increase overall and cardiovascular mortality and affect the quality of life. So far, only angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers have been shown to slow the progression of CKD.

SGLT2 inhibitors like dapagliflozin have been shown in large trials in patients with type 2 diabetes mellitus to have a beneficial effect on cardiovascular and renal endpoints. In the DAPA-HF trial, dapagliflozin impressively reduced the worsening of patients with heart failure and lowered cardiovascular mortality - regardless of whether they had diabetes at the same time.

The DAPA-CKD trial, therefore, looked at how dapagliflozin works compared to placebo in patients with CKD.

DAPA-CKD study meets all endpoints

The randomized, double-blind, placebo-controlled international multicentre study enrolled 4,304 subjects with a glomerular filtration rate (GFR) between 25 and 75 ml/min per 1.73 m² body surface area and urinary albumin to creatinine ratio (UACR) of 200 to 5,000 mg/g. In addition to ACE inhibitor or angiotensin receptor antagonist, they were randomly assigned dapagliflozin (10 mg/day) or placebo.

The average age of the participants was 62, and about a third were women. 68% had type 2 diabetes mellitus, with an average systolic blood pressure of 137 mmHg and a GFR of 43 ml/min per 1.73 m³.

The primary endpoint was the combination of a GFR decrease by ≥ 50%, end-stage renal disease (ESRD), renal or cardiovascular death. Secondary endpoints included the combination of ≥ 50% decrease in GFR, ESRD, and renal and cardiovascular death, the combination of cardiovascular death and hospitalization for heart failure, and all-cause mortality.

After a routine interim analysis, the study was terminated prematurely due to the unexpectedly high efficacy of dapagliflozin.

During a median follow-up of 2.4 years, the primary endpoint occurred in 197/2,152 patients in the dapagliflozin study arm and 312/2,152 patients on placebo (HR: 0.61; 95% CI 0.51-0.72; p = 0.000000028). This means that dapagliflozin reduced the risk for this endpoint by 39%.

Dapagliflozin reduced all three secondary endpoints:

There was no difference in tolerability between dapagliflozin and placebo. No ketoacidosis was observed in the dapagliflozin group and no case of hypoglycemia in non-diabetics.

Mathieu called the trial a real winner with really spectacular results. However, he said it was not a therapy that could only be used in endocrinology, cardiology or nephrology. The majority of the patients eligible for these therapies are treated by family physicians, and therefore, this finding must reach them.

Her conclusion was that it was a challenge for societies to formulate clear guidelines, for clinicians to follow these guidelines, for regulatory authorities to adopt the approvals accordingly, and for pharmaceutical companies to demand reasonable prices in order to finally bring these drugs to the patients who, based on the evidence now available, can benefit from them.

Sources:
Symposium DAPA-CDK-Trial, Virtual EASD Annual Meeting 2020 S32
Heerspink H, et al Dapagliflozin in patients with chronic kidney disease. N Engl J Med. published online on 24 September 2020.

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