AstraZeneca's Dapagliflozin Reduces All-Cause Mortality by 31% in Chronic Kidney Disease Patients, Demonstrating Transformative Potential in Phase III DAPA-CKD Trial

Today, AstraZeneca announced that its blockbuster SGLT2 inhibitor dapagliflozin (brand name Farxiga) reduced the risk of severe decline in renal function and kidney death by 44% in a Phase 3 clinical trial involving patients with chronic kidney disease (CKD). Furthermore, dapagliflozin significantly lowered the risks of hospitalization for heart failure and cardiovascular death, leading to a 31% reduction in all-cause mortality. This suggests that adding dapagliflozin to standard care for CKD patients is expected to significantly extend patient survival. Notably, dapagliflozin demonstrated consistent efficacy in patients both with and without type 2 diabetes.

Dapagliflozin was initially approved for controlling blood glucose levels in patients with diabetes; however, recent research has continuously expanded the range of patient populations benefiting from this drug. In May this year, it received approval from the U.S. FDA as the first SGLT2 inhibitor to reduce the risk of cardiovascular death and hospitalization due to heart failure in patients with heart failure, regardless of whether they have type 2 diabetes. The outstanding results from Phase III clinical trials in patients with chronic kidney disease suggest that it is poised to become the first SGLT2 inhibitor to significantly improve survival benefits in patients with chronic kidney disease (with or without type 2 diabetes). AstraZeneca stated in a press release that this breakthrough is expected to transform the treatment paradigm for chronic kidney disease.

Chronic kidney disease (CKD) is a severe, progressive condition affecting nearly 700 million people worldwide. The most common causes of CKD are diabetes, hypertension, and glomerulonephritis. In the most severe cases (i.e., end-stage kidney disease, ESKD), the decline in renal function and kidney damage necessitates dialysis or kidney transplantation. Most patients with CKD die from cardiovascular causes before progressing to end-stage kidney disease.

Dapagliflozin is a first-in-class oral SGLT2 inhibitor. SGLT2 is a transporter protein in the kidneys that facilitates glucose reabsorption. SGLT2 inhibitors lower blood glucose levels by inhibiting the function of SGLT2, thereby promoting the excretion of more glucose in the urine. Last August, the FDA granted dapagliflozin Fast Track designation to slow the progression of kidney failure in patients and to prevent cardiovascular disease and kidney failure in patients with chronic kidney disease (CKD).

In this randomized, double-blind, placebo-controlled, multicenter, international Phase 3 clinical trial named DAPA-CKD, 4,304 patients with stage 2–4 chronic kidney disease (CKD) and elevated urinary albumin excretion received either dapagliflozin or placebo in addition to standard care. The trial enrolled patients from around the world, with Asian patients accounting for 35% of the study population. Among the CKD patients participating in the trial, nearly 68% had comorbid type 2 diabetes.

The primary endpoint of the trial was a composite endpoint comprising significant decline in renal function (defined as a sustained reduction in glomerular filtration rate of more than 50%), end-stage renal disease, renal death, and cardiovascular death. The trial results demonstrated that dapagliflozin reduced the risk of this composite endpoint by 39%.

Image source: Reference [2]

In the prespecified subgroup analysis, dapagliflozin reduced the risk of the primary endpoint by 36% in patients with chronic kidney disease (CKD) and type 2 diabetes, and by 50% in patients with CKD without type 2 diabetes. These results demonstrate that dapagliflozin also provides clinical benefits for CKD patients without type 2 diabetes.

▲Dapagliflozin significantly reduced the risk of the primary endpoint in CKD patients with and without type 2 diabetes (Image source: Reference [2])

Advances in the Use of SGLT2 Inhibitors for the Treatment of Chronic Kidney Disease

SGLT2 inhibitors currently approved by the FDA include AstraZeneca’s dapagliflozin, Janssen’s canagliflozin (brand name Invokana), Lilly/Boehringer Ingelheim’s empagliflozin (brand name Jardiance), and Pfizer/MSD’s ertugliflozin (brand name Steglatro).

Canagliflozin received FDA approval last year to reduce the risk of end-stage renal disease (ESRD), decline in kidney function, cardiovascular death, and hospitalization due to heart failure in adult patients with diabetic kidney disease and type 2 diabetes. In Phase 3 clinical trials for the treatment of heart failure, empagliflozin demonstrated an effect in slowing the decline in kidney function among exploratory clinical endpoints (see WuXi AppTec’s report today for details). Boehringer Ingelheim and Eli Lilly have initiated Phase 3 clinical trials to further evaluate the efficacy of empagliflozin in patients with chronic kidney disease.

References:

[1] Farxiga demonstrated unprecedented reduction in the risk of kidney failure and cardiovascular or renal death in patients with chronic kidney disease in the Phase III DAPA-CKD trial. Retrieved August 30, 2020, from https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2020/farxiga-demonstrated-reduction-in-the-risk-of-kidney-failure-and-cardiovascular-or-renal-death-in-patients-with-ckd-in-the-phase-iii-dapa-ckd-trial.html

[2] Farxiga demonstrated unprecedented reduction in the risk of kidney failure and cardiovascular or renal death in patients with chronic kidney disease in the Phase III DAPA-CKD trial. Retrieved August 30, 2020, from https://www.epresspack.net/phase-3-DAPA-CKD-trial/

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