THE BOTTOM LINE
Among adult patients with chronic kidney disease (CKD) and albuminuria, with or without type 2 diabetes (T2D), already on stable doses of ACE inhibitor or ARB, dapagliflozin significantly lowered the risk of the composite endpoint of a sustained decline in the estimated glomerular filtration rate (eGFR) of at least 50%, end-stage kidney disease, and death from renal or cardiovascular causes.
WHY THIS IS IMPORTANT
Chronic kidney disease (CKD) is a major health problem in the USA and around the world. It lowers quality of life, progresses to end-stage kidney disease, and can cause death. Two classes of medication, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB), have been shown to slow the progression of CKD, primarily in patients with T2D1. Sodium glucose co-transporter 2 (SGLT2) inhibitors, such as dapagliflozin, reduce CKD progression in T2D, but their therapeutic role in patients without diabetes is unclear2,3. Here, we report a study of effect of dapagliflozin on CKD patients with and without T2D4.
FACTS
Structure of Study
A randomized, double-blind, placebo-controlled trial of 4304 patients that included patients aged 18 years or older, with or without T2D, having eGFR between 25 and 75 mL/min/1.73 m2, and urinary albumin creatine ratio (UACR) > 200 mg/g.
Participants were excluded if they had type 1 diabetes, prior immunotherapy in past 6 months, NYHA class IV heart failure symptoms, malignancy, major adverse cardiovascular event, lupus nephritis, polycystic kidney disease, or anti-neutrophil cytoplasmic antibody-associated vasculitis.
A total of 2152 participants received dapagliflozin 10 mg, and 2152 participants received matching placebo. Of note, 67.5% of all participants had T2D. All participants were on the maximally tolerated dose of an ACE inhibitor or ARB for 4 weeks prior to trial enrollment. Each group had follow-up at 2 weeks and at 2, 4, and 8 months. The median study duration was 2.4 years.
The primary outcome was the composite endpoint of a sustained decline in eGFR of at least 50%, end-stage kidney disease, and death from renal or cardiovascular causes.
Adverse events were defined as discontinuation of study regimen, any serious adverse event, amputation, DKA, fracture, renal-related adverse event, major hypoglycemia, or volume depletion.
Results of the Study
Mean participant age was 62 years, 67% male, average BMI 29.5, average urinary albumin-to-creatine ratio (UACR) 965 mg/g, 67.5% with T2D, and 37.4% with prior cardiovascular disease. There were no significant demographic or clinical differences between the two cohorts.
The endpoint occurred in 9.2% of the patients in the dapagliflozin arm and in 14.5% of the patients in the placebo arm (HR 0.61, 95% CI 0.51–0.72), P <0.001. (Fig. 1).
In a prespecified subgroup analysis, both those with and without T2D benefited from the treatment.
The independent data monitoring committee stopped the trial because of efficacy.
Dapagliflozin did not increase the risk for serious adverse events with the exception of volume depletion (5.9% vs. 4.2%, risk difference 1.7%, number needed to harm 59) over 2.4 years of follow-up.
Figure 1.
Primary composite endpoint event rates for placebo and dapagliflozin cohorts.
STUDY QUALITY/APPLICABILITY
This was a high-quality randomized clinical trial. An important study limitation is that its results are only generalizable to patients with CKD and albuminuria. It is unclear whether the intervention will be equally effective in patients without albuminuria. In addition, it is important to note that dapagliflozin, which is manufactured by AstraZeneca, funded this study.
TIPS FOR DISCUSSION WITH PATIENTS
In patients with chronic kidney disease and albuminuria who are on an ACE-I or ARB medication, adding dapagliflozin can further slow the progression of chronic kidney disease and reduce the death rate.
Severe hypoglycemia or diabetic ketoacidosis was not seen in non-diabetic patients on dapagliflozin.
Volume depletion occurred in more patients with dapagliflozin, so it is important to maintain adequate hydration while taking dapagliflozin.
Declarations
Conflict of Interest
The authors declare that they do not have a conflict of interest.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
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