By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

The FDA has approved dapagliflozin tablets to treat adults with chronic kidney disease (CKD) at risk for disease progression. The drug is a sodium-glucose cotransporter-2 (SGLT2) inhibitor approved in 2014 to improve glycemic control in type 2 diabetes mellitus (T2DM). In April 2021, the FDA gave fast-track, breakthrough therapy, and priority review for the new indication. Dapagliflozin is marketed as Farxiga.

INDICATIONS

Dapagliflozin can be prescribed to lower the risk of hospitalization for heart failure in adults with CKD at risk for progression, end-stage kidney disease, cardiovascular (CV) death, and sustained estimated glomerular filtration rate (eGFR) decline.1

Farxiga also can be prescribed to cut the risk of hospitalization for heart failure and CV death in adults with heart failure with reduced ejection fraction (New York Heart Association class II-IV) and to improve glycemic control in patients with T2DM.

DOSAGE

The recommended dose is 10 mg orally once daily.1 Initiation of treatment is not recommended if eGFR is < 25 mL/min/1.73m2. Dapagliflozin is available as 5 mg and 10 mg tablets.

POTENTIAL ADVANTAGES

Dapagliflozin lowers the risk of composite endpoints of sustained decline in eGFR, end-stage kidney disease, or death from renal or CV causes vs. placebo, regardless of the presence or absence of T2DM.1,2

POTENTIAL DISADVANTAGES

Effectiveness in patients with type 1 diabetes, polycystic kidney disease, lupus nephritis, or antineutrophil cytoplasmic antibody-associated vasculitis has not been established because these were excluded from the clinical trial.1

COMMENTS

The efficacy of dapagliflozin on renal outcomes and CV mortality in patients with CKD was evaluated in a randomized, double-blind, placebo-controlled study (DAPA-CKD).1,2 Subjects with CKD were defined as eGFR between 25 mL/min/1.73m2 and 75 mL/min/1.73m2 and urine albumin to creatinine ratio (UACR) between 200 mg/g and 5,000 mg/g on standard background therapy (i.e., maximally tolerated dose of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker). At baseline, 67.5% had T2DM, 53% were white, and 67% were men (mean eGFR = 43 mL/min/1.73m2; median UACR = 950 mg/g). Subjects were randomized to placebo (n = 2,152) or dapagliflozin 10 mg daily (n = 2,152). The median follow-up time was 28.5 months. The primary endpoint was first time to the composite of ≥ 50% sustained decline in eGFR, progression to end-stage kidney disease (eGFR < 15 mL/min/1.73m2, initiation of chronic dialysis, or renal transplantation), or CV or renal death.

The study ended early when researchers found the evidence of efficacy was overwhelming. Dapagliflozin reduced the primary composite endpoint by 39% (9.2% vs. 14.5%; HR, 0.61; 95% CI, 0.51-0.72). The main contribution to the composite endpoint was decline in eGFR (5.2% vs. 9.3%). In a prespecified subgroup analysis, dapagliflozin was efficacious in patients with diabetes (HR, 0.64; 95% CI, 0.52-0.79) and patients without diabetes (HR, 0.50; 95% CI, 0.35-0.72).3

In an additional prespecified subgroup analysis, dapagliflozin also was efficacious independent of the presence or absence of concomitant CV disease.4 CV disease was defined as the presence of coronary heart disease, cerebrovascular disease, peripheral artery disease, heart failure, valvular heart disease, cardiac arrhythmias, or presence of cardiac devices other than cardiac resynchronization therapy. The primary outcome was a composite of ≥ 50% reduction in eGFR and onset of end-stage kidney disease or death from renal or CV causes. HRs were identical for each subgroup (0.61).

CLINICAL IMPLICATIONS

SGLT2 inhibitors have become first-line agents in the treatment of T2DM. In addition to their antihyperglycemic effect, improved CV and renal outcomes have been shown with three in the class so far (canagliflozin, empagliflozin, and dapagliflozin).5 The favorable effects on renal hemodynamics appears to be independent of their glucose-lowering effects.6 Current evidence shows dapagliflozin is effective in both patients with or without T2DM, prompting the FDA’s approval for CKD at risk for disease progression regardless of diabetes status. Few options are available to slow the progression of CKD. Dapagliflozin adds a new option for these patients. 

REFERENCES

  1. AstraZeneca Pharmaceuticals LP. Farxiga prescribing information. April 2021.
  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.
  3. Wheeler DC, Stefánsson BV, Jongs N, et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: A prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol 2021;9:22-31.
  4. McMurray JJV, Wheeler DC, Stefánsson BV, et al. Effect of dapagliflozin on clinical outcomes in patients with chronic kidney disease, with and without cardiovascular disease. Circulation 2021;143:438-448.
  5. Heerspink HJL, Kosiborod M, Inzucchi SE, Cherney DZI. Renoprotective effects of sodium-glucose cotransporter-2 inhibitors. Kidney Int 2018;94:26-39.
  6. van Bommel EJM, Muskiet MHA, van Baar MJB, et al. The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial. Kidney Int 2020;97:202-212.