Sodium-glucose cotransporter-2 inhibitors

Clinical question

How do sodium-glucose cotransporter-2 inhibitors (SGLT2Is) affect patient outcomes in chronic kidney disease (CKD)?

Bottom line

For every 100 patients with CKD taking an SGLT2I for 5 years, approximately 3 or 4 fewer will develop end-stage kidney disease and 3 to 4 fewer will die from any cause versus placebo. Sotagliflozin is not better than placebo for these outcomes.

Evidence

Results were statistically significant unless noted.

• Two systematic reviews of relevant RCTs included patients with CKD.^1,2

  • - In 1 review of 52,827 patients with cardiovascular and CKD risks, among those with CKD at 5 years¹:

    • — End-stage kidney disease: 8.9% vs 12% (placebo), number needed to treat (NNT)=33.

    • — Cardiovascular death: 11% vs 14% (placebo), NNT=27.

    • — Overall mortality: 19% vs 22% (placebo), NNT=31.

  • - In the other review (8 RCTs) involving 26,106 patients with baseline CKD, at 2.5 years²:

    • — Cardiovascular disease: 10% vs 11% (placebo), NNT=91.

    • — Composite kidney outcome (40% to 60% estimated glomerular filtration rate decline, end-stage kidney disease, or renal death): 4.8% vs 6.9% (placebo), NNT=48.

  • - Limitations: included RCTs not specific to CKD patients.

• In 3 industry-funded RCTs (with CKD patients),^3-5 mean estimated glomerular filtration rate was about 40 to 55 mL/min/1.73 m², albumin-to-creatinine ratio was about 75 to 105 mg/mmol, and 67% to 100% of patients had diabetes.

  • - In a trial of 4401 patients taking 100 mg of canagliflozin daily,³ at 2.6 years:

    • — End-stage kidney disease: 5.3% vs 7.5% (placebo), NNT=45.

    • — Cardiovascular death: 5.0% vs 6.4% (placebo), NNT=71.

    • — All-cause mortality: 7.6% vs 9.1% (placebo), NNT=67.

  • - In another trial of 4304 patients taking 10 mg of dapagliflozin,⁴ at 2.4 years:

    • — End-stage kidney disease: 5.1% vs 7.5% (placebo), NNT=42.

    • — Cardiovascular death: 3.0% vs 3.7% (placebo), not statistically different.

    • — All-cause mortality: 4.7% vs 6.8% (placebo), NNT=48.

  • - In a third trial of 10,584 patients taking 200 mg to 400 mg of sotagliflozin daily,⁵ at 1.3 years:

    • — No differences in composite kidney outcome, cardiovascular death, or all-cause mortality.

Context

• Metformin and SGLT2Is are recommended first-line therapies for those with type 2 diabetes and CKD.⁶

Implementation

On average, SGLT2Is lower systolic blood pressure by about 4 mm Hg in those with CKD taking renin-angiotensin-aldosterone system blockers.⁷ Hemoglobin A_1c reductions of about 0.3% are seen in patients with CKD initiating SGLT2I therapy (most already using metformin, insulin, or sulphonylureas), while reductions of up to 0.6% or 1.0% are seen in patients with diabetes with less intensive background antihyperglycemic therapy.^7,8 To add an SGLT2I, existing non–renin-angiotensin-aldosterone antihypertensives or antihyperglycemics may need to be minimized.⁶