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Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials.

Publication ,  Journal Article
Nuffield Department of Population Health Renal Studies Group, ; SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium,
Published in: Lancet
November 19, 2022

BACKGROUND: Large trials have shown that sodium glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of adverse kidney and cardiovascular outcomes in patients with heart failure or chronic kidney disease, or with type 2 diabetes and high risk of atherosclerotic cardiovascular disease. None of the trials recruiting patients with and without diabetes were designed to assess outcomes separately in patients without diabetes. METHODS: We did a systematic review and meta-analysis of SGLT2 inhibitor trials. We searched the MEDLINE and Embase databases for trials published from database inception to Sept 5, 2022. SGLT2 inhibitor trials that were double-blind, placebo-controlled, performed in adults (age ≥18 years), large (≥500 participants per group), and at least 6 months in duration were included. Summary-level data used for analysis were extracted from published reports or provided by trial investigators, and inverse-variance-weighted meta-analyses were conducted to estimate treatment effects. The main efficacy outcomes were kidney disease progression (standardised to a definition of a sustained ≥50% decrease in estimated glomerular filtration rate [eGFR] from randomisation, a sustained low eGFR, end-stage kidney disease, or death from kidney failure), acute kidney injury, and a composite of cardiovascular death or hospitalisation for heart failure. Other outcomes were death from cardiovascular and non-cardiovascular disease considered separately, and the main safety outcomes were ketoacidosis and lower limb amputation. This study is registered with PROSPERO, CRD42022351618. FINDINGS: We identified 13 trials involving 90 413 participants. After exclusion of four participants with uncertain diabetes status, we analysed 90 409 participants (74 804 [82·7%] participants with diabetes [>99% with type 2 diabetes] and 15 605 [17·3%] without diabetes; trial-level mean baseline eGFR range 37-85 mL/min per 1·73 m2). Compared with placebo, allocation to an SGLT2 inhibitor reduced the risk of kidney disease progression by 37% (relative risk [RR] 0·63, 95% CI 0·58-0·69) with similar RRs in patients with and without diabetes. In the four chronic kidney disease trials, RRs were similar irrespective of primary kidney diagnosis. SGLT2 inhibitors reduced the risk of acute kidney injury by 23% (0·77, 0·70-0·84) and the risk of cardiovascular death or hospitalisation for heart failure by 23% (0·77, 0·74-0·81), again with similar effects in those with and without diabetes. SGLT2 inhibitors also reduced the risk of cardiovascular death (0·86, 0·81-0·92) but did not significantly reduce the risk of non-cardiovascular death (0·94, 0·88-1·02). For these mortality outcomes, RRs were similar in patients with and without diabetes. For all outcomes, results were broadly similar irrespective of trial mean baseline eGFR. Based on estimates of absolute effects, the absolute benefits of SGLT2 inhibition outweighed any serious hazards of ketoacidosis or amputation. INTERPRETATION: In addition to the established cardiovascular benefits of SGLT2 inhibitors, the randomised data support their use for modifying risk of kidney disease progression and acute kidney injury, not only in patients with type 2 diabetes at high cardiovascular risk, but also in patients with chronic kidney disease or heart failure irrespective of diabetes status, primary kidney disease, or kidney function. FUNDING: UK Medical Research Council and Kidney Research UK.

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Published In

Lancet

DOI

EISSN

1474-547X

Publication Date

November 19, 2022

Volume

400

Issue

10365

Start / End Page

1788 / 1801

Location

England

Related Subject Headings

  • Sodium-Glucose Transporter 2 Inhibitors
  • Sodium-Glucose Transporter 2
  • Sodium
  • Renal Insufficiency, Chronic
  • Randomized Controlled Trials as Topic
  • Kidney
  • Ketosis
  • Humans
  • Heart Failure
  • Glucose
 

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Nuffield Department of Population Health Renal Studies Group, ., & SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium, . (2022). Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet, 400(10365), 1788–1801. https://doi.org/10.1016/S0140-6736(22)02074-8
Nuffield Department of Population Health Renal Studies Group, Margaret A., and Margaret A. SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium. “Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials.Lancet 400, no. 10365 (November 19, 2022): 1788–1801. https://doi.org/10.1016/S0140-6736(22)02074-8.
Nuffield Department of Population Health Renal Studies Group, SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet. 2022 Nov 19;400(10365):1788–801.
Nuffield Department of Population Health Renal Studies Group, Margaret A., and Margaret A. SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium. “Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials.Lancet, vol. 400, no. 10365, Nov. 2022, pp. 1788–801. Pubmed, doi:10.1016/S0140-6736(22)02074-8.
Nuffield Department of Population Health Renal Studies Group, SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet. 2022 Nov 19;400(10365):1788–1801.
Journal cover image

Published In

Lancet

DOI

EISSN

1474-547X

Publication Date

November 19, 2022

Volume

400

Issue

10365

Start / End Page

1788 / 1801

Location

England

Related Subject Headings

  • Sodium-Glucose Transporter 2 Inhibitors
  • Sodium-Glucose Transporter 2
  • Sodium
  • Renal Insufficiency, Chronic
  • Randomized Controlled Trials as Topic
  • Kidney
  • Ketosis
  • Humans
  • Heart Failure
  • Glucose