SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis.
By B. Neuen, T. Young, H. Heerspink, B. Neal, V. Perkovic, L. Billot, K. Mahaffey, D. Charytan, D. Wheeler, Clare Arnott and 3 more. The Lancet Diabetes and Endocrinology, 2019
717 citations recorded by the source corpus.
BACKGROUND The effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors on kidney failure, particularly the need for dialysis or transplantation or death due to kidney disease, is uncertain. Additionally, previous studies have been underpowered to robustly assess heterogeneity of effects on kidney outcomes by different levels of estimated glomerular filtration rate (eGFR) and albuminuria. We aimed to do a systematic review and meta-analysis to assess the effects of SGLT2 inhibitors on major kidney outcomes in patients with type 2 diabetes and to determine the consistency of effect size across trials and different levels of eGFR and albuminuria. METHODS We did a systematic review and meta-analysis of randomised, controlled, cardiovascular or kidney outcome trials of SGLT2 inhibitors that reported effects on major kidney outcomes in people with type 2 diabetes. We searched MEDLINE and Embase from database inception to June 14, 2019, to identify eligible trials. The primary outcome was a composite of dialysis, transplantation, or death due to kidney disease. We used random-effects models to obtain summary relative risks (RRs) with 95% CIs and random-effects meta-regression to explore effect modification by subgroups of baseline eGFR, albuminuria, and use of renin-angiotensin system (RAS) blockade. This review is registered with PROSPERO (CRD42019131774). FINDINGS From 2085 records identified, four studies met our inclusion criteria, assessing three SGLT2 inhibitors: empagliflozin (EMPA-REG OUTCOME), canagliflozin (CANVAS Program and CREDENCE), and dapagliflozin (DECLARE-TIMI 58). From a total of 38 723 participants, 252 required dialysis or transplantation or died of kidney disease, 335 developed end-stage kidney disease, and 943 had acute kidney injury. SGLT2 inhibitors substantially reduced the risk of dialysis, transplantation, or death due to kidney disease (RR 0·67, 95% CI 0·52-0·86, p=0·0019), an effect consistent across studies (I2=0%, pheterogeneity=0·53). SGLT2 inhibitors also reduced end-stage kidney disease (0·65, 0·53-0·81, p<0·0001), and acute kidney injury (0·75, 0·66-0·85, p<0·0001), with consistent benefits across studies. Although we identified some evidence that the proportional effect of SGLT2 inhibitors might attenuate with declining kidney function (ptrend=0·073), there was clear, separate evidence of benefit for all eGFR subgroups, including for participants with a baseline eGFR 30-45 mL/min per 1·73 m2 (RR 0·70, 95% CI 0·54-0·91, p=0·0080). Renoprotection was also consistent across studies irrespective of baseline albuminuria (ptrend=0·66) and use of RAS blockade (pheterogeneity=0·31). INTERPRETATION SGLT2 inhibitors reduced the risk of dialysis, transplantation, or death due to kidney disease in individuals with type 2 diabetes and provided protection against acute kidney injury. These data provide substantive evidence supporting the use of SGLT2 inhibitors to prevent major kidney outcomes in people with type 2 diabetes. FUNDING None.
Subfields: Endocrinology, Diabetes and Metabolism, Nephrology, Pulmonary and Respiratory Medicine
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In Endocrinology, Diabetes and Metabolism
Citations in the corpus
- Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2022, neutral): “Of note, the beneficial kidney effects of canagliflozin, dapagliflozin and empagliflozin were also evident for hard kidney outcomes including chronic dialysis and kidney transplantation [252].”
- Diabetes Management in Chronic Kidney Disease: A Consensus Report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) (2022, methodology): “Although short-term studies demonstrated added benefit of the combination of ACEi and ARBs in albuminuria reduction, long-term studies showed no benefit and more adverse events, particularly hyperkalemia and AKI, and thus avoidance of this combination is recommended. ns-MRAs The steroidal mineraloco”
- Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). (2022, background): “Subgroup meta-analyses based on participants’ kidney function indicated that the salutary effects of SGLT2i on MACE, cardiovascular death or HHF, and a composite kidney outcome (substantial loss of kidney function, end-stage kidney disease, or death due to kidney disease) do not significantly differ”
- Diabetic vascular diseases: molecular mechanisms and therapeutic strategies (2023, background): “Upregulated SGLT expression promotes glucose uptake, which affects the tubular-glomerular feedback mechanism, leading to glomerular hypertension.(137,138) Plasma levels of kallikrein, thrombin, and coagulation factors are elevated in hyperglycemic states.”