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SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis

https://doi.org/10.1016/S2213-8587(19)30256-6Get rights and content

Summary

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.

Introduction

About 2·6 million people are estimated to have received dialysis or undergone kidney transplantation for kidney failure in 2010, and this number is projected to more than double by 2030.1 In many countries, more than half of all patients entering dialysis programmes have type 2 diabetes, making this disease a leading cause of kidney failure worldwide.2 Kidney failure due to type 2 diabetes is a large and growing challenge, not only for patients, their families, and caregivers, but also for health systems and governments.3

Treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) has been shown to prevent major adverse kidney outcomes in people with diabetes, and these drugs are recommended by clinical practice guidelines for the treatment of people with type 2 diabetes who have, or are at high risk of, kidney disease.4, 5, 6, 7, 8 However, the residual risk remains high, and new treatments are urgently needed to reduce the growing burden of kidney failure.

Research in context

Evidence before this study

Large-scale randomised cardiovascular outcome trials of sodium-glucose co-transporter-2 (SGLT2) inhibitors in people with type 2 diabetes have suggested promising effects of these drugs on albuminuria and creatinine-based kidney outcomes. However, these trials included few participants at high risk of clinically important kidney outcomes and, as a result, the effect of SGLT2 inhibitors on kidney outcomes that are of greatest concern to patients—namely, the need for long-term dialysis or transplantation, or death due to kidney disease—is unclear. Additionally, SGLT2 inhibitors are not approved for use in patients with estimated glomerular filtration rate (eGFR) lower than 45 mL/min per 1·73 m2 in most countries, mainly because their glucose-lowering effect is substantially dependent on kidney function. In a 2018 meta-analysis of these trials, the renoprotective effect of SGLT2 inhibitors was reported to be attenuated with declining kidney function. However, fewer than a sixth of participants studied had a baseline eGFR lower than 60 mL/min per 1·73 m2, and even fewer had baseline eGFR lower than 45 mL/min per 1·73 m2. Therefore, the ability to robustly assess effects in people with reduced kidney function was limited, especially because few patient-level kidney outcomes occurred. Although, collectively, these trials have suggested that SGLT2 inhibitors might protect against acute kidney injury, the safety of these drugs in patients at high risk of adverse kidney outcomes has remained a concern. In 2019, the primary results of the CREDENCE trial were reported—this trial was designed specifically to examine the effect of SGLT2 inhibition (with canagliflozin) in patients with type 2 diabetes at high risk of kidney disease progression. Therefore, we did a systematic review and meta-analysis of randomised, controlled, event-driven trials in patients with type 2 diabetes that reported effects of SGLT2 inhibition on major kidney outcomes. We searched MEDLINE and Embase from database inception to June 14, 2019, to identify potentially relevant studies.

Added value of this study

Our systematic review and meta-analysis summarises and pools data from four studies including a total of 38 723 participants across six continents. We identified clear evidence that SGLT2 inhibitors reduce the risk of dialysis, transplantation, or death due to kidney disease, as well as a range of other major kidney outcomes, and that these drugs also provide protection against acute kidney injury. Additionally, we identified benefit at all levels of kidney function, including a proportional risk reduction of about 30% in the composite kidney outcome in participants with baseline eGFR lower than 45 mL/min per 1·73 m2, in whom these drugs are mostly not approved for use.

Implications of all the available evidence

To the best of our knowledge, these results provide the strongest evidence yet that SGLT2 inhibitors should be routinely offered to individuals with type 2 diabetes at risk of progressive kidney disease. The clear evidence of renoprotection across the spectrum of kidney function studied to date calls into question the existing restrictions on the use of SGLT2 inhibitors in people with reduced kidney function and suggests that many more individuals with type 2 diabetes at high risk of kidney failure are likely to benefit from treatment with these drugs.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors are glucose-lowering drugs that also lower blood pressure, bodyweight, and albuminuria and might have direct haemodynamic effects on the kidney.9 Large-scale cardiovascular outcome trials10, 11, 12, 13, 14, 15 of SGLT2 inhibitors, which were originally designed to meet regulatory requirements and ensure cardiovascular safety, have shown promising effects on a range of albuminuria and serum creatinine-based kidney outcomes in patients with, or at high risk of, atherosclerotic cardiovascular disease. Most participants in these trials were at low risk of clinically important kidney outcomes and, as a result, event rates for kidney failure were low, with few participants requiring dialysis or kidney transplantation, or dying from kidney disease, in each trial. Because these trials were also not explicitly designed to provide definitive information on renoprotective effects, kidney endpoints were not always prespecified or adjudicated and the distinction between acute and chronic reductions in estimated glomerular filtration rate (eGFR) was not possible in all studies.

The results of a 2018 meta-analysis14 of cardiovascular outcome trials suggested that the effect of SGLT2 inhibitors on kidney outcomes attenuates with declining eGFR. However, less than a sixth of participants in the analysis had baseline eGFR lower than 60 mL/min per 1·73 m2 and thus, the ability to robustly assess effect modification by kidney function was limited. Additionally, because very few participants with baseline eGFR lower than 45 mL/min per 1·73 m2 were assessed in the cardiovascular outcome trials of SGLT2 inhibitors, whether these patients derive protection against kidney failure outcomes has also been unclear, given that the glycaemic efficacy of SGLT2 inhibitors is substantially attenuated in this population. Similarly, most participants in cardiovascular outcome trials of SGTL2 inhibitors had normal albuminuria and, therefore, the consistency of treatment effect across different levels of albuminuria is unclear. Although these trials have collectively suggested protection against acute kidney injury,16 the safety of SGLT2 inhibitors in patients at high risk of adverse kidney outcomes has not been well established. In 2019, the results of the CREDENCE trial17—the first study designed to specifically assess the effect of an SGLT2 inhibitor (canagliflozin) on a primary kidney outcome in people with established diabetic kidney disease—were reported.

Therefore, we did a systematic review and meta-analysis to assess the consistency of effect size across trials of SGLT2 inhibitors and different levels of kidney function and albuminuria, summarise results, and integrate available data for the effects of SGLT2 inhibition on the risk of clinically important kidney outcomes in people with type 2 diabetes.

Section snippets

Search strategy and selection criteria

For this systematic review and meta-analysis, we searched MEDLINE and Embase from database inception to June 14, 2019, for English-language publications using search terms including “sodium-glucose transporter” and related phrases, the names of individual SGLT2 inhibitor drugs, and terms related to randomised clinical trials. Details of the search strategy, including text words and medical subject headings, are provided in the appendix (p 2). We included all randomised, controlled,

Results

We identified 2085 records through database searching and screened their summaries for eligibility, after removal of duplicates. Of 58 full-text articles assessed, we identified four separate studies, comprising five individual trials, after applying the study selection criteria (appendix pp 3,13). We used data from several secondary analyses of these studies in this meta-analysis.10, 11, 12, 13, 15, 21, 22, 23, 24 Sustained kidney outcomes in the EMPA-REG OUTCOME trial were reported in a

Discussion

The development of kidney failure is among the most important consequences of diabetic kidney disease and is of great concern to patients. The evidence from completed trials summarised in this systematic review and meta-analysis shows that SGLT2 inhibitors can reduce the risk of dialysis, transplantation, or death due to kidney disease, with compelling evidence of benefits on a broad range of other clinically important kidney outcomes. Importantly, renoprotection was achieved across all levels

References (46)

  • EJ Lewis et al.

    Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes

    N Engl J Med

    (2001)
  • BM Brenner et al.

    Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy

    N Engl J Med

    (2001)
  • JL Gross et al.

    Diabetic nephropathy: diagnosis, prevention, and treatment

    Diabetes Care

    (2005)
  • HJ Heerspink et al.

    Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications

    Circulation

    (2016)
  • C Wanner et al.

    Empagliflozin and progression of kidney disease in type 2 diabetes

    N Engl J Med

    (2016)
  • BL Neuen et al.

    Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function: data from the CANVAS program

    Circulation

    (2018)
  • C Wanner et al.

    Empagliflozin and clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease

    Circulation

    (2017)
  • TA Zelniker et al.

    SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials

    Lancet

    (2018)
  • RE Gilbert et al.

    Acute kidney injury with sodium-glucose co-transporter-2 inhibitors: a meta-analysis of cardiovascular outcome trials

    Diabetes Obes Metab

    (2019)
  • V Perkovic et al.

    Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

    N Engl J Med

    (2019)
  • JP Higgins et al.

    The Cochrane Collaboration's tool for assessing risk of bias in randomised trials

    BMJ

    (2011)
  • HJ Heerspink et al.

    GFR decline and subsequent risk of established kidney outcomes: a meta-analysis of 37 randomized controlled trials

    Am J Kidney Dis

    (2014)
  • B Neal et al.

    Optimizing the analysis strategy for the CANVAS Program: a prespecified plan for the integrated analyses of the CANVAS and CANVAS-R trials

    Diabetes Obes Metab

    (2017)
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