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Renal outcomes associated with glucose-lowering agents: Systematic review and meta-analysis of randomized outcome trials

Published:December 22, 2021DOI:https://doi.org/10.1016/j.ejim.2021.12.018

      Highlights

      • Worsening kidney function and macroalbuminuria incidence are reduced following glucose-lowering.
      • GLP1 agonists and SGLPT2 inhibitors are associated with protection against both worsening of kidney function and macroalbuminuria.
      • DPP4 inhibitors are not associated with renal event protection.
      • Although there is a linear relationship between reduction of glucose levels and macroalbuminuria after adjustment for confounders, glucose-lowering is not associated with kidney function decline.

      Abstract

      Although the clinical questions of the recent glucose-lowering trials are principally oriented towards preventing macrovascular events, an updated review regarding renal outcome prevention is lacking. We assessed the impact of different antihyperglycemic classes on kidney damage progression. A systematic review and meta-analysis was performed by searching PubMed, Cochrane Collaboration Library, Medline, and previous overviews through June 2021 (any language) for earlier and contemporary glucose-lowering trials, including patients with, but not limited to, type 2 diabetes mellitus vs. placebo or less intense treatment. Incidences of kidney function worsening and macroalbuminuria development was extracted, and risk ratios and 95% confidence intervals (CI) under the random-effects model were calculated. The association between outcome reductions and glycohemoglobin (HBA1c) reductions was investigated through the meta-regression analyses. Among 27 eligible trials (n = 198,532 patients) an averaged HBA1c reduction of 0.6 ± 0.3% was followed by a reduction of 17% (95% CI, 8–25%) in worsening of kidney function, and of 25% (95% CI, 19–32%) in macroalbuminuria. Analog of human glucagon-like peptide 1 (GLP1)-agonists, and sodium-glucose cotransporter (SGLT2)-inhibitors, considered separately, compared with placebo, were associated with a significant reduction of both renal outcomes, at variance with dipeptidyl peptidase 4 (DPP4)-inhibitors, where no outcome change was observed. Logarithmic risk ratios of macroalbuminuria were related to HBA1c reductions, in contrast to the worsening of kidney function related to systolic blood pressure reduction. Worsening of kidney function and macroalbuminuria development were reduced following glucose-lowering. GLP1 agonists and SGLPT2 inhibitors were associated with protection against both outcomes, while DPP4 inhibitors do not provide renal protection.

      Keywords

      Abbreviation:

      AMPLITUDE-O (Efpeglenatide and cardiovascular outcomes in type 2 diabetes), BP (blood pressure), CI (confidence interval), DDP4 (dipeptidyl peptidase 4), CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration), GFR (glomerular filtration rate), HBA1c (GLP1, analog of human glucagon-like peptide 1, glycohemoglobin), HARMONY OUTCOMES (Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease), MDRD (Modification of Diet in Renal Disease), RCTs (randomized controlled trials), RoB2 (revised Cochrane Risk of Bias tool), SGLT2 (sodium-glucose cotransporter), DM (diabetes mellitus)

      1. Introduction

      Large-scale cardiovascular outcome trials and meta-analyses of new antihyperglycemic agents in patients with type 2 diabetes mellitus (DM) demonstrated that these new agents reduce cardiovascular events, including heart failure hospitalizations, and may slow the progression of kidney disease [
      • Thomopoulos C.
      • Bazoukis G.
      • Ilias I.
      • Tsioufis C.
      • Makris T.
      Effects of glucose-lowering on outcome incidence in diabetes mellitus and the modulating role of blood pressure and other clinical variables: overview, meta-analysis of randomized trials.
      ,
      • Kristensen S.L.
      • Rørth R.
      • Jhund P.S.
      • Docherty K.F.
      • Sattar N.
      • Preiss D.
      • Køber L.
      • Petrie M.C.
      • McMurray J.J.V.
      Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.
      ,
      • Zelniker T.A.
      • Wiviott S.D.
      • Raz I.
      • Im K.
      • Goodrich E.L.
      • Furtado R.H.M.
      • Bonaca M.P.
      • Mosenzon O.
      • Kato E.T.
      • Cahn A.
      • Bhatt D.L.
      • Leiter L.A.
      • McGuire D.K.
      • Wilding J.P.H.
      • Sabatine M.S.
      Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus.
      ]. For this reason, in more recent trials, antihyperglycemic agents are also tested in mixed cohorts of patients with and without DM, presenting a very high baseline cardiovascular risk, in general [
      • Zelniker T.A.
      • Wiviott S.D.
      • Raz I.
      • Im K.
      • Goodrich E.L.
      • Furtado R.H.M.
      • Bonaca M.P.
      • Mosenzon O.
      • Kato E.T.
      • Cahn A.
      • Bhatt D.L.
      • Leiter L.A.
      • McGuire D.K.
      • Wilding J.P.H.
      • Sabatine M.S.
      Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus.
      ]. Although the clinical questions of the recent trials are principally oriented towards preventing macrovascular events, the role of glucose-lowering in the prevention of microvascular complications shall not be ignored [
      • Beckman J.A.
      • Creager M.A.
      Vascular complications of diabetes.
      ]. Among microvascular complications, the natural history of diabetic nephropathy is characterized by initial glomerular hyperfiltration and progressive increase of albuminuria, followed by a gradual decline in glomerular filtration rate (GFR) until the development of end-stage renal disease [
      • Tonneijck L.
      • Muskiet M.H.
      • Smits M.M.
      • et al.
      Glomerular hyperfiltration in diabetes: mechanisms, clinical significance, and treatment.
      ]. However, no systematic review has been conducted to address the renal effects of glucose-lowering in glycohemoglobin (HBA1c) reduction, including earlier and contemporary antihyperglycemic agents. This might be important to 1) update our knowledge in the field, 2) comprehensively study the contribution of new glucose-lowering agents to the progression of kidney damage, and 3) evaluate the effect modification by additional variables such as baseline HBA1c levels, ongoing HBA1c levels, blood pressure (BP), and baseline cardiovascular risk. To reach the above objectives concerning renal outcomes, we conducted a systematic review and meta-analysis of glucose-lowering randomized controlled (vs. placebo or less intense glucose-lowering) trials (RCTs), including patients with but not limited to type 2 DM.

      2. Methods

      2.1 Trial eligibility

      The present systematic review and meta-analysis intended to include RCTs where 1) an active drug was compared with placebo to investigate the consequences of HBA1c differences (intentional glucose-lowering trials, placebo-controlled), 2) a more intense regimen was compared with a less intense (intentional glucose-lowering, more vs. less intense), 3) an active drug was compared with placebo, and a between-group difference of at least 0.2% in HBA1c involuntarily occurred, though, the design was not that of investigating the effect of HBA1c differences (non-intentional glucose-lowering trials).
      Trials had to meet the following predetermined criteria: 1) type 2 DM patients, or mixed cohorts of patients with and without type 2 DM (i.e., glucose intolerance or normoglycemia), 2) protocol including measurement of at least one type of renal events as a primary or non-primary endpoint, 3) HBA1c values measured at baseline and follow-up, 4) follow-up of at least six months; 5) a minimum of at least five events during follow-up, and 6) publication within 6th June 2021. Both injectable and oral agents were included. Regarding the excluded trials: 1) trials of acute care; 2) trials exclusively in type 1 DM, glucose intolerance or mixed cohorts of type 1 and type 2 DM; 3) trials where multiple interventions were applied (e.g., glucose-lowering by lifestyle or other interventions); and 4) head-to-head drug comparison trials. Two authors (K.C. and C.Th.) completed the database search by consulting PubMed between 1990 and 6th June 2021 (any language), the Cochrane Collaboration Library database, Medline, and the reference list of all previous major meta-analyses and overviews of glucose-lowering trials. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      • PRISMA Group
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ].

      2.2 Data extraction and outcomes

      Two authors (K.C. and C.Th.) extracted the data; in case of missing information or doubt, the trial authors were consulted. Any differences throughout the extraction procedure were resolved by discussion. We extracted data (i.e., event rates) related to the outcomes under consideration, as well as the baseline and achieved HBA1c, baseline and ongoing BP, body mass index, age, the prevalence of male gender, hypertension and heart failure prevalence, the cardiovascular death rate in the placebo or less active arm of each trial to calculate the ten-year baseline fatal CV risk, type 2 DM duration, baseline GFR, the modality in estimating GFR (i.e., according to MDRD [Modification of Diet in Renal Disease] or CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration] equations), and serum creatinine levels, baseline macroalbuminuria. Two renal outcomes were considered: 1) composite of worsening of kidney function: doubling of serum creatinine or GFR reduction of at least 30% - as defined in the original articles - renal death, end-stage renal disease, renal dialysis or renal transplantation, and 2) incident macroalbuminuria. The two authors (K.C. and C.Th.) independently extracted outcomes with discrepancies resolved by discussion.

      2.3 Classification of trials by relevant variables

      Trials were stratified according to 1) different contemporary drug classes (i.e., selective dipeptidyl peptidase 4 [DDP4]-inhibitors, the analog of human glucagon like peptide 1 [GLP1]-agonists, and sodium-glucose cotransporter [SGLT2]-inhibitors), 2) the average HBA1c at baseline, into 2 categories of ≥8% and <8%, and 3) the achieved HBA1c levels in the more active glucose-lowering group, into 2 groups, ≥7 or 7.5% vs. <7 or 7.5%, respectively. Also, achieved HBA1c was the average value of the measure throughout the follow-up or the end-follow-up HBA1c. Furthermore, trials were divided into two groups in line with a ten-year duration of type 2 DM. Finally, we classified trials by the baseline fatal ten-year cardiovascular risk, and we used the cutoff of 10% to divide trials into those of higher or lower risk.

      2.4 Risk of bias assessment

      The Revised Cochrane Risk of Bias tool (RoB2) was used to assess the quality of all outcomes [
      • Sterne J.A.C.
      • Savovic J.
      • Page M.J.
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      ]. RoB 2 is structured in five mandatory bias domains to address important pathways by which bias may be introduced in each trial outcome result. The overall risk of bias was qualitatively determined by the amount of bias in each separate risk domain.

      2.5 Statistical analyses

      All intentional (active drug vs. placebo and more vs. less intense treatment) and non-intentional glucose-lowering trials were considered together for our primary analysis. All analyses were pre-specified and conducted using data tabulated in the original publications. Baseline patient characteristics and ongoing HBA1c and BP differences between randomized treatments were the means of every individual trial value weighted by the number of patients within each group. For every comparison group, the null hypothesis of no difference between randomized treatments was tested. Risk ratio estimates [with 95% confidence interval (CI)] were combined using a random-effects model. The logarithm risk ratio for every trial was weighted by the reciprocal of the variance of the logarithm risk ratio. The I2 statistics quantified the proportion of inconsistency across studies not explained by chance. Significant heterogeneity was ascribed whenever the X2Q statistics were accompanied by a P-value > 0.1.
      Risk ratios and their 95% CI were reported using the Mantel-Haenszel method. The effects of glucose-lowering on each outcome were illustrated with the forest plots under the appropriate model. Random-effects meta-regression models with inverse variance-weighting were constructed to examine whether the achieved HBA1c difference (independent variable) between the randomized groups explained the variance of risk ratio estimates before and after adjustment for confounders. Sensitivity analyses were performed to exclude the effect of 1) higher risk of bias studies, 2) earlier studies, 3) trials with heart failure prevalence of at least 15%, and 4) trials estimating GFR by the CKD-EPI equation. A Q-test of risk reductions was reported to indicate the differences in groups of trials stratified by different clinical variables (i.e., ten-year fatal cardiovascular risk; DM duration at baseline; baseline HBA1c; achieved HBA1c) across predetermined thresholds. Publication bias was investigated graphically by the funnel plots of precision and the Duval and Tweedie trim-and-fill test. All statistical analyses were processed using the Comprehensive Meta Analysis version 3 (Biostat, Englewood, New Jersey, USA). A P value less than 0.05 was considered to indicate statistical significance in each analysis.

      3. Results

      3.1 Studies and patients

      The searching strategy (Supplemental Figure S1, Supplemental Table S1) identified 27 eligible studies [
      • Shichiri M.
      • Kishikawa H.
      • Ohkubo Y.
      • Wake N.
      Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients.
      ,
      UK Prospective Diabetes Study (UKPDS) Group
      Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
      ,
      UK Prospective Diabetes Study (UKPDS) Group
      Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).
      ,
      • Patel A.
      • MacMahon S.
      • Chalmers J.
      • Neal B.
      • Billot L.
      • Woodward M.
      • ADVANCE Collaborative Group
      • et al.
      Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
      ,
      • Chan J.C.
      • So W.Y.
      • Yeung C.Y.
      • Ko G.T.
      • Lau I.T.
      • Tsang M.W.
      • SURE Study Group
      • et al.
      Effects of structured versus usual care on renal endpoint in type 2 diabetes: the SURE study: a randomized multicenter translational study.
      ,
      • Duckworth W.
      • Abraira C.
      • Moritz T.
      • Reda D.
      • Emanuele N.
      • Reaven P.D.
      • VADT Investigators
      • et al.
      Glucose control and vascular complications in veterans with type 2 diabetes.
      ,
      • Gerstein H.C.
      • Miller M.E.
      • Byington R.P.
      • Goff Jr, D.C.
      • Bigger J.T.
      • Buse J.B.
      • Action to Control Cardiovascular Risk in Diabetes Study Group
      • et al.
      Effects of intensive glucose lowering in type 2 diabetes.
      ,
      • White W.B.
      • Cannon C.P.
      • Heller S.R.
      • Nissen S.E.
      • Bergenstal R.M.
      • Bakris G.L.
      • EXAMINE Investigators
      • et al.
      Alogliptin after acute coronary syndrome in patients with type 2 diabetes.
      ,
      • Scirica B.M.
      • Bhatt D.L.
      • Braunwald E.
      • Steg P.G.
      • Davidson J.
      • Hirshberg B.
      • SAVOR-TIMI 53 Steering Committee and Investigators
      • et al.
      Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
      ,
      • Frye R.L.
      • August P.
      • Brooks M.M.
      • Hardison R.M.
      • Kelsey S.F.
      • MacGregor J.M.
      • BARI 2D Study Group
      • et al.
      A randomized trial of therapies for type 2 diabetes and coronary artery disease.
      ,
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • Fitchett D.
      • Bluhmki E.
      • Hantel S.
      • EMPA-REG OUTCOME Investigators
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ,
      • Green J.B.
      • Bethel M.A.
      • Armstrong P.W.
      • Buse J.B.
      • Engel S.S.
      • Garg J.
      • TECOS Study Group
      • et al.
      Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.
      ,
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • Kristensen P.
      • Mann J.F.
      • Nauck M.A.
      • LEADER Trial Investigators
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      ,
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • Eliaschewitz F.G.
      • Jo´dar E.
      • Leiter L.A.
      • SUSTAIN-6 Investigators
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • de Zeeuw D.
      • Fulcher G.
      • Erondu N.
      • CANVAS Program Collaborative Group
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ,
      • Rosenstock J.
      • Perkovic V.
      • Johansen O.E.
      • Cooper M.E.
      • Kahn S.E.
      • Marx N.
      • CARMELINA Investigators
      • et al.
      Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial.
      ,
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • Mosenzon O.
      • Kato E.T.
      • Cahn A.
      • DECLARE–TIMI 58 Investigators
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ,
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • Dickstein K.
      • Gerstein H.C.
      • Køber L.V.
      • ELIXA Investigators
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      ,
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • D'Agostino Sr, R.B.
      • Granger C.B.
      • Jones N.P.
      • Harmony Outcomes Committees and Investigators
      • et al.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomized placebo-controlled trial.
      ,
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • Bompoint S.
      • Heerspink H.J.L.
      • Charytan D.M.
      • Edwards R.
      • Agarwal R.
      • Bakris G.
      • Bull S.
      • Cannon C.P.
      • Capuano G.
      • Chu P.L.
      • de Zeeuw D.
      • Greene T.
      • Levin A.
      • Pollock C.
      • Wheeler D.C.
      • Yavin Y.
      • Zhang H.
      • Zinman B.
      • Meininger G.
      • Brenner B.M.
      • Mahaffey K.W.
      • CREDENCE Trial Investigators
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ,
      • Holman R.R.
      • Bethel M.A.
      • Mentz R.J.
      • Thompson V.P.
      • Lokhnygina Y.
      • Buse J.B.
      • EXSCEL Study Group
      • et al.
      Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      ,
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • Diaz R.
      • Lakshmanan M.
      • Pais P.
      • Probstfield J.
      • Riesmeyer J.S.
      • Riddle M.C.
      • Rydén L.
      • Xavier D.
      • Atisso C.M.
      • Dyal L.
      • Hall S.
      • Rao-Melacini P.
      • Wong G.
      • Avezum A.
      • Basile J.
      • Chung N.
      • Conget I.
      • Cushman W.C.
      • Franek E.
      • Hancu N.
      • Hanefeld M.
      • Holt S.
      • Jansky P.
      • Keltai M.
      • Lanas F.
      • Leiter L.A.
      • Lopez-Jaramillo P.
      • Cardona Munoz E.G.
      • Pirags V.
      • Pogosova N.
      • Raubenheimer P.J.
      • Shaw J.E.
      • Sheu W.H.
      • Temelkova-Kurktschiev T
      • REWIND Investigators
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      ,
      • Petrie M.C.
      • Verma S.
      • Docherty K.F.
      • Inzucchi S.E.
      • Anand I.
      • Belohlávek J.
      • Böhm M.
      • Chiang C.E.
      • Chopra V.K.
      • de Boer R.A.
      • Desai A.S.
      • Diez M.
      • Drozdz J.
      • Dukát A.
      • Ge J.
      • Howlett J.
      • Katova T.
      • Kitakaze M.
      • Ljungman C.E.A.
      • Merkely B.
      • Nicolau J.C.
      • O'Meara E.
      • Vinh P.N.
      • Schou M.
      • Tereshchenko S.
      • Køber L.
      • Kosiborod M.N.
      • Langkilde A.M.
      • Martinez F.A.
      • Ponikowski P.
      • Sabatine M.S.
      • Sjöstrand M.
      • Solomon S.D.
      • Johanson P.
      • Greasley P.J.
      • Boulton D.
      • Bengtsson O.
      • Jhund P.S.
      • McMurray J.J.V.
      Effect of dapagliflozin on worsening heart failure and cardiovascular death in patients with heart failure with and without diabetes.
      ,
      • Heerspink H.J.L.
      • Stefánsson B.V.
      • Correa-Rotter R.
      • Chertow G.M.
      • Greene T.
      • Hou F.F.
      • Mann J.F.E.
      • McMurray J.J.V.
      • Lindberg M.
      • Rossing P.
      • Sjöström C.D.
      • Toto R.D.
      • Langkilde A.M.
      • Wheeler D.C.
      • DAPA-CKD Trial Committees and Investigators
      dapagliflozin in patients with chronic kidney disease.
      ,
      • Bhatt D.L.
      • Szarek M.
      • Pitt B.
      • Cannon C.P.
      • Leiter L.A.
      • McGuire D.K.
      • Lewis J.B.
      • Riddle M.C.
      • Inzucchi S.E.
      • Kosiborod M.N.
      • Cherney D.Z.I.
      • Dwyer J.P.
      • Scirica B.M.
      • Bailey C.J.
      • Díaz R.
      • Ray K.K.
      • Udell J.A.
      • Lopes R.D.
      • Lapuerta P.
      • Steg PG
      • SCORED Investigators
      Sotagliflozin in patients with diabetes and chronic kidney disease.
      ,
      • Cannon C.P.
      • Pratley R.
      • Dagogo-Jack S.
      • Mancuso J.
      • Huyck S.
      • Masiukiewicz U.
      • Charbonnel B.
      • Frederich R.
      • Gallo S.
      • Cosentino F.
      • Shih W.J.
      • Gantz I.
      • Terra S.G.
      • Cherney D.Z.I.
      • McGuire D.K.
      • Investigators VERTIS CV
      Cardiovascular outcomes with ertugliflozin in type 2 diabetes.
      ,
      • Gerstein H.C.
      • Sattar N.
      • Rosenstock J.
      • Ramasundarahettige C.
      • Pratley R.
      • Lopes R.D.
      • Lam C.S.P.
      • Khurmi N.S.
      • Heenan L.
      • Del Prato S.
      • Dyal L.
      • Branch K.
      • AMPLITUDE-O Trial Investigators
      Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes.
      ] out of 36 relevant papers [
      • Shichiri M.
      • Kishikawa H.
      • Ohkubo Y.
      • Wake N.
      Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients.
      ,
      UK Prospective Diabetes Study (UKPDS) Group
      Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
      ,
      UK Prospective Diabetes Study (UKPDS) Group
      Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).
      ,
      • Patel A.
      • MacMahon S.
      • Chalmers J.
      • Neal B.
      • Billot L.
      • Woodward M.
      • ADVANCE Collaborative Group
      • et al.
      Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
      ,
      • Chan J.C.
      • So W.Y.
      • Yeung C.Y.
      • Ko G.T.
      • Lau I.T.
      • Tsang M.W.
      • SURE Study Group
      • et al.
      Effects of structured versus usual care on renal endpoint in type 2 diabetes: the SURE study: a randomized multicenter translational study.
      ,
      • Duckworth W.
      • Abraira C.
      • Moritz T.
      • Reda D.
      • Emanuele N.
      • Reaven P.D.
      • VADT Investigators
      • et al.
      Glucose control and vascular complications in veterans with type 2 diabetes.
      ,
      • Gerstein H.C.
      • Miller M.E.
      • Byington R.P.
      • Goff Jr, D.C.
      • Bigger J.T.
      • Buse J.B.
      • Action to Control Cardiovascular Risk in Diabetes Study Group
      • et al.
      Effects of intensive glucose lowering in type 2 diabetes.
      ,
      • White W.B.
      • Cannon C.P.
      • Heller S.R.
      • Nissen S.E.
      • Bergenstal R.M.
      • Bakris G.L.
      • EXAMINE Investigators
      • et al.
      Alogliptin after acute coronary syndrome in patients with type 2 diabetes.
      ,
      • Scirica B.M.
      • Bhatt D.L.
      • Braunwald E.
      • Steg P.G.
      • Davidson J.
      • Hirshberg B.
      • SAVOR-TIMI 53 Steering Committee and Investigators
      • et al.
      Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
      ,
      • Frye R.L.
      • August P.
      • Brooks M.M.
      • Hardison R.M.
      • Kelsey S.F.
      • MacGregor J.M.
      • BARI 2D Study Group
      • et al.
      A randomized trial of therapies for type 2 diabetes and coronary artery disease.
      ,
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • Fitchett D.
      • Bluhmki E.
      • Hantel S.
      • EMPA-REG OUTCOME Investigators
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ,
      • Green J.B.
      • Bethel M.A.
      • Armstrong P.W.
      • Buse J.B.
      • Engel S.S.
      • Garg J.
      • TECOS Study Group
      • et al.
      Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.
      ,
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • Kristensen P.
      • Mann J.F.
      • Nauck M.A.
      • LEADER Trial Investigators
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      ,
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • Eliaschewitz F.G.
      • Jo´dar E.
      • Leiter L.A.
      • SUSTAIN-6 Investigators
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • de Zeeuw D.
      • Fulcher G.
      • Erondu N.
      • CANVAS Program Collaborative Group
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ,
      • Rosenstock J.
      • Perkovic V.
      • Johansen O.E.
      • Cooper M.E.
      • Kahn S.E.
      • Marx N.
      • CARMELINA Investigators
      • et al.
      Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial.
      ,
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • Mosenzon O.
      • Kato E.T.
      • Cahn A.
      • DECLARE–TIMI 58 Investigators
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ,
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • Dickstein K.
      • Gerstein H.C.
      • Køber L.V.
      • ELIXA Investigators
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      ,
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • D'Agostino Sr, R.B.
      • Granger C.B.
      • Jones N.P.
      • Harmony Outcomes Committees and Investigators
      • et al.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomized placebo-controlled trial.
      ,
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • Bompoint S.
      • Heerspink H.J.L.
      • Charytan D.M.
      • Edwards R.
      • Agarwal R.
      • Bakris G.
      • Bull S.
      • Cannon C.P.
      • Capuano G.
      • Chu P.L.
      • de Zeeuw D.
      • Greene T.
      • Levin A.
      • Pollock C.
      • Wheeler D.C.
      • Yavin Y.
      • Zhang H.
      • Zinman B.
      • Meininger G.
      • Brenner B.M.
      • Mahaffey K.W.
      • CREDENCE Trial Investigators
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ,
      • Holman R.R.
      • Bethel M.A.
      • Mentz R.J.
      • Thompson V.P.
      • Lokhnygina Y.
      • Buse J.B.
      • EXSCEL Study Group
      • et al.
      Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      ,
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • Diaz R.
      • Lakshmanan M.
      • Pais P.
      • Probstfield J.
      • Riesmeyer J.S.
      • Riddle M.C.
      • Rydén L.
      • Xavier D.
      • Atisso C.M.
      • Dyal L.
      • Hall S.
      • Rao-Melacini P.
      • Wong G.
      • Avezum A.
      • Basile J.
      • Chung N.
      • Conget I.
      • Cushman W.C.
      • Franek E.
      • Hancu N.
      • Hanefeld M.
      • Holt S.
      • Jansky P.
      • Keltai M.
      • Lanas F.
      • Leiter L.A.
      • Lopez-Jaramillo P.
      • Cardona Munoz E.G.
      • Pirags V.
      • Pogosova N.
      • Raubenheimer P.J.
      • Shaw J.E.
      • Sheu W.H.
      • Temelkova-Kurktschiev T
      • REWIND Investigators
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      ,
      • Petrie M.C.
      • Verma S.
      • Docherty K.F.
      • Inzucchi S.E.
      • Anand I.
      • Belohlávek J.
      • Böhm M.
      • Chiang C.E.
      • Chopra V.K.
      • de Boer R.A.
      • Desai A.S.
      • Diez M.
      • Drozdz J.
      • Dukát A.
      • Ge J.
      • Howlett J.
      • Katova T.
      • Kitakaze M.
      • Ljungman C.E.A.
      • Merkely B.
      • Nicolau J.C.
      • O'Meara E.
      • Vinh P.N.
      • Schou M.
      • Tereshchenko S.
      • Køber L.
      • Kosiborod M.N.
      • Langkilde A.M.
      • Martinez F.A.
      • Ponikowski P.
      • Sabatine M.S.
      • Sjöstrand M.
      • Solomon S.D.
      • Johanson P.
      • Greasley P.J.
      • Boulton D.
      • Bengtsson O.
      • Jhund P.S.
      • McMurray J.J.V.
      Effect of dapagliflozin on worsening heart failure and cardiovascular death in patients with heart failure with and without diabetes.
      ,
      • Heerspink H.J.L.
      • Stefánsson B.V.
      • Correa-Rotter R.
      • Chertow G.M.
      • Greene T.
      • Hou F.F.
      • Mann J.F.E.
      • McMurray J.J.V.
      • Lindberg M.
      • Rossing P.
      • Sjöström C.D.
      • Toto R.D.
      • Langkilde A.M.
      • Wheeler D.C.
      • DAPA-CKD Trial Committees and Investigators
      dapagliflozin in patients with chronic kidney disease.
      ,
      • Bhatt D.L.
      • Szarek M.
      • Pitt B.
      • Cannon C.P.
      • Leiter L.A.
      • McGuire D.K.
      • Lewis J.B.
      • Riddle M.C.
      • Inzucchi S.E.
      • Kosiborod M.N.
      • Cherney D.Z.I.
      • Dwyer J.P.
      • Scirica B.M.
      • Bailey C.J.
      • Díaz R.
      • Ray K.K.
      • Udell J.A.
      • Lopes R.D.
      • Lapuerta P.
      • Steg PG
      • SCORED Investigators
      Sotagliflozin in patients with diabetes and chronic kidney disease.
      ,
      • Cannon C.P.
      • Pratley R.
      • Dagogo-Jack S.
      • Mancuso J.
      • Huyck S.
      • Masiukiewicz U.
      • Charbonnel B.
      • Frederich R.
      • Gallo S.
      • Cosentino F.
      • Shih W.J.
      • Gantz I.
      • Terra S.G.
      • Cherney D.Z.I.
      • McGuire D.K.
      • Investigators VERTIS CV
      Cardiovascular outcomes with ertugliflozin in type 2 diabetes.
      ,
      • Gerstein H.C.
      • Sattar N.
      • Rosenstock J.
      • Ramasundarahettige C.
      • Pratley R.
      • Lopes R.D.
      • Lam C.S.P.
      • Khurmi N.S.
      • Heenan L.
      • Del Prato S.
      • Dyal L.
      • Branch K.
      • AMPLITUDE-O Trial Investigators
      Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes.
      ,
      • Ismail-Beigi F.
      • Craven T.
      • Banerji M.A.
      • Basile J.
      • Calles J.
      • Cohen R.M.
      • Cuddihy R.
      • Cushman W.C.
      • Genuth S.
      • Grimm Jr, R.H.
      • Hamilton B.P.
      • Hoogwerf B.
      • Karl D.
      • Katz L.
      • Krikorian A.
      • O'Connor P.
      • Pop-Busui R.
      • Schubart U.
      • Simmons D.
      • Taylor H.
      • Thomas A.
      • Weiss D.
      • Hramiak I.
      • ACCORD Trial Group
      Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial.
      ,
      • August P.
      • Hardison R.M.
      • Hage F.G.
      • Marroquin O.C.
      • McGill J.B.
      • Rosenberg Y.
      • Steffes M.
      • Wall B.M.
      • Molitch M.
      • 2D Study Group B.A.R.I.
      Change in albuminuria and eGFR following insulin sensitization therapy versus insulin provision therapy in the BARI 2D study.
      ,
      • Perkovic V.
      • de Zeeuw D.
      • Mahaffey K.W.
      • Fulcher G.
      • Erondu N.
      • Shaw W.
      • Barrett T.D.
      • Weidner-Wells M.
      • Deng H.
      • Matthews D.R.
      • Neal B.
      Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials.
      ,
      • Muskiet M.H.A.
      • Tonneijck L.
      • Huang Y.
      • Liu M.
      • Saremi A.
      • Heerspink H.J.L.
      • van Raalte D.H.
      Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial.
      ,
      • Bethel M.A.
      • Mentz R.J.
      • Merrill P.
      • Buse J.B.
      • Chan J.C.
      • Goodman S.G.
      • Iqbal N.
      • Jakuboniene N.
      • Katona B.
      • Lokhnygina Y.
      • Lopes R.D.
      • Maggioni A.P.
      • Ohman P.
      • Tankova T.
      • Bakris G.L.
      • Hernandez A.F.
      • Holman R.R.
      Microvascular and cardiovascular outcomes according to renal function in patients treated with once-weekly exenatide: insights from the EXSCEL trial.
      ,
      • Mann J.F.E.
      • Ørsted D.D.
      • Brown-Frandsen K.
      • Marso S.P.
      • Poulter N.R.
      • Rasmussen S.
      • Tornøe K.
      • Zinman B.
      • Buse J.B.
      LEADER steering committee and investigators. liraglutide and renal outcomes in type 2 diabetes.
      ,
      • Mosenzon O.
      • Leibowitz G.
      • Bhatt D.L.
      • Cahn A.
      • Hirshberg B.
      • Wei C.
      • Im K.
      • Rozenberg A.
      • Yanuv I.
      • Stahre C.
      • Ray K.K.
      • Iqbal N.
      • Braunwald E.
      • Scirica B.M.
      • Raz I.
      Effect of saxagliptin on renal outcomes in the SAVOR-TIMI 53 trial.
      ,
      • Cornel J.H.
      • Bakris G.L.
      • Stevens S.R.
      • Alvarsson M.
      • Bax W.A.
      • Chuang L.M.
      • Engel S.S.
      • Lopes R.D.
      • McGuire D.K.
      • Riefflin A.
      • Rodbard H.W.
      • Sinay I.
      • Tankova T.
      • Wainstein J.
      • Peterson E.D.
      • Holman R.R.
      • Study Group T.E.C.O.S.
      Effect of sitagliptin on kidney function and respective cardiovascular outcomes in type 2 diabetes: outcomes From TECOS.
      ,
      • Wanner C.
      • Inzucchi S.E.
      • Lachin J.M.
      • Fitchett D.
      • von Eynatten M.
      • Mattheus M.
      • Johansen O.E.
      • Woerle H.J.
      • Broedl U.C.
      • Zinman B.
      • EMPA-REG OUTCOME Investigators
      Empagliflozin and progression of kidney disease in type 2 diabetes.
      ], while excluded studies at the full-length stage (reason of exclusion included) are reported in Supplemental Table S2. The baseline characteristics of the included trials are presented in Table 1 (n = 198,532 patients; mean follow-up, 3.3 ± 1.7 years; mean age, 63.8 ± 2.7 years; men, 64.7 ± 6.3%). Averaged baseline HBA1c was 8 ± 0.5%, while the same measure was reduced to 7.4 ± 0.5% in the more active glucose-lowering arm with an averaged attained HBA1c difference between groups of −0.6 ± 0.3%. Trials reporting data for the composite renal outcome of worsening of kidney function (n = 26; 191,631 patients) or follow-up macroalbuminuria (n = 15; 103,003 patients) are found in Supplemental Table S3. According to the risk of bias assessment procedure, the risk of bias was generally low in almost 70% (n = 19) of trials. In contrast, in eight trials, certain bias domains produced a judgment of some concerns (Supplemental Figure S2).
      Table 1Baseline characteristics of patients included in trials.
      Trial name [REF]Sample sizeComparisonFollow up (y)Age (y)Males (%)HBA1c (%)HBA1c active attained (%)HbA1c attained difference (%)DM duration (y)10y CVR (%)BMI (kg/m2)Cr (mg/dl)eGFR (ml/min/m2)Macro-albuminuria (%)HF (%)HTN (%)SBP/DBP attained difference (mmHg)
      KUMAMOTO
      • Shichiri M.
      • Kishikawa H.
      • Ohkubo Y.
      • Wake N.
      Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients.
      110More vs Less intense851489.27.1−2.48.46.820.4NANA*00NA−1/−2
      UKPDS-33
      UK Prospective Diabetes Study (UKPDS) Group
      Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
      3867Intensive vs Conventional1053617.17−0.9<111.127.50.9282.6*1.90120.8/0.4
      UKPDS-34
      UK Prospective Diabetes Study (UKPDS) Group
      Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).
      1704Intensive vs Conventional10.753477.27.4−0.6<113.831.40.8982.2*2.2015NA/NA
      ADVANCE
      • Patel A.
      • MacMahon S.
      • Chalmers J.
      • Neal B.
      • Billot L.
      • Woodward M.
      • ADVANCE Collaborative Group
      • et al.
      Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
      11,140Intensive vs Standard566587.26.5−0.8810.4280.9872.7*3.9NA75−2.4/−0.8
      SURE
      • Chan J.C.
      • So W.Y.
      • Yeung C.Y.
      • Ko G.T.
      • Lau I.T.
      • Tsang M.W.
      • SURE Study Group
      • et al.
      Effects of structured versus usual care on renal endpoint in type 2 diabetes: the SURE study: a randomized multicenter translational study.
      205More or Less intensive265678.37.3−0.714.227.225.42.2531.3*NA7.596−2/−3
      VADT
      • Duckworth W.
      • Abraira C.
      • Moritz T.
      • Reda D.
      • Emanuele N.
      • Reaven P.D.
      • VADT Investigators
      • et al.
      Glucose control and vascular complications in veterans with type 2 diabetes.
      1791Intensive vs Standard5.660979.46.9−1.511.56.631.2181.8*NANA72.32/−1
      ACCORD [
      • Gerstein H.C.
      • Miller M.E.
      • Byington R.P.
      • Goff Jr, D.C.
      • Bigger J.T.
      • Buse J.B.
      • Action to Control Cardiovascular Risk in Diabetes Study Group
      • et al.
      Effects of intensive glucose lowering in type 2 diabetes.
      ,
      • Ismail-Beigi F.
      • Craven T.
      • Banerji M.A.
      • Basile J.
      • Calles J.
      • Cohen R.M.
      • Cuddihy R.
      • Cushman W.C.
      • Genuth S.
      • Grimm Jr, R.H.
      • Hamilton B.P.
      • Hoogwerf B.
      • Karl D.
      • Katz L.
      • Krikorian A.
      • O'Connor P.
      • Pop-Busui R.
      • Schubart U.
      • Simmons D.
      • Taylor H.
      • Thomas A.
      • Weiss D.
      • Hramiak I.
      • ACCORD Trial Group
      Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial.
      ]
      10,251Intensive vs Standard3.562628.16.4−1.1105.232.20.990*74.987−1/−1
      EXAMINE
      • White W.B.
      • Cannon C.P.
      • Heller S.R.
      • Nissen S.E.
      • Bergenstal R.M.
      • Bakris G.L.
      • EXAMINE Investigators
      • et al.
      Alogliptin after acute coronary syndrome in patients with type 2 diabetes.
      5380Alogliptin vs Placebo1.5616887.7−0.37.232.428.7NA71.1*NA2883−1.3/−0.1
      SAVOR-TIMI-53 [
      • Scirica B.M.
      • Bhatt D.L.
      • Braunwald E.
      • Steg P.G.
      • Davidson J.
      • Hirshberg B.
      • SAVOR-TIMI 53 Steering Committee and Investigators
      • et al.
      Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
      ,
      • Mosenzon O.
      • Leibowitz G.
      • Bhatt D.L.
      • Cahn A.
      • Hirshberg B.
      • Wei C.
      • Im K.
      • Rozenberg A.
      • Yanuv I.
      • Stahre C.
      • Ray K.K.
      • Iqbal N.
      • Braunwald E.
      • Scirica B.M.
      • Raz I.
      Effect of saxagliptin on renal outcomes in the SAVOR-TIMI 53 trial.
      ]
      16,492Saxagliptin vs Placebo2.1656787.7−0.210.315.131.2NA72.7*9.912.682.40/0
      BARI 2D [
      • Frye R.L.
      • August P.
      • Brooks M.M.
      • Hardison R.M.
      • Kelsey S.F.
      • MacGregor J.M.
      • BARI 2D Study Group
      • et al.
      A randomized trial of therapies for type 2 diabetes and coronary artery disease.
      ,
      • August P.
      • Hardison R.M.
      • Hage F.G.
      • Marroquin O.C.
      • McGill J.B.
      • Rosenberg Y.
      • Steffes M.
      • Wall B.M.
      • Molitch M.
      • 2D Study Group B.A.R.I.
      Change in albuminuria and eGFR following insulin sensitization therapy versus insulin provision therapy in the BARI 2D study.
      ]
      2368More vs Less intense562707.7NA−0.48.313.531.6NA76.6*9NA83−0.2/−0.3
      EMPAREG OUTCOME [
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • Fitchett D.
      • Bluhmki E.
      • Hantel S.
      • EMPA-REG OUTCOME Investigators
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ,
      • Wanner C.
      • Inzucchi S.E.
      • Lachin J.M.
      • Fitchett D.
      • von Eynatten M.
      • Mattheus M.
      • Johansen O.E.
      • Woerle H.J.
      • Broedl U.C.
      • Zinman B.
      • EMPA-REG OUTCOME Investigators
      Empagliflozin and progression of kidney disease in type 2 diabetes.
      ]
      7020Empagliflozin vs Placebo3.1637287.8−0.4>1018.930.71.0373.8*11.110.295−4/−1
      TECOS [
      • Green J.B.
      • Bethel M.A.
      • Armstrong P.W.
      • Buse J.B.
      • Engel S.S.
      • Garg J.
      • TECOS Study Group
      • et al.
      Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.
      ,
      • Cornel J.H.
      • Bakris G.L.
      • Stevens S.R.
      • Alvarsson M.
      • Bax W.A.
      • Chuang L.M.
      • Engel S.S.
      • Lopes R.D.
      • McGuire D.K.
      • Riefflin A.
      • Rodbard H.W.
      • Sinay I.
      • Tankova T.
      • Wainstein J.
      • Peterson E.D.
      • Holman R.R.
      • Study Group T.E.C.O.S.
      Effect of sitagliptin on kidney function and respective cardiovascular outcomes in type 2 diabetes: outcomes From TECOS.
      ]
      14,735Sitagliptin vs Placebo365707.2NA−0.411.616.630.2NA74.9*NA1878.8−0.5/−0.1
      LEADER [
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • Kristensen P.
      • Mann J.F.
      • Nauck M.A.
      • LEADER Trial Investigators
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      ,
      • Mann J.F.E.
      • Ørsted D.D.
      • Brown-Frandsen K.
      • Marso S.P.
      • Poulter N.R.
      • Rasmussen S.
      • Tornøe K.
      • Zinman B.
      • Buse J.B.
      LEADER steering committee and investigators. liraglutide and renal outcomes in type 2 diabetes.
      ]
      9340Liraglutide vs Placebo3.864648.7NA−0.412.915.732.5NANA*NA17.992−1.2/−0.6
      SUSTAIN-6
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • Eliaschewitz F.G.
      • Jo´dar E.
      • Leiter L.A.
      • SUSTAIN-6 Investigators
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      3297Semaglutide vs Placebo2.264608.77.3−113.912.732.8NANA*NA23.692.8−2.1/−0.1
      CANVAS Program [
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • de Zeeuw D.
      • Fulcher G.
      • Erondu N.
      • CANVAS Program Collaborative Group
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ,
      • Perkovic V.
      • de Zeeuw D.
      • Mahaffey K.W.
      • Fulcher G.
      • Erondu N.
      • Shaw W.
      • Barrett T.D.
      • Weidner-Wells M.
      • Deng H.
      • Matthews D.R.
      • Neal B.
      Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials.
      ]
      10,142Canagliflozin vs Placebo3.963.463.38.2NA−0.613.735.732NA76.57.614.490−3.9/−1.4
      CARMELINA
      • Rosenstock J.
      • Perkovic V.
      • Johansen O.E.
      • Cooper M.E.
      • Kahn S.E.
      • Marx N.
      • CARMELINA Investigators
      • et al.
      Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial.
      6991Linagliptin vs Placebo2.266647.9ΝΑ−0.514.734.431.3NA54.5*38.92791.2−0.2/0
      DECLARE-TIMI-58
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • Mosenzon O.
      • Kato E.T.
      • Cahn A.
      • DECLARE–TIMI 58 Investigators
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      17,160Dapagliflozin vs Placebo4.264638.37.9−0.4116.932NA85.1NA10.189−2.7/−0.7
      ELIXA [
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • Dickstein K.
      • Gerstein H.C.
      • Køber L.V.
      • ELIXA Investigators
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      ,
      • Muskiet M.H.A.
      • Tonneijck L.
      • Huang Y.
      • Liu M.
      • Saremi A.
      • Heerspink H.J.L.
      • van Raalte D.H.
      Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial.
      ]
      6068Lixisenatide vs Placebo2.160707.77.1−0.39.324.830.2NA75.2*6.52277−0.8/NA
      HARMONY OUTCOMES
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • D'Agostino Sr, R.B.
      • Granger C.B.
      • Jones N.P.
      • Harmony Outcomes Committees and Investigators
      • et al.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomized placebo-controlled trial.
      9463Albigutide vs Placebo1.664708.7NA−0.514.117.232NA79*NA2087−0.7/−0.1
      CREDENCE
      • Perkovic V.
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      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      4401Canagliflozin vs Placebo2.663668.37.9−0.11624.331.3NA56.3*8814.896.8−2.4/−1.4
      EXSCEL [
      • Holman R.R.
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      Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      ,
      • Bethel M.A.
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      Microvascular and cardiovascular outcomes according to renal function in patients treated with once-weekly exenatide: insights from the EXSCEL trial.
      ]
      14,752Exenatide vs Placebo3.262628NA−0.51216.231.7NA76*NA16.286−1.6/0.3
      REWIND
      • Gerstein H.C.
      • Colhoun H.M.
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      • Conget I.
      • Cushman W.C.
      • Franek E.
      • Hancu N.
      • Hanefeld M.
      • Holt S.
      • Jansky P.
      • Keltai M.
      • Lanas F.
      • Leiter L.A.
      • Lopez-Jaramillo P.
      • Cardona Munoz E.G.
      • Pirags V.
      • Pogosova N.
      • Raubenheimer P.J.
      • Shaw J.E.
      • Sheu W.H.
      • Temelkova-Kurktschiev T
      • REWIND Investigators
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      9901Dulaglutide vs Placebo5.466547.2NA−0.610.512.932.30.9674.7*8.38.693.3−1.7/NA
      DAPA-HF
      • Petrie M.C.
      • Verma S.
      • Docherty K.F.
      • Inzucchi S.E.
      • Anand I.
      • Belohlávek J.
      • Böhm M.
      • Chiang C.E.
      • Chopra V.K.
      • de Boer R.A.
      • Desai A.S.
      • Diez M.
      • Drozdz J.
      • Dukát A.
      • Ge J.
      • Howlett J.
      • Katova T.
      • Kitakaze M.
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      • Merkely B.
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      • Vinh P.N.
      • Schou M.
      • Tereshchenko S.
      • Køber L.
      • Kosiborod M.N.
      • Langkilde A.M.
      • Martinez F.A.
      • Ponikowski P.
      • Sabatine M.S.
      • Sjöstrand M.
      • Solomon S.D.
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      • Bengtsson O.
      • Jhund P.S.
      • McMurray J.J.V.
      Effect of dapagliflozin on worsening heart failure and cardiovascular death in patients with heart failure with and without diabetes.
      4744Dapagliflozin vs Placebo1.566777.47.1−0.3ΝΑ9329.41.1862.8*NA10074.7−1.6/NA
      DAPA-CKD
      • Heerspink H.J.L.
      • Stefánsson B.V.
      • Correa-Rotter R.
      • Chertow G.M.
      • Greene T.
      • Hou F.F.
      • Mann J.F.E.
      • McMurray J.J.V.
      • Lindberg M.
      • Rossing P.
      • Sjöström C.D.
      • Toto R.D.
      • Langkilde A.M.
      • Wheeler D.C.
      • DAPA-CKD Trial Committees and Investigators
      dapagliflozin in patients with chronic kidney disease.
      4304Dapagliflozin vs Placebo2.461.9677.1ΝΑNANA15.429.6NA43NA10.8NANA/NA
      SCORED
      • Bhatt D.L.
      • Szarek M.
      • Pitt B.
      • Cannon C.P.
      • Leiter L.A.
      • McGuire D.K.
      • Lewis J.B.
      • Riddle M.C.
      • Inzucchi S.E.
      • Kosiborod M.N.
      • Cherney D.Z.I.
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      • Lapuerta P.
      • Steg PG
      • SCORED Investigators
      Sotagliflozin in patients with diabetes and chronic kidney disease.
      10,584Sotagliflozin vs Placebo1.369558.37.7−0.4NA2.531.7NA44.7*30.83188−2.5/−0.8
      VERTIS CV
      • Cannon C.P.
      • Pratley R.
      • Dagogo-Jack S.
      • Mancuso J.
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      • Masiukiewicz U.
      • Charbonnel B.
      • Frederich R.
      • Gallo S.
      • Cosentino F.
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      • Gantz I.
      • Terra S.G.
      • Cherney D.Z.I.
      • McGuire D.K.
      • Investigators VERTIS CV
      Cardiovascular outcomes with ertugliflozin in type 2 diabetes.
      8246Ertugliflozin vs Placebo3.564708.27.5−0.51319.132NA75.7*NA23.596−2.3/NA
      AMPLITUDE-O
      • Gerstein H.C.
      • Sattar N.
      • Rosenstock J.
      • Ramasundarahettige C.
      • Pratley R.
      • Lopes R.D.
      • Lam C.S.P.
      • Khurmi N.S.
      • Heenan L.
      • Del Prato S.
      • Dyal L.
      • Branch K.
      • AMPLITUDE-O Trial Investigators
      Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes.
      4076Efpeglenatide vs Placebo1.864.5678.97.5−1.415.420.432.7NA72.4*ΝΑ1891.3−1.5/−0.6
      OVERALL198,5323.3 ± 1.763.8 ± 2.764.7 ± 6.38 ± 0.57.4 ± 0.5−0.6 ± 0.311.2 ± 2.817.9 ± 14.531.2 ± 1.30.98± 0.1172.9 ± 11.315.6 ± 18.618.2 ± 15.284.4 ± 13.8−1.6 ± 1.2/ −0.5 ± 0.5
      BMI, body mass index; Cr, serum creatinine; CVR, cardiovascular risk; DBP, diastolic blood pressure; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HF, heart failure; HTN, hypertension; NA, not applicable; SBP, systolic blood pressure; y, years.
      *Trials in which MDRD formula was used for eGFR estimation.

      3.2 Outcome data

      Glucose-lowering reduced the composite renal outcome, on average, by 17% (95% CI, 8%−25%), and macroalbuminuria development by 25% (95% CI, 19%−32%); however, the heterogeneity among trials for both outcomes was high (Fig. 1). GLP1-agonists (HBA1c reduction, 0.57±0.27%) and SGLT2 inhibitors (HBA1c reduction, 0.42±0.12%), considered separately, compared to placebo, were associated with a significant reduction of the composite renal outcome, at variance with DPP4 inhibitors (HBA1c reduction, 0.33±0.11%) where no outcome change was observed (Fig. 2). Although either SGLT2 inhibitors or GLP1-agonists vs. placebo significantly reduced incident macroalbuminuria by 23% (95% CI, 16%−30%) and 36% (95% CI, 24%−47%), respectively, no analysis for DPP4 inhibitors was possible, because relevant outcome data (Fig. 2) were reported by only one trial [
      • Scirica B.M.
      • Bhatt D.L.
      • Braunwald E.
      • Steg P.G.
      • Davidson J.
      • Hirshberg B.
      • SAVOR-TIMI 53 Steering Committee and Investigators
      • et al.
      Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
      ].
      Fig. 1
      Fig. 1Risk reduction of renal outcomes following glucose-lowering by different classes of antihyperglycemic agents. CI, confidence interval; MH-RR, Mantel–Haenszel risk ratios; n, number.
      Fig. 2
      Fig. 2Effect of glucose-lowering by selected contemporary antihyperglycemic agents on renal outcomes. CI, confidence interval; MH-RR, Mantel–Haenszel risk ratios; n, number.

      3.3 Explanatory analyses

      3.3.1 Sensitivity analyses

      Considering the low risk of bias trials, the reduction of both outcomes by any pharmacological glucose-lowering intervention remained significant and consistent with the primary analysis results (Supplemental Table S4A). Further sensitivity analyses, restricted to contemporary drugs only (GLP1-agonists, SGLT2-inhibitors with or without DDP4-inhibitors), indicated that both outcomes remain reduced following glucose-lowering (Supplemental Table S4B and Table S4C). Restricting the analyses to trials with low heart failure prevalence (Supplemental Table S4D) or trials in which the MDRD equation estimated GFR (Supplemental Table S4E) outcome changes again remained significant.

      3.3.2 Subgroup analyses

      All subgroup analyses are presented in Supplemental Table S5. Glucose-lowering from baseline HBA1c levels of 8% or above, compared with the lower threshold, was not associated with a differential outcome incidence for both outcomes. When two different on-treatment targets of HBA1c were considered (i.e., 7% or 7.5%), the higher or, the lower achieved HBA1c target was not accompanied by a differential macroalbuminuria incidence. At the same time, the composite renal outcome was significantly reduced to a greater extent whenever a higher achieved HBA1c target was pursued. A less than 10-year baseline DM duration or a less than 10% fatal CV risk did not present any differential outcome incidence, compared with the respective higher thresholds for DM duration and baseline CV risk.

      3.3.3 Meta-regression analyses

      No proportional relationship between HBA1c lowering and the composite renal outcome reduction was observed before (Fig. 3A) or after adjustment for age, gender, DM duration, attained systolic/diastolic BP difference, and baseline fatal CV risk (Fig. 3B). The higher the glucose-lowering, the greater the reduction of macroalbuminuria before (Fig. 3C) and after adjustment for the same confounders (Fig. 3D). Of note, the multivariable analysis also revealed that for every 1 mmHg systolic BP reduction between treatment arms, there was a reduction of kidney function worsening by 2% (Fig. 3B). The relationship between outcome changes and systolic or diastolic attained BP difference is separately reported in Supplemental Figure S3, before and after adjustment for confounders.
      Fig. 3
      Fig. 3Meta-regression analyses for the proportional relationship between outcome risk change and extent of glucose-lowering in terms of glycohemoglobin reduction, before (panel A and C) and after (panel B and D) adjustment for confounders. CVR, cardiovascular risk; DBP, diastolic blood pressure; DM, type 2 diabetes mellitus; HBA1c, glycohemoglobin; SBP, systolic blood pressure; y, year.
      Fig. 3
      Fig. 3Meta-regression analyses for the proportional relationship between outcome risk change and extent of glucose-lowering in terms of glycohemoglobin reduction, before (panel A and C) and after (panel B and D) adjustment for confounders. CVR, cardiovascular risk; DBP, diastolic blood pressure; DM, type 2 diabetes mellitus; HBA1c, glycohemoglobin; SBP, systolic blood pressure; y, year.

      3.4 Publication bias

      The funnel plots (Supplemental Figure S4) for both outcomes were rather symmetrical; however, the trim-and-fill test indicated that two trials for each outcome might be imputed to achieve "statistical symmetry" (Supplemental Table S6). After imputation, the overall size effect for both outcomes remained significant and denied significant publication bias.

      4. Discussion

      The present meta-analysis, including 27 large outcome glucose-lowering RTCs with approximately 200,000 patients, demonstrated that 1) worsening of kidney function and incident macroalbuminuria were significantly reduced by glucose-lowering, 2) HBA1c reduction and macroalbuminuria development were associated with a concordant log-linear relationship, after adjustment for relevant confounders, including baseline CV risk and attained BP difference, while this relationship was not extended to the worsening of kidney function, 3) higher attained HBA1c levels in the more intense glucose-lowering group across a more or less conservative treatment target (i.e., less than 7% or 7.5%, respectively) were associated with a lower degree of kidney function worsening, and 4) both GLP-1 agonists and SGLP2 inhibitors reduced worsening of kidney function, and incident macroalbuminuria, while DPP4-inhibitors were not associated with renal outcome changes.
      We included earlier glucose-lowering RCTs and contemporary cardiovascular safety trials conducted following the regulatory authorities' guidelines for newer antidiabetic agents' approval to comprehensively address whether a reduction of distinct renal outcomes accompanies glucose-lowering or not. We also updated previous meta-analytical efforts focusing on renal effects of different contemporary antidiabetic drug classes. Our present analysis included various explanatory analyses based on different effect modifiers that have not been systematically considered elsewhere. Our finding that glucose-lowering reduces kidney function worsening was not observed in a previous analysis which included only 6 earlier RCTs [
      • Boussageon R.
      • Bejan-Angoulvant T.
      • Saadatian-Elahi M.
      • Lafont S.
      • Bergeonneau C.
      • Kassaï B.
      • Erpeldinger S.
      • Wright J.M.
      • Gueyffier F.
      • Cornu C.
      Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials.
      ]. At the same time, it is also hardly comparable to previous studies that have used a composite outcome of worsening kidney function and macroalbuminuria [
      • Hemmingsen B.
      • Lund S.S.
      • Gluud C.
      • Vaag A.
      • Almdal T.
      • Hemmingsen C.
      • Wetterslev J.
      Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials.
      ,
      • Hemmingsen B.
      • Lund S.S.
      • Gluud C.
      • Vaag A.
      • Almdal T.
      • Hemmingsen C.
      • Wetterslev J.
      Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus.
      ]. In 7 trials - all included in our analysis – Coca et al. [
      • Coca S.G.
      • Ismail-Beigi F.
      • Haq N.
      • Krumholz H.M.
      • Parikh C.R.
      Role of intensive glucose control in development of renal end points in type 2 diabetes mellitus: systematic review and meta-analysis intensive glucose control in type 2 diabetes.
      ] showed that macroalbuminuria incidence was reduced by 26% following glucose-lowering while doubling serum creatinine and end-stage renal disease remained unchanged whenever these outcomes were considered separately. In our meta-regression models, after adjustment for confounders, worsening kidney function was not associated with glucose-lowering. Every 1 mmHg systolic BP reduction, the composite renal outcome of kidney function deterioration was proportionally reduced by 16%. On the other hand, macroalbuminuria after adjustment was reduced by 27% for every 1% of attained HBA1c difference.
      Thus, we hypothesize that worsening kidney function is more strongly related to BP-lowering, at variance with the changes of macroalbuminuria that are mostly associated with glucose-lowering. However, subgroup analyses by different targets of the attained glucose-lowering indicated that worsening kidney function was more pronounced whenever lower glucose targets were achieved; this finding was not reproduced for incident macroalbuminuria.
      The finding that GLP-1 agonists and SGLP2-inhibitors reduce worsening kidney function and macroalbuminuria are without precedents [
      • Kristensen S.L.
      • Rørth R.
      • Jhund P.S.
      • Docherty K.F.
      • Sattar N.
      • Preiss D.
      • Køber L.
      • Petrie M.C.
      • McMurray J.J.V.
      Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.
      ,
      • Zelniker T.A.
      • Wiviott S.D.
      • Raz I.
      • Im K.
      • Goodrich E.L.
      • Furtado R.H.M.
      • Bonaca M.P.
      • Mosenzon O.
      • Kato E.T.
      • Cahn A.
      • Bhatt D.L.
      • Leiter L.A.
      • McGuire D.K.
      • Wilding J.P.H.
      • Sabatine M.S.
      Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus.
      ,
      • O'Hara D.V.
      • Parkhill T.R.
      • Badve S.V.
      • Jun M.
      • Jardine M.J.
      • Perkovic V.
      The effects of dipeptidyl peptidase-4 inhibitors on kidney outcomes.
      ]. Compared to the analysis by Kristensen et al. [
      • Kristensen S.L.
      • Rørth R.
      • Jhund P.S.
      • Docherty K.F.
      • Sattar N.
      • Preiss D.
      • Køber L.
      • Petrie M.C.
      • McMurray J.J.V.
      Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.
      ] focused on GLP-1 agonists, we included almost 15,000 additional patients. In addition, we reported unpublished data of the Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (HARMONY Outcomes) [
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • D'Agostino Sr, R.B.
      • Granger C.B.
      • Jones N.P.
      • Harmony Outcomes Committees and Investigators
      • et al.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomized placebo-controlled trial.
      ] and data of the Efpeglenatide and cardiovascular outcomes in type 2 diabetes (AMPLITUDE-O) published subsequently [
      • Gerstein H.C.
      • Sattar N.
      • Rosenstock J.
      • Ramasundarahettige C.
      • Pratley R.
      • Lopes R.D.
      • Lam C.S.P.
      • Khurmi N.S.
      • Heenan L.
      • Del Prato S.
      • Dyal L.
      • Branch K.
      • AMPLITUDE-O Trial Investigators
      Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes.
      ]. We also considered macroalbuminuria separately to neutralize the risk of duplicate outcome event reporting. Compared to the analysis by Zelniker et al. [
      • Zelniker T.A.
      • Wiviott S.D.
      • Raz I.
      • Im K.
      • Goodrich E.L.
      • Furtado R.H.M.
      • Bonaca M.P.
      • Mosenzon O.
      • Kato E.T.
      • Cahn A.
      • Bhatt D.L.
      • Leiter L.A.
      • McGuire D.K.
      • Wilding J.P.H.
      • Sabatine M.S.
      Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus.
      ] in which only 3 studies of SGLT2-inhibitors were available, we included five additional trials with almost 30,000 additional patients.
      Regarding the variable reduction of risk estimates for both outcomes, we cannot compare GLP1-agonists and SGLP2 inhibitors because these estimates emerged from different trial populations. Therefore, greater outcome reductions observed for SGLP2 inhibitors cannot be translated as higher protection than GLP1 agonists. Thus, only a head-to-head comparison between these antidiabetic drug classes can address whether one class provides better renal protection over the other. Furthermore, our study can hardly be compared with a previous meta-analysis that investigated the effect of DPP4 inhibitors on renal outcomes because renal outcomes were drawn from a synthesis of trials against placebo and other active comparators [
      • O'Hara D.V.
      • Parkhill T.R.
      • Badve S.V.
      • Jun M.
      • Jardine M.J.
      • Perkovic V.
      The effects of dipeptidyl peptidase-4 inhibitors on kidney outcomes.
      ]. However, when only DPP4 inhibitor trials vs. placebo were used, the development of end-stage renal disease or renal death was not reduced following treatment.
      The strengths of our meta-analysis are the following: a large number of trials included over almost 20 years, the stratification of glucose-lowering trials by drug class, and the adjustment of meta-regression analyses for important confounders. Regarding limitations, subgroup analyses have the disadvantage of including patients out of the range selected for the definition of predetermined strata. Our meta-regression analyses shall be seen with caution because this type of analysis is less sensitive than traditional meta-analyses. We acknowledge that individual-patient data analysis would have provided more refined results, but that was difficult due to no access to study-level data. Finally, most of the trials included in this meta-analysis were industry-sponsored; hence, averaged outcome risk estimates may be inflated [
      • Lundh A.
      • Lexchin J.
      • Mintzes B.
      • Schroll J.B.
      • Bero L.
      Industry sponsorship and research outcome.
      ].
      Our meta-analysis generates the hypothesis that worsening kidney function and macroalbuminuria incidence were reduced following glucose-lowering. However, a linear relationship may be valid only for macroalbuminuria. GLP1 agonists and SGLPT2 inhibitors, considered separately, are associated with protection against both worsening of kidney function and macroalbuminuria, while DPP4 inhibitors are not associated with renal event protection.

      Acknowledgments

      We thank Prof. John JV McMurray for providing unpublished data from the HARMONY OUTCOMES trial.

      Authors role

      C.Th. was responsible for the design of the study, preparation of the first draft of the manuscript; KC and DP have completed the systematic review and extracted data; DP and C.Th. conducted the meta-analyses; but all authors have substantially contributed to data interpretation, critical revision of the article for important intellectual content, and have given final approval of the version to be published.

      Conflict of interest

      None.

      Appendix. Supplementary materials

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