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Kidney Outcomes With Glucagon-Like Peptide-1 Receptor Agonists in Patients With Type 2 Diabetes

  • Author Footnotes
    1 Equal contributors.
    Ofri Mosenzon
    Correspondence
    Address correspondence to Ofri Mosenzon, MD, MSc, The Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Ein Kerem Medical Center, P.O.B 12000, Jerusalem 9112001, Israel.
    Footnotes
    1 Equal contributors.
    Affiliations
    Faculty of Medicine, Hebrew University of Jerusalem, Israel; Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem, Israel
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  • Author Footnotes
    1 Equal contributors.
    Meir Schechter
    Footnotes
    1 Equal contributors.
    Affiliations
    Faculty of Medicine, Hebrew University of Jerusalem, Israel; Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem, Israel
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  • Gil Leibowitz
    Affiliations
    Faculty of Medicine, Hebrew University of Jerusalem, Israel; Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem, Israel
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  • Author Footnotes
    1 Equal contributors.
      Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are highly effective in reducing glycemia in patients with type 2 diabetes (T2D). These medications effectively reduce cardiovascular (CV) risk in patients with T2D and established CV disease or with multiple risk factors. In addition, treatment with GLP-1 RA may exert protective effects on the diabetic kidney. Herein, we summarize the findings regarding the kidney safety and efficacy of GLP-1 RAs in patients with T2D. We review data from GLP-1 RAs phase 3 kidney studies, CV outcome trials, as well as real-world evidence. The accumulating data show that treatment with GLP-1 RAs is safe, well-tolerated, and effective in patients with different levels of kidney dysfunction. Furthermore, CV outcome trials suggest that GLP-1 RAs reduce albuminuria and may attenuate the decline in kidney function over time. The ongoing FLOW trial studying the effects of semaglutide in patients with diabetic kidney disease is expected to shed light on the effects of GLP-1 RAs on kidney outcomes and clarify their role in the management of patients with T2D and kidney disease.

      Key words

      • Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are safe and effective in the treatment of patients with type 2 diabetes and estimated glomerular filtration rate > 15 mL/min/1.73 m2.
      • GLP-1 RAs reduce adverse cardiovascular outcomes, in patients with type 2 diabetes and diverse background cardiovascular risk and kidney function.
      • GLP-1 RAs reduce albuminuria and may have beneficial effects on other kidney outcomes.
      • The FLOW trial is the first long-term kidney outcome trial, studying the effects of the GLP-1 RA, semaglutide, on kidney outcomes; this study will shed light on the role of GLP-1 RAs in the treatment of diabetic kidney disease.
      The management of diabetic kidney disease (DKD) has dramatically evolved in the last 5 years. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been repeatedly shown to prevent the development and progression of DKD in various cardiovascular outcome trials (CVOTs) (EMPA-REG OUTCOME, CANVAS program, DECLARE-TIMI 58, VERTIS-CV, SCORED
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      • Wanner C.
      • Inzucchi S.E.
      • Lachin J.M.
      • et al.
      Empagliflozin and progression of kidney disease in type 2 diabetes.
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      • Mosenzon O.
      • Wiviott S.D.
      • Cahn A.
      • et al.
      Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial.
      • Cannon C.P.
      • Pratley R.
      • Dagogo-Jack S.
      • et al.
      Cardiovascular outcomes with Ertugliflozin in type 2 diabetes.
      • Bhatt D.L.
      • Szarek M.
      • Pitt B.
      • et al.
      Sotagliflozin in patients with diabetes and chronic kidney disease.
      ) and kidney outcomes trials (CREDENCE, DAPA-CKD
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ,
      • Heerspink H.J.L.
      • Stefánsson B.V.
      • Correa-Rotter R.
      • et al.
      Dapagliflozin in patients with chronic kidney disease.
      ). In light of these striking findings, the Kidney Disease: Improving Global Outcomes (KDIGO) 2020
      • de Boer I.H.
      • Caramori M.L.
      • Chan J.C.N.
      • et al.
      Executive summary of the 2020 KDIGO Diabetes Management in CKD Guideline: evidence-based advances in monitoring and treatment.
      and the American Diabetes Association 2021 Standards of Care recommend SGLT2i as the first-line treatment in patients with DKD.
      American Diabetes Association
      9. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes-2021.
      More recently, finerenone, a nonsteroidal selective mineralocorticoid receptor antagonist, has been shown to reduce adverse kidney outcomes in patients with DKD (FIDELIO-DKD).
      • Bakris G.L.
      • Agarwal R.
      • Chan J.C.
      • et al.
      Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial.
      ,
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      Thus, SGLT2i and probably finerenone together with angiotensin-converting-enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs)
      • Lewis E.J.
      • Hunsicker L.G.
      • Bain R.P.
      • Rohde R.D.
      The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.
      • Lewis E.J.
      • Hunsicker L.G.
      • Clarke W.R.
      • et al.
      Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.
      • Brenner B.M.
      • Cooper M.E.
      • de Zeeuw D.
      • et al.
      Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.
      have become the cornerstone in the treatment of DKD (Figs 1 and 2).
      Figure thumbnail gr1
      Figure 1The cornerstone treatments of diabetic kidney disease. Main cardiovascular and kidney outcome trials that emphasize populations with diabetic kidney disease (DKD). Lewis and colleagues NEJM 1993
      • Lewis E.J.
      • Hunsicker L.G.
      • Bain R.P.
      • Rohde R.D.
      The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.
      ; Lewis and colleagues NEJM 2001
      • Lewis E.J.
      • Hunsicker L.G.
      • Clarke W.R.
      • et al.
      Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.
      ; Brenner and colleagues NEJM 2001
      • Brenner B.M.
      • Cooper M.E.
      • de Zeeuw D.
      • et al.
      Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.
      ; Perkovic and colleagues NEJM 2019
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ; Heerspink and colleagues NEJM 2020
      • Heerspink H.J.L.
      • Stefánsson B.V.
      • Correa-Rotter R.
      • et al.
      Dapagliflozin in patients with chronic kidney disease.
      ; Bhatt and colleagues NEJM 2020
      • Bhatt D.L.
      • Szarek M.
      • Pitt B.
      • et al.
      Sotagliflozin in patients with diabetes and chronic kidney disease.
      ; Bakris and colleagues NEJM 2020
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      ; Pitt and colleagues NEJM 2021.
      • Pitt B.
      • Filippatos G.
      • Agarwal R.
      • et al.
      Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
      Abbreviation: NEJM, New England Journal of Medicine.
      Figure thumbnail gr2
      Figure 2KOTs in Patients with CKD and T2D: Baseline Characteristics According to KDIGO classification. Composite primary outcome of CREDENCE: new ESKD, doubling of the serum creatinine or death from renal or cardiovascular causes. FIDELIO-DKD: onset of kidney failure, a sustained decrease of eGFR ≥ 40% from baseline or renal death. FLOW: New ESKD, persistent ≥50% reduction in eGFR, renal death or CV death. Abbreviations: eGFR, estimated glomerular filtration rate; UACR, urinary albumin to creatinine ratio; KOTs, kidney outcome trials; CKD, chronic kidney disease; T2D, type 2 diabetes; KDIGO, Kidney Disease: Improving Global Outcomes; ESKD, end-stage kidney disease; CV, cardiovascular.
      Even under optimal treatment, however, the risk for adverse kidney outcomes remains high in patients with DKD. In the CREDENCE trial, patients treated with both ACEi/ARB and the SGLT2i canagliflozin had a primary outcome event rate of 43.2 per 1000 patient-years.
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      In the FIDELIO-DKD trial, patients were treated with finerenone on top of treatment with ACEi/ARB, and the primary outcome event rate was 75.9 per 1000 patient-years. Thus, even under best available treatment, the residual risk for progression of DKD and death is substantial.
      The KDIGO 2020 updated guidelines state that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are the preferred additional agents for the treatment of hyperglycemia in patients with type 2 diabetes (T2D) and DKD, as second-line treatment after initial treatment with lifestyle intervention, metformin, and SGLT2i.
      • de Boer I.H.
      • Caramori M.L.
      • Chan J.C.N.
      • et al.
      Executive summary of the 2020 KDIGO Diabetes Management in CKD Guideline: evidence-based advances in monitoring and treatment.
      This recommendation stems from CVOTs showing that treatment with GLP-1 RAs reduces the risk for cardiovascular morbidity and mortality, particularly in patients with established atherosclerotic cardiovascular disease (CVD), prevents the onset of macroalbuminuria, and possibly attenuates the decline in estimated glomerular filtration rate (eGFR). The American Diabetes Association 2021 Standards of Care state that while SGLT2is are the preferred first-line treatment in patients with albuminuric DKD; and in those without albuminuria, either GLP-1 RA or SGLT2i can be chosen as a first-line treatment.
      American Diabetes Association
      9. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes-2021.
      However, while the cardiovascular (CV) protective effects of GLP-1 RAs are widely accepted, their kidney protective effects are still under debate. Herein we summarize the data emerging from clinical trials on the kidney effects of GLP-1 RAs.

      Effects of GLP-1 RAs on Kidney Outcomes in Clinical Trials

      Kidney outcomes in clinical trials can be divided into three main categories (Fig 3): (1) surrogate markers, change in urinary albumin to creatinine ratio (UACR) or in UACR subcategories, or rate of change in kidney functions over time (eGFR ”slopes”); (2) intermediate outcomes, doubling of serum creatinine (57% decrease in eGFR) or categorical changes in eGFR (30%, 40%, 50%); and (3) “hard” kidney endpoints, which include end-stage kidney disease (ESKD), renal replacement therapy (RRT), and kidney death. While phase 2-3 trials often use surrogate markers or, at most, intermediate markers as their main kidney outcomes, analyses of real-world evidence (RWE) and CVOTs often use a composite endpoint consisting of different combinations of kidney outcomes, thereby increasing the statistical power of the trial and decreasing the number of the rare “harder” endpoints needed (Fig 3). The most commonly used composite kidney endpoints are (1) the “cardio-renal” outcome that includes reduction in eGFR, ESKD, RRT, kidney and CV death (often replaced by all-cause mortality [ACM] in RWE studies), and (2) the “renal specific” outcome that includes all the aforementioned outcomes, excluding CV death/ACM (Fig 3). For the purpose of this kidney-focused review, clinical trials with GLP-1 RAs will be classified into three different categories: (1) phase 2-3 clinical trials in patients with kidney dysfunction in which the primary outcome is based on glycemia; (2) RWE analyses comparing the incidence of adverse kidney events in patients that initiated different types of glucose-lowering agents; and (3) CVOTs that usually incorporate composite kidney outcomes as part of their secondary or exploratory analyses.
      Figure thumbnail gr3
      Figure 3Commonly used kidney outcomes in clinical trials. Abbreviations: RRT, renal replacement therapy; ESKD, end-stage kidney disease; eGFR, estimated glomerular filtration rate; CKD, chronic kidney disease.

       Effects of GLP-1 RAs in Phase 2-3 Clinical Trials in Patients With Kidney Dysfunction

      Several randomized controlled trials tested the safety and efficacy of different GLP-1 RAs in patients with moderate to severe kidney dysfunction as part of their phase 2-3 programs. These studies include HARMONY 8, comparing albiglutide vs sitagliptin
      • Leiter L.A.
      • Carr M.C.
      • Stewart M.
      • et al.
      Efficacy and safety of the once-weekly GLP-1 receptor agonist albiglutide versus sitagliptin in patients with type 2 diabetes and renal impairment: a randomized phase III study.
      ; LIRA-RENAL, comparing liraglutide vs placebo
      • Davies M.J.
      • Bain S.C.
      • Atkin S.L.
      • et al.
      Efficacy and safety of liraglutide versus placebo as Add-on to glucose-lowering therapy in patients with type 2 diabetes and moderate renal impairment (LIRA-RENAL): a randomized clinical trial.
      ; AWARD-7, comparing dulaglutide vs insulin glargine
      • Tuttle K.R.
      • Lakshmanan M.C.
      • Rayner B.
      • et al.
      Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial.
      ; and PIONEER 5, comparing oral semaglutide vs placebo.
      • Mosenzon O.
      • Blicher T.M.
      • Rosenlund S.
      • et al.
      Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.
      The study populations' baseline kidney eGFR and urinary albumin excretion varied between the trials (Table 1). The primary endpoint in all these studies was change in HbA1c. GLP-1 RAs were superior to placebo (liraglutide, oral semaglutide)
      • Davies M.J.
      • Bain S.C.
      • Atkin S.L.
      • et al.
      Efficacy and safety of liraglutide versus placebo as Add-on to glucose-lowering therapy in patients with type 2 diabetes and moderate renal impairment (LIRA-RENAL): a randomized clinical trial.
      ,
      • Mosenzon O.
      • Blicher T.M.
      • Rosenlund S.
      • et al.
      Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.
      or to sitagliptin (albiglutide),
      • Leiter L.A.
      • Carr M.C.
      • Stewart M.
      • et al.
      Efficacy and safety of the once-weekly GLP-1 receptor agonist albiglutide versus sitagliptin in patients with type 2 diabetes and renal impairment: a randomized phase III study.
      whereas the dulaglutide effect was similar to insulin glargine,
      • Tuttle K.R.
      • Lakshmanan M.C.
      • Rayner B.
      • et al.
      Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial.
      indicating that GLP-1 RAs are indeed effective in reducing glycemia in patients with kidney dysfunction. In addition, GLP-1 RAs reduced body weight with a variable magnitude in different trials. These studies assessed the effects of GLP-1 RAs on surrogate kidney markers, such as UACR; however, they were underpowered and too short (26 or 52 weeks) for determining treatment effect on hard kidney endpoints. HARMONY 8 and LIRA-RENAL showed that GLP-1 RAs are safe and have no deleterious effects on kidney function.
      • Leiter L.A.
      • Carr M.C.
      • Stewart M.
      • et al.
      Efficacy and safety of the once-weekly GLP-1 receptor agonist albiglutide versus sitagliptin in patients with type 2 diabetes and renal impairment: a randomized phase III study.
      ,
      • Davies M.J.
      • Bain S.C.
      • Atkin S.L.
      • et al.
      Efficacy and safety of liraglutide versus placebo as Add-on to glucose-lowering therapy in patients with type 2 diabetes and moderate renal impairment (LIRA-RENAL): a randomized clinical trial.
      Furthermore, PIONEER 5 showed that compared with placebo, treatment with oral semaglutide seemed to be associated with decreased albuminuria.
      • Mosenzon O.
      • Blicher T.M.
      • Rosenlund S.
      • et al.
      Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.
      Interestingly, in the AWARD 7 trial, despite similar glycemic control obtained with dulaglutide and glargine insulin treatment, patients on dulaglutide experienced a slower decline in eGFR.
      • Tuttle K.R.
      • Lakshmanan M.C.
      • Rayner B.
      • et al.
      Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial.
      Table 1Renal Baseline Characteristics and Main Outcomes of Phase 2-3 Trials With GLP-1 RA in Patients With DKD
      TrialPopulationInterventionResults
      NKey CriteriaBaseline eGFRBaseline UACRDrug vs ComparatorDurationPrimary OutcomeRenal Outcome
      HARMONY 8 (2014)
      • Leiter L.A.
      • Carr M.C.
      • Stewart M.
      • et al.
      Efficacy and safety of the once-weekly GLP-1 receptor agonist albiglutide versus sitagliptin in patients with type 2 diabetes and renal impairment: a randomized phase III study.
      507eGFR 15-<90 mL/min/1.73 m2.

      HbA1c 7-10%

      BMI 20-45 kg/m2

      Without clinically significant CVD
      ≥60 to ≤89 51.7%

      ≥30 to ≤59 41.0%

      ≥15 to ≤29 7.3% (mL/min/1.73 m2)
      -1:1

      Albiglutide 30-50 mg/w + placebo vs placebo + sitagliptin (eGFR 50-89
      eGFR values are in ml/min/1.73 m2. UACR values are in mg/g.
      100 mg; 30-50
      eGFR values are in ml/min/1.73 m2. UACR values are in mg/g.
      50 mg; <30
      eGFR values are in ml/min/1.73 m2. UACR values are in mg/g.
      25 mg)/d
      52-w
      The duration of the HARMONY 8 and the AWARD-7 trials was 52 wks, but the primary outcome was defined following 26 wks of treatment.
      HbA1c treatment difference at 26 w −0.32% (albiglutide vs sitagliptin)Safe, no clear differences
      LIRA-Renal (2016)
      • Davies M.J.
      • Bain S.C.
      • Atkin S.L.
      • et al.
      Efficacy and safety of liraglutide versus placebo as Add-on to glucose-lowering therapy in patients with type 2 diabetes and moderate renal impairment (LIRA-RENAL): a randomized clinical trial.
      279eGFR 30-59 mL/min/1.73 m2

      HbA1c 7-10%

      BMI 20-45 kg/m2
      Geometric mean (CV) 45.4 (0.23) mL/min/1.73 m2Geometric mean (CV) 55.5 (7.58) (liraglutide); 69.8 (5.75) (placebo)1:1 liraglutide 1.8 mg/day vs placebo26-wHbA1c treatment difference at 26 w −0.66% (liraglutide vs placebo)eGFR estimated treatment ratio at 26 w of 0.98 (liraglutide vs placebo)
      AWARD-7 (2018)
      • Tuttle K.R.
      • Lakshmanan M.C.
      • Rayner B.
      • et al.
      Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial.
      577eGFR 15-<60 mL/min/1.73 m2

      HbA1c 7.5-10.5%

      BMI 23-45 kg/m2

      Treated with insulin.
      Geometric mean (SD) 36.0 (0.5) mL/min/1.73 m2
      In the AWARD-7 trial, eGFR was measured using both cystatin-c and plasma creatinine. To allow comparisons with the other trials, we selected to show eGFR measures based on plasma creatinine levels. For the same reason, although follow-up data are available for 52 wks, the table shows the kidney outcomes after 26 wks.
      Median (IQR) 213.7 (45.8-868.0) (1.5 mg); 233.6 (36.7-946.5) (0.75 mg); 195.6 (30.1-1015.1) (insulin glargine)1:1:1 dulaglutide 1.5 mg/w vs dulaglutide 0.75 mg/w vs daily insulin glargine52-w
      The duration of the HARMONY 8 and the AWARD-7 trials was 52 wks, but the primary outcome was defined following 26 wks of treatment.
      Treatment difference in HbA1c at 26 w = −0.05% (1.5 mg) and 0.02% (0.75 mg) dulaglutide vs insulin glargineAt 26 w change from baseline eGFR: −1.9 (insulin glargine); −0.1 (dulaglutide 1.5 mg); −0.4 (dulaglutide 0.75 mg) ml/min/1.73 m2
      In the AWARD-7 trial, eGFR was measured using both cystatin-c and plasma creatinine. To allow comparisons with the other trials, we selected to show eGFR measures based on plasma creatinine levels. For the same reason, although follow-up data are available for 52 wks, the table shows the kidney outcomes after 26 wks.
      PIONEER 5 (2019)
      • Mosenzon O.
      • Blicher T.M.
      • Rosenlund S.
      • et al.
      Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.
      324eGFR 30-59 mL/min/1.73 m2

      HbA1c 7.0-9.5%
      Mean (SD) 48 (10) mL/min/1.73 m2Median (IQR) 16.0 (6.3-99.8)1:1

      Oral semaglutide 14 mg/d vs placebo
      26-wTreatment difference in HbA1c at 26 w = −0.8% oral semaglutide vs placeboMedian eGFR ratio (wk 31 to baseline) was 1.02 (oral semaglutide) and 1.00 (placebo).

      Geometric mean UACR ratio (w 26 to baseline) was 0.86 (oral semaglutide) and 1.19 (placebo)
      Abbreviations: BMI, body mass index; CVD, cardiovascular disease; DKD, diabetic kidney disease; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide-1 receptor agonist; IQR, interquartile range; SD, standard deviation; UACR, urinary albumin to creatinine ratio.
      eGFR values are in ml/min/1.73 m2. UACR values are in mg/g.
      The duration of the HARMONY 8 and the AWARD-7 trials was 52 wks, but the primary outcome was defined following 26 wks of treatment.
      In the AWARD-7 trial, eGFR was measured using both cystatin-c and plasma creatinine. To allow comparisons with the other trials, we selected to show eGFR measures based on plasma creatinine levels. For the same reason, although follow-up data are available for 52 wks, the table shows the kidney outcomes after 26 wks.
      Collectively, these studies demonstrate that treatment with GLP-1 RAs is safe and effective in improving glycemia and in reducing body weight over a wide range of baseline eGFR. They further suggest that at least certain drugs in this class may protect the diabetic kidney.

       GLP-1 RAs Effect on Kidney Outcomes in RWE Studies

      The risk for adverse kidney outcomes among patients treated with GLP-1 RAs in real-life setting was examined in a couple of large cohorts of T2D.
      • Pasternak B.
      • Wintzell V.
      • Eliasson B.
      • et al.
      Use of glucagon-like peptide 1 receptor agonists and risk of serious renal events: Scandinavian cohort study.
      ,
      • Xie Y.
      • Bowe B.
      • Gibson A.K.
      • et al.
      Comparative Effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas on risk of kidney outcomes: Emulation of a Target trial using health Care databases.
      Pasternak and colleagues reported findings from the Scandinavian registry, which compared the incidence of serious kidney events (RRT, death from kidney causes, and hospitalization for renal events) in 38,731 new users of GLP-1 RAs propensity-scored matched with initiators of dipeptidyl peptidase-4 inhibitors (DPP4i).
      • Pasternak B.
      • Wintzell V.
      • Eliasson B.
      • et al.
      Use of glucagon-like peptide 1 receptor agonists and risk of serious renal events: Scandinavian cohort study.
      DPP4i were used as the comparator drugs mainly because this class has minimal side effects and an excellent kidney safety profile,
      • Muskiet M.H.A.
      • Wheeler D.C.
      • Heerspink H.J.L.
      New pharmacological strategies for protecting kidney function in type 2 diabetes.
      which render them the treatment of choice in vulnerable patients. The incidence rate of serious kidney events was 4.8 vs 6.3 events per 1000 person-years among patients treated with GLP-1 RAs and DPP4i, respectively (hazard ratio [HR] = 0.76 [95% confidence interval (CI), 0.68-0.85]). Subgroup analysis showed no significant interaction across sex, age, and history of CVD subgroups. Importantly, the risk reduction in patients with a history of chronic kidney disease (CKD), treated with GLP-1 RA vs DPP4i, was even greater (HR = 0.54 [95% CI, 0.44-0.68] vs 0.82 [0.72-0.93], respectively; P value for interaction 0.002). A similar beneficial effect was observed in “on treatment” analysis (HR = 0.60 [95% CI, 0.49-0.74]). However, the follow-up period in this analysis was approximately 1 year in both groups.
      Xie and colleagues reported the U.S Veterans Affairs database of a composite cardio-renal outcome (eGFR decline >50%, ESKD, or ACM) in propensity-scored matched patients with T2D initiating treatment with GLP-1 RAs (n = 23,711), SGLT2is (n = 18,544), DPP-4i (n = 39,399) and sulfonylureas (SU) (n = 134,904).
      • Xie Y.
      • Bowe B.
      • Gibson A.K.
      • et al.
      Comparative Effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas on risk of kidney outcomes: Emulation of a Target trial using health Care databases.
      Risks were compared between all the treatment arms using survival models adjusted for predefined high-dimensional covariates. There were no significant differences in cardio-renal outcomes in patients that were treated with GLP-1 RAs compared with those treated with SGLT2i (HR = 0.95 [95% CI, 0.87-1.04]), whereas the risk was reduced with GLP-1 RAs compared with DPP4i and SU (HR = 0.79 [95% CI, 0.74-0.85]) and (HR = 0.72 [95% CI, 0.67-0.77]), respectively. Subgroup analyses according to eGFR categories, metformin use, CVD, body mass index, age, and per-protocol use further showed that treatment with GLP-1 RAs was superior to that with SU and DPP4i and similar to that with SGLT2i. The inherent limitation of this study is its observational and retrospective design, which might lead to the presence of confounding factors. In addition, the database of the Veterans Affairs health system contains mainly older white males, which limits the generalization of the findings to other populations. Nevertheless, the well-designed study protocol, the relative completeness of the Veterans Affairs database, and the four-arm design render the findings of this trial most valuable. Interestingly, in this study, kidney outcomes with GLP-1 RAs initiators were similar to those initiating SGLT2i, which are considered the most effective renoprotective glucose-lowering agents currently available. This finding should be interpreted with caution considering the competing endpoint of ACM which may have affected the results. The study reported the crude numbers of fatalities in the different treatment groups; however, a multivariate analysis of the treatment effect on the adjusted risk for ACM was not reported.

       Kidney Outcomes from GLP-1 RAs CVOTs

      In the available CVOTs, large heterogeneous populations of patients with T2D were followed for a relatively long period of time. This design enables one to assess the impact of different treatments, including GLP-1 RA on clinically significant CV and kidney outcomes.
      In 2008, the FDA required the pharmaceutical industry to perform CVOTs to confirm the CV safety of new glucose-lowering agents.

      FDA. Diabetes Mellitus -- Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. Available at: https://www.fda.gov/media/71297/download. Published 2008. Accessed November 23, 2019.

      Since then, eight GLP-1 RA CVOTs have been completed; seven reported their final results (ELIXA, LEADER, SUSTAIN 6, EXSCEL, HARMONY Outcomes, REWIND, PIONEER 6).
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      • Holman R.R.
      • Bethel M.A.
      • Mentz R.J.
      • et al.
      Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • et al.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      Another trial, the FREEDOM-CVO

      Intarcia Therapeutics, Inc. Intarcia Announces Successful Cardiovascular Safety Results in Phase 3 FREEDOM-CVO Trial for ITCA 650, an Investigational Therapy for Type 2 Diabetes. Available at: https://www.prnewswire.com/news-releases/intarcia-announces-successful-cardiovascular-safety-results-in-phase-3-freedom-cvo-trial-for-itca-650-an-investigational-therapy-for-type-2-diabetes-300264245.html. Published 2016. Accessed January 31, 2021.

      with exenatide administered in a mini-pump, was reported in a press release, achieving CV noninferiority; as the data have not yet been published, it will not be further discussed in this review. In addition, the AMPLITUDE-O trial comparing efpeglenatide (a once-weekly [OW] exendin-based GLP-1 RA) vs placebo in patients with T2D and high CV risk, with or without CKD, was recently completed; we await its results. Table 2 and Fig 4 compare the kidney data of the seven GLP-1 RA CVOTs that have been published while writing this review.
      Table 2Baseline Characteristics and Main Renal Outcomes of CVOTs With GLP-1 RA
      TrialPopulationInterventionCardiovascular and Renal Endpoints
      Key Inclusion Criteria# ptsBaseline Kidney Characteristic
      Units for baseline eGFR are in mL/min/1.73 m2 and for baseline UACR in mg/g.
      Mean eGFR (SD), Mean Geometric UACR
      βMean (SD) eGFR and Geometric mean UACR-unless otherwise specify.
      DrugDurationPrimary Outcome Overall and by eGFR Categories
      Units for baseline eGFR are in mL/min/1.73 m2 and for baseline UACR in mg/g.
      Primary Prespecified Renal Endpoint and Its Hierarchy Within the TrialPrimary Renal OutcomeChange in eGFRChange in UACR
      ELIXA, 2015Acute coronary event within 180 d.
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      6068
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      eGFR 76.0 (21.3)
      • Bentley-Lewis R.
      • Aguilar D.
      • Riddle M.C.
      • et al.
      Rationale, design, and baseline characteristics in evaluation of LIXisenatide in acute coronary syndrome, a long-term cardiovascular end point trial of lixisenatide versus placebo.


      Median UACR [CI]
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      ,
      • Muskiet M.H.A.
      • Tonneijck L.
      • Huang Y.
      • et al.
      Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial.
      10.54 [6.00-33.62]
      Lixisenatide 20 μg/d s.c.108 wks (entire trial, 25 mo)4-point MACE

      HR [95% CI] = 1.02 [0.89-1.17]

      By BL eGFR: NA
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      Percent change from baseline in UACR at wk 108. [2′ outcome. 3rd in order]
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      Placebo +34%

      Lixisenatide +24%

      P = 0.004
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      Similar in both treatment groups, across different renal subpopulations.
      • Muskiet M.H.A.
      • Tonneijck L.
      • Huang Y.
      • et al.
      Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial.
      LSM % change (lixisenatide vs placebo)

      −1.69% P = 0.7398 for UACR < 30 mg/g

      −21.10% P = 0.0502 for UACR 30-300 mg/g

      −39.18% P = 0.0070 for UACR > 300 mg/g
      • Muskiet M.H.A.
      • Tonneijck L.
      • Huang Y.
      • et al.
      Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial.
      LEADER, 20161. ≥50 YO and clinical evidence of CVD or CKD stage 3

      2. ≥60 YO and ≥CV risk factor
      9340eGFR 80.

      Geometric mean UACR ~21
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      ,
      • Mann J.F.E.
      • Ørsted D.D.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and renal outcomes in type 2 diabetes.
      Liraglutide 1.8 mg/d s.c.36 mo (median follow-up of entire trial = 3.84 y)
      • Mann J.F.E.
      • Ørsted D.D.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and renal outcomes in type 2 diabetes.
      3-point MACE

      HR [95% CI] = 0.87 [0.78-0.97]

      By BL eGFR:

      ≥60 HR [95% CI] = 0.94 [0.83-1.07]

      <60 HR [95% CI] = 0.69 [0.57-0.85] Pinteraction = 0.01
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      Time to occurrence of a composite outcome:

      1. New onset of persistent UACR > 300

      2. Serum cre∗2 with eGFR ≤ 45

      3. Continuous RRT

      4. Renal death [2′ outcome. Part of microvascular composite (4th), or alone (5th)].
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      1.5 (liraglutide) vs 1.9 (placebo) events per 100 patient-years

      HR 0.78; P = 0.003.
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      A decrease of −7.44 mL/min/1.73 m2 (liraglutide) −7.82 (placebo)

      P = 0.01
      • Mann J.F.E.
      • Ørsted D.D.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and renal outcomes in type 2 diabetes.
      Increase of 1.8 mg/g (liraglutide) and 6.3 mg/g (placebo)

      P < 0.001
      • Mann J.F.E.
      • Ørsted D.D.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and renal outcomes in type 2 diabetes.
      SUSTAIN-6, 20161. ≥50 YO and clinical evidence of CVD or CKD stage 3

      2. ≥60 YO and ≥CV risk factor
      3297eGFR 76.1 (26.5)

      Geometric mean UACR (RSD) 38.6 (26.5)
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Mann J.F.E.
      • Hansen T.
      • Idorn T.
      • et al.
      Effects of once-weekly subcutaneous semaglutide on kidney function and safety in patients with type 2 diabetes: a post-hoc analysis of the SUSTAIN 1-7 randomised controlled trials.
      Semaglutide 0.5 or 1.0 mg/wk s.c.104 wks3-point MACE

      HR [95% CI] = 0.74 [0.58-0.95]

      By BL eGFR:

      ≥60 HR [95% CI] = 0.67 [0.48-0.92]

      <60 HR [95% CI] = 0.84 [0.57-1.25] Pinteraction = 0.37
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      Time to occurrence of a composite outcome:

      1. New onset of persistent UACR > 300

      2. Serum cre∗2 with eGFR ≤ 45

      3. Continuous RRT

      4. Renal death
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      [2′ outcome. 4th in order.]
      1.86 (semaglutide) vs 3.06 (placebo) events per 100 patient-years

      HR 0.64; P = 0.005.
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      Decrease of -5.0 mL/min/1.73 m2 (semaglutide 0.5 mg); −4.1 (semaglutide 1.0 mg); −5.1 (placebo).
      • Mann J.F.E.
      • Hansen T.
      • Idorn T.
      • et al.
      Effects of once-weekly subcutaneous semaglutide on kidney function and safety in patients with type 2 diabetes: a post-hoc analysis of the SUSTAIN 1-7 randomised controlled trials.
      Compared with placebo estimated treatment ratios of 0.75 (semaglutide 0.5 mg) and 0.66 (semaglutide 1 mg)
      • Mann J.F.E.
      • Hansen T.
      • Idorn T.
      • et al.
      Effects of once-weekly subcutaneous semaglutide on kidney function and safety in patients with type 2 diabetes: a post-hoc analysis of the SUSTAIN 1-7 randomised controlled trials.
      EXSCEL, 2017Patients with (~73.1%) or without (26.9%) previous CV event14,752Median eGFR (Q1, Q3), 76.6 (61.3, 92.0)

      UACR, not measured
      • Holman R.R.
      • Bethel M.A.
      • Mentz R.J.
      • et al.
      Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      Exenatide 2 mg/wk s.c.Median follow-up of 3.2 y.
      • Holman R.R.
      • Bethel M.A.
      • Mentz R.J.
      • et al.
      Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      3-point MACE

      HR [95% CI] = 0.91 [0.83-1.00]

      By BL eGFR:

      ≥60 HR [95% CI] = 0.86 [0.77-0.97]

      <60 HR [95% CI] = 1.01 [0.86-1.19] Pinteraction = 0.12
      • Holman R.R.
      • Bethel M.A.
      • Mentz R.J.
      • et al.
      Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      Not predefined

      Post hoc analysis of: 1.40% decrease in eGFR

      2. Renal replacement

      3. Renal death

      4. New macroalbuminuria

      Only local lab. Results
      • Bethel M.A.
      • Mentz R.J.
      • Merrill P.
      • et al.
      Renal outcomes in the exenatide study of cardiovascular event lowering (EXSCEL).
      HR 0.88; P = 0.065

      Adjusted HR: 0.85; P = 0.027
      • Bethel M.A.
      • Mentz R.J.
      • Merrill P.
      • et al.
      Renal outcomes in the exenatide study of cardiovascular event lowering (EXSCEL).
      Exenatide vs placebo +0.21 [−0.27, 0.70] mL/min.1.73 m2 (LSM difference [95% CI])

      P = 0.39
      • Bethel M.A.
      • Mentz R.J.
      • Merrill P.
      • et al.
      Renal outcomes in the exenatide study of cardiovascular event lowering (EXSCEL).
      New macroalbuminuria in 2.2% (exenatide) vs 2.5% (placebo) P = 0.19
      • Bethel M.A.
      • Mentz R.J.
      • Merrill P.
      • et al.
      Renal outcomes in the exenatide study of cardiovascular event lowering (EXSCEL).
      Harmony

      Outcomes

      2018
      ≥40 YO and previous CVD
      • Green J.B.
      • Hernandez A.F.
      • D'Agostino R.B.
      • et al.
      Harmony outcomes: a randomized, double-blind, placebo-controlled trial of the effect of albiglutide on major cardiovascular events in patients with type 2 diabetes mellitus-Rationale, design, and baseline characteristics.
      9463eGFR 76.0 (25.5)

      UACR, not measured
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • et al.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
      Albiglutide 50 mg/wk s.c.Median duration of 1.6 y.3-point MACE

      HR [95% CI] = 0.78 [0.68-0.90]

      By BL eGFR:

      ≥90 HR [95% CI] = 0·79 [0.59-1.07]

      ≥60-<90 HR [95% CI] = 0.69 [0.56-0.85]

      <60 HR [95% CI] = 0.93 [0.73-1.20] Pinteraction = 0.19
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • et al.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
      Change in eGFR [Safety outcome. 5th in order]Compared with placebo, albiglutide group had a slight reduction in eGFR (ml/min/1.73 m2) at 8 months (−1.11, 95% CI −1·84 to −0·39) and 16 months (-0.43, 95%CI −1·26 to 0·41).
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • et al.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
      Not measured
      REWIND, 20191. ≥50-54 YO and previous CVD

      2. ≥55 YO and evidence of renal or vascular disease

      3. ≥60 and ≥ 2 risk factors.
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      9901eGFR 76.9 (22.7)

      Median UACR (IQR) 16.2 (6.19-61.0)

      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial.
      Dulaglutide 1.5 mg/wk s.c.Median follow-up of 5.4 y.3-point MACE + death from unknown cause

      HR [95% CI] = 0.88 [0.79-0.99]
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.


      By BL eGFR: NA
      1. New UACR > 30

      2. Sustained ≥30% decline in eGFR

      3. Chronic RRT.
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      [2′ outcome. Part of composite microvascular outcome, 1st in order]
      3.47 (semaglutide) vs 4.07 (placebo) events per 100 patient-years

      HR 0.85; P = 0.0004.
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      Overall between-group difference of change from baseline of 0.42 mL/min/1.73 m2

      P = 0.12
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial.
      Lower UACR values in dulaglutide than placebo (LSM proportional difference 0.82)

      P < 0.0001
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial.
      PIONEER-6, 20191. ≥50 YO and clinical evidence of CVD or CKD stage 3

      2. ≥60 YO and ≥CV risk factor
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      3183eGFR 74 (21)

      UACR, not measured
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      Semaglutide 14 mg/d oralThe median time was 15.9 mo.3-point MACE

      HR [95% CI] = 0.79 [0.57-1.11]

      By BL eGFR:

      ≥60 HR [95% CI] = 0.81 [0.54-1.22]

      <60 HR [95% CI] = 0.74 [0.41-1.33] Pinteraction = 0.80
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      Not predefined-Not reportedNot measured
      Abbreviations: BL, baseline; CI, confidence interval; CKD, chronic kidney disease; cre, creatinine; CV, cardiovascular; CVD, cardiovascular disease; CVOT, cardiovascular outcome trial; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HR, hazard ratio; LSM, least square mean; NA, not available; RSD, relative standard deviation; RRT, renal replacement therapy; SD, standard deviation; UACR, urinary albumin to creatinine ratio; YO, years old.
      Units for baseline eGFR are in mL/min/1.73 m2 and for baseline UACR in mg/g.
      βMean (SD) eGFR and Geometric mean UACR-unless otherwise specify.
      Figure thumbnail gr4
      Figure 4Baseline kidney characteristics of cardiovascular outcome trials (CVOTs) with GLP-1 RAs. (A) Baseline eGFR. In the AMPLITUDE-O trial, the only available categorization is baseline eGFR > 60 and eGFR < 60 mL/min/1.73 m2. (B) Baseline UACR. Unlike eGFR, UACR values are not normally distributed. When calculating baseline UACR as a continuous variable, some studies reported the median value (ELIXA, REWIND, and AMPLITUDE-O) while others reported the geometric mean value (LEADER and SUSTAIN-6). To distinguish between these values, median UACR is presented in black and geometric mean in blue. Abbreviations: eGFR, estimated glomerular filtration rate; UACR, urinary albumin to creatinine ratio; CVOT, cardiovascular outcome trial; GLP-1 RA, glucagon-like peptide-1 receptor agonist.

       Baseline CV and Kidney Characteristics in GLP-1 RA CVOTs

      The GLP-1 RA CVOTs recruited patients at risk for development of CVD or patients with established CVD. However, the extent of CV risk varied between trials. As an example, the ELIXA trial
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      included only patients that were within 180 days after an acute coronary event, whereas in the REWIND trial,
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      ~70% of the participants were without previous CVD. The HARMONY Outcomes, LEADER, SUSTAIN 6, EXSCEL, and PIONEER 6 trials
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      • Holman R.R.
      • Bethel M.A.
      • Mentz R.J.
      • et al.
      Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      ,
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      included mainly patients with established CVD. Of relevance, LEADER, SUSTAIN 6, PIONEER 6, and REWIND included patients with eGFR < 60 mL/min/1.73 m2 in the established CVD strata. The reported mean eGFR (median at EXSCEL) of the patients included in the different trials was similar, ~75-80 mL/min/1.73 m2
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      • Holman R.R.
      • Bethel M.A.
      • Mentz R.J.
      • et al.
      Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • et al.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
      ,
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Bentley-Lewis R.
      • Aguilar D.
      • Riddle M.C.
      • et al.
      Rationale, design, and baseline characteristics in evaluation of LIXisenatide in acute coronary syndrome, a long-term cardiovascular end point trial of lixisenatide versus placebo.
      ,
      • Mann J.F.E.
      • Hansen T.
      • Idorn T.
      • et al.
      Effects of once-weekly subcutaneous semaglutide on kidney function and safety in patients with type 2 diabetes: a post-hoc analysis of the SUSTAIN 1-7 randomised controlled trials.
      ,
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial.
      (Table 2, Fig 4). It should be noted that only a small number of patients in these trials had eGFR < 30 mL/min/1.73 m2 at baseline, rendering it impossible to extrapolate the described CV and kidney effects of GLP-1 RAs to patients with advanced, stage 4-5 CKD. Baseline UACR
      • Muskiet M.H.A.
      • Tonneijck L.
      • Huang Y.
      • et al.
      Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial.
      • Mann J.F.E.
      • Ørsted D.D.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and renal outcomes in type 2 diabetes.
      • Mann J.F.E.
      • Hansen T.
      • Idorn T.
      • et al.
      Effects of once-weekly subcutaneous semaglutide on kidney function and safety in patients with type 2 diabetes: a post-hoc analysis of the SUSTAIN 1-7 randomised controlled trials.
      ,
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial.
      of most participants was in the normoalbuminuric range, and up to ~15% of the participants had proteinuria (UACR >300 mg/dL; Table 2, Fig 4).
      Overall, most patients included in the GLP-1 RA CVOTs did not have kidney disease at baseline, which limits the ability to demonstrate beneficial effects of treatments on kidney outcomes within the timeframe of these trials. The length of exposure also varied between trials, ranging from a median of 5.4 years in REWIND
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      to 15.9 months in PIONEER 6
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      (Table 2). Finally, the degree of compliance with study drug also varied between trials, eg, 76% at EXSCEL
      • Holman R.R.
      • Bethel M.A.
      • Mentz R.J.
      • et al.
      Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      vs 86.5% at SUSTAIN 6.
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.

       Cardiovascular Outcomes in GLP-1 RA CVOTs–Overall and by Baseline Kidney Function

      Four CVOTs with GLP-1 RAs (LEADER, SUSTAIN 6, HARMONY Outcomes, and REWIND
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      ,
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ,
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • et al.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
      ,
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      ) consistently showed that GLP-1 RAs are superior to placebo with regard to the primary outcome of 3-point major adverse cardiovascular event (MACE): first occurrence of nonfatal myocardial infarction or nonfatal stroke or death from CV causes (in REWIND also death from unknown causes
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      ). Other trials achieved noninferiority but failed to show superiority (ELIXA, EXSCEL, and PIONEER 6
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      ,
      • Holman R.R.
      • Bethel M.A.
      • Mentz R.J.
      • et al.
      Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      ,
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ). The CVOTs also provided data on the CV efficacy and safety in patients with varying kidney functions at baseline (Table 2).
      In the ELIXA trial, the risk for 4-point MACE (3-point MACE and hospitalization for unstable angina) was similar with lixisenatide and placebo. Although the exact numbers were not reported, the between-arm differences did not seem to be affected by baseline eGFR.
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      In the LEADER trial, the beneficial effects of liraglutide on the composite CV outcome was greater in patients with baseline eGFR < 60 mL/min/1.73 m2 than in those with higher eGFR (HR = 0.69 [95% CI, 0.57-0.85] vs HR = 0.94 [95% CI, 0.83-1.07], respectively, Pinteraction = 0.01).
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      Similarly, Mann and colleagues
      • Mann J.F.E.
      • Fonseca V.
      • Mosenzon O.
      • et al.
      Effects of liraglutide versus placebo on cardiovascular events in patients with type 2 diabetes mellitus and chronic kidney disease.
      demonstrated greater efficacy of liraglutide in patients with eGFR < 60 mL/min/1.73 m2 than in those with higher eGFR in reduction of the expanded composite CV outcome (the 3-point MACE plus coronary revascularization or hospitalization for unstable angina pectoris or heart failure). There were, however, no differences in the effects of liraglutide on CV outcome according to baseline UACR categories.
      • Mann J.F.E.
      • Fonseca V.
      • Mosenzon O.
      • et al.
      Effects of liraglutide versus placebo on cardiovascular events in patients with type 2 diabetes mellitus and chronic kidney disease.
      In the LEADER trial, participants with CKD had more serious adverse events than patients without CKD in both treatment arms
      • Mann J.F.E.
      • Fonseca V.A.
      • Poulter N.R.
      • et al.
      Safety of liraglutide in type 2 diabetes and chronic kidney disease.
      ; however, serious adverse events leading to treatment discontinuation were less frequent in patients with CKD treated with liraglutide than in those treated with placebo.
      • Mann J.F.E.
      • Fonseca V.A.
      • Poulter N.R.
      • et al.
      Safety of liraglutide in type 2 diabetes and chronic kidney disease.
      In the SUSTAIN 6 trial, there was no interaction between reduction in the risk for MACE with semaglutide and stratification to baseline eGFR.
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      In a post hoc analysis of both the LEADER and SUSTAIN 6 trials, patients with microvascular complications (nephropathy, retinopathy, and/or neuropathy) had increased risk for 3-point MACE compared with patients without complications.
      • Verma S.
      • Bain S.C.
      • Honoré J.B.
      • et al.
      Impact of microvascular disease on cardiovascular outcomes in type 2 diabetes: results from the LEADER and SUSTAIN 6 clinical trials.
      However, the beneficial effects of liraglutide and semaglutide effects were similar in patients with or without microvascular complications, except for neuropathy in SUSTAIN 6.
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      In the EXSCEL trial, there were fewer cardiovascular events in patients that were treated with OW exenatide than with placebo; however, the difference did not reach statistical significance (P = 0.06). The trend for superiority was observed in the overall population and in patients with eGFR ≥ 60 mL/min/1.73 m2 but not in those with lower eGFR (Pinteraction = 0.12) (Table 2). In the HARMONY Outcomes trial, the primary endpoint was reported according to three baseline eGFR categories: <60 vs ≥ 60 to <90 vs ≥ 90 mL/min/1.73 m2; there was no interaction between baseline eGFR, treatment allocation and the primary outcome (Pinteraction = 0.186). To the best of our knowledge, in the REWIND trial,
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      the effect of dulaglutide on cardiovascular events in different eGFR subgroups was not reported. In PIONEER 6, which was a relatively small study of short duration, the semaglutide effect on MACE did not interact with baseline eGFR (Pinteraction = 0.80).
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      Finally, in a meta-analysis of GLP-1 RA CVOTs by Søren and colleagues,
      • Kristensen S.L.
      • Rørth R.
      • Jhund P.S.
      • et al.
      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.
      there was no difference in the primary CV outcome between patients with eGFR < 60 mL/min/1.73 m2 and those with higher eGFR.
      Collectively, these findings clearly show that the beneficial effects of GLP-1 RAs on cardiovascular outcomes are preserved irrespective of kidney function at baseline. Furthermore, it is possible that the beneficial effects are in fact greater in patients with kidney dysfunction, although this was inconsistent in different trials. Additional studies are required to test this hypothesis.

       Kidney Outcomes in the GLP-1 RA CVOTs

      Kidney outcomes in GLP-1 RA CVOTs can be generally divided into composite outcomes that include change in albuminuria (and more specifically new onset of persistent proteinuria; UACR >300 mg/dL) or composite kidney outcomes that are only eGFR based. Another issue to consider while comparing kidney outcomes in different trials is whether the analysis was based on predefined outcomes or a post hoc analysis, as well as the hierarchy of the kidney endpoint within the entire trial analysis (Table 2).
      In the ELIXA trial, lixisenatide reduced UACR in patients with microalbuminuria and macroalbuminuria, but not with normoalbuminuria.
      • Muskiet M.H.A.
      • Tonneijck L.
      • Huang Y.
      • et al.
      Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial.
      Lixisenatide reduced the risk for new-onset macroalbuminuria even after adjustment for baseline HbA1c, in-trial HbA1c, and for kidney risk factors; however, no significant differences in eGFR decline were identified between treatment arms in any UACR subgroup. In conclusion, lixisenatide reduced progression of UACR specifically in macroalbuminuric patients, but did not affect eGFR.
      • Muskiet M.H.A.
      • Tonneijck L.
      • Huang Y.
      • et al.
      Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial.
      In the LEADER trial, the composite kidney outcome was new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine levels, ESKD, or death due to kidney disease
      • Mann J.F.E.
      • Ørsted D.D.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and renal outcomes in type 2 diabetes.
      (Table 2). This outcome was lower with liraglutide vs placebo (HR = 0.78 [95% CI, 0.67-0.92]; P = 0.003), mainly due to reduction in new onset of persistent macroalbuminuria. The improvement in kidney outcome was persistent across baseline eGFR and UACR subgroups (all P values for interaction ≥0.20).
      • Mann J.F.E.
      • Ørsted D.D.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and renal outcomes in type 2 diabetes.
      The decline in eGFR was slightly slower in the liraglutide arm than in the placebo arm, and the difference was more pronounced in the subpopulation (~2000 patients) with a baseline eGFR of 30 to 59 mL/minute/1.73 m2. UACR increased less in the liraglutide arm, yielding a 17% lower UACR at 36 months than in placebo. The importance of UACR reduction was emphasized in a post-hoc analysis,
      • Persson F.
      • Bain S.C.
      • Mosenzon O.
      • et al.
      Changes in albuminuria predict cardiovascular and renal outcomes in type 2 diabetes: a post hoc analysis of the LEADER trial.
      which demonstrated that a 30% reduction in albuminuria during the first year of the trial was associated with fewer cardiovascular and kidney outcomes than in patients that had an increase in UACR during this period, irrespective of treatment arm. Moreover, in an exploratory mediation analysis, the reduction in UACR was indicated as a potentially significant mediator (29% and 33% mediation in two different analyses) for the improvement in the 3-point MACE demonstrated with liraglutide in the LEADER trial.
      • Buse J.B.
      • Bain S.C.
      • Mann J.F.E.
      • et al.
      Cardiovascular risk reduction with liraglutide: an exploratory mediation analysis of the LEADER trial.
      To summarize, in the LEADER trial, besides a reduction in UACR, there might be kidney protection with liraglutide in the vulnerable population of patients with CKD stage 3. The LEADER trial is the CVOT with GLP-1 RA that so far provides the largest amount of data regarding the impact of a GLP-1 RA on kidney function.
      The composite kidney outcome in SUSTAIN 6 was defined identically as in LEADER (Table 2). New or worsening nephropathy occurred less frequently in the semaglutide arm than in the placebo arm (HR = 0.64 [95% CI, 0.46-0.88]; P = 0.005). This difference, however, was driven by reduction in the incidence of persistent macroalbuminuria (HR = 0.54 [95% CI, 0.37-0.77]; P = 0.001), while no other component of the composite kidney outcome was significantly different with SC semaglutide.
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      The overall decline in eGFR during the trial was similar between semaglutide and placebo and did not differ between baseline kidney function subgroups. Interestingly, the decline in eGFR from baseline to week 16 was greater with semaglutide than with placebo (somewhat resembling the initial drop in eGFR with the initiation of ACEi, ARB, and SGLT2i).
      • Mann J.F.E.
      • Hansen T.
      • Idorn T.
      • et al.
      Effects of once-weekly subcutaneous semaglutide on kidney function and safety in patients with type 2 diabetes: a post-hoc analysis of the SUSTAIN 1-7 randomised controlled trials.
      Greater reductions in UACR were observed with semaglutide; however, UACR did not change between arms in those with normoalbuminuria at baseline.
      • Mann J.F.E.
      • Hansen T.
      • Idorn T.
      • et al.
      Effects of once-weekly subcutaneous semaglutide on kidney function and safety in patients with type 2 diabetes: a post-hoc analysis of the SUSTAIN 1-7 randomised controlled trials.
      In conclusion, in SUSTAIN 6, SC semaglutide OW was associated with initial reduction in eGFR that plateaued, reduction in UACR (except for patients with baseline normoalbuminuria), and no increase in the risk of kidney adverse events.
      In the EXSCEL trial, most laboratory tests were performed in local laboratories, rather than at a central laboratory
      • Holman R.R.
      • Bethel M.A.
      • Mentz R.J.
      • et al.
      Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      ; moreover, no composite kidney outcome was predefined in the trial protocol. These limitations curtail our ability to draw definitive conclusions regarding exenatide effects on kidney functions. In a post-hoc analysis, a composite kidney outcome of 40% reduction in eGFR, RRT, kidney death, or new onset macroalbuminuria did not show a significant difference between exenatide OW and placebo (HR = 0.88; 95% CI, 0.76-1.01, P = 0.065). However, after adjustment for multiple variables, the adjusted HR demonstrated a borderline significant risk reduction with exenatide OW vs placebo.
      • Bethel M.A.
      • Mentz R.J.
      • Merrill P.
      • et al.
      Renal outcomes in the exenatide study of cardiovascular event lowering (EXSCEL).
      Considering these methodological limitations, one may refer to these findings as supportive evidence, which mainly demonstrate the kidney safety of exenatide OW.
      In the HARMONY Outcomes trial, kidney impairment was predefined as an adverse event of special interest and was not different between treatment arms; there was a slight difference in mean eGFR between treatment arms at 8 and 16 months
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • et al.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
      (Table 2). This short trial (median follow-up 1.6 years), despite its somewhat surprising CV superiority results, can therefore only support the kidney safety of albiglutide.
      In the REWIND trial, the prespecified composite kidney outcome was part of the composite microvascular outcome and defined as the first occurrence of new macroalbuminuria, a sustained decline in eGFR of 30% or more from baseline, or chronic RRT. The improvement with dulaglutide vs placebo (HR = 0.85 [95% CI, 0.77-0.93]; P = 0.0004) was driven mainly by reduction in the incidence of new macroalbuminuria, with nonsignificant reduction in the other components. However, sensitivity analyses showed that sustained decline from baseline eGFR by at least 40% or 50% was reduced in dulaglutide-treated patients compared with controls. UACR was lower in the dulaglutide group than in the placebo group, while the overall difference in eGFR did not differ between treatment arms. Similar to EXSCEL, both blood and urine samples were reported by the investigators based on annual tests that were performed in local laboratories, rather than by a central laboratory. In summary, the kidney analysis of the REWIND trial further supports the beneficial effect of GLP-1 RA on kidney outcomes, mainly on reduction of macroalbuminuria, in a heterogeneous population which represents well the general T2D patient population, including those without established CVD.
      Finally, in the PIONEER 6 trial, no specific kidney outcome was predefined, and UACR was not tested.
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      Semaglutide did not affect the change in eGFR, and there was no increase in the risk for serious kidney adverse events. The overall kidney safety and possible efficacy of oral semaglutide will be further investigated as secondary endpoints in the ongoing postmarketing CVOT with oral semaglutide (the SOUL trial), which is expected to be larger and of longer duration (ClinicalTrial.gov NCT03914326
      A heart disease study of semaglutide in patients with type 2 diabetes - Full Text view - ClinicalTrials.gov.
      ).

       Metaanalysis of Kidney Outcomes From CVOTs With GLP-1 RAs

      Søren and colleagues' metanalysis of GLP-1 RAs CVOTs
      • Kristensen S.L.
      • Rørth R.
      • Jhund P.S.
      • et al.
      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.
      demonstrated a significant reduction in albuminuria-containing composite kidney outcomes with GLP-1 RAs. However, the albuminuria-independent composite kidney outcomes were only numerically reduced with GLP-1 RAs with larger heterogeneity between trials. In this analysis, HARMONY Outcomes and PIONEER 6 were excluded because of incomplete reporting of kidney outcomes. It should also be noted that the definition of the composite kidney outcome varied between trials. Despite these limitations, this analysis further supports the view that the beneficial effects of GLP-1 RAs on kidney outcomes are mainly due to reduction in urine albumin excretion.

       Kidney Outcome Trial With GLP-1 RA: The FLOW Trial and Other Ongoing Trials

      The FLOW trial is the only ongoing designated kidney outcome trial with a GLP-1 RA (ClinicalTrial.gov NCT03819153
      A research study to see how semaglutide works compared to placebo in people with type 2 diabetes and chronic kidney disease - Full text view - ClinicalTrials.gov.
      ; Table 3). This phase 3, double-blind study aims to randomize 3508 patients to treatment with SC semaglutide OW compared with placebo. Main inclusion criteria are diagnosis with T2D and kidney impairment defined as either one of the following: (1) eGFR ≥ 50 and ≤ 75 mL/min/1.73 m2 and UACR > 300 and < 5000 mg/g; (2) eGFR ≥ 25 and < 50 mL/min/1.73 m2 and UACR > 100 and < 5000 mg/g. Participants have to be treated with maximum labeled and/or tolerated doses of ACEi or ARB. Although being an event-driven trial, it is planned to last for at least 5 years or more. Started in June 2019, it is planned to be completed by August 2024. FLOW's primary composite outcome is defined as time to first occurrence of persistent eGFR decline ≥50%, reaching ESKD (ie, persistent eGFR < 15 mL/min/1.73 m2 or RRT) or death from kidney or CV causes. Secondary outcomes include eGFR slope, time to first occurrence of a MACE, or all-cause death.
      Table 3Ongoing Trials With GLP-1 RA and Prespecified Renal Outcomes
      TrialPopulationsInterventionEndpoints
      Key Inclusion Criteria# Patients (Estimated)DrugDurationPrimary OutcomePrimary Renal OutcomeHierarchy Renal Endpoint
      Kidney outcome trial
       Trial with semaglutideFLOW
      A research study to see how semaglutide works compared to placebo in people with type 2 diabetes and chronic kidney disease - Full text view - ClinicalTrials.gov.


      NCT03819153
      ≥18 YO (20 in Japan), T2D, HbA1c < 10%. Renal impairment: (1) eGFR 50-75 & UACR 300-5000

      (2) eGFR 25-50 & UACR 100-5000

      Treated with RAAS blockade
      3160Semaglutide 1.0 mg/wk s.c.3-5 y

      August 2024
      Time to event of a cardiorenal composite outcome (1) persistent ≥50% reduction in eGFR; (2) new ESKD (eGFR < 15 or chronic RRT); (3) renal death; (4) CV death

      Additional outcomes will investigate various renal endpoints: eGFR slope, change in UACR and more
      Primary outcome
      Cardiovascular and other outcome trials
       Trials with semaglutideSOUL
      A heart disease study of semaglutide in patients with type 2 diabetes - Full Text view - ClinicalTrials.gov.


      NCT03914326
      ≥50 Y.O, HbA1c 6.5%-10.0% and either ASCVD or CKD (eGFR < 60 mL/min/1.73 m2)9642Semaglutide 14 mg/day oral3.5-5 years

      July 2024
      Time to event, 3-P MACE (CV death, non-fatal MI, or non-fatal stroke)A composite cardiorenal outcome. Time to occurrence of: (1) CV death; (2) renal death; (3) persistent ≥50% reduction in eGFR; (4) new persistent eGFR<15 mL/min/1.73 m2; (5) initiation of chronic RRT

      Other renal outcomes include the components of the composite outcome and total eGFR slope
      Secondary outcome, 1st in order.
      SELECT
      Semaglutide effects on heart disease and stroke in patients with overweight or obesity - Full text view - ClinicalTrials.gov.


      NCT03574597
      ≥45 YO with BMI ≥ 27 kg/m2, HbA1c < 6.5%, and established CVD

      Without T1D or T2D
      17,500Semaglutide 2.4 mg/wk s.c.31-59 mo,

      September 2023
      Time to event, 3-P MACE (CV death, nonfatal MI, or nonfatal stroke)A composite renal outcome: (1) new persistent UACR > 300 mg/g;

      (2) persistent ≥50% reduction in eGFR;

      (3) new persistent eGFR < 15 mL/min/1.73 m2;

      (4) initiation of chronic RRT;

      (5) renal death;
      Secondary outcome, 12th in order
      FOCUS
      A research study to Look at How semaglutide compared to placebo affects diabetic eye disease in people with type 2 diabetes - Full text view - ClinicalTrials.gov.


      NCT03811561
      ≥18 YO, T2D, HbA1c 7-10%, and diabetic eye disease1500Semaglutide 1.0 mg/wk s.c.≤5 y

      November 2025
      Presence of at least 3 steps Early Treatment Diabetic Retinopathy Study (ETDRS) subject level progression--
       AMPLITUDE-O
      • Gerstein H.C.
      • Branch K.
      • Heenan L.
      • et al.
      Design and baseline characteristics of the AMPLITUDE-O cardiovascular outcomes trial of efpeglenatide, a weekly glucagon-like peptide-1 receptor agonist.


      NCT03496298
      ≥18 YO with CVD or ≥50men ≥55women YO with eGFR 25-59.9 mL/min/1.73 m2 and at least one additional CV risk factor

      HbA1c > 7%
      4076Efpeglenatide 4/6 mg/wk s.c.Up to 36 mo

      April 2021
      Time to event, 3-P MACE (CV death, nonfatal MI, or nonfatal stroke)A composite renal outcome: (1) new UACR > 300 mg/g + >30% increase in UACR; (2) sustained ≥40% decrease in eGFR; (3) new persistent eGFR < 15 mL/min/1.73 m2;

      (4) initiation of chronic RRT.
      Secondary outcome, 2nd in order.
       SURPASS-CVOT
      A study of Tirzepatide (LY3298176) compared with dulaglutide on major cardiovascular events in participants with type 2 diabetes - Full text view - ClinicalTrials.gov.


      NCT04255433
      ≥40 YO, T2D, HbA1c 7-10.5%, ASCVD, BMI ≥ 25 kg/m212,500Tirzepatide once a week vs dulaglutide once a wk s.c.≤54 mo

      October 2024
      Time to event, 3-P MACE (CV death, nonfatal MI, or nonfatal stroke)UACR change from baseline

      Additional renal outcomes: new or worsening nephropathy
      Secondary outcome, 8th in order
      Abbreviations: ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; cre, creatinine; CV, cardiovascular; CVD, cardiovascular disease; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; GLP-1 RA, glucagon-like receptor 1 agonists; MACE, major adverse cardiovascular event; MI, myocardial infarction; RAAS, renin-angiotensin-aldosterone system; RRT, renal replacement therapy; T2D, type 2 diabetes; UACR, urinary albumin to creatinine ratio; YO, years old.
      FLOW is the first GLP-1 RA kidney outcome trial and is expected to be a landmark trial in the field. It is planned to be a large cohort of high KDIGO-risk patients that will be followed for a long period. Importantly, participants' randomization is stratified by baseline use of SGLT2i; this will enable studying the effects of combined treatment with SGLT2i and GLP-1 RA on kidney outcomes.
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      ,
      • Ruilope L.M.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial.
      The inclusion of patients with UACR > 100 mg/g limits the trial's external validity to patients with nonproteinuric CKD.
      While the FLOW trial is the only designated kidney outcome trial with GLP-1 RA, there are a few additional ongoing large trials that will provide valuable data regarding the kidney effects of GLP-1 RA (Table 3). There are three trials with different formulations of semaglutide (Table 3): (1) the SOUL trial,
      A heart disease study of semaglutide in patients with type 2 diabetes - Full Text view - ClinicalTrials.gov.
      comparing oral semaglutide (14 mg/day) to placebo in patients with T2D and previous CVD. Its primary composite kidney outcome is cardio-renal; (2) the SELECT trial (NCT03574597
      Semaglutide effects on heart disease and stroke in patients with overweight or obesity - Full text view - ClinicalTrials.gov.
      ) comparing SC OW semaglutide (up to 2.4 mg) to placebo, in overweight or obese, nondiabetic patients with CVD; and (3) the FOCUS trial (NCT03811561
      A research study to Look at How semaglutide compared to placebo affects diabetic eye disease in people with type 2 diabetes - Full text view - ClinicalTrials.gov.
      ), a safety diabetic retinopathy trial assessing the retinal safety of semaglutide 1.0 mg QW vs placebo in patients with diabetic retinopathy at baseline. As diabetic nephropathy and retinopathy often coexist, the kidney outcomes of this trial might be of importance.
      The AMPLITUDE-O trial is the soon-to-be-published CVOT with OW efpeglenatide.
      • Gerstein H.C.
      • Branch K.
      • Heenan L.
      • et al.
      Design and baseline characteristics of the AMPLITUDE-O cardiovascular outcomes trial of efpeglenatide, a weekly glucagon-like peptide-1 receptor agonist.
      In this trial, the composite kidney outcome was placed high in the hierarchical testing order and its somewhat unique outcome comprising both new proteinuria UACR > 300 mg/g with >30% increase in UACR as part of a renal-specific outcome. Finally, the CVOT of the combined glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RA tirzepatide - SURPASS-CVOT (NCT04255433
      A study of Tirzepatide (LY3298176) compared with dulaglutide on major cardiovascular events in participants with type 2 diabetes - Full text view - ClinicalTrials.gov.
      ) is an active controlled trial compared with dulaglutide. However, kidney outcomes in this trial, as they are published so far, are not well defined and are mainly albuminuria-based outcomes.

      Conclusion

      The accumulating data from multiple studies, including early phase 2-3 trials, CVOTs, and RWE, clearly show that GLP-1 RAs are safe and effective in reducing glycemia and body weight, including in patients with kidney impairment, with eGFR as low as 15 mL/min/1.73 m2. This has important clinical implications as the therapeutic options for patients with eGFR < 30 mL/min/1.73 m2 are limited. These patients are often treated with insulin, which is associated with increased risk for hypoglycemia, potentially life-threatening in this vulnerable population. Data are lacking regarding the safety and efficacy of GLP-1 RAs in patients with ESKD treated with hemodialysis,
      • Yajima T.
      • Yajima K.
      • Hayashi M.
      • Takahashi H.
      • Yasuda K.
      Improved glycemic control with once-weekly dulaglutide in addition to insulin therapy in type 2 diabetes mellitus patients on hemodialysis evaluated by continuous glucose monitoring.
      and there are limited data on the effects in kidney transplant recipients.
      • Kukla A.
      • Hill J.
      • Merzkani M.
      • et al.
      The use of GLP1R agonists for the treatment of type 2 diabetes in kidney transplant recipients.
      ,
      • Singh P.
      • Pesavento T.E.
      • Washburn K.
      • Walsh D.
      • Meng S.
      Largest single-centre experience of dulaglutide for management of diabetes mellitus in solid organ transplant recipients.
      GLP-1 RAs have beneficial cardiovascular effects in patients with and without kidney dysfunction. The beneficial effects of GLP-1 RAs are similar and probably even greater in patients with DKD than in those without kidney disease. This might be explained by the fact that the cardiovascular risk of patients with kidney impairment is high; therefore, the impact of effective intervention treatments, such as GLP-1 RA, is more prominent.
      Finally, the evidence show that GLP-1 RAs have kidney-protective effects. The most consistent findings are reduction of new macroalbuminuria. The long-term effects on kidney function and the risk to develop ESKD have yet to be demonstrated. The FLOW trial will most likely be able to address this question regarding semaglutide.
      A research study to see how semaglutide works compared to placebo in people with type 2 diabetes and chronic kidney disease - Full text view - ClinicalTrials.gov.
      Further designated kidney outcome trials are required to clarify the impact of GLP-1 RAs on the natural history of DKD and their role in the therapeutic algorithm of DKD.
      With all data available for new agents for the treatment of CKD in patients with T2D, the place of GLP-1 RAs remains to be better defined. Simialr to the KDIGO approach,
      • de Boer I.H.
      • Caramori M.L.
      • Chan J.C.N.
      • et al.
      Executive summary of the 2020 KDIGO Diabetes Management in CKD Guideline: evidence-based advances in monitoring and treatment.
      we think that despite all the data presented in the review, the benefit of SGLT2i in patients with DKD still outweigh the benefits of GLP-1 RA in this population, and therefore, whenever possible, SGLT2i (with or without metformin) should be the first line of choice for glycemic control in patients with T2D and CKD. However, looking into the future, we envision that treatment of patients with DKD will combine several renoprotective agents that will be administered in a personalized manner. Similar to the treatment of heart failure with reduced ejection fraction, where five different groups of agents are often used together,
      • Bhatt D.L.
      • Verma S.
      • Braunwald E.
      The DAPA-HF trial: a Momentous Victory in the war against heart failure.
      we suggest that the “5 pillars of treatment of DKD” should include treatment of all risk factors (blood pressure, glycemic control, and so on), ACEi/ARBs, SGLT2i, mineralocorticoid receptor antagonist, and most likely, specifically if the FLOW trial fulfills the promise it holds, a GLP-1 RA (Fig 1).

      Acknowledgments

      No funding was received for this work. The authors are grateful to Ms. Rebecca Sprung and Prof. Erol Cerasi for critically editing and reviewing the manuscript.

      References

        • Zinman B.
        • Wanner C.
        • Lachin J.M.
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        N Engl J Med. 2015; 373: 2117-2128
        • Wanner C.
        • Inzucchi S.E.
        • Lachin J.M.
        • et al.
        Empagliflozin and progression of kidney disease in type 2 diabetes.
        N Engl J Med. 2016; 375: 323-334
        • Neal B.
        • Perkovic V.
        • Mahaffey K.W.
        • et al.
        Canagliflozin and cardiovascular and renal events in type 2 diabetes.
        N Engl J Med. 2017; 377: 644-657
        • Wiviott S.D.
        • Raz I.
        • Bonaca M.P.
        • et al.
        Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2019; 380: 347-357
        • Mosenzon O.
        • Wiviott S.D.
        • Cahn A.
        • et al.
        Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial.
        Lancet Diabetes Endocrinol. 2019; 7: 606-617
        • Cannon C.P.
        • Pratley R.
        • Dagogo-Jack S.
        • et al.
        Cardiovascular outcomes with Ertugliflozin in type 2 diabetes.
        N Engl J Med. 2020; 383: 1425-1435
        • Bhatt D.L.
        • Szarek M.
        • Pitt B.
        • et al.
        Sotagliflozin in patients with diabetes and chronic kidney disease.
        N Engl J Med. 2021; 384: 129-139
        • Perkovic V.
        • Jardine M.J.
        • Neal B.
        • et al.
        Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
        N Engl J Med. 2019; 380: 2295-2306
        • Heerspink H.J.L.
        • Stefánsson B.V.
        • Correa-Rotter R.
        • et al.
        Dapagliflozin in patients with chronic kidney disease.
        N Engl J Med. 2020; 383: 1436-1446
        • de Boer I.H.
        • Caramori M.L.
        • Chan J.C.N.
        • et al.
        Executive summary of the 2020 KDIGO Diabetes Management in CKD Guideline: evidence-based advances in monitoring and treatment.
        Kidney Int. 2020; 98: 839-848
        • American Diabetes Association
        9. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes-2021.
        Diabetes Care. 2021; 44: S111-S124
        • Bakris G.L.
        • Agarwal R.
        • Chan J.C.
        • et al.
        Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial.
        JAMA. 2015; 314: 884-894
        • Bakris G.L.
        • Agarwal R.
        • Anker S.D.
        • et al.
        Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
        N Engl J Med. 2020; 383: 2219-2229
        • Lewis E.J.
        • Hunsicker L.G.
        • Bain R.P.
        • Rohde R.D.
        The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.
        N Engl J Med. 1993; 329: 1456-1462
        • Lewis E.J.
        • Hunsicker L.G.
        • Clarke W.R.
        • et al.
        Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.
        N Engl J Med. 2001; 345: 851-860
        • Brenner B.M.
        • Cooper M.E.
        • de Zeeuw D.
        • et al.
        Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.
        N Engl J Med. 2001; 345: 861-869
        • Leiter L.A.
        • Carr M.C.
        • Stewart M.
        • et al.
        Efficacy and safety of the once-weekly GLP-1 receptor agonist albiglutide versus sitagliptin in patients with type 2 diabetes and renal impairment: a randomized phase III study.
        Diabetes Care. 2014; 37: 2723-2730
        • Davies M.J.
        • Bain S.C.
        • Atkin S.L.
        • et al.
        Efficacy and safety of liraglutide versus placebo as Add-on to glucose-lowering therapy in patients with type 2 diabetes and moderate renal impairment (LIRA-RENAL): a randomized clinical trial.
        Diabetes Care. 2016; 39: 222-230
        • Tuttle K.R.
        • Lakshmanan M.C.
        • Rayner B.
        • et al.
        Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial.
        Lancet Diabetes Endocrinol. 2018; 6: 605-617
        • Mosenzon O.
        • Blicher T.M.
        • Rosenlund S.
        • et al.
        Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.
        Lancet Diabetes Endocrinol. 2019; 7: 515-527
        • Pasternak B.
        • Wintzell V.
        • Eliasson B.
        • et al.
        Use of glucagon-like peptide 1 receptor agonists and risk of serious renal events: Scandinavian cohort study.
        Diabetes Care. 2020; 43: 1326-1335
        • Xie Y.
        • Bowe B.
        • Gibson A.K.
        • et al.
        Comparative Effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas on risk of kidney outcomes: Emulation of a Target trial using health Care databases.
        Diabetes Care. 2020; 43: 2859-2869
        • Muskiet M.H.A.
        • Wheeler D.C.
        • Heerspink H.J.L.
        New pharmacological strategies for protecting kidney function in type 2 diabetes.
        Lancet Diabetes Endocrinol. 2019; 7: 397-412
      1. FDA. Diabetes Mellitus -- Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. Available at: https://www.fda.gov/media/71297/download. Published 2008. Accessed November 23, 2019.

        • Pfeffer M.A.
        • Claggett B.
        • Diaz R.
        • et al.
        Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
        N Engl J Med. 2015; 373: 2247-2257
        • Marso S.P.
        • Daniels G.H.
        • Brown-Frandsen K.
        • et al.
        Liraglutide and cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2016; 375: 311-322
        • Marso S.P.
        • Bain S.C.
        • Consoli A.
        • et al.
        Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
        N Engl J Med. 2016; 375: 1834-1844
        • Holman R.R.
        • Bethel M.A.
        • Mentz R.J.
        • et al.
        Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2017; 377: 1228-1239
        • Hernandez A.F.
        • Green J.B.
        • Janmohamed S.
        • et al.
        Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
        Lancet. 2018; 392: 1519-1529
        • Gerstein H.C.
        • Colhoun H.M.
        • Dagenais G.R.
        • et al.
        Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
        Lancet. 2019; 394: 121-130
        • Husain M.
        • Birkenfeld A.L.
        • Donsmark M.
        • et al.
        Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
        N Engl J Med. 2019; 381: 841-851
      2. Intarcia Therapeutics, Inc. Intarcia Announces Successful Cardiovascular Safety Results in Phase 3 FREEDOM-CVO Trial for ITCA 650, an Investigational Therapy for Type 2 Diabetes. Available at: https://www.prnewswire.com/news-releases/intarcia-announces-successful-cardiovascular-safety-results-in-phase-3-freedom-cvo-trial-for-itca-650-an-investigational-therapy-for-type-2-diabetes-300264245.html. Published 2016. Accessed January 31, 2021.

        • Bentley-Lewis R.
        • Aguilar D.
        • Riddle M.C.
        • et al.
        Rationale, design, and baseline characteristics in evaluation of LIXisenatide in acute coronary syndrome, a long-term cardiovascular end point trial of lixisenatide versus placebo.
        Am Heart J. 2015; 169: 631-638.e7
        • Muskiet M.H.A.
        • Tonneijck L.
        • Huang Y.
        • et al.
        Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial.
        Lancet Diabetes Endocrinol. 2018; 6: 859-869
        • Mann J.F.E.
        • Ørsted D.D.
        • Brown-Frandsen K.
        • et al.
        Liraglutide and renal outcomes in type 2 diabetes.
        N Engl J Med. 2017; 377: 839-848
        • Mann J.F.E.
        • Hansen T.
        • Idorn T.
        • et al.
        Effects of once-weekly subcutaneous semaglutide on kidney function and safety in patients with type 2 diabetes: a post-hoc analysis of the SUSTAIN 1-7 randomised controlled trials.
        Lancet Diabetes Endocrinol. 2020; 8: 880-893
        • Bethel M.A.
        • Mentz R.J.
        • Merrill P.
        • et al.
        Renal outcomes in the exenatide study of cardiovascular event lowering (EXSCEL).
        Diabetes. 2018; 67: 522
        • Green J.B.
        • Hernandez A.F.
        • D'Agostino R.B.
        • et al.
        Harmony outcomes: a randomized, double-blind, placebo-controlled trial of the effect of albiglutide on major cardiovascular events in patients with type 2 diabetes mellitus-Rationale, design, and baseline characteristics.
        Am Heart J. 2018; 203: 30-38
        • Gerstein H.C.
        • Colhoun H.M.
        • Dagenais G.R.
        • et al.
        Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial.
        Lancet. 2019; 394: 131-138
        • Mann J.F.E.
        • Fonseca V.
        • Mosenzon O.
        • et al.
        Effects of liraglutide versus placebo on cardiovascular events in patients with type 2 diabetes mellitus and chronic kidney disease.
        Circulation. 2018; 138: 2908-2918
        • Mann J.F.E.
        • Fonseca V.A.
        • Poulter N.R.
        • et al.
        Safety of liraglutide in type 2 diabetes and chronic kidney disease.
        Clin J Am Soc Nephrol. 2020; 15: 465-473
        • Verma S.
        • Bain S.C.
        • Honoré J.B.
        • et al.
        Impact of microvascular disease on cardiovascular outcomes in type 2 diabetes: results from the LEADER and SUSTAIN 6 clinical trials.
        Diabetes Obes Metab. 2020; 22: 2193-2198
        • Kristensen S.L.
        • Rørth R.
        • Jhund P.S.
        • et al.
        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.
        Lancet Diabetes Endocrinol. 2019; 7: 776-785
        • Persson F.
        • Bain S.C.
        • Mosenzon O.
        • et al.
        Changes in albuminuria predict cardiovascular and renal outcomes in type 2 diabetes: a post hoc analysis of the LEADER trial.
        Diabetes Care January. 2021; 44: 1020-1026
        • Buse J.B.
        • Bain S.C.
        • Mann J.F.E.
        • et al.
        Cardiovascular risk reduction with liraglutide: an exploratory mediation analysis of the LEADER trial.
        Diabetes Care. 2020; 43: 1546-1552
      3. A heart disease study of semaglutide in patients with type 2 diabetes - Full Text view - ClinicalTrials.gov.
        (Available at:)
        https://clinicaltrials.gov/ct2/show/NCT03914326
        Date accessed: November 23, 2019
      4. A research study to see how semaglutide works compared to placebo in people with type 2 diabetes and chronic kidney disease - Full text view - ClinicalTrials.gov.
        (Available at:)
      5. Semaglutide effects on heart disease and stroke in patients with overweight or obesity - Full text view - ClinicalTrials.gov.
        (Available at:)
      6. A research study to Look at How semaglutide compared to placebo affects diabetic eye disease in people with type 2 diabetes - Full text view - ClinicalTrials.gov.
        (Available at:)
        • Gerstein H.C.
        • Branch K.
        • Heenan L.
        • et al.
        Design and baseline characteristics of the AMPLITUDE-O cardiovascular outcomes trial of efpeglenatide, a weekly glucagon-like peptide-1 receptor agonist.
        Diabetes Obes Metab. 2020; 23: 318-323
      7. A study of Tirzepatide (LY3298176) compared with dulaglutide on major cardiovascular events in participants with type 2 diabetes - Full text view - ClinicalTrials.gov.
        (Available at:)
        • Ruilope L.M.
        • Agarwal R.
        • Anker S.D.
        • et al.
        Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial.
        Am J Nephrol. 2019; 50: 345-356
        • Yajima T.
        • Yajima K.
        • Hayashi M.
        • Takahashi H.
        • Yasuda K.
        Improved glycemic control with once-weekly dulaglutide in addition to insulin therapy in type 2 diabetes mellitus patients on hemodialysis evaluated by continuous glucose monitoring.
        J Diabetes Complicat. 2018; 32: 310-315
        • Kukla A.
        • Hill J.
        • Merzkani M.
        • et al.
        The use of GLP1R agonists for the treatment of type 2 diabetes in kidney transplant recipients.
        Transpl Direct. 2020; 6: e524
        • Singh P.
        • Pesavento T.E.
        • Washburn K.
        • Walsh D.
        • Meng S.
        Largest single-centre experience of dulaglutide for management of diabetes mellitus in solid organ transplant recipients.
        Diabetes Obes Metab. 2019; 21: 1061-1065
        • Bhatt D.L.
        • Verma S.
        • Braunwald E.
        The DAPA-HF trial: a Momentous Victory in the war against heart failure.
        Cell Metab. 2019; 30: 847-849
        • Pitt B.
        • Filippatos G.
        • Agarwal R.
        • et al.
        Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
        N Engl J Med. 2021; 385: 2252-2263