Table 1.

Large glucagon-like peptide-1 receptor antagonist clinical trials with renal outcomes or measures reported

Study, GLP-1RA, ClinicalTrials.gov Identifier	Population; subgroups	Follow-up or study duration	Change in HbA1c	Renal outcomes or measures	Summary of renal outcomes
ELIXA [39, 44] Lixisenatide (10 or 20 μg, once-daily inj.) vs. placebo NCT01147250	N = 5978 People with T2DM and a recent coronary artery event Normoalbuminuria = UACR < 30 mg/g, n = 4441; microalbuminuria =  UACR ≥ 30 to < 300 mg/g, n = 1148; and macroalbuminuria UACR =  ≥ 300 mg//g, n = 389 Percentage CVD: :100%	Median follow-up: 108 weeks	Average difference of − 0.27 percentage points (95% CI − 0.31 to − 0.22; p < 0.001) between lixisenatide and placebo across all visits	Renal measures: eGFR and UACR	Composite renal outcome:  HR 0.84 (95% CI 0.68–1.02; p = 0.083) Lixisenatide reduces progression of UACR in patients with macroalbuminuria  Placebo-adjusted LSM percentage change in UACR from baseline with lixisenatide: − 39.18% (95% CI − 68.53 to − 9.84; p = 0.0070) Lixisenatide was associated with a reduced risk of new-onset macroalbuminuria compared with placebo when adjusted for:  Baseline HbA1c: HR 0.808; 95% CI 0.660–0.991; p = 0.0404  Baseline and on-trial HbA1c: HR 0.815; 95% CI 0.665–0.999; p = 0.0491 No significant differences in eGFR decline were identified between treatment groups  LSM percentage change in eGFR stratified by baseline albuminuria status:   Normoalbuminuria LSM − 0.42 (SE 0.7; 95% CI  − 1.80 to 0.96; p = 0.5549)   Microalbuminuria LSM − 2.64 (SE 1.85; 95% CI − 6.26 to 0.98; p = 0.1530)   Macroalbuminuria LSM − 0.03 (SE 3.64; 95% CI − 7.19 to 7.14; p = 0.9944)
LIRA-RENAL [48] Liraglutide (1.8 mg, once-daily inj.) vs. placebo NCT01620489	N = 279 People with T2DM and moderate renal impairment (eGFR 30–59 ml/min/1.73 m2) Percentage CVD:  Not defined	26 weeks	Reduction of 1.05% [− 11.4 mmol/mol] in liraglutide at 26 weeks Reduction of − 0.38% [− 4.18 mmol/mol] in placebo at 26 weeks ETD of – 0.66% [− 7.25 mmol/mol] (95% CI − 0.90 to − 0.43 [− 9.82 to − 4.69]; p < 0.0001)	Renal measures: Changes in eGFR and UACR when compared to placebo at 26 weeks	At 26 weeks, no changes in renal function were observed when compared to placebo  eGFR ETR = 0.98 (95% CI 0.94–1.02; p = 0.36)  UACR ETR = 0.83 (95% CI 0.62–1.10; p = 0.19)
LEADER [26, 30] Liraglutide (1.8 mg, once-daily inj.) vs. placebo NCT01179048	N = 9340 People with T2DM Percentage CVD: 81%	Median follow-up: 3.84 years	Mean difference of − 0.40 percentage points (95% CI − 0.45 to − 0.34) between liraglutide and placebo at 36 months	Composite outcome: New onset macroalbuminuria, sustained serum creatinine duplication, initiation of renal replacement therapy, or renal death Individual outcome: New onset macroalbuminuria	The renal composite outcome, and persistent macroalbuminuria occurred less in the liraglutide group than in the placebo group Composite renal outcome:  HR 0.78 (95% CI 0.67–0.92; p = 0.003) Individual component:  Persistent macroalbuminuria: HR 0.74 (95% CI 0.60–0.91; p = 0.004)
SUSTAIN-6 [27] Semaglutide (0.5 or 1.0 mg, once-weekly inj.) vs. placebo NCT01720446	N = 3297 People with T2DM Percentage CVD:= 83%	Median follow-up: 104 weeks	Decrease from 8.7% [71.6 mmol/mol] at baseline to 7.6% [59.7 mmol/mol] at 104 weeks in 0.5 mg semaglutide group Mean difference (ETD) of − 0.7 percentage points [− 7.2 mmol/mol] (95% CI −  0.8 to − 0.5 [− 8.7 to − 5.7], p < 0.0001) between 0.5 mg semaglutide and placebo at 104 weeks Decrease from 8.7% [71.6 mmol/mol] at baseline to 7.3% [56.2 mmol/mol] at 104 weeks in 1.0 mg semaglutide group Mean difference (ETD) of − 1.1 percentage points [− 11.5 mmol/mol] (95% CI −  1.2 to −  0.9 [− 13.0 to − 10.0], p < 0.0001) between 1.0 mg semaglutide and placebo at 104 weeks	Composite outcome: New onset macroalbuminuria, doubling serum creatinine reaching eGFR < 45 ml/min/1.73 m2, initiation of renal replacement therapy, or renal death Individual outcome: Persistent albuminuria	The renal composite outcome and persistent macroalbuminuria occurred less in the semaglutide group than in the placebo group Composite renal outcome: HR 0.64 (95% CI 0.46–0.88; p = 0.005) Individual component: Persistent macroalbuminuria: HR 0.54 (95% CI 0.37–0.77; p = 0.001)
EXSCEL [40, 49] Exenatide (2 mg, once-weekly inj.) vs. placebo NCT01144338	N = 14,752 People with T2DM Percentage CVD: 73%	Median follow-up: 3.2 years	Difference of − 0.7 percentage points (95% CI − 0.7 to − 0.6) between exenatide and placebo at 6 months Overall LSM difference of − 0.53% (95% CI, − 0.57 to − 0.50, p < 0.001) in exenatide compared to placebo during the course of the trial	New macroalbuminuria Composite outcome 1: 40% eGFR decline, renal replacement, renal death Composite outcome 2: 40% eGFR decline, renal replacement, renal death, new albuminuria	Exenatide did not reduce the rate of new onset macroalbuminuria: HR 0.87 (95% CI 0.70–1.07; p = 0.19);  adjusted HR 0.84 (95% CI 0.67 to 1.04; p = 0.11) Neither renal composite was reduced with exenatide in unadjusted analyses Composite outcome 1: HR 0.88 (95% CI 0.74–1.05; p = 0.16); adjusted HR 0.87 (95% CI 0.73 to 1.04; p = 0.13) Composite outcome 2:  HR 0.88 (95% CI 0.76–1.01; p = 0.07); adjusted HR 0.85 (95% CI 0.74–0.98; p = 0.03)
AWARD-7 [33] Dulaglutide (0.75 or 1.5 mg, once-weekly inj.) vs. insulin glargine NCT01621178	N = 577 People with T2DM and moderate-to-severe CKD (stages III–IV) Percentage CVD: Not defined	26 and 52 weeks	LSM change from baseline to 26 weeks:  1.5 mg dulaglutide:  − 1.2% (SE 0.1) [− 13.0 mmol/mol (SE 1.4)]  0.75 mg dulaglutide: − 1.1% (SE 0.1) [− 12.2 mmol/mol (SE 1.3)]  Insulin glargine: − 1.1% (SE 0.1) [− 12.4 mmol/mol (SE 1.3)] LSM change from baseline to 52 weeks:  1.5 mg dulaglutide: − 1.1% (SE 0.1) [− 12.0 mmol/mol (SE 1.4)]  0.75 mg dulaglutide: − 1.1% (SE 0.1) [− 12.0 mmol/mol (SE 1.3)]  Insulin glargine: − 1.0% (SE 0.1) [− 10.9 mmol/mol (SE 1.3)] All p < 0.0001	Secondary outcomes: Difference in eGFR and UACR compared to insulin glargine at 52 weeks	eGFR was higher with dulaglutide than insulin glargine at 52 weeks  1.5 mg dulaglutide: 34.0 ml/min/1.73 m2 (SEM 0.7, p = 0.005)  0.75 mg dulaglutide: 33.8 ml/min/1.73 m2 (SEM 0.7, p = 0.009) insulin glargine: 31.3 ml/min/1.73 m2 (SEM 0.7) eGFR decline in UACR > 300 mg/g group  0.5 ml/min/1.73 m2 1.5 mg dulaglutide (vs. insulin glargine, p = 0.0223)  0.7 ml/min/1.73 m2 0.75 mg dulaglutide (vs. insulin glargine, p = 0.0272)  5.5 ml/min/1.7 3m2 insulin glargine (vs. baseline, p = 0.0004) No significant difference in UACR compared to insulin glargine  1.5 mg dulaglutide: LSM -22.5% (95% CI − 35.1 to − 7.5)  0.75 mg dulaglutide: LSM -20.1% (95% CI − 33.1 to − 4.6)   Insulin glargine: LSM − 13.0% (95% CI − 27.1 to 3.9)
HARMONY Outcomes [22] Albiglutide (30 or 50 mg, once-weekly inj.) vs. placebo NCT02465515	N = 9463 People with T2DM with CVD Percentage CVD: 100%	Median follow-up: 1.5 years	Difference of albiglutide compared to placebo at 8 months: − 0.63% (95% CI − 0.69 to − 0.58) Difference of albiglutide compared to placebo at 16 months: − 0.52% (95% CI − 0.58 to − 0.45)	Mean difference in eGFR between participants receiving albiglutide and those receiving placebo at 8 and 16 months	Albiglutide demonstrated a decrease in eGFR decline at 6 and 18 months when compared to placebo  − 1.11 ml/min/1.73 m2 (95% CI − 1.84 to − 0.39) at 8 months  − 0.43 ml/min/1.73 m2 (95% CI − 1.26 to 0.41) at 16 months
REWIND [29, 32] Dulaglutide (1.5 mg, once-weekly inj.) vs placebo NCT01394952	N = 9901 People with T2DM with CVD risk or event Macroalbuminuria: n = 791 (7.9%) Mean eGFR: 76.9 ml/min/1.73 m2 (SD 22.7) Baseline prevalence of albuminuria: n = 3467 (35.0%) Percentage CVD: 31%	Median follow-up: 5.4 years	LSM between-group difference of 0.61% (95% CI 0.58–0.65, p < 0.0001) between dulaglutide and placebo during the entire follow up period	Composite outcome: New onset macroalbuminuria, sustained decline of eGFR < 30%, or initiation of renal replacement therapy Individual outcome: New onset macroalbuminuria, sustained decline in eGFR (≥ 40% / ≥ 50%)	Dulaglutide associated with reduced composite renal outcomes when compared to placebo Composite renal outcome:  HR 0.85 (95% CI 0.77–0.93; p = 0.0004) Individual components:  New macroalbuminuria: HR 0.77 (95% CI 0.68–0.87; p < 0.0001)   Sustained decline in eGFR < 30%: HR 0.89 (95% CI 0.78–1.01; p = 0.066)  Chronic renal replacement therapy: HR 0.75 (95% CI 0.39–1.44; p = 0.39)

Studies listed in order of publication date. The PIONEER-6 cardiovascular outcome trial is not listed as defined renal measures or outcomes were not reported

CI Confidence interval, CVD cardiovascular disease, eGFR estimated glomerular filtration rate, ETD estimated treatment difference, ETR end of treatment response, GLP-1RA glucagon-like peptide-1 receptor antagonist, HbA1c glycated hemoglobin, HR hazard ratio, inj. injection, LSM least squares mean, SD standard deviation, SEM standard error of the mean, T2DM type 2 diabetes mellitus, UACR urinary-to-albumin ratio