TABLE 2.
Summary of renal outcome-related trials using SGLT2i, GLP-1RAs, DPP-4i.
| Trial | Drug | Study design | Patient characteristics | Treatment dose (median duration) | Primary renal outcome | HR (95%CI), p-value |
|---|---|---|---|---|---|---|
| DAPA-CKD (Heerspink et al., 2020) | Dapagliflozin | randomized, double-blind, placebo-controlled study | with or without T2D who had an eGFR of 25–75 mL/min/1.73m2 and a UACR of 200–5000(N = 4744) | 10 mg once daily (2.4 years) | The first occurrence of any of the following: a decline of at least 50% in the eGFR (confirmed by a second Scr measurement after ≥28 days), the onset of ESKD (defined as maintenance dialysis for ≥28 days, kidney transplantation, or an eGFR of <15 mL/min/1.73 m2 confirmed by a second measurement after ≥28 days), or death from renal or cardiovascular causes | 0.61 (0.51–0.72), p < 0.001 |
| DIAMOND (Cherney et al., 2020) | Dapagliflozin | randomized, double-blind, placebo-controlled study | aged 18–75 years, with CKD, without T2D, with a 24 h urinary protein excretion >500–3500 mg, eGFR≥25 mL/min/1.73m2, and who were on stable RAS blockade (N = 58) | 10 mg/d (treat 6 weeks with 6-week washout in between) | The percentage change from baseline in 24 h proteinuria during dapagliflozin treatment relative to placebo | dapagliflozin versus placebo was −6·6 mL/min/1·73 m2 (−9·0 to −4·2; p < 0·0001) |
| CREDENCE (Perkovic et al., 2019) | Canagliflozin | randomized, double-blind, placebo-controlled study | aged ≥30, had T2DM, also required to have CKD (defined as an eGFR of 30 to <90 mL/min/1.73m2), UACR>300 to 5000(N = 4401) | 100 mg once daily (2.62 years) | A composite of ESKD, doubling of the Scr level from baseline (average of randomization and pre-randomization value) sustained for at least 30 days according to central laboratory assessment, or death from renal or cardiovascular disease | 0.70 (0.59–0.82), p = 0.00001 |
| EMPA-KIDNEY (Herrington et al., 2023) | Empagliflozin | randomized, double-blind, placebo-controlled study | with or without T2DM, eGFR of at least 20 but less than 45 mL/min/1.73m2, regardless of the level of albuminuria, or with an eGFR of at least 45 but less than 90 mL/min/1.73m2 with UACR of at least 200 at the screening visit (N = 6609) | 10 mg once daily (2 years) | The first occurrence of ESRD or death from cardiovascular causes; the initiation of maintenance dialysis or receipt of a kidney transplant, a sustained decrease in the eGFR to less than 10 mL/min/1.73m2, a sustained decrease from baseline in the eGFR of at least 40%, or death from renal causes | 0.72 (0.6–0.82), p < 0.001 |
| LEADER (Mann et al., 2017) prespecified secondary analysis | Liraglutide | randomized, double-blind, placebo-controlled study | aged ≥50, T2D with at least one cardiovascular coexisting condition or an age of 60 years or more with at least one cardiovascular risk factor (N = 9340) | 1.8 mg once daily (s.c.) (3.5 years) | The composite renal outcome consisted of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level and an eGFR of 45 or less mL/minute/1.73m2, the need for continuous RRT with no reversible cause of the renal disease, or death from renal disease | 0.78 (0.67–0.92), p = 0.003 |
| AMPLITUDE-O (Gerstein et al., 2021) | Efpeglenatide | randomized, double-blind, placebo-controlled study | aged ≥18, T2D, had a history of cardiovascular disease or ≥50 (men); ≥55 (women) and had kidney disease defined as an eGFR of 25.0–59.9 mL/min/1.73m2, and at least one additional cardiovascular risk factor (N = 4076) | 2 mg/week for 4 weeks, then 4 mg/week for 4 weeks, and then 6 mg/week until the end (1.81 years) | A composite renal outcome incident macroalbuminuria defined as a UACR>300, plus an increase in the UACR of ≥30% from baseline, a sustained decrease in the eGFR of ≥40% for ≥30 days, renal-replacement therapy for ≥90 days, or a sustained eGFR of <15 mL/min/1.73m2 for ≥30 days | 0.68 (0.57–0.79), p < 0.001 |
| FLOW (Rossing et al., 2023) | Semaglutide | phase 3b, randomized, double-blind, placebo-controlled study | aged ≥18 years or ≥20 years in Japan with pre-existing CKD with high albuminuria, low eGFR, T2D, HbA1c ≤ 10% (<86 mmol/mol) and on stable treatment with the maximum labelled or tolerated dose of a RAAS blocking agent (N = 3534) | 0.25 mg/week for 4 weeks, then 0.5 mg/week for 4 weeks, and then 1.0 mg/week until the end (s.c.) | Ongoing | Ongoing |
| GUARD (Yoon et al., 2017) | Gemigliptin | randomized, double-blind, placebo-controlled study | aged 19–75 years, diagnosed with T2D, and confirmed to have moderate (eGFR: 30–59 mL/min/1.73m2) to severe (eGFR: 15–29 mL/min/1.73m2) (N = 132) | 50 mg daily (12 weeks) | Changes in eGFR, UACR at Week 12 | gemigliptin group, the mean decrease in UACR was significant, MA (−41.9 mg/g creatinine, p = 0.03) and macroalbuminuria (−528.9 mg/g creatinine, p < 0.001) |
| GUARD-extension (Han et al., 2018) | Gemigliptin | randomized, double-blind, placebo-controlled study | Patients who had completed the 12-week study and consented to participate in the extended study were enrolled. (N = 102) | 50 mg of gemigliptin daily; 5 mg of linagliptin daily | Changes in eGFR, UACR at Week 52 | eGFR decreased by 3.86 mL/min/1.73m2 in the gemigliptin group and 1.85 mL/min/1.73m2 in the placebo/linagliptin group. The UACR did not change significantly in either group between baseline and week 52 |
UACR: urine albumin creatine ratio, CKD: chronic kidney disease, eGFR: estimated Glomerular Filtration Rate, ESKD: End-Stage Kidney Disease, T2D: Type 2 Diabetes, MA: microalbuminuria, RAS: renin angiotensin system, SCr: Serum Creatine rate, RRT: renal replacement therapy.