Table 2.
Summary of Selected Large Clinical Trials with SGLT2i, DPP-4 Inhibitors, PKCβ Inhibitors, Anti-inflammatory Agents, Mineralocorticoid Receptor Antagonists, and Endothelin Receptor Antagonists
| Study | Treatment Arms | Duration | Patient Cohort | Outcome |
|---|---|---|---|---|
| SGLT2i | ||||
| Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) NCT01131676 | Empagliflozin 10 mg or 25 mg daily vs. placebo | Up to 4.6 years | 7020 T2D patients with established CV complications (≥18 years) | Primary: 14% reduction in 3-point MACE pooled from 10 mg and 25 mg empagliflozin doses Secondary: 35% reduction in hospitalization for HF, 39% reduction in the composite renal endpoint (new macroalbuminuria, doubling of serum creatinine and GFR ≤45, renal replacement therapy, renal death) |
| Canagliflozin Cardiovascular Assessment Study (CANVAS Program) NCT01032629 | Canagliflozin 100 mg or 300 mg daily vs. placebo | 3.6 years | 10,142 T2D patients with established vascular complications or ≥2 CV risk factors (>30 years) | Primary: 14% reduction in 3-point MACE Secondary: 27% reduction in progression of albuminuria, 70% increase in regression of albuminuria, 40% reduction in the composite renal endpoint (40% reduction in eGFR, renal replacement therapy, renal death) |
| Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy (CREDENCE) NCT02065791 | Canagliflozin 100 mg daily vs. placebo | 2.6 years | 4401 T2D patients with Stage 2 or 3 CKD and macroalbuminuria and on ACEi/ARB | Primary: 30% reduction in ESKD, S-creatinine doubling, renal/CV death Secondary: 20% reduction in MACE; 39% reduction in hospitalization for CHF; 34% reduction in composite renal endpoint (ESKD, doubling of serum Cr, renal death) |
| Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI 58) NCT01730534 | Dapagliflozin 10 mg vs. placebo | 4.2 years | 17,160 T2D patients with high risk for CV events | Primary: No reduction in MACE; 17% reduction in CV death, hospitalization resulting from HF Secondary: 24% reduction in renal composite endpoint (≥40% decrease in eGFR to <60 and/or ESRD and/or renal or CV death |
| DAPA-CKD NCT02065791 | Dapagliflozin vs. placebo | Ongoing | T2D with DKD or nondiabetic kidney disease with eGFR ≥25 to ≤75 and mL/min/1.73 m2 UACR ≥200 to ≤5000 mg/g | Ongoing: Kidney composite endpoint (≥50% sustained decline in eGFR, ESKD, or kidney or CVD death) |
| EMPA-KIDNEY (NCT03594110) | Empagliflozin vs. placebo | Ongoing | DKD (T2D or T1D) or nondiabetic kidney disease with eGFR ≥20 to <45 mL/min/1.73 m2OR eGFR ≥45 to <90 mL/min/1.73 m2 with UACR ≥200 mg/g | Ongoing: Composite outcome of time to first occurrence of kidney disease progression (ESKD, sustained decline in eGFR to <10 mL/min/1.73 m2, ESKD, kidney death, or a sustained decline of ≥40% in eGFR from randomization), or cardiovascular death |
| DPP-4 Inhibitors | ||||
| The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) NCT00790205 | Sitagliptin 100 mg vs. placebo | 3 years | 14,671 T2D patients with established CV disease (≥50 years) | Primary: No reduction in 4-point MACE, hospitalization for unstable angina |
| The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus Thrombolysis in Myocardial Infarction (SAVOR-TIMI 53) NCT01107886 | Saxagliptin 5 mg vs. placebo | 2.1 years | 16,492 T2D patients with established CV disease or multiple risk factors for CV disease | Primary: No reduction in 3-point MACE |
| Cardiovascular Outcomes Study of Alogliptin in Patients with Type 2 Diabetes and Acute Coronary Syndrome (EXAMINE) NCT00968708 | Alogliptin 25 mg vs. placebo | 18 months | 5380 T2D patients with recent acute coronary syndrome event | Primary: No reduction in 3-point MACE |
| The Cardiovascular and Renal Microvascular Outcome Study With Linagliptin (CARMELINA) NCT01897532 | Linagliptin 5 mg vs. placebo | 1.9 years | 6991 T2D patients with high risk for CV events, BMI ≤45 | Primary: No reduction in 3-point MACE. Secondary: No reduction in the composite of adjudication-confirmed ESRD, death due to renal failure, or a sustained decrease of at least 50% in eGFR from baseline |
| Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes (CAROLINA) NCT01243424 | Linagliptin 5 mg vs. Glimepiride 1–4 mg | >6 years | 6 033 T2D patients at increased CV risk or established CV disease | Primary: No reduction in the composite endpoint of MACE or hospitalization for unstable angina pectoris |
| PKCβ Inhibitors | ||||
| Treatment of Peripheral Neuropathy in Patients With Diabetes NCT00044421 | Ruboxistaurin mesylate 32 mg vs. placebo | 2.7 years | 707 T2D participants with diabetic neuropathy | Patients treated with ruboxistaurin had lower urinary albumin-to-creatinine ratio and higher estimated GFR |
| Anti-inflammatory Agents | ||||
| The Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS) NCT01327846 | Canakinumab 300 mg vs canakinumab 150 mg vs placebo | 3.7 years | 10,061 adults with a history of myocardial infarction and systemic inflammation (elevated high sensitivity CRP >2 mg/mL) -40% had T2D and 46% of patient with CKD in the trial had T2D | 15% reduction in 3-point MACE. Subsequent post hoc analyses demonstrated that the risk of MACE was reduced in people with CKD and in those with albuminuria or diabetes. |
| A Study to Evaluate the Safety and Efficacy of CCX140-B in Subjects With Diabetic Nephropathy NCT01447147 | CCX140-B 10 mg (CCR2 inhibitor) vs CCX140-B 5 mg vs. placebo | 52 weeks | 332 T2D patients with proteinuria, GFR ≥25 mL/min/1.73 m2 | Albuminuria lowering |
| Effects of Selonsertib in Patients with Diabetic Kidney Disease NCT02177786 | 1:1:1:1 allocation to selonsertib (oral daily doses of 2, 6, or 18 mg) or placebo | 48 weeks | 333 adults moderate-to-advanced DKD (eGFR of 15–60 mL/min/1.73 m2 at screening) and albuminuria, defined as a urine albumin-to-creatinine ratio (UACR) ≥600 mg/g if stage 3a CKD, UACR) ≥300 mg/g if stage 3b CKD, and UACR) ≥150 mg/g if stage 4 CKD | Primary endpoint: no difference in eGFR at 48 weeks. B In post hoc analyses, from 4 and 48 weeks, eGFR decline was reduced by 71% for the 18-mg group vs. placebo (difference 3.11 mL/min/1.73 m2 per year, P = 0.043). Effects on urine albumin-to-creatinine ratio did not differ between selonsertib and placebo. |
| A Multicenter Clinical Trial of Allopurinol to Prevent Kidney Function Loss in Type 1 Diabetes NCT02017171 | Allopurinol vs. placebo | Ongoing Start date: February 2014 Completion date: June 30, 2019 | 530 patients with T1D and microalbuminuria or moderate macroalbuminuria or evidence of kidney function decline regardless of albuminuria | Primary endpoint: iohexol GFR at the end of the 2-month washout period |
| Mineralocorticoid Receptor Antagonists | ||||
| MinerAlocorticoid Receptor Antagonist Tolerability Study–Heart Failure ARTS-HF NCT01807221 | Finerenone (multiple doses) vs. eplerenone | 90 days | 1066 patients with worsening HF and reduced ejection fraction and CKD and/or T2D | Finerenone reduced a composite endpoint of death from any cause, cardiovascular hospitalizations, or emergency presentation for worsening HF; reduced albuminuria |
| ARTS–Diabetic Nephropathy ARTS-DN NCT1874431 | Finerenone (multiple doses) vs. placebo | 90 days | 823 T2D patients with high or very high albuminuria who are on ACEs or ARBs | Reduced albuminuria |
| Efficacy and Safety of Finerenone in Subjects with Type 2 Diabetes Mellitus and Diabetic Kidney Disease (FIDELIO-DKD) NCT02540993 | Finerenone (10 mg vs. 20 mg vs. placebo) | Ongoing Start date September 17, 2015 Estimated end date May 25 2020 | 5734 T2D patients with DKD (persistent high albuminuria or very high albuminuria) | Ongoing Primary endpoint – time to first occurrence of the composite of onset of kidney failure, a sustained decrease of eGFR ≥40% from baseline over at least 4 weeks and renal death |
| Efficacy and Safety of Finerenone in Subjects with Type 2 Diabetes Mellitus and a Clinical Diagnosis of Diabetic Kidney Disease (FIGARO-DKD) NCT02540993 | Finerenone (10 mg vs. 20 mg vs. placebo) | Ongoing Start date September 17, 2015 Estimated end date June 21, 2021 | 7437 T2D patients with DKD (persistent high albuminuria or very high albuminuria) | Ongoing Primary endpoint – time to first occurrence of the composite endpoint of cardiovascular death and nonfatal cardiovascular events (myocardial infarction, stroke, or hospitalization for heart failure) |
| Endothelin Receptor Antagonists | ||||
| SONAR NCT01858532 | Atrasentan 0.75 mg vs. placebo | 2.2 years | 2648 patients with T2D, eGFR 25–75 mL/min/1.73 m2 and ACR 300-500 mg/g on RAAS blockers | Early termination (lower number of events), 35% relative risk reduction of doubling of serum creatinine or ESKD |
Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; CHF, congestive heart failure; CKD, chronic kidney disease; Cr, creatinine; CV, cardiovascular; DPP, dipeptidyl peptidase; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; GFR, glomerular filtration rate; HF, heart failure; MACE, myocardial infarction, nonfatal stroke, and cardiovascular death; MI, myocardial infarction; PKCβ, protein kinase C β; SGLT2i, sodium glucose co-transporter 2 inhibitors; T2D, type 2 diabetes; UACR, urine albumin-to-creatinine ratio.