antagonist) DM2, UACR$30 mg/g, eGFR.30 ml/min per 1.73 m2 No difference in eGFR, 17%–40% albuminuria reduction dose dependent SCr is in milligrams per deciliter. Protein to creatinine ratio is in milligrams per gram. eGFR is in milliliters per minute per 1.73 m2. UAE is in milligrams per day. UACR is in milligrams per gram. PKC, protein kinase C; DM2, diabetes mellitus type 2; PIONEER, A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Evaluate the Safety and Efficacy of Pyridorin (Pyridoxamine Dihydrochloride) in SubjectsWith Nephropathy Due to Type 2 Diabetes; PYR-311, pyridoxamine-311; AGE, advance glycation end product; HTN, hypertension; SCr, serum creatinine; PREDIAN, Effect of Pentoxifylline on Renal Function and Urinary Albumin Excretion in Patients with Diabetic Kidney Disease; UAE, urine albumin excretion; JAK1/2, Janus kinases 1/2; RADAR, Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With AtRasentan—A Phase 2b, Prospective, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate Safety and Efficacy; RADAR/JAPAN, RADAR in Japan; ETA, endothelin A; UACR, urinary albumin-to-creatinine ratio; SONAR, A Randomized, Multicountry, Multicenter, Double-Blind, Parallel, Placebo-Controlled Study of the Effects of Atrasentan on Renal Outcomes in SubjectsWith Type 2 Diabetes and Nephropathy; PERL, A Pilot Study of Allopurinol to Prevent GFR Loss in Type 1 Diabetes; DM1, diabetes mellitus type 1; ARTS-DN, A Randomized, Double-blind, Placebo-controlled, Multi-Center Study to Assess the Safety and Efficacy of Different Oral Doses of BAY94-8862 in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Nephropathy. 2040 Clinical Journal of the American Society of Nephrology Table 5. Kidney outcomes in clinical trials of newer antihyperglycemic therapies Name of the Study Tested Intervention/Drugs Study Population Outcomes SAVOR-TIMI (84) Saxagliptin (DPP-4 inhibitor) DM2, HbA1c$6.5%, high risk for CV events Improvement in and/or less deterioration in ACR categories from baseline to end of trial (P50.02, P,0.001, and P50.05 for normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively); no changes in eGFR CARMELINA (85) Linagliptin (DPP-4 inhibitor) DM2, 6.5%$HbA1c#10%, albuminuria, macrovascualar complications, eGFR.15 ml/min per 1.73 m2 In progress, estimated completion in January of 2018 LEADER (75) Liraglutide (GLP-1 receptor agonist) DM2, HbA1c.7%, eGFR,60 ml/min per 1.73 m2, CV coexisting disease Lower incidence of nephropathy (newonset albuminuria, doubling of SCr and CrCl,45 ml/min per 1.73 m2; need for RRT, death to renal causes [1.5 number of events per 100patientsperyearversus 1.9numberof events per 100 patients per year; P50.003]) AWARD-7, (86) Dulaglutide (GLP-1 receptor agonist) DM2, 7.5%$HbA1c#10.5%, 15$eGFR#60 ml/min per 1.73 m2 In progress, estimated completion in July of 2018 EMPA-REG OUTCOME (78) Empaglifozin (SGLT-2 inhibitor) DM2, eGFR$30 ml/min per 1.73 m2, high CV risk 44% Relative risk reduction of doubling of SCr (1.5% versus 2.6%); 38% relative risk reduction of progression to macroalbuminuria (11.2% versus 16.2%); 55% relative risk reduction of initiation of RRT (0.3% versus 0.6%); slowing GFR decline (annual decrease 0.1960.11 versus 1.6760.13 ml/min per 1.73 m2; P,0.001) CREDENCE (87) Canaglifozin (SGLT-2 inhibitor) DM2, 6.5%$HbA1c#12%, high CV risk, 300 mg/g$UACR#5000 mg/g, 30$eGFR#90 ml/min per 1.73 m2 In progress, estimated completion in June of 2019 eGFR is in milliliters per minute per 1.73 m2. UACR is in milligrams per gram. SAVOR-TIMI, Does Saxagliptin Reduce the Risk of Cardiovascular Events When Used Alone or Added to Other Diabetes Medications; DPP-4, dipeptidyl peptidase-4 inhibitor; DM2, diabetes mellitus type 2; HbA1c, hemoglobin A1c; CV, cardiovascular; ACR, albumin-to-creatinine ratio; CARMELINA, Cardiovascular and Renal Microvascular Outcome StudyWith Linagliptin in PatientsWith Type 2 Diabetes Mellitus; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; GLP-1, glucagon-like peptide-1; SCr, serum creatinine; CrCl, creatinine clearance; AWARD-7, A Study Comparing Dulaglutide With Insulin Glargine on Glycemic Control in Participants With Type 2 Diabetes (T2D) and Moderate or Severe Chronic Kidney Disease (CKD); EMPA-REG OUTCOME, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; SGLT-2, sodium-glucose cotransporter 2; CREDENCE, Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy; UACR, urine albumin-to-creatinine ratio. Clin J Am Soc Nephrol 12: 2032–2045, December, 2017 Diabetic Kidney Disease, Alicic et al. 2041 stage 3 (75). Recently released data from clinical trials of semaglutide and dulaglutide consistently show reduced risk of albuminuria onset and progression (75,76). The consistency of these data across glucagon-like peptide-1 receptor agonists persuasively suggests a class effect of protection from DKD. The mechanisms of action may be multifactorial and include glycemic control, weight control, and direct effects on the kidney. In the Empagliflozin Cardiovascular