Possible enhancement of autophagy Multidimensional effects with eGFR >45 mL/min/1.73 m2 Multidimensional effects that persist at eGFR >45 mL/min/1.73 m2 CHRONIC KIDNEY DISEASE AND TYPE 2 DIABETES 31 and high-dose (1.5 mg weekly) groups. Notably, the gradients of eGFR decline between dulaglutide and insulin were maintained even among patients with a urine albumin-to-creatinine ratio >300 mg/g creatinine, who are at higher risk of CKD progression, with eGFR declines of −0.7 and −0.5 mL/min/1.73 m2 for dulaglutide 1.5 mg and 0.75 mg, respectively, compared to −5.5 mL/min/1.73 m2 for insulin. Compared to patients in the insulin group, fewer patients who received high-dose dulaglutide reached the composite renal endpoint of ESRD or >40% decline in eGFR (10.8 vs. 5.2%, P 5,700 participants with type 2 diabetes and moderate to severe CKD who were on a maximally tolerated RAS blocker. Over a median duration of 2.6 years, finerenone was associated with an 18% relative risk reduction (HR 0.82, 95% CI 0.73–0.93, P = 0.001) in the primary renal outcome, which was a composite of time to kidney failure, sustained eGFR decrease ≥40% from baseline, or renal death. There was also a 14% relative risk reduction (HR 0.86, 95% CI 0.75–0.99, P = 0.03) in the secondary cardiac outcome, which was a composite of time to death from cardiac causes, nonfatal myocardial infarction, nonfatal stroke or HHF (9). Adverse effects were balanced between finerenone and placebo. Of interest was the emergence of cardiovascular benefits as early as the first month in the experimental arm compared to renal benefits, which did not emerge until 12 months but then persisted throughout the study duration. These findings are in line with known underlying mechanisms of finerenone: mild natriuresis translating into a 2.4-mmHg reduction in systolic blood pressure and presumptive anti-fibrotic and anti-inflammatory effects halting progression of renal tissue remodeling. These clinical benefits may take several months to see, and this was especially true in FIDELIO-DKD, in which specific inflammatory and fibrosis markers were not incorporated into the study. Parallel to FIDELIO-DKD is another phase 3 trial, FIGARO-DKD (Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease) (318), a trial involving >7,000 people that is expected to be completed in summer 2021 will provide insight into this drug’s cardiorenal efficacy and safety in people with type 2 diabetes and less advanced DKD. Readers should note, however, that, as of March 2021, finerenone was under evaluation but not yet approved by the FDA. Summary More than 400 million people are living with diabetes worldwide, and that number is projected to continue increasing steadily (269), driven by aging population trends, expanding urbanization, sedentary lifestyles, and rising obesity rates. Diabetes is the leading cause of CKD; combined with hypertension and prediabetes, it accounts for 75% of CKD causality (138). DKD, a “disease multiplier,” is associated with significant cardiorenal morbidity and mortality. Treatment of DKD, when previously limited to RAS blockade and management of traditional metabolic risk factors for cardiovascular disease and CKD, did not sufficiently halt kidney disease progression (Figure 1). This outlook has changed in recent years with the advent of SGLT2 inhibitors and nonsteroidal MR antagonists, as well as, potentially, GLP1 receptor agonists. Contemporary standard management of DKD now includes the use of an SGLT2 inhibitor alone or in combination with a GLP-1 receptor agonist if atherosclerotic disease is present, on top of an RAS blocker in individuals with cardiovascular and kidney disease (277). However, even under optimal conditions, there remains residual cardiorenal risk significant enough to spur the search for other therapeutic options. In addition to these drug classes, we have strong evidence from nonsteroidal MR antagonists showing both relative safety and clear efficacy in slowing DKD progression and reducing cardiovascular events (319). Other agents that remain to be proven but have data supporting a possible role include the endothelin receptor antagonists. For example, atrasentan still holds some promise in a subset of patients whose cardiac status can handle a small increase in volume when it is dosed carefully. With distinct mechanisms of action and non-overlapping side effect profiles, some of these drug classes may even be combined to create additive or synergistic effects. This possibility was illustrated in a post hoc analysis of the SONAR (Study of Diabetic Nephropathy With Atrasentan) trial (320), in which patients with type 2 diabetes and CKD achieved larger reductions in albuminuria and body weight, a surrogate for fluid retention, when they were given an SGLT2 inhibitor in combination with atrasentan compared to those who took atrasentan alone. Finally, praliciguat, a soluble guanylate cyclase stimulator, remains to be tested to determine whether it can offer additional slowing of renal disease beyond relaxing vascular tone and reversing tissue remodeling (321). These data, when taken together, suggest that nephrologists can finally celebrate the availability of new agents that slow CKD progression in diabetes from eGFR reduction of ~10–12 mL/ min/year in 1980 to