incongruent finding is that the ACCORD Trial was underpowered to show between-group differences, Figure 6. | Different pathways and networks involved in the initiation and progression of diabetic kidney disease. AGE, advanced glycation end product; CTGF, connective tissue growth factor; JAKSTAT, Janus kinase/signal transducer and activator of transcription; PKC, protein kinase C; RAAS, renin-angiotensin-aldosterone system; ROS, reactive oxygen species; SAA, serum amyloid A; VEGF-A, vascular endothelial growth factor A. *JAK/STAT signaling can be unchanged (↔) or upregulated (↑) in early and later stages of diabetes, respectively. 2038 Clinical Journal of the American Society of Nephrology because CV morbidity and mortality occurred at substantially lower rates than predicted. However, in the SPRINT participants who had CKD at study entry, intensive BP treatment did not reduce incidence of ESRD, cause a 50% decline in eGFR, or cause $30% decline in eGFR to a value of ,60 ml/min per 1.73 m2. Furthermore, hospitalizations or emergency room visits for AKI occurred more frequently in the intensive treatment group than the standard regimen group (4.4% versus 2.6%; hazard ratio, 1.71) (64,67). Similarly, the ACCORD Trial detected a signal suggestive of a possible negative effect of intensive BP control on kidney function. Even among participants who had normal kidney function at baseline, instances of eGFR#30 ml/min per 1.73 m2 were almost doubled in the intensive treatment group (99 in the intensive treatment group versus 52 in the standard treatment group; P,0.001) (66). Novel Therapies and Approaches Despite current approaches to management of diabetes and hypertension and use of ACE inhibitors and ARB, there is still large residual risk in DKD. Novel agents targeting mechanisms, such as glomerular hyperfiltration, inflammation, and fibrosis, have been a major focus for development of new treatments. Agents that have shown promise include ruboxistaurin, a protein kinase C-b inhibitor (68); baricitinib, a selective Janus kinase 1 and Janus kinase 2 inhibitor (69); pentoxifylline, an anti-inflammatory and antifibrotic agent (70); atrasentan, a selective endothelin A receptor antagonist (71,72); and finerenone, a highly selective nonsteroidal mineralocorticoid receptor antagonist (Table 4) (73). However, thus far, there are no available phase 3 clinical trial data for these agents, and none are approved for use in DKD. Since the year 2008, the US Food and Drug Administration has mandated that new antihyperglycemic therapies seeking approval for the treatment of DM2 must show CV safety. Three agents within the glucagon-like peptide-1 receptor agonist class of medications, lixisenatide, liraglutide, and semaglutide, currently have CV outcome trial data available. The Evaluation of Lixisenatide in Acute Coronary Syndrome Trial showed that the addition of lixisenatide to standard care did not significantly alter the rate of major CV events (74). In contrast, in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) Study and the Trial to Evaluate Cardiovascular and Other Long-Term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN6), fewer participants reached the primary composite CV end point in the liraglutide and semaglutide groups compared with those receiving placebo (hazard ratio, 0.87; P50.01 for superiority and hazard ratio, 0.74; P,0.001 for noninferiority, respectively) (75,76). Notably, similar benefits on CV outcomes were observed in the LEADER Study and the SUSTAIN-6 subsets with moderate to severe CKD. Studies in patients with DKD have additionally shown that liraglutide lowered albuminuria levels in patients with normal kidney function or earlystage CKD and showed improved glycemic control in CKD Figure 7. | Normal and diabetic nephron with altered renal hemodynamics. Clin J Am Soc Nephrol 12: 2032–2045, December, 2017 Diabetic Kidney Disease, Alicic et al. 2039 Table 4. Studies of novel treatments for diabetic kidney disease Name of the Study Tested Intervention/Drugs Study Population Outcomes Tuttle et al., 2005 (68) Ruboxistaurin (PKC inhibitor) DM2, macroalbuminuria Decreased albuminuria, stabilized kidney function PIONEER (81) PYR-311 (anti-AGE treatment) DM2, HTN, 1.3#SCr#3.0 mg/dl, protein-to-creatinine ratio $1200 mg/g Halted PREDIAN (70) Pentoxifylline (anti-inflammatory, antifibrotic action) DM2, eGFR515–60 ml/min per 1.73, UAE.300 mg/24 h Pentoxifylline group: eGFR decline 4.3 ml/ min per 1.73 m2 less than control group; mean difference in albuminuria of 21% Study to Test Safety and Efficacy of Baricitinib in Participants with Diabetic Kidney Disease (69) Baricitinib, JAK1/2 inhibitor DM2, eGFR520–75 ml/min per 1.73 m2, macroalbuminuria Albuminuria reduction by 40% in the highest treatment group; no effect on eGFR RADAR and RADAR/JAPAN (71) Atrasentan (ETA) DM2, eGFR530–75 ml/min per 1.73 m2, UACR5300–3500 mg/g 35% Reduction of albuminuria SONAR, ongoing (72) Atrasentan (ETA) HTN, eGFR515–90 ml/min per 1.73 m2, UACR.30,5000 mg/g Ongoing PERL, ongoing (82) Allopurinol (xanthine oxidase) DM1, eGFR540–99 ml/min per 1.73 m2, UAE518–5000 mg/d Ongoing ARTS-DN, 2015 (83) Finerenone (steroid mineralocorticoid receptor