Background We investigated the efficacy and safety of apararenone (MT-3995), a non-steroidal compound with mineralocorticoid receptor agonist activity, in patients with stage 2 diabetic nephropathy (DN). Methods The study had two parts: a dose–response, parallel-group, randomized, double-blind, placebo-controlled, multicenter, phase 2, 24-week study and an open-label, uncontrolled, 28-week extension study. Primary and secondary endpoints were the 24-week percent change from baseline in urine albumin to creatine ratio (UACR) and 24- and 52-week UACR remission rates. Safety parameters were changes from baseline in estimated glomerular filtration rate (eGFR) and serum potassium at 24 and 52 weeks, and incidences of adverse events (AEs) and adverse drug reactions (ADRs). Results In the dose–response period, 73 patients received placebo and 73, 74, and 73 received apararenone 2.5 mg, 5 mg, and 10 mg, respectively. As a percentage of baseline, mean UACR decreased to 62.9%, 50.8%, and 46.5% in the 2.5 mg, 5 mg, and 10 mg apararenone groups, respectively, at week 24 (placebo: 113.7% at week 24; all P < 0.001 vs placebo). UACR remission rates at week 24 were 0.0%, 7.8%, 29.0%, and 28.1% in the placebo and apararenone 2.5 mg, 5 mg, and 10 mg groups, respectively. eGFR tended to decrease and serum potassium tended to increase, but these events were not clinically significant. AE incidence increased with dose while ADR incidence did not. Conclusion The UACR-lowering effect of apararenone administered once daily for 24 weeks in patients with stage 2 DN was confirmed, and the 52-week administration was safe and tolerable. Clinical trial registration NCT02517320 (dose–response study) and NCT02676401 (extension study)

Aims/Introduction The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial has shown the effects of canagliflozin on preventing clinically important kidney outcomes in patients with type 2 diabetes mellitus and chronic kidney disease; however, not many Japanese patients were included in the trial. The present study evaluated the efficacy and safety of canagliflozin in Japanese chronic kidney disease patients with type 2 diabetes mellitus. Materials and Methods In this multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, phase III study, chronic kidney disease patients with type 2 diabetes mellitus were randomly assigned to receive either 100 mg canagliflozin or a matching placebo once daily for 104 weeks. The primary efficacy end‐point was the incidence of a 30% decline in estimated glomerular filtration rate. Results Overall, 308 patients were randomized to the canagliflozin (n = 154) and placebo (n = 154) groups. The incidence of a 30% decline in estimated glomerular filtration rate at week 104 was 18.2% and 29.5%, respectively, and the point estimate of the intergroup difference (placebo − canagliflozin) was 11.3% (95% confidence interval 1.2–21.5, P = 0.029), which was significant. The overall incidence of adverse events was similar in the two groups. Conclusions This study suggests that canagliflozin safely reduces the risk of end‐stage renal disease in Japanese chronic kidney disease patients with type 2 diabetes mellitus.

Aim To evaluate the efficacy, safety, and tolerability of apararenone 10 mg/day in patients with nonalcoholic steatohepatitis (NASH). Methods In this multicenter, randomized, double‐blind, placebo‐controlled phase II study, patients received apararenone 10 mg or placebo once daily for 72 weeks. The primary efficacy end‐point was percent change in serum alanine aminotransferase (ALT) from baseline to 24 weeks after randomization. Secondary efficacy end‐points included changes in liver fibrosis markers. Adverse drug reactions (ADRs) and serum potassium levels were evaluated. Results Forty‐eight patients were randomly assigned to treatment (placebo, 23; apararenone, 25). The percent change in ALT at 24 weeks was −3.0% and −13.7% with placebo and apararenone, respectively (p = 0.308). The apararenone group showed greater reductions from baseline in fibrosis markers (type IV collagen 7S and procollagen‐3 N‐terminal peptide) and noninvasive tests of fibrosis (enhanced liver fibrosis score and Fibrosis‐4 index) at all time points versus placebo. The percentage of patients with improvement of 1 point or more in fibrosis stage/without nonalcoholic fatty liver disease activity score worsening was 41.7% with apararenone and 26.1% with placebo (p = 0.203). Adverse drug reactions were reported in three (13.0%) and three (12.5%) patients in the placebo and apararenone groups, respectively. Serum potassium levels increased in the apararenone group during the study and decreased to near baseline after the end of treatment. Conclusions In patients with NASH, apararenone 10 mg/day for 72 weeks was effective in decreasing ALT levels, improved multiple potential fibrosis markers, and was safe and well tolerated. Pathological findings showed anti‐inflammatory and antifibrotic effects of apararenone.

Aims/Introduction The relationship between glycated hemoglobin (HbA1c) and cardiovascular events in older adults was investigated using a Japanese administrative medical database. Materials and Methods Anonymized medical data on patients with diabetes mellitus aged ≥65 years for the period from January 2010 to December 2019 were extracted from the EBM Provider database. The primary end‐point was a composite of cardiovascular events, whereas the other end‐points included severe hypoglycemia and fracture. The association between cardiovascular events and HbA1c at the index date (i.e., approximately 10 months after initial diabetes mellitus diagnosis) was evaluated using the Cox proportional hazards model. Results Among the 3,186,751 patients in the database, 3,946 older adults with diabetes mellitus were eligible for inclusion and were subsequently grouped according to HbA1c quartiles at the index date. Cardiovascular events occurred in 142 patients. Patients with HbA1c in the highest quartile had significantly higher risk of hospitalization for cardiovascular disease than those with HbA1c in the lowest quartile (hazard ratio 1.948; 95% confidence interval 1.252–3.031, P = 0.003). However, the events risk was similar across subgroups with HbA1c <7.2%. The incidence of hypoglycemia and fracture was not significantly associated with the level of glycemic control. Conclusions Among older adults with diabetes mellitus, those with poor glycemic control were at higher risk for cardiovascular events compared with those with better glycemic control. However, strict glycemic control had no effect on cardiovascular risk in patients with HbA1c <7.2%.

Aims/Introduction This study aimed to investigate the effects of sodium–glucose cotransporter 2 inhibitors (SGLT2i) on new prescriptions of drugs, including antihypertensives, antigout/antihyperuricemics and antidyslipidemics, for the treatment of lifestyle‐related diseases in Japanese patients with diabetes mellitus using the JMDC Claims Database. Materials and Methods Patients with type 2 diabetes mellitus who were newly treated with SGLT2i or other oral antidiabetic drugs and had not been prescribed any antihypertensives, antigout/antihyperuricemics or antidyslipidemics for at least 1 year were extracted from the database. Using propensity score calibration matching (1:1), we assessed the proportion of patients who started the aforementioned concomitant medications within 2 years, and the risk ratio of SGLT2i to other antidiabetic medication groups was calculated. Results In 856,796 patients with diabetes mellitus, 734, 1,197 and 703 propensity score calibration‐matched patients in each group were analyzed for the prescription of antihypertensives, antigout/antihyperuricemics and antidyslipidemics, respectively. The new prescriptions of antihypertensives and antigout/antihyperuricemics were lower in the SGLT2i group than those in the other oral antidiabetic drug group (risk ratio 0.66 and 0.37, respectively), whereas those of antidyslipidemics were more common in the SGLT2i group (risk ratio 1.43). Conclusions New prescriptions of antihypertensives or antigout/antihyperuricemics were lower for patients taking SGLT2i than those taking other oral antidiabetic drugs, probably due to a reduction of blood pressure and uric acid levels by SGLT2i. The more frequent prescriptions of antidyslipidemics might partially reflect a moderate increase in low‐density lipoprotein cholesterol levels as a result of sodium–glucose cotransporter 2 inhibition.