A randomized controlled study of finerenone versus placebo in Japanese patients with type 2 diabetes mellitus and diabetic nephropathy.

AIMS: Finerenone (BAY 94-8862) is a novel non-steroidal mineralocorticoid receptor antagonist. The aim of this study was to compare the efficacy and safety of seven once-daily oral doses of finerenone (1.25-20mg) and placebo in 96 patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) receiving a RAS blocker. METHODS: ARTS-DN Japan was a multicenter, randomized, double-blind, placebo-controlled, phase 2b study. RESULTS: Analysis of the urinary albumin-to-creatinine ratio (UACR) at day 90 relative to baseline indicated a nominally significant effect of finerenone. The UACR at day 90 relative to baseline for each finerenone treatment group was numerically reduced compared with placebo. No serious adverse events (AEs) or deaths were reported and no patients experienced treatment-emergent AEs resulting in discontinuation of study drug. Small mean increases in serum potassium level were observed in the finerenone treatment groups (0.025-0.167mmol/L) compared with the placebo group (-0.075mmol/L); no patients developed hyperkalemia. CONCLUSION: When given in addition to a RAS inhibitor, finerenone reduced albuminuria without adverse effects on serum potassium levels or renal function in Japanese patients with T2DM and DN.

Relationship between a low ankle brachial index and all-cause death and cardiovascular events in subjects with and without diabetes.

AIMS: The association between a low ankle brachial index(ABI) and mortality and vascular morbidity in Japanese individuals with diabetes and the independence of this association from other risk factors have not yet been examined in the primary care setting among a large number of patients. METHODS: An observational prospective cohort study was performed among 3,004 Japanese individuals(2,598 patients with diabetes) to examine all-cause death and cardiovascular disease(CVD) in relation to low ABI(＜0.9) values and other risk factors. RESULTS: Low ABI values were found in 127 subjects(4.2%) and was associated with smoking, diabetes, hypertension, pulse pressure, glycosylated hemoglobin A1C, lipid profiles, glomerular filtration rate, uric acid and prevalent CVD at baseline. Over 13,242 person-years, 93 deaths and 117 cases of CVD occurred. In a multivariate Cox regression analysis, the hazard ratio for low-normal ABI values was 3.97(95% CI, 2.29 to 6.88) for all-cause death and 2.86(95% CI, 1.83-4.49) for fatal and non-fatal CVD and all-cause death. Similar hazard ratios were found when the subjects were confined to those with diabetes. All risk analyses indicated that age, a low ABI, diabetes, a history of CVD and smoking remained significantly and independently predictive of CVD and all-cause death. CONCLUSIONS: A low ABI exhibits significant cross-sectional associations with conventional risk factors and further more with the glomerular filtration rate, uric acid level and presence of prevalent CVD at baseline, and a low ABI independently predicts subsequent death and cardiovascular events. These findings support the concept that a low ABI is an integrated marker of an excess risk of death and cardiovascular events, independent of conventional risk factors.

Association between remission of macroalbuminuria and preservation of renal function in patients with type 2 diabetes with overt proteinuria.

OBJECTIVE: Studies on the rate of remission of macroalbuminuria in patients with type 2 diabetes mellitus (T2DM) and the effects of reduction in albuminuria on renal prognosis in a primary care setting are absolutely lacking. RESEARCH DESIGN AND METHODS: A total of 211 T2DM patients with albuminuria≥300 mg/g were enrolled in a prospective observational study (mean of 4.5 years). The incidence of patients with remission of macroalbuminuria at every 1-year study time point after starting intensified diabetes treatment and the factors associated with remission were evaluated. The association of reduction in albuminuria with renal events (doubling of serum creatinine and end-stage renal disease) was also investigated. RESULTS: During the 5-year study period, remission to microalbuminuria occurred in 116 patients and the 5-year cumulative incidence was 58.3%. Notably, most cases (82.8%) obtained remission at the 1-year study time point. The remission rate increased with achieving therapeutic targets for blood pressure and blood glucose. Remission and reduction in albuminuria of ≥50% were associated with preservation of renal function. In particular, patients who obtained both remission and 50% reduction at the 1-year study time point exhibited a significantly reduced risk for renal events as compared with those with no remission and no reduction (adjusted hazard ratio 0.30 [95% CI 0.12-0.76]). CONCLUSIONS: Remission of macroalbuminuria occurs frequently and is associated with the preservation of renal function in T2DM patients. The initial adequate diabetes treatment aimed at reducing albuminuria may lead to improved renal prognosis in the primary care setting.

Flow-mediated dilation is associated with microalbuminuria independent of cardiovascular risk factors in type 2 diabetes - interrelations with arterial thickness and stiffness.

AIMS: To investigate whether endothelial dysfunction assessed by brachial artery flow-mediated dilation (FMD) is associated with urinary albumin excretion (UAE) and is interrelated with carotid intima-media thickness (IMT) and pulse-wave velocity (PWV) in type 2 diabetes. METHODS: We measured FMD, IMT and PWV in 158 subjects with type 2 diabetes (normo- 49, micro- 64, macroalbuminuria 45), explored the determinants of FMD, and analyzed the relationship of FMD with traditional cardiovascular risk factors according to IMT and PWV levels. RESULTS: Microalbuminuria was significantly associated with lower FMD, higher IMT and higher PWV compared to normoalbuminuria (p < 0.001 for all). FMD was significantly correlated with IMT and PWV, and also with traditional risk factors, UAE, glomerular filtration rate, diabetic retinopathy, and neuropathy. Multivariate regression analysis revealed that UAE remained a significant determinant of FMD independent of traditional risk factors, metabolic control, and renal function. The relationship of FMD with IMT and PWV was less pronounced in subjects with increased IMT and PWV. CONCLUSIONS: In individuals with type 2 diabetes, FMD is impaired in subjects with microalbuminuria and is associated with IMT and PWV only when these values are not increased, i.e., at an early stage of atherosclerosis.

Risks for glomerular filtration rate decline in association with progression of albuminuria in type 2 diabetes.

BACKGROUND: The aim of this study was to investigate the annual rate of glomerular filtration rate (GFR) decline and risks for this decline in association with albuminuria progression in type 2 diabetes. METHODS: An observational 4-year cohort study was performed on 1002 subjects with preserved GFR (699 normoalbuminuric), and the predictive value of baseline variables on the GFR slope was investigated. GFR decliner and albuminuria progressor were defined as a GFR slope <-4.0%/year and changes in the geometric mean of urinary albumin from baseline to follow-up >150%, respectively. RESULTS: Annual rates of GFR decline (percent per year, median and interquartile range) were -2.58 (-4.70 to -0.48) in normoalbuminuria, -3.49 (-5.93 to -1.11) in microalbuminuria and -6.58 (-10.64 to -3.53) in macroalbuminuria. Subjects cross-classified according to GFR decliner/albuminuria progressor consisted of 51% (-/-), 13% (-/+), 28% (+/-) and 8% (+/+). Common risks for GFR decline and albuminuria progression were retinopathy, neuropathy, hemoglobin A(1C) (HbA(1C)) and urinary albumin. Independent significant risks for GFR decline were baseline GFR, systolic blood pressure (SBP), total protein (TP) and hypertension. Proportions with progression to albuminuria were similar between GFR decliners and non-decliners. Multiple linear regression analysis indicated that GFR slope was predicted by baseline variables of urinary albumin, GFR, HbA(1C), SBP, plasma TP and retinopathy. These risks appeared variable according to high or low levels of urinary albumin and GFR. CONCLUSIONS: Urinary albumin excretion is only one risk factor for albuminuria progression and GFR decline, and other important factors were implicated as important for prevention of end-stage renal disease.

Contribution of glimepiride to basal-prandial insulin therapy in patients with type 2 diabetes.

AIM: To investigate the efficacy of continuing glimepiride in combination with basal-prandial insulin therapy in type 2 diabetes. METHODS: An open crossover study was performed with arms of discontinuation and continuation of glimepiride in 25 subjects with mean diabetes duration of 17 years and 5 years of insulin treatment combined with glimepiride plus metformin. At entry and at the end of each 3-month arm, meal tolerance tests were performed for measurements of blood glucose and C-peptide. RESULTS: In terms of between-treatment differences (discontinuation vs. continuation arm of glimepiride) during meal tolerance tests performed at the ends of arms, significant increases in plasma glucose were seen on the discontinuation arm at 0-, 30-, and 60-min, while significant decreases in serum C-peptide were observed at 60- and 120-min. A1C values of the discontinuation arm significantly increased (from 6.6 ± 0.6 at baseline to 7.7 ± 0.8 at 3-months, p<0.0001). Increases in A1C were closely correlated with decreases in area under the curve of meal-stimulated serum C-peptide (r=-0.61, p<0.0001). CONCLUSIONS: Since endogenous insulin secretion is more physiological than subcutaneous insulin injection, continuing glimepiride may remain beneficial, partly through enhancing insulin secretion, in individuals with a long duration of diabetes and basal-prandial insulin therapy.

Determinants of decline in glomerular filtration rate in nonproteinuric subjects with or without diabetes and hypertension.

BACKGROUND AND OBJECTIVES: This study investigated whether the slope of estimated GFR is different between nonproteinuric subjects with and without diabetes, and what clinical factors are associated with the GFR slope. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: An observational cohort study was performed in 923 subjects, and the predictive value of baseline variables on the GFR slope was investigated. RESULTS: On the basis of the median 3-yr follow-up and 7 measurements of GFR, GFR slope (%/yr, median and interquartile range) was significantly larger in subjects with diabetes (-2.39 (-4.86 to 0.15), n=729) than in those without diabetes (-1.02 (-4.28 to 1.37), n=194), and this difference remained significant with or without presence of hypertension. After adjustments for confounding factors, predictors of GFR decline were found to be baseline high values of glycosylated hemoglobin A1C(HbA1C), GFR, systolic blood pressure, and low plasma total protein in subjects with diabetes, whereas only the latter two were significant in subjects without diabetes. In subjects with diabetes, the high GFR was accounted for by high HbA1C at baseline, and the predictors of GFR decline differed between those with and without hypertension, or with high and low baseline GFR. Any combination of the predictors showed increased risk for GFR decline. CONCLUSIONS: GFR slope is substantially affected by multiple factors at various stages. The degree of chronic hyperglycemia is likely to play a crucial role in elevating GFR and accelerating the decline in patients with type 2 diabetes even from the normoalbuminuric stage.