Efficacy of L-carnitine supplementation for improving lean body mass and physical function in patients on hemodialysis: a randomized controlled trial.

BACKGROUND: Carnitine deficiency is common in patients on hemodialysis. However, the efficacy of L-carnitine supplementation for improving lean body mass (LBM) and physical function has not yet been evaluated. METHODS: In this multicenter, prospective, parallel, randomized, controlled trial, 91 patients on hemodialysis who developed carnitine deficiency were randomly assigned to receive injections of 1,000 mg L-carnitine 3 times per week after each hemodialysis session (L-carnitine group) or no injections (control group) with monitoring for 12 months. RESULTS: The data for 84 of the 91 patients were available for analysis (L-carnitine group, n = 42; control group, n = 42). Dry weight and body mass index did not significantly change in the L-carnitine group, but significantly decreased in the control group. Arm muscle area (AMA) did not change significantly in the L-carnitine group but decreased significantly in the control group; the difference in mean AMA between the groups was 6.22% (95% confidence interval [CI] 1.90-10.5; P = 0.037). Hand grip strength did not change significantly in the L-carnitine group, but decreased significantly in the control group. The difference in change in hand grip strength between the groups was 4.27% (95% CI 0.42-8.12; P = 0.030). Furthermore, LBM did not change significantly in the L-carnitine group but decreased significantly in the control group; the difference in mean LBM between the groups was 2.92 % (95% CI 1.28-4.61; P = 0.0007). CONCLUSIONS: L-carnitine supplementation is useful in patients who develop carnitine deficiency on hemodialysis because it maintains physical function and LBM.

Efficacy and safety of saxagliptin, a dipeptidyl peptidase-4 inhibitor, in hemodialysis patients with diabetic nephropathy: A randomized open-label prospective trial.

AIMS: Saxagliptin is a dipeptidyl peptidase-4 inhibitor that was approved in Japan for the treatment of type 2 diabetes in 2013. We examined its efficacy and safety in Japanese hemodialysis patients with diabetic nephropathy. METHODS: In this prospective, open-label, parallel-group study, Japanese hemodialysis patients were randomized to receive either oral saxagliptin (2.5mg/day) or usual care (control group) for 24weeks. Before randomization, patients received fixed doses of conventional antidiabetic drugs (oral drugs and/or insulin) for 8weeks; these drugs were continued during the study. Endpoints included changes in glycated albumin (GA), hemoglobin A1c (HbA1c), postprandial plasma glucose (PPG), and adverse events. RESULTS: Both groups included 41 patients. Mean GA, HbA1c, and PPG decreased significantly in the saxagliptin group (-3.4%, -0.6% [-7mmol/mol], and -38.3mg/dL, respectively; all P<0.0001) but not in the control group (0%, -0.1% [-1mmol/mol], and -3.7mg/dL, respectively) (P<0.0001, P<0.001, and P<0.0001, respectively). In saxagliptin-treated patients, the reduction in GA was significantly greater when saxagliptin was administered as monotherapy than in combination therapy (-4.2% vs. -3.0%, P=0.012) despite similar baseline values (24.5% vs. 23.3%). Reductions in GA, HbA1c, and PPG were greater in patients whose baseline values exceeded the median (23.8% for GA, 6.6% for HbA1c, and 180mg/dL for PPG). There were no adverse events associated with saxagliptin. CONCLUSIONS: Saxagliptin (2.5mg/day) was effective and well tolerated when used as monotherapy or combined with other antidiabetic drugs in Japanese hemodialysis patients with type 2 diabetes. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000018445.

Levocarnitine Improves Cardiac Function in Hemodialysis Patients With Left Ventricular Hypertrophy: A Randomized Controlled Trial.

BACKGROUND: Levocarnitine deficiency in hemodialysis patients is common. Although the effect of levocarnitine therapy on uremic anemia has been studied in small trials, its effects on cardiac function remain unclear. STUDY DESIGN: Multicenter, prospective, open-label, parallel, randomized, controlled trial. SETTING & PARTICIPANTS: Patients undergoing maintenance hemodialysis with carnitine deficiency (free carnitine plasma concentration < 40µmol/L) enrolled in 3 hemodialysis centers. INTERVENTION: Random assignment to treatment for 12 months with oral levocarnitine therapy at a dose of 20mg/kg/d or control group (no levocarnitine therapy). OUTCOMES & MEASUREMENTS: Cardiac function was assessed by echocardiography. The primary end point was change in ejection fraction from baseline at the end of the study. Secondary end points included changes in left ventricular mass index and clinical parameters from baseline at the end of the study. RESULTS: 222 patients were randomly assigned, of whom 148 patients (levocarnitine group, n=75; control group, n=73) were analyzed. Ejection fraction increased from baseline to the end of the study in the levocarnitine group by 5.43% (95% CI, 4.53%-6.32%), but not in the control group (change, -0.14%; between-group difference, 5.57% [95% CI, 4.48%-6.66%]; P<0.001). Left ventricular mass index decreased from baseline to the end of the study in the levocarnitine group (change of -8.89 [95% CI, -11.7 to -6.09] g/m(2)), but not in the control group (change of 1.62g/m(2); between-group difference, 10.50 [95% CI, 7.51 to 13.60] g/m(2); P<0.001). Levocarnitine therapy reduced N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and improved the erythropoietin responsiveness index, whereas no such effects were observed in the control group. LIMITATIONS: Not a double-blinded study. CONCLUSIONS: Levocarnitine therapy is useful for hemodialysis patients with carnitine deficiency; these patients may benefit from such therapy, with amelioration of cardiac function and reduction of left ventricular mass index.

Oral zinc supplementation reduces the erythropoietin responsiveness index in patients on hemodialysis.

BACKGROUND: In hemodialysis (HD) patients, zinc depletion caused by inadequate intake, malabsorption, and removal by HD treatment leads to erythropoiesis-stimulating agent (ESA) hyporesponsiveness. This study investigated the effects of zinc supplementation in HD patients with zinc deficiency on changes in the erythropoietin responsiveness index (ERI). METHODS: Patients on HD with low serum zinc levels (<65 µg/dL) were randomly assigned to two groups: The polaprezinc group (who received daily polaprezinc, containing 34 mg/day of zinc) (n = 35) and the control group (no supplementation) (n = 35) for 12 months. All the 70 patients had been taking epoetin alpha as treatment for renal anemia. ERI was measured with the following equation: Weekly ESA dose (units)/dry weight (kg)/hemoglobin (g/dL). RESULTS: There were no significant changes in hemoglobin levels within groups or between the control and polaprezinc groups during the study period. Although reticulocyte counts were increased immediately after zinc supplementation, this change was transient. Serum zinc levels were significantly increased and serum copper levels were significantly decreased in the polaprezinc group after three months; this persisted throughout the study period. Although there was no significant change in the serum iron or transferrin saturation levels in the polaprezinc group during the study period, serum ferritin levels significantly decreased following polaprezinc treatment. Further, in the polaprezinc group, ESA dosage and ERI were significantly decreased at 10 months and nine months, respectively, as compared with the baseline value. Multiple stepwise regression analysis revealed that the change in the serum zinc level was an independent predictor of lowered ERI. CONCLUSIONS: Zinc supplementation reduces ERI in patients undergoing HD and may be a novel therapeutic strategy for patients with renal anemia and low serum zinc levels.

Effects of levocarnitine on brachial-ankle pulse wave velocity in hemodialysis patients: a randomized controlled trial.

BACKGROUND AND AIMS: Atherosclerotic cardiovascular disease is the most common cause of mortality in patients with end-stage kidney disease. Chronic kidney disease patients often exhibit a deficiency in L-carnitine due to loss during hemodialysis (HD). We studied the effects of L-carnitine supplementation on brachial-ankle pulse wave velocity (baPWV), a marker of atherosclerosis, in HD patients. METHODS: This was a prospective, open-label, randomized, parallel controlled, multi-center trial testing the anti-atherosclerotic efficacy of oral L-carnitine administration (20 mg/kg/day). HD patients (n = 176, mean age, 67.2 ± 10.3 years old; mean duration of HD, 54 ± 51 months) with plasma free L-carnitine deficiency (<40 µmol/L) were randomly assigned to the oral L-carnitine group (n = 88) or control group (n = 88) and monitored during 12 months of treatment. RESULTS: There were no significant differences in baseline clinical variables between the L-carnitine and control groups. L-carnitine supplementation for 12 months significantly increased total, free, and acyl carnitine levels, and reduced the acyl/free carnitine ratio. The baPWV value decreased from 2085 ± 478 cm/s at baseline to 1972 ± 440 cm/s after six months (p < 0.05) to 1933 ± 363 cm/s after 12 months (p < 0.001) of L-carnitine administration, while no significant changes in baPWV were observed in the control group. Baseline baPWV was the only factor significantly correlated with the decrease in baPWV. CONCLUSIONS: L-carnitine supplementation significantly reduced baPWV in HD patients. L-carnitine may be a novel therapeutic strategy for preventing the progression of atherosclerotic cardiovascular disease.

The dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin improves glycemic control in type 2 diabetic patients undergoing hemodialysis.

The potent and selective dipeptidyl peptidase-4 inhibitor vildagliptin improves glycemic control in patients with type 2 diabetes through incretin hormone-mediated increases in both α- and ß-cell responsiveness to glucose. We conducted a prospective, open-label, parallel group, controlled study of 51 patients with type 2 diabetic patients undergoing hemodialysis (HD) during the 24-week study period. Patients were assigned to two groups: the vildagliptin group (n = 30) and the control group (n = 21). Vildagliptin was administered at 50 mg/day for the first 8 weeks. Then doses were titrated by dose-doubling to a maximum of 100 mg/day if hemoglobin A1c (HbA1c) or glycated albumin (GA) target levels had not been reached. No vildagliptin was administered to the controls. The average final dose of vildagliptin was 80 ± 5 mg daily. After 24 weeks, vildagliptin had decreased average HbA1c levels from 6.7 % baseline to 6.1 %, average GA levels from 24.5 % baseline to 20.5 % and average postprandial plasma glucose levels from 186 mg/dL baseline to 140 mg/dL (all p < 0.0001). In the control group, we observed no such changes. Vildagliptin efficacy did not differ according to age or body mass index, but the GA reduction was significantly greater in the anti-diabetic agents-naïve group. Furthermore, in patients with higher baseline GA levels, a higher vildagliptin dosage was required to produce a noticeable effect. No serious adverse effects such as hypoglycemia or liver impairment were observed in any patient. Vildagliptin was effective as a treatment for diabetic patients undergoing HD.

Efficacy of pioglitazone on type 2 diabetic patients with hemodialysis.

AIMS: Unfortunately, growing number of type 2 diabetic hemodialysis (HD) patients with insulin resistance are now being diagnosed in Japan. Worse still, PPARgammaagonists such as pioglitazone are now contraindicated in diabetic HD patients in Japan. In this study we evaluated the efficacy of pioglitazone in diabetics on HD. METHODS: Following a 12-week baseline period, we enrolled a study population of poorly controlled diabetic HD patients who had mean hemoglobin A1c (HbA1c) levels greater than 6.5% at baseline and who were not receiving insulin injection therapy. The patients were administered pioglitazone 15mg daily with their morning meal for the first 4 weeks. Subsequently, the doses were titrated by dose-doubling to a maximum of 30mg/day if no adverse effects appeared. The efficacy was determined by monitoring glycemic control (plasma glucose and HbA1c), and insulin resistance (plasma immunoreactive insulin (IRI) and homeostasis model assessment for insulin resistance (HOMA-R)). Safety and tolerance were determined by monitoring clinical and laboratory parameters. RESULTS: Pioglitazone was effective in reducing plasma glucose and HbA1c from the baseline levels from week 4 after the commencement of treatment. The agent was also effective in reducing triglycerides. Plasma IRI and HOMA-R, two parameters of insulin resistance, decreased significantly at 4 weeks, and the decreases continued for 24 weeks. Systolic and diastolic blood pressures were statistically lower at 8 weeks. No serious adverse effects such as hypoglycemia, liver impairment, or rhabdomyolysis were observed in any of the patients. CONCLUSIONS: Pioglitazone was effective in the treatment of diabetics on dialysis therapy. Pioglitazone might have the potential to reduce the number of type 2 diabetics on HD who ultimately require insulin injection therapy.