A double‐blind,placebo‐controlled phase II study of the efficacy and safety of 2,2‐dimethylbutyrate (HQK‐1001), an oral fetal globin inducer,in sickle cell disease

This placebo‐controlled phase II study evaluated the pharmacodynamics, efficacy and safety of 2,2‐dimethylbutyrate (HQK‐1001), a fetal globin gene‐inducing short‐chain fatty acid derivative, administered orally at 15 mg/kg twice daily for 48 weeks in 76 subjects with sickle cell disease (SCD). The median age was 26 years (range: 12–55 years) and 37 subjects (49%) were treated previously with hydroxycarbamide. Sixty subjects (79%) had Hb SS and 16 (21%) had S/β⁰ thalassemia. The study was terminated after a planned interim analysis showed no significant increase in fetal hemoglobin (Hb F) and a trend for more pain crises in the HQK‐1001 group. For 54 subjects with Week 24 data, the mean absolute increase in Hb F was 0.9% (95% confidence interval (CI): 0.1–1.6%) with HQK‐1001 and 0.2% (95% CI: ?0.7–1.1%) with placebo. Absolute increases in Hb F greater than 3% were noted in 9 of 38 subjects (24%) administered HQK‐1001 and 1 of 38 subjects (3%) administered placebo. The mean changes in hemoglobin at Week 24 were comparable between the two groups. The mean annualized rate of pain crises was 3.5 with HQK‐1001 and 1.7 with placebo. The most common adverse events in the HQK‐1001 group, usually graded as mild or moderate, consisted of nausea, headache, vomiting, abdominal pain, and fatigue. Additional studies of HQK‐1001 at this dose and schedule are not recommended in SCD. Intermittent HQK‐1001 administration, rather than a daily regimen, may be better tolerated and more effective, as shown previously with arginine butyrate, and warrants further evaluation. Am. J. Hematol. 89:709–713, 2014. © 2014 Wiley Periodicals, Inc.     

Intermittent Oral Dosing of Roxadustat in Peritoneal Dialysis Chronic Kidney Disease Patients with Anemia: A Randomized,Phase 3, Multicenter,Open‐Label Study

Roxadustat is an oral hypoxia‐inducible factor prolyl hydroxylase inhibitor developed to treat anemia in chronic kidney disease (CKD) patients. This Phase 3, randomized, open‐label, 24‐week study investigated the efficacy and safety of roxadustat in Japanese CKD patients with anemia on peritoneal dialysis (PD) who were previously treated or not treated with erythropoiesis stimulating agents (ESAs). Patients not previously receiving ESA (ESA‐Naïve group) were randomized to roxadustat at a starting dose of 50 or 70 mg three times weekly; patients previously receiving ESA (ESA‐Converted group) switched from ESA to roxadustat 70 or 100 mg three times weekly depending on the prior ESA dose. Outcomes included maintenance rate of average hemoglobin (Hb) level within 10–12 g/dL at weeks 18–24, cumulative response rate at end of treatment (Hb thresholds, 10.0 g/dL or 10.5 g/dL; Hb increase, ≥1.0 g/dL), and average Hb levels at weeks 18–24. Safety was assessed by occurrence of treatment‐emergent adverse events (TEAEs). Fifty‐six patients were enrolled (ESA‐Naïve, n = 13; ESA‐Converted, n = 43). Maintenance rates (weeks 18–24) were 92.3% (95% CI: 64.0–99.8; ESA‐Naïve) and 74.4% (95% CI: 58.8–86.5; ESA‐Converted). Cumulative response rate was 100.0% in the ESA‐Naïve group. Average Hb levels (weeks 18–24) were 11.05 g/dL (95% CI: 10.67–11.42; ESA‐Naïve) and 10.93 g/dL (95% CI: 10.73–11.13; ESA‐Converted). Common TEAEs included nasopharyngitis and back pain. Roxadustat was well tolerated and effective in maintaining target Hb levels in CKD patients on PD who were previously treated or not treated with ESA.     

A randomized phase I/II trial of HQK‐1001, an oral fetal globin gene inducer,in β‐thalassaemia intermedia and HbE/β‐thalassaemia

β‐thalassaemia intermedia (BTI) syndromes cause haemolytic anaemia, ineffective erythropoiesis, and widespread complications. Higher fetal globin expression within genotypes reduces globin imbalance and ameliorates anaemia. Sodium 2,2 dimethylbutyrate (HQK‐1001), an orally bioavailable short‐chain fatty acid derivative, induces γ‐globin expression experimentally and is well‐tolerated in normal subjects. Accordingly, a randomized, blinded, placebo‐controlled, Phase I/II trial was performed in 21 adult BTI patients (14 with HbE/β⁰ thalassaemia and seven with β⁺/β⁰ thalassaemia intermedia, to determine effective doses for fetal globin induction, safety, and tolerability. HQK‐1001 or placebo were administered once daily for 8 weeks at four dose levels (10, 20, 30, or 40 mg/kg per day), and subjects were monitored for laboratory and clinical events. Pharmacokinetic profiles demonstrated a t_1/2 of 10–12 h. Adverse events with HQK‐1001 treatment were not significantly different from placebo treatment. The 20 mg/kg treatment doses increased median HbF above baseline levels by 6·6% and 4·4 g/l (P < 0·01) in 8/9 subjects; total haemoglobin (Hb) increased by a mean of 11 g/l in 4/9 subjects. These findings identified a safe oral therapeutic which induces fetal globin in BTI. Further investigation of HQK‐1001 with longer dosing to definitively evaluate its haematological potential appears warranted.     

Low Hemoglobin Levels and Hypo‐Responsiveness to Erythropoiesis‐Stimulating Agent Associated With Poor Survival in Incident Japanese Hemodialysis Patients

Although erythropoiesis‐stimulating agents (ESAs) are effective at treating anemia, the association between hemoglobin (Hb) levels and survival is still unclear, especially for the incident Japanese hemodialysis (HD) population. The Japan Erythropoietin Treatment (JET) Study is an open multi‐center, prospective, observational study designed to evaluate the relationship between the maintenance of Hb levels and new HD patient prognosis after the first administration of epoetin beta. Landmark analyses were performed to examine the relationship between Hb levels at 6 months and survival. Among a total of 10 310 patients, 6631 completed the initial 6 months of epoetin beta treatment (induction phase) and were followed up for a further 2.5 years (maintenance phase). Three‐year survival rate of patients with <9 g/dL Hb levels after 6 months was 74.1%, which was significantly lower than 89.3% for patients with Hb levels 10 to 11 g/dL; the adjusted hazard ratio (HR) was 2.08 (95% CI, 1.57–2.77; P < 0.0001). Moreover, the 3‐year survival rate for poor responders defined by Hb levels <10 g/dL and weekly epoetin beta doses ≥9000 IU during the induction phase was 71.6%, which was significantly lower than 89.4% for the group, which had Hb levels 10 to 11 g/dL excluding poor responders and those with excursion; the HR was 1.71 (95% CI, 1.13–2.60; P = 0.0118). Adverse events related to the treatment were reported in 71 of 10 310 patients (0.69%). These findings suggest that the achieved low Hb levels and poor response to ESA therapy are significantly associated with high mortality.     

High Target Hemoglobin With Erythropoiesis‐Stimulating Agents Has Advantages in the Renal Function of Non‐Dialysis Chronic Kidney Disease Patients

We investigated the long‐term effects of maintaining high hemoglobin (Hb) on renal function in patients with chronic kidney disease not on dialysis. Subjects (Hb < 10 g/dL and serum creatinine (Cr) 2–6 mg/dL) were randomized to either a high Hb group (N = 161, 11.0 ≤ Hb < 13.0 g/dL) receiving darbepoetin alfa or to a low Hb group (N = 160, 9.0 ≤ Hb < 11.0 g/dL) with epoetin alfa, stratified according to baseline Hb and serum Cr levels, comorbidity of diabetes, and study centers. Primary endpoints were composites of the following events: doubling of serum Cr, initiation of dialysis, renal transplantation, or death. Three‐year cumulative renal survival rates (95% CI) were 39.9% (30.7–49.1%) and 32.4% (24.0–40.8%) in the high and low Hb groups, respectively (log‐rank test; P = 0.111). A Cox proportional‐hazards model adjusted by age, sex and the randomization factors showed a significantly lower event rate in the high Hb group (P = 0.035). The estimated hazard ratio (95% CI) for the high versus the low Hb group was 0.71 (0.52–0.98), the risk reduction was 29% in the high Hb group. Incidences of serious adverse cardiovascular events did not differ significantly between the high and low Hb groups (3.1% and 4.4%, respectively). No safety issues were noted in either group. Maintaining higher Hb levels with darbepoetin alfa better preserved renal function in patients with chronic kidney disease not on dialysis.     

A phase 1/2 trial of HQK‐1001, an oral fetal globin inducer,in sickle cell disease

Therapeutics which reduce the pathology in sickle cell syndromes are needed, particularly noncytotoxic therapeutics. Fetal hemoglobin (HbF, α₂γ₂) is established as a major regulator of disease severity; increased HbF levels correlate with milder clinical courses and improved survival. Accordingly, sodium dimethylbutyrate (HQK‐1001), an orally‐bioavailable, promoter‐targeted fetal globin gene‐inducing agent, was evaluated in a randomized, blinded, dose‐ranging Phase I/II trial in 24 adult patients with HbSS or S/β thalassemia, to determine safety and tolerability of three escalating dose levels. The study therapeutic was administered once daily for two 6‐week cycles, with a two‐week interim dose holiday. Twenty‐one patients completed the study. Five patients received study drug at 10 or 20 mg/kg doses, seven patients received study drug at 30 mg/kg/dose, and 4 patients received placebo. HQK‐1001 was well‐tolerated with no unexpected drug‐related adverse events; a dose‐limiting toxicity was not identified. Plasma drug levels were sustained above targeted levels for 24 hr. Increases in HbF above baseline were observed particularly with 30 mg/kg/day doses; in five of seven treated patients, a mean absolute increase in HbF of 0.2 g/dl and a mean increase in total hemoglobin (Hgb) of 0.83 g/dl above baseline were observed, whereas no increases occurred in placebo‐treated controls. These findings of favorable PK profiles, tolerability, early rises in HbF, and total Hgb indicate that trials of longer duration appear warranted to more definitively evaluate the therapeutic potential of HQK‐1001 in sickle cell disease. Am. J. Hematol., 2012. © 2012 Wiley Periodicals, Inc.     

The relationship between hyperuricemia and anemia and metabolic syndrome in Korean adults: The Korea National Health and Nutrition Examination Survey 2019

AimThe present study was conducted to assess the relationship between hyperuricemia and anemia in Korean adults with or without metabolic syndrome (MetS).MethodsData from 6073 adults (age ≥ 20 years) in the Eighth Korean National Health and Nutrition Examination Survey (2019) were analyzed.ResultsSeveral key findings were identified. First, after adjusting for the related variables, the hemoglobin [Hb] level in the hyperuricemia subgroup (uric acid [UA] ≥ 7.0 mg/dL in men or ≥ 6.0 mg/dL in women) was higher than in the normouricemia subgroup (UA < 7.0 mg/dL in men or < 6.0 mg/dL in women) in subjects with non-MetS (p = 0.005), whereas it was lower than in the normouricemia subgroup in subjects with MetS (p = 0.032). Second, after adjusting for the related variables, the odds ratio (OR) of anemia (Hb < 13.0 g/dL in men or < 12 g/dL in women), using the normouricemia subgroup as a reference, was negatively significant for the hyperuricemia subgroup in subjects with non-MetS (OR, 0.478; 95 % CI, 0.300–0.761) but positively significant for the hyperuricemia subgroup in subjects with MetS (OR, 1.765; 95 % CI, 1.160–2.198).ConclusionsHyperuricemia was associated with a decrease in anemia in non-MetS but an increase in anemia in MetS.     

Role of IL‐28B and inosine triphosphatase polymorphisms in efficacy and safety of Peg‐Interferon and ribavirin in chronic hepatitis C compensated cirrhosis with and without oesophageal varices

Summary. Genetic factors can influence the outcome of antiviral therapy in chronic hepatitis C (HCV). We evaluated the role of interleukin‐28B single nucleotide polymorphisms (SNPs) and inosine triphosphatase (ITPA) gene variants in HCV cirrhosis treated with Peg‐Interferon and ribavirin. A prospective cohort of 233 patients with compensated cirrhosis received 1–1.5 μg/kg/week of Peg‐Interferon alpha‐2b plus 1000–1200 mg/day of RBV for 48 weeks. A sustained virologic response (SVR) was achieved in 27% of patients. On multivariate logistic analysis, the absence of oesophageal varices (OR 3.64 CI 95% 1.27–10.44 P = 0.016), infection with genotype 2 or 3 (OR 4.06, CI 95% 1.08–15.26, P = 0.038), C/C alleles of rs12979860 SNP (OR 7.04, CI 95% 2.40–20.72, P < 0.001) and rapid virologic response (RVR) (OR 78.29, CI 95% 16.07–381.29, P < 0.001) were independently associated with SVR. Patients who experienced post‐treatment relapse received lower total doses of Peg‐Interferon (52.0 ± 15.8 μg/kg vs 65.7 ± 13.3 μg/kg, P < 0.001) and lower total dose of RBV (3829 ± 1210 mg vs 4709 ± 954 mg, P < 0.001) than patients who achieved an SVR. ITPA variants predictive of high ITPase activity were associated with reduction of haemoglobin ≥3 g/dL in the first 4 weeks (P < 0.001), and with reduction of haemoglobin <10 g/dL (P = 0.03) on treatment. In conclusion, combination therapy with Peg‐Interferon and RBV in patients with HCV cirrhosis must be guided by virus genotype, severity of portal hypertension, favourable IL‐28B polymorphisms and ITPA variants, and RVR on treatment.     

Low dose erythropoietin‐beta improves anemia and maintains ribavirin dose in chronic hepatitis C patients receiving combination therapy with ribavirin plus pegylated interferon Alfa‐2b

Aim: Anemia during combination therapy with pegylated interferon alfa‐2b plus ribavirin (RBV) for chronic hepatitis C virus (HCV) patients usually leads to RBV dose reduction or discontinuation. This study evaluated the effect of erythropoietin‐beta (EPO‐β) to maintain RBV dose and hemoglobin (Hb) level in chronic HCV patients treated with antiviral combination therapy. Methods: Eighty‐eight chronic HCV patients who developed anemia during therapy were enrolled into this retrospective study: 55 in the EPO‐β group and 33 in the untreated group. The study endpoints were to assess the RBV maintenance and the changes in Hb. Results: A higher percentage of patients with RBV maintenance was observed in the EPO‐β group compared with the untreated group (nadir Hb level <10.5 g/dL; 70% vs. 38%, P = 0.020; nadir Hb < 10 g/dL; 62% vs. 27%, P = 0.046). The mean Hb change from week 12 to week 20 was higher in the EPO‐β group when compared with the untreated group, especially for patients receiving a total EPO‐β dose of more than 16 000 U (+0.70 g/dL vs. ?0.32 g/dL, P = 0.023) and of 10 000 U‐14 000 U (+0.60 g/dL vs. ?0.32 g/dL, P = 0.023). Conclusions: Low‐dose EPO‐β can maintain RBV dose and increase Hb levels in anemic chronic HCV patients receiving combination therapy.     

Association between promoter and coding region mutations of UDP-glucuronosyltransferase 1A1 and beta-thalassemia/Hb E with cholelithiasis

Background and objectives:  Cholelithiasis has been observed with high incidence in beta‐thalassemia/hemoglobin E (β‐thal/Hb E). Recent studies have shown that a variant TATA‐box in the promoter region of the UDP‐glucuronosyltransferase 1A1 (UGT1A1) gene is associated with the development of cholelithiasis. The coding region mutation (G71R) of the UGT1A1 gene was higher in Asians than those in Caucasians. The relationship between the variant UGT1A1 promoter and coding region gene and cholelithiasis in β‐thal/Hb E subjects were investigated. Methods:  One hundred and seventeen β‐thal/Hb E subjects entered this study. The TATA‐box and G71R mutations were analyzed by fragment size analysis and restriction fragment length polymorphism methods, respectively. Results:  The incidence of cholelithiasis was higher in heterozygous (68.3%) and homozygous (100%) subjects compared with normal UGT1A1 haplotype (61.4%). Total bilirubin level (6.0 ± 2.03 mg/dL) in the homozygous group was significantly higher than that of wild type (3.31 ± 1.83 ng/dL). Prevalence of cholelithiasis increased with age (OR = 1.1, 95% CI = 1.03–1.12, P < 0.001). Female gender (OR = 3.7, 95% CI = 1.3–10.6, P < 0.01) and elevated liver enzyme (OR = 1.02, 95%CI = 1.0–1.04, P < 0.02) were two other risk factors for cholethiasis in β‐thal/Hb E. Conclusion:  This study shows that the combined TATA‐box variants and G71R mutations of the UGT1A1 is associated with cholelithiasis in β‐thal/Hb E.     

Glucose homeostasis abnormalities among Cameroon patients with newly diagnosed hypertension

The authors assessed the frequency of glucose homeostasis abnormalities among 839 Cameroonians with newly diagnosed hypertension (mean age: 50.8±11 years; 49.9% female) in a cross‐sectional survey conducted at the Douala General Hospital, Douala, Cameroon. In all participants, blood pressure, fasting plasma glucose (FPG), and lipids were recorded. Impaired fasting glycemia was described as an FPG level between 100 and 125 mg/dL and provisional diabetes as an FPG level ≥126 mg/dL. The FPG was 101±30 mg/dL. The overall proportion of abnormal glucose homeostasis was 38.3%, while 7.7% of patients (n=65) had known diabetes. A total of 23.7% (n=199) had impaired fasting glycemia and 6.8% (n=57) had provisional diabetes. Multivariable logistic regression revealed that male sex (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.15–2.06), age older than 55 years (OR, 1.55; 95% CI, 1.15–2.09), and low‐density lipoprotein cholesterol >1 g/L (OR, 1.34; 95% CI, 1.00–1.82) were independently associated with abnormal glucose homeostasis (all P<.05). Glucose homeostasis abnormalities are highly prevalent among Cameroonian patients with newly diagnosed hypertension.     

Multicenter study of darbepoetin alfa in the treatment of anemia secondary to chronic renal insufficiency on dialysis

This Spanish single-arm, multicenter, prospective clinical trial assessed the maintenance of hemoglobin concentrations (Hb) between 10-13 g/dL with unit doses of darbepoetin alfa and the safety of the treatment in dialysis patients. Eight-hundred twenty-six patients with chronic renal failure (CRF) (94% receiving haemodialysis and 6% receiving peritoneal dialysis) previously maintained on stable recombinant human erythropoietin (r-HuEPO) therapy with stable hemoglobin (Hb) concentrations (mean Hb concentration = 11.7 g/dL) were switched to darbepoetin alfa at a reduced dosing frequency for 24 weeks (a 20-week titration phase plus a 4-week treatment evaluation phase). Subjects receiving r-HuEPO two or three times weekly were switched to darbepoetin alfa once weekly, and those. who were receiving r-HuEPO once weekly were switched to darbepoetin alfa once every two weeks. The initial dose of darbepoetin alfa was determined from the r-HuEPO dose at inclusion into the study using a formula equating the peptide mass of the two molecules and rounding to the nearest available prefilled syringe dose. Overall, 86.8% of patients completed the 24-weeks of study. Changing the treatment from r-HuEPO to darbepoetin alfa and increasing the dose interval did not result in any clinically significant change in the Hb concentration. From base-line to the evaluation phase, the mean Hb fell 0.09 (95% CI, -0.2; -0.0) g/dl, with an increase of 0.19 (95% CI, 0.0;0.3) g/dL i.v. and a decrease of 0.22 (95% CI, -0.3; -0.1) g/dL s.c.). This maintenance of the mean Hb concentration was accompanied by a mean 9.8% reduction of the darbepoetin alfa dose (19.7% (95% CI, -24.9; -14.2) i.v. and 4.7% (95% CI, -8.5; -0.7) s.c. Treatment with darbepoetin alfa was well tolerated and no unexpected adverse events were reported. In conclusion, the replacement of previous r-HuEPO treatment by darbepoetin alfa in the therapy of anemia secondary to chronic renal failure in diaiyzed patients was effective, well tolerated, and decreased the frequency of dose administration compared with the previous r-HuEPO treatment. Darbepoetin alfa administered once weekly or once every two weeks maintained the baseline Hb levels whilst allowing dose reduction, which was higher in patients receiving i.v. darbepoetin alfa.     

An open-label study of darbepoetin alfa administered once monthly for the maintenance of haemoglobin concentrations in patients with chronic kidney disease not receiving dialysis

OBJECTIVE: To demonstrate the efficacy and safety of once-monthly (QM) darbepoetin alfa administration in maintaining haemoglobin (Hb) 11.0-13.0 g dL(-1) in subjects with chronic kidney disease (CKD) not receiving dialysis and previously treated with darbepoetin alfa every other week (Q2W). SUBJECTS: This open-label study enrolled subjects > or =18 years of age who had glomerular filtration rate > or =15 and < or =60 mL min(-1)/1.73 m(2), had Hb 11.0-13.0 g dL(-1), and were receiving Q2W darbepoetin alfa. DESIGN: Subjects were switched to QM darbepoetin alfa therapy for 28 weeks; the QM dose was titrated to maintain Hb levels. Primary end-point: proportion of subjects maintaining Hb > or =11.0 g dL(-1) during the final 8 weeks of the study (evaluation phase). Secondary end-points: Hb concentration during evaluation, darbepoetin alfa dose during the study, adverse events, laboratory parameters, and blood pressure. RESULTS: The study enrolled 152 subjects (female 52%, white 64%). Mean Hb > or =11.0 g dL(-1) during evaluation was achieved by 76% of the 150 subjects who received at least one dose of darbepoetin alfa [95% confidence interval (CI): 68%, 83%]. Mean (SD) Hb during evaluation was 11.71 (0.92) g dL(-1). Eighty-five per cent of 129 subjects who completed the study (95% CI: 78%, 91%) had Hb > or =11.0 g dL(-1) during evaluation. The dose of darbepoetin alfa over the study period was median (95% CI) 124.4 mug (106.2, 140.0). Darbepoetin alpha administered QM was well tolerated in study subjects. CONCLUSION: Darbepoetin alpha administered QM maintained Hb in study subjects with CKD not receiving dialysis.     

Association of Thiazide‐Type Diuretics With Glycemic Changes in Hypertensive Patients: A Systematic Review and Meta‐Analysis of Randomized Controlled Clinical Trials

Patients receiving thiazide diuretics have a higher risk of impaired glucose tolerance or even incident diabetes, but the change of blood glucose level varies across different trials. The aim of this study was to investigate the glycemic changes in hypertensive patients with thiazide‐type diuretics. Twenty‐six randomized trials involving 16,162 participants were included. Thiazide‐type diuretics were found to increase fasting plasma glucose (FPG) compared with nonthiazide agents or placebo or nontreatment (mean difference [MD], 0.27 mmol/L [4.86 mg/dL]; 95% confidence interval [CI], 0.15–0.39). Patients receiving lower doses of thiazides (hydrochlorothiazide or chlorthalidone ≤25 mg daily) had less change in FPG (MD, 0.15 mmol/L [2.7 mg/dL]; 95% CI, 0.03–0.27) than those receiving higher doses (MD, 0.60 mmol/L [10.8 mg/dL]; 95% CI, 0.39–0.82), revealed by the subgroup analysis of thiazides vs calcium channel blockers. Thiazide‐type diuretics are associated with significant but small adverse glycemic effects in hypertensive patients. Treatment with a lower dose might reduce or avoid glycemic changes.     

Prevalence and predictive factors of diabetes in hepatitis virus positive liver cirrhosis with fasting plasma glucose level of <126 mg/dL

Aim: The aim of this study was to evaluate the prevalence and predictive factors of diabetes in hepatitis virus positive liver cirrhotic patients with fasting plasma glucose (FPG) level of <126 mg/dL. Methods: A total of 263 patients with hepatitis C virus (HCV) or hepatitis B virus (HBV) positive liver cirrhosis, FPG level of <126 mg/dL, and had diabetes status evaluated by the use of 75‐g oral glucose tolerance test (OGTT), were enrolled in this study. Plasma glucose and insulin levels were analyzed periodically for 3 h after oral glucose loading. Diabetes was defined as a 2‐h post‐load glucose on the OGTT of ≥200 mg/dL. The prevalence of diabetes by use of OGTT and predictive factors for diabetes were evaluated by the use of the Mann–Whitney U‐test, Fisher's exact probability test or multivariate analysis by logistic regression. Hypoalbuminemia was defined as serum albumin level of <3.9 g/dL. Elevated indocyanine green retention rate at 15 min (ICG _R15) was regarded as ≥ 25%. Results: Out of 263 patients, 44 (16.7%) were diagnosed as having diabetes. Multivariate analysis showed that diabetes occurred when patients had hypoalbuminemia of <3.9 g/dL (odds ratio [OR] 2.33; 95% confidential interval [CI] = 1.04–5.24; P = 0.040) and ICG _R15 of <25% (OR 2.36; 95%CI = 1.01–5.58). Conclusions: Hypoalbuminemia and elevated ICG _R15 in hepatitis virus related cirrhotic patients with FPG level of <126 mg/day enhance diabetes pattern after OGTT with significant difference.     

A 24‐Week Anemia Correction Study of Daprodustat in Japanese Dialysis Patients

Daprodustat is an oral hypoxia‐inducible factor prolyl hydroxylase inhibitor developed for treating anemia of chronic kidney disease. This 24‐week, phase 3, open‐label study (NCT02829320) evaluated whether daprodustat could achieve and maintain target hemoglobin levels in Japanese hemodialysis patients with anemia not receiving an erythropoiesis‐stimulating agent. Twenty‐eight patients received daprodustat 4 mg once daily for 4 weeks, after which doses were adjusted to achieve a hemoglobin target of 10.0 to 12.0 g/dL (inclusive). Baseline mean hemoglobin was 9.10 g/dL and mean change from baseline at 4 weeks was 0.79 g/dL (95% CI, 0.53 to 1.05). Mean hemoglobin levels reached the target range by week 8 and were maintained within this range through week 24. Daprodustat 4 mg once daily increased hemoglobin over the first 4 weeks. Throughout the 24‐week study, daprodustat achieved and maintained hemoglobin within the target range and no new safety concerns were identified in hemodialysis patients not receiving erythropoiesis‐stimulating agents.     

Cardiovascular risk modification in participants with coronary disease screened by the Kidney Early Evaluation Program

Background: Coronary artery disease (CAD) identifies the need for intensive treatment of risk factors among individuals with chronic kidney disease (CKD), a high‐risk, complex cardiovascular risk state. Methods: An estimated glomerular filtration rate <60 mL/min/1.73 m² or a urine albumin : creatinine ratio (ACR) ≥ 30 mg/g (3.4 mg/mmol) defined CKD. Results: Of 70 454 volunteers screened the mean age was 53.5 ± 15.7 years and 68.3% were female. A total of 5410 (7.7%) had a self‐reported history of CAD; 1295 (1.8%) had a history of prior percutaneous coronary intervention (PCI); and 1124 (1.6%) had a prior history of coronary artery bypass surgery (CABG). Multivariate analysis for the outcome of suboptimal CAD risk management (composite of systolic blood pressure ≥130 mmHg, glucose ≥125 mg/dL (6.9 mmol/L) for diabetics, total cholesterol ≥200 mg/dL (5.2 mmol/L), or current smoking; n= 38 746/53 403, 72.5%) revealed older age (per year) (odds ratio (OR) = 1.04, 95% confidence interval (CI) 1.03–1.04, P < 0.0001), male gender (OR = 1.40, 95% CI 1.34–1.47, P < 0.0001), ACR ≥ 30 mg/g (3.4 mg/mmol) (OR = 1.66, 95% CI 1.55–1.79, P < 0.0001), body mass index (per kg/m²) (OR = 1.06, 95% CI 1.06–1.06, P < 0.0001), CAD without a history of revascularization (OR = 1.14, 95% CI 1.02–1.28, P= 0.02) and care received by a nephrologist (OR = 1.49, 95% CI 1.22–1.83, P < 0.0001) were associated with worse risk factor control. Prior coronary revascularization and being under the care of a cardiologist were not associated with either improved or suboptimal risk factor control. Conclusions: Chronic kidney disease is associated with overall poor rates of CAD risk factor control.     

Small dense low‐density lipoprotein cholesterol is a promising biomarker for secondary prevention in older men with stable coronary artery disease

Aim

The study objective was to investigate whether small dense low‐density lipoprotein cholesterol (sdLDL‐C) is superior to low‐density lipoprotein cholesterol (LDL‐C) and other biomarkers to predict future cardiovascular events (CE) in secondary prevention.

Methods

sdLDL‐C measured by a homogeneous assay, remnant lipoprotein cholesterol, LDL particle diameter and other biomarkers were compared in 345 men aged ≥65 years with stable coronary artery disease. Baseline LDL‐C was 100.5 ± 30.1 mg/dL. CE including cardiovascular death, onset of acute coronary syndrome, need for arterial revascularization, hospitalization for heart failure, surgery procedure for cardiovascular disease and hospitalization for stroke were monitored for 5 years.

Results

CE occurred in 96 patients during the study period. LDL‐C, sdLDL‐C non‐high‐density lipoprotein cholesterol, apolipoprotein B, remnant lipoprotein cholesterol, glucose, glycated hemoglobin and brain natriuretic peptide were significantly higher; LDL particle diameter and apolipoprotein A‐1 were significantly lower in patients with than in those without CE. Age‐adjusted Cox regression analysis showed that sdLDL‐C per 10 mg/dL, but not LDL‐C, was significantly associated with CE (HR 1.206, 95% CI 1.006–1.446). A significant association of sdLDL‐C and incident CE was observed in statin users (HR 1.252, 95% CI 1.017–1.540), diabetes patients (HR 1.219, 95% CI 1.018–1.460), patients without diabetes (HR 1.257, 95% CI 1.019–1.551) and patients with hypertriglyceridemia (HR 1. 376, 95% CI 1.070–1.770).

Conclusions

sdLDL‐C was the most effective predictor of residual risk of future CE in stable coronary artery disease patients using statins and in high‐risk coronary artery disease patients with diabetes or hypertriglyceridemia. Geriatr Gerontol Int 2018; 18: 965–972 .     

Pharmacokinetic and pharmacodynamic profile of the sodium‐glucose co‐transporter‐2 inhibitor empagliflozin in young people with Type 2 diabetes: a randomized trial

Aims

To assess the pharmacokinetic and pharmacodynamic profile of a single dose of empagliflozin in young people with Type 2 diabetes to identify the appropriate doses for further paediatric development.

Methods

We conducted a single‐dose, open‐label, randomized, parallel‐group study with empagliflozin 5 mg, 10 mg and 25 mg in young people with Type 2 diabetes aged 10–17 years.

Results

Of 39 participants screened, 27 were randomized and completed the study; their mean (± sd ) age was 14.1±2.0 years and body weight was 96.7±23.5 kg. Compared with similar studies in adults with Type 2 diabetes, the maximum observed plasma concentrations were slightly lower with the 10‐mg and 25‐mg doses, and the area under the plasma concentration–time curve was slightly lower with the 10‐mg but slightly higher with the 25‐mg dose. The adjusted mean increases in urinary glucose excretion were 53 g/24 h (95% CI 32,74), 73 g/24 h (95% CI 52,94) and 87 g/24 h (95% CI 68,107), and the adjusted mean decreases in fasting plasma glucose were 0.9 mmol/l (95% CI –1.6,–0.1), 0.9 mmol/l (95% CI –1.7,–0.2) and 1.1 mmol/l (95% CI –1.8,–0.5) for the 5‐ 10‐ and 25‐mg doses, respectively. There were no serious adverse events and one investigator‐reported drug‐related event (dehydration).

Conclusions

After a single oral dose of empagliflozin, adults and young people with Type 2 diabetes had similar exposure–response relationships after adjusting for significant covariates. These data support testing 10‐mg and/or 25‐mg doses of empagliflozin in an upcoming paediatric phase III Type 2 diabetes trial. (ClinicalTrials.gov registration no.: NCT02121483).