Hypoxia-inducible factor prolyl hydroxylase inhibitors stabilize levels of hypoxia-inducible factor that upregulate transcription of multiple genes associated with the response to hypoxia, including production of erythropoietin. We conducted two phase 2a studies to explore the relationship between the dose of the hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 and hemoglobin response in patients with anemia of CKD (baseline hemoglobin 8.5-11.0 g/dl) not undergoing dialysis and not receiving recombinant human erythropoietin (nondialysis study) and in patients with anemia of CKD (baseline hemoglobin 9.5-12.0 g/dl) on hemodialysis and being treated with stable doses of recombinant human erythropoietin (hemodialysis study). Participants were randomized 1:1:1:1 to a once-daily oral dose of GSK1278863 (0.5 mg, 2 mg, or 5 mg) or control (placebo for the nondialysis study; continuing on recombinant human erythropoietin for the hemodialysis study) for 4 weeks, with a 2-week follow-up. In the nondialysis study, GSK1278863 produced dosedependent effects on hemoglobin, with the highest dose resulting in a mean increase of 1 g/dl at week 4. In the hemodialysis study, treatment with GSK1278863 in the 5-mg arm maintained mean hemoglobin concentrations after the switch from recombinant human erythropoietin, whereas mean hemoglobin decreased in the lower-dose arms. In both studies, the effects on hemoglobin occurred with elevations in endogenous erythropoietin within the range usually observed in the respective populations and markedly lower than those in the recombinant human erythropoietin control arm in the hemodialysis study, and without clinically significant elevations in plasma vascular endothelial growth factor concentrations. GSK1278863 was generally safe and well tolerated at the doses and duration studied. GSK1278863 may prove an effective alternative for managing anemia of CKD. 27: 123427: -124427: , 201627: . doi: 10.1681 Advanced CKD is frequently associated with anemia 1,2 and its pathogenesis is multifactorial, inclusive of a relative deficiency of erythropoietin (EPO) and impaired absorption and utilization of iron. 3 Current guidelines and recommendations for anemia management in CKD advise treatment with supplemental iron and recombinant human erythropoietins (rhEPOs) if appropriate. rhEPO therapy led to a correction of hemoglobin levels in the majority of dialysis patients 12 and a reduction in the need for red blood cell transfusions. 12 However, several large randomized trials of rhEPO have reported adverse cardiovascular outcomes. The Normal Hematocrit Study, which aimed to normalize hematocrit at 42% versus maintaining it at 30%, was terminated early because of concerns from the independent data monitoring committee around the higher all-cause mortality rate in the normal hematocrit arm compared with the low hematocrit arm, even though the prespecified termination criterion of an overall 5% significance was not met. The Correction of Hemoglobin and Outcomes in Renal Insufficien...

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OBJECTIVE -The goals of this study were to determine whether improvements in metabolic control can ameliorate the cognitive dysfunction associated with type 2 diabetes and evaluate the possibility that such improvements are mediated by changes in circulating insulin or insulin resistance. RESEARCH DESIGN AND METHODS -This randomized double-blind trial enrolled145 subjects at 18 centers in the U.S. Older adults with type 2 diabetes receiving metformin monotherapy received add-on therapy with either rosiglitazone, a thiazolidinedione insulin sensitizer, or glyburide. Cognitive function was assessed at baseline and week 24 using the Digit Symbol Substitution Test, the Rey Auditory Verbal Learning Test, and the Cambridge Neuropsychological Test Automated Battery.RESULTS -Pretreatment fasting plasma glucose (FPG) in both groups was similar, and after 24 weeks both treatment groups showed similar significant reductions in FPG (2.1-2.3 mmol/l). Working memory improved with both rosiglitazone (P Ͻ 0.001) and glyburide (P ϭ 0.017). Improvement (25-31% reduction in errors) was most evident on the Paired Associates Learning Test and was significantly correlated (r ϭ 0.30) with improved glycemic control as measured by FPG.CONCLUSIONS -Similar and statistically significant cognitive improvement was observed with both rosiglitazone and glyburide therapy, and the magnitude of this effect was correlated with the degree to which FPG improved. These results suggest that a cognitive benefit is achievable with pharmacological interventions targeting glycemic control. Diabetes Care 29:345-351, 2006O lder adults with type 2 diabetes have an increased risk of cognitive dysfunction. Memory and mental processing speed are the cognitive domains most often compromised, whereas other cognitive skills (e.g., attention, problem-solving, and general intelligence) tend to be unaffected (1-3). Whether cognitive deterioration is a direct consequence of chronically elevated blood glucose levels or whether it reflects diabetes-associated hyperinsulinemia has not yet been determined, but increasing evidence suggests that elevated insulin levels may be associated with adverse effects on cognition (4 -6) and an increased risk of Alzheimer's dementia (7).If chronically elevated glucose and/or insulin levels are linked to poorer cognitive performance, one might predict that efforts to improve glycemic control or reduce hyperinsulinemia would ameliorate cognitive function or attenuate its decline. Results from three small studies provide only limited support for that possibility. Gradman et al. (8) treated 23 diabetic adults with glipizide for up to 7 months and found both a reduction in fasting plasma glucose (FPG) levels and marked improvement on a verbal learning test; other cognitive skills were unaffected. By comparison, no changes in either FPG or cognition were seen in an untreated group of 13 nondiabetic control subjects. Circumscribed improvements in cognition have also been reported in 16 diabetic adults over a 7-month period (9) and in two gr...

BackgroundThis study evaluated the hemoglobin dose response, other efficacy measures and safety of daprodustat, an orally administered, hypoxia-inducible factor prolyl hydroxylase inhibitor in development for anemia of chronic kidney disease.MethodsParticipants (n = 216) with baseline hemoglobin levels of 9–11.5 g/dL on hemodialysis (HD) previously receiving stable doses of recombinant human erythropoietin (rhEPO) were randomized in a 24-week dose-range, efficacy and safety study. Participants discontinued rhEPO and then were randomized to receive daily daprodustat (4, 6, 8, 10 or 12 mg) or control (placebo for 4 weeks then open-label rhEPO as required). After 4 weeks, doses were titrated to achieve a hemoglobin target of 10–11.5 g/dL. The primary outcome was characterization of the dose–response relationship between daprodustat and hemoglobin at 4 weeks; additionally, the efficacy and safety of daprodustat were assessed over 24 weeks.ResultsOver the first 4 weeks, the mean hemoglobin change from baseline increased dose-dependently from −0.29  (daprodustat 4 mg) to 0.69 g/dL (daprodustat 10 and 12 mg). The mean change from baseline hemoglobin (10.4 g/dL) at 24 weeks was 0.03 and −0.11 g/dL for the combined daprodustat and control groups, respectively. The median maximum observed plasma EPO levels in the control group were ∼14-fold higher than in the combined daprodustat group. Daprodustat demonstrated an adverse event profile consistent with the HD population.ConclusionsDaprodustat produced dose-dependent changes in hemoglobin over the first 4 weeks after switching from a stable dose of rhEPO as well as maintained hemoglobin target levels over 24 weeks.