Long-Term Safety of Dapagliflozin in Older Patients with Type 2 Diabetes Mellitus: A Pooled Analysis of Phase IIb/III Studies.

Objective: To evaluate the 104-week safety of dapagliflozin in older patients with type 2 diabetes mellitus.

Methods: Pooled analysis assessing general safety (nine phase III studies ≤104 weeks) and cardiovascular safety (21 phase IIb/III studies ≤208 weeks) by age (<65; ≥65; ≥75 years). Patients with type 2 diabetes mellitus (±background glucose-lowering therapy) received: dapagliflozin 10 mg (n = 2026) vs.

Osmotic diuresis with SGLT2 inhibition: analysis of events related to volume reduction in dapagliflozin clinical trials.

Objective: Dapagliflozin reduces hyperglycemia in type 2 diabetes mellitus (T2DM) and lowers blood pressure, at least in part, secondary to mild diuresis consequent to dapagliflozin-induced glucosuria. While blood-pressure lowering may contribute to cardiovascular risk reduction, dapagliflozin-induced diuresis may potentially contribute to adverse events (AEs) of volume reduction. The present analysis compared the frequency of AEs of volume reduction between dapagliflozin and placebo.

Effect of the SGLT2 Inhibitor Dapagliflozin on Potassium Levels in Patients with Type 2 Diabetes Mellitus: A Pooled Analysis.

Introduction: Hyperkalemia risk is increased in diabetes, particularly in patients with renal impairment or those receiving angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) or potassium-sparing diuretics. Conversely, other diuretics can increase hypokalemia risk. We assessed the effects of the sodium glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin on serum potassium levels in a pooled analysis of clinical trials in patients with type 2 diabetes mellitus (T2DM).

Effects of dapagliflozin on blood pressure in hypertensive diabetic patients on renin-angiotensin system blockade.

Hypertension and type 2 diabetes mellitus (T2DM) are risk factors for cardiovascular disease. Dapagliflozin improves glycemic control and systolic blood pressure (SBP) in T2DM patients. This double-blind phase III study evaluated the effects of dapagliflozin on glycemic control and blood pressure in patients with inadequately controlled T2DM and hypertension, despite ongoing therapy with a renin-angiotensin system blocker.

Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study.

Background: Hypertension is a common comorbidity in patients with type 2 diabetes mellitus and a major risk factor for microvascular and macrovascular disease. Although the blood pressure-lowering effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors are already established, guidance is needed on how to use these drugs in patients already receiving antihypertensive therapy. We aimed to compare blood pressure and glycaemic effects of the SGLT2 inhibitor dapagliflozin with placebo in patients with inadequately controlled type 2 diabetes mellitus and hypertension.

Dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes mellitus: a randomized, blinded, prospective phase III study.

Objective: Dapagliflozin is a highly selective, orally active inhibitor of renal sodium-glucose cotransporter 2 that reduces hyperglycemia by increasing urinary glucose excretion. The goal of this study was to evaluate dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes whose disease was inadequately controlled with diet and exercise.

Methods: In this Phase III, multicenter, parallel-group, double-blind study, drug-naive patients with glycosylated hemoglobin (HbA1c) levels ≥7.

Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial.

Background: Management of type 2 diabetes with metformin often does not provide adequate glycemic control, thereby necessitating add-on treatment. In a 24-week clinical trial, dapagliflozin, an investigational sodium glucose cotransporter 2 inhibitor, improved glycemic control in patients inadequately controlled with metformin. The present study is an extension that was undertaken to evaluate dapagliflozin as long-term therapy in this population.

Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis.

Farnesoid X receptor (FXR) is a bile acid-activated transcription factor that is a member of the nuclear hormone receptor superfamily. Fxr-null mice exhibit a phenotype similar to Byler disease, an inherited cholestatic liver disorder. In the liver, activation of FXR induces transcription of transporter genes involved in promoting bile acid clearance and represses genes involved in bile acid biosynthesis.

Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis.

The nuclear bile acid receptor FXR has been proposed to play a central role in the feedback repression of the gene encoding cholesterol 7 alpha-hydroxylase (CYP7A1), the first and rate-limiting step in the biosynthesis of bile acids. We demonstrate that FXR directly regulates expression of fibroblast growth factor-19 (FGF-19), a secreted growth factor that signals through the FGFR4 cell-surface receptor tyrosine kinase. In turn, FGF-19 strongly suppresses expression of CYP7A1 in primary cultures of human hepatocytes and mouse liver through a c-Jun N-terminal kinase (JNK)-dependent pathway.

Application of toxicogenomics to drug development.

The application of advanced modern biomedical and chemical research technologies in the pharmaceutical industry has led to a significant increase in the number of potential drug targets and lead candidates. Whereas the drug discovery process is enhanced significantly, the failure rate of new compounds due to toxicity remains very high. The pharmaceutical industry is setting high hopes on the new discipline of toxicogenomics to revolutionize the process of drug toxicity assessment by reducing the bottleneck of new drug candidates and minimizing late-stage developmental failures.

The Chediak-Higashi protein interacts with SNARE complex and signal transduction proteins.

Background: Chediak-Higashi syndrome (CHS) is an inherited immunodeficiency disease characterized by giant lysosomes and impaired leukocyte degranulation. CHS results from mutations in the lysosomal trafficking regulator (LYST) gene, which encodes a 425-kD cytoplasmic protein of unknown function. The goal of this study was to identify proteins that interact with LYST as a first step in understanding how LYST modulates lysosomal exocytosis.