Pharmacodynamic differences between canagliflozin and dapagliflozin: results of a randomized, double-blind, crossover study.

AIMS: To compare the pharmacodynamic effects of the highest approved doses of the sodium glucose co-transporter 2 (SGLT2) inhibitors canagliflozin and dapagliflozin on urinary glucose excretion (UGE), renal threshold for glucose excretion (RTG ) and postprandial plasma glucose (PPG) excursion in healthy participants in a randomized, double-blind, two-period crossover study. METHODS: In each treatment period, participants (n = 54) received canagliflozin 300 mg or dapagliflozin 10 mg for 4 days (20 min before breakfast). A mixed-meal tolerance test (600 kcal; 75 g glucose) was performed at baseline and on day 4 of each treatment period to assess changes in incremental PPG (PPGΔAUC0-2 h ). We measured 24-h UGE and plasma glucose on day 4 to determine 24-h mean RTG . RESULTS: Canagliflozin 300 mg and dapagliflozin 10 mg had similar effects on UGE and RTG for 4 h after dosing, but canagliflozin was associated with higher UGE and greater RTG reductions for the remainder of the day. Mean 24-h UGE was ∼25% higher with canagliflozin than with dapagliflozin (51.4 vs. 40.8 g), and 24-h mean RTG was ∼0.4 mmol/l (7 mg/dl) lower with canagliflozin than with dapagliflozin (3.79 vs. 4.17 mmol/l; p < 0.0001). Dapagliflozin had no effect on PPG excursion; canagliflozin delayed and reduced PPG excursion (between-treatment difference in PPGΔAUC0-2 h from baseline expressed as a percentage of baseline mean, -10.2%; p = 0.0122). Canagliflozin and dapagliflozin were generally well tolerated. CONCLUSIONS: In healthy participants, canagliflozin 300 mg provided greater 24-h UGE, a lower RTG and smaller PPG excursions than dapagliflozin 10 mg.

CCR2 antagonism in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study.

AIMS: Macrophage recruitment through C-C motif chemokine receptor-2 (CCR2) into adipose tissue is believed to play a role in the development of insulin resistance and type 2 diabetes mellitus (T2DM). The objective of this Phase 2 proof-of-concept study was to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of JNJ-41443532, an orally bioavailable CCR2 antagonist, in patients with T2DM. METHODS: This was a 4-week, double-blind, placebo-controlled, randomized, multicenter study. A total of 89 patients were randomized to receive either 250- or 1000-mg of JNJ-41443532 twice daily, 30-mg of pioglitazone once daily (reference arm), or placebo. The primary endpoint was change from baseline in 23-h weighted mean glucose (WMG); secondary endpoints included change from baseline in fasting plasma glucose (FPG), insulin resistance (Homeostatic Model Assessment [HOMA-IR]), insulin secretion (HOMA-%B) and body weight. RESULTS: Absorption of JNJ-41443532 into the systemic circulation occurred at a median tmax of 2 h, and the mean t½ was approximately 8 h for both doses; plasma systemic exposures increased slightly more than dose-proportionally. After 4 weeks, reductions in 23-h WMG and FPG were observed in all treatment groups compared with placebo and were significantly lower for 250-mg JNJ-41443532 and pioglitazone. HOMA-IR was lower for all treatment groups, but significantly lower only for pioglitazone. Conversely, HOMA-%B was increased for all groups, but significantly increased only for 250-mg JNJ-41443532. All groups, including placebo, had decreased body weight over time. There were no clinically significant findings during routine safety assessments and the incidence of treatment-emergent adverse events was similar across all groups. CONCLUSIONS: Administration of JNJ-41443532 resulted in modest improvement in glycaemic parameters compared with placebo, and was generally well tolerated in patients with T2DM.

Effects of JNJ-38431055, a novel GPR119 receptor agonist, in randomized, double-blind, placebo-controlled studies in subjects with type 2 diabetes.

AIM: G-protein coupled receptor agonists are currently under investigation for their potential utility in patients with type 2 diabetes mellitus (T2DM). The objective was to determine the pharmacokinetics, pharmacodynamics, safety and tolerability of GPR119 agonist, JNJ-38431055 in T2DM subjects. METHODS: This was a randomized, double-blind, placebo- and positive-controled, single-dose cross-over study and a randomized, double-blind, placebo-controled multiple-dose parallel design study. The study was conducted at 4 US research centres. Two different experiments involving 25 and 32 different subjects were performed in male and female subjects, aged 25-60 years, mean body mass index between 22 and 39.9 kg/m2 who had T2DM diagnosed 6 months to 10 years before screening. JNJ-38431055 (100 and 500 mg) or sitagliptin (100 mg) as a single-dose or JNJ-38431055 (500 mg) once daily for 14 consecutive days were tested. Effects on stimulated plasma glucose, insulin, C-peptide and incretin concentrations were pre-specified outcomes. RESULTS: JNJ-38431055 was well tolerated and not associated with hypoglycaemia. Plasma systemic exposure of JNJ-38431055 increased as the dose increased, was approximately two-fold greater after multiple-dose administration, and attained steady-state after approximately 8 days. Compared with placebo, single-dose administration of oral JNJ-38431055 decreased glucose excursion during an oral glucose tolerance test, but multiple-dose administration did not alter 24-h weighted mean glucose. Multiple dosing of JNJ-38431055 increased post-meal total glucagon-like peptide 1 and gastric insulinotropic peptide concentrations compared to baseline. CONCLUSIONS: These studies provide evidence of limited glucose lowering and incretin activity for JNJ-38431055 in subjects with T2DM.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of JNJ-38431055, a novel GPR119 receptor agonist and potential antidiabetes agent, in healthy male subjects.

The incidence of type 2 diabetes mellitus is increasing worldwide. Several G-protein-coupled receptor agonists are being studied for their efficacy as antidiabetes agents. JNJ-38431055 is a novel, potent, and orally available selective agonist of the glucose-dependent insulinotropic (GPR119) receptor. Double-blind, randomized, placebo-controlled studies were conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of JNJ-38431055 (2.5-800 mg) in healthy male volunteers. The systemic exposure of JNJ-38431055 in plasma increased in proportion to the dose and was not influenced by coadministration of food. The terminal elimination half-life was ~13 h when administered as an oral suspension formulation. JNJ-38431055 was well tolerated and was not associated with hypoglycemia. As compared with placebo, single-dose oral JNJ-38431055 increased postmeal plasma glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) concentrations but did not significantly decrease glucose excursion or increase insulin secretion. However, in a graded glucose infusion study, JNJ-38431055 was shown to induce a higher insulin secretion rate (ISR) relative to placebo at elevated plasma glucose levels. These studies provide evidence for the potential efficacy of JNJ-38431055 as an antidiabetes agent in humans.

Human herpesvirus-6B active infection associated with relapsing bilateral anterior optic neuritis.

BACKGROUND AND OBJECTIVES: Human herpesvirus-6 (HHV-6) is the causative agent of exanthem subitum. Both HHV-6 variants, A and B, have been associated with central nervous system (CNS) diseases, suggesting a wide neuropathogenic potential. We describe a case of recurrent bilateral anterior optic neuritis with HHV-6 active infection associated with clinical relapses. CASE REPORT: A 23-year old woman presented with progressive visual impairment, bilateral papillitis and painful ocular movements. Nested polymerase chain reaction (PCR) for DNA viruses, HHV-6 variant specific real time quantitative PCR, serological analysis and retrotranscription PCR (RT-PCR) for HHV-6 mRNA transcripts were performed. Nested PCR in PBMC and CSF samples was negative for all viruses but positive for HHV-6 DNA, subtyped as HHV-6B. The disease had a relapsing/remitting course. During relapses PBMC samples remained positive for HHV-6 DNA, and HHV-6 active infection was confirmed by the presence of anti-HHV-6 IgM and of HHV-6 U27 mRNA transcript. High viremia levels and relapses were overlapping. After the last relapse, the patient was successfully treated with gancyclovir. CONCLUSIONS: The case reported here suggests a possible association of HHV-6 in bilateral optic neuritis. HHV-6 could be monitored when bilateral optic neuritis is identified, in order to establish an appropriate antiviral therapy.