Derek J. Nunez

Novel Gut-Based Pharmacology of Metformin in Patients with Type 2 Diabetes Mellitus

Metformin, a biguanide derivate, has pleiotropic effects beyond glucose reduction, including improvement of lipid profiles and lowering microvascular and macrovascular complications associated with type 2 diabetes mellitus (T2DM). These effects have been ascribed to adenosine monophosphate-activated protein kinase (AMPK) activation in the liver and skeletal muscle. However, metformin effects are not attenuated when AMPK is knocked out and intravenous metformin is less effective than oral medication, raising the possibility of important gut pharmacology. We hypothesized that the pharmacology of metformin includes alteration of bile acid recirculation and gut microbiota resulting in enhanced enteroendocrine hormone secretion. In this study we evaluated T2DM subjects on and off metformin monotherapy to characterize the gut-based mechanisms of metformin. Subjects were studied at 4 time points: (i) at baseline on metformin, (ii) 7 days after stopping metformin, (iii) when fasting blood glucose (FBG) had risen by 25% after stopping metformin, and (iv) when FBG returned to baseline levels after restarting the metformin. At these timepoints we profiled glucose, insulin, gut hormones (glucagon-like peptide-1 (GLP-1), peptide tyrosine-tyrosine (PYY) and glucose-dependent insulinotropic peptide (GIP) and bile acids in blood, as well as duodenal and faecal bile acids and gut microbiota. We found that metformin withdrawal was associated with a reduction of active and total GLP-1 and elevation of serum bile acids, especially cholic acid and its conjugates. These effects reversed when metformin was restarted. Effects on circulating PYY were more modest, while GIP changes were negligible. Microbiota abundance of the phylum Firmicutes was positively correlated with changes in cholic acid and conjugates, while Bacteroidetes abundance was negatively correlated. Firmicutes and Bacteroidetes representation were also correlated with levels of serum PYY. Our study suggests that metformin has complex effects due to gut-based pharmacology which might provide insights into novel therapeutic approaches to treat T2DM and associated metabolic diseases. Trial Registration: www.ClinicalTrials.gov NCT01357876

Validation of a quantitative magnetic resonance method for measuring human body composition.

Objective: To evaluate a novel quantitative magnetic resonance (QMR) methodology (EchoMRI‐AH, Echo Medical Systems) for measurement of whole‐body fat and lean mass in humans.

Angiotensin II receptor expression and inhibition in the chronically hypoxic rat lung

1 Angiotensin II (All) binding density and the effect of chronic All receptor blockade were examined in the rat model of hypoxia‐induced pulmonary hypertension. 2 [125I]‐[Sar1, Ile8]AII binding capacity was increased in lung membranes from rats exposed to hypoxia (10% fractional inspired O2) for 7 days compared to normal rats (Bmax 108 ± 12 vs 77 ± 3 fmol mg−1protein; P < 0.05), with no significant change in dissociation constant. Competition with specific AII receptor subtype antagonists demonstrated that AT1 is the predominant subtype in both normal and hypoxic lung. 3 Rats treated intravenously with the AT1 antagonist, GR138950C, 1 mg kg−1 day−1 rather than saline alone during 7 days of exposure to hypoxia developed less pulmonary hypertension (pulmonary arterial pressure: 21.3 ± 1.7 vs 28.3 ± 1.1 mmHg; P < 0.05), right ventricular hypertrophy (right/left ventricle weight ratio: 0.35 ±0.01 vs 0.45 ± 0.01; P < 0.05) and pulmonary artery remodelling (abundance of thick‐walled pulmonary vessels: 9.6 ± 1.4% vs 20.1 ±0.9%; P < 0.05). 4 The reduction in cardiac hypertrophy and pulmonary remodelling with the AT1 antagonist was greater than that achieved by a dose of sodium nitroprusside (SNP) that produced a comparable attenuation of the rise in pulmonary arterial pressure during hypoxia. 5 The data suggest that AII, via the AT1 receptor, has a role in the early pathogenesis of hypoxia‐induced pulmonary hypertension in the rat.

Single‐Dose Pharmacokinetics and Pharmacodynamics of Sergliflozin Etabonate, a Novel Inhibitor of Glucose Reabsorption, in Healthy Volunteers and Patients With Type 2 Diabetes Mellitus

Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of sodium‐dependent glucose cotransporter 2 (SGLT2). The pharmacokinetics and pharmacodynamics of sergliflozin were evaluated following single oral dose administration of sergliflozin etabonate (5–500 mg) in healthy volunteers (n = 22) and patients with type 2 diabetes mellitus (n = 8). The prodrug was rapidly and extensively converted to sergliflozin; the latter displayed linear kinetics, reached maximum plasma concentrations at ∼30 to 45 minutes postdose (tmax), and had a plasma elimination half‐life (t1/2) of ∼0.5 to 1 hour. Both prodrug and active entity showed low glomerular filtration and/or extensive renal tubular reabsorption, with <0.5% of the administered dose being recovered in the urine. In both populations, sergliflozin etabonate produced a dose‐related glucosuria under fasting conditions and following glucose loading but did not appreciably affect urinary electrolyte excretion or fluid balance. The magnitude and duration of the glucosuric effect closely paralleled plasma sergliflozin concentrations. Sergliflozin did not significantly affect fasting plasma glucose levels but produced transient attenuation of the plasma glucose AUC following glucose challenge. Single doses of sergliflozin etabonate 5 to 500 mg were well tolerated, and there were no clinically significant adverse laboratory findings.

Multiple‐Dose Pharmacokinetics and Pharmacodynamics of Sergliflozin Etabonate, a Novel Inhibitor of Glucose Reabsorption, in Healthy Overweight and Obese Subjects: A Randomized Double‐Blind Study

Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of the sodium‐dependent glucose cotransporter‐2 in the renal tubule. The pharmacokinetics and pharmacodynamics of sergliflozin were examined during administration of sergliflozin etabonate (500 or 1000 mg) or placebo 3 times daily (tid) for 14 days in healthy overweight or obese human volunteers (n = 18). At the doses tested, sergliflozin showed less than dose‐proportional pharmacokinetic characteristics. Mean half‐life of the active entity was approximately 2 hours; there was no evidence of drug accumulation. Sergliflozin etabonate produced rapid and sustained suppression of renal glucose reabsorption, resulting in a dose‐related glucosuria, and a transient increase in urinary electrolyte and fluid loss; plasma glucose, insulin, and electrolyte levels were unchanged. Sergliflozin etabonate produced a rapid, dose‐related reduction in body weight (mean changes of −0.09, −1.55, and −1.74 kg from baseline to day 15 with placebo, sergliflozin etabonate 500 mg, and sergliflozin etabonate 1000 mg, respectively), apparently through increased urinary calorie loss rather than through osmotic diuresis. Sergliflozin etabonate 500 or 1000 mg tid was generally well tolerated; no clinically significant adverse events were identified. Renal function (creatinine clearance) was not affected by sergliflozin etabonate, although urinary microalbumin, N‐acetyl‐beta‐D‐glucosaminidase, and β2‐microglobulin levels tended to increase.

The Biomarkers Consortium: Practice and Pitfalls of Open-Source Precompetitive Collaboration

Precompetitive collaboration is a growing driver for innovation and increased productivity in biomedical science and drug development. The Biomarkers Consortium, a public–private platform for precompetitive collaboration specific to biomarkers, demonstrated that adiponectin has potential utility as a predictor of metabolic responses to peroxisome proliferator–activated receptor (PPAR) agonists in individuals with type 2 diabetes. Despite the challenges overcome by this project, the most important lesson learned is that cross‐company precompetitive collaboration is a feasible robust approach to biomarker qualification.

Utility of adiponectin as a biomarker predictive of glycemic efficacy is demonstrated by collaborative pooling of data from clinical trials conducted by multiple sponsors.

This study, conducted under the Metabolic Disorders Steering Committee of the Biomarkers Consortium (a public–private partnership managed by the Foundation for the National Institutes of Health (FNIH)), analyzed blinded data on 2,688 type 2 diabetes (T2D) patients from randomized clinical trials conducted by four pharmaceutical companies. An increase in the levels of adiponectin was observed after peroxisome proliferator–activated receptor (PPAR)–agonist treatment (P < 0.0001), but not after treatment with non–PPAR drugs. This increase correlated with decreases in levels of glucose, hemoglobin A1c (HbA1c), hematocrit, and triglycerides, and increases in levels of blood urea nitrogen, creatinine, and high–density lipoprotein cholesterol (HDL–C). Early (6–8 weeks) increases in levels of adiponectin after treatment with PPAR agonists showed a negative correlation (r = −0.21, P < 0.0001) with subsequent changes in levels of HbA1c. Changes in adiponectin level did not appear to be associated with baseline level of HbA1c. Logistic regression demonstrated that an increase in the level of adiponectin predicts a decrease in the level of HbA1c. These analyses confirm previously demonstrated relationships between adiponectin levels and metabolic parameters and support the robust predictive utility of adiponectin across the spectrum of glucose tolerance. Cross–company precompetitive collaboration is a feasible and powerful approach to biomarker qualification.

Gut Hormone Pharmacology of a Novel GPR119 Agonist (GSK1292263), Metformin, and Sitagliptin in Type 2 Diabetes Mellitus: Results from Two Randomized Studies

GPR119 receptor agonists improve glucose metabolism and alter gut hormone profiles in animal models and healthy subjects. We therefore investigated the pharmacology of GSK1292263 (GSK263), a selective GPR119 agonist, in two randomized, placebo-controlled studies that enrolled subjects with type 2 diabetes. Study 1 had drug-naive subjects or subjects who had stopped their diabetic medications, and Study 2 had subjects taking metformin. GSK263 was administered as single (25–800 mg; n = 45) or multiple doses (100–600 mg/day for 14 days; n = 96). Placebo and sitagliptin 100 mg/day were administered as comparators. In Study 1, sitagliptin was co-administered with GSK263 or placebo on Day 14 of dosing. Oral glucose and meal challenges were used to assess the effects on plasma glucose, insulin, C-peptide, glucagon, peptide tyrosine-tyrosine (PYY), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). After 13 days of dosing, GSK263 significantly increased plasma total PYY levels by ∼five-fold compared with placebo, reaching peak concentrations of ∼50 pM after each of the three standardized meals with the 300 mg BID dose. Co-dosing of GSK263 and metformin augmented peak concentrations to ∼100 pM at lunchtime. GSK263 had no effect on active or total GLP-1 or GIP, but co-dosing with metformin increased post-prandial total GLP-1, with little effect on active GLP-1. Sitagliptin increased active GLP-1, but caused a profound suppression of total PYY, GLP-1, and GIP when dosed alone or with GSK263. This suppression of peptides was reduced when sitagliptin was co-dosed with metformin. GSK263 had no significant effect on circulating glucose, insulin, C-peptide or glucagon levels. We conclude that GSK263 did not improve glucose control in type 2 diabetics, but it had profound effects on circulating PYY. The gut hormone effects of this GPR119 agonist were modulated when co-dosed with metformin and sitagliptin. Metformin may modulate negative feedback loops controlling the secretion of enteroendocrine peptides. Trial Registration: Clinicaltrials.gov NCT01119846 Clinicaltrials.gov NCT01128621

Evaluation of drug interactions of GSK1292263 (a GPR119 agonist) with statins: from in vitro data to clinical study design

1. This work investigated the drug interaction potential of GSK1292263, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by GSK1292263, and a clinical drug interaction study investigated the effect of GSK1292263 (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, GSK1292263 demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), Pgp, OATP1B3, or OCT2. However, GSK1292263 inhibited BCRP and OATP1B1, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with GSK1292263, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, GSK1292263 did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by GSK1292263.

Remogliflozin Etabonate, a Selective Inhibitor of the Sodium-Glucose Transporter 2, Improves Serum Glucose Profiles in Type 1 Diabetes

OBJECTIVE Remogliflozin etabonate (RE), an inhibitor of the sodium-glucose transporter 2, improves glucose profiles in type 2 diabetes. This study assessed safety, tolerability, pharmacokinetics, and pharmacodynamics of RE in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS Ten subjects managed with continuous subcutaneous insulin infusion were enrolled. In addition to basal insulin, subjects received five randomized treatments: placebo, prandial insulin, 50 mg RE, 150 mg RE, and mg RE 500. RESULTS Adverse events and incidence of hypoglycemia with RE did not differ from placebo and prandial insulin groups. RE significantly increased urine glucose excretion and reduced the rise in plasma glucose concentration after oral glucose. RE reduced incremental adjusted weighted mean glucose (0–4 h) values by 42–49 mg/dL and mean glucose (0–10 h) by 52–69 mg/dL. CONCLUSIONS RE can be safely administered with insulin in type 1 diabetes and reduces plasma glucose concentrations compared with placebo.