Gary A. Herman

Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses.

Sitagliptin (MK‐0431 [(2R)‐4‐oxo‐4‐(3‐[trifluoromethyl]‐5,6‐dihydro[1,2,4]triazolo[4,3‐a]pyrazin‐7[8H]‐yl)‐1‐(2,4,5‐trifluorophenyl)butan‐2‐amine]) is an orally active, potent, and selective inhibitor of dipeptidyl peptidase IV (DPP‐IV) currently in phase III development for the treatment of type 2 diabetes.

Effect of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, on Blood Pressure in Nondiabetic Patients With Mild to Moderate Hypertension

The effect of sitagliptin, a dipeptidyl peptidase‐4 inhibitor, on ambulatory blood pressure was assessed in nondiabetic patients with mild to moderate hypertension in a randomized, double‐blind, placebo‐controlled, 3‐period crossover study. Nineteen patients on stable treatment with antihypertensive agent(s) received sitagliptin 100 mg b.i.d., 50 mg b.i.d., or placebo for 5 days, with at least a 7‐day washout interval between periods. Twenty‐four‐hour ambulatory blood pressure, including systolic blood pressure, diastolic blood pressure, and mean arterial pressure, were monitored on days 1 and 5. Relative to placebo on day 1, the mean difference in 24‐hour systolic blood pressure was −0.9 mm Hg (90% confidence interval: −2.9 to 1.1; P = .46) with sitagliptin 50 mg b.i.d. and −2.8 mm Hg (90% confidence interval: −4.9 to −0.8; P < .05) with 100 mg b.i.d. On day 5, the mean difference in 24‐hour systolic blood pressure was −2.0 mm Hg (90% confidence interval: −3.5 to −0.4; P < .05) with 50 mg b.i.d. and −2.2 mm Hg (90% confidence interval: −3.7 to −0.6; P < .05) with 100 mg b.i.d. relative to placebo. For 24‐hour diastolic blood pressure, there were no between‐group differences in mean 24‐hour diastolic blood pressure on day 1. On day 5, sitagliptin 50 mg and 100 mg b.i.d significantly (P < .05) lowered mean 24‐hour diastolic blood pressure by −1.8 mm Hg (90% confidence interval: −2.8 to −0.8) and −1.6 mm Hg (90% confidence interval: −2.6 to −0.7), respectively, relative to placebo. Sitagliptin produced small but statistically significant reductions of 2 mm Hg to 3 mm Hg in 24‐hour ambulatory blood pressure measurements acutely (day 1) and at steady state (day 5), and was generally well tolerated in nondiabetic patients with mild to moderate hypertension.

The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake

Cannabinoid 1 receptor (CB1R) inverse agonists are emerging as a potential obesity therapy. However, the physiological mechanisms by which these agents modulate human energy balance are incompletely elucidated. Here, we describe a comprehensive clinical research study of taranabant, a structurally novel acyclic CB1R inverse agonist. Positron emission tomography imaging using the selective CB1R tracer [(18)F]MK-9470 confirmed central nervous system receptor occupancy levels ( approximately 10%-40%) associated with energy balance/weight-loss effects in animals. In a 12-week weight-loss study, taranabant induced statistically significant weight loss compared to placebo in obese subjects over the entire range of evaluated doses (0.5, 2, 4, and 6 mg once per day) (p < 0.001). Taranabant treatment was associated with dose-related increased incidence of clinical adverse events, including mild to moderate gastrointestinal and psychiatric effects. Mechanism-of-action studies suggest that engagement of the CB1R by taranabant leads to weight loss by reducing food intake and increasing energy expenditure and fat oxidation.

Once-daily sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 diabetes*

ABSTRACT Objective: Sitagliptin, an oral, potent, and selective dipeptidyl peptidase-4 (DPP‑4) inhibitor was evaluated as once-daily monotherapy in a 12-week randomized, double-blind, placebo-controlled, parallel group, dose-ranging study. Additionally, the glycemic response to sitagliptin 100 mg daily was evaluated as a once-daily (100 mg once-daily) or twice-daily (50 mg twice-daily) dosing regimen. Research design and methods: In a multinational, double-blind, randomized, placebo-controlled, parallel-group, dose-range finding study, 555 patients, 23–74 years of age, with HbA1c of 6.5–10.0% were randomized to one of five treatment groups: placebo, sitagliptin 25, 50 or 100 mg once-daily, or sitagliptin 50 mg twice-daily for 12 weeks. The efficacy analysis was based on the all-patients-treated population using an ANCOVA model. Results: Mean baseline HbA1c ranged from 7.6 to 7.8% across treatment groups, with 29% of all patients with values ≤ 7%. After 12 weeks, treatment with all doses of sitagliptin significantly ( p < 0.05) reduced HbA1c by –0.39 to –0.56% and fasting plasma glucose by –11.0 to –17.2 mg/dLrelative to placebo, with the greatest reduction observed in the 100-mg once-daily group. Mean daily glucose was significantly ( p < 0.05) reduced by –14.0 to –22.6 mg/dL with all doses of sitagliptin relative to placebo. HOMA‑β was significantly ( p < 0.05) increased by 11.3–15.2 with all sitagliptin doses relative to placebo. QUICKI and HOMA‑IR were not significantly changed with sitagliptin treatment. There were no significant differences observed between the sitagliptin 100 mg once-daily and 50 mg twice-daily groups for any parameter. For sitagliptin, the incidence of adverse events of hypoglycemia was low, with one event in each of the 25- and 50-mg once-daily and 50-mg twice-daily treatment groups and two events in the 100 mg once-daily treatment group. There was no mean change in body weight with sitagliptin relative to placebo. Study duration may be a limitation because the extent of the glycemic response and the safety and tolerability may not have been fully elucidated in this 12-week study. Conclusion: Sitagliptin monotherapy improved indices of glycemic control compared to placebo and was generally well-tolerated in patients with type 2 diabetes. The glycemic response to treatment with sitagliptin 100 mg/day was similar between the sitagliptin 100-mg once-daily and 50-mg twice-daily dose regimens.

Pharmacokinetics and Pharmacodynamic Effects of the Oral DPP-4 Inhibitor Sitagliptin in Middle-Aged Obese Subjects

Sitagliptin (MK‐0431) is an oral, potent, and selective dipeptidyl peptidase‐IV (DPP‐4) inhibitor developed for the treatment of type 2 diabetes. This multicenter, randomized, double‐blind, placebo‐controlled study examined the pharmacokinetic and pharmacodynamic effects of sitagliptin in obese subjects. Middle‐aged (45–63 years), nondiabetic, obese (body mass index: 30–40 kg/m2) men and women were randomized to sitagliptin 200 mg bid (n = 24) or placebo (n = 8) for 28 days. Steady‐state plasma concentrations of sitagliptin were achieved within 2 days of starting treatment, and >90% of the dose was excreted unchanged in urine. Sitagliptin treatment led to ∼90% inhibition of plasma DPP‐4 activity, increased active glucagon‐like peptide‐1 (GLP‐1) levels by 2.7‐fold (P < .001), and decreased post—oral glucose tolerance test glucose excursion by 35% (P < .050) compared to placebo. In nondiabetic obese subjects, treatment with sitagliptin 200 mg bid was generally well tolerated without associated hypoglycemia and led to maximal inhibition of plasma DPP‐4 activity, increased active GLP‐1, and reduced glycemic excursion.

Dipeptidyl Peptidase-4 Inhibitors Administered in Combination With Metformin Result in an Additive Increase in the Plasma Concentration of Active GLP-1

The aim of the study was to investigate the effects of a dipeptidyl peptidase‐4 (DPP‐4) inhibitor, of metformin, and of the combination of the two agents, on incretin hormone concentrations. Active and inactive (or total) incretin plasma concentrations, plasma DPP‐4 activity, and preproglucagon (GCG) gene expression were determined after administration of each agent alone or in combination to mice with diet‐induced obesity (DIO) and to healthy human subjects. In mice, metformin increased Gcg expression in the large intestine and elevated the plasma concentrations of inactive glucagon‐like peptide 1 (GLP‐1) (9–36) and glucagon. In healthy subjects, a DPP‐4 inhibitor elevated both active GLP‐1 and glucose dependent insulinotropic polypeptide (GIP), metformin increased total GLP‐1 (but not GIP), and the combination resulted in additive increases in active GLP‐1 plasma concentrations. Metformin did not inhibit plasma DPP‐4 activity either in vitro or in vivo. The study results show that metformin is not a DPP‐4 inhibitor but rather enhances precursor GCG expression in the large intestine, resulting in increased total GLP‐1 concentrations. DPP‐4 inhibitors and metformin have complementary mechanisms of action and additive effects with respect to increasing the concentrations of active GLP‐1 in plasma.

Dipeptidyl Peptidase‐4 Inhibitors for the Treatment of Type 2 Diabetes: Focus On Sitagliptin

Dipeptidyl peptidase‐4 (DPP‐4) inhibitors represent a new class of oral antihyperglycemic agents to treat patients with type 2 diabetes. 1 DPP‐4 inhibitors improve fasting and postprandial glycemic control without hypoglycemia or weight gain. 1 This article focuses on the physiology, clinical pharmacology, tolerability, and clinical utility of the DPP‐4 inhibitor sitagliptin in the management of type 2 diabetes.

Metabolism And Excretion of the Dipeptidyl Peptidase 4 Inhibitor [14C]Sitagliptin in Humans

The metabolism and excretion of [14C]sitagliptin, an orally active, potent and selective dipeptidyl peptidase 4 inhibitor, were investigated in humans after a single oral dose of 83 mg/193 μCi. Urine, feces, and plasma were collected at regular intervals for up to 7 days. The primary route of excretion of radioactivity was via the kidneys, with a mean value of 87% of the administered dose recovered in urine. Mean fecal excretion was 13% of the administered dose. Parent drug was the major radioactive component in plasma, urine, and feces, with only 16% of the dose excreted as metabolites (13% in urine and 3% in feces), indicating that sitagliptin was eliminated primarily by renal excretion. Approximately 74% of plasma AUC of total radioactivity was accounted for by parent drug. Six metabolites were detected at trace levels, each representing <1 to 7% of the radioactivity in plasma. These metabolites were the N-sulfate and N-carbamoyl glucuronic acid conjugates of parent drug, a mixture of hydroxylated derivatives, an ether glucuronide of a hydroxylated metabolite, and two metabolites formed by oxidative desaturation of the piperazine ring followed by cyclization. These metabolites were detected also in urine, at low levels. Metabolite profiles in feces were similar to those in urine and plasma, except that the glucuronides were not detected in feces. CYP3A4 was the major cytochrome P450 isozyme responsible for the limited oxidative metabolism of sitagliptin, with some minor contribution from CYP2C8.

Tolerability and pharmacokinetics of metformin and the dipeptidyl peptidase-4 inhibitor sitagliptin when co-administered in patients with type 2 diabetes

ABSTRACT Objective: As part of the clinical development of sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of type 2 diabetes, the potential for pharmacokinetic interactions with other antihyperglycemic agents used in managing patients with type 2 diabetes are being carefully evaluated. The purposes of this study were to evaluate the tolerability of co-administered sitagliptin and metformin and effects of sitagliptin on metformin pharmacokinetics as well as metformin on sitagliptin pharmacokinetics under steady-state conditions. Methods: This placebo-controlled, multiple-dose, crossover study in patients with type 2 diabetes assessed the tolerability of co-administered sitagliptin (50 mg b.i.d.) with metformin (1000 mg b.i.d.). Patients received, in a randomized crossover manner, three treatments (each of 7 days duration): 50 mg sitagliptin twice daily and placebo to metformin twice daily; 1000 mg of metformin twice daily and placebo to sitagliptin twice daily; concomitant administration of 50 mg of sitagliptin twice daily and 1000 mg of metformin twice daily. Following dosing on Day 7 of each treatment period, these pharmacokinetic parameters were determined for plasma sitagliptin and metformin: area under the plasma concentrations–time curve over the dosing interval (AUC0–12 h), maximum observed plasma concentrations (Cmax), and time of occurrence of maximum observed plasma concentrations (Tmax). Renal clearance was also determined for sitagliptin. Results: In this study, no adverse experiences were reported by 11 of 13 patients. Two patients had adverse experiences, which were not related to study drugs as determined by the investigators. The mean metformin plasma concentration–time profiles were nearly identical with or without sitagliptin co-administration [metformin AUC0–12 h geometric mean ratio (GMR; [metformin + sitagliptin]/metformin)] was 1.02 (90% CI 0.95, 1.09). Similarly metformin administration did not alter the plasma sitagliptin pharmacokinetics [sitagliptin AUC0–12 h GMR ([sitagliptin + metformin]/sitagliptin)] was 1.02 (90% CI 0.97, 1.08) or renal clearance of sitagliptin. No efficacy measurements (glycosylated hemoglobin or fasting plasma glucose) were obtained during this study. Urinary pharmacokinetics for metformin were not determined due to the lack of effect of sitagliptin on plasma metformin pharmacokinetics. Conclusions: In this study, co-administration of sitagliptin and metformin was generally well tolerated in patients with type 2 diabetes and did not meaningfully alter the steady-state pharmacokinetics of either agent.

Potent and Selective Agonism of the Melanocortin Receptor 4 With MK-0493 Does Not Induce Weight Loss in Obese Human Subjects: Energy Intake Predicts Lack of Weight Loss Efficacy

MK‐0493 is a novel, potent, and selective agonist of the melanocortin receptor 4 (MC4R), one of the best‐validated genetic targets and considered one of the most promising for the development of antiobesity therapeutics. An ad libitum energy‐intake model was qualified with excellent reproducibility: the geometric mean ratio (GMR) with 95% confidence interval (CI) for total energy intake over a period of 24 h for 30 mg sibutramine/placebo was 0.82 (0.76, 0.88), and for 10 mg sibutramine/placebo it was 0.98 (0.91, 1.05). MK‐0493 showed a small and marginally significant effect on 24‐h energy intake, whereas 30 mg of sibutramine caused a significant reduction in total 24‐h energy intake; specifically, the GMR (95% CI) for 30 mg sibutramine/placebo was 0.79 (0.74, 0.85). MK‐0493 was associated with modest weight reduction from baseline but had only small, statistically insignificant effects relative to placebo after 12 weeks in a fixed‐dose study and also after 18 weeks of stepped‐titration dosing. We conclude that agonism of MC4R is not likely to represent a viable approach to the development of antiobesity therapeutics.