Background— The glucagon-like peptide 1 receptor (GLP-1R) is believed to mediate glucoregulatory and cardiovascular effects of the incretin hormone GLP-1(7-36) (GLP-1), which is rapidly degraded by dipeptidyl peptidase-4 (DPP-4) to GLP-1(9-36), a truncated metabolite generally thought to be inactive. Novel drugs for the treatment of diabetes include analogues of GLP-1 and inhibitors of DPP-4; however, the cardiovascular effects of distinct GLP-1 peptides have received limited attention. Methods and Results— Here, we show that endothelium and cardiac and vascular myocytes express a functional GLP-1R as GLP-1 administration increased glucose uptake, cAMP and cGMP release, left ventricular developed pressure, and coronary flow in isolated mouse hearts. GLP-1 also increased functional recovery and cardiomyocyte viability after ischemia-reperfusion injury of isolated hearts and dilated preconstricted arteries from wild-type mice. Unexpectedly, many of these actions of GLP-1 were preserved in Glp1r−/− mice. Fur...

Cardioprotective and Vasodilatory Actions of Glucagon-Like Peptide 1 Receptor Are Mediated Through Both Glucagon-Like Peptide 1 Receptor–Dependent and –Independent Pathways

OBJECTIVE —To examine the efficacy and safety of once-daily oral sitagliptin as monotherapy in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS —In a randomized, double-blind, placebo-controlled study, 741 patients (baseline HbA1c [A1C] 8.0%) were randomized to sitagliptin 100 or 200 mg or placebo for 24 weeks.

RESULTS —Sitagliptin 100 and 200 mg produced significant ( P < 0.001) placebo-subtracted reductions in A1C (−0.79 and −0.94%, respectively) and fasting plasma glucose (−1.0 mmol/l [−17.1 mg/dl] and −1.2 mmol/l [−21.3 mg/dl], respectively). Patients with baseline A1C ≥9% had greater reductions in placebo-subtracted A1C with sitagliptin 100 and 200 mg (−1.52 and −1.50%, respectively) than those with baseline A1C <8% (−0.57 and −0.65%) or ≥8 to <9.0% (−0.80 and −1.13%, respectively). In a meal tolerance test, sitagliptin 100 and 200 mg significantly decreased 2-h postprandial glucose (PPG) (placebo-subtracted PPG −2.6 mmol/l [−46.7 mg/dl] and −3.0 mmol/l [−54.1 mg/dl], respectively). Results for the above key efficacy parameters were not significantly different between sitagliptin doses. Homeostasis model assessment of β-cell function and proinsulin-to-insulin ratio improved with sitagliptin. The incidence of hypoglycemia was similar, and overall gastrointestinal adverse experiences were slightly higher with sitagliptin. No meaningful body weight changes from baseline were observed with sitagliptin 100 (−0.2 kg) or 200 mg (−0.1 kg). The body weight change with placebo (−1.1 kg) was significantly ( P < 0.01) different from that observed with sitagliptin.

CONCLUSIONS —In this 24-week study, once-daily sitagliptin monotherapy improved glycemic control in the fasting and postprandial states, improved measures of β-cell function, and was well tolerated in patients with type 2 diabetes.

/pdf/effect-of-the-dipeptidyl-peptidase-4-inhibitor-sitagliptin-2y6uca98wk.pdf

Effect of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin as Monotherapy on Glycemic Control in Patients With Type 2 Diabetes

OBJECTIVE —The efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, added to ongoing metformin therapy, were assessed in patients with type 2 diabetes who had inadequate glycemic control (HbA 1c [A1C] ≥7 and ≤10%) with metformin alone. RESEARCH DESIGN AND METHODS —After a screening diet/exercise run-in period, a metformin dose titration/stabilization period, and a 2-week, single-blind, placebo run-in period, 701 patients, aged 19–78 years, with mild to moderate hyperglycemia (mean A1C 8.0%) receiving ongoing metformin (≥1,500 mg/day) were randomly assigned to receive the addition of placebo or sitagliptin 100 mg once-daily in a 1:2 ratio for 24 weeks. Patients exceeding specific glycemic limits were provided rescue therapy (pioglitazone) until the end of the study. The efficacy analyses were based on an all-patients-treated population using an ANCOVA and excluded data obtained after glycemic rescue. RESULTS —At week 24, sitagliptin treatment led to significant reductions compared with placebo in A1C (−0.65%), fasting plasma glucose, and 2-h postmeal glucose. Fasting insulin, fasting C-peptide, fasting proinsulin-to-insulin ratio, postmeal insulin and C-peptide areas under the curve (AUCs), postmeal insulin AUC–to–glucose AUC ratio, homeostasis model assessment of β-cell function, and quantitative insulin sensitivity check index were significantly improved with sitagliptin relative to placebo. A significantly greater proportion of patients achieved an A1C CONCLUSIONS —Sitagliptin 100 mg once-daily added to ongoing metformin therapy was efficacious and well tolerated in patients with type 2 diabetes who had inadequate glycemic control with metformin alone.

https://care.diabetesjournals.org/content/diacare/29/12/2638.full.pdf

Efficacy and Safety of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Added to Ongoing Metformin Therapy in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Alone

Aim: To compare the efficacy and safety of sitagliptin vs glipizide in patients with type 2 diabetes and inadequate glycaemic control [haemoglobin A1c (HbA1c) ≥ 65 and ≤10%] on metformin monotherapy

Methods:  After a metformin dose titration/stabilization period (≥1500 mg/day), 1172 patients were randomized to the addition of sitagliptin 100 mg qd (N = 588) or glipizide 5 mg/day (uptitrated to a potential maximum 20 mg/day) (N = 584) for 52 weeks The primary analysis assessed whether sitagliptin was non-inferior to glipizide regarding HbA1c changes from baseline at Week 52 using a per-protocol approach

Results:  From a mean baseline of 75%, HbA1c changes from baseline were −067% at Week 52 in both groups, confirming non-inferiority The proportions achieving an HbA1c < 7% were 63% (sitagliptin) and 59% (glipizide) Fasting plasma glucose changes from baseline were −056 mmol/l (−100 mg/dl) and −042 mmol/l (−75 mg/dl) for sitagliptin and glipizide, respectively The proportion of patients experiencing hypoglycaemia episodes was significantly (p < 0001) higher with glipizide (32%) than with sitagliptin (5%), with 657 events in glipizide-treated patients compared with 50 events in sitagliptin-treated patients Sitagliptin led to weight loss (change from baseline =−15 kg) compared with weight gain (+11 kg) with glipizide [between-treatment difference (95% confidence interval) =−25 kg (−31, −20); p < 0001]

Conclusions:  In this study, the addition of sitagliptin compared with glipizide provided similar HbA1c-lowering efficacy over 52 weeks in patients on ongoing metformin therapy Sitagliptin was generally well tolerated, with a lower risk of hypoglycaemia relative to glipizide and with weight loss compared with weight gain with glipizide

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1463-1326.2006.00704.x

Efficacy and safety of the dipeptidyl peptidase‐4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double‐blind, non‐inferiority trial

The prevalence of obesity has dramatically increased in recent years and now includes a significant proportion of the world’s children, adolescents and adults. Obesity is linked to a number of co-morbidities, the most prominent being type 2 diabetes mellitus. While many agents are available to treat these conditions, the current knowledge regarding their disposition in the obese remains limited.

Effect of Obesity on the Pharmacokinetics of Drugs in Humans

Context: In response to a meal, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are released and modulate glycemic control Normally these incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4) DPP-4 inhibitors are a novel class of oral antihyperglycemic agents in development for the treatment of type 2 diabetes The degree of DPP-4 inhibition and the level of active incretin augmentation required for glucose lowering efficacy after an oral glucose tolerance test (OGTT) were evaluated Objective: The objective of the study was to examine the pharmacodynamics, pharmacokinetics, and tolerability of sitagliptin Design: This was a randomized, double-blind, placebo-controlled, three-period, single-dose crossover study Setting: The study was conducted at six investigational sites Patients: The study population consisted of 58 patients with type 2 diabetes who were not on antihyperglycemic agents Interventions: Interventions included sitagliptin 25 mg, sitaglipti

Effect of Single Oral Doses of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, on Incretin and Plasma Glucose Levels after an Oral Glucose Tolerance Test in Patients with Type 2 Diabetes

Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers.

Background Sitagliptin is a highly selective dipeptidyl peptidase-4 inhibitor for the treatment of patients with type 2 diabetes. Sitagliptin is primarily excreted by renal elimination as unchanged drug, with only a small percentage (~16%) undergoing hepatic metabolism. Objectives The primary purpose of this study was to evaluate the influence of moderate hepatic insufficiency on the pharmacokinetics of sitagliptin. Methods In an open-label study, a single 100-mg oral dose of sitagliptin was administered to 10 male or female patients with moderate hepatic insufficiency (Child-Pugh’s scores ranged from 7 to 9) and 10 healthy control subjects matched to each patient for race, gender, age (± 5 yrs) and body mass index (BMI kg/m 2 ± 5%). After administration of each dose, blood and urine samples were collected to assess sitagliptin pharmacokinetics. Results The mean AUC0-∞ and Cmax for sitagliptin were numerically, but not significantly (p>0.050), higher in patients with moderate hepatic insufficiency compared with healthy matched control subjects by 21% and 13%, respectively. These slight differences were also not considered to be clinically meaningful. Moderate hepatic insufficiency had no statistically significant effect on the Tmax, apparent terminal t1/2, fraction of the oral dose excreted into urine (fe,0-) and renal clearance (ClR) (p>0.100) of sitagliptin. Sitagliptin was generally well tolerated by both patients and subjects; all adverse experiences were transient and rated as mild in intensity.

Catherine Stevens

Papers

Effect of Single Oral Doses of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, on Incretin and Plasma Glucose Levels after an Oral Glucose Tolerance Test in Patients with Type 2 Diabetes

Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers.

Effect of moderate hepatic insufficiency on the pharmacokinetics of sitagliptin.

Lack of erectogenic activity of a novel selective melanocortin-4 receptor agonist in a clinical experimental model.