Markers Of Β-cell Function Research Articles

Efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes: a 54-week study

ABSTRACTObjective: To assess the 54-week efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes and inadequate glycemic control (HbA1c 7.5–11%) on diet and exercise.Methods and materials: This was multinational study conducted at 140 clinical sites in 18 countries. Following an initial 24-week, double-blind, placebo-controlled period, patients entered a double-blind continuation period for an additional 30 weeks. Following the week 24 evaluation, patients remained on their previously assigned active, oral treatments: sitagliptin 50 mg b.i.d. + metformin 1000 mg b.i.d. (S100 + M2000), sitagliptin 50 mg b.i.d. + metformin 500 mg b.i.d. (S100 + M1000), metformin 1000 mg b.i.d. (M2000), metformin 500 mg b.i.d. (M1000), and sitagliptin 100 mg q.d. (S100). Patients initially randomized to placebo were switched to M2000 (designated PBO/M2000) at week 24. This report summarizes the overall safety and tolerability data for the 54-week study and presents efficacy results for patients randomized to continuous treatments who entered the 30-week continuation period.Results: Of the 1091 randomized patients, 906 completed the 24-week placebo-controlled phase and 885 patients continued into the 30-week continuation period (S100 + M2000 n = 161, S100+M1000 n = 160, M2000 n = 153, M1000 n = 147, S100 n = 141, PBO/M2000 n = 123). At baseline, patients included in the efficacy analysis had mean age of 54 years, mean BMI of 32 kg/m2, mean HbA1c of 8.7% (8.5–8.8% across groups), and mean duration of type 2 diabetes of 4 years. At week 54, in the all-patients-treated analysis of continuing patients, least-squares (LS) mean changes in HbA1c from baseline were −1.8% (S100 + M2000), −1.4% (S100 + M1000), −1.3% (M2000), −1.0% (M1000), and −0.8% (S100). The proportions of continuing patients with an HbA1c < 7% at week 54 were 67% (S100 + M2000), 48% (S100 + M1000), 44% (M2000), 25% (M1000), and 23% (S100). For the patients completing treatment through week 54, LS mean changes in HbA1c from baseline were −1.9% (S100 + M2000), −1.7% (S100 + M1000), −1.6% (M2000), −1.2% (M1000), and −1.4% (S100). Glycemic response was generally durable over time across treatments. All treatments improved measures of β-cell function (e.g., HOMA-β, proinsulin/insulin ratio). Mean body weight decreased from baseline in the combination and metformin monotherapy groups and was unchanged from baseline in the sitagliptin monotherapy group. The incidence of hypoglycemia was low (1–3%) across treatment groups. The incidence of gastrointestinal adverse experiences with the co-administration of sitagliptin and metformin was similar to that observed with metformin alone.Limitations: The patient population evaluated in the 54-week efficacy analysis was a population of patients who entered the continuation period without receiving glycemic rescue therapy in the 24-week placebo-controlled period. Because the baseline HbA1c inclusion criteria ranged from 7.5 to 11% and the glycemic rescue criterion was an HbA1c > 8% after week 24, there was a greater likelihood of glycemic rescue in the monotherapy groups; this led to more missing data in the continuation all-patients-treated population(CAPT) analysis and fewer patients contributing to the completers analysis in the monotherapy groups.Conclusions: In this study, initial treatment with sitagliptin, metformin, or the combination therapy of sitagliptin and metformin provided substantial and durable glycemic control, improved markers of β-cell function, and was generally well-tolerated over 54 weeks in patients with type 2 diabetes.

Sitagliptin phosphate: A DPP-4 inhibitor for the treatment of type 2 diabetes mellitus

Background: Sitagliptin phosphate, the first dipeptidyl peptidase 4 (DPP-4) inhibitor, provides a new treatment option for patients with type 2 diabetes. Objective: The purpose of this article is to review the pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, adverse effects, and cost of sitagliptin in adults with type 2 diabetes. Methods: A literature search of MEDLINE (1966-May 10, 2007), Iowa Drug Information Service (1966-May 10, 2007), and International Pharmaceutical Abstracts (1970-May 10, 2007) was performed using the terms sitagliptin and MK-0431. English-language, original research and review articles were reviewed, as were citations from these articles. The 2005 and 2006 American Diabetes Association Scientific Abstracts were searched, and the US Food and Drug Administration review of the new drug application for sitagliptin and select information from the manufacturer were consulted. Results: By inhibiting DPP-4, sitagliptin enhances postprandial levels of active glucagon-like peptide-1 (GLP-1), leading to a rise in insulin release and decrease in glucagon secretion from pancreatic α-cells. Sitagliptin is 87% orally bioavailable, undergoes minimal hepatic metabolism, and is primarily excreted unchanged (~79%) in the urine. At doses ≥100 mg QD, DPP-4 activity is inhibited by >80%, with a consequent 2-fold rise in active GLP-1 levels. The reduction in glycosylated hemoglobin (HbA 1c) observed with 100 mg QD of sitagliptin in Phase III monotherapy trials ranged from ~0.5% to 0.6% ( P ≤ 0.001 vs placebo). In Phase III combination trials, HbA 1c was reduced by ~0.7% when added to metformin and ~0.9% with pioglitazone ( P < 0.001 vs placebo). Markers of β-cell function, including proinsulin/insulin ratio and homeostasis model assessment of β-cell function, were improved with sitagliptin treatment. In studies, sitagliptin has been well tolerated; significant hypoglycemia and weight gain have not been noted. Conclusions: When used alone or in combination with metformin or pioglitazone, sitagliptin has been associated with significant reductions in HbA 1c and has been well tolerated. Before its place in therapy can be firmly established, long-term studies evaluating the safety of prolonged DPP-4 inhibition are necessary.

CART knock out mice have impaired insulin secretion and glucose intolerance, altered beta cell morphology and increased body weight

CART peptides are anorexigenic and are widely expressed in the central and peripheral nervous systems, as well as in endocrine cells in the pituitary, adrenal medulla and the pancreatic islets. To study the role of CART in islet function, we used CART null mutant mice (CART KO mice) and examined insulin secretion in vivo and in vitro, and expression of islet hormones and markers of β-cell function using immunocytochemistry. We also studied CART expression in the normal pancreas. In addition, body weight development and food intake were documented. We found that in the normal mouse pancreas, CART was expressed in numerous pancreatic nerve fibers, both in the exocrine and endocrine portion of the gland. CART was also expressed in nerve cell bodies in the ganglia. Double immunostaining revealed expression in parasympathetic (vasoactive intestinal polypeptide (VIP)-containing) and in fewer sensory fibers (calcitonin gene-related peptide (CGRP)-containing). Although the expression of islet hormones appeared normal, CART KO islets displayed age dependent reduction of pancreatic duodenal homeobox 1 (PDX-1) and glucose transporter-2 (GLUT-2) immunoreactivity, indicating β-cell dysfunction. Consistent with this, CART KO mice displayed impaired glucose-stimulated insulin secretion both in vivo after an intravenous glucose challenge and in vitro following incubation of isolated islets in the presence of glucose. The impaired insulin secretion in vivo was associated with impaired glucose elimination, and was apparent already in young mice with no difference in body weight. In addition, CART KO mice displayed increased body weight at the age of 40 weeks, without any difference in food intake. We conclude that CART is required for maintaining normal islet function in mice.