Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to determine the absolute bioavailability of sitagliptin, an orally active, potent and highly selective dipeptidyl peptidase-4 inhibitor recently approved in the United States for the treatment of type 2 diabetes. The effect of a high fat meal on sitagliptin pharmacokinetics was also assessed. The study was performed in two parts. Intravenous doses (2 h infusion) of 25, 50 and 100 mg were administered double-blind to 10 (8 active, 2 placebo) subjects in a fixed-sequence manner in Part I. In Part II, 12 subjects were randomized to each of three open-label treatments: an intravenous 100 mg dose; a single oral 100 mg final market image tablet administered following a high fat meal and a single oral 100 mg final market image tablet administered fasted. Following each dose, plasma and urine were collected at pre-specified times for evaluation of sitagliptin pharmacokinetics. All doses were generally well tolerated in both parts of the study. Following rising intravenous doses of sitagliptin, AUC(0-infinity) increased dose-proportionally, indicating that plasma clearance is independent of dose over the dose range evaluated. Renal clearance of unchanged sitagliptin accounted for approximately 70% of the total plasma clearance of sitagliptin, indicating that sitagliptin is primarily cleared via renal excretion. Averaged across doses, the mean total plasma clearance was 416 ml/min. The mean absolute bioavailability of sitagliptin was 87% with a 90% CI of (81%, 93%). The AUC(0-infinity) and C(max) geometric mean ratios (fed/fasted) and 90% CIs were 1.03 (0.97, 1.11) and 0.94 (0.86, 1.03), respectively, and were contained within the bounds of (0.80, 1.25). Additionally, the high-fat meal had no significant effect on T(max) or apparent terminal t(1/2). Thus, food does not affect the pharmacokinetics of sitagliptin and therefore can be administered without regard to food.
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PMID:Absolute bioavailability of sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers. 1757 59

Sitagliptin (Januvia, Merck Pharmaceuticals) is a dipeptidyl-peptidase inhibitor (DPP-4 inhibitor) that has recently been approved for the therapy of type 2 diabetes. Like other DPP-4 inhibitors its action is mediated by increasing levels of the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). Sitagliptin is effective in lowering HbA1c, and fasting as well as postprandial glucose in monotherapy and in combination with other oral antidiabetic agents. It stimulates insulin secretion when hyperglycemia is present and inhibits glucagon secretion. In clinical studies it is weight neutral. This article gives an overview of the mechanism of action, the pharmacology, and the clinical efficacy and safety of sitagliptin in type 2 diabetes therapy.
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PMID:Review of sitagliptin phosphate: a novel treatment for type 2 diabetes. 1758 Jul 30

A recently published American Diabetes Association/European Association for the Study of Diabetes consensus statement on the management of hyperglycaemia in type 2 diabetes emphasises the achievement and maintenance of normal glycaemic control and the rapid addition of medications and transition to new regimens when glycaemic goals are not achieved or sustained. An algorithm for the use of available interventions is supplied to help practitioners avoid prolonged periods of inadequate glycaemic control. Recommendations include rapid transition to combination treatment with oral agents and with insulin plus oral agents. The currently available oral agents are reviewed here with respect to the consensus statement recommendations, and the characteristics of the new class of oral dipeptidyl peptidase-4 inhibitors are summarised. These agents offer clinically meaningful reductions in HbA1c without significant risk of hypoglycaemia and without causing weight gain; they also offer the theoretical potential of improving or maintaining beta-cell function and thus, favourably affecting the progressive loss of function that is characteristic of type 2 diabetes. Potential uses of these agents in the context of the consensus statement recommendations are considered.
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PMID:Potential role of oral DPP-4 inhibitors in the ADA/EASD consensus statement algorithm for achieving and maintaining tight glycaemic control in type 2 diabetes: recommendations for oral antidiabetic agents. 1759 73

The vast majority of patients with type 2 diabetes are overweight or obese. Lifestyle intervention to lose weight is recommended in most diabetic patients to improve glycaemic control and reduce associated risk factors for microvascular and macrovascular complications. Even modest weight loss can significantly improve glucose homeostasis and lessen cardiometabolic risk factors, although achieving this level of weight reduction remains difficult for many patients. Complicating the matter, many agents used to target hyperglycaemia are associated with weight gain, making management of overweight or obese patients with type 2 diabetes quite challenging. Incretin-based therapies with the new classes of glucagon-like peptide-1 mimetics (e.g. exenatide, liraglutide) and dipeptidyl peptidase 4 (DPP-4) inhibitors (e.g. sitagliptin, vildagliptin) may be of particular value in the treatment of overweight/obese type 2 diabetic patients because of their efficacy in improving glycaemic control and their favourable or neutral effects on body weight. In addition, DPP-4 inhibitors have a low risk for causing hypoglycaemia, undesirable gastrointestinal effects, or other prominent adverse effects that might limit their use. These classes of drugs hold promise for the treatment of type 2 diabetes, alone or in combination with other classes of antidiabetic agents.
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PMID:Antidiabetic medications in overweight/obese patients with type 2 diabetes: drawbacks of current drugs and potential advantages of incretin-based treatment on body weight. 1759 74

Type 2 diabetes mellitus is a common chronic disease that causes significant morbidity and mortality worldwide. The primary goal of treatment is to target glycemic control by maintaining the glycosylated hemoglobin level near 6-7% without predisposing patients to hypoglycemia. Diabetes results from a combination of increased hepatic glucose production, decreased insulin secretion from beta cells, and insulin resistance in the peripheral tissues. Currently available antidiabetic agents work by different mechanisms to lower blood glucose levels. Unfortunately, each of them has its tolerability and safety concerns that limit its use and dose titration. Sitagliptin is the first antidiabetic agent from the class of dipeptidyl peptidase-4 enzyme inhibitors. It increases the amount of circulating incretins, which stimulate insulin secretion and inhibit glucose production. Sitagliptin was approved by the US Food and Drug Administration (FDA) for use with diet and exercise to improve glycemic control in adult patients with type 2 diabetes. It can be used alone or in combination with metformin or a thiazolidinedione (pioglitazone or rosiglitazone) when treatment with either drug alone provides inadequate glucose control. The usual adult dose is 100 mg once daily. A dose of 25-50 mg once daily is recommended for patients with moderate-to-severe renal impairment. In randomized, placebo-controlled trials that lasted for up to 6 months, sitagliptin lowered glycosylated hemoglobin levels by 0.5-0.8%. In a 52-week clinical trial, sitagliptin was shown to be noninferior to glipizide as an add-on agent in patients inadequately controlled on metformin alone. Sitagliptin was well tolerated with the most common side effects being gastrointestinal complaints (up to 16%), including abdominal pain, nausea and diarrhea; hypoglycemia and body weight gain occurred at similar rates compared with placebo. Overall, sitagliptin provides a treatment option for patients with type 2 diabetes as a monotherapy, or as an adjunct to metformin or a thiazolidinedione when patients achieve inadequate glycemic control while on either of the agents. It is also an alternative therapy for those patients who have contraindications or intolerability to other antidiabetic agents.
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PMID:Sitagliptin: a novel drug for the treatment of type 2 diabetes. 1770 Mar 85

Given the enormous public health and economic burden posed by the global epidemic of type 2 diabetes mellitus (T2DM), intervention in the prediabetes stage of disease to prevent progression to T2DM and its vascular complications seems the most sensible approach. Precisely how best to intervene remains the subject of much debate. Prudent lifestyle changes have been shown to significantly reduce the risk of progression in individuals with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Although lifestyle modifications are notoriously difficult to maintain, there is evidence that intensive intervention results in continued preventive benefit after the stopping of structured counselling. A number of drug therapies, including metformin, acarbose, orlistat and rosiglitazone, have also been proven effective in preventing progression from IFG/IGT, but unresolved issues still remain. Specifically, whether large numbers of individuals with glucose dysregulation who may never progress to T2DM should be exposed to the risk of pharmacological adverse effects is a topic of discussion and debate. Furthermore, there are limited data on the effectiveness of implementing interventions during the prediabetic state to prevent cardiovascular complications that may be hyperglycaemia related. A recent American Diabetes Association (ADA) consensus statement on IFG/IGT recommends lifestyle modification for individuals with IFG or IGT. Of note, the ADA consensus statement introduces the option of adding metformin treatment to lifestyle changes in those individuals who have combined IFG/IGT plus an additional risk factor for progression and who also have some features that increase the likelihood of benefiting from metformin treatment. The dipeptidyl peptidase-4 inhibitors are a new class of oral antidiabetic agents that, in addition to being effective in improving glycaemic control, may exert beneficial effects in preserving beta-cell function. These characteristics, combined with a low risk of hypoglycaemia, weight neutrality and what appears - so far - to be a relatively benign tolerability profile, make these agents intriguing candidates for preventive treatment.
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PMID:Reflecting on type 2 diabetes prevention: more questions than answers! 1787 41

Incretins are gut peptides that potentiate nutrient-stimulated insulin secretion following meal ingestion. Activities of the dominant incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide, include glucose-dependent stimulation of insulin secretion and, in preclinical models, improvement in islet beta-cell mass. GLP-1 additionally reduces glucagon secretion, inhibits gastric emptying and promotes satiety. Patients with type 2 diabetes mellitus (T2DM) exhibit reduced total and intact GLP-1 levels, and exogenous administration of the hormone via continuous infusion results in glucose profiles similar to those in non-diabetic subjects. Incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4). Thus, strategies to enhance incretin activity have included development of GLP-1 receptor agonists resistant to the action of DPP-4 (e.g. exenatide and liraglutide) and DPP-4 inhibitors that act to increase concentrations of endogenous intact incretins (e.g. sitagliptin and vildagliptin). Clinical trials of these incretin-based therapies have shown them to be effective in improving glycaemic control in patients with T2DM.
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PMID:Incretin-based treatment of type 2 diabetes: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. 1787 44

Vildagliptin is a potent selective inhibitor of dipeptidyl peptidase-4 (DPP-4) that improves glycaemic control by increasing islet alpha-cell and beta-cell responsiveness to glucose. In patients with type 2 diabetes mellitus (T2DM), vildagliptin improves beta-cell function, measured as insulin secretory rate relative to glucose level, and reduces glucagon secretion and endogenous glucose production in the postprandial period, resulting in reduced glucose levels. In clinical trials in T2DM, vildagliptin 100 mg/day monotherapy is effective in reducing haemoglobin A1c (HbA1c) across the spectrum of hyperglycaemia and has maintained efficacy over long-term treatment with neutral effects on body weight and lipids. Vildagliptin is associated with a low risk of hypoglycaemia, and has an adverse event profile comparable to placebo, including a reduced rate of gastrointestinal adverse effects compared with metformin and a reduced rate of oedema compared with rosiglitazone. As add-on combination therapy, vildagliptin produces significant further reductions in HbA1c in patients receiving metformin, pioglitazone, glimepiride and insulin, and has been found to reduce frequency of hypoglycaemia as an add-on to insulin. Preliminary findings indicate that the improved islet cell function underlying the efficacy of vildagliptin in T2DM is also observed in patients with impaired glucose tolerance, with vildagliptin treatment resulting in reduced glycaemic excursions. The overall profile of vildagliptin and the preliminary evidence of beneficial effects in the prediabetic state suggest that DPP-4 inhibition could be an effective strategy to prevent or delay progression from the prediabetic state to overt T2DM.
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PMID:The DPP-4 inhibitor vildagliptin: robust glycaemic control in type 2 diabetes and beyond. 1787 45

The epidemic of type 2 diabetes worldwide continues unabated. Despite a number of existing therapies, treatment goals are seldom fully achieved. While insulin resistance and beta cell failure remain important in the pathogenesis of the condition, the role of incretin hormones in glucose homeostasis has recently become clearer. Incretins have several glucoregulatory mechanisms, and a novel approach to the treatment of type 2 diabetes focuses on enhancing and prolonging the physiological actions of these hormones. Gliptins inhibit the enzyme dipeptidyl peptidase-IV (DPP-IV), which degrades incretin hormones. These drugs are a promising new class of oral hypoglycaemic medication, which appear to be weight-neutral and have few side-effects, although the published clinical studies are mainly regulatory licensing studies. As these drugs now are available for clinical use, we discuss the mechanism of action, efficacy and potential adverse effects of this new class of oral hypoglycaemic agent.
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PMID:Gliptins: a new class of oral hypoglycaemic agent. 1788 15

Dipeptidyl peptidase (DPP-IV) rapidly metabolizes hormones such as glucagon-like peptide-1(7-36)amide. This study evaluated circulating DPP-IV activity in type 2 diabetic patients in relation to GLP-1 degradation and metabolic control. Blood samples were collected from type 2 diabetic patients in three main categories: good glycaemic control (HbA(1c) <7%, upper limit of non-diabetic range), moderate glycaemic control (HbA(1c) 7-9%) and poor glycaemic control (HbA(1c) >9%). Age- and sex-matched non-diabetic subjects were used as controls. Circulating DPP-IV activity of healthy control subjects was 22.5+/-0.7 nmol/ml/min (n=70). In the combined groups of type 2 diabetic subjects, circulating DPP-IV activity was significantly decreased at 18.1+/-0.7 nmol/ml/min (p<0.001, n=54). DPP-IV activity was negatively correlated with both glucose (p<0.01) and HbA(1c) (p<0.01) in this population. Furthermore, DPP-IV activity was reduced 1.2-fold (p<0.01, n=25), 1.3-fold (p<0.001, n=19) and 1.3-fold (p<0.05, n=10) in good, moderate and poorly controlled diabetic groups, 18.7+/-1.0, 17.4+/-1.4 and 18.0+/-1.5 nmol/ml/min, respectively. Degradation of GLP-1 by in vitro incubation with pooled plasma samples from healthy and type 2 diabetic subjects revealed decreased degradation to the inactive metabolite, GLP-1(9-36), in the diabetic group. These data indicate decreased DPP-IV activity and GLP-1 degradation in type 2 diabetes. DPP-IV enzyme activity appears to be depressed in response to poor glycaemic control.
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PMID:Decreased dipeptidyl peptidase-IV activity and glucagon-like peptide-1(7-36)amide degradation in type 2 diabetic subjects. 1790 81


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