Related Articles

Type 2 diabetes is associated with decreased incretin hormone response to an oral glucose load, and a progressive decline in postprandial glucagon-like peptide-1 (GLP-1) secretion. Incretin-based therapies offer a new option for treatment of type 2 diabetes. Saxagliptin, a potent, selective dipeptidyl peptidase-4 (DPP-4) inhibitor specifically designed for extended inhibition of the DPP-4 enzyme, causes increased endogenous GLP-1 concentration. In a phase 3 clinical trials program of 24 weeks duration, saxagliptin was studied in 6 multicenter, multinational, randomized, controlled studies and in combination with 3 of the most commonly administered oral antidiabetic drugs: metformin, glyburide and a thiozolidinedione (TZD). Saxagliptin provided significant reductions in hemoglobin HbA1c when given with metformin, glyburide, a TZD, or as monotherapy. Saxagliptin also reduced fasting plasma glucose and 2-hour post-prandial glucose in each of these studies, and was weight and lipid neutral. Saxagliptin was well tolerated and had a low risk of hypoglycemia when used as monotherapy.

Saxagliptin is a novel dipeptidyl peptidase-4 inhibitor (DPP-4 inhibitor) for the treatment of type 2 diabetes, with a duration profile for once daily dosing. It is highly selective for DPP-4 in comparison to other enzymes of the dipeptidyl peptidase family. DPP-4 inhibitors elevate plasma concentrations of the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). This effect results in a glucose-dependent stimulation of insulin secretion and an inhibition of glucagon secretion without an intrinsic risk for hypoglycemia. In comparison to sulfonylureas and thiazolidinediones that promote weight gain, DPP-4 inhibitors are weight neutral. Saxagliptin has been approved by the FDA for the US and by the EMEA for Europe in 2009. Clinical trials showed a dose-dependent inhibition of DPP-4 by saxagliptin in doses ranging from 2.5 to 100 mg daily without serious side effects. Type 2 diabetic patients receiving 5 mg to 10 mg saxagliptin once daily had a significant lowering of HbA1c and glycemic parameters along with good tolerability and safety. Saxagliptin has demonstrated a good efficacy for glycemic parameters in various patient populations either in monotherapy or in combination with metformin and other oral antidiabetic drugs as well as a favorable cardiovascular profile. With its high selectivity for DPP-4 and its clinical and cardiovascular profile, saxagliptin is an attractive novel DPP-4 inhibitor.

Saxagliptin (Onglyza™) is a potent, selective, once-daily dipeptidyl peptidase-4 (DPP-4) inhibitor indicated for improving glycemic control in patients with type 2 diabetes (T2D). By blocking DPP-4, saxagliptin increases and prolongs the effects of incretins, a group of peptide hormones released by intestinal cells after meals, which stimulate glucose-dependent insulin secretion to lower blood glucose. In controlled clinical trials, saxagliptin administered as monotherapy or in combination with metformin, glyburide, or a thiazolidinedione improved glycemic control in a clinically significant manner, reflected by significant decreases in glycated hemoglobin (monotherapy, −0.5%; add-on to metformin, thiazolidinedione, or sulfonylurea, −0.6% to 0.9%; initial combination with metformin, −2.5%), fasting plasma glucose, and postprandial glucose compared with controls. Additionally, saxagliptin improved β-cell function, reflected as increases in homeostasis model assessment (HOMA)-2β. Saxagliptin was generally well tolerated; it did not increase hypoglycemia compared with controls, and was weight neutral. A meta-analysis of Phase II and III trials showed that saxagliptin did not increase the risk of major cardiovascular events. Professional organizations have updated their guidelines for T2D to include a DPP-4 inhibitor as an early treatment option—either as initial therapy in combination with metformin, or as add-on therapy for patients whose glycemia is inadequately controlled by a single oral antidiabetic drug.

The prevalence of type 2 diabetes mellitus is high and growing rapidly. Suboptimal glycemic control provides opportunities for new treatment options to improve the morbidity and mortality of this progressive disease. Saxagliptin, a selective DPP-4 inhibitor, increases endogenous incretin levels and incretin acitivty. In controlled clinical trials saxagliptin reduces both fasting and postprandial glucose and works in monotherapy and in combination with metformin, TZDs and sulfonylureas. Saxagliptin has a very favourable side effect profile and may have other beneficial non-glycemic effects. The authors review the current available evidence for the safety, efficacy and saxagliptin’s place in therapy for type 2 diabetes mellitus. As understanding of the incretin hormones (GLP-1, GIP) expand we may see additional important non-glycemic effects that may affect the chronic management of type 2 diabetes mellitus.

Type 2 diabetes mellitus (DM) is a prevalent disorder that affects children, adolescents, and adults worldwide. In addition to risks of microvascular disease, patients with type 2 DM often have multiple risk factors of macrovascular disease; for example, approximately 90% of patients with type 2 DM are overweight/obese. Type 2 DM is a complex disease that involves a variety of pathophysiologic abnormalities, including insulin resistance, increased hepatic glucose production, and abnormalities in the secretion of hormones, such as insulin, glucagon, amylin, and incretins. Incretins are gut-derived peptides with a variety of glucoregulatory functions. Incretin dysfunction can be treated with glucagon-like peptide 1 (GLP-1) receptor agonists (eg, exenatide and liraglutide) or inhibitors of dipeptidyl peptidase 4 (DPP-4) (eg, sitagliptin and saxagliptin), the enzyme that degrades GLP-1. The GLP-1 receptor agonists and DPP-4 inhibitors both elevate GLP-1 activity and substantially improve glycemic control. The GLP-1 receptor agonists are more effective in lowering blood glucose and result in substantial weight loss, whereas therapy with DPP-4 inhibitors lowers blood glucose levels to a lesser degree, and they are weight neutral. Treatment with GLP-1 receptor agonists has demonstrated durable glycemic control and improvement in multiple cardiovascular disease risk factors. In addition, unlike insulin or sulfonylureas, treatment with a GLP-1 receptor agonist or a DPP-4 inhibitor has not been associated with substantial hypoglycemia. These factors should be considered when selecting monotherapy or elements of combination therapy for patients with type 2 DM who are overweight/obese, for patients who have experienced hypoglycemia with other agents, and when achieving glycemic targets is difficult.

Background

Alogliptin is an oral antihyperglycemic agent that is a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4). Inhibition of DPP-4 elevates levels of the incretin hormones glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) by preventing their degradation.

Objective

To review the evolution of alogliptin and its pharmacokinetics, pharmacodynamics, clinical efficacy and adverse effects. In addition, we compared alogliptin to other DPP-4 inhibitors.

Methods

A comprehensive literature search was performed using the term ‘alogliptin’. Original research articles and review articles as well as scientific abstracts were included.

Results

Alogliptin raises postprandial levels of GLP-1. It has excellent bioavailability exhibiting a median Tmax ranging from 1 to 2 hours and a mean half-life of 12.4 to 21.4 hours across all doses. When given as monotherapy, mean hemoglobin A1c (HbA1c) reductions achieved were 0.5% to 0.6%. Combination therapy yielded similar reductions (−0.5% with metformin, −0.6% with glyburide, −0.8% with pioglitazone and −0.6% with insulin). Administration of alogliptin does not promote weight loss but has not resulted in weight gain. The agent is relatively well tolerated with few adverse effects, the major finding being a marginally higher rate of skin events, primarily pruritus.

Conclusions

Alogliptin causes significant reductions in HbA1c when used alone or in combination with other oral agents in patients with type 2 diabetes similar to other DPP-4 inhibitors in current clinical use. The side effect profile also does not differ from that of other DPP-4 inhibitors. However, long-term studies are necessary before the place of alogliptin in the management of type 2 diabetes can be established.

Saxagliptin is a potent, selective DPP4 inhibitor. Highlights from abstracts presented at the 2010 meetings of the European Association for the Study of Diabetes and the American Diabetes Association include studies and analyses that shed light on the promising role for saxagliptin within the management of type 2 diabetes mellitus. Data show that saxagliptin combination therapy improves HbA1c levels compared with placebo, particularly in patients with high HbA1c at baseline, long duration of disease, low baseline creatinine clearance, and low homeostasis model assessment 2 β-cell function at baseline. These efficacy benefits are achieved without any increase in hypoglycemia or other adverse events. The study results also show that the saxagliptin plus metformin combination is a good candidate for initial therapy in drug-naïve patients treated for as long as 72 weeks. Survey data presented confirm that hypoglycemia (and fear of hypoglycemia) is a barrier to patients' acceptance of diabetes treatment, limiting its efficacy. Therefore, therapies such as saxagliptin that have a low risk of hypoglycemia may be more acceptable to patients in helping them to achieve glycemic control and to optimize their quality of life. In patients with renal impairment, for whom metformin is contraindicated, saxagliptin monotherapy is a promising option for antidiabetic management as, when given at a reduced dose, it is well-tolerated with a safety profile similar to that of placebo.

The glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors have become important options for the management of patients with type 2 diabetes mellitus. While the GLP-1R agonists and DPP-4 inhibitors act on the incretin system to regulate glucose homeostasis, there are important clinical differences among the five agents currently available in the U.S. For example, the GLP-1R agonists require subcutaneous administration, produce pharmacological levels of GLP-1 activity, promote weight loss, have a more robust glucose-lowering effect, and have a higher incidence of adverse gastrointestinal effects. In contrast, the DPP-4 inhibitors are taken orally, increase the half-life of endogenous GLP-1, are weight neutral, and are more commonly associated with nasopharyngitis. Differences in efficacy, safety, tolerability, and cost among the incretin-based therapies are important to consider in the primary care management of patients with type 2 diabetes mellitus.

In recent years the incretin therapies have provided a new treatment option for patients with type 2 diabetes mellitus (T2DM). The incretin therapies focus on the increasing levels of the two incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This results in increased glucose dependent insulin synthesis and release. GLP-1 receptor agonists such as liraglutide and exenatide exert an intrinsic biological effect on GLP-1 receptors directly stimulating the release of insulin from pancreatic beta cells. DPP-4 inhibitors such as sitagliptin and linagliptin prevent the inactivation of endogenous GLP-1 and GIP through competitive inhibition of the DPP-4 enzyme. Both incretin therapies have good safety and tolerability profiles and interact minimally with a number of medications commonly prescribed in T2DM. This paper focuses on the pharmacological basis by which the incretin therapies function and how this knowledge can inform and benefit clinical decisions. Each individual incretin agent has benefits and pitfalls relating to aspects such as glycaemic and nonglycaemic efficacy, safety and tolerability, ease of administration, and cost. Overall, a personalized medicine approach has been found to be favourable, tailoring the incretin agent to benefit and suit patient's needs such as renal impairment (RI) or hepatic impairment (HI).

Background

Progressive remodeling after myocardial infarction (MI) is a leading cause of morbidity and mortality. Recently, glucagon-like peptide (GLP)-1 was shown to have cardioprotective effects, but treatment with GLP-1 is limited by its short half-life. It is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), an enzyme which inhibits GLP-1 activity. We hypothesized that the DPP-4 inhibitor vildagliptin will increase levels of GLP-1 and may exert protective effects on cardiac function after MI.

Methods

Sprague-Dawley rats were either subjected to coronary ligation to induce MI and left ventricular (LV) remodeling, or sham operation. Parts of the rats with an MI were pre-treated for 2 days with the DPP-4 inhibitor vildagliptin (MI-Vildagliptin immediate, MI-VI, 15 mg/kg/day). The remainder of the rats was, three weeks after coronary artery ligation, subjected to treatment with DPP-4 inhibitor vildagliptin (MI-Vildagliptin Late, MI-VL) or control (MI). At 12 weeks, echocardiography and invasive hemodynamics were measured and molecular analysis and immunohistochemistry were performed.

Results

Vildagliptin inhibited the DPP-4 enzymatic activity by almost 70% and increased active GLP-1 levels by about 3-fold in plasma in both treated groups (p < 0.05 vs. non-treated groups). Cardiac function (ejection fraction) was decreased in all 3 MI groups compared with Sham group (p < 0.05); treatment with vildagliptin, either early or late, did not reverse cardiac remodeling. ANP (atrial natriuretic peptide) and BNP (brain natriuretic peptide) mRNA levels were significantly increased in all 3 MI groups, but no significant reductions were observed in both vildagliptin groups. Vildagliptin also did not change cardiomyocyte size or capillary density after MI. No effects were detected on glucose level and body weight in the post-MI remodeling model.

Conclusion

Vildagliptin increases the active GLP-1 level via inhibition of DPP-4, but it has no substantial protective effects on cardiac function in this well established long-term post-MI cardiac remodeling model.

Treatment options for type 2 diabetes based on the action of the incretin hormone glucagon-like peptide-1 (GLP-1) were first introduced in 2005. These comprise the injectable GLP-1 receptor agonists solely acting on the GLP-1 receptor on the one hand and orally active dipeptidyl-peptidase inhibitors (DPP-4 inhibitors) raising endogenous GLP-1 and other hormone levels by inhibiting the degrading enzyme DPP-4. In adult medicine, both treatment options are attractive and more commonly used because of their action and safety profile. The incretin-based therapies stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner and carry no intrinsic risk of hypoglycaemia. GLP-1 receptor agonists allow weight loss, whereas DPP-4 inhibitors are weight neutral. This review gives an overview of the mechanism of action and the substances and clinical data available.

Postprandial hyperglycemia in type 2 diabetes is characterized by impaired insulin secretion and action, decreased glucose effectiveness and defective suppression of glucagon secretion. Newly available therapies for type 2 diabetes target the pathway of the incretin hormone glucagon-like peptide-1 (GLP-1). Oral inhibitors of dipeptidyl peptidase-4 (DPP-4) raise the level of endogenous GLP-1 by inhibiting its clearance thereby lowering fasting and postprandial glucose concentrations. Unlike compounds which act as agonists of the GLP-1 receptor, DPP-4 inhibitors are not associated with significant effects on gastrointestinal motility, which led to a controversy around the mechanisms responsible for their glucose-lowering effects. Here we review the evidence in regards to the mechanisms whereby DPP-4 inhibitors lower glucose concentrations. Their effects are most likely mediated by an increase in endogenous GLP-1, although additional mechanisms may be involved. The pharmacology, efficacy and safety of vildagliptin, a novel DPP-4 inhibitor, are also discussed.

Background

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that has a wide range of effects on glucose metabolism and cardiovascular function (e.g., improving insulin sensitivity, reduction in appetite, modulation of heart rate, blood pressure and myocardial contractility). Metabolic syndrome (MetS) is associated with an increased risk of developing atherosclerotic cardiovascular diseases. Novel glycemic control drugs, the dipeptidyl-peptidase-4 (DPP-4) inhibitors, work by inhibiting the inactivation of incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). In spite of good effects of these drugs in diabetic patients, circulating levels of incretins and their role in MetS are largely unknown.

Methods

To examine relationships between incretin hormones and MetS risk factors, we measured circulating levels of incretins in obese high-risk patients for cardiovascular disease. Fasting serum GLP-1 and GIP levels were measured by ELISA. We performed a cross-sectional analysis of metabolic variables in the fasting state in two subject groups: with MetS (n = 60) and pre-MetS (n = 37).

Results

Fasting levels of Serum GLP -1 in the peripheral circulation were significantly increased correlated with the accumulation of MetS risk factors components (r = 0. 470, P < 0.001). There was a significant interaction between circulating GLP-1 and GIP, serum high-density lipoprotein cholesterol, triglyceride, and serum uric acid concentrations but not waist circumference, fasting glucose, HbA1c, or presence of diabetes.

Conclusion

Circulating levels of GLP-1 in relation to the accumulation in MetS factors suggested that MetS patients with elevated levels of GLP-1 are high-risk patients for cardiovascular disease, independent with the presence of diabetes.

The incretin hormones, glucagon-like peptide-1 (GLP-1) and its receptor agonist (exendin-4), are well known for glucose homeostasis, insulinotropic effect, and effects on weight loss and food intake. However, due to the rapid degradation of GLP-1 by dipeptidylpeptidase-IV (DPP-IV) enzyme and renal elimination of exendin-4, their clinical applications have been restricted. Although exendin-4 has longer half-life than GLP-1, it still requires frequent injections to maintain efficacy for the treatment of diabetes. In recent decades, various polymeric delivery systems have been developed for the delivery of GLP-1 and exendin-4 genes or peptides for their long-term action and the extra production in ectopic tissues. Herein, we discuss the modification of the expression cassettes and peptides for long-term production and secretion of the native peptides. In addition, the characteristics of nonviral or viral system used for a delivery of a modified GLP-1 or exendin-4 are described. Furthermore, recent efforts to improve the biological half-life of GLP-1 or exendin-4 peptide via chemical conjugation with various smart polymers via chemical conjugation compared with native peptide are discussed.

Novel incretin-based drugs, such as glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i), have been last introduced in the pharmacological treatment of type 2 diabetes. In the last few years, the interest on the relationship of gut hormones with bone metabolism in diabetes has been increasing. The aim of present paper is to examine in vitro and in vivo evidence on the connections between incretin hormones and bone metabolism. We also discuss results of clinical trials and metaanalysis, explore the effects of incretin drugs in vitro on osteogenic cells and osteoclasts, and speculate on the possibility of different effects of GLP-1 RA and DPP-4i on the risk of bone fractures risk in humans. Although existing preliminary evidence suggests a protective effect on the bone, at least for DPP-4i, further controlled, long-term studies with measurement of bone markers, bone density, and clinical fractures rates are needed to substantiate and confirm those findings.

Background

Many patients with diabetes mellitus (DM) require a combination of antidiabetic drugs with complementary mechanisms of action to lower their hemoglobin A1c levels to achieve therapeutic targets and reduce the risk of cardiovascular complications. Linagliptin is a novel member of the dipeptidyl peptidase-4 (DPP-4) inhibitor class of antidiabetic drugs. DPP-4 inhibitors increase incretin (glucagon-like peptide-1 and gastric inhibitory polypeptide) levels, inhibit glucagon release and, more importantly, increase insulin secretion and inhibit gastric emptying. Currently, phase III clinical studies with linagliptin are underway to evaluate its clinical efficacy and safety. Linagliptin is expected to be one of the most appropriate therapies for Japanese patients with DM, as deficient insulin secretion is a greater concern than insulin resistance in this population. The number of patients with DM in Japan is increasing and this trend is predicted to continue. Several antidiabetic drugs are currently marketed in Japan; however there is no information describing the effective dose of linagliptin for Japanese patients with DM.

Methods

This prospective, randomized, double-blind study will compare linagliptin with placebo over a 12-week period. The study has also been designed to evaluate the safety and efficacy of linagliptin by comparing it with another antidiabetic, voglibose, over a 26-week treatment period. Four treatment groups have been established for these comparisons. A phase IIb/III combined study design has been utilized for this purpose and the approach for calculating sample size is described.

Discussion

This is the first phase IIb/III study to examine the long-term safety and efficacy of linagliptin in diabetes patients in the Japanese population.

Trial registration

Clinicaltrials.gov (NCT00654381).

The first dipeptidyl-peptidase-IV (DPP-4) inhibitor for the treatment of type 2 diabetes became available in 2006. Since then, the number of DPP-4 inhibitors has increased and DPP-4 inhibitors have developed into an important drug class. DPP-4 inhibitors act by increasing endogenous GLP-1 and GIP concentrations. Via this mechanism, insulin secretion is glucose-dependently stimulated and glucagon secretion inhibited. This results in a low risk for hypoglycemia. Furthermore, DPP-4 inhibitors are weight-neutral. Linagliptin is a novel DPP-4 inhibitor that, in contrast to the other members of this drug class, is eliminated by a biliary/hepatic route rather than by renal elimination. This property allows the use of linagliptin in type 2 diabetic patients with normal kidney function as well as in patients with renal insufficiency without dose adjustments. In comparative clinical studies, linagliptin was noninferior to other established antidiabetic agents, especially to metformin and sulfonylurea. It showed a superior safety profile over glimepiride regarding hypoglycemia, weight gain, a composite cardiovascular endpoint, and stroke. This review gives an overview on the efficacy and safety of linagliptin in comparison to the classical oral antidiabetic drugs as well as to the other DPP-4 inhibitors.

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.

Background

Activating G-protein coupled receptor 119 (GPR119) by its agonists can stimulate glucagon like peptide-1 (GLP-1) release. GLP-1 is rapidly degraded and inactivated by dipeptidylpeptidase-IV (DPP-IV). We studied the efficiency of combining PSN632408, a GPR119 agonist, with sitagliptin, a DPP-IV inhibitor, on β-cell regeneration in diabetic mice.

Materials & Methods

Diabetes in C57BL/6 mice was induced by streptozotocin. PSN632408 and sitagliptin alone or in combination were administered to diabetic mice for 7 weeks along with BrdU daily. Nonfasting blood glucose levels were monitored. After treatment, oral glucose tolerance test (OGTT), plasma active GLP-1 levels, β-cell mass along with α- and β-cell replication, and β-cell neogenesis were evaluated.

Results

Normoglycemia was not achieved in vehicle-treated mice. By contrast, 32% (6 of 19) of PSN632408-treated diabetic mice, 36% (5 of 14) sitagliptin-treated diabetic mice, and 59% (13 of 22) diabetic mice treated with PSN632408 and sitagliptin combination achieved normoglycemia after 7 weeks treatment. Combination therapy significantly increased plasma active GLP-1 levels, improved glucose clearance, stimulated both α- and β-cell replication, and augmented β-cell mass. Furthermore, treatment with combination therapy induced β-cell neogenesis from pancreatic duct-derived cells.

Conclusion

Our results demonstrate that combining a GPR119 agonist with a DPP-IV inhibitor may offer a novel therapeutic strategy for stimulating β-cell regeneration and reversing diabetes.

Background

Many medicines, including several cholesterol-lowering agents (eg, lovastatin, simvastatin), antihypertensives (eg, diltiazem, nifedipine, verapamil), and antifungals (eg, ketoconazole) are metabolized by and/or inhibit the cytochrome P450 (CYP) 3A4 metabolic pathway. These types of medicines are commonly coprescribed to treat comorbidities in patients with type 2 diabetes mellitus (T2DM) and the potential for drug-drug interactions of these medicines with new medicines for T2DM must be carefully evaluated.

Objective

To investigate the effects of CYP3A4 substrates or inhibitors, simvastatin (substrate), diltiazem (moderate inhibitor), and ketoconazole (strong inhibitor) on the pharmacokinetics and safety of saxagliptin, a CYP3A4/5 substrate; and the effects of saxagliptin on these agents in three separate studies.

Methods

Healthy subjects were administered saxagliptin 10 mg or 100 mg. Simvastatin, diltiazem extended-release, and ketoconazole doses of 40 mg once daily, 360 mg once daily, and 200 mg twice daily, respectively, were used to determine two-way pharmacokinetic interactions.

Results

Coadministration of simvastatin, diltiazem extended-release, or ketoconazole increased mean area under the concentration-time curve values (AUC) of saxagliptin by 12%, 109%, and 145%, respectively, versus saxagliptin alone. Mean exposure (AUC) of the CYP3A4-generated active metabolite of saxagliptin, 5-hydroxy saxagliptin, decreased with coadministration of simvastatin, diltiazem, and ketoconazole by 2%, 34%, and 88%, respectively. All adverse events were considered mild or moderate in all three studies; there were no serious adverse events or deaths.

Conclusion

Saxagliptin, when coadministered with simvastatin, diltiazem extended-release, or ketoconazole, was safe and generally well tolerated in healthy subjects. Clinically meaningful interactions of saxagliptin with simvastatin and diltiazem extended-release are not expected. The dose of saxagliptin does not need to be adjusted when coadministered with a substrate or moderate inhibitor of CYP3A4. A limitation to the lowest clinical dose of saxagliptin (2.5 mg) is proposed when it is coadministered with a potent CYP3A4 inhibitor such as ketoconazole.

Patients with type 2 diabetes mellitus (T2DM) are at high risk for cardiovascular (CV) disease; however, conclusive evidence that glycemic control leads to improved cardiovascular outcomes is lacking. Saxagliptin is a potent, selective dipeptidyl peptidase-4 inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Saxagliptin was evaluated in a series of phase III trials as monotherapy; add-on therapy to metformin, a sulfonylurea, or a thiazolidinedione; and as initial therapy in combination with metformin. Saxagliptin consistently improved glycemic control (as reflected by significant decreases in glycated hemoglobin, fasting plasma glucose, and postprandial glucose compared with controls) and was generally well tolerated. In these analyses, saxagliptin had clinically neutral effects on body weight, blood pressure, lipid levels, and other markers of CV risk compared with controls. A retrospective meta-analysis of 8 phase II and phase III trials found no evidence that saxagliptin increases CV risk in patients with T2DM (Cox proportional hazard ratio, 0.43; 95% CI, 0.23-0.80 for major adverse cardiovascular events retrospectively adjudicated). Instead, it raised the hypothesis that saxagliptin may reduce the risk of major adverse CV events. A long-term CV outcome trial, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-THrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) is currently ongoing to determine whether saxagliptin reduces CV risk in T2DM.

Insulin secretion from pancreatic β cells is stimulated by glucagon-like peptide-1 (GLP-1), a blood glucose-lowering hormone that is released from enteroendocrine L cells of the distal intestine after the ingestion of a meal. GLP-1 mimetics (e.g., Byetta) and GLP-1 analogs (e.g., Victoza) activate the β cell GLP-1 receptor (GLP-1R), and these compounds stimulate insulin secretion while also lowering levels of blood glucose in patients diagnosed with type 2 diabetes mellitus (T2DM). An additional therapeutic option for the treatment of T2DM involves the administration of dipeptidyl peptidase-IV (DPP-IV) inhibitors (e.g., Januvia, Galvus). These compounds slow metabolic degradation of intestinally released GLP-1, thereby raising post-prandial levels of circulating GLP-1 substantially. Investigational compounds that stimulate GLP-1 secretion also exist, and in this regard a noteworthy advance is the demonstration that small molecule GPR119 agonists (e.g., AR231453) stimulate L cell GLP-1 secretion while also directly stimulating β cell insulin release. In this review, we summarize what is currently known concerning the signal transduction properties of the β cell GLP-1R as they relate to insulin secretion. Emphasized are the cyclic AMP, protein kinase A, and Epac2 mediated actions of GLP-1 to regulate ATP-sensitive K+ channels, voltage-dependent K+ channels, TRPM2 cation channels, intracellular Ca2+ release channels, and Ca2+-dependent exocytosis. We also discuss new evidence that provides a conceptual framework with which to understand why GLP-1R agonists are less likely to induce hypoglycemia when they are administered for the treatment of T2DM.

Drugs that augment the incretin system [glucagon like peptide (GLP) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors] represent a novel class of anti-hyperglycemic agents that have shown to improve the health and survival of beta-cells (improvement in postprandial hyperglycemia) and suppress glucagon (improvement in fasting hyperglycemia). The incretins represent a large family of molecules referred to as the “glucagon superfamily of peptide hormones” of which more than 90% of the physiological effects of incretins are accomplished by GLP-17-37 and GLP17-36 amide and gastric insulinotropic peptide (GIP). GLP-1 mediates its effects via the GLP-1 receptor, which has a wide tissue distribution [pancreas, lung, heart, vascular smooth muscle cells, endothelial cells, macrophages and monocytes, kidney, gastrointestinal tract (stomach and intestine), central nervous system (neoortex, cerebellum, hypothalamus, hippocampus, brainstem nucleus tractus solitarius) and peripheral nervous system]. This would imply that the incretin system has effects outside the pancreas. Over time data has accumulated to suggest that therapies that augment the incretin system has beneficial pleiotrophic effects. The incretins have shown to possess a cardiac-friendly profile, preserve neuronal cells and safeguard from neuronal degeneration, improve hepatic inflammation and hepatosteatosis, improve insulin resistance, promote weight loss and induce satiety. There is growing evidence that they may also be renoprotective promoting wound healing and bone health.

Inhibitors of the protease dipeptidyl peptidase IV (DPP-IV) are promising new drugs for the treatment of type 2 diabetes. They are thought to act by inhibiting the breakdown of glucagon-like peptide-1 and, thereby, selectively enhancing insulin release under conditions when it is physiologically required. These drugs are selective for DPP-IV, but the enzyme itself has a broad range of substrates other than glucagon-like peptide-1. Other high affinity substrates of DPP-IV including peptide YY may also play a role in the regulation of energy homeostasis. Moreover, DPP-IV is also known as CD26 and considered to be a moonlighting protein because it has a wide range of other functions unrelated to energy homeostasis, e.g. in immunity. The potential role of DPP-IV inhibition on substrates other than glucagon-like peptide-1 in diabetes patients remains to be elucidated.

OBJECTIVE

Glucagon-like peptide-1 (7-36)amide (GLP-1) is cleaved by dipeptidyl peptidase-4 (DPP-4) to GLP-1 (9-36)amide. We examined whether chemical inhibition or genetic elimination of DPP-4 activity affects cardiovascular function in normoglycemic and diabetic mice after experimental myocardial infarction.

RESEARCH DESIGN AND METHODS

Cardiac structure and function was assessed by hemodynamic monitoring and echocardiography in DPP-4 knockout (Dpp4−/−) mice versus wild-type (Dpp4+/+) littermate controls and after left anterior descending (LAD) coronary artery ligation–induced myocardial infarction (MI). Effects of sustained DPP-4 inhibition with sitagliptin versus treatment with metformin were ascertained after experimental MI in a high-fat diet–streptozotocin model of murine diabetes. Functional recovery from ischemia-reperfusion (I/R) injury was measured in isolated hearts from Dpp4−/− versus Dpp4+/+ littermates and from normoglycemic wild-type (WT) mice treated with sitagliptin or metformin. Cardioprotective signaling in the murine heart was examined by RT-PCR and Western blot analyses.

RESULTS

Dpp4−/− mice exhibited normal indexes of cardiac structure and function. Survival post-MI was modestly improved in normoglycemic Dpp4−/− mice. Increased cardiac expression of phosphorylated AKT (pAKT), pGSK3β, and atrial natriuretic peptide (ANP) was detected in the nonischemic Dpp4−/− heart, and HO-1, ANP, and pGSK3β proteins were induced in nonischemic hearts from diabetic mice treated with sitagliptin or metformin. Sitagliptin and metformin treatment of wild-type diabetic mice reduced mortality after myocardial infarction. Sitagliptin improved functional recovery after I/R injury ex vivo in WT mice with similar protection from I/R injury also manifest in hearts from Dpp4−/− versus Dpp4+/+ mice.

CONCLUSIONS

Genetic disruption or chemical inhibition of DPP-4 does not impair cardiovascular function in the normoglycemic or diabetic mouse heart.