exenatide and alogliptin

Effective, evidence-based management of type 2 diabetes (T2D) requires the integration of the best available evidence with clinical experience and patient preferences.. Studies published from 2000 to 2012 evaluating glucagon-like peptide-1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) were identified using PubMed. The author contextualized the study findings with his clinical experience.. Incretin-based therapy targets multiple dysfunctional organs in T2D. Injectable GLP-1RAs provide substantial glycemic control and weight reduction; while oral DPP-4 inhibitors provide moderate glycemic control and weight neutrality. Both classes are effective, well tolerated, and associated with a low incidence of hypoglycemia when used alone or in combination with other antidiabetes agents. GLP-1RAs are associated with transient nausea and, like DPP-4 inhibitors, rare pancreatitis.. Data indicate and clinical experience confirms that incretins are well tolerated in appropriate patients and provide sustained glycemic control and weight loss or weight neutrality throughout T2D progression.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Linagliptin; Liraglutide; Peptides; Piperidines; Purines; Pyrazines; Quinazolines; Receptors, Glucagon; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Uracil; Venoms; Weight Loss

Aging is characterized by a progressive increase in the prevalence of type 2 diabetes mellitus (T2DM), which approaches 20% by age 70 years. Older patients with T2DM are a very heterogeneous group with multiple comorbidities, an increased risk of hypoglycemia, and a greater susceptibility to adverse effects of antihyperglycemic drugs, making treatment of T2DM in this population challenging. The risk of severe hypoglycemia likely represents the greatest barrier to T2DM care in the elderly. Although recent guidelines recommend more flexibility in treating this population with individualized targets, inadequate glycemic control is still closely linked to poor outcome in elderly patients. Incretins (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]) are hormones released post-meal from intestinal endocrine cells that stimulate insulin secretion and suppress postprandial glucagon secretion in a glucose-dependent manner. "Incretin therapies," comprising the injectable GLP-1 analogs and oral dipeptidyl peptidase-4 (DPP-4) inhibitors, are promising new therapies for use in older patients because of their consistent efficacy and low risk of hypoglycemia. However, data with these new agents are still scarce in this population, which has not been particularly well represented in clinical trials, highlighting the need for additional specific studies. The objective of this article is to provide an overview of the available data and potential role of these novel incretin therapies in managing T2DM in the elderly. With the exception of the DPP-4 inhibitor vildagliptin, there is no published trial to date dedicated to this population, although a few studies are currently ongoing. Therefore, available data from elderly subgroups of individual studies were also reviewed when available, as well as pooled analyses by age subgroups across clinical programs conducted with incretin therapies.

Topics: Adamantane; Age Factors; Aged; Aging; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Linagliptin; Liraglutide; Male; Middle Aged; Nitriles; Peptides; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Uracil; Venoms; Vildagliptin

Successful management of type 2 diabetes mellitus (T2DM) requires attention to additional conditions often associated with hyperglycemia including overweight or obesity, dyslipidemia and hypertension, as each has some relationship with microvascular or macrovascular complications. Because control of cardiovascular risk factors is as important as glucose control in T2DM, these risk factors need to be addressed, and it is critical that antidiabetes medications do not exacerbate these risk factors. A patient-centered approach to treatment in which clinicians maximize patient involvement in the selection of antidiabetes therapy may lead to increased adherence and improved clinical outcomes. The incretin hormones, which include glucagon-like peptide-1 (GLP-1), are involved in glucoregulation and have become an important focus of T2DM research and treatment. Incretin-based therapies, such as the glucagon-like peptide-1 receptor agonists and the dipeptidyl peptidase-IV inhibitors, have shown beneficial effects on hyperglycemia, weight, blood pressure and lipids with a low incidence of hypoglycemia.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemic Agents; Liraglutide; Nitriles; Obesity; Patient Compliance; Peptides; Piperidines; Precision Medicine; Primary Health Care; Pyrazines; Pyrrolidines; Risk Factors; Sitagliptin Phosphate; Triazoles; Uracil; Venoms; Vildagliptin

Glucagon-like peptide-1 (GLP-1) receptor agonists (liraglutide, exenatide, lixisenatide) have recently been used as anti-diabetes drugs. We examined relationships of the binding occupancy of GLP-1 receptors (Φ) and their clinical efficacy after administration of GLP-1 receptor agonists. Next, by focusing on changes of GLP-1 concentration after administration of dipeptidyl peptidase-4 (DPP-4) inhibitors (vildagliptin, alogliptin, sitagliptin, linagliptin), we analyzed the relationship between Φ and clinical efficacy. Furthermore, using Φ as a common parameter, we compared the clinical efficacy elicited by GLP-1 receptor agonists and DPP-4 inhibitors using a theoretical analysis method. The present results showed that GLP-1 receptor agonists produced their clinical effect at a relatively low level of Φ (1.1-10.7%) at a usual dose. Furthermore, it was suggested that the drugs might achieve their full effect at an extraordinarily low level of Φ. It was also revealed that the Φ value of DPP-4 inhibitors (0.83-1.3%) was at the lower end or lower than that of GLP-1 receptor agonists at a usual dose. Accordingly, the predicted value for hemoglobin A

Topics: Adamantane; Algorithms; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Monitoring; Exenatide; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Ligands; Liraglutide; Models, Molecular; Molecular Targeted Therapy; Nitriles; Peptides; Piperidines; Pyrrolidines; Reproducibility of Results; Sitagliptin Phosphate; Uracil; Venoms; Vildagliptin

Dipeptidyl peptidase (DPP)-4 is an enzyme that cleaves and inactivates incretin hormones capable of stimulating insulin secretion from pancreatic β-cells. DPP-4 inhibitors are now widely used for the treatment of type 2 diabetes. Experimental studies have suggested a renoprotective role of DPP-4 inhibitors in various models of diabetic kidney disease, which may be independent of lowering blood glucose levels. In the present study, we examined the effect of DPP-4 inhibitors in the rat Thy-1 glomerulonephritis model, a nondiabetic glomerular injury model. Rats were injected with OX-7 (1.2 mg/kg iv) and treated with the DPP-4 inhibitor alogliptin (20 mg·kg(-1)·day(-1)) or vehicle for 7 days orally by gavage. Alogliptin significantly reduced the number of CD68-positive inflammatory macrophages in the kidney, which was associated with a nonsignificant tendency to ameliorate glomerular injury and reduce proteinuria. Another DPP-4 inhibitor, anagliptin (300 mg·kg(-1)·day(-1) mixed with food) and a glucagon-like peptide-1 receptor agonist, exendin-4 (10 mg/kg sc), similarly reduced CD68-positive macrophage infiltration to the kidney. Furthermore, ex vivo transmigration assays using peritoneal macrophages revealed that exendin-4, but not alogliptin, dose dependently reduced monocyte chemotactic protein-1-stimulated macrophage infiltration. These data suggest that DPP-4 inhibitors reduced macrophage infiltration directly via glucagon-like peptide-1-dependent signaling in the rat Thy-1 nephritis model and indicate that the control of inflammation by DPP-4 inhibitors is useful for the treatment of nondiabetic kidney disease models.

Topics: Animals; Anti-Inflammatory Agents; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antilymphocyte Serum; Cell Line; Chemokine CCL2; Chemotaxis; Cytoprotection; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Exenatide; Glomerulonephritis; Glucagon-Like Peptide-1 Receptor; Kidney Glomerulus; Macrophages, Peritoneal; Male; Mice, Inbred C57BL; Peptides; Piperidines; Proteinuria; Pyrimidines; Rats, Sprague-Dawley; Receptors, Glucagon; Signal Transduction; Uracil; Venoms

Accumulating evidence of the beyond-glucose lowering effects of a gut-released hormone, glucagon-like peptide-1 (GLP-1), has been reported in the context of remote organ connections of the cardiovascular system. Specifically, GLP-1 appears to prevent apoptosis, and inhibition of dipeptidyl peptidase-4 (DPP-4), which cleaves GLP-1, is renoprotective in rodent ischemia-reperfusion injury models. Whether this renoprotection involves enhanced GLP-1 signaling is unclear, however, because DPP-4 cleaves other molecules as well. Thus, we investigated whether modulation of GLP-1 signaling attenuates cisplatin (CP)-induced AKI. Mice injected with 15 mg/kg CP had increased BUN and serum creatinine and CP caused remarkable pathologic renal injury, including tubular necrosis. Apoptosis was also detected in the tubular epithelial cells of CP-treated mice using immunoassays for single-stranded DNA and activated caspase-3. Treatment with a DPP-4 inhibitor, alogliptin (AG), significantly reduced CP-induced renal injury and reduced the renal mRNA expression ratios of Bax/Bcl-2 and Bim/Bcl-2. AG treatment increased the blood levels of GLP-1, but reversed the CP-induced increase in the levels of other DPP-4 substrates such as stromal cell-derived factor-1 and neuropeptide Y. Furthermore, the GLP-1 receptor agonist exendin-4 reduced CP-induced renal injury and apoptosis, and suppression of renal GLP-1 receptor expression in vivo by small interfering RNA reversed the renoprotective effects of AG. These data suggest that enhancing GLP-1 signaling ameliorates CP-induced AKI via antiapoptotic effects and that this gut-kidney axis could be a new therapeutic target in AKI.

Topics: Acute Kidney Injury; Animals; Antineoplastic Agents; Apoptosis; Cisplatin; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Peptides; Piperidines; Receptors, Glucagon; Reperfusion Injury; RNA, Small Interfering; Uracil; Venoms

Topics: Adamantane; Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Linagliptin; Liraglutide; Nitriles; Peptides; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Triazoles; Uracil; Venoms; Vildagliptin

Activation of the glucagon-like peptide (GLP)-1 receptor (GLP-1R) and inhibition of dipeptidyl peptidase-4 (DPP-4) are new antidiabetic strategies. The GLP-1R and DPP-4 are also expressed in the renal proximal tubular brush border, where they may regulate Na(+) reabsorption. Exendin-4 (EX4) is a naturally occurring antidiabetic polypeptide (from the saliva of the lizard Heloderma suspectum) and GLP-1R agonist; however, part of its nonglucoregulatory effects are through GLP-1R-independent mechanisms. DPP-4 cleaves and inactivates GLP-1; thus the natriuretic effect of DPP-4 inhibition may be mediated by the GLP-1R. We report that parenteral application of EX4 in wild-type mice induced a diuresis and natriuresis associated with increases in glomerular filtration rate, fractional urinary fluid and Na(+) excretion, and renal membrane expression of the Na(+)/H(+) exchanger NHE3 phosphorylated at S552 and S605, established consensus sites for cAMP-dependent PKA. These effects were absent in mice lacking the GLP-1R and independent of adenylyl cyclase 6. In comparison, parenteral application of the DPP-4 inhibitor alogliptin reduced plasma DPP-4 activity by 95% and induced a diuresis and natriuresis independent of the presence of the GLP-1R or changes in phosphorylated NHE3. The inhibitory effect on renal fluid and Na(+) reabsorption of EX4, but not alogliptin, was preserved in diabetic db/db mice and associated with a modest reduction in blood pressure. These results reveal mechanistic differences in how EX4 vs. DPP-4 inhibition induces diuresis and natriuresis under normal states, with preservation of GLP-1R-mediated, but not DPP-4 inhibitor-dependent, natriuretic mechanisms in a mouse model of obese type 2 diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Kidney; Mice; Mice, Knockout; Natriuresis; Natriuretic Agents; Obesity; Peptides; Phosphorylation; Piperidines; Receptors, Glucagon; Uracil; Venoms

We examined the impact of FDA's 2008 guidelines for addressing cardiovascular risks of new therapies for type 2 diabetes on clinical trials. We focused on the new class of incretin-modulating drugs, exenatide, sitagliptin, saxagliptin and liraglutide, which were approved in 2005-2010. We contrasted these findings with those from 2 different groups: 1. diabetes drugs approved in the same timeframe but with a non-incretin mechanism of action (colesevelam HCl and bromocriptine mesylate) and 2. diabetes drugs with NDAs delayed and not yet approved within the same time frame (vildagliptin, alogliptin, insulin inhalation powder, and exenatide long acting release). The new guidelines have had an important impact on clinical development. Review time has increased over 2-fold. The increase is seen even if a drug with the same mechanism of action has been already approved. Whereas exenatide (approved in 2005) required 10 months of regulatory review, the approval of liraglutide in 2010 required more than twice as long (21 months). In contrast, the marketing authorization of liraglutide in the EU required 14 months. Additionally, the manufacturer of vildagliptin announced in June 2008, 30 months after the NDA was filed, that a re-submission to meet FDA's demands was not planned. The drug however received marketing authorization in the EU in 2007. The number of randomized patients and patient-years in NDAs increased more than 2.5 and 4 fold, respectively since the guidelines. The significant cost increases and negative publicity because of rare adverse reactions will adversely affect future clinical research in type 2 diabetes and not address its burgeoning health care impact.

Topics: Adamantane; Allylamine; Cardiovascular Diseases; Colesevelam Hydrochloride; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Investigational New Drug Application; Liraglutide; Nitriles; Peptides; Piperidines; Practice Guidelines as Topic; Pyrazines; Pyrrolidines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Time Factors; Triazoles; United States; United States Food and Drug Administration; Uracil; Venoms; Vildagliptin