alogliptin and Cardiovascular-Diseases

Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral antidiabetic drugs that safely reduce the blood glucose level over the long term. In Japan, DPP-4 inhibitors have become the oral antidiabetic drugs most frequently prescribed for patients with type 2 diabetes. However, the results of several cardiovascular outcomes studies have suggested that some DPP-4 inhibitors may increase the risk of hospitalization for heart failure. In patients with diabetes, heart failure is the most frequent cardiovascular condition, and it has a negative impact on the quality of life as well as being a potentially fatal complication. Therefore, it is important to determine whether an increased risk of heart failure is associated with certain DPP-4 inhibitors or is a class effect of these drugs. This review explores the mechanism by which DPP-4 inhibitors may increase the risk of heart failure and possible differences among these drugs. The available research suggests that DPP-4 inhibitors cause sympathetic activation as a class effect and this may increase the risk of heart failure. Unlike other DPP-4 inhibitors, sitagliptin and alogliptin are mainly excreted in the urine and suppress renal sodium-hydrogen exchanger 3 activity. These two drugs did not increase the risk of hospitalization for heart failure in large-scale cardiovascular outcomes studies.

Topics: Adult; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Japan; Male; Middle Aged; Piperidines; Quality of Life; Sitagliptin Phosphate; Uracil

Regulatory requirements mandate that new drugs for treatment of patients with type 2 diabetes mellitus (T2DM), such as dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, are evaluated to show that they do not increase cardiovascular (CV) risk.. A systematic review was undertaken to evaluate the association between DPP-4 inhibitor and GLP-1 receptor agonist use and major adverse cardiac events (MACE). The National Institutes of Health Medline database was searched for pooled analyses, meta-analyses, and randomized controlled trials (RCTs) of DPP-4 inhibitors and GLP-1 receptor agonists that included CV endpoints.. Thirty-six articles met the inclusion criteria encompassing 11 pooled analyses, 17 meta-analyses, and eight RCTs (including secondary analyses). Over the short term (up to 4 years), patients with T2DM exposed to a DPP-4 inhibitor or GLP-1 receptor agonist were not at increased risk for MACE (or its component endpoints) compared with those who received comparator agents. Two meta-analyses showed a significant reduction in the incidence of MACE associated with DPP-4 inhibitor therapy as a drug class, but this beneficial effect was not observed in other meta-analyses that included large RCT CV outcome studies. In four RCTs that evaluated alogliptin, saxagliptin, sitagliptin, or lixisenatide, there was no overall increased risk for MACE relative to placebo in T2DM patients at high risk for CV events or with established CV disease, although there was an increased rate of hospitalization for heart failure associated with saxagliptin. A fifth RCT showed that liraglutide reduced MACE risk by 13% versus placebo.. Overall, incretin therapy does not appear to increase risk for MACE in the short term.

Topics: Adamantane; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Meta-Analysis as Topic; Peptides; Piperidines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Uracil

The incretin-based therapies, dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs, are important new classes of therapy for type 2 diabetes mellitus (T2DM). These agents prolong the action of the incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), by inhibiting their breakdown. The incretin hormones improve glycemic control in T2DM by increasing insulin secretion and suppressing glucagon levels. The cardiovascular (CV) effects of the incretin-based therapies have been of substantial interest since 2008, when the US Food and Drug Administration began to require that all new therapies for diabetes undergo rigorous assessment of CV safety through large-scale CV outcome trials. This article reviews the most recent CV outcome trials of the DPP-4 inhibitors (SAVOR-TIMI 53, EXAMINE, and TECOS) as evidence that the incretin-based therapies have acceptable CV safety profiles for patients with T2DM. The studies differ with regard to patient population, trial duration, and heart failure outcomes but show similar findings for CV death, nonfatal myocardial infarction, and stroke, as well as hospitalization for unstable angina.

Topics: Adamantane; Cardiovascular Diseases; Cardiovascular System; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Heart Failure; Humans; Hypoglycemic Agents; Incretins; Piperidines; Sitagliptin Phosphate; Uracil

Cardiovascular disease (CVD) is the greatest burden of type 2 diabetes mellitus (T2DM) in terms of morbility, mortality and costs for individuals and societies. Therefore, its prevention is a major goal in diabetes care. Optimal treatment of hyperglycemia is certainly instrumental to CVD prevention. Optimal treatment means both establishing the most appropriate glycemic target for the given individual and selecting the medication(s) with the most favourable benefit/safety ratio. CVD safety, if not a clear CVD benefit, is certainly required for all antidiabetic agents. Dipeptidyl-peptidase-4 (DPP-4) inhibitors are among the classes of antidiabetic agents most recently made available for diabetes care. A major question to be addressed is the effect of these compounds on CVD. Expectations were high for their mechanism of action, which targets also post-prandial glucose and minimize hypoglycemia risk, thereby providing a sort of global glucose control, and for some potentially beneficial extra-glycemic effects. This article reviews the existing literature on this issue.. Data published so far document that DPP-4 inhibitors have a wide spectrum of glycemic and extra-glycemic effects potentially reducing the risk of CVD as well as favourable effects on intermediate or surrogate CVD endpoints. These data heralded a better CVD outcome. Accordingly, pooling CVD safety data from phase 3 and 4 studies conducted with DPP-4 inhibitors suggested that their use might translate into a better CVD outcome. Data from three CVD outcome RCTs with alogliptin, saxagliptin and sitagliptin documented no harm but did not show any benefit on major CVD events. A modest but significant increased risk of hospitalization for heart failure was observed with saxagliptin and with alogliptin (only in subjects with no history of heart failure before randomization) but not with sitagliptin. A study currently in progress with linagliptin will provide further insights in the issue of CVD safety and benefit.. It should be considered that most alternative oral antidiabetic agents generally do not possess a better CVD risk profile than DPP-4 inhibitors and that some of them, indeed, should be used with caution because of potentially adverse effects on heart and vasculature. Overall, the selection of antidiabetic agent(s) with the most favourable CVD profile is mandatory but still challenging in diabetes care.

Topics: Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Clinical Trials, Phase IV as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Endpoint Determination; Humans; Hypoglycemic Agents; Linagliptin; Meta-Analysis as Topic; Observational Studies as Topic; Piperidines; Randomized Controlled Trials as Topic; Risk Factors; Sitagliptin Phosphate; Uracil

Cardiovascular (CV) disease is the leading cause of mortality and morbidity in patients with type 2 diabetes mellitus (T2DM). However, improving glycaemic control alone has not decreased CV events. Therapies that improve glycaemic control, CV disease risk factors and CV function are more likely to be successful. Dipeptidyl peptidase-4 (DPP-4) inhibitors prevent breakdown of incretin hormones glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic peptide and improve glycaemic control in patients with T2DM. DPP-4 acts on other substrates, many associated with cardioprotection. Thus, inhibition of DPP-4 may lead to elevations in these potentially beneficial substrates. Data from animal studies and small observational studies in humans suggest that DPP-4 inhibitors may potentially reduce CV risk. However, recently completed CV outcome trials in patients with T2DM and CV disease or at high risk of adverse CV events have shown that the DPP-4 inhibitors saxagliptin and alogliptin neither increased nor decreased major adverse CV events.

Topics: Adamantane; Animals; Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Incretins; Piperidines; Protective Factors; Risk Assessment; Risk Factors; Treatment Outcome; Uracil

To investigate relationships between glycated haemoglobin (HbA1c) and reported hypoglycaemia and risk of major adverse cardiovascular events (MACE).. The EXAMINE trial randomized 5380 patients with type 2 diabetes (T2DM) and a recent acute coronary syndrome (ACS) event, in 49 countries, to double-blind treatment with alogliptin or placebo in addition to standard of care. We used Cox proportional hazards models to analyse relationships among MACE, HbA1c levels and hypoglycaemic events.. Patients randomized to alogliptin achieved lower HbA1c levels than the placebo group in all baseline HbA1c categories without differences in hypoglycaemia rates. No systematic change was found in MACE rates according to baseline HbA1c (P. There were no relationships between baseline HbA1c levels or HbA1c levels after 1 month of treatment and the risk of MACE. Alogliptin improved glycaemic control without increasing hypoglycaemia. Reported events of hypoglycaemia and serious hypoglycaemia were associated with MACE. These data underscore the safety of alogliptin in improving glycaemic control in T2DM post-ACS. Further study of hypoglycaemia as an independent risk factor for MACE in patients with T2DM and coronary disease is needed.

Topics: Acute Coronary Syndrome; Cardiovascular Diseases; Cohort Studies; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incidence; Male; Middle Aged; Piperidines; Risk Factors; Secondary Prevention; Severity of Illness Index; Uracil

To investigate adiponectin levels and cardiovascular (CV) outcomes in patients with diabetes and recent acute coronary syndrome (ACS).. We analysed baseline adiponectin concentration and CV outcomes in 5213 patients with type 2 diabetes enrolled in the EXAMINE trial of alogliptin vs placebo 15 to 90 days (median 45 days) after ACS. Event rates at 18 months are reported.. The median (interquartile range) baseline adiponectin concentration was 5.2 (3.5-7.9) μg/mL. Patients with the highest baseline adiponectin concentration (quartile [Q]4) were at significantly higher risk of death from a CV event (8.4% vs 1.7%; P < .0001), hospitalization for heart failure (HF; 7.5% vs 1.7%; P < .0001), and all-cause mortality (10.8% vs 2.4%; P < .0001) compared with those in Q1. After adjusting for age, sex, index event, HF, estimated glomerular filtration rate and hypertension, adiponectin concentration in Q4 remained associated with an increased risk of death from CV causes (hazard ratio [HR] 2.43, 95% confidence interval [CI] 1.52, 3.88), all-cause mortality (HR 2.45, 95% CI 1.65, 3.64), and HF (HR 2.44, 95% CI 1.47, 4.05), without change after stratification by body mass index. There was no significant difference in the rate of myocardial infarction or stroke.. In this contemporary population of patients with diabetes and ACS, adiponectin concentration was independently associated with increased risk of death from CV causes, all-cause mortality, and hospitalization for HF. The relationship between adiponectin and CV outcomes is complex and deserves further study.

Topics: Acute Coronary Syndrome; Adiponectin; Aged; Biomarkers; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Mortality; Piperidines; Proportional Hazards Models; Risk; Secondary Prevention; Uracil

We evaluated the risk of cardiovascular (CV) death in all Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) study participants and in those who experienced an on-study, major nonfatal CV event.. The study randomly assigned 5,380 patients with type 2 diabetes to alogliptin or placebo within 15 to 90 days of an acute coronary syndrome (ACS). Deaths and nonfatal CV events (myocardial infarction [MI], stroke, hospitalized heart failure [HHF], and hospitalization for unstable angina [UA]) were adjudicated. Patients were monitored until censoring or death, regardless of a prior postrandomized nonfatal CV event. Time-updated multivariable Cox models were used to estimate the risk of death in the absence of or after each nonfatal event.. Rates of CV death were 4.1% for alogliptin and 4.9% for placebo (hazard ratio [HR] 0.85; 95% CI 0.66, 1.10). A total of 736 patients (13.7%) experienced a first nonfatal CV event (5.9% MI, 1.1% stroke, 3.0% HHF, and 3.8% UA). Compared with patients not experiencing a nonfatal event, the adjusted HR (95% CI) for death was 3.12 after MI (2.13, 4.58; P < 0.0001) 4.96 after HHF (3.29, 7.47; P < 0.0001), 3.08 after stroke (1.29, 7.37; P = 0.011), and 1.66 after UA (0.81, 3.37; P = 0.164). Mortality rates after a nonfatal event were comparable for alogliptin and placebo.. In patients with type 2 diabetes and a recent ACS, the risk of CV death was higher after a postrandomization, nonfatal CV event, particularly heart failure, compared with those who did not experience a CV event. The risk of CV death was similar between alogliptin and placebo.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Hospitalization; Humans; Hypoglycemic Agents; Male; Middle Aged; Multivariate Analysis; Piperidines; Proportional Hazards Models; Risk; Uracil

To evaluate the long-term durability of the efficacy of alogliptin compared with glipizide in combination with metformin in people with type 2 diabetes inadequately controlled on stable-dose metformin.. This multicentre, double-blind, active-controlled study randomized 2639 patients aged 18-80 years to 104 weeks of treatment with metformin in addition to alogliptin 12.5 mg once daily (n = 880), alogliptin 25 mg once daily (n = 885) or glipizide 5 mg once daily, titrated to a maximum of 20 mg (n = 874). The primary endpoint was least square mean change from baseline in HbA1c level at 104 weeks.. The mean patient age was 55.4 years, the mean diabetes duration was 5.5 years and the mean baseline HbA1c was 7.6%. HbA1c reductions at week 104 were -0.68%, -0.72% and -0.59% for alogliptin 12.5 and 25 mg and glipizide, respectively [both doses met the criteria for non-inferiority to glipizide (p<0.001); alogliptin 25 mg met superiority criteria (p=0.010)]. Fasting plasma glucose concentration decreased by 0.05 and 0.18 mmol/l for alogliptin 12.5 and 25 mg, respectively, and increased by 0.30 mmol/l for glipizide (p < 0.001 for both comparisons with glipizide). Mean weight changes were -0.68, -0.89 and 0.95 kg for alogliptin 12.5 and 25 mg and glipizide, respectively (p < 0.001 for both comparisons with glipizide). Hypoglycaemia occurred in 23.2% of patients in the glipizide group vs. 2.5 and 1.4% of patients in the alogliptin 12.5 and 25 mg groups, respectively. Pancreatitis occurred in one patient in the alogliptin 25 mg group and three in the glipizide group.. Alogliptin efficacy was sustained over 2 years in patients with inadequate glycaemic control on metformin alone.

Topics: Adult; Aged; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Glipizide; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Pancreatitis; Piperidines; Treatment Outcome; Uracil

As there have been concerns that some classes or agents for the treatment of type 2 diabetes may increase CV risk, we evaluated the cardiovascular profile of the dipeptidyl peptidase-4 inhibitor alogliptin.. We evaluated the incidence of CV events in patients treated with alogliptin, placebo or comparator antihyperglycaemic drugs in the clinical trial database for alogliptin using the composite major adverse cardiovascular event (MACE) endpoints of CV death, non-fatal myocardial infarction and non-fatal stroke.. The pooled analysis included 4168 patients exposed to alogliptin 12.5 and 25 mg daily for 2023 patient-years compared to 691 patients treated with placebo for 263 patient-years and 1169 patients treated with other antidiabetic agents (metformin, sulfonylureas and thiazolidinediones) for 703 patient-years. CV events were adjudicated by an expert endpoint committee blinded to treatment allocation. The incidence rates of the combined MACE were not significantly different between patients treated with alogliptin and comparator therapies (hazard ratio=0.635, 95% confidence interval, 0.0, 1.41). Additionally, other types of serious CV events were not significantly different between patients treated with alogliptin and comparator therapies.. These analyses have not shown a signal of increased CV risk with alogliptin in patients with type 2 diabetes. Future results from the adequately powered EXAMINE trial will definitively assess the CV safety profile of aloglipin in patients with type 2 diabetes mellitus.

Topics: Aged; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Humans; Incidence; Male; Middle Aged; Piperidines; Proportional Hazards Models; Severity of Illness Index; Uracil

To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome.. We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.. A total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, -0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo.. Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708.).

Topics: Aged; Angina, Unstable; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Myocardial Infarction; Piperidines; Uracil

Comprehensive safety evaluation of new drugs for diabetes mellitus is needed in the area of cardiovascular (CV) outcomes, particularly in populations with high CV risk. Alogliptin, a dipeptidyl peptidase 4 inhibitor, is under development for the treatment of type 2 diabetes mellitus alone or in combination with other antidiabetic therapies. Long-term CV safety of alogliptin is being established in a randomized, placebo-controlled clinical study in patients with acute coronary syndrome (ACS) using an analytical approach that has both an interim and final assessment. The primary CV end point for this trial is a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. Approximately 5,400 men and women with type 2 diabetes and ACS (acute myocardial infarction or unstable angina) are being recruited and will be followed up for up to 4.5 years postrandomization. The statistical plan for the trial uses a design that evaluates the hazard ratio (HR) of alogliptin to placebo first based on the primary CV composite end point after accrual of 80 to 150 primary CV events and again when there are 550 to 650 primary CV events. In the first series of analyses, the upper bound of a group-sequential 1-sided repeated CI for the HR must be ≤1.8 for registration in the United States. At end of study, the upper bound of a subsequent group-sequential 1-sided repeated CI for the HR must be ≤1.3. For both group sequential analyses, the repeated CIs are calculated to insure simultaneous coverage probabilities of 97.5% for the true HR. Study progress: More than 2,000 ACS patients were randomized as of June 2011. EXAMINE will define the CV safety profile of this dipeptidyl peptidase 4 inhibitor in patients at high risk for CV events.

Topics: Acute Coronary Syndrome; Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Male; Middle Aged; Piperidines; Prospective Studies; Treatment Outcome; Uracil

Topics: Adamantane; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Heart Failure; Humans; Hypoglycemic Agents; Piperidines; Risk Factors; Sitagliptin Phosphate; Uracil

Topics: Adamantane; Benzhydryl Compounds; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glucosides; Humans; Hypoglycemic Agents; Liraglutide; Peptides; Piperidines; Risk; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Uracil

Topics: Adamantane; Blood Glucose; Cardiovascular Diseases; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Piperidines; Uracil

Topics: Adamantane; Cardiovascular Diseases; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Piperidines; Randomized Controlled Trials as Topic; Treatment Failure; Uracil

Topics: Adamantane; Blood Glucose; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptides; Drug Approval; Humans; Hypoglycemic Agents; Piperidines; Uracil

Topics: Adamantane; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Drug Approval; Humans; Hypoglycemic Agents; Piperidines; Treatment Outcome; Uracil

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