alogliptin and Diabetic-Cardiomyopathies

Background Blood pressure ( BP ) treatment goals in patients with diabetes mellitus and increased cardiovascular risk remain controversial. Our study objective was to determine cardiovascular outcomes according to achieved BP s over the average follow-up period in the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care) trial. Methods and Results EXAMINE was a cardiovascular outcomes trial in 5380 patients with type 2 diabetes mellitus and recent acute coronary syndromes. Risks of major adverse cardiac events and cardiovascular death or heart failure were analyzed using a Cox proportional hazards model with adjustment for baseline covariates in 10-mm Hg increments of clinician-measured systolic BP from ≤100 to >160 mm Hg and diastolic BP from ≤60 to >100 mm Hg averaged during the 24 months after randomization. Based on 2015 guidelines from the American College of Cardiology, the American Heart Association and the American Society of Hypertension and 2017 American Diabetes Association guidelines, systolic BP s of 131 to 140 mm Hg and diastolic BP s of 81 to 90 mm Hg were the reference groups. A U-shaped relationship between cardiovascular outcomes and BP s was observed. Importantly, compared with the systolic BP reference group, adjusted hazard ratios for major adverse cardiac events and cardiovascular death or heart failure were significantly higher in patients with systolic BP s <130 mm Hg. Similarly, compared with the diastolic BP reference group, adjusted hazard ratios for major adverse cardiac events and for cardiovascular death or heart failure were significantly higher for diastolic BP s <80 mm Hg. Conclusions In patients with type 2 diabetes mellitus and recent acute coronary syndrome, average BP s <130/80 mm Hg were associated with worsened cardiovascular outcomes. These data suggest that intensive control of BP in patients with type 2 diabetes mellitus and ischemic heart disease should be evaluated in a prospective randomized trial. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00968708.

Topics: Aged; Analysis of Variance; Blood Pressure Determination; Cause of Death; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Double-Blind Method; Female; Heart Failure; Hospitalization; Humans; Hypertension; Hypoglycemic Agents; Male; Middle Aged; Myocardial Ischemia; Piperidines; Prognosis; Prospective Studies; United States; 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

The EXAMINE trial showed non-inferiority of the DPP-4 inhibitor alogliptin to placebo on major adverse cardiac event (MACE) rates in patients with type 2 diabetes and recent acute coronary syndromes. Concerns about excessive rates of in-hospital heart failure in another DPP-4 inhibitor trial have been reported. We therefore assessed hospital admission for heart failure in the EXAMINE trial.. Patients with type 2 diabetes and an acute coronary syndrome event in the previous 15-90 days were randomly assigned alogliptin or placebo plus standard treatment for diabetes and cardiovascular disease prevention. The prespecified exploratory extended MACE endpoint was all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, urgent revascularisation due to unstable angina, and hospital admission for heart failure. The post-hoc analyses were of cardiovascular death and hospital admission for heart failure, assessed by history of heart failure and brain natriuretic peptide (BNP) concentration at baseline. We also assessed changes in N-terminal pro-BNP (NT-pro-BNP) from baseline to 6 months. This study is registered with ClinicalTrials.gov, number NCT00968708.. 5380 patients were assigned to alogliptin (n=2701) or placebo (n=2679) and followed up for a median of 533 days (IQR 280-751). The exploratory extended MACE endpoint was seen in 433 (16·0%) patients assigned to alogliptin and in 441 (16·5%) assigned to placebo (hazard ratio [HR] 0·98, 95% CI 0·86-1·12). Hospital admission for heart failure was the first event in 85 (3·1%) patients taking alogliptin compared with 79 (2·9%) taking placebo (HR 1·07, 95% CI 0·79-1·46). Alogliptin had no effect on composite events of cardiovascular death and hospital admission for heart failure in the post hoc analysis (HR 1·00, 95% CI 0·82-1·21) and results did not differ by baseline BNP concentration. NT-pro-BNP concentrations decreased significantly and similarly in the two groups.. In patients with type 2 diabetes and recent acute coronary syndromes, alogliptin did not increase the risk of heart failure outcomes.. Takeda Development Center Americas.

Topics: Acute Coronary Syndrome; Aged; Angina, Unstable; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Double-Blind Method; Female; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Peptide Fragments; Piperidines; Risk Factors; Stroke; 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

There are increasing evidence that left ventricle diastolic dysfunction is the initial functional alteration in the diabetic myocardium. In this study, we hypothesized that alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function and structure in diabetic rabbits.. A total of 30 rabbits were randomized into control group (CON, n = 10), alloxan-induced diabetic group (DM, n = 10) and alogliptin-treated (12.5 mg/kd/day for 12 weeks) diabetic group (DM-A, n = 10). Echocardiographic and hemodynamic studies were performed in vivo. Mitochondrial morphology, respiratory function, membrane potential and reactive oxygen species (ROS) generation rate of left ventricular tissue were assessed. The serum concentrations of glucagon-like peptide-1, insulin, inflammatory and oxidative stress markers were measured. Protein expression of TGF-β1, NF-κB p65 and mitochondrial biogenesis related proteins were determined by Western blotting.. DM rabbits exhibited left ventricular hypertrophy, left atrial dilation, increased E/e' ratio and normal left ventricular ejection fraction. Elevated left ventricular end diastolic pressure combined with decreased maximal decreasing rate of left intraventricular pressure (- dp/dtmax) were observed. Alogliptin alleviated ventricular hypertrophy, interstitial fibrosis and diastolic dysfunction in diabetic rabbits. These changes were associated with decreased mitochondrial ROS production rate, prevented mitochondrial membrane depolarization and improved mitochondrial swelling. It also improved mitochondrial biogenesis by PGC-1α/NRF1/Tfam signaling pathway.. The DPP-4 inhibitor alogliptin prevents cardiac diastolic dysfunction by inhibiting ventricular remodeling, explicable by improved mitochondrial function and increased mitochondrial biogenesis.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Diastole; Dipeptidyl-Peptidase IV Inhibitors; Fibrosis; Hypertrophy, Left Ventricular; Membrane Potential, Mitochondrial; Mitochondria, Heart; Nuclear Respiratory Factor 1; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Piperidines; Rabbits; Reactive Oxygen Species; Signal Transduction; Stroke Volume; Transcription Factors; Uracil; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Pressure; Ventricular Remodeling