sitagliptin-phosphate and Heart-Failure

Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) assessed the cardiovascular (CV) safety of sitagliptin versus placebo on CV outcomes in patients with type 2 diabetes and CV disease and found sitagliptin noninferior to placebo. Subsequently, based on feedback from FDA, the Sponsor of the trial, Merck & Co., Inc., engaged a separate academic research organization, the TIMI Study Group, to re-adjudicate a prespecified set of originally adjudicated events.. TIMI adjudicated in a blinded fashion all potential hospitalization for heart failure (HHF) events, all potential MACE+ events previously adjudicated as not an endpoint event, and a random subset (~10%) of MACE+ events previously adjudicated as an endpoint event. An updated study-level meta-analysis of four randomized, placebo-controlled, CV outcomes trials with dipeptidyl peptidase 4 (DPP-4) inhibitors was then performed.. The results of this independent re-adjudication process and analyses of CV outcomes from TECOS were consistent with the original adjudication results and overall study findings. An updated study-level meta-analysis showed no overall significant risk for HHF with DPP-4 inhibitors, but with statistical heterogeneity.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Risk Factors; Sitagliptin Phosphate

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

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

Several randomized, controlled clinical trials were initiated some years ago in order to evaluate the cardiovascular safety of the new antidiabetic drugs in patients with type 2 diabetes due to requirements from regulatory bodies. Four trials with incretin-based drugs (saxagliptin, alogliptin, sitagliptin and lixisenatide) have been completed so far. Based on the primary outcome endpoints of these trials no cardiovascular risks were found with incretins in patients with type 2 diabetes. As for saxagliptin, the hospitalization for heart failure was investigated as a secondary endpoint, and an increased risk was observed in the respective trial; however, this observation was widely debated later in the literature. Together with ongoing trials of other novel antihyperglycemic agents, these data will provide more robust evidence about the cardiovascular safety of incretin-based antidiabetic treatment in patients with type 2 diabetes.

Topics: Adamantane; Cardiovascular System; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Evidence-Based Medicine; Heart Failure; Humans; Hypoglycemic Agents; Incretins; Peptides; Piperidines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Time Factors; Uracil

Type 2 diabetes is not only an independent risk factor for cardiovascular (CV) disease but is also associated with a greater incidence of heart failure (HF). The aim of this review is to examine the effects of oral antidiabetic drugs on CV disease and HF.. Trials of anti-diabetic agents are now designed to assess CV safety, but frequently HF is not included as a primary endpoint. However, HF in patients with diabetes is more frequent than other CV events and seems to be underestimated. A burning question is therefore if the most used trial design to monitor CV safety, i.e. non-inferiority, allows clinical translation of trial findings. Available data further suggest that the CV effects of anti-diabetic drugs may be rather class-specific and are only partly due to their glucose-lowering actions. Metformin, recommended as first line in most guidelines, shows positive CV effects while other classes like thiazolidinediones may precipitate HF. Experimental results on the relatively novel dipeptidyl peptidase IV (DPP IV) inhibitors imply CV protective effects, but the non-inferiority trials published to date show an overall neutral CV outcome and a potential increase in HF by saxagliptin. However, results on sitagliptin of the recently released TECOS indicate that HF is not a class-dependent effect of DPP IV inhibitors.. Further basic research and long-term outcome studies to clarify the effects of antidiabetic agents on CV and HF are required so that we can select the optimal antidiabetic therapy for our patients.

Topics: Adamantane; Administration, Oral; Blood Glucose; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Heart Failure; Humans; Hypoglycemic Agents; Metformin; Risk Factors; Sitagliptin Phosphate; Thiazolidinediones

The treatment of diabetes mellitus type 2 is effective, but still is not optimal. DPP4 inhibitors (gliptins) are a new group of peroral antidiabetic drugs. The third clinical mortality study with gliptins in patients with diabetes mellitus type 2 was finished in 2015. The studies are known under acronym TECOS, SAVOR and EXAMINE and the tested drugs are sitagliptin, saxagliptin and alogliptin. The studies included about 37,000 patients. The studies confirmed the cardiovascular safety of the DPP4 inhibitors, but the question about increased heart failure remains open. The effectiveness of lowering glycaemia (glycated haemoglobin) was confirmed and also the pancreatic safety is confirmed.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Heart Failure; Humans; Hypoglycemic Agents; Piperidines; Sitagliptin Phosphate; Uracil

Although recent reports suggest an association between saxagliptin and an increased risk of admissions for heart failure, it is not clear whether dipeptidyl peptidase IV (DPP-IV) inhibition contributes to heart failure in high-risk patients. The purpose of this research is to understand heart failure risk among high-risk patients with type 2 diabetes.. This is a systematic review of data published in full papers and abstract form using the terms DPP-IV inhibitors and heart failure published since October 2013. Data from insurance and hospital databases were combined with those from multiple published trials, including the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial; Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care (EXAMINE), and Vildagliptin in Ventricular Dysfunction Diabetes (VIVIDD) trial as well as pooled analyses of linagliptin and saxagliptin placebo-controlled trials to examine heart failure among patients represented in those datasets.. A meta-analysis of the 9 datasets showed an increase in heart failure with dipeptidyl peptidase IV inhibitors of 15% (P = 0.017). There was no statistical heterogeneity, nor was there a statistical difference between cohort studies and randomized, controlled trials (P = 0.3), even though cohort studies alone were not significant (relative risk: 1.1; P = 0.32). Removing SAVOR-TIMI 53 data produced an insignificant increase in heart failure of 12% (P = 0.09) in the rest of the studies. In the randomized, controlled trials, the increased risk was 24% (P = 0.002). There was no statistical difference between those studies with and without baseline cardiovascular disease (P = 0.58), although the cardiovascular disease studies were borderline significant (P = 0.06). There was no publication bias.. There are data from studies using sitagliptin, saxagliptin, and alogliptin showing that these agents may increase the risk of hospitalization for heart failure. More data are required for a definitive conclusion.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Heart Failure; Hospitalization; Humans; Nitriles; Piperidines; Pyrrolidines; Sitagliptin Phosphate; Uracil; Vildagliptin

C-type natriuretic peptide (CNP) is a cardioprotective peptide with high affinity for the ectoenzyme neutral endopeptidase (neprilysin). We aimed to determine whether angiotensin receptor-neprilysin inhibitor treatment acutely affects circulating concentrations of bioactive CNP and its molecular amino-terminal precursor (NT-proCNP).. We included 9 and 10 healthy young men in 2 randomized crossover trials with sacubitril/valsartan vs control (Trial 1) and sacubitril/valsartan and sitagliptin vs sitagliptin (Trial 2). The participants were randomized to a single dose of sacubitril/valsartan (194/206 mg) or control at the first visit 30 min prior to a standardized meal intake. We obtained blood samples at 12 time points over 5 h and measured plasma concentrations of NT-proCNP in both trials and CNP in Trial 2.. NT-proCNP concentrations increased 3.5 h after sacubitril/valsartan treatment, and at 4.5 h concentrations were 42% and 65% higher compared with control in Trial 1 and Trial 2, respectively. The total area under the curve (tAUC)15-270 min was 22% higher (P = 0.007) in Trial 1 and 17% higher with treatment (P = 0.017) in Trial 2. Concentrations of bioactive CNP followed a similar temporal pattern with an increase of 93% at 4.5 h and a 31% higher tAUC15-270 min compared with control (P = 0.001) in Trial 2.. Sacubitril/valsartan augments circulating concentrations of both bioactive CNP and NT-proCNP in healthy young men. The increase in bioactive CNP is most likely caused by de novo synthesis and secretion rather than diminished breakdown through neprilysin inhibition.ClinicalTrials.gov registration number NCT03717688.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Biphenyl Compounds; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Neprilysin; Peptide Fragments; Sitagliptin Phosphate; Tetrazoles; Valsartan

Sacubitril/valsartan is a neprilysin-inhibitor/angiotensin II receptor blocker used for the treatment of heart failure. Recently, a post-hoc analysis of a 3-year randomized controlled trial showed improved glycaemic control with sacubitril/valsartan in patients with heart failure and type 2 diabetes. We previously reported that sacubitril/valsartan combined with a dipeptidyl peptidase-4 inhibitor increases active glucagon-like peptide-1 (GLP-1) in healthy individuals. We now hypothesized that administration of sacubitril/valsartan with or without a dipeptidyl peptidase-4 inhibitor would lower postprandial glucose concentrations (primary outcome) in patients with type 2 diabetes via increased active GLP-1.. We performed a crossover trial in 12 patients with obesity and type 2 diabetes. A mixed meal was ingested following five respective interventions: (a) a single dose of sacubitril/valsartan; (b) sitagliptin; (c) sacubitril/valsartan + sitagliptin; (d) control (no treatment); and (e) valsartan alone. Glucose, gut and pancreatic hormone responses were measured.. Postprandial plasma glucose increased by 57% (incremental area under the curve 0-240 min) (p = .0003) and increased peak plasma glucose by 1.7 mM (95% CI: 0.6-2.9) (p = .003) after sacubitril/valsartan compared with control, whereas postprandial glucose levels did not change significantly after sacubitril/valsartan + sitagliptin. Glucagon, GLP-1 and C-peptide concentrations increased after sacubitril/valsartan, but insulin and glucose-dependent insulinotropic polypeptide did not change.. The glucose-lowering effects of long-term sacubitril/valsartan treatment reported in patients with heart failure and type 2 diabetes may not depend on changes in entero-pancreatic hormones. Neprilysin inhibition results in hyperglucagonaemia and this may explain the worsen glucose tolerance observed in this study.. gov (NCT03893526).

Topics: Aged; Aminobutyrates; Angiotensin Receptor Antagonists; Biphenyl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Glucagon-Like Peptide 1; Glucose Tolerance Test; Heart Failure; Humans; Hypoglycemic Agents; Male; Middle Aged; Neprilysin; Sitagliptin Phosphate; Tetrazoles; Valsartan

Data are lacking on the comparative effectiveness of commonly used glucose-lowering medications, when added to metformin, with respect to microvascular and cardiovascular disease outcomes in persons with type 2 diabetes.. We assessed the comparative effectiveness of four commonly used glucose-lowering medications, added to metformin, in achieving and maintaining a glycated hemoglobin level of less than 7.0% in participants with type 2 diabetes. The randomly assigned therapies were insulin glargine U-100 (hereafter, glargine), glimepiride, liraglutide, and sitagliptin. Prespecified secondary outcomes with respect to microvascular and cardiovascular disease included hypertension and dyslipidemia, confirmed moderately or severely increased albuminuria or an estimated glomerular filtration rate of less than 60 ml per minute per 1.73 m. During a mean 5.0 years of follow-up in 5047 participants, there were no material differences among the interventions with respect to the development of hypertension or dyslipidemia or with respect to microvascular outcomes; the mean overall rate (i.e., events per 100 participant-years) of moderately increased albuminuria levels was 2.6, of severely increased albuminuria levels 1.1, of renal impairment 2.9, and of diabetic peripheral neuropathy 16.7. The treatment groups did not differ with respect to MACE (overall rate, 1.0), hospitalization for heart failure (0.4), death from cardiovascular causes (0.3), or all deaths (0.6). There were small differences with respect to rates of any cardiovascular disease, with 1.9, 1.9, 1.4, and 2.0 in the glargine, glimepiride, liraglutide, and sitagliptin groups, respectively. When one treatment was compared with the combined results of the other three treatments, the hazard ratios for any cardiovascular disease were 1.1 (95% confidence interval [CI], 0.9 to 1.3) in the glargine group, 1.1 (95% CI, 0.9 to 1.4) in the glimepiride group, 0.7 (95% CI, 0.6 to 0.9) in the liraglutide group, and 1.2 (95% CI, 1.0 to 1.5) in the sitagliptin group.. In participants with type 2 diabetes, the incidences of microvascular complications and death were not materially different among the four treatment groups. The findings indicated possible differences among the groups in the incidence of any cardiovascular disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; GRADE ClinicalTrials.gov number, NCT01794143.).

Topics: Albuminuria; Blood Glucose; Cardiovascular Diseases; Comparative Effectiveness Research; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Drug Therapy, Combination; Dyslipidemias; Glomerular Filtration Rate; Glycated Hemoglobin; Heart Failure; Humans; Hypertension; Hypoglycemic Agents; Insulin Glargine; Liraglutide; Metformin; Microvessels; Sitagliptin Phosphate; Sulfonylurea Compounds

Whether glycaemic control is associated with cardiovascular outcomes in patients with type 2 diabetes (T2D) is unclear. Consequently, we assessed the relationship between glycated haemoglobin (HbA. Secondary analysis of 14 656 TECOS participants with time to event analyses using multivariable Cox proportional hazard models. During a median 3.0 (interquartile range 2.3-3.8) year follow-up, 456 (3.1% of 14 656) patients had first hospitalization for heart failure (HF), 1084 (11.5%) died, 1406 (9.6%) died or were hospitalized for HF, and 1689 (11.5%) had a non-HF cardiovascular event (cardiovascular death, non-fatal stroke, non-fatal myocardial infarction, or hospitalization for unstable angina). Associations between baseline or time-varying HbA. Glycated haemogobin exhibits a U-shaped association with cardiovascular outcomes in patients with T2D and atherosclerotic vascular disease, with nadir around 7%.. ClinicalTrials.gov Identifier: NCT00790205.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Male; Randomized Controlled Trials as Topic; Risk Factors; Sitagliptin Phosphate

To examine the effects of the DPP-4i sitagliptin on CV outcomes during and after incident MI in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS).. TECOS randomized 14,671 participants with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) to sitagliptin or placebo, in addition to usual care. For those who had a within-trial MI, we analyzed case fatality, and for those with a nonfatal MI, we examined a composite cardiovascular (CV) outcome (CV death or hospitalization for heart failure [hHF]) by treatment group, using Cox proportional hazards models left-censored at the time of the first within-trial MI, without and with adjustment for potential confounders, in intention-to-treat analyses.. During TECOS, 616 participants had ≥ 1 MI (sitagliptin group 300, placebo group 316, HR 0.95, 95% CI 0.81-1.11, P = 0.49), of which 25 were fatal [11 and 14, respectively]). Of the 591 patients with a nonfatal MI, 87 (15%) died subsequently, with 66 (11%) being CV deaths, and 57 (10%) experiencing hHF. The composite outcome occurred in 58 (20.1%; 13.9 per 100 person-years) sitagliptin group participants and 50 (16.6%; 11.7 per 100 person-years) placebo group participants (HR 1.21, 95% CI 0.83-1.77, P = 0.32, adjusted HR 1.23, 95% CI 0.83-1.82, P = 0.31). On-treatment sensitivity analyses also showed no significant between-group differences in post-MI outcomes.. In patients with type 2 diabetes and ASCVD experiencing an MI, sitagliptin did not reduce subsequent risk of CV death or hHF, contrary to expectations derived from preclinical animal models. Trial registration clinicaltrials.gov no. NCT00790205.

Topics: Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Heart Failure; Hospitalization; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Risk Assessment; Risk Factors; Sitagliptin Phosphate; Time Factors; Treatment Outcome

International differences in management/outcomes among patients with type 2 diabetes and heart failure (HF) are not well characterized. We sought to evaluate geographic variation in treatment and outcomes among these patients. METHODS AND RESULTS: Among 14,671 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), those with HF at baseline and a documented ejection fraction (EF) (N = 1591; 10.8%) were categorized by enrollment region (North America, Latin America, Western Europe, Eastern Europe, and Asia Pacific). Cox models were used to examine the association between geographic region and the primary outcome of all-cause mortality (ACM) or hospitalization for HF (hHF) in addition to ACM alone. Analyses were stratified by those with EF <40% or EF ≥40%. The majority of participants with HF were enrolled in Eastern Europe (53%). Overall, 1,267 (79.6%) had EF ≥40%. β-Blocker (83%) and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (86%) use was high across all regions in patients with EF <40%. During a median follow-up of 2.9 years, Eastern European participants had lower rates of ACM/hHF compared with North Americans (adjusted hazard ratio: 0.45; 95% CI: 0.32-0.64). These differences were seen only in the EF ≥40% subgroup and not the EF <40% subgroup. ACM was similar among Eastern European and North American participants (adjusted hazard ratio: 0.79; 95% CI: 0.44-1.45). CONCLUSIONS: Significant variation exists in the clinical features and outcomes of HF patients across regions in TECOS. Patients from Eastern Europe had lower risk-adjusted ACM/hHF than those in North America, driven by those with EF ≥40%. These data may inform the design of future international trials.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin-Converting Enzyme Inhibitors; Asia; Cause of Death; Diabetes Mellitus, Type 2; Diuretics; Double-Blind Method; Europe; Female; Follow-Up Studies; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Kaplan-Meier Estimate; Latin America; Male; Middle Aged; North America; Proportional Hazards Models; Sitagliptin Phosphate; Stroke Volume; Treatment Outcome

The effects of β-blocker therapy in patients with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (ASCVD) are unclear. We sought to evaluate associations between β-blocker use in T2D with ASCVD and cardiovascular (CV) outcomes.. In patients with T2D and ASCVD enrolled in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), an inverse probability of treatment-weighted Cox proportional hazards model was used to examine the association between baseline β-blocker therapy (at randomization) and the primary CV composite (defined as CV death, non-fatal myocardial infarction [MI], non-fatal stroke, or hospitalization for unstable angina), including in subgroups with prior MI and heart failure (HF); other outcomes evaluated included individual components of the primary composite, hospitalization for HF, and severe hypoglycemic events.. Of the 14,671 patients randomized, 9322 (64%) were on a β-blocker at baseline; these patients were more likely to have prior MI or HF. Over a median 3.0 (25th, 75th percentile: 2.2, 3.6) years, the risk of the primary CV composite was significantly higher with baseline β-blocker use versus no β-blocker use (4.5 vs. 3.4 events/100-patient years, adjusted hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.05-1.29); no significant interaction was noted for patients with versus without prior MI or HF. Baseline β-blocker use was not associated with risks for severe hypoglycemic events (HR 1.14, 95% CI 0.88-1.48).. In this observational analysis of T2D and ASCVD, baseline β-blocker use was not associated with risks for severe hypoglycemia yet also was not associated with CV risk reduction over 3 years of follow-up, supporting a randomized examination of chronic β-blocker therapy in this patient population. (TECOS ClinicalTrials.gov number, NCT00790205).

Topics: Adrenergic beta-Antagonists; Aged; Angina, Unstable; Atherosclerosis; Atrial Fibrillation; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Heart Failure; Hospitalization; Humans; Hypoglycemia; Hypoglycemic Agents; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Sitagliptin Phosphate; Stroke; Treatment Outcome

Previous trial results have suggested that dipeptidyl peptidase 4 inhibitor (DPP4i) use might increase heart failure (HF) risk in type 2 diabetes mellitus (T2DM). The DPP4i sitagliptin has been shown to be noninferior to placebo with regard to primary and secondary composite atherosclerotic cardiovascular (CV) outcomes in the Trial Evaluating Cardiovascular Outcomes With Sitagliptin (TECOS).. To assess the association of sitagliptin use with hospitalization for HF (hHF) and related outcomes.. TECOS was a randomized, double-blind, placebo-controlled study evaluating the CV safety of sitagliptin vs placebo, each added to usual antihyperglycemic therapy and CV care among patients with T2DM and prevalent atherosclerotic vascular disease. The median follow-up was 2.9 years. The setting was 673 sites in 38 countries. Participants included 14 671 patients with T2DM and atherosclerotic vascular disease. The study dates were December 2008 through March 2015.. Patients were randomized to sitagliptin vs placebo added to standard care.. Prespecified secondary analyses compared the effect on hHF, hHF or CV death, and hHF or all-cause death composite outcomes overall and in prespecified subgroups. Supportive analyses included total hHF events (first plus recurrent) and post-hHF death. Meta-analyses evaluated DPP4i effects on hHF and on hHF or CV death.. Of 14 671 patients, 7332 were randomized to sitagliptin and 7339 to placebo. Hospitalization for HF occurred in 3.1% (n = 228) and 3.1% (n = 229) of the sitagliptin and placebo groups, respectively (unadjusted hazard ratio, 1.00; 95% CI, 0.83-1.19). There was also no difference in total hHF events between the sitagliptin (n = 345) and placebo (n = 347) groups (unadjusted hazard ratio, 1.00; 95% CI, 0.80-1.25). Post-hHF all-cause death was similar in the sitagliptin and placebo groups (29.8% vs 28.8%, respectively), as was CV death (22.4% vs 23.1%, respectively). No heterogeneity for the effect of sitagliptin on hHF was observed in subgroup analyses across 21 factors (P > .10 for all interactions). Meta-analysis of the hHF results from the 3 reported DPP4i CV outcomes trials revealed moderate heterogeneity (I2 = 44.9, P = .16).. Sitagliptin use does not affect the risk for hHF in T2DM, both overall and among high-risk patient subgroups.. clinicaltrials.gov Identifier: NCT00790205.

Topics: Aged; Atherosclerosis; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Heart Failure; Hospital Mortality; Hospitalization; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Prevalence; Risk Factors; Sitagliptin Phosphate

Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease.. In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.. During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). There were no significant between-group differences in rates of acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32).. Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events. (Funded by Merck Sharp & Dohme; TECOS ClinicalTrials.gov number, NCT00790205.).

Topics: Administration, Oral; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Follow-Up Studies; Glycated Hemoglobin; Heart Diseases; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Kaplan-Meier Estimate; Pyrazines; Sitagliptin Phosphate; Triazoles

The effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with heart failure (HF) in routine clinical practice is not extensively studied. This study aimed to evaluate the comparative effectiveness of SGLT2i vs. sitagliptin in older adults with HF and type 2 diabetes and to investigate whether there were any differences between agents within the SGLT2i class or for reduced and preserved ejection fraction.. Using Medicare claims data (April 2013 to December 2019), 16 253 SGLT2i initiators vs. 43 352 initiators of sitagliptin aged ≥65 years with type 2 diabetes and HF were included. The primary outcome was a composite of all-cause mortality, hospitalization for HF or urgent visit requiring intravenous diuretics; secondary outcomes included its individual components. Propensity score fine stratification weighted Cox regression was used to adjust for 100 pre-exposure characteristics. Mean age was 74 years; 49.8% were women. Initiation of SGLT2i vs. sitagliptin was associated with a lower risk of the primary composite outcome [adjusted hazard ratio (HR) 0.72; 95% confidence interval 0.67-0.77]. The adjusted HRs were 0.70 (0.63-0.78) for all-cause mortality, 0.64 (0.58-0.70) for hospitalization for HF, and 0.77 (0.69-0.86) for urgent visit requiring intravenous diuretics. Similar associations with the primary composite outcome were observed for all three agents within the SGLT2i class, for reduced and preserved ejection fraction, and subgroups based on demographics, comorbidities, and other HF treatments. Bias-calibrated HRs for the primary endpoint using negative and positive control outcomes ranged between 0.81 and 0.89, suggesting that the observed benefit could not be fully explained by residual confounding.. In routine US clinical practice, SGLT2i demonstrated robust clinical effectiveness in older adults with HF and type 2 diabetes compared with sitagliptin, with no evidence of heterogeneity across the SGLT2i class or across ejection fraction.

Topics: Aged; Benzhydryl Compounds; Canagliflozin; Cohort Studies; Diabetes Mellitus, Type 2; Female; Glucosides; Heart Failure; Heart Failure, Diastolic; Hospitalization; Humans; Male; Medicare; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Topics: Cohort Studies; Diabetes Mellitus, Type 2; Glucose; Heart Failure; Humans; Sitagliptin Phosphate; Sodium; Sodium-Glucose Transporter 2 Inhibitors

Cardiovascular effects of dipeptidyl peptidase-4 inhibitors (DPP4i) versus sulfonylureas (SU) remain controversial in observational studies. This study aimed to evaluate the influence of DPP4i on major adverse cardiovascular events (MACEs), including acute myocardial infarction, cerebrovascular disease, heart failure, cardiogenic shock, malignant dysrhythmia, and revascularisation.. We conducted a nationwide cohort study using claims data from the National Health Insurance in Taiwan from 2007 to 2013. We enrolled type 2 diabetes patients who received DPP4i or SU in addition to metformin. DPP4i users were matched to SU users using propensity scores at a ratio of 1:1. The study outcomes were hospitalisation for MACE, heart failure, acute myocardial infarction, cerebrovascular disease, coronary revascularisation, and hypoglycaemia.. There were 37,317 matched pairs of DPP4i and SU users with a mean follow-up of 2.1 years. Compared with SU users, DPP4i users showed a significantly lower risk of hospitalisation for MACE (HR 0.79 [95% CI 0.75-0.82]), heart failure (0.86 [0.79-0.93]), acute myocardial infarction (0.76 [0.68-0.92]), and cerebrovascular disease (0.72 [0.67-0.77]). Both sitagliptin (0.89 [0.85-0.94]) and vildagliptin ([0.77 [0.60-0.99]) showed a significantly lower risk of hospitalisation for MACE, but saxagliptin showed a borderline significantly higher risk of hospitalisation for heart failure (1.59 [1.00-2.55]).. DPP4i showed better cardioprotective effects than SU, especially among patients receiving sitagliptin or vildagliptin.

Topics: Cerebrovascular Disorders; Cohort Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Heart Failure; Humans; Hypoglycemic Agents; Metformin; Myocardial Infarction; Sitagliptin Phosphate; Sulfonylurea Compounds; Treatment Outcome; Vildagliptin

The effect of sodium glucose cotransporter 2 inhibitors (SGLT2i) on the total (first and recurrent) burden of cardiovascular (CV) hospitalizations, including hospitalization for heart failure, myocardial infarction, and stroke, is poorly understood.. To assess the effect of empagliflozin, an SGLT2i, on total CV hospitalizations among older adults with T2D.. Using data from Medicare fee-for-service (08/2014-09/2017), we identified 1:1 propensity score-matched cohorts of patients with T2D initiating empagliflozin versus sitagliptin or empagliflozin versus glucagon-like peptide-1 receptor agonists (GLP-1RA), balancing >140 baseline covariates. We compared the risk of first and recurrent hospitalizations with any CV condition as the primary discharge diagnosis (ICD-9: 390-459; ICD-10: I00-I99), hospitalizations for heart failure (HHF), and myocardial infarctions (MI) or stroke. We estimated treatment effects based on the Ghosh-Lin semiparametric model for recurrent events as primary and joint frailty model as secondary analysis.. We included 11,429 matched-pairs of empagliflozin and sitagliptin initiators and 17,502 matched-pairs of empagliflozin and GLP1-RA initiators with an average age of 72 years. Empagliflozin was associated with a reduced risk of total CV hospitalizations (0.80 [0.69-0.93] vs sitagliptin; 0.88 [0.77-1.00] vs GLP-1RA) and total HHF (0.70 [0.51-0.98] vs sitagliptin; 0.76 [0.56-1.03] vs GLP1-RA) over a mean follow up of 6.3 months. No differences between treatments were observed for MI or stroke. Results were consistent for joint frailty models.. Empagliflozin, compared to sitagliptin or to a lesser extent GLP1-RA, was associated with a reduction in the burden of total CV hospitalizations and HHF in older patients with T2D.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Heart Failure; Humans; Hypoglycemic Agents; Medicare; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Stroke; United States

Limited evidence is available on the comparative effectiveness of empagliflozin vs alternative second-line glucose-lowering agents in patients with type 2 diabetes (T2D) receiving routine care who have a broad spectrum of cardiorenal risk.. To evaluate the association of empagliflozin with cardiovascular outcomes relative to liraglutide and sitagliptin, stratified by age, sex, baseline atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease (CKD).. This retrospective comparative effectiveness cohort study used deidentified Medicare claims data from August 1, 2014, to September 30, 2018, with follow-up from drug initiation until treatment changes, death, or gap in Medicare enrollment (>30 days). Data analysis was performed from October 1, 2021, to April 30, 2022. Medicare fee-for-service beneficiaries older than 65 years with T2D were included. A total of 45 788 patients (22 894 propensity score-matched pairs initiating treatment with either empagliflozin or liraglutide) were included in cohort 1, and 45 624 patients (22 812 propensity score-matched pairs initiating treatment with either empagliflozin or sitagliptin) were included in cohort 2.. Empagliflozin vs liraglutide (cohort 1) or empagliflozin vs sitagliptin (cohort 2).. Primary outcomes were (1) modified major adverse cardiovascular events (MACEs), including a composite of myocardial infarction, stroke, and all-cause mortality, and (2) hospitalization for heart failure (HHF). Hazard ratios (HRs) and rate differences (RDs) per 1000 person-years were estimated, adjusting for 143 baseline covariates using 1:1 propensity score matching.. Among 45 788 patients in cohort 1, the mean (SD) age was 71.9 (5.1) years; 23 396 patients (51.1%) were female, 22 392 (48.9%) were male, and 38 049 (83.1%) were White. Among 45 624 patients in cohort 2, the mean (SD) age was 72.1 (5.1) years; 21 418 patients (46.9%) were female, 24 206 (53.1%) were male, and 37 814 (82.9%) were White. Relative to patients initiating liraglutide, those initiating empagliflozin had a similar risk of the modified MACE outcome (HR, 0.90; 95% CI, 0.79-1.03) and a reduced risk of HHF (HR, 0.66; 95% CI, 0.52-0.82). Across subgroups, empagliflozin was associated with a lower risk of the modified MACE outcome in patients with a history of ASCVD (HR, 0.83; 95% CI, 0.71-0.98) and HF (HR, 0.77; 95% CI, 0.60-1.00) compared with liraglutide, and potential heterogeneity in estimates was observed by sex (male: HR, 0.85 [95% CI, 0.71-1.01]; female: HR, 1.16 [95% CI, 0.94-1.42]; P = .02 for homogeneity). However, reductions in the risk of HHF were observed across most subgroups (eg, ASCVD: HR, 0.66 [95% CI, 0.51-0.85]; HF: HR, 0.66 [95% CI, 0.49-0.88]). Compared with sitagliptin, empagliflozin was associated with reduced risks of the modified MACE outcome (HR, 0.68; 95% CI, 0.60-0.77) and HHF (HR, 0.45; 95% CI, 0.36-0.56), which were consistent across all subgroups. Absolute benefits of empagliflozin vs sitagliptin were larger in patients with a history of ASCVD (modified MACE: RD, -17.6 [95% CI, -24.9 to -10.4]; HHF: RD, -16.7 [95% CI, -21.7 to -11.9]), HF (modified MACE: RD, -41.1 [95% CI, -59.9 to -22.6]; HHF: RD, -50.4 [95% CI, -67.5 to -33.9]), or CKD (modified MACE: RD, -26.7 [95% CI, -41.3 to -12.3]; HHF: RD, -31.9 [95% CI, -43.5 to -20.8]).. In this comparative effectiveness study of older adults, empagliflozin was associated with a lower risk of HHF (relative to both liraglutide and sitagliptin) and the modified MACE outcome (relative to sitagliptin), with larger absolute benefits in patients with established cardiorenal diseases. These findings suggest that older adults with T2D might benefit more from empagliflozin vs liraglutide or sitagliptin with respect to the risk of HHF; with respect to the risk of MACEs, empagliflozin might be preferable to liraglutide only in patients with cardiovascular disease history and to sitagliptin across all patient subgroups.

Topics: Aged; Atherosclerosis; Cohort Studies; Diabetes Mellitus, Type 2; Female; Glucose; Heart Failure; Humans; Hypoglycemic Agents; Liraglutide; Male; Medicare; Myocardial Infarction; Renal Insufficiency, Chronic; Retrospective Studies; Sitagliptin Phosphate; United States

Topics: Aged; Ambulatory Care; Anti-Arrhythmia Agents; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents, Second-Generation; Calcium Channel Blockers; Citalopram; Cyclooxygenase Inhibitors; Diltiazem; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Heart Failure; Humans; Hypoglycemic Agents; Potentially Inappropriate Medication List; Practice Patterns, Physicians'; Sitagliptin Phosphate; Sotalol; Thiazolidinediones; Tumor Necrosis Factor Inhibitors; United States

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is commonly prescribed to patients with type 2 diabetes. As this drug is primarily eliminated by the kidney, a reduced dose is recommended for patients with CKD. Some evidence suggests that sitagliptin is associated with a higher risk of congestive heart failure, particularly at higher doses. We compare the 1-year risk of death or hospitalization with congestive heart failure in patients with CKD newly prescribed sitagliptin at >50 versus ≤50 mg/d.. This population-based cohort study included older adults (>66 years) with type 2 diabetes and an eGFR<45 ml/min per 1.73 m. Of 9215 patients, 6518 started sitagliptin at >50 mg/d, and 2697 started sitagliptin at ≤50 mg/d. The 1-year risk of death or hospitalization with congestive heart failure did not differ significantly between groups (79 versus 126 events per 1000 person-years; weighted hazard ratio, 0.88; 95% confidence interval, 0.67 to 1.14); hospitalization with pancreatitis (weighted hazard ratio, 0.98; 95% confidence interval, 0.32 to 3.03) and hypoglycemia (weighted hazard ratio, 1.10; 95% confidence interval, 0.64 to 1.90) also did not differ significantly between groups. Patients starting sitagliptin at >50 mg/d had lower mean glycated hemoglobin concentrations (weighted between-group difference, -0.12%; 95% confidence interval, -0.19 to -0.06) and a lower risk of all-cause hospitalization (weighted hazard ratio, 0.81; 95% confidence interval, 0.66 to 0.98).. The risk of death or congestive heart failure was not higher in older adults with CKD starting sitagliptin at >50 versus ≤50 mg/d.. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_11_25_CJN08310520_final.mp3.

Topics: Age Factors; Aged; Aged, 80 and over; Blood Glucose; Databases, Factual; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glomerular Filtration Rate; Heart Failure; Hospitalization; Humans; Kidney; Male; Ontario; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Sitagliptin Phosphate; Time Factors; Treatment Outcome

The EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patients) showed that empagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces the risk of hospitalization for heart failure (HHF) by 35%, on top of standard of care in patients with type 2 diabetes mellitus (T2D) and established cardiovascular disease. The EMPRISE (Empagliflozin Comparative Effectiveness and Safety) study aims to assess empagliflozin's effectiveness, safety, and healthcare utilization in routine care from August 2014 through September 2019. In this first interim analysis, we investigated the risk of HHF among T2D patients initiating empagliflozin versus sitagliptin, a dipeptidyl peptidase-4 inhibitor.. Within 2 commercial and 1 federal (Medicare) claims data sources in the United States, we identified a 1:1 propensity score-matched cohort of T2D patients ≥18 years old initiating empagliflozin or sitagliptin from August 2014 through September 2016. The HHF outcome was defined as a HF discharge diagnosis in the primary position (HHF-specific); a broader definition was based on a HF discharge diagnosis in any position (HHF-broad). Hazard ratios (HRs) and 95% CIs were estimated controlling for over 140 baseline characteristics in each data source and pooled by fixed-effects meta-analysis.. After propensity-score matching, we identified 16,443 patient pairs who initiated empagliflozin or sitagliptin. Average age was approximately 59 years, almost 54% of the participants were males, and approximately 25% had records of existing cardiovascular disease. Compared with sitagliptin, the initiation of empagliflozin decreased the risk of HHF-specific by 50% (HR, 0.50; 95% CI, 0.28-0.91), and the risk of HHF-broad by 49% (HR, 0.51;95% CI, 0.39-0.68), over a mean follow-up of 5.3 months. The results were consistent in patients with and without baseline cardiovascular disease, and for empagliflozin at both the 10- and 25-mg daily doses; analyses comparing empagliflozin versus the dipeptidyl peptidase-4 inhibitor class, and comparing sodium-glucose cotransporter-2 inhibitor versus dipeptidyl peptidase-4 inhibitor classes also produced consistent findings.. The first interim analysis from EMPRISE showed that compared with sitagliptin, the initiation of empagliflozin was associated with a decreased risk of HHF among patients with T2D as treated in routine care, with and without a history of cardiovascular disease.. URL: https://www.clinicaltrials.gov . Unique identifier: NCT03363464.

Topics: Aged; Benzhydryl Compounds; Comparative Effectiveness Research; Databases, Factual; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucosides; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Risk Assessment; Risk Factors; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Time Factors; Treatment Outcome; United States

In 2008, the US Food and Drug Administration (FDA) issued Draft Guidance on investigating cardiovascular risk with oral diabetic drugs, including dipeptidyl peptidase-4 inhibitors (DPP-4i). In 2014, underpowered, post hoc analyses of clinical trials suggested an increased risk of heart failure with the use of these products. As such, we assessed disproportionate reporting of major adverse cardiac events (MACE) among reports for DPP-4i submitted to the FDA Adverse Event Reporting System (FAERS) from 2006 to 2015.. We assessed the empirical Bayes geometric mean (EBGM) and its lower bound (EB05) of the relative reporting ratio for MACE among DPP-4i reports in the full FAERS database and in a subset of reports limited to cardiovascular and diabetic drugs. We then compared the EB05 in these 2 analyses and calculated the percent positive agreement for signals of disproportional reporting (SDRs) involving MACE.. Of 180.3 million adverse event reports, 13.4 million were for diabetic and cardiovascular drugs. In the cardiovascular subset, there was an SDR for heart failure with linagliptin (EB05 = 2782.47) and saxagliptin (EB05 = 2.40), myocardial infarction with alogliptin (EB05 = 290.11), and cerebral infarction with sitagliptin (EB05 = 2.80). Of the 14 MACE, 8 had a percent positive agreement ≥50% for an SDR in both analyses. Overall, the cardiovascular subset elicited 11 more SDRs for DPP-4i than the full dataset.. Postmarketing surveillance of DPP-4i through FAERS suggest increased reporting of MACE, supporting the current FDA warning of heart failure risk. This suggests the need for additional longitudinal, observational research into the association of DPP-4i and other MACE.

Topics: Adamantane; Administration, Oral; Adverse Drug Reaction Reporting Systems; Aged; Bayes Theorem; Databases, Factual; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Heart Failure; Humans; Linagliptin; Male; Middle Aged; Piperidines; Practice Guidelines as Topic; Sitagliptin Phosphate; United States; United States Food and Drug Administration; Uracil

Saxagliptin statistically significantly increased the risk of hospitalization for heart failure compared with placebo in the clinical trial of SAVOR-TIMI 53. Neither the reason why only saxagliptin among several dipeptidyl peptidase-4 (DPP-4) inhibitors increased the risk, nor the clinical implication of the result has been explained.. To evaluate the risk of hospitalization for heart failure associated with DPP-4 inhibitors by using an alternative measure to the hazard ratio.. We used the difference in restricted mean survival time (RMST) between DPP-4 inhibitors and placebo to evaluate the risk of cardiovascular events, including hospitalization for heart failure associated with DPP-4 inhibitors. Three randomized clinical trials with cardiovascular events as a primary end point-EXAMINE (alogliptin), SAVOR-TIMI 53 (saxagliptin), and TECOS (sitagliptin)-were reevaluated by estimating the RMSTs for the DPP-4 inhibitors and placebo based on the reconstructed individual patient data for each time-to-event outcome from publicly available information.. The differences of RMSTs (DPP-4 inhibitors minus placebo) for hospitalization for heart failure were -4 days [-6, -2] in the SAVOR-TIMI 53 (720 days follow-up), -3 days [-9, 3] in the EXAMINE (900 days follow-up), and 1 day [-5, 7] in the TECOS (1440 days follow-up). There were no substantial differences in the risk of other cardiovascular outcomes between DPP-4 inhibitors and placebo.. There are no substantial clinically relevant differences in the risk of cardiovascular events, including hospitalization for heart failure, between 3 of the DPP-4 inhibitors and placebo.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Heart Failure; Hospitalization; Humans; Piperidines; Proportional Hazards Models; Randomized Controlled Trials as Topic; Risk; Sitagliptin Phosphate; Uracil

Heart failure with preserved ejection fraction (HFpEF) is a systemic syndrome driven by co-morbidities, and its pathophysiology is poorly understood. Several studies suggesting that dipeptidyl peptidase 4 (DPP4) might be involved in the pathophysiology of heart failure have prompted experimental and clinical investigations of DPP4 inhibitors in the cardiovascular system. Here we have investigated whether the DPP4 inhibitor sitagliptin affected the progression of HFpEF independently of its effects on glycaemia.. Treatment with sitagliptin attenuated diastolic dysfunction, reduced mortality and reduced cardiac DPP4 activity, along with increased circulating GLP-1 and myocardial expression of GLP-1 receptors. Myocardial levels of pro-inflammatory cytokines (TNF-α, IL-6 and CCL2) were reduced. Sitagliptin treatment decreased the levels of endothelial NOS monomer, responsible for generation of ROS, while the amount of NO-producing dimeric form increased. Markers of oxidative and nitrosative stress were decreased. Moreover, increased collagen deposition and activation of pro-fibrotic signalling, inducing elevated myocardial stiffness, were attenuated by sitagliptin treatment.. Sitagliptin positively modulated active relaxation and passive diastolic compliance by decreasing inflammation-related endothelial dysfunction and fibrosis, associated with HFpEF.. This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.

Topics: Animals; Anti-Inflammatory Agents; Blood Pressure; Diastole; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Fibrosis; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart; Heart Failure; Male; Myocardium; Nitric Oxide; Rats, Inbred Dahl; Sitagliptin Phosphate; Stroke Volume

To examine whether patients using sitagliptin at the time of an acute coronary syndrome event are at increased risk of incident heart failure compared with those not exposed.. Using US claims data, people with diabetes without a history of heart failure in the 3 years before hospitalization for acute coronary syndrome were identified for the period 2004 to 2010. We used a nested case-control design, whereby cases were patients who developed incident heart failure <30 days after admission to hospital for acute coronary syndrome and were matched by age and sex with up to 10 controls with no heart failure. Subjects exposed or not exposed to sitagliptin in the 90 days before acute coronary syndrome admission were compared using conditional logistic regression after adjustment for clinical and laboratory data, healthcare utilization and propensity scores.. In total, 457 cases of heart failure developing de novo after diagnosis of acute coronary syndrome were matched to 4570 controls. The average age of the subjects was 55 years and 65% were male. Overall, 11 of 147 (7%) people exposed to sitagliptin developed heart failure compared with 446 of the 4880 people not exposed (9%, adjusted odds ratio 0.75, 95% CI 0.38-1.46; P=0.40). Sitagliptin exposure before acute coronary syndrome was not associated with an increased risk of death or heart failure combined (7% vs 9%, adjusted odds ratio 0.66, 95% CI 0.34-1.28).. In our sample of patients who are at high risk of heart failure after acute coronary syndrome, sitagliptin exposure was not associated with an increased risk of de novo heart failure.

Topics: Acute Coronary Syndrome; Case-Control Studies; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Electronic Health Records; Female; Follow-Up Studies; Heart Failure; Hospitalization; Humans; Incidence; Insurance, Health; Logistic Models; Male; Middle Aged; Patient Readmission; Propensity Score; Risk; Sitagliptin Phosphate; United States

To examine, among patients with type 2 diabetes, the association between hospitalization for heart failure (hHF) and treatment with dipeptidyl peptidase 4 inhibitors (DPP-4is) versus sulfonylureas (SUs), and treatment with saxagliptin versus sitagliptin.. This was a retrospective, observational study using a U.S. insurance claims database. Patients initiated treatment between 1 August 2010 and 30 August 2013, and had no use of the comparator treatments in the prior 12 months (baseline). Each comparison consisted of patients matched 1:1 on a propensity score. Time to each outcome was compared between matched groups using Cox models. Analyses were stratified by the presence of baseline cardiovascular disease (CVD). Secondary analyses examined associations between comparator treatments and other selected cardiovascular events.. After matching, the study included 218,556 patients in comparisons of DPP-4i and SU, and 112,888 in comparisons of saxagliptin and sitagliptin. The hazard ratios (HRs) of hHF were as follows: DPP-4i versus SU (reference): HR 0.95 (95% CI 0.78-1.15), P = 0.580 for patients with baseline CVD; HR 0.59 (95% CI 0.38-0.89), P = 0.013 for patients without baseline CVD; saxagliptin versus sitagliptin (reference): HR 0.95 (95% CI 0.70-1.28), P = 0.712 for patients with baseline CVD; HR 0.99 (95% CI 0.56-1.75), P = 0.972 for patients without baseline CVD. Comparisons of the individual secondary and composite cardiovascular outcomes followed a similar pattern.. In patients with type 2 diabetes, there was no association between hHF, or other selected cardiovascular outcomes, and treatment with a DPP-4i relative to SU or treatment with saxagliptin relative to sitagliptin.

Topics: Adamantane; Adult; Aged; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Follow-Up Studies; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Male; Middle Aged; Propensity Score; Proportional Hazards Models; Retrospective Studies; Sitagliptin Phosphate; Sulfonylurea Compounds; Treatment Outcome

We tested the possible association between dipeptidyl peptidase-4 inhibitors (DPP-4-I) use and heart failure (HF) occurrence by assessing the publicly available US-FDA Adverse Event Reporting System (FAERS).. FAERS data reporting HF and DPP-4-Is use in the period from the fourth quarter of 2006 through 2013 were extracted, using the Standardized MedDRA Query "Cardiac failure". Disproportionality (case/non-case method) was implemented by calculating Reporting Odds Ratios (RORs) with 95% Confidence Interval (CI): (1) exploratory analysis on the entire FAERS (using rosiglitazone as positive control); (2) consolidated analyses by therapeutic area (within antidiabetics), correcting for event- and drug-related competition bias and adjusting for co-reported drugs as confounders.. HF during DPP4-I use was recorded in 390 reports (4.4% of total reports). In exploratory analysis, statistically significant ROR emerged for DPP-4-I as a class (ROR = 1.17; 95% CI = 1.05-1.29), saxagliptin (1.68; 1.29-2.17), vildagliptin (2.39; 1.38-4.14), and rosiglitazone (13.98; 13.30-14.70). In consolidated analyses, the ROR for saxagliptin (2.60; 1.92-3.50) and vildagliptin (4.07; 2.28-7.27) increased, and became also significant for sitagliptin (1.61; 1.40-1.86). Concomitant drugs were reported in more than 50% of cases; the adjusted RORs of saxagliptin (2.30; 1.70-3.10), vildagliptin (3.15; 1.76-5.63), and sitagliptin (1.48; 1.28-1.71) were nonetheless significant.. FAERS data are consistent with clinical studies on a possible association between saxagliptin and HF. The disproportionate reporting of HF with sitagliptin, conflicting with a recent phase IV trial, suggests that cardiovascular safety requires close post-marketing vigilance by clinicians of individual DPP-4-I in the community until the issue of class effect is solved.

Topics: Adamantane; Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Europe; Female; Heart Failure; Humans; Japan; Male; Middle Aged; Retrospective Studies; Risk Assessment; Risk Factors; Sitagliptin Phosphate; Time Factors; Treatment Outcome; United States; United States Food and Drug Administration; Young Adult

Recent postmarketing trials produced conflicting results about the risk for hospitalized heart failure (hHF) associated with dipeptidyl peptidase-4 (DPP-4) inhibitors, creating uncertainty about the safety of these antihyperglycemic agents.. To examine the associations of hHF with saxagliptin and sitagliptin.. Population-based, retrospective, new-user cohort study.. 18 health insurance and health system data partners in the U.S. Food and Drug Administration's Mini-Sentinel program.. Patients aged 18 years or older with type 2 diabetes who initiated therapy with saxagliptin, sitagliptin, pioglitazone, second-generation sulfonylureas, or long-acting insulin products from 2006 to 2013.. Hospitalized HF, identified by International Classification of Diseases, Ninth Revision, Clinical Modification codes 402.x1, 404.x1, 404.x3, and 428.xx recorded as the principal discharge diagnosis.. 78 553 saxagliptin users and 298 124 sitagliptin users contributed an average of 7 to 9 months of follow-up data to 1 or more pairwise comparisons. The risk for hHF was not higher with DPP-4 inhibitors than with the other study drugs. The hazard ratios from the disease risk score (DRS)-stratified analyses were 0.83 (95% CI, 0.70 to 0.99) for saxagliptin versus sitagliptin, 0.63 (CI, 0.47 to 0.85) for saxagliptin versus pioglitazone, 0.69 (CI, 0.54 to 0.87) for saxagliptin versus sulfonylureas, and 0.61 (CI, 0.50 to 0.73) for saxagliptin versus insulin. The DRS-stratified hazard ratios were 0.74 (CI, 0.64 to 0.85) for sitagliptin versus pioglitazone, 0.86 (CI, 0.77 to 0.95) for sitagliptin versus sulfonylureas, and 0.71 (CI, 0.64 to 0.78) for sitagliptin versus insulin. Results from the 1:1 propensity score-matched analyses were similar. Results were also similar in subgroups of patients with and without prior cardiovascular disease and in a subgroup defined by the 2 highest DRS deciles.. Residual confounding and short follow-up.. In this large cohort study, a higher risk for hHF was not observed in users of saxagliptin or sitagliptin compared with other selected antihyperglycemic agents.. U.S. Food and Drug Administration.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Pioglitazone; Retrospective Studies; Risk Factors; Sitagliptin Phosphate; Sulfonylurea Compounds; Thiazolidinediones

Circulating dipeptidyl peptidase IV (DPPIV) activity correlates with cardiac dysfunction in humans and experimental heart failure (HF) models. Similarly, inflammatory markers are associated with poorer outcomes in HF patients. However, the contributions of DPPIV to inflammation in HF remain elusive. Therefore, this study aimed to investigate whether the cardioprotective effects of DPPIV inhibition after myocardial injury are accompanied by reduced cardiac inflammation, whether circulating DPPIV activity correlates with the levels of systemic inflammatory markers in HF patients, and whether leukocytes and/or splenocytes may be one of the sources of circulating DPPIV in HF. Experimental HF was induced in male Wistar rats by left ventricular myocardial injury after radiofrequency catheter ablation. The rats were divided into three groups: sham, HF, and HF + DPPIV inhibitor (sitagliptin). Six weeks after surgery, cardiac function, perfusion and inflammatory status were evaluated. Sitagliptin treatment improved cardiac function and perfusion, reduced macrophage infiltration, and diminished the levels of inflammatory biomarkers including TNF-α, IL-1β, and CCL2. In HF patients, serum DPPIV activity correlated with CCL2, suggesting that leukocytes may be the source of circulating DPPIV in HF. Unexpectedly, DPPIV release was higher in splenocytes from HF rats and similar in HF circulating mononuclear cells compared with those from sham, suggesting an organ-specific modulation of DPPIV in HF. Collectively, our data provide new evidence that the cardioprotective effects of DPPIV inhibition in HF may be due to suppression of inflammatory cytokines. Moreover, they suggest that a vicious circle between DPPIV and inflammation may contribute to HF development and progression.

Topics: Animals; Biomarkers; Chemokine CCL2; Dipeptidyl-Peptidase IV Inhibitors; Heart; Heart Failure; Inflammation; Interleukin-1beta; Macrophages; Male; Rats; Rats, Wistar; Sitagliptin Phosphate; Tumor Necrosis Factor-alpha

Saxagliptin has been reported to be associated with an increased risk of hospitalization for heart failure (HF). The objective of this study was to test whether the increased risk is drug specific or a class effect for dipeptidyl peptidase-4 (DPP-4) inhibitors.. Diabetic patients prescribed sitagliptin, saxagliptin, and vildagliptin between 2011 and 2013 were identified from Taiwan's National Health Insurance (NHI) claims database. The outcome of interest was the first hospitalization for HF. The patients were followed for one year from drug initiation to outcome occurrence, death, or study termination (December 31, 2013). A Cox proportional hazards regression model was used to calculate the hazard ratios (HR) and their 95% confidence intervals, using sitagliptin as the reference group.. A total of 239,669 patients, including 159,330 sitagliptin, 38,561 saxagliptin, and 41,778 vildagliptin initiators, were included in the analysis. With a follow-up period ranging from 269days (vildagliptin) to 313days (sitagliptin), the crude incidence rate of HF was 2.77, 2.63, and 1.91 per 100 person-years for sitagliptin, saxagliptin, and vildagliptin, respectively. Saxagliptin had a similar risk (HR: 0.98, 95% CI: 0.91-1.06) to sitagliptin, while vildagliptin was associated with a lower risk of HF (HR: 0.85, 95% CI: 0.78-0.93). Auxiliary analyses using acarbose (n=130,800) as a reference group consistently showed no increased risk of HF associated with DDP-4 inhibitors.. Three DPP-4 inhibitors studied seem to be safe regarding the risk of HF, while the reduced risk of vildagliptin might be a spurious association or a chance finding.

Topics: Adamantane; Aged; Cohort Studies; Diabetes Mellitus; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Follow-Up Studies; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Nitriles; Pyrrolidines; Risk Factors; Sitagliptin Phosphate; Taiwan; Treatment Outcome; Vildagliptin

This study evaluated the risk of heart failure hospitalization in a 1:1 matched pair sample of sitagliptin ever and never users derived from the Taiwan's National Health Insurance. A total of 85,859 ever users and 85,859 never users matched on 8 digits of propensity score were followed for the first event of heart failure hospitalization until December 31, 2011. The treatment effect (for ever versus never users, and for tertiles of cumulative duration of therapy) was estimated by Cox regression incorporated with the inverse probability of treatment weighting using propensity score. Additionally, adjusted hazard ratios for heart failure were estimated for the baseline characteristics in sitagliptin ever users. Results showed that the incidence of heart failure hospitalization was 1,020.16 and 832.54 per 100,000 person-years, respectively, for ever and never users, with an overall hazard ratio (95% confidence intervals) of 1.262 (1.167-1.364). While compared to never users, the respective hazard ratio for the first, second, and third tertile of cumulative duration < 3.7, 3.7-10.3 and >10.3 months was 2.721 (2.449-3.023), 1.472 (1.318-1.645) and 0.515 (0.447-0.594). Older age, longer diabetes duration, male sex, and use of insulin, sulfonylurea, calcium channel blockers, aspirin, ticlopidine, clopidogrel and dipyridamole were significantly associated with a higher risk in sitagliptin users, but dyslipidemia and use of metformin and statin were protective. In conclusion, sitagliptin increases the risk of heart failure hospitalization within one year of its use, but reduces the risk thereafter. Some factors predisposing to sitagliptin-related heart failure are worthy of attention in clinical practice.

Topics: Adult; Aged; Cohort Studies; Diabetes Complications; Diabetes Mellitus, Type 2; Female; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Incidence; Insurance, Health; Male; Middle Aged; Probability; Proportional Hazards Models; Regression Analysis; Sitagliptin Phosphate; Taiwan

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

The incidence of heart failure hospitalization (HHF) after taking sitagliptin in type 2 diabetes (T2DM) patients with end stage renal disease (ESRD) on dialysis is unclear. In this population-based cohort study, we identified individuals with T2DM and ESRD on dialysis who were treated with sitagliptin between 2009 and 2011 and randomly selected a control cohort matched by age, sex, duration of T2DM, hypertension medications, use of statin and aspirin, sulfonylureas, glinides, and insulin usage, atherosclerotic heart disease, congestive heart failure and chronic obstructive pulmonary disease at a 1:4 ratio. Multivariable Cox proportional hazards regression analysis was used to evaluate HHF risk. The overall incidence of HHF was higher in the sitagliptin cohort than in the control cohort (1130 vs. 754 per 10000 person-years; adjusted hazard ratio (HR): 1.52, 95% CI = 1.21-1.90). There was a significant trend towards increased HHF risk associated with increased sitagliptin dose (p for trend < 0.01). Subjects at greater risk of HHF after taking sitagliptin were those without severe hypoglycemia, without ACE inhibitors treatment, with history of heart failure or receiving hemodialysis rather than peritoneal dialysis. In conclusion, use of sitagliptin was associated with an increased risk of HHF in patients with T2DM on dialysis.

Topics: Aged; Cohort Studies; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Heart Failure; Hospitalization; Humans; Incidence; Male; Middle Aged; Placebos; Renal Dialysis; Risk Factors; Sitagliptin Phosphate

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Heart Failure; Humans; Pyrazines; Risk; Sitagliptin Phosphate

The cardiovascular safety of dipeptidyl peptidase-4 inhibitors (gliptins) has been well studied. Favourable effects of these oral antidiabetic agents have been reported in meta-analyses of phase II-III randomised controlled trials. Three large prospective trials, which were specifically designed to investigate cardiovascular safety, showed non-inferiority of saxagliptin (SAVOR-TIMI 53), alogliptin (EXA-MINE) and sitagliptin (TECOS) versus placebo as far as major cardiovascular events are concerned, including mortality. The suspected increase in the rate of hospitalisation due to congestive heart failure reported in SAVOR-TIMI 53 was neither found in EXAMINE nor recently confirmed in TECOS. Direct comparative trials, evaluating not only safety but also efficacy, with other oral antidiabetic medications would be of major interest.

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Dipeptidyl-Peptidase IV Inhibitors; Heart Failure; Humans; Patient Safety; Sitagliptin Phosphate

The study objective was to evaluate the effects of sitagliptin in patients with type 2 diabetes (T2D) and heart failure (HF).. There is uncertainty in the literature about whether dipeptidyl peptidase (DPP)-4 inhibitors cause harm in patients with HF and T2D.. We analyzed data from a national commercially insured U.S. claims database. Patients with incident HF were identified from individuals with T2D initially treated with metformin or sulfonylurea and followed over time. Subjects subsequently using sitagliptin were compared with those not using sitagliptin in the 90 days before our primary outcome of all-cause hospital admission or death using a nested case-control analysis after adjustment for demographics and clinical and laboratory data. HF-specific hospital admission or death also was assessed.. A total of 7,620 patients with diabetes and incident HF met our inclusion criteria. Mean (SD) age was 54 years (9), and 58% (3,180) were male. Overall, 887 patients (12%) were exposed to sitagliptin therapy (521 patient years of exposure) after incident HF. Our primary composite endpoint occurred in 4,137 patients (54%). After adjustment, sitagliptin users were not at an increased risk for the primary endpoint (7.1% vs. 9.2%, adjusted odds ratio [aOR]: 0.84, 95% confidence interval [CI]: 0.69 to 1.03) or each component (hospital admission 7.5% vs. 9.2%, aOR: 0.93, 95% CI: 0.76 to 1.14; death 6.9% vs. 9.3%, aOR: 1.16, 95% CI: 0.68 to 1.97). However, sitagliptin use was associated with an increased risk of HF hospitalizations (12.5% vs. 9.0%, aOR: 1.84, 95% CI: 1.16 to 2.92).. Sitagliptin use was not associated with an increased risk of all-cause hospitalizations or death, but was associated with an increased risk of HF-related hospitalizations among patients with T2D with pre-existing HF.

Topics: Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Pyrazines; Retrospective Studies; Risk Factors; Sitagliptin Phosphate; Treatment Outcome; Triazoles

Saxagliptin was associated with an increased risk of hospitalization for heart failure (HHF) in diabetic patients with high cardiovascular risk. This study assessed the risk of HHF during an exposure to sitagliptin in general diabetic patients.. In Taiwan National Health Insurance research database, a study of the beneficiaries aged ≥ 45 years with diabetes treated with or without sitagliptin between March 2009 and July 2011 was conducted. Patients treated with sitagliptin were matched to patients never exposed to a dipeptidyl peptidase-4 (DPP-4) inhibitor by the propensity score methodology. The outcome measures were the first and the total number of HHF, and mortality for heart failure or all causes.. A total of 8288 matched pairs of patients were analyzed. During a median of 1.5 years, the first event of HHF occurred in 339 patients with sitagliptin and 275 patients never exposed to a DPP-4 inhibitor (hazard ratio: 1.21, 95% confidence interval: 1.04-1.42, P = 0.017); all-cause mortality was similar (hazard ratio: 0.87, 95% confidence interval: 0.74-1.03, P = 0.109). The risk for HHF was proportional to exposure (hazard ratio: 1.09, 95% confidence interval: 1.06-1.11, P < 0.001 for every 10% increase in adherence to sitagliptin). Overall, there were 935 events of HHF, in which the association between the number of HHF and the adherence to sitagliptin was linear. The greatest total number of HHF occurred in the patients with the highest adherence.. The use of sitagliptin was associated with a higher risk of HHF but no excessive risk for mortality was observed.

Topics: Diabetes Mellitus; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Male; Middle Aged; Morbidity; Population Surveillance; Propensity Score; Pyrazines; Retrospective Studies; Risk Assessment; Risk Factors; Sitagliptin Phosphate; Taiwan; Triazoles

The present study addresses the hypothesis that the activity of dipeptidyl peptidase IV (DPPIV), an enzyme that inactivates peptides that possess cardioprotective actions, correlates with adverse outcomes in heart failure (HF). The therapeutic potential of DPPIV inhibition in preventing cardiac dysfunction is also investigated.. Measurements of DPPIV activity in blood samples obtained from 190 patients with HF and 42 controls demonstrated that patients with HF exhibited an increase of ≈130% in circulating DPPIV activity compared with healthy subjects. Furthermore, an inverse correlation was observed between serum DPPIV activity and left ventricular (LV) ejection fraction in patients with HF. Similarly, radiofrequency LV ablation-induced HF rats displayed higher DPPIV activity in the plasma (≈50%) and heart tissue (≈3.5-fold) compared with sham-operated rats. Moreover, positive correlations were observed between the plasma DPPIV activity and LV end-diastolic pressure and lung congestion. Two days after surgery, 1 group of LV ablation-induced HF rats was treated with the DPPIV inhibitor sitagliptin (40 mg/kg BID) for 6 weeks, whereas the remaining rats were administered water. Hemodynamic measurements demonstrated that radiofrequency LV-ablated rats treated with sitagliptin exhibited a significant attenuation of HF-related cardiac dysfunction, including LV end-diastolic pressure, systolic performance, and chamber stiffness. Sitagliptin treatment also attenuated cardiac remodeling and cardiomyocyte apoptosis and minimized pulmonary congestion.. Collectively, the results presented herein associate circulating DPPIV activity with poorer cardiovascular outcomes in human and experimental HF. Moreover, the results demonstrate that long-term DPPIV inhibition mitigates the development and progression of HF in rats.

Topics: Adult; Aged; Animals; Apoptosis; Biomarkers; Case-Control Studies; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Female; Glucagon-Like Peptide 1; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardium; Natriuretic Peptide, Brain; Pulmonary Edema; Pyrazines; Rats; Rats, Wistar; Sitagliptin Phosphate; Triazoles; Up-Regulation; Ventricular Function, Left; Ventricular Remodeling

Recent studies indicate that brain natriuretic peptide (BNP(1-32)) may be truncated into BNP(3-32) by dipeptidyl peptidase IV (DPP4) and that BNP(3-32) has reduced biological activities compared with BNP(1-32). We investigated if DPP4 contributes to the cardiorenal alterations and to the attenuated response to BNP seen in heart failure.. Haemodynamic and renal assessment was performed in 12 pigs at baseline, 4 weeks after pacing-induced heart failure, and during BNP infusion. They were randomized to either placebo or treatment with a DPP4 inhibitor, sitagliptin. After 4 weeks of pacing, heart rate was reduced compared with baseline in the sitagliptin group (60 ± 2 vs. 95 ± 16 b.p.m., P < 0.01), and an increase in stroke volume was observed in the sitagliptin group compared with placebo (+24 ± 6% vs. -17 ± 7%, P < 0.01). Glomerular filtration rate declined at week 4 compared with baseline in the placebo group (1.3 ± 0.4 vs. 2.3 ± 0.3 mL/kg/min, P < 0.01) but remained preserved in the sitagliptin group [1.8 ± 0.2 vs. 2.0 ± 0.3 mL/kg/min, P = NS (non-significant)]. In the sitagliptin group, BNP infusion improved end-systolic elastance (68 ± 5 vs. 31 ± 4 mmHg/kg/mL, P < 0.05), ventricular-arterial coupling, and mechanical efficiency. Compared with controls (n = 6), myocardial gene expression of BNP, interleukin-6, Na(+)-Ca(2+) exchanger, and calmodulin was up-regulated in the placebo group, but not in the sitagliptin group.. In pacing-induced heart failure, DPP4 inhibition preserves the glomerular filtration rate, modulates stroke volume and heart rate, and potentiates the positive inotropic effect of exogenous BNP at no energy expense.

Topics: Animals; Calmodulin; Cardiac Pacing, Artificial; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Female; Glomerular Filtration Rate; Heart Failure; Heart Rate; Hemodynamics; Interleukin-6; Natriuretic Peptide, Brain; Pyrazines; Sitagliptin Phosphate; Sodium-Calcium Exchanger; Swine; Triazoles