Trial Evaluating Cardiovascular Outcomes With Sitagliptin Research Articles

Time-dependent event accumulation in a cardiovascular outcome trial of patients with type 2 diabetes and established atherosclerotic cardiovascular disease

BackgroundEstimating cardiovascular (CV) event accrual is important for outcome trial planning. Limited data exist describing event accrual patterns in patients with type 2 diabetes (T2D). We compared apparent CV event accrual patterns with true event rates in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS).MethodsCentrally adjudicated event dates and accrual rates for a 4-point major adverse CV event composite (MACE-4; includes CV death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina hospitalization), MACE-4 components, all-cause mortality (ACM), and heart failure hospitalization were compiled. We used three graphical methods (Weibull probability plot, plot of negative log of the Kaplan–Meier survival distribution estimate, and the Epanechnikov kernel-smoothed estimate of the hazard rate) to examine hazard rate morphology over time for the 7 outcomes.ResultsPlots for all outcomes showed real-time constant event hazard rates for the duration of the follow-up, confirmed by Weibull shape parameters. The Weibull shape parameters for ACM (1.14, 95% CI 1.08–1.21) and CV death (1.08, 95% CI 1.01–1.16) were not sufficiently > 1 as to require non-constant hazard rate models to accurately depict the data. The time lag between event occurrence and event adjudication being completed, the adjudication gap, improved over the course of the trial.ConclusionsIn TECOS, the nonfatal event hazard rates were constant over time. Small increases over time in the hazard rate for fatal events would not require complex modelling to predict event accrual, providing confidence in traditional modelling methods for predicting CV outcome trial event rates in this population. The adjudication gap provides a useful metric to monitor within-trial event accrual patterns.Clinical trial registrationClinicaltrials.gov NCT00790205.

Development and validation of a model to predict cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease

BackgroundAmong individuals with atherosclerotic cardiovascular disease (ASCVD), type 2 diabetes mellitus (T2DM) is common and confers increased risk for morbidity and mortality. Differentiating risk is key to optimize efficiency of treatment selection. Our objective was to develop and validate a model to predict risk of major adverse cardiovascular events (MACE) comprising the first event of cardiovascular death, myocardial infarction (MI), or stroke for individuals with both T2DM and ASCVD.MethodsUsing data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), we used Cox proportional hazards models to predict MACE among participants with T2DM and ASCVD. All baseline covariates collected in the trial were considered for inclusion, although some were excluded immediately because of large missingness or collinearity. A full model was developed using stepwise selection in each of 25 imputed datasets, and comprised candidate variables selected in 20 of the 25 datasets. A parsimonious model with a maximum of 10 degrees of freedom was created using Cox models with least absolute shrinkage and selection operator (LASSO), where the adjusted R-square was used as criterion for selection. The model was then externally validated among a cohort of participants with similar criteria in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial. Discrimination of both models was assessed using Harrell’s C-index and model calibration by the Greenwood-Nam-D’Agostino statistic based on 4-year event rates.ResultsOverall, 1491 (10.2%) of 14,671 participants in TECOS and 130 (9.3%) in the ACCORD validation cohort (n = 1404) had MACE over 3 years’ median follow-up. The final model included 9 characteristics (prior stroke, age, chronic kidney disease, prior MI, sex, heart failure, insulin use, atrial fibrillation, and microvascular complications). The model had moderate discrimination in both the internal and external validation samples (C-index = 0.65 and 0.61, respectively). The model was well calibrated across the risk spectrum—from a cumulative MACE rate of 6% at 4 years in the lowest risk quintile to 26% in the highest risk quintile.ConclusionAmong patients with T2DM and prevalent ASCVD, this 9-factor risk model can quantify the risk of future ASCVD complications and inform decision making for treatments and intensity.

Re-adjudication of the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) with study-level meta-analysis of hospitalization for heart failure from cardiovascular outcomes trials with dipeptidyl peptidase-4 (DPP-4)inhibitors.

BackgroundTrial 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.MethodsTIMI 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.ResultsAfter re‐adjudication of potential HHF events in the intent‐to‐treat population, there were 224 patients with a confirmed event in the sitagliptin arm (1.05/100 person‐years) and 239 patients in the placebo arm (1.13/100 person‐years), corresponding to a hazard ratio (HR) of 0.94 (95% confidence interval [95% CI]: 0.78–1.13, p = .49). Concordance between the outcome of the original adjudication and the re‐adjudication for HHF events was 82.7%. The meta‐analysis of CV outcomes trials with DPP‐4 inhibitors with placebo and involving 43 522 patients yielded an HR of 1.07 (95% CI: 0.83–1.39), with moderate heterogeneity (p = .45, I 2 = 62.07%).ConclusionThe 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.

Cluster Analysis of Cardiovascular Phenotypes in Patients With Type 2 Diabetes and Established Atherosclerotic Cardiovascular Disease: A Potential Approach to Precision Medicine.

Phenotypic heterogeneity among patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) is ill defined. We used cluster analysis machine-learning algorithms to identify phenotypes among trial participants with T2DM and ASCVD. We used data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study (n = 14,671), a cardiovascular outcome safety trial comparing sitagliptin with placebo in patients with T2DM and ASCVD (median follow-up 3.0 years). Cluster analysis using 40 baseline variables was conducted, with associations between clusters and the primary composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina) assessed by Cox proportional hazards models. We replicated the results using the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial. Four distinct phenotypes were identified: cluster I included Caucasian men with a high prevalence of coronary artery disease; cluster II included Asian patients with a low BMI; cluster III included women with noncoronary ASCVD disease; and cluster IV included patients with heart failure and kidney dysfunction. The primary outcome occurred, respectively, in 11.6%, 8.6%, 10.3%, and 16.8% of patients in clusters I to IV. The crude difference in cardiovascular risk for the highest versus lowest risk cluster (cluster IV vs. II) was statistically significant (hazard ratio 2.74 [95% CI 2.29-3.29]). Similar phenotypes and outcomes were identified in EXSCEL. In patients with T2DM and ASCVD, cluster analysis identified four clinically distinct groups. Further cardiovascular phenotyping is warranted to inform patient care and optimize clinical trial designs.

Abstract 14727: Meteorin-like Glial Cell Differentiation Regulator is a Novel Protein Biomarker of Cardiovascular Outcomes in Patients With Diabetes and Vascular Disease: A TECOS Substudy

Introduction: To date, there are limited data on the potential role of proteomic biomarkers to predict future cardiovascular (CV) events among patients with type 2 diabetes mellitus (DM). Hypothesis: Specific protein biomarkers will be predictive of major adverse CV events (MACE) and incident heart failure hospitalization (HFH) among patients with DM. Methods: Using the Olink aptamer-based platform, we performed proteomic profiling (>700 proteins) on 440 paired cases and matched controls from placebo-assigned participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Cases were defined as having met the primary composite outcome of MACE or incident HFH and matched to controls on baseline prevalent heart failure, coronary artery disease, BMI, hemoglobin A1C, creatinine, low-density lipoprotein cholesterol, fasting status and ejection fraction. Conditional logistic regression was used to determine the association between log-transformed relative protein expression and incident MACE or HFH. False-discovery-rate (FDR) was used to adjust for multiple comparisons. Results: We identified three specific proteins that were significantly associated with prevalent MACE or HFH: METRNL, Notch 3, and ROR1 (OR 2.1, 1.6, 1.7 and q-value 0.01, 0.02, and 0.05 respectively) (Figure 1). METRNL, in particular, performed similarly to the established biomarker NT-proBNP (Figure 1). When MACE and HFH were analyzed separately, METRNL, in particular, remained strongly associated with both outcomes (OR 2.0, p<0.001 and OR 2.7, p=0.05). Conclusions: Three novel protein biomarkers, in particular METRNL (a circulating adipokine that regulates insulin-sensitivity), may identify diabetic patients at high risk for subsequent HF and MACE. Additional studies are needed to replicate these findings and uncover the biologic mechanism linking adipokine signaling and heart failure.

Abstract 15589: Mitochondrial Metabolites Predict Cardiovascular Outcomes and Heart Failure in People With Type 2 Diabetes Mellitus and Vascular Disease: A Tecos Substudy

Introduction: People with type 2 diabetes mellitus (DM) have a large burden of cardiovascular (CV) morbidity and mortality, but the likelihood of these outcomes varies and existing risk calculators do not fully capture risk for individuals. Hypothesis: Circulating metabolites characterizing mitochondrial dysfunction may be novel predictors for CV outcomes. Methods: We performed targeted mass-spectrometry metabolite profiling (45 acylcarnitines, 15 amino acids) on baseline plasma samples from 568 cases (498 with major adverse cardiac events (MACE) and 131 with incident hospitalization for heart failure (hHF)) and 568 matched controls (without events) from the patients assigned to placebo in Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Matching was based on history of HF, coronary artery disease, BMI, hemoglobin A1C, creatinine, low-density lipoprotein cholesterol, fasting status and ejection fraction. Principal components analysis (PCA) was used for dimensionality reduction, and conditional logistic regression to determine association of PCA factors with MACE or hHF and for individual metabolites within significant factors (false discovery rate q<0.05) Results: Of 12 PCA-derived metabolite factors, three were associated significantly with MACE or hHF; these factors were composed of: 1) short-chain dicarboxylacylcarnitines and long chain acylcarnitines (OR 1.50, q=0.03); 2) medium chain acylcarnitines (OR 1.28, q=0.001); 3) C5:1 and one medium-chain dicarboxylacylcarnitine (OR 1.17, q=0.03). Of these three factors, none were significantly associated with the individual components of MACE. Ten individual metabolites, including short- and medium-chain dicarboxylacylcarnitines and medium- and long-chain acylcarnitines, remained significantly associated with MACE (q<0.05). Two metabolites, one short-chain dicarboxylacylcarnitine and one medium-chain acylcarnitine were associated with hHF (q<0.05). Conclusions: Metabolites reporting on dysregulated mitochondrial fatty acid oxidation and endoplasmic reticulum stress are elevated in individuals with DM who progress to MACE and/or hHF. These biomarkers may improve CV risk prediction in DM patients and help highlight emerging risk mechanisms.

November 2020 at a glance: focus on comorbidities and medical treatment.

The role of glycaemic control in patients with heart failure (HF) and concomitant diabetes is controversial. Insulin treatment is associated with poorer outcomes in these patients.1, 2 McAlister et al.3 investigated the relationship between glycaemic control, i.e. glycated haemoglobin (HbA1c), and cardiovascular (CV) outcomes in patients with type 2 diabetes mellitus and atherosclerosis from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Results showed a U-shaped association between baseline HbA1c and CV outcome, with the lowest risk when HbA1c was around 7%.3 Iron deficiency impairs cardiac contractility through decreased mitochondrial function.4 Hirsch et al.5 assessed iron concentrations in non-ischaemic HF with reduced ejection fraction (HFrEF), using endomyocardial biopsies. Lower iron concentrations were associated with a greater severity of HF. Hyperkalaemia is frequent in HFrEF patients, above all when on renin–angiotensin–aldosterone system inhibitors.6, 7 An administrative database analysis showed the association of hyperkalaemia with mortality and CV events in HF patients on renin–angiotensin–aldosterone system inhibitors.8 In the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, both hypokalaemia and hyperkalaemia were associated with a higher risk of CV death, compared with potassium levels between 4.1 and 4.9 mmol/L (hazard ratio 2.40 and 1.42, respectively). No interaction between serum potassium and sacubitril/valsartan efficacy vs. enalapril was found.9 Frailty is a major independent determinant of outcomes in HF.10 A new Frailty Score has recently been developed.11 The FRAGILE-HF study was a prospective multicentre study investigating the prevalence, overlap, and prognostic implications of physical and social frailties and cognitive dysfunction in patients hospitalized with HF. Patients with a greater number of frailty domains had higher mortality and HF rehospitalization.12 The prevalence of frailty is increased in HF with preserved ejection fraction (HFpEF) patients and is associated with worse outcome.13 Similarly, frailty was highly prevalent in HFrEF patients and was associated with poor quality of life and outcomes in a retrospective analysis of PARADIGM-HF and ATMOSPHERE.14 Biomarkers, namely natriuretic peptides, play a major role in the management of HF.15 Aimo et al.16 analysed the prognostic value and the influence of age on circulating levels of biomarkers in 5301 patients with chronic HF. N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT) and soluble suppression of tumorigenesis-2 (sST2) predicted outcomes. sST2 was less influenced by age than the other two biomarkers. In the Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction (PARAGON-HF) trial, serum uric acid (SUA) was an independent predictor of poor outcome in HFpEF. Sacubitril/valsartan reduced SUA levels and the need for SUA-related drugs.17 Sex-based differences in biomarkers, health status, and reverse cardiac remodelling in HFrEF patients treated with sacubitril/valsartan in the Prospective Study of Biomarkers, Symptom Improvement and Ventricular Remodelling During Entresto Therapy for HF (PROVE-HF) were analysed by Ibrahim et al.18 Sex is a major determinant of clinical characteristics and outcomes in patients with HFrEF and HFpEF.19-21 In the study by Ibrahim et al.18, women treated with sacubitril/valsartan had more rapid reduction in NT-proBNP plasma levels and reverse cardiac remodelling and a larger improvement in quality of life. McEwan et al.22 showed the cost-effectiveness of dapagliflozin for the treatment of HFrEF with significant life-year and quality-adjusted life-year gains for the patients treated. The Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in HF (GALACTIC-HF) trial assessed the safety and efficacy of the cardiac myosin activator omecamtiv mecarbil in HFrEF patients. The baseline characteristics of enrolled patients are presented in this issue. The trial enrolled well-treated and high-risk inpatients and outpatients, representative of recent HF registries and trials.23

Series: Cardiovascular outcome trials for diabetes drugs Sitagliptin and TECOS

TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin) was an investigator-initiated cardiovascular outcome trial with sitagliptin. It compared sitagliptin and placebo in 14,671 subjects with type 2 diabetes and demonstrated non-inferiority for major cardiovascular events plus hospitalisation for unstable angina (cardiovascular death, myocardial infarction, stroke, unstable angina) but not superiority. Rates of hospitalisation for heart failure did not differ between the sitagliptin and placebo groups, and there were no significant between-group differences in rates of acute pancreatitis or pancreatic cancer. The clinical role for dipeptidyl peptidase-4 (DPP-4) inhibitors is diminishing as they have not been demonstrated to reduce cardiovascular events and are not associated with weight reduction, but if a DPP-4 inhibitor is indicated, the results of TECOS show that sitagliptin appears safer than saxagliptin or alogliptin.

Associations between β-blocker therapy and cardiovascular outcomes in patients with diabetes and established cardiovascular disease

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).

Sitagliptin does not reduce the risk of cardiovascular death or hospitalization for heart failure following myocardial infarction in patients with diabetes: observations from TECOS

BackgroundTo 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).MethodsTECOS 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.ResultsDuring 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.ConclusionsIn 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

International variation in characteristics and clinical outcomes of patients with type 2 diabetes and heart failure: Insights from TECOS

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.

1466-P: Estimating Cardiovascular Risk in People with Type 2 Diabetes and Cardiovascular Disease: UKPDS Outcomes Model

Background and Aims: Type 2 diabetes (T2D) cardiovascular (CV) risk calculators focus mainly on those without CVD. We evaluated a T2D clinical outcomes simulation model (UKPDS Outcomes Model v2 [OM2]) estimates of CV risk in TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin) participants with T2D and CVD. Materials and Methods: We compared estimated 3-year CV event and all-cause mortality (ACM) rates with observed rates. Covariates included: sex, ethnicity, age, diabetes duration, atrial fibrillation, albuminuria; baseline plus annual measures of smoking, HDL and LDL-cholesterol, weight, systolic blood pressure, HbA1c, heart rate, white cell count, haemoglobin, estimated glomerular filtration rate; and prior history of ischaemic heart disease, heart failure, amputation, blindness, kidney failure, stroke, myocardial infarction (MI) or diabetic foot ulcer. Results: 1491/14671 (10.2%) participants experienced ≥1 major CV event over median 3.0 years follow-up. Predicted compared with observed rates were 6.4% vs. 5.1% for CV death, 7.7% vs. 4.2% ≥1 MI event and 3.5% vs. 2.5% for ≥1 stroke event (Table). Discrimination was fair (aROC&amp;gt;0.6) for stroke, CV death and ACM, but poor for MI. Simulated relative risks matched those observed. Conclusion: OM2 overestimates absolute CV and ACM risk in TECOS participants, but correctly simulates the lack of sitagliptin impact. Disclosure R.L. Coleman: None. A.M. Gray: Advisory Panel; Self; Sanofi-Aventis. D.K. McGuire: Consultant; Self; Eisai Co., Ltd., Eli Lilly and Company, Pfizer Inc. Research Support; Self; Janssen Pharmaceuticals, Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. R.R. Holman: Advisory Panel; Self; Bayer AG, Novartis AG, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Bayer AG, Merck Sharp &amp; Dohme Corp. Other Relationship; Self; AstraZeneca, Bayer AG, GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc.

Antithrombotic treatment gap among patients with atrial fibrillation and type 2 diabetes

BackgroundWe investigated the use of different antithrombotic therapies at baseline among patients with a history of atrial fibrillation (AF), type 2 diabetes, and established atherosclerotic cardiovascular disease (ASCVD) enrolled in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). MethodsTECOS participants with a history of AF were stratified by CHA2DS2-VASc score and their antithrombotic use evaluated. Cox proportional hazards models were employed to explore possible associations between history of AF and prespecified clinical outcomes after adjusting for key baseline characteristics. ResultsOf the 14,671 TECOS participants, 1167 (8%) had a history of AF, of whom 51.6% were using vitamin K antagonists (VKA); 31.2% used VKA alone, 16.9% used aspirin plus VKA, 1.8% used clopidogrel plus VKA, and 1.7% used aspirin and clopidogrel plus VKA. Aspirin was used by 56.8%: 30.9% used aspirin alone and 7.3% aspirin plus clopidogrel. Clopidogrel alone was used by 2.9%, and 7.3% were not using any antithrombotic medication. Participants with a history of AF had a higher risk of cardiovascular events, including hospitalization for heart failure and all-cause mortality, than those without AF. White, older men with prior myocardial infarction, heart failure, peripheral artery disease, or prior stroke were more likely to develop new-onset AF than others without these characteristics. ConclusionsAlmost half of high-risk AF patients with diabetes and established ASCVD in TECOS were not treated with anticoagulation therapy despite clear guideline recommendations for such therapy, highlighting the challenge and potential for clinical improvements in managing these patients in clinical practice.Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00790205.

Heart Failure Hospitalization with DPP-4 Inhibitors: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Background:Heart failure hospitalization (hHF) with dipeptyl-dipeptidase-4 inhibitors (DPP-4Is) remains at the center stage since the publication of Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction (SAVOR-TIMI) in 2013 showing significant increase with saxagliptin, compared to placebo. This outcome led to additional label of hHF to both saxagliptin and alogliptin in April 2016 and eventual labelling of hHF to all the four approved DPP-4Is in United States in August 2017, by US Food Drug Administration. To note, neither Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), nor Cardiovascular and Renal Microvascular Outcome Study with Linagliptin (CARMELINA), showed any signals of hHF with these two agents. These developments have seriously generated an uncertainty among clinicians with regards to hHF effect of DPP-4Is in type 2 diabetic patients with high risk of cardiovascular (CV) disease.Aims and Objectives:We systematically searched the database of PubMed, Embase, Cochrane Central library, ClinicalTrials.gov, and International conference presentation from the inception up to October 25, 2018 using MeSH and specific key words. We retrieved all those studies that explicitly looked for hHF as a prespecified end point and were conducted for ≥52 weeks. Subsequently, we conducted the meta-analysis using comprehensive meta-analysis software Version 3, using different sensitivity analysis to study the effect of DPP-4Is on hHF in both dedicated CV outcome trials as well as randomized controlled trials.Results:The meta-analysis of four exclusive dedicated CV outcome trials (N = 43,522) did not find significant increase in hHF with DPP-4 inhibitors (Fixed model Relative Risk [RR] 1.06; 95% Confidence Interval [CI], 0.96-1.17; P = 0.25; I2: 53.95%, tau2: 0.012, P = 0.089). Meta-analysis of all randomized controlled trials that explicitly looked for hHF for ≥52 weeks (N = 48,199) also did not show any significant increase in hHF (fixed model peto odds ratio 1.05; 95% CI 0.95–1.15, P = 0.36; I2: 43.74%, tau2: 0.016, P = 0.10).Conclusions:This meta-analysis suggests no significant increase in hHF with DPP-4 inhibitors, although a nonsignificant heterogeneity across the trials might limit this observation.

Cardiovascular Event Hazards over Time in TECOS

Background: Event accumulation patterns in event-driven trials inform forecasting of trial size and duration. It is hypothesized that trials enrol a healthier cohort who have lower early cardiovascular (CV) event rates that increase during follow-up as surviving patients age and accumulate comorbidities. We present hazard rate patterns for incident CV events in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Methods: Using adjudicated endpoints from the intention-to-treat population, Weibull models show whether hazards for these CV events were increasing (shape parameter&amp;gt;1), decreasing (&amp;lt;1), or constant (=1) over time: MACE-4 composite (CV death, nonfatal myocardial infarction [NFMI], nonfatal stroke [NFSt], and unstable angina hospitalization [UA]); fatal (F) or NFMI, F/NFSt, UA, CV death, all-cause mortality (ACM), and heart failure hospitalization (HF). Results: The Figure shows hazard rate over time. Weibull shape point estimates (95% CI) were MACE-4 0.96 (0.92, 1.01); ACM 1.14 (1.08, 1.21); CV death 1.(1.01, 1.16); F/NFMI 0.96 (0.89, 1.03); F/NFSt 0.93 (0.85, 1.03); UA 0.90 (0.79, 1.01); HF 0.98 (0.90, 1.08). Annual event rates (per 100 pt-years) were CV death: 1.5, 1.6, 2.0, 1.9, 2.7; ACM: 2.1, 2.3, 2.8, 3.0, 3.8. Conclusions: Hazard rates were constant for all events except CV death and ACM, which had small significant increased risk over time. Our findings may inform the planning and conduct of future trials in diabetes. Disclosure M. Bethel: Research Support; Self; AstraZeneca, Merck Sharp &amp; Dohme Corp., Merck Serono. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca. Other Relationship; Self; Sanofi. Consultant; Self; Theracos, Inc.. Research Support; Self; GlaxoSmithKline plc. H. Sourij: Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Novo Nordisk A/S, Amgen Inc., Sanofi, MSD K.K.. Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH, MSD K.K., GI Dynamics Inc.. S.R. Stevens: None. Y. Lokhnygina: None. R.D. Lopes: Consultant; Self; Bayer AG, Boehringer Ingelheim GmbH. Other Relationship; Self; Bristol-Myers Squibb Company. Consultant; Self; Daiichi Sankyo Company, Limited. Other Relationship; Self; GlaxoSmithKline plc., Medtronic. Consultant; Self; Merck &amp; Co., Inc.. Other Relationship; Self; Pfizer Inc.. A. Adler: None. D.K. McGuire: Consultant; Self; AstraZeneca, Sanofi-Aventis, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Merck &amp; Co., Inc., Pfizer Inc., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Sanofi-Aventis, Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S, Lexicon Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Esperion Therapeutics. E. Peterson: Research Support; Self; Merck &amp; Co., Inc.. Consultant; Self; Merck &amp; Co., Inc.. Research Support; Self; AstraZeneca. Consultant; Self; AstraZeneca. R.R. Holman: Research Support; Self; AstraZeneca, Merck &amp; Co., Inc., Bayer AG. Advisory Panel; Self; Elcelyx Therapeutics, Inc., Novartis AG, Novo Nordisk A/S. Other Relationship; Self; Bayer AG. Advisory Panel; Self; Merck &amp; Co., Inc.. Other Relationship; Self; AstraZeneca.

Sex differences in management and outcomes of patients with type 2 diabetes and cardiovascular disease: A report from TECOS.

To examine sex differences in baseline characteristics and outcomes in patients with type 2 diabetes and atherosclerotic vascular disease. Cox models were used to analyse the association between sex and outcomes in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a randomized, placebo-controlled trial assessing the impact of sitagliptin on cardiovascular (CV) outcomes in patients with type 2 diabetes and atherosclerotic vascular disease. A total of 4297 women and 10 374 men were followed for a median of 3.0 years. Women were slightly older and more often had cerebrovascular disease and peripheral arterial disease but less often coronary heart disease than men. At baseline, women were less likely to use aspirin or statins. The primary composite outcome of CV death, myocardial infarction, stroke, or hospitalization for unstable angina occurred in 418 women (9.7%) and 1272 men (12.3%; 3.48 vs 4.38 events/100 participant-years, crude hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.71-0.89, adjusted HR 0.64, 95% CI 0.55-0.74; P < .0001). Women also had a significantly lower risk of secondary CV outcomes and all-cause death. In this large prospective study of people with type 2 diabetes and CV disease, women had different CV disease burden, worse CV risk factor profiles, and less use of indicated medications than men. Despite this, women had significantly lower risk of CV events, suggesting that the cardioprotective effects of female sex extend to populations with type 2 diabetes.

Longitudinal medical resources and costs among type 2 diabetes patients participating in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS).

TECOS, a cardiovascular safety trial (ClinicalTrials.gov identifier: NCT00790205) involving 14 671 patients with type 2 diabetes and cardiovascular disease, demonstrated that sitagliptin was non-inferior to placebo for the primary composite cardiovascular outcome when added to best usual care. This study tested hypotheses that medical resource use and costs differed between these 2 treatment strategies. Information concerning medical resource use was collected on case report forms throughout the trial and was valued using US costs for: Medicare payments for hospitalizations, medical procedures and outpatient visits, and wholesale acquisition costs (WAC) for diabetes-related medications. Hierarchical generalized linear models were used to compare resource use and US costs, accounting for variable intercountry practice patterns. Sensitivity analyses included resource valuation using English costs for a UK perspective. There were no significant differences in hospitalizations, inpatient days, medical procedures, or outpatient visits during follow-up (mean and median 3.0 years in both groups). Hospitalization rates appeared to diverge after 2 years, with lower rates among sitagliptin-treated vs placebo patients after 2.5 years (relative rate, 0.90 [95% CI, 0.83-0.97]; P = .01). Mean medical costs, exclusive of study medication, were 11 937 USD in the sitagliptin arm and 12 409 USD in the placebo arm (P = .06). Mean sitagliptin costs based on undiscounted WAC were 9978 USD per patient. Differential UK total costs including study drug costs were smaller (911 GBP), primarily because of lower mean costs for sitagliptin (1072 GBP). Lower hospitalization rates across time with sitagliptin slightly offset sitagliptin treatment costs over 3 years in type 2 diabetes patients at high risk for cardiovascular events.

Increased Risk of Severe Hypoglycemic Events Before and After Cardiovascular Outcomes in TECOS Suggests an At-Risk Type 2 Diabetes Frail Patient Phenotype.

Severe hypoglycemic events (SHEs) in type 2 diabetes are associated with subsequent cardiovascular (CV) event risk. We examined whether CV events were associated with subsequent SHE risk. Time-dependent associations between SHEs and a composite CV end point (fatal/nonfatal myocardial infarction or stroke, hospitalization for unstable angina, hospitalization for heart failure [hHF]) were examined post hoc in 14,671 TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin) participants with type 2 diabetes and CV disease followed for a median of 3.0 years. SHEs were uncommon and unassociated with sitagliptin therapy (N = 160 [2.2%], 0.78/100 patient-years vs. N = 143 [1.9%], 0.70/100 patient-years for placebo; hazard ratio [HR] 1.12 [95% CI 0.89, 1.40], P = 0.33). Patients with (versus without) SHEs were older with longer diabetes duration, lower body weight, and lower estimated glomerular filtration rate; were more frequently women, nonwhite, and insulin treated; and more often had microalbuminuria or macroalbuminuria. Analyses adjusted for clinical factors showed SHEs were associated with increased risk of the primary composite CV end point (1.55 [1.06, 2.28], P = 0.025), all-cause death (1.83 [1.22, 2.75], P = 0.004), and CV death (1.72 [1.02, 2.87], P = 0.040). Conversely, nonfatal myocardial infarction (3.02 [1.83, 4.96], P < 0.001), nonfatal stroke (2.77 [1.36, 5.63], P = 0.005), and hHF (3.68 [2.13, 6.36], P < 0.001) were associated with increased risk of SHEs. Fully adjusted models showed no association between SHEs and subsequent CV or hHF events, but the association between CV events and subsequent SHEs remained robust. These findings, showing greater risk of SHEs after CV events and greater risk of CV events after SHEs, suggest a common at-risk type 2 diabetes frail patient phenotype.

Longitudinal medical resources and costs among type 2 diabetes patients participating in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS)

Longitudinal medical resources and costs among type 2 diabetes patients participating in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS)

Modelling incremental benefits on complications rates when targeting lower HbA1c levels in people with Type 2 diabetes and cardiovascular disease.

Glucose-lowering interventions in Type2 diabetes mellitus have demonstrated reductions in microvascular complications and modest reductions in macrovascular complications. However, the degree to which targeting different HbA1c reductions might reduce risk is unclear. Participant-level data for Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) participants with established cardiovascular disease were used in a Type2 diabetes-specific simulation model to quantify the likely impact of different HbA1c decrements on complication rates. Ten-year micro- and macrovascular rates were estimated with HbA1c levels fixed at 86, 75, 64, 53 and 42mmol/mol (10%, 9%, 8%, 7% and 6%) while holding other risk factors constant at their baseline levels. Cumulative relative risk reductions for each outcome were derived for each HbA1c decrement. Of 5717 participants studied, 72.0% were men and 74.2% White European, with a mean (sd) age of 66.2 (7.9)years, systolic blood pressure 134 (16.9)mmHg, LDL-cholesterol 2.3 (0.9)mmol/l, HDL-cholesterol 1.13 (0.3)mmol/l and median Type2 diabetes duration 9.6 (5.1-15.6)years. Ten-year cumulative relative risk reductions for modelled HbA1c values of 75, 64, 53 and 42mmol/mol, relative to 86mmol/mol, were 4.6%, 9.3%, 15.1% and 20.2% for myocardial infarction; 6.0%, 12.8%, 19.6% and 25.8% for stroke; 14.4%, 26.6%, 37.1% and 46.4% for diabetes-related ulcer; 21.5%, 39.0%, 52.3% and 63.1% for amputation; and 13.6%, 25.4%, 36.0% and 44.7 for single-eye blindness. These simulated complication rates might help inform the degree to which complications might be reduced by targeting particular HbA1c reductions in Type2 diabetes.