Rationale, design, and organization of a randomized, controlled Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) in patients with type 2 diabetes and established cardiovascular disease

ArticleinAmerican heart journal 166(6):983-989.e7 · December 2013with141 Reads
DOI: 10.1016/j.ahj.2013.09.003 · Source: PubMed
Abstract
Sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, lowers blood glucose when administered as monotherapy or in combination with other antihyperglycemic agents. TECOS will evaluate the effects of adding sitagliptin to usual diabetes care on cardiovascular outcomes and clinical safety. TECOS is a pragmatic, academically run, multinational, randomized, double-blind, placebo-controlled, event-driven trial recruiting approximately 14,000 patients in 38 countries who have type 2 diabetes (T2DM), are at least 50 years old, have cardiovascular disease, and have an hemoglobin A1c value between 6.5% and 8.0%. Eligible participants will be receiving stable mono- or dual therapy with metformin, sulfonylurea, or pioglitazone, or insulin alone or in combination with metformin. Randomization is 1:1 to double-blind sitagliptin or matching placebo, in addition to existing therapy in a usual care setting. Follow-up occurs at 4-month intervals in year 1 and then twice yearly until 1300 confirmed primary end points have occurred. Glycemic equipoise between randomized groups is a desired aim. The primary composite cardiovascular endpoint is time to the first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina, with cardiovascular events adjudicated by an independent committee blinded to study therapy. TECOS is a pragmatic-design cardiovascular outcome trial assessing the cardiovascular effects of sitagliptin when added to usual T2DM management.
    • "clinicaltrial.gov/ct2/show/NCT00894868), but the results have not been published in full so far. In addition, another cardiovascular outcome study with a DPP4 inhibitor, the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), will be soon available [72, 73]. Those trials will certainly add further insight. "
    [Show abstract] [Hide abstract] ABSTRACT: Heart failure (HF) is one of the leading causes of morbidity and mortality. Several risk factors have been identified that have been consistently associated with the development of HF, including type 2 diabetes and glucose-lowering agents. However, different drugs for type 2 diabetes may have diverse, and even divergent, effects on heart failure. The insulin-sensitizing thiazolidinediones have been associated with increased rates of HF in randomized controlled trials, whereas for other drugs, this relationship is less clear. Before the publication of the SAVOR-TIMI53 trial, available data suggested that DPP4 inhibitors could have a protective effect with respect to incident HF. The possibility of a causal finding cannot be ruled out, but it appears rather unlikely, considering that another cardiovascular outcome study showed a trend toward an increased risk with a different molecule of the same class, and that some epidemiological studies associated sitagliptin to an increased risk of HF. This review explores the possible mechanisms underlying the association of DPP4 inhibitor use with an increased risk for incident HF.
    Article · Aug 2015
    • "Furthermore , a retrospective cohort study of Japanese diabetic patients suggested that treatment with DPP-4 inhibitors does not increase the risk of acute pancreatitis [28]. The prospective TECOS study is currently examining the risk of pancreatitis and pancreatic carcinoma in patients treated with sitagliptin [29, 30] , and the results are expected to provide more insight into this issue. A recent analysis stratified by renal function was performed in the SAVOR-TIMI 53 Trial, a large-scale clinical study of 16492 patients with T2DM that evaluated the impact of saxagliptin (another DPP-4 inhibitor) on cardiovascular disorders. "
    [Show abstract] [Hide abstract] ABSTRACT: There have only been a few reports about use of dipeptidyl peptidase 4 (DPP-4) inhibitors in elderly patients with type 2 diabetes mellitus (T2DM), suggesting that the safety of these agents has not been sufficiently demonstrated. We performed a comparative review of the efficacy and safety of sitagliptin for Japanese patients with T2DM managed in the real-world clinical setting. An age-stratified analysis was performed of 831 patients who were treated with sitagliptin for 2 years. Parameters assessed included the hemoglobin A1c (HbA1c), body weight, serum creatinine, and adverse events. HbA1c and the incidence of hypoglycemia were also evaluated in patients treated with sitagliptin and a sulfonylurea (SU), who were divided into three age groups (<65 years, 65-74 years, and ≥75 years). Comparison of glycemic control parameters, laboratory values, and adverse events revealed significant improvement of HbA1c, casual postprandial plasma glucose, and fasting plasma glucose in each age group with no change in body weight. Serum creatinine increased significantly in all age groups. Hypoglycemia only occurred in patients who received combined treatment with an SU and sitagliptin, and there was no age-related difference in its incidence. HbA1c was improved by 2 years of sitagliptin therapy in all three age groups, and age did not seem to influence the incidence of hypoglycemic events. These results confirm the efficacy and safety of sitagliptin in patients ≥ 75 years old, suggesting that it is also useful for treating elderly patients with T2DM.
    Full-text · Article · Jul 2015
    • "In light of the controversy surrounding the safety of DPP-4 inhibitors, a well-designed, randomized double-blinded clinical trial is needed. The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) is an ongoing multinational clinical trial aiming to evaluate the efficacy of sitagliptin for reducing cardiovascular risk in patients with type 2 diabetes who have documented vascular disease in the coronary, cerebral, or peripheral arteries [27]. Although the TECOS trials enrolled patients who were at elevated cardiovascular risk, our study is unique in that only subjects who suffered a recent AMI were included. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: The cardiovascular safety and efficacy of sitagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, in type 2 diabetic patients after acute myocardial infarction (AMI) has so far remained uncertain. Methods: We analyzed data from the National Health Insurance Research Database (NHIRD), a government-operated, population-based database, from March 1st, 2009 to December 31st, 2011. Type 2 diabetic patients hospitalized for AMI were included in our study. We compared subjects using sitagliptin with comparison group to evaluate its cardiovascular safety and efficacy. The primary endpoint was a composite of cardiovascular death, myocardial infarction, and ischemic stroke. Results: We identified a total of 3,282 type 2 diabetic patients hospitalized for AMI (mean follow-up 1.15 years). Of these patients, 547 (16.7%) who were exposed to sitagliptin were defined as the sitagliptin group and 2,735 (83.3 %) who did not use sitagliptin were the comparison group. The incidence of primary composite cardiovascular outcomes was 9.50 per 100 person-years in the sitagliptin group and was 9.70 per 100 person-years in the comparison group (hazard ratio (HR), 0.97; 95% CI, 0.73-1.29, P=0.849). Compared to the non-sitagliptin group, the sitagliptin group had similar risks of all-cause mortality, hospitalization for heart failure (HF) or percutaneous coronary intervention (PCI) with a HR of 0.82 (95% CI, 0.61-1.11, P=0.195), 0.93 (95% CI, 0.67-1.29, P=0.660), and 0.93 (95% CI, 0.75-1.14, P=0.473), respectively. Conclusion: The use of sitagliptin in type 2 diabetic patients with recent AMI was not associated with increased risk of adverse cardiovascular events.
    Full-text · Article · Jun 2015
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