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

doi:10.1016/j.ahj.2013.09.003

American Heart Journal

Volume 166, Issue 6, December 2013, Pages 983-989.e7

https://doi.org/10.1016/j.ahj.2013.09.003 Get rights and content

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 A_1c 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.

Section snippets

TECOS: an overview

TECOS will assess the balance of risk and benefit from a cardiovascular perspective for sitagliptin, an orally administered dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of T2DM.¹⁴ DPP-4 inhibitors block the metabolism and inactivation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, thereby increasing the concentrations of active forms of these hormones, resulting in increased insulin secretion and suppression of

Trial design

TECOS is a randomized, double-blind, controlled trial comparing sitagliptin and placebo when added to best usual care in patients with T2DM and cardiovascular disease. Participants, healthcare providers, data collectors, event adjudicators, the sponsor, and the sponsor’s academic partners are blinded to participants’ assigned therapy.

Trial population

TECOS will enroll approximately 14,000 participants from 38 countries. Sites are distributed with the aim of enrolling one third of participants from each of

Discussion

TECOS is a pragmatic-design, randomized, international, double-blind, placebo-controlled clinical outcomes trial assessing the cardiovascular impact of sitagliptin when added to the usual management of T2DM. Given cardiovascular safety concerns raised in relation to some other classes of antihyperglycemic therapies, this is a timely assessment of the first-in-class DPP-4 inhibitor in accordance with recent FDA and EMA guidances.12., 13.

Although TECOS will first assess sitagliptin for

Disclosures

Conflicts of Interest. JBG reports receiving institutional research support from Amylin (now BMS) and Merck and compensation for lectures and consulting from Merck and Takeda. MAB reports research support from Merck, Amylin, Lilly, Novartis, and Bayer. S.P. has acted as consultant and speaker for Novartis and Amylin and received grants supporting clinical studies from Merck, Novo Nordisk, Pfizer, Amylin and Hospira. AR reports no potential conflicts of interest. KDK and DRS are employees of and

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Cited by (117)

Pleiotropic effects of anti-diabetic drugs: A comprehensive review
2020, European Journal of Pharmacology
Citation Excerpt :
To the best of our knowledge, four clinical studies for analysing cardiovascular safety of DPP-4 inhibitors have been completed and published. The EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin vs. Standard of Care) study for alogliptin (Cannon et al., 2013; White et al., 2011), the Savor-TIMI-53 study (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) for saxagliptin (Mosenzon et al., 2013; Scirica et al., 2013), the TECOS study (Trial Evaluating Cardiovascular Outcomes With Sitagliptin) for sitagliptin (Green et al., 2013, 2015) and the CARMELINA study (Cardiovascular safety and Clinical Outcome with Linagliptin) for linagliptin (Aroor et al., 2018; Rosenstock et al., 2019) are the four studies which have shown homogenous results for cardiovascular safety profile. However, a significant increase in rate of hospitalization due to heart failure was seen in the Savor-TIMI-53 study conducted for saxagliptin (Scirica et al., 2013), thereby restricting its use in patients with heart failure (Gallwitz, 2019).
Diabetes mellitus characterized by hyperglycaemia presents an array of comorbidities such as cardiovascular and renal failure, dyslipidemia, and cognitive impairments. Populations above the age of 60 are in an urgent need of effective therapies to deal with the complications associated with diabetes mellitus. Widely used anti-diabetic drugs have good safety profiles and multiple reports indicate their pleiotropic effects in diabetic patients or models. This review has been written with the objective of identifying the widely-marketed anti-diabetic drugs which can be efficiently repurposed for the treatment of other diseases or disorders. It is an updated, comprehensive review, describing the protective role of various classes of anti-diabetic drugs in mitigating the macro and micro vascular complications of diabetes mellitus, and differentiating these drugs on the basis of their mode of action. Notably, metformin, the anti-diabetic drug most commonly explored for cancer therapy, has also exhibited some antimicrobial effects. Unlike class specific effects, few instances of drug specific effects in managing cardiovascular complications have also been reported. A major drawback is that the pleiotropic effects of anti-diabetic drugs have been mostly investigated only in diabetic patients. Thus, for effective repurposing, more clinical trials devoted to analyse the effects of anti-diabetic drugs in patients irrespective of their diabetic condition, are required.
Low-density lipoprotein cholesterol treatment and outcomes in patients with type 2 diabetes and established cardiovascular disease: Insights from TECOS
2020, American Heart Journal
Type 2 diabetes (T2D) patients are at increased risk for cardiovascular (CV) events. Most guidelines recommend treating low-density lipoprotein cholesterol (LDL-C) levels to ≤70 mg/dL (1.8 mM) for patients with T2D and established atherosclerotic CV disease, and some a more aggressive target of ≤55 mg/dL (1.4 mM). Our objective was to assess the degree to which these LDL-C targets are achieved in routine practice.
Using data from TECOS, an international pragmatic CV outcomes trial of sitagliptin vs placebo, we assessed lipid-lowering treatment among patients with T2D and CV disease, baseline lipid values, and the association between baseline LDL-C and 5-year risk for major adverse cardiac events (MACE; ie, CV death, nonfatal myocardial infarction, or nonfatal stroke).
Overall, 11,066 of 14,671 TECOS participants (75.4%) had LDL-C measured at baseline. Median age was 65 years, 72% were male, and median T2D duration was 10 years. Overall, 82.5% of patients were on statins; only 5.8% were on ezetimibe. At baseline, 14.3% had LDL-C ≤55 mg/dL, 18.4% between 55.1 and 70 mg/dL, 35% between 70.1 and 100 mg/dL, and 32.3% >100 mg/dL. Each 10 mg/dL higher LDL-C value was associated with a higher risk of MACE (HR 1.05, 95% CI 1.03–1.07) or CV death (HR 1.06, 95% CI 1.04–1.09).
Although most high-risk patients with T2D and CV disease were on lipid-lowering therapy, only 1:3 had LDL-C <70 mg/dL and 1:6 had LDL-C <55 mg/dL. Each 10 mg/dL higher LDL-C value was associated with a 5% and 6% higher 5-year incidence of MACE and CV death, respectively. (TECOS, NCT00790205).
Association of obesity with cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease: Insights from TECOS
2020, American Heart Journal
Citation Excerpt :
Details of the TECOS (ClinicalTrials.gov: NCT00790205) design have been previously described.34
Obesity is a risk factor for type 2 diabetes (T2D) and cardiovascular disease (CVD). Whether obesity affects outcomes among those with T2D and atherosclerotic CVD (ASCVD) remains uncertain. Our objective was to investigate the relationship between body mass index (BMI) and ASCVD outcomes among TECOS participants with T2D and ASCVD.
BMI categories were defined as underweight/normal weight (BMI <25 kg/m²), overweight (25-29.9 kg/m²), obese class I (30-34.9 kg/m²), obese class II (35-39.9 kg/m²), and obese class III (≥ 40 kg/m²). Asian-specific BMI categories were applied to Asian participants. Kaplan-Meier survival analysis and Cox proportional hazards models were used to examine associations between baseline BMI and a composite CV outcome (CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina).
For 14,534 TECOS patients with available BMI, mean age was 65.5 years; 29.3% were female, 32.0% non-White, and 23.1% insulin-treated, with median 3 years' follow-up. At baseline, 11.6% (n = 1686) were underweight/normal weight, 38.1% (n = 5532) overweight, 32.2% (n = 4683) obese class I, 12.4% (n = 1806) obese class II, and 5.7% (n = 827) obese class III. The composite CV outcome occurred in 11.4% (n = 1663) of participants; the outcome risk was lower, compared with under/normal weight, in overweight (HR 0.83, 95% CI 0.71-0.98) and obese class I (HR 0.79, 95% CI 0.67-0.93) individuals. Obesity was not associated with worse glycemic control.
The majority of TECOS participants with ASCVD and T2D were overweight or obese, yet overweight or obese class I individuals had lower CV risk than those who were under/normal weight. These results suggest the presence of an obesity paradox, but this paradox may reflect an epidemiological artifact rather than a true negative association between normal weight and clinical outcomes.
Associations between β-blocker therapy and cardiovascular outcomes in patients with diabetes and established cardiovascular disease
2019, American Heart Journal
Citation Excerpt :
TECOS was a randomized, double-blind, multinational clinical trial of sitagliptin or placebo in addition to usual care in patients ≥50 years of age with T2D and established ASCVD (coronary artery disease, ischemic cerebrovascular disease, and/or atherosclerotic peripheral arterial disease) conducted between December 2008 and March 2015. Details of the TECOS trial design and its main outcomes have been previously published.17,18 The protocol was approved by ethics committees associated with all TECOS sites, and all participants provided written informed consent for trial participation.
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).
International variation in characteristics and clinical outcomes of patients with type 2 diabetes and heart failure: Insights from TECOS
2019, American Heart Journal
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.
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).
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.
Antithrombotic treatment gap among patients with atrial fibrillation and type 2 diabetes
2019, International Journal of Cardiology
We 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).
TECOS 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.
Of 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.
Almost 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.

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: James A. de Lemos, MD, served as guest editor for this article.

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

Section snippets

TECOS: an overview

Trial design

Trial population

Discussion

Disclosures

J Nutrition Metab Cardiovasc Dis

J Nutr Metab Cardiovasc Dis

Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Interventional Trial

Diabetes Care

Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23)

BMJ

Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies

Lancet

The effect of intensive diabetes treatment on the development and progression of long-term complications in insulin-dependent diabetes mellitus

N Engl J Med

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

Lancet

for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in type 1 diabetes mellitus

N Engl J Med

10-year follow-up of intensive glucose control in type 2 diabetes

N Engl J Med

Intensive glucose control and macrovascular outcomes in type 2 diabetes

Diabetologia

Effects of intensive glucose lowering in type 2 diabetes

N Engl J Med

Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes

N Engl J Med

Guideline on clinical investigation of medicinal products in the treatment of diabetes mellitus

Trial Design
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