TECOS

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Green JB, et al. "Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes". The New England Journal of Medicine. 2015. 373(3):232-242.
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Clinical Question

Among patients with type 2 diabetes and cardiovascular disease, does addition of sitagliptin to usual care increase the risk of adverse long-term cardiovascular events, compared to usual care only?

Bottom Line

Among patients with type 2 diabetes and cardiovascular disease, sitagliptin added to usual care did not increase the risk of major adverse cardiovascular events, hospitalization due to heart failure, or other adverse events.

Major Points

Concerns regarding the long-term cardiovascular safety of antihyperglycemic agents have been raised in several studies.[1] A meta-analysis published in 2007 suggested that rosiglitazone was associated with a significant increase in the risk of myocardial infarction (MI).[2] In 2009, the RECORD trial showed that addition of rosiglitazone to metformin or sulfonylurea significantly increased the risk of heart failure.[3]

Sitagliptin is a dipeptidyl peptidase 4 (DPP-4) inhibitor which increases the level of glucagon-like peptide‑1 and glucose-dependent insulinotropic polypeptide. The net effect is a reduction in glucagon level and increased insulin secretion. The SAVOR-TIMI 53 trial and EXAMINE trial showed that the DPP-4 inhibitors sitagliptin and alogliptin did not increase or decrease the risk of major adverse CV events. [4][5] However, the SAVOR-TIMI 53 showed that patients who received sitagliptin had a significantly higher rate of hospitalization for heart failure (3.5% vs. 2.8%; HR 1.27; 95% CI 1.07-1.51; P=0.007).

The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) randomized 14,671 patients with type 2 diabetes (T2DM) and cardiovascular (CV) disease to receive either sitagliptin or placebo added to their existing therapy. The primary outcome of the trial is the composite of CV mortality, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina. The primary outcome occurred in 11.4% of patients in the sitagliptin group as compared to 11.6% in placebo (HR 0.98; 95% CI 0.89-1.08; P=0.65 for superiority). Sitagliptin was non-inferior to placebo for the primary outcome (HR 0.98; 95% CI 0.88-1.09; P<0.001 for non-inferiority). Additionally, sitagliptin did not increase the rate of hospitalization due to heart failure, or other adverse outcomes including pancreatitis and pancreatic cancer.

The ongoing CARMELINA trial is examining the CV and renal safety of linagliptin in diabetic patients with high CV risk as compared to placebo.[6] In a similar group of patients, the ongoing CAROLINA study is assessing the CV safety of linaglitin compared to the sulfonylurea glimepiride.[7]

Guidelines

The 2018 American Diabetes Association Standards of Medical Care in Diabetes incorporate guidance based on the results of this study by classifying sitagliptin as a medication with neutral cardiovascular effects.

Design

  • Multicenter, double-blind, randomized, placebo-controlled trial[8]
  • N=14,735 (14,671 included in intention-to-treat analysis)
    • Sitagliptin (n=7,332)
    • Placebo (n=7,339)
  • Setting: 673 centres in 38 countries
  • Enrollment: 2008-2012
  • Median follow-up: 3 years
  • Analysis: non-inferiority
  • Primary outcome: CV mortality, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina

Population

Inclusion Criteria

  • Age ≥50 years
  • T2DM
    • Treated with stable doses of 1 or 2 oral antihyperglycemic agents (metformin, pioglitazone, or sulfonylurea) or insulin (with or without metformin) for ≥3 months prior to enrollment
    • HbA1c of 6.5-8.0%
  • CV disease defined as a history of major coronary artery disease, ischemic cerebrovascular disease, or atherosclerotic peripheral arterial disease (PAD).

Exclusion Criteria

  • Took DPP-4 inhibitor, glucagon-like peptide-1 receptor agonist, or thiazolidinedione other than pioglitazone 3 months prior to the trial
  • ≥2 episodes of severe hypoglycemia (requiring third-party assistance) 12 months prior to the trial
  • eGFR <30 ml/min/1.73m2at baseline

Baseline Characteristics

From patients in the sitagliptin group

  • Demographics: Age 65.4±7.9 years; Females 29.1%; White race 67.6%
  • BMI: 30.2±5.6 kg/m2
  • Duration of diabetes: 11.6±8.1 years; HbA1c: 7.2±0.5%
  • Treatment for diabetes:
    • Metformin: 81%
    • Sulfonylurea: 45.6%
    • Thiazolidinedione: 2.7%
    • Insulin: 23.5%
  • PMH: CV disease 73.6%; cerebrovascular disease 24.6%; PAD 16.6%; heart failure: 17.8%; Current or ex-smoker: 51.1%
  • BP: systolic 135±16.9 mm Hg; diastolic 77.1±10.3 mm Hg
  • Cholesterol: Total 166.1±44.8 mg/dL; LDL-C 91.2±63.8 mg/dL; HDL-C 43.5±12.0 mg/dL; Triglycerides 166.0±101.0 mg/dL
  • eGFR: 74.9±21.3 ml/min/1.73m2

Interventions

Randomized to receive add-on sitaglitpin or placebo in a 1:1 ratio in a double-blind manner

  • Sitagliptin dose was 100 mg daily or 50 mg daily if baseline eGFR was ≥30 and <50 ml/min/1.73m2
  • Open-label antihyperglycemic agents treatment was encouraged during the study, with the aim of achieving appropriate HbA1c target
  • Patients who experienced ≥2 hypoglycemic episodes between study visits discontinued the study medication
  • Overall, 26.1% of patients in the sitagliptin group and 27.5% of patients in the placebo group discontinued the study medication

Outcomes

Comparisons are sitagliptin vs. placebo. Results from intention-to-treat (ITT) population are reported unless otherwise specified

Primary Outcomes

CV mortality, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina
11.4% vs.11.6% (4.06/100 person-years vs. 4.17/100 person-years; HR in ITT population 0.98; 95% CI 0.89-1.08; P=0.65 for superiority)
9.6% vs. 9.6% (3.73/100 vs. 3.82/100 person-yr; HR in per-protocol analysis, 0.98; 95% CI 0.88-1.09; P<0.001 for non-inferiority)

Secondary Outcomes

CV mortality, nonfatal MI, nonfatal stroke
10.2% vs.10.2% (3.58/100 vs. 3.62/100 person-yr; HR in ITT population 0.99; 95% CI 0.89-1.10; P=0.84 for superiority)
8.4% vs. 8.3% (3.24/100 vs. 3.28/100 person-yr; HR in per-protocol analysis 0.99; 95% CI 0.89-1.11; P<0.001 for non-inferiority)
Hospitalization for heart failure
3.1% vs. 3.1% (1.07/100 vs. 1.09/100 person-yr; HR 1.00; 95% CI 0.83-1.20; P=0.98)
Hospitalization for heart failure or CV mortality
7.3% vs. 7.2% (2.54/100 vs. 2.50/100 person-yr; HR 1.02; 95% CI 0.90-1.15; P=0.74)
CV mortality
5.2% vs. 5.0% (1.72/100 vs. 1.67/100 person-yr; HR 1.03; 95% CI 0.89-1.19; P=0.71)
All-case mortality
7.5% vs. 7.3% (2.48/100 vs. 2.45/100 person-yr; HR 1.01; 95% CI 0.90-1.14; P=0.88)

Additional analysis

Mean HbA1c
at 4 months, the sitagliptin group had mean values of 0.4% lower than the placebo group. This difference narrowed subsequently (overall least-squares mean difference of −0.29% in sitagliptin group; 95% CI −0.32 to −0.27)
Requirement for additional antihyperglycemic agents
1591 vs. 2046 patients (HR 0.72; 95% CI 0.68-0.77; P<0.001)
Requirement for long-term insulin therapy
542 vs. 744 patients (HR 0.70; 95% CI 0.63-0.79; P<0.001)

Subgroup Analysis

For the primary outcome

BMI

  • <30 kg/m2: no difference
  • ≥30 kg/m2: favors sitagliptin
  • P-value for interaction 0.03

There were no significant interactions for age, gender, race, history of diabetes, use of sulfonylurea, metformin, thiazolidinedione, insulin, statins, ACE-i, diuretics, calcium channel blockers, beta-blockers and aspirin at baseline; systolic and diastolic BP, history of hypertension or heart failure, smoking status, renal function or HbA1c

Safety outcomes

Acute pancreatitis
0.3% vs. 0.2% (0.11/100 vs. 0.06/100 person-yr; HR 1.93; 95% CI 0.96-3.88; P=0.07)
Pancreatic cancer
0.1% vs 0.2% (0.04/100 vs. 0.07/100 person-yr; HR 0.66; 95% CI 0.28-1.51; P=0.32)
Severe hypoglycemia
2.2% vs 1.9% (0.78/100 vs. 0.70/100 person-yr; HR 1.12; 95% CI 0.89-1.40; P=0.33)

Infections

18.4% vs 17.7% (P=NS)

Death from non-CV cause

2.3% vs 2.3% (P=NS)

Serious adverse events

  • Gastrointestinal disorder: 1.8% vs 1.4% (P=NS)
  • Benign, malignant, or unspecified neoplasm: 4.7% vs. 5.1% (P=NS)
  • Injury, poisoning, or procedural complication: 2.0 vs. 1.8%

Criticisms

  • The patients recruited had moderate hyperglycemia. Additionally, those with severe renal insufficiency were excluded.[8]
  • There's a possible confounding effect on CV outcomes due to the greater use of antihyperglycemic agents in the placebo group (82.2% vs. 81% in the sitagliptin group; P=NS).[8]
  • There was limited data regarding the urinary albumin:creatinine ratio.[8]

Funding

Merck Sharp & Dohme

Further Reading

  1. Udell JA, Cavender MA, Bhatt DL, Chatterjee S, Farkouh ME, Scirica BM.Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol 2015;3:356-366
  2. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457-2471
  3. Home PD, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. The Lancet. 2009. 373(9681):2125-2135
  4. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-1326
  5. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327-1335
  6. CARMELINA: A Multicenter, International, Randomized, Parallel Group, Double-blind, Placebo-controlled, Cardiovascular Safety and Renal Microvascular Outcome Study With Linagliptin, 5 mg Once Daily in Patients With Type 2 Diabetes Mellitus at High Vascular Risk. In: ClinicalTrials.gov [Internet. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2015 Dec 05]. Available from: https://clinicaltrials.gov/ct2/show/NCT01243424 NLM Identifier: NCT01243424]
  7. A Multicentre, International, Randomised, Parallel Group, Double Blind Study to Evaluate Cardiovascular Safety of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes Mellitus at High Cardiovascular Risk. In: ClinicalTrials.gov [Internet. Bethesda (MD): National Library of Medicine (US). 2000- [2015 Dec 05]. Available from: https://clinicaltrials.gov/ct2/show/NCT01243424 NLM Identifier: NCT01243424]
  8. 8.0 8.1 8.2 8.3 Green JB, Bethel MA, Paul SK, et al. 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. Am Heart J 2013;166:983.e7-989.e7