Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial

Diabetologia. 2012 Jan;55(1):36-45. doi: 10.1007/s00125-011-2357-4. Epub 2011 Oct 29.


Aims/objective: Conflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial aimed to assess the effects of TZDs (rosiglitazone and pioglitazone) on cardiovascular outcomes and the effects of vitamin D (cholecalciferol) on cancers and mortality.

Methods: A large multicentre 3 × 2 factorial double-blind placebo-controlled randomised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged ≥ 50 years whose HbA(1c) was 6.5-9.5% (48-80 mmol/mol) when using two or fewer glucose-lowering drugs were randomised by a central computer system to placebo (n = 541), rosiglitazone 4-8 mg/day (n = 399) or pioglitazone 30-45 mg/day (n = 392); 1,221 participants were randomised to placebo (n = 614) or vitamin D 1,000 IU/day (n = 607). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infarction, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All randomised participants were included in the primary analysis.

Results: From the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants (0.9%) in the placebo groups and three participants (0.4%) in the TZD groups (two allocated to pioglitazone, one to rosiglitazone). In the vitamin D arm, the primary outcome occurred in three participants (0.5%) in the placebo group and in two participants (0.3%) receiving vitamin D. Adverse events were comparable in all groups.

Conclusions/interpretation: Uncertainty persists regarding the clinically relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial.

Trial registration: NCT00879970.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cardiovascular Diseases / complications
  • Cardiovascular Diseases / epidemiology
  • Cardiovascular Diseases / prevention & control
  • Cholecalciferol / adverse effects
  • Cholecalciferol / therapeutic use*
  • Combined Modality Therapy
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / diet therapy*
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dietary Supplements*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Early Termination of Clinical Trials
  • Female
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / therapeutic use*
  • Incidence
  • Male
  • Middle Aged
  • Neoplasms / complications
  • Neoplasms / epidemiology
  • Neoplasms / prevention & control
  • Pioglitazone
  • Risk Factors
  • Rosiglitazone
  • Thiazolidinediones / administration & dosage
  • Thiazolidinediones / adverse effects
  • Thiazolidinediones / therapeutic use*


  • Hypoglycemic Agents
  • Thiazolidinediones
  • Rosiglitazone
  • Cholecalciferol
  • Pioglitazone

Associated data