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

Z Punthakee; J Bosch; G Dagenais; Ricardo Gredilla Diaz; R Holman; J L Probstfield; A Ramachandran; M C Riddle; L E Rydén; B Zinman; R Afzal; S Yusuf; H C Gerstein; TIDE Trial Investigators; Christian Tobias Torp-Pedersen

doi:10.1007/s00125-011-2357-4

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

Z Punthakee, J Bosch, G Dagenais, Ricardo Gredilla Diaz, R Holman, J L Probstfield, A Ramachandran, M C Riddle, L E Rydén, B Zinman, R Afzal, S Yusuf, H C Gerstein, TIDE Trial Investigators, Christian Tobias Torp-Pedersen

39 Citations (Scopus)

Abstract

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 HbA1c 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.

Original language	English
Journal	Diabetologia
Volume	55
Issue number	1
Pages (from-to)	36-45
Number of pages	10
ISSN	0012-186X
DOIs	https://doi.org/10.1007/s00125-011-2357-4
Publication status	Published - Jan 2012

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Punthakee, Z., Bosch, J., Dagenais, G., Diaz, R. G., Holman, R., Probstfield, J. L., Ramachandran, A., Riddle, M. C., Rydén, L. E., Zinman, B., Afzal, R., Yusuf, S., Gerstein, H. C., TIDE Trial Investigators, & Torp-Pedersen, C. T. (2012). Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial. Diabetologia, 55(1), 36-45. https://doi.org/10.1007/s00125-011-2357-4

Punthakee, Z, Bosch, J, Dagenais, G, Diaz, RG, Holman, R, Probstfield, JL, Ramachandran, A, Riddle, MC, Rydén, LE, Zinman, B, Afzal, R, Yusuf, S, Gerstein, HC, TIDE Trial Investigators & Torp-Pedersen, CT 2012, 'Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial', Diabetologia, vol. 55, no. 1, pp. 36-45. https://doi.org/10.1007/s00125-011-2357-4

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

abstract = "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 HbA1c 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.",

author = "Z Punthakee and J Bosch and G Dagenais and Diaz, {Ricardo Gredilla} and R Holman and Probstfield, {J L} and A Ramachandran and Riddle, {M C} and Ryd{\'e}n, {L E} and B Zinman and R Afzal and S Yusuf and Gerstein, {H C} and Torp-Pedersen, {Christian Tobias} and Torp-Pedersen, {Christian Tobias}",

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T1 - Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial

AU - Punthakee, Z

AU - Bosch, J

AU - Dagenais, G

AU - Diaz, Ricardo Gredilla

AU - Holman, R

AU - Probstfield, J L

AU - Ramachandran, A

AU - Riddle, M C

AU - Rydén, L E

AU - Zinman, B

AU - Afzal, R

AU - Yusuf, S

AU - Gerstein, H C

AU - TIDE Trial Investigators

AU - Torp-Pedersen, Christian Tobias

PY - 2012/1

Y1 - 2012/1

N2 - 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 HbA1c 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.

AB - 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 HbA1c 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.

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DO - 10.1007/s00125-011-2357-4

M3 - Journal article

C2 - 22038523

SN - 0012-186X

VL - 55

SP - 36

EP - 45

JO - Diabetologia

JF - Diabetologia

IS - 1

ER -

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

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