PROactive study
2006; Elsevier BV; Volume: 367; Issue: 9504 Linguagem: Inglês
10.1016/s0140-6736(06)67914-2
ISSN1474-547X
AutoresR Holman, Ravi Retnakaran, Andrew Farmer, Richard Stevens,
Tópico(s)Diabetes Treatment and Management
ResumoThe PROactive study1Dormandy JA Charbonnel B Eckland DJA et al.on behalf of the PROactive investigatorsSecondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.Lancet. 2005; 366: 1279-1289Summary Full Text Full Text PDF PubMed Scopus (3648) Google Scholar has provided an exploratory estimate of the relative risk reduction attributable to pioglitazone for a composite endpoint of all-cause mortality, non-fatal myocardial infarction, and stroke. Although this secondary endpoint was not prespecified and is not significant when adjusted for multiple testing,2Freemantle N How well does the evidence on pioglitazone back up researchers' claims for a reduction in macrovascular events.BMJ. 2005; 331: 836-838Crossref PubMed Scopus (42) Google Scholar it is of interest because of the possibility that the observed 16% relative risk reduction might not be mediated through established macrovascular risk factors such as blood pressure, lipids, and glycaemia.We have used the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model,3Clarke PM Gray AM Briggs A et al.A model to estimate the lifetime health outcomes of patients with type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model (UKPDS 68).Diabetologia. 2004; 47: 1747-1759Crossref PubMed Scopus (457) Google Scholar which can simulate health outcomes for patients with type 2 diabetes on the basis of their initial characteristics and changes in risk factors over time, to assess expected PROactive outcomes given the reported risk factor changes. We computer-generated a cohort matched for baseline characteristics (age, ethnic origin, sex, body-mass index, glycosylated haemoglobin [HbA1c], lipids, blood pressure, smoking status, and peripheral vascular disease) to the PROactive study participants.1Dormandy JA Charbonnel B Eckland DJA et al.on behalf of the PROactive investigatorsSecondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.Lancet. 2005; 366: 1279-1289Summary Full Text Full Text PDF PubMed Scopus (3648) Google Scholar, 4Charbonnel B Normandy JA Erdmann E Massi-Benedetti Skene A The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients.Diabetes Care. 2004; 27: 1647-1653Crossref PubMed Scopus (235) Google Scholar The outcomes model then estimated likely 3-year differences in rates of secondary endpoints and congestive heart failure that would be associated with the noted 0·5% decrease in HbA1c, 3 mm Hg reduction in systolic blood pressure, 0·10 mmol/L increase in HDL cholesterol, and 4·0 kg increase in bodyweight compared with placebo. Because the current model does not simulate repeat macrovascular events, outcomes were estimated for the subgroup of patients in PROactive with baseline ischaemic heart disease but not previous myocardial infarction or stroke.The relative risk reduction of 13% obtained with respect to the secondary endpoint was well within the 95% CI (2–28%) seen in PROactive. Sensitivity analyses adjusting for baseline differences between PROactive study groups, applying changes in HbA1c, systolic blood pressure, HDL cholesterol, and weight in proportion to baseline values, or applying treatment effects gradually over the first year, gave similar results (relative risk reductions of 14%, 12%, and 11%, respectively). The model-estimated 11% favourable relative risk reduction in congestive heart failure associated with the reported risk factor changes contrasts sharply with the 39% relative risk increase (p=0·007) in heart failure needing hospital admission seen with pioglitazone in the PROactive study.The non-significant 10% relative risk reduction seen with pioglitazone for the PROactive primary cardiovascular endpoint was substantially less than the 20% or more on which Dormandy and colleagues based their power calculation.4Charbonnel B Normandy JA Erdmann E Massi-Benedetti Skene A The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients.Diabetes Care. 2004; 27: 1647-1653Crossref PubMed Scopus (235) Google Scholar Our analysis supports the explanation that any macrovascular benefits seen reflect the modest improvements obtained in established risk factors, with little evidence that changes seen previously in novel risk factors with pioglitazone have any substantive effect. More worryingly, the estimated macrovascular benefits are offset by an increased risk of heart failure and concerns about increased peripheral revascularisation rates.In the primary prospective analysis of 753 overweight patients randomly assigned metformin or dietary treatment after diagnosis of type 2 diabetes in the UKPDS,5UKPDS GroupEffect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).Lancet. 1998; 352: 854-865Summary Full Text Full Text PDF PubMed Scopus (7398) Google Scholar metformin was associated with a 39% relative risk reduction in myocardial infarction (p=0·010) and 36% relative risk reduction in all-cause mortality (p=0·011), effects not thought to be mediated through established risk factors. Metformin is the only antidiabetic agent that has been shown definitively to reduce macrovascular risk in overweight type 2 diabetic patients5UKPDS GroupEffect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).Lancet. 1998; 352: 854-865Summary Full Text Full Text PDF PubMed Scopus (7398) Google Scholar and it remains the first-line agent of choice recommended by most treatment guidelines.RS has received a speaker's honorarium from Takeda. The other authors declare that they have no conflict of interest. The PROactive study1Dormandy JA Charbonnel B Eckland DJA et al.on behalf of the PROactive investigatorsSecondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.Lancet. 2005; 366: 1279-1289Summary Full Text Full Text PDF PubMed Scopus (3648) Google Scholar has provided an exploratory estimate of the relative risk reduction attributable to pioglitazone for a composite endpoint of all-cause mortality, non-fatal myocardial infarction, and stroke. Although this secondary endpoint was not prespecified and is not significant when adjusted for multiple testing,2Freemantle N How well does the evidence on pioglitazone back up researchers' claims for a reduction in macrovascular events.BMJ. 2005; 331: 836-838Crossref PubMed Scopus (42) Google Scholar it is of interest because of the possibility that the observed 16% relative risk reduction might not be mediated through established macrovascular risk factors such as blood pressure, lipids, and glycaemia. We have used the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model,3Clarke PM Gray AM Briggs A et al.A model to estimate the lifetime health outcomes of patients with type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model (UKPDS 68).Diabetologia. 2004; 47: 1747-1759Crossref PubMed Scopus (457) Google Scholar which can simulate health outcomes for patients with type 2 diabetes on the basis of their initial characteristics and changes in risk factors over time, to assess expected PROactive outcomes given the reported risk factor changes. We computer-generated a cohort matched for baseline characteristics (age, ethnic origin, sex, body-mass index, glycosylated haemoglobin [HbA1c], lipids, blood pressure, smoking status, and peripheral vascular disease) to the PROactive study participants.1Dormandy JA Charbonnel B Eckland DJA et al.on behalf of the PROactive investigatorsSecondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.Lancet. 2005; 366: 1279-1289Summary Full Text Full Text PDF PubMed Scopus (3648) Google Scholar, 4Charbonnel B Normandy JA Erdmann E Massi-Benedetti Skene A The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients.Diabetes Care. 2004; 27: 1647-1653Crossref PubMed Scopus (235) Google Scholar The outcomes model then estimated likely 3-year differences in rates of secondary endpoints and congestive heart failure that would be associated with the noted 0·5% decrease in HbA1c, 3 mm Hg reduction in systolic blood pressure, 0·10 mmol/L increase in HDL cholesterol, and 4·0 kg increase in bodyweight compared with placebo. Because the current model does not simulate repeat macrovascular events, outcomes were estimated for the subgroup of patients in PROactive with baseline ischaemic heart disease but not previous myocardial infarction or stroke. The relative risk reduction of 13% obtained with respect to the secondary endpoint was well within the 95% CI (2–28%) seen in PROactive. Sensitivity analyses adjusting for baseline differences between PROactive study groups, applying changes in HbA1c, systolic blood pressure, HDL cholesterol, and weight in proportion to baseline values, or applying treatment effects gradually over the first year, gave similar results (relative risk reductions of 14%, 12%, and 11%, respectively). The model-estimated 11% favourable relative risk reduction in congestive heart failure associated with the reported risk factor changes contrasts sharply with the 39% relative risk increase (p=0·007) in heart failure needing hospital admission seen with pioglitazone in the PROactive study. The non-significant 10% relative risk reduction seen with pioglitazone for the PROactive primary cardiovascular endpoint was substantially less than the 20% or more on which Dormandy and colleagues based their power calculation.4Charbonnel B Normandy JA Erdmann E Massi-Benedetti Skene A The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients.Diabetes Care. 2004; 27: 1647-1653Crossref PubMed Scopus (235) Google Scholar Our analysis supports the explanation that any macrovascular benefits seen reflect the modest improvements obtained in established risk factors, with little evidence that changes seen previously in novel risk factors with pioglitazone have any substantive effect. More worryingly, the estimated macrovascular benefits are offset by an increased risk of heart failure and concerns about increased peripheral revascularisation rates. In the primary prospective analysis of 753 overweight patients randomly assigned metformin or dietary treatment after diagnosis of type 2 diabetes in the UKPDS,5UKPDS GroupEffect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).Lancet. 1998; 352: 854-865Summary Full Text Full Text PDF PubMed Scopus (7398) Google Scholar metformin was associated with a 39% relative risk reduction in myocardial infarction (p=0·010) and 36% relative risk reduction in all-cause mortality (p=0·011), effects not thought to be mediated through established risk factors. Metformin is the only antidiabetic agent that has been shown definitively to reduce macrovascular risk in overweight type 2 diabetic patients5UKPDS GroupEffect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).Lancet. 1998; 352: 854-865Summary Full Text Full Text PDF PubMed Scopus (7398) Google Scholar and it remains the first-line agent of choice recommended by most treatment guidelines. RS has received a speaker's honorarium from Takeda. The other authors declare that they have no conflict of interest. PROactive study – Authors' replyMark Goldstein raises the issue of bladder cancer in PROactive. The incidence of cancers overall was similar between groups, although imbalances in some categories of cancer were seen. For example, the incidence of breast cancer was significantly higher in the placebo group, whereas the incidence of bladder cancer was non-significantly higher with pioglitazone. Owing to the expected variability associated with the small number of cases in each cancer category, we did not conclude that pioglitazone protected against breast cancer. Full-Text PDF
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