PROactive: Time for a Critical Appraisal
PROactive: Time for a Critical Appraisal
The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) remains the only completed cardiovascular (CV) outcomes study with a thiazolidinedione. It has provided valuable information on the impact of pioglitazone on CV outcomes in a high-risk population of patients with type 2 diabetes and established macrovascular disease. The investigators in PROactive chose a challenging primary composite endpoint that included events in multiple vascular beds (cerebral, cardiac, and peripheral), as well as both disease-related and procedural endpoints. They also pre-specified a more conventional main secondary composite endpoint of all-cause mortality, myocardial infarction, and stroke. Since the results of PROactive were first presented, there has been much debate on the relative merits of the statistically non-significant 10% decrease in the primary endpoint vs. the statistically significant 16% decrease in the main secondary endpoint seen with pioglitazone. However, PROactive includes more information than just these two main endpoints and has provided an extensive safety data set, as well as new insights into the impact of pioglitazone in different patient subpopulations. In this article, we consider all the results from PROactive presented to date and offer our own appraisal of how these findings shape the CV efficacy and safety profile of pioglitazone.
Type 2 diabetes mellitus (T2DM) markedly increases the risk of cardiovascular disease (CVD), including myocardial infarction (MI), stroke, peripheral vascular disease, and CV death. Patients with T2DM who have not previously experienced an MI are more likely to experience an MI than non-diabetic individuals who have had a previous MI. Thus, the importance of reducing CV risk in people with T2DM is well established.
Although both primary and secondary intervention studies with metformin, antihypertensives, or statins in people with diabetes and/or CVD show consistent improvements in CV outcomes in people with T2DM, they also reveal a significant residual risk compared with those without diabetes (for review, see reference 21). Furthermore, improvements in long-term mortality after a CV event have been harder to achieve in people with diabetes. This underscores the need for better strategies and novel interventions in this high-risk patient group.
In addition to hyperglycaemia, dyslipidaemia, hypertension, obesity (especially visceral), endothelial dysfunction, and hypercoaguability, multiple prospective studies have demonstrated that insulin resistance per se is an independent risk factor for atherosclerotic CVD. At the molecular level, impaired insulin signalling is a characteristic feature of T2DM, obesity, hypertension, and dyslipidaemia (Figure 1). Despite the defect in insulin-stimulated glucose uptake in skeletal and arterial smooth muscle, the MAP kinase pathway retains normal sensitivity to insulin, and the compensatory hyperinsulinaemia (to the underlying insulin resistance) leads to the stimulation of multiple pathways involved in the development of atherosclerosis. Because thiazolidinediones are the only glucose-lowering agents that improve insulin signalling/sensitivity in muscle and inhibit the MAP kinase pathway, while improving dyslipidaemia, reducing elevated blood glucose levels, inhibiting inflammation (decreased hsCRP), enhancing endothelial function, and ameliorating the hypercoaguable state, thiazolidinediones may provide an opportunity to address the excess burden of atherosclerotic disease in this high-risk group. Individual thiazolidinediones have beneficial, but differing, effects on established and emerging risk factors for CVD. For example, there is a notable difference between the two currently approved thiazolidinediones on their effect on lipids. Thus, rosiglitazone increases LDL cholesterol and apo B100 and tends to raise triglycerides, whereas pioglitazone is neutral with respect to LDL cholesterol, lowers apo B100, and reduces plasma triglyceride levels. Pioglitazone also is more effective in raising HDL cholesterol and converting LDL lipid subfractions to larger, more buoyant particles, possibly due to a decrease in atherogenic Apo B particles (each LDL particle contains one Apo B particle).
(Enlarge Image)
Figure 1.
Insulin signal transduction system.
The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) was designed to ascertain whether the potential metabolic and CV benefits described earlier for pioglitazone would translate into a significant reduction in the risk of macrovascular events in patients with type 2 diabetes and established macrovascular disease (MI, stroke, prior coronary intervention procedure, acute coronary syndrome (ACS), other objective evidence of coronary artery disease, or obstructive arterial disease in the leg) above and beyond the benefit achieved with that obtained with a regimen adherent to contemporary guidelines for the treatment of hyperglycaemia, hypertension, dyslipidaemia, etc. The underlying hypothesis in PROactive was that pioglitazone would confer benefits in multiple vascular beds (i.e. cerebral, cardiac, and peripheral) beyond standard guideline-driven therapy. These considerations reflected the choice of the primary composite endpoint. Another key objective of PROactive was to characterize further the safety of pioglitazone in this high-risk T2DM population.
As a double blind, randomized, placebo-controlled study with only one interventional therapy (pioglitazone), it was anticipated that PROactive would provide an answer to the question—does treatment with pioglitazone improve macrovascular outcomes over and above guideline-driven therapy? However, both the statistical and clinical significance of the macrovascular benefit of pioglitazone reported in PROactive have been—and continue to be—an area of active debate. In this article, we provide our appraisal of the key findings from PROactive now that further analyses have been made available to address some of the unanswered questions that have arisen since PROactive was first presented.
Abstract and Introduction
Abstract
The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) remains the only completed cardiovascular (CV) outcomes study with a thiazolidinedione. It has provided valuable information on the impact of pioglitazone on CV outcomes in a high-risk population of patients with type 2 diabetes and established macrovascular disease. The investigators in PROactive chose a challenging primary composite endpoint that included events in multiple vascular beds (cerebral, cardiac, and peripheral), as well as both disease-related and procedural endpoints. They also pre-specified a more conventional main secondary composite endpoint of all-cause mortality, myocardial infarction, and stroke. Since the results of PROactive were first presented, there has been much debate on the relative merits of the statistically non-significant 10% decrease in the primary endpoint vs. the statistically significant 16% decrease in the main secondary endpoint seen with pioglitazone. However, PROactive includes more information than just these two main endpoints and has provided an extensive safety data set, as well as new insights into the impact of pioglitazone in different patient subpopulations. In this article, we consider all the results from PROactive presented to date and offer our own appraisal of how these findings shape the CV efficacy and safety profile of pioglitazone.
Introduction: Rationale for the PROactive Study
Type 2 diabetes mellitus (T2DM) markedly increases the risk of cardiovascular disease (CVD), including myocardial infarction (MI), stroke, peripheral vascular disease, and CV death. Patients with T2DM who have not previously experienced an MI are more likely to experience an MI than non-diabetic individuals who have had a previous MI. Thus, the importance of reducing CV risk in people with T2DM is well established.
Although both primary and secondary intervention studies with metformin, antihypertensives, or statins in people with diabetes and/or CVD show consistent improvements in CV outcomes in people with T2DM, they also reveal a significant residual risk compared with those without diabetes (for review, see reference 21). Furthermore, improvements in long-term mortality after a CV event have been harder to achieve in people with diabetes. This underscores the need for better strategies and novel interventions in this high-risk patient group.
In addition to hyperglycaemia, dyslipidaemia, hypertension, obesity (especially visceral), endothelial dysfunction, and hypercoaguability, multiple prospective studies have demonstrated that insulin resistance per se is an independent risk factor for atherosclerotic CVD. At the molecular level, impaired insulin signalling is a characteristic feature of T2DM, obesity, hypertension, and dyslipidaemia (Figure 1). Despite the defect in insulin-stimulated glucose uptake in skeletal and arterial smooth muscle, the MAP kinase pathway retains normal sensitivity to insulin, and the compensatory hyperinsulinaemia (to the underlying insulin resistance) leads to the stimulation of multiple pathways involved in the development of atherosclerosis. Because thiazolidinediones are the only glucose-lowering agents that improve insulin signalling/sensitivity in muscle and inhibit the MAP kinase pathway, while improving dyslipidaemia, reducing elevated blood glucose levels, inhibiting inflammation (decreased hsCRP), enhancing endothelial function, and ameliorating the hypercoaguable state, thiazolidinediones may provide an opportunity to address the excess burden of atherosclerotic disease in this high-risk group. Individual thiazolidinediones have beneficial, but differing, effects on established and emerging risk factors for CVD. For example, there is a notable difference between the two currently approved thiazolidinediones on their effect on lipids. Thus, rosiglitazone increases LDL cholesterol and apo B100 and tends to raise triglycerides, whereas pioglitazone is neutral with respect to LDL cholesterol, lowers apo B100, and reduces plasma triglyceride levels. Pioglitazone also is more effective in raising HDL cholesterol and converting LDL lipid subfractions to larger, more buoyant particles, possibly due to a decrease in atherogenic Apo B particles (each LDL particle contains one Apo B particle).
(Enlarge Image)
Figure 1.
Insulin signal transduction system.
The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) was designed to ascertain whether the potential metabolic and CV benefits described earlier for pioglitazone would translate into a significant reduction in the risk of macrovascular events in patients with type 2 diabetes and established macrovascular disease (MI, stroke, prior coronary intervention procedure, acute coronary syndrome (ACS), other objective evidence of coronary artery disease, or obstructive arterial disease in the leg) above and beyond the benefit achieved with that obtained with a regimen adherent to contemporary guidelines for the treatment of hyperglycaemia, hypertension, dyslipidaemia, etc. The underlying hypothesis in PROactive was that pioglitazone would confer benefits in multiple vascular beds (i.e. cerebral, cardiac, and peripheral) beyond standard guideline-driven therapy. These considerations reflected the choice of the primary composite endpoint. Another key objective of PROactive was to characterize further the safety of pioglitazone in this high-risk T2DM population.
As a double blind, randomized, placebo-controlled study with only one interventional therapy (pioglitazone), it was anticipated that PROactive would provide an answer to the question—does treatment with pioglitazone improve macrovascular outcomes over and above guideline-driven therapy? However, both the statistical and clinical significance of the macrovascular benefit of pioglitazone reported in PROactive have been—and continue to be—an area of active debate. In this article, we provide our appraisal of the key findings from PROactive now that further analyses have been made available to address some of the unanswered questions that have arisen since PROactive was first presented.
