Lancet 2006; 367:25-26
RR Holman, R Retnakaran, A Farmer and R Stevens
The PROactive study 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, 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, 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. 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. 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, 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 patients and it remains the first-line agent of choice recommended by most treatment guidelines.