Key result
Pioglitazone did not significantly reduce the primary composite of macrovascular events compared to placebo (19.7% vs 21.7%; HR 0.90; 95% CI 0.80-1.02; P=0.095).
Why the study?
Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke, and indirect evidence suggested PPAR gamma agonists could reduce macrovascular complications.
Does pioglitazone reduce macrovascular morbidity and mortality in high-risk patients with type 2 diabetes and prior macrovascular disease?
RCT (n=5,238)
Yes
Does pioglitazone reduce macrovascular morbidity and mortality in high-risk patients with type 2 diabetes and prior macrovascular disease?
Hazard Ratio: 0.9 (95% CI 0.8–1.02)
Absolute Event Rate: 19.7% vs 21.7%
p-value: p=0.095
In patients with type 2 diabetes and macrovascular disease, pioglitazone did not significantly reduce the broad primary composite outcome but significantly reduced a secondary hard composite of all-cause mortality, non-fatal MI, and stroke, alongside an increased risk of heart failure hospitalization.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Although the study is globally negative, a new 'main secondary endpoint' appeared—ie, a new composite not described in the study protocol published in 2004. The conclusions of the study are based solely on this composite.”
“The primary endpoint combining hard cardiovascular endpoints with procedure-dependent peripheral vascular endpoints did not reach statistical significance (a 10% reduction in seven combined vascular events was observed). However, arguably the more clinically pertinent secondary endpoint of death, non-fatal myocardial infarction and stroke showed a relative risk reduction of 16% (P=0.027).”
“some good news, some bad news, and some unknowns”
Pioglitazone misses primary macrovascular composite in high-risk T2D; challenges PPAR-γ agonist expectations and leaves open secondary benefits versus HF risk.
BACKGROUND: Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor gamma (PPAR gamma) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes. METHODS: We did a prospective, randomised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease. We recruited patients from primary-care practices and hospitals. We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), to be taken in addition to their glucose-lowering drugs and other medications. Our primary endpoint was the composite of all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN NCT00174993. FINDINGS: Two patients were lost to follow-up, but were included in analyses. The average time of observation was 34.5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0.90, 95% CI 0.80-1.02, p=0.095). The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0.84, 0.72-0.98, p=0.027). Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified. 6% (149 of 2065) and 4% (108 of 2633) of those in the pioglitazone and placebo groups, respectively, were admitted to hospital with heart failure; mortality rates from heart failure did not differ between groups. INTERPRETATION: Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events.
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Dormandy et al. (2005) conducted an RCT in Type 2 diabetes with evidence of macrovascular disease (n=5,238). Pioglitazone vs. Matching placebo was evaluated on Composite of all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle (HR 0.90, 95% CI 0.80-1.02, p=0.095). Pioglitazone did not significantly reduce the primary composite of macrovascular events compared to placebo (19.7% vs 21.7%; HR 0.90; 95% CI 0.80-1.02; P=0.095).
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