Secondary 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.

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.

Inverse relation of body weight and weight change with mortality and morbidity in patients with type 2 diabetes and cardiovascular co-morbidity: an analysis of the PROactive study population.

CONTEXT: Although weight reduction is a recommended goal in type 2 diabetes mellitus (T2DM), weight loss is linked to impaired survival in patients with some chronic cardiovascular diseases. OBJECTIVE: To assess the association of weight and weight change with mortality and non-fatal cardiovascular outcomes (hospitalisation, myocardial infarction and stroke) in T2DM patients with cardiovascular co-morbidity and the effect of pioglitazone-induced weight change on mortality. SETTING AND PARTICIPANTS: We assessed in a post hoc analysis body weight and weight change in relation to outcome in 5202 patients from the PROactive trial population who had T2DM and evidence of pre-existing cardiovascular disease. Patients were randomized to treatment with pioglitazone or placebo in addition to their concomitant glucose-lowering and cardiovascular medication. Mean follow up was 34.5 months. MAIN OUTCOME MEASURE: The impact of body weight and body weight change on all-cause mortality, cardiovascular mortality, on non-fatal cardiovascular events and on hospitalisation. RESULTS: The lowest mortality was seen in patients with BMI 30-35 kg/m(2) at baseline. In comparison to this (reference group), patients in the placebo group with BMI <22 kg/m(2) (Hazard Ratio (95% confidence intervals) 2.96 [1.27 to 6.86]; P=0.012) and BMI 22 to 25 kg/m(2) (HR 1.88 [1.11 to 3.21]; P=0.019) had a higher all-cause mortality. Weight loss was associated with increased total mortality (HR per 1% body weight: 1.13 [1.11 to 1.16]; P<0.0001), with increased cardiovascular mortality, all-cause hospitalisation and the composite of death, myocardial infarction and stroke. Weight loss of ≥7.5% body weight (seen in 18.3% of patients) was the strongest cut-point to predict impaired survival (multivariable adjusted HR 4.42 [3.30 to 5.94]. Weight gain was not associated with increased mortality. Weight gain in patients treated with pioglitazone (mean+4.0±6.1 kg) predicted a better prognosis (HR per 1% weight gain: 0.96 [0.92 to 1.00] P=0.037) compared to patients without weight gain. CONCLUSION: Among patients with T2DM and cardiovascular co-morbidity, overweight and obese patients had a lower mortality compared to patients with normal weight. Weight loss but not weight gain was associated with increased mortality and morbidity. There may be an "obesity paradox" in patients with type 2 diabetes and cardiovascular risk. The original PROactive trial is registered as an International Standard Randomized Controlled Trial (Number ISRCTN NCT00174993).

The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study.

OBJECTIVES: This analysis from the PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) study assesses the effects of pioglitazone on mortality and macrovascular morbidity in patients with type 2 diabetes and a previous myocardial infarction (MI). BACKGROUND: People with type 2 diabetes have an increased incidence of MI compared with the general population. Those with diabetes and MI have a worse prognosis than nondiabetic patients with cardiovascular disease. METHODS: The PROactive study was a prospective, multicenter, double-blind, placebo-controlled trial of 5,238 patients with type 2 diabetes and macrovascular disease. Patients were randomized to either pioglitazone or placebo in addition to their other glucose-lowering and cardiovascular medication. Treatment of diabetes, dyslipidemia, and hypertension was encouraged according to the International Diabetes Federation guidelines. Patients were followed for a mean of 2.85 years. The primary end point was the time to first occurrence of macrovascular events or death. Of the total cohort, the subgroup of patients who had a previous MI (n = 2,445 [46.7%]; n = 1,230 in the pioglitazone group and n = 1,215 in the placebo group) was evaluated using prespecified and post-hoc analyses. RESULTS: Pioglitazone had a statistically significant beneficial effect on the prespecified end point of fatal and nonfatal MI (28% risk reduction [RR]; p = 0.045) and acute coronary syndrome (ACS) (37% RR; p = 0.035). There was a 19% RR in the cardiac composite end point of nonfatal MI (excluding silent MI), coronary revascularization, ACS, and cardiac death (p = 0.033). The difference in the primary end point defined in the main PROactive study did not reach significance in the MI population (12% RR; p = 0.135). The rates of heart failure requiring hospitalization were 7.5% (92 of 1,230) with pioglitazone and 5.2% (63 of 1,215) with placebo. Fatal heart failure rates were similar (1.4% [17 of the 92] with pioglitazone versus 0.9% [11 of the 63] with placebo). CONCLUSIONS: In high-risk patients with type 2 diabetes and previous MI, pioglitazone significantly reduced the occurrence of fatal and nonfatal MI and ACS. (PROspective pioglitAzone Clinical Trial In macroVascular Events; http://www.clinicaltrials.gov/ct/show/NCT00174993?order = 1; ISRCTN NCT00174993).

Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08).

OBJECTIVE: PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) enrolled patients with type 2 diabetes and preexisting cardiovascular disease. These patients were at high risk for heart failure, so any therapeutic benefit could potentially be offset by risk of associated heart failure mortality. We analyzed the heart failure cases to assess the effects of treatment on morbidity and mortality after reports of serious heart failure. RESEARCH DESIGN AND METHODS: PROactive was an outcome study in 5,238 patients randomized to pioglitazone or placebo. Patients with New York Heart Association Class II-IV heart failure at screening were excluded. A serious adverse event of heart failure was defined as heart failure that required hospitalization or prolonged a hospitalization stay, was fatal or life threatening, or resulted in persistent significant disability or incapacity. Heart failure risk was evaluated by multivariate regression. RESULTS: More pioglitazone (5.7%) than placebo patients (4.1%) had a serious heart failure event during the study (P = 0.007). However, mortality due to heart failure was similar (25 of 2,605 [0.96%] for pioglitazone vs. 22 of 2,633 [0.84%] for placebo; P = 0.639). Among patients with a serious heart failure event, subsequent all-cause mortality was proportionately lower with pioglitazone (40 of 149 [26.8%] vs. 37 of 108 [34.3%] with placebo; P = 0.1338). Proportionately fewer pioglitazone patients with serious heart failure went on to have an event in the primary (47.7% with pioglitazone vs. 57.4% with placebo; P = 0.0593) or main secondary end point (34.9% with pioglitazone vs. 47.2% with placebo; P = 0.025). CONCLUSIONS: Although the incidence of serious heart failure was increased with pioglitazone versus placebo in the total PROactive population of patients with type 2 diabetes and macrovascular disease, subsequent mortality or morbidity was not increased in patients with serious heart failure.