Pioglitazone in Combination with Insulin – An Overview of Results from PROactive
Table 1: Baseline Characteristics of Participants in PROactive According to Baseline Insulin Use Receiving Insulin at Baseline
Male (n) Age (years)
Duration of diabetes (years) Body mass index (kg/m2)
HbA1c (%) Microvascular disease (n)
Pioglitazone (n=864) 503 (58.2%) 61.7±7.5 12.8±7.1 31.6±4.7 8.4±1.4
544 (63.0%)
Data are mean ± SD or n (%). HbA1c = glycated haemoglobin. Source: adapted from Charbonnel B, et al., 2010.27
at the impact of a single glucose-lowering agent (pioglitazone) on macrovascular outcomes compared with placebo when added to background guideline-driven therapy (glucose-lowering and CV medications), thus providing a relatively unambiguous assessment of the CV and metabolic effects of pioglitazone. PROactive remains (at the time of writing) the only completed placebo-controlled outcomes study looking at the effects of a single glucose-lowering drug in type 2 diabetes, although many similar studies are now ongoing (see
www.clinicaltrials.gov) in the light of recent regulatory guidelines on the CV safety of glucose-lowering drugs.29,30
PROactive
also remains the only completed outcomes study of glucose- lowering therapy exclusively in a high-risk population with established macrovascular disease.
PROactive was an event-driven study with an average observation period of 34.5 months. The primary endpoint was a complex composite of macrovascular events, including all-cause mortality, myocardial infarction (MI; including silent MI), stroke, acute coronary syndrome (ACS), endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. In the final analysis for the overall population, there was a trend towards reduced risk in the pioglitazone group for this primary endpoint (HR=0.90, 95% CI [0.80, 1.02], p=0.095). However, there was a significant risk reduction for the predefined main secondary composite outcome of all-cause mortality, MI (excluding silent MI) and stroke [HR=0.84, 95% CI [0.72, 0.98], p=0.27]. Subsequent analyses also showed significant risk reductions for a host of other composite macrovascular endpoints, as well as significant reductions in recurrent MI and recurrent stroke.18,20,22
Analyses of metabolic effects showed that pioglitazone provided a
median -0.8% improvement in HbA1c, which was stable throughout the study and significantly greater than the 0.3% reduction seen in the placebo group.16
There were also significant improvements in
HDL cholesterol, triglycerides and the low-density lipoprotein (LDL)/HDL ratio compared with placebo.16
When PROactive was designed, oedema (not associated with other signs of heart failure) and heart failure were classified as adverse events of special interest. The incidence of oedema was known to be increased among thiazolidinedione-treated patients and oedema (rather than any direct effect on cardiac function) had been implicated as a potential driver of heart failure events reported in previous studies with this drug class.31,32
As expected, pioglitazone
was associated with an increased rate of oedema compared with placebo in PROactive.16
Overall, 26.4% of patients in the pioglitazone
group reported non-serious oedema compared with 15.1% in the placebo group, and this led to discontinuation in 2.7 versus 0.8% of
EUROPEAN ENDOCRINOLOGY
Figure 1: Glycaemic Control (A) and Insulin Dose (B) Over Time with Pioglitazone or Placebo in Patients Receiving Insulin at Baseline in PROactive
A 9 8.5
8
7.5 7
6.5 6
5.5 5
Baseline
B 60 50
40 30 Baseline 6 12 18 Months Pioglitazone Placebo
†p<0.0001 versus placebo; §p<0.0371 versus placebo. HbA1c = glycated haemoglobin. Source: adapted from Charbonnel B, et al., 2010.27
24 30 Final visit 6 12 18 Months † † § † † † † † † † † † † 24 30 Final visit † † † †
Placebo (n=896) 547 (61.0%) 61.2±7.5 13.1±7.1 31.9±4.7 8.5±1.4
537 (59.9%)
Pioglitazone (n=1,741) 1,232 (70.8%) 62.0±7.6 7.8±6.2 30.3±4.7 7.9±1.5
569 (32.7%)
Not Receiving Insulin at Baseline
Placebo (n=1,737) 1,181 (68.0%) 61.8±7.9 7.8±6.4 30.6±4.8 7.9±1.4
539 (31.0%)
patients, respectively. There were only five cases of serious oedema in the pioglitazone group and three in the placebo group.
In line with this finding, heart failure was reported in 10.8% of pioglitazone-treated patients versus 7.5% on placebo, whereas serious heart failure was reported in 5.7 versus 4.1%, respectively [HR=1.41, 95% CI (1.10, 1.80), p=0.007].16,19
Reassuringly, however,
mortality owing to heart failure was similar with pioglitazone and placebo (0.96 versus 0.84%, p=0.639).19
Furthermore, among those
developing serious heart failure, overall mortality rates were also similar between the pioglitazone and placebo groups (26.8 versus 34.3%, p=0.1338) and pioglitazone was associated with a significant reduction in the main secondary endpoint [34.9 versus 47.2%; HR=0.64, 95% CI (0.44, 0.95), p=0.025].19
Thus, the heart failure
associated with pioglitazone in PROactive appeared to follow a relatively benign course and did not negate the potential for pioglitazone to reduce macrovascular risk. Overall, the safety and tolerability of pioglitazone was predictable and manageable in line with previous efficacy/safety studies in lower-risk patients.33
25
Insulin dose (U)
HbA1c
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