Pioglitazone in Combination with Insulin—An Overview of Results from PROactive
Table 2: Selected Key Outcomes in PROactive According to Insulin Use at Baseline Endpoint
Insulin Use at Baseline
Primary endpoint (composite of all-cause mortality, Overall MI [including silent MI], stroke, ACS, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle) Main secondary endpoint (composite of all-cause mortality, MI [excluding silent MI] and stroke)
Insulin No insulin
Overall Insulin
No insulin
Composite of CV mortality, MI (excluding silent MI) and stroke
Serious heart failure
Overall Insulin
No insulin
Overall Insulin
No insulin Edema (without heart failure)
Overall Insulin
No insulin
Pioglitazone Group Events, n/N (%)
514/2,605 (19.7) 186/864 (21.5) 328/1,741 (18.8)
Placebo Group Events, n/N (%)
572/2,633 (21.7) 224/896 (25.0) 348/1,737 (20.0)
358/2,633 (13.6) 147/896 (16.4) 211/1,737 (12.1)
Hazard Ratio (95% CI)
0.90 (0.80, 1.02) 0.86 (0.70, 1.04) 0.94 (0.80, 1.09)
p for interaction between subgroup and treatment = 0.4780 301/2,605 (11.6) 120/864 (13.9) 181/1,741 (10.4)
313/2,633 (11.9) 130/896 (14.5) 183/1,737 (10.5)
108/2,633 (4.1) 47/896 (5.2) 61/1,737 (3.5)
0.84 (0.72, 0.98) 0.85 (0.67, 1.08) 0.84 (0.69, 1.03)
p for interaction between subgroup and treatment = 0.9723 257/2,605 (9.9) 107/864 (12.4) 150/1,741 (8.6)
p for interaction between subgroup and treatment = 0.7329 149/2,605 (5.7) 54/864 (6.3) 95/1,741 (5.5)
p for interaction between subgroup and treatment = 0.3216 563/2,605 (21.6) 204/864 (23.6) 359/1,741 (20.6)
341/2,633 (13.0) 126/896 (14.1) 215/1,737 (12.4)
p for interaction between subgroup and treatment = 0.8874 ACS = acute coronary syndrome; CI = confidence interval; CV = cardiovascular; MI = myocardial infarction. Source: adapted from Erdmann E, et al., 2010.28
0.82 (0.70, 0.97) 0.85 (0.66, 1.10) 0.81 (0.65, 1.00)
1.41 (1.10, 1.80) 1.21 (0.82, 1.79) 1.56 (1.13, 2.15)
1.82 (1.59, 2.08) 1.84 (1.48, 2.30) 1.81 (1.53, 2.14)
p
0.0954 0.1173 0.3893
0.0277 0.1783 0.0915
0.0201 0.2276 0.0503
0.0071 0.3430 0.0067
<0.0001 <0.0001 <0.0001
Mean HbA1c levels decreased from 8.4 to 7.4 % (-0.93 %) at the final visit in the pioglitazone group and this was achieved alongside a significant
reduction in insulin requirements from a mean of 46.5 U/d to 42.1 U/d (see Figure 1B).27
This was a significantly greater improvement in HbA1c than in
As well as decreasing daily insulin requirements, pioglitazone enabled patients to decrease the complexity of their insulin regimens significantly in terms of the number of injections per day compared with placebo.27
the placebo group (8.5 to 8.1 %; -0.45 %). It should be noted that the small improvement in the placebo group required an increase in insulin use from 46.7 U/d to 54.9 U/d. Improvements were achieved after approximately six months, were maintained for the duration of the study and were independent of baseline insulin regimen. The magnitude of these effects was similar to that seen in the overall patient population (-0.8 % pioglitazone, -0.3 % placebo) or those on metformin and/or a sulfonylurea at baseline.16,24,25
Pioglitazone also enabled significantly more
patients (8.6 %) to discontinue insulin therapy permanently compared with placebo (1.7 %, p<0.0001), as well as enabling more patients to discontinue concomitant oral agents.27
In those not using insulin at baseline, significantly
fewer patients on pioglitazone (11 %) progressed to permanent insulin use compared with placebo (22 %; HR=0.47, 95 % CI [0.39, 0.56], p<0.0001).16
An analysis compared the more insulin-resistant patients (defined as
baseline insulin dose and HbA1c both median or greater) with the less insulin-resistant ones (defined as baseline insulin dose and HbA1c both less than median), the HbA1c to insulin doses ratio at baseline was used as a potential index of insulin sensitivity.27
The median insulin dose at
baseline was 42 U/d and the median HbA1c was 8.3 %. In the patients categorized as less insulin-resistant at baseline, the mean baseline
HbA1c was 7.3 % and insulin dose was 24 U/d, versus 9.6 % and 69 U/d in the more insulin-resistant patients (according to their insulin doses
and HbA1c both median or greater). The HbA1c was more or less stable US ENDOCRINOLOGY
in the less insulin-resistant patients. In the more insulin-resistant patients, it decreased by 1.3 % from 9.6 to 8.3 % at final visit. In these
patients with a baseline HbA1c of 9.6 % or more, despite relatively high insulin doses of 69 U/d or more, the HbA1c decrease shown in the placebo group was related to the intensification of insulin treatment
(mean increase in insulin dose of 7 U/d from 69 to 76 U/d, associated with the intensification of the insulin regimen), whereas the greater
HbA1c decrease (-1.65 versus -0.92 %) on pioglitazone was obtained without any change in the insulin regimen and with lower doses of insulin (mean decrease in insulin units of 11 U/d from 68 to 57 U/d).
A separate analysis looked at how baseline glucose-lowering therapy affected lipid changes in PROactive.26
In the subgroup of patients on insulin
therapy, pioglitazone provided significant improvements in triglycerides and HDL cholesterol compared with placebo (see Figure 3). There were also significant improvements in the LDL:HDL cholesterol ratio. The lipid effects were consistent across all baseline glucose-lowering therapy
subgroups, despite the higher baseline HbA1c and longer duration of diabetes in insulin-treated patients (see Figure 3).26,27 Cardiovascular Outcomes
The main macrovascular outcomes in the subgroup of patients on insulin at baseline were consistent with the results reported for the overall population (see Figures 2A and 2B).16,27
For the primary composite
Although a significant reduction was seen for this secondary endpoint in the overall population, there was less power to detect any differences in the smaller insulin-treated subgroup.
endpoint, there was a non-significant trend toward benefit with pioglitazone compared with placebo (HR=0.86, 95 % CI [0.70, 1.02], p=0.1173). There was also a trend toward benefit for the main secondary composite endpoint (HR=0.85, 95 % CI [0.67, 1.08], p=0.1783).27
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