Diabetes Management
A separate analysis also investigated whether the impact of pioglitazone on CV risk differed between those on insulin and those not on insulin at baseline (see Table 2).28
Edema might also be one of the factors contributing to the weight gain typically associated with pioglitazone or insulin.33
The impact on the primary and main secondary
outcomes (as well as the composite of CV mortality, MI, and stroke) was similar regardless of baseline insulin use, and there were no significant interactions between the subgroup and randomized treatments. The main CV endpoint outcomes described above thus demonstrate that, as in the overall PROactive population, pioglitazone therapy is associated with a trend toward a macrovascular benefit compared with placebo when added to insulin therapy.
Safety and Tolerability
The CV outcomes results also demonstrate clearly that pioglitazone has a good macrovascular safety profile among insulin-treated patients, as seen in the overall PROactive population.33
The adverse event profile of
pioglitazone was similar to that of placebo, with the exceptions of edema and hypoglycemia, which were more frequent with pioglitazone, the latter being consistent with better glycemic control in the pioglitazone group.27,28
As both insulin and pioglitazone individually are associated with edema, and thus possible exacerbation of heart failure, these two aspects of safety and tolerability were of particular interest in the insulin-therapy subgroup in PROactive. Previous clinical studies suggested that the edema risk is greater when pioglitazone is added to insulin,12,31
which might relate
to the two therapies affecting fluid retention in different bodily compartments (mainly extracellular and extravascular with pioglitazone, but intravascular with insulin).34
However, although pioglitazone increased
edema in the insulin-treated subgroup in PROactive (~80 % relative increase in risk versus placebo), an almost identical increase in risk was seen in the non-insulin-treated subgroup (see Table 2).27,28
Furthermore, in
absolute terms, the risk of edema was only increased slightly in patients receiving insulin versus those not receiving insulin in either the pioglitazone (23.6 versus 20.6 %, respectively, for edema in the absence of heart failure) or the placebo groups (14.1 versus 12.4 %).28
Notably, there
were only four events of serious edema among insulin-treated patients in the pioglitazone group and two in the placebo group.27
Thus, in the
PROactive population, the increase in edema associated with pioglitazone therapy was predictable irrespective of baseline insulin therapy and insulin therapy itself had only a minor impact.
Overall rates of heart failure were significantly higher in insulin-treated (12.0 %) versus non-insulin-treated patients (7.7 %, p<0.0001), which suggests that, for whatever reasons (longer duration of the disease, poorer control, insulin itself, etc.), insulin-treated patients are at higher risk of heart failure. Within the insulin-treated group, heart failure events were reported more often with pioglitazone (13.5 versus 10.5 % for placebo, p<0.05).27
Conclusions
PROactive remains the only completed placebo-controlled CV outcomes study looking at the effects of a single glucose-lowering agent in type 2 diabetes and the only study exclusively in a high-CV-risk population with established macrovascular disease. From the results of PROactive alongside meta-analyses of efficacy/safety RCTs and large-scale surrogate CV endpoints studies (using carotid intima media thickness [cIMT] measurements and coronary vessel intravascular ultrasound), pioglitazone has one of the best characterized CV profiles of any glucose-lowering agent.33,39–41
Overall, the evidence suggests that
pioglitazone has good CV safety and could even provide some macrovascular benefit. The recent subgroup analyses from PROactive described here now extend these findings specifically to pioglitazone as an add-on therapy to insulin and suggest a similar good CV profile and trend toward macrovascular benefit in this patient population. This is particularly important in insulin-treated patients, as they tend to have more advanced disease and thus represent a more vulnerable population with higher CV risk.
Although the risk of serious heart failure with pioglitazone relative to placebo was consistent with the increased risk seen in the overall population, it did not appear to be enhanced among insulin-treated patients (HR=1.21, 95 % CI [0.82, 1.79], p=0.3430; see Table 2).28
Rates of fatal heart
In absolute terms, rates of serious heart failure associated with pioglitazone were not significantly different in insulin-treated and non-insulin-treated patients (6.3 versus 5.5 %, respectively) and the placebo rate among insulin-treated patients (5.2 %).27,28
failure among insulin-treated patients were similar for pioglitazone and placebo (1.4 versus 1.1 %, respectively).27
114
From a metabolic perspective, pioglitazone provided improvements in glycemic control and lipids that were consistent irrespective of baseline glucose-lowering therapy. The improvements in HDL cholesterol provided by pioglitazone might be particularly relevant, as this appears to be the one of the main drivers of the anti-atherosclerotic effects of pioglitazone (based on analysis of the ability of pioglitazone to slow cIMT progression in the CHICAGO study).42
Clearly, pioglitazone might not be the most appropriate option in all patients on insulin therapy. However, the subgroup analyses from
US ENDOCRINOLOGY In the insulin-therapy
subgroup, pioglitazone was associated with a 4.2 kg increase in body weight from baseline, which was marginally greater than the +3.6 kg seen in the overall population.16,26
Weight gain correlated with the decline
in HbA1c, consistent with a calorie-sparing effect from better glycemic control.15
Most of the weight gain occurred within the first year and stabilized within the second year.16
The magnitude of this weight gain is
consistent with previous long-term (2–3 year) studies of pioglitazone as either monotherapy or add-on therapy to other glucose-lowering agents, where increases of 2.5–5 kg have been reported.35–37
In
shorter-term studies (≤6 months) looking specifically at pioglitazone add-on to insulin, weight gain of approximately 4 kg has typically been reported.8–12
By contrast, weight remained stable (-0.1 kg change) among insulin-treated patients in the placebo group (similar to the -0.4 kg change in the overall population), suggesting that any insulin-associated weight change had stabilized by the start of the study.
Insulin-treated patients would be expected to experience more hypoglycemic events than those not requiring insulin,38
and this was
confirmed in PROactive (all hypoglycemia, 35.5 versus 18.4 %, respectively; serious hypoglycemia, 1.3 versus 0.3 %).27
Within the insulin subgroup,
pioglitazone-treated patients also had a higher rate of hypoglycemia compared with placebo (all hypoglycemia, 42.1 versus 29.0 %, respectively; serious hypoglycemia, 1.9 versus 0.8 %) consistent with better glycemic control.27
Baseline sulfonylurea use did not influence hypoglycemia rates.27
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