Diabetes Management
Pioglitazone in Combination with Insulin – An Overview of Results from PROactive
Bernard Charbonnel
Professor of Endocrinology and Metabolic Diseases, University of Nantes and Department of Internal Medicine, Endocrinology and Diabetes, Hôtel Dieu, University Hospital of Nantes
Abstract
Pioglitazone provides one of several add-on therapy options for patients with unsatisfactory glycaemic control treated with insulin. Although pioglitazone has the beneficial feature of low hypoglycaemia risk, it has an overlapping adverse event profile with insulin in terms of oedema (with the potential to exacerbate heart failure) and weight gain, leading to possible concern over their use in combination. Fortunately, subgroup analyses from the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) have provided valuable insights into the efficacy and safety profile of pioglitazone in patients on established insulin therapy. Pioglitazone improved glycaemic control and lipids, while enabling patients to reduce their insulin requirements. Oedema and weight were predictable with no excess exacerbation of heart failure with the combination. Importantly, pioglitazone had a good macrovascular safety profile (with a trend towards benefit), consistent with the overall population. This article provides an overview of the results from the insulin-treated subgroup in PROactive and highlights some of the clinical implications for pioglitazone–insulin combination therapy.
Keywords Type 2 diabetes, pioglitazone, insulin, glycaemic control, tolerability, safety, oedema, weight gain, heart failure, cardiovascular disease, outcomes
Disclosure: Bernard Charbonnel was a member of the PROactive Executive Committee and has received fees for consultancy, speaking, travel or accommodation from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Lilly, Merck, Sharpe & Dohme, Novartis, Novo Nordisk, Roche, sanofi-aventis and Takeda. Received: 11 January 2011 Accepted: 21 March 2011 Citation: European Endocrinology, 2011;7(1):24–9 Correspondence: Bernard Charbonnel, Clinique d’endocrinologie, maladies metaboliques et nutrition, CHU de Nantes, Hôtel Dieu, 1 place Alexis Ricordeau, 44093 Nantes Cedex 1, France. E:
bernard.charbonnel@
univ-nantes.fr
Many patients with type 2 diabetes require insulin therapy during the course of their disease, either as monotherapy or as an addition to existing oral glucose-lowering therapy.1–3
However, this might not
always be sufficient to maintain adequate glycaemic control and additional therapies might therefore be required.1–3
Randomised The oral glucose-
lowering drug pioglitazone is one of several options available for add-on therapy in patients whose glycaemic control remains unsatisfactory on insulin treatment regimens.2–7
controlled trials (RCTs) have shown that pioglitazone provides significant improvements in glycaemic control and lipid profile in insulin-treated patients with type 2 diabetes.8–13
In one recent meta-
analysis of four efficacy/safety RCTs, the addition of pioglitazone to insulin therapy provided a 1.22% reduction in glycated haemoglobin
(HbA1c) from baseline, as well as a 1.63mmol/L improvement in fasting plasma glucose, a 0.21mmol/L improvement in high-density lipoprotein (HDL) cholesterol, and a 0.05mmol/L improvement in triglycerides.13
Oedema and weight gain are well-characterised adverse events associated with pioglitazone use regardless of background therapy, whereas pioglitazone use per se is generally associated with a low risk of hypoglycaemia.14,15
Improved glycaemic
control provided by pioglitazone probably contributes to any increased risk of insulin-induced hypoglycaemia and, at least to some extent, weight gain.14,15
24
The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) was a landmark cardiovascular (CV) outcomes study looking at the impact of pioglitazone on macrovascular endpoints in high-CV-risk patients with type 2 diabetes.16,17
Since publication of
the main results in 2005, PROactive has continued to provide a wealth of information on the CV safety/efficacy profile and metabolic effects of pioglitazone via a range of predefined and post- hoc analyses.17–28
Recently, several analyses have looked specifically at the subgroup of patients entering the study on insulin therapy, thus adding considerably to the existing data set on pioglitazone– insulin combination therapy.26–28
The main adverse events associated with pioglitazone in these insulin-treated patients included oedema, weight gain and hypoglycaemia.12,13
This article provide an overview of the key metabolic effects, impact on CV outcomes and the safety/tolerability profile of pioglitazone among insulin-treated patients in PROactive and briefly discusses the clinical implications of these findings. Relevant publications were identified via PubMed searches using the terms ‘pioglitazone AND insulin AND (combination OR addition OR concomitant OR proactive)’.
PROactive – Study Characteristics and Main Overall Findings
PROactive was a randomised, double-blind, multicentre, placebo- controlled, parallel-group study in 5,238 patients with type 2 diabetes and pre-existing macrovascular disease.16
The study looked © TOUCH BRIEFINGS 2011
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