|Adding pioglitazone to insulin containing regimens in type 2 diabetes: systematic review and meta-analysis
|Clar C, Royle P, Waugh N
The review concluded that when added to insulin regimens, pioglitazone conferred a small advantage in terms of glycated haemoglobin in type 2 diabetes patients with previous inadequate glucose control, but at the cost of increased hypoglycaemia and weight gain. The review was well conducted and the authors' conclusions appear likely to be reliable.
To investigate the extent to which adding pioglitazone to insulin-containing regimens affects glycaemic control, hypoglycaemia, weight change, lipids, and adverse events.
MEDLINE, EMBASE, and the Cochrane Library were searched for studies published between 1996 and 2008; search terms were reported. Conference abstracts, trial registers and reference lists of retrieved studies were also searched.
Randomised controlled trials (RCTs) of pioglitazone in combination with any insulin regimen in any patients with type 2 diabetes were eligible for inclusion. Comparator treatments had to be the same insulin regimen given on its own (with or without any additional oral medication). Trials had to run for at least 12 weeks.
Eligible outcomes were glycated haemoglobin, frequency of hypoglycaemia, glycaemic excursions, total daily dose of insulin, weight change, changes in cardiovascular risk factors, and adverse events.
All included trials were of patients with previously inadequate glucose control, with mean ages ranging from 46 to 59 years (where reported), mean body mass index ranging between 29 and 37kg/m2, and diabetes duration ranging between six and 14 years. Pioglitazone doses ranged from 15 to 45mg/day; insulin regimens also varied. Some trials allowed use of other co-interventions. Trial duration ranged from 12 weeks to 34.5 months.
Two reviewers independently selected studies for inclusion, with discrepancies resolved by discussion.
Assessment of study quality
Trial quality was assessed according to the following criteria: method of randomisation, allocation concealment, blinding of participants and outcome assessors, use of intention-to-treat analysis, losses to follow-up, use of a power calculation, and comparability of groups at baseline.
The authors did not state how many reviewers performed the quality assessment.
Data were extracted in order to calculate risk ratios (RR) or mean differences with 95% confidence intervals (CI). If a measure of variability was not given and standard deviations were available for at least half the studies, the mean of the standard deviations of the remaining studies was used.
Data were extracted by one reviewer and checked by another, with disagreements resolved by discussion, or by a third reviewer.
Methods of synthesis
A random-effects model was used to calculate pooled risk ratios or weighted mean differences (WMD). Heterogeneity was assessed using the χ2 test.
Subgroup analyses examined various factors, including the effect of study quality and drug doses/regimens.
A narrative synthesis was used when an absence of variability data precluded meta-analysis.
Results of the review
Eight RCTs were included in the review (n=3,092 participants); two were reported as abstracts. Sample sizes ranged from 20 to 1,760 participants. Seven trials were double-blind, six used a power calculation, four described use of adequate randomisation, three described adequate allocation concealment, and five described using an intention-to-treat analysis.
Meta-analyses: The mean reduction in glycated haemoglobin (HbA1c) level was greater in patients taking pioglitazone (WMD -0.58%, 95% CI -0.70 to -0.46; eight RCTs; I2=18%), but hypoglycaemic episodes were slightly more frequent in patients taking pioglitazone (RR 1.27, 95% CI 0.99 to 1.63; six RCTs; I2=76%) and heterogeneity was statistically significant. Subgroup analyses were also reported and revealed no significant differences between any groups.
Narrative synthesis: In most trials, patients who did not take pioglitazone gained less weight than patients who did (mean difference 2.91kg, range 3.85 to -3.50kg; six RCTs). All six trials reporting insulin doses found reduced doses in patients taking pioglitazone. Of the four trials reporting lipids, no significant differences were found for any parameters, apart from high-density lipoprotein-cholesterol, where all trials reported significantly increased levels in the pioglitazone groups. Where reported, there were no significant differences between the groups in withdrawals due to adverse events, but peripheral oedema was more frequent in the pioglitazone groups.
When added to insulin regimens, pioglitazone conferred a small advantage in terms of glycated haemoglobin in type 2 diabetes patients with previous inadequate glucose control, but at the cost of increased hypoglycaemia and weight gain.
The review addressed a clear question, supported by appropriate eligibility criteria. An adequate search was made for relevant trials (including searches for unpublished trials). The authors did not state whether there were any language restrictions, so the possibility of language bias could not be ruled out. Suitable methods were used to minimise the risk of reviewer error and bias when selecting studies and extracting data (although similar details relating to the quality assessment were not given).
Comprehensive details about trials were tabulated (and summarised in the text). Trial quality was thoroughly assessed and was used in interpreting the review results. Appropriate methods were used to pool, summarise data and assess heterogeneity.
The review was generally well conducted and the authors' conclusions appear likely to be reliable.
Implications of the review for practice and research
Practice: The authors stated that starting patients on insulin does not mean that all further intensifications need to occur by adding more insulin. They added that the effect on adherence of adding another medication needs to be considered, as does the extra cost.
Research: The authors did not state any implications for research.
Health Technology Assessment Programme of the National Institute for Health Research.
Clar C, Royle P, Waugh N. Adding pioglitazone to insulin containing regimens in type 2 diabetes: systematic review and meta-analysis. PLoS ONE 2009; 4(7):e6112
Other publications of related interest
Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH. Pioglitazone for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD006060. DOI: 10.1002/14651858.CD006060.pub2.
Subject indexing assigned by NLM
Blood Glucose /analysis; Body Weight; Diabetes Mellitus, Type 2 /drug therapy; Drug Therapy, Combination; Humans; Hypoglycemic Agents /administration & dosage /adverse effects /therapeutic use; Insulin /administration & dosage /adverse effects /therapeutic use; Lipids /blood; Thiazolidinediones /administration & dosage /adverse effects /therapeutic use
Database entry date
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.