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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

The addition of pioglitazone in type 2 diabetics poorly controlled on insulin therapy: a meta-analysis

A Tan, Y Cao, N Xia, Z Mo, and F Gao.

Review published: 2010.

Link to full article: [Journal publisher]

CRD summary

This review concluded that pioglitazone may improve glucose metabolism and lipid parameters in patients with type 2 diabetes inadequately controlled on insulin. The inappropriate synthesis employed means that the authors' conclusions should be treated with a considerable degree of caution since they are not based on randomised data.

Authors' objectives

To assess the impact of pioglitazone on glycaemic control and lipid parameters, together with the risk of adverse events, when incorporated into the treatment regimen of patients with type 2 diabetes inadequately controlled on insulin.


PubMed, EMBASE and the Cochrane Library were searched up to February 2009. Bibliographies of identified studies and relevant reviews and meta-analyses were also screened. Search terms were reported.

Study selection

Randomised controlled trials (RCTs) in patients with type 2 diabetes inadequately controlled by insulin, with a duration of at least 12 weeks and at least one trial arm assessing insulin plus pioglitazone therapy, were eligible for inclusion. Trials were required to report more than one of the following outcomes: glycated haemoglobin A1c, fasting blood glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides (all at baseline and completion), hypoglycaemia or oedema events.

All included trials allowed concomitant lipid-lowering therapy provided that no changes were made during the trial period, but only one trial permitted other oral antihyperglycaemic medication (metformin). Diagnostic criteria were reported in half the trials: one trial used World Health Organisation criteria, and one trial used the criteria of the American Diabetes Association.

Doses of pioglitazone ranged from 15mg/day to 45mg/day. The proportion of females in trial arms using pioglitazone ranged from 45.0 to 58.9%. The mean age of participants ranged from 52.5 to 58.9 years; mean body mass index (BMI) ranged from 30.7kg/m2 to 34.3kg/m2. The mean duration of diabetes ranged from 7.7 to 13.6 years, where reported. Trial duration ranged from 16 to 25 weeks.

It appeared that more than one reviewer was involved in the selection of studies.

Assessment of study quality

Two reviewers independently assessed the trials for methodological quality using the criteria of allocation concealment, randomisation and blinding. Trials were graded as adequate, unclear or inadequate for each criterion.

Data extraction

Intention-to-treat data were extracted to allow the calculation of mean differences from baseline, with standard errors, for the efficacy outcomes and relative risks (RR) with 95% confidence intervals (CI) for the adverse events. Data were independently extracted by two reviewers with disagreements resolved through consensus.

Methods of synthesis

Pooled mean differences from baseline for the pioglitazone arms and relative risks, with 95% confidence intervals, were calculated using fixed-effect meta-analyses; if statistically significant unexplained heterogeneity was detected, a random-effects model was employed. Statistical heterogeneity was assessed using the Χ2 statistic. Sensitivity analyses were conducted omitting each trial in turn.

Results of the review

Four RCTs were included in the review (n=1,321 participants). Allocation concealment and double-blinding were adequate in all trials. Randomisation was adequate in two trials and not reported in two. Drop-out rates ranged from 9 to 30%.

There was a statistically significant reduction in glycated haemoglobin A1c compared with baseline in the groups treated with pioglitazone (WMD -1.22%, 95% CI -1.44 to -1.01). There was statistically significant heterogeneity (p<0.001).

Fasting blood glucose was significantly reduced compared with baseline in the pioglitazone-treated groups (reduction of 1.63mmol/L, 95% CI 0.75 to 2.50), with significant heterogeneity (p<0.001).

There was also a reduction of daily insulin doses compared with baseline by between 3 and 12U/day in pioglitazone arms.

Compared with baseline, lipid parameters showed an increase in both low-density lipoprotein cholesterol (0.13 mmol/L, 95% CI 0.09 to 0.17) and high-density lipoprotein cholesterol (0.21mmol/L, 95% CI 0.13 to 0.28) and a reduction in triglycerides (0.05mmol/L, 95% CI 0.01 to 0.09); there was significant heterogeneity in the high-density lipoprotein cholesterol analysis (p<0.001).

There were statistically significant increases in hypoglycaemia (RR 1.57, 95% CI 1.12 to 2.20) and oedema (RR 2.42, 95% CI 1.67 to 3.50).

Authors' conclusions

In patients with type 2 diabetes inadequately controlled on insulin, pioglitazone may significantly improve glucose metabolism and might have a positive effect on important components of the lipid profile; this may in turn reduce the risk of cardiovascular events. Additionally, the adverse events were well-tolerated.

CRD commentary

The review question and inclusion criteria were clear. Three relevant databases were searched, reducing the risk of relevant studies being omitted. The authors reported using methods designed to reduce reviewer bias and error at all stages of the review process.

Three key criteria were used to assess trial quality. The decision to use meta-analysis was reasonable and included attempts to assess and explore heterogeneity. However, the statistical approach involved treating each trial arm involving pioglitazone separately; this discarded the benefits of using data from RCTs and was inappropriate.

Whilst the authors' conclusions reflected the results obtained from this process (although the lipid parameters showed conflicting results), they must be regarded with a considerable degree of caution.

Implications of the review for practice and research

The authors did not state any implications for practice or further research.


Not stated.

Bibliographic details

Tan A, Cao Y, Xia N, Mo Z, Gao F. The addition of pioglitazone in type 2 diabetics poorly controlled on insulin therapy: a meta-analysis. European Journal of Internal Medicine 2010; 21(5): 398-403. [PubMed: 20816593]

Indexing Status

Subject indexing assigned by NLM


Cardiovascular Diseases /epidemiology; Diabetes Mellitus, Type 2 /drug therapy /epidemiology; Drug Therapy, Combination; Humans; Hypoglycemic Agents /administration & dosage /adverse effects; Insulin /administration & dosage /adverse effects; Risk Factors; Thiazolidinediones /administration & dosage /adverse effects



Database entry date


Record Status

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.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 20816593