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. 2018 Sep 24;2018(9):CD011798. doi: 10.1002/14651858.CD011798.pub2

Pfutzner 2011.

Methods

  • Study design: phase 2, parallel RCT

  • Study time frame: not reported

  • Duration of follow‐up: 6 months
Participants

  • Country: Germany

  • Setting: multicentre (12 sites)

  • Inclusion criteria: patients with type 2 DM (WHO criteria); HbA1c ≥ 48 mmol/mol (6.5%); persistent albuminuria (≥ 30 mg/g (3.39 mg/mmol) in at least 2 out of 3 consecutive morning spot urine samples) and who were receiving stable RAS‐blocking treatment

  • Number (randomised/completed): treatment group (20/15); control group (19/11)

  • Mean age ± SD (years): treatment group (68.9 ± 6.8); control group (69.6 ± 9.4)

  • Sex (M/F): treatment group (14/6); control group (13/6)

  • Exclusion criteria: diagnosis of clinical heart failure; eGFR ≤ 30 mL/min/1.73 m2
Interventions Treatment group

  • Pioglitazone: 1 x 30 mg/d at breakfast for 6 months. Advice for insulin dosage adaptation and choice of insulin was at the discretion of the investigator. At the discretion of the investigator, the initial insulin dose was reduced by 10% at the randomisation visit. Insulin was titrated to target a FBG level of 4.44 to 6.67 mmol/L. Patients were allowed to use any further concomitant medications that they required as far as they did not belong to those representing exclusion criteria. If medically acceptable, all concomitant medications had to be kept constant during the investigation.


Control group

  • Placebo for 6 months


Both groups

  • Advice for insulin dosage adaptation and choice of insulin was at the discretion of the investigator. At the discretion of the investigator, the initial insulin dose was reduced by 10% at the randomisation visit. Insulin was titrated to target a FBG level of 4.44 – 6.67 mmol/L. Patients were allowed to use any further concomitant medications that they required as far as they did not belong to those representing exclusion criteria. If medically acceptable, all concomitant medications had to be kept constant during the investigation.
Outcomes

  • The change in the daily insulin dose (basal and prandial) after 6 months of treatment with either pioglitazone or placebo given in addition to insulin. The total daily insulin dose was defined as the mean of the daily insulin dose on 3 consecutive days before the respective visits

  • The number of patients with a reduction of the daily insulin dose of ≥ 30%

  • Laboratory parameters such as HbA1c, glucose, C‐peptide, intact proinsulin, adiponectin, relaxin, fetuin A, carbonyl protein, angiotensin, high‐sensitivity CRP, calcification markers (MPO, matrix Gla protein), lipids (cholesterol, HDL, LDL, triglycerides), matrix metallopeptidase 9 (MMP‐9), monocyte chemotactic protein‐1 (MCP‐1), soluble E‐selectin, oxidized LDL (ox LDL), PIO in serum, iPTH, and N‐terminal fragment of pro‐brain natriuretic peptide (NT‐proBNP)

  • Laboratory efficacy parameters were measured using blood collected prior to dialysis at visit 2 (baseline), visit 5 (12 weeks later), and visit 7 (6 months later)

  • The influence of the treatment on cardiac function was furthermore evaluated as the change in the ultrafiltrate volumes during the course of the study. Another objective was the safety surveillance including assessment of adverse events (AE) and safety laboratory parameters.
Notes

  • Funding source: The study was sponsored by TAKEDA Pharma GmbH, Aachen, Germany
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Study was described as randomised, method of randomisation was not reported
Allocation concealment (selection bias) Unclear risk Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk “After written informed consent was obtained from each participant, patients were randomised to either receive an additional treatment with pioglitazone (1 x 30 mg/day at breakfast) or placebo for 6 months”.
Also the study was reported to be a double‐blind study.
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information to permit judgement
Incomplete outcome data (attrition bias) 
 All outcomes High risk There was greater discontinuation in the control group compared to the pioglitazone group: 4/19 (21.1%) pioglitazone versus 6/17 (35.3%) control group.
Selective reporting (reporting bias) Unclear risk The prespecified outcomes were not available on a clinical trials database
Other bias High risk Conflicts of interest: The study was sponsored by TAKEDA Pharma GmbH, Aachen, Germany.