Decreased risk of liver cancer with thiazolidinediones therapy in patients with type 2 diabetes: Results from a meta-analysis


  • Potential conflict of interest: Nothing to report.

    Supported by grants Shanghai Natural Science Foundation of China (Grant No. 12ZR1447500), and State Key Program of National Natural Science of China (Grant No. 81230057).

We read with great interest the article by Chang et al.,[1] who demonstrated that the use of thiazolidinediones (TZDs) is associated with a decreased liver cancer incidence in diabetic patients. Similar results were also described in other studies. To further test the protective potential of TZDs therapy against liver cancer in diabetic patients, we conducted a systematic review and meta-analysis of studies reporting liver cancer among adults with type 2 diabetes taking TZDs.

By searching the literature in the PubMed and ISI Web of Knowledge databases from inception through October 1, 2012, we included five studies comprising 900,522 patients with type 2 diabetes mellitus in the meta-analysis (Table 1). Compared with non-TZD treatments, TZDs were associated with a significantly lower risk of liver cancer among patients with diabetes (pooled hazard ratio [HR] 0.73; 95% confidence interval [CI]: 0.63-0.85; P < 0.005) (Fig. 1). There was no evidence for the presence of significant heterogeneity between the five studies (Q = 7.84, P = 0.17; I2 = 36.2%), and no significant publication bias was detected by Begg's funnel plots and Egger's tests (P = 0.21).

Table 1. Characteristics of Studies Included in the Meta-Analysis of the Risk of Liver Cancer Associated With Thiazolidinedione Use
SourceStudy TypeRegionMedication StudiedTotal Participants (events)Follow-up TimeAdjustment Variables
Exposed GroupComparison Group
  1. Abbreviations: NA, not applicable; NR, not reported; RCT, randomized controlled trial.
Oliveria et al., 2008CohortUSATZD (with no insulin use)No TZD Use (with no insulin use)191,223(39)Mean, 3.9 yearsNA
Home et al., 2009RCTUKRosiglitazone (monotherapy)No TZD Use (Metformin Or Glibenclamide Monotherapy)4,447 (11)Mean, 5.5 yearsAge, sex, HBV, HCV, cirrhosis and alcoholism
Hassan et al., 2010Case-ControlUSATZDNo TZD Use1,524(420)NRAge, sex, race, education level, smoking, alcohol consumption, family history of cancer, HBV, HCV
Chang et al., 2012Case-ControlTaiwanPioglitazoneNo pioglitazone use606,583 (10,741)Median, 7.9 yearsGlinides, nephropathy, neuropathy, chronic liver disease, statins, retinopathy, calcium channel blockers, ACE inhibitors, PVD, depression, beta-blockers, aspirin, chronic kidney disease, chronic lung disease, cerebrovascular disease and other diabetic medicine
RosiglitazoneNo rosiglitazone use
Lai et al., 2012CohortTaiwanTZDNo TZD Use96,745(679)Mean, 5.6 yearsSex, age, and comorbidities (including cirrhosis, alcoholic liver damage, hepatitis B, and hepatitis C)
Figure 1.

Forest plot for the association between TZD treatments and liver cancer risk in the diabetes patients. The black diamond denotes the pooled HR. Gray squares indicate the HR in each study, with square sizes inversely proportional to the standard error of the HR. Horizontal lines represent 95% CI. The unbroken vertical line is at the null value (HR = 1.0). A value less than 1.0 indicates an decreased risk of liver cancer with TZD use. aHR between pioglitazone use and liver cancer risk; bHR between rosiglitazone use and liver cancer risk.

Considering the fact that metformin treatment is associated with reduced risk of cancer in epidemiological studies,[2] the potential protective effect of other insulin-sensitizing hypoglycemic agents such as TZDs should be considered, along with other more direct, peroxisome proliferator-activated receptor γ (PPAR-γ)-dependent or -independent effects of the drug.[2] Previous studies have examined the potential association between TZDs treatment and cancer risk with contradictory outcomes. We performed a meta-analysis to overcome the limitation of small sample size and inadequate statistical power of single studies and further examined the potential role of TZD use in influencing liver cancer susceptibility. As a result, the current available data supported the recent hypothesis of a decreased risk of liver cancer associated with TZDs. Due to the limited number of studies included in this analysis, we did not perform subgroup analysis including pioglitazone and rosiglitazone. Future well-designed studies with larger cohorts are of great value to confirm these findings.

  • Feng Wang Ph.D.

  • Shu-Zhi Zhao Ph.D.

  • Ming-Yue Zhang M.S.

  • Yan-Lei Ma Ph.D.

  • Peng Zhang Ph.D.

  • Huan-Long Qin M.D.

  • Department of Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China

  • Department of Ophthalmology, First People's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai, China

  • Department of Thoracic Surgery, Affiliated Hospital of Weifang Medical University, Weifang, China