We read with great interest the article by Chang et al., 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).
|Source||Study Type||Region||Medication Studied||Total Participants (events)||Follow-up Time||Adjustment Variables|
|Exposed Group||Comparison Group|
|Oliveria et al., 2008||Cohort||USA||TZD (with no insulin use)||No TZD Use (with no insulin use)||191,223(39)||Mean, 3.9 years||NA|
|Home et al., 2009||RCT||UK||Rosiglitazone (monotherapy)||No TZD Use (Metformin Or Glibenclamide Monotherapy)||4,447 (11)||Mean, 5.5 years||Age, sex, HBV, HCV, cirrhosis and alcoholism|
|Hassan et al., 2010||Case-Control||USA||TZD||No TZD Use||1,524(420)||NR||Age, sex, race, education level, smoking, alcohol consumption, family history of cancer, HBV, HCV|
|Chang et al., 2012||Case-Control||Taiwan||Pioglitazone||No pioglitazone use||606,583 (10,741)||Median, 7.9 years||Glinides, 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|
|Rosiglitazone||No rosiglitazone use|
|Lai et al., 2012||Cohort||Taiwan||TZD||No TZD Use||96,745(679)||Mean, 5.6 years||Sex, age, and comorbidities (including cirrhosis, alcoholic liver damage, hepatitis B, and hepatitis C)|
Considering the fact that metformin treatment is associated with reduced risk of cancer in epidemiological studies, 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. 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