Thiazolidinediones Were Associated With Higher Risk of Cardiovascular Events in Patients With Type 2 Diabetes and Cirrhosis

Fu-Shun Yen; James Cheng-Chung Wei; Lu-Ting Chiu; Chih-Cheng Hsu; Ming-Chih Hou; Chii-Min Hwu


Liver International. 2021;41(1):110-122. 

In This Article

Abstract and Introduction


Background & Aims: Type 2 diabetes mellitus (T2DM) management in patients with cirrhosis is complicated. No clinical trials have investigated appropriate antidiabetic drug use in these patients. This study compared the risks of all-cause mortality, major adverse cardiovascular events (MACE) and hepatic outcomes between patients with T2DM and cirrhosis using and not using thiazolidinedione (TZD).

Methods: We selected 1,705 propensity score–matched TZD users and nonusers from a Taiwan National Health Insurance Research Database cohort of T2DM patients with compensated cirrhosis between January 1, 2000, and December 31, 2012 and followed them until December 31, 2013. Cox proportional hazards models with robust sandwich standard error estimates were used to assess risks of investigated outcomes for TZD users.

Results: MACE incidence rates during follow-up were 2.14 and 1.30 per 100 patient-years for TZD users and nonusers, respectively (adjusted hazard ratio [aHR] 1.70; 95% confidence interval [CI], 1.32–2.19). On the basis of TZD use, the aHRs (95% CIs) for stroke, ischemic heart disease and heart failure were 1.81 (1.28–2.55), 1.59 (1.03–2.44) and 2.09 (1.22–3.60) respectively. Compared with TZD nonusers, rosiglitazone users had significantly higher aHR [1.67 (1.26–2.20)] and pioglitazone users had no significant difference of aHR [1.12 (0.90–1.64)]. All-cause mortality, hepatocellular carcinoma, decompensated cirrhosis and hepatic failure risks did not differ significantly between TZD users and nonusers.

Conclusions: Compared with nonuser, TZD users demonstrated significantly higher MACE risks. Therefore, the risks of cardiovascular complications should be considered when prescribing TZDs to patients with T2DM and cirrhosis.


Type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic disease worldwide; approximately 1 in 10 people live with T2DM.[1] T2DM is also associated with numerous comorbidities, including cardiovascular complications, renal disorders and liver diseases. In particular, cirrhosis is the 13th leading cause of death globally.[2] T2DM can aggravate cirrhosis complications (including ascites, oesophageal varices, hepatic encephalopathy, bacterial infections, renal dysfunction and hepatocellular carcinoma) and increase the related mortality rate.[3]

T2DM management in patients with cirrhosis is difficult: diet control is inadequate in some patients with malnutrition, exercise is unfeasible for weak patients, metformin use may increase lactic acidosis risk (especially in patients with alcoholism) and insulin secretagogue or insulin use may increase hypoglycaemia risk.[4] Most drugs are metabolized by the liver, and patients with cirrhosis have a reduced ability to excrete excess medication; this can lead to increased toxicity.[5] Thus far, no safe and efficacious T2DM therapy applicable to patients with cirrhosis has been reported.

Because of portosystemic shunts and reduced hepatic mass, patients with cirrhosis generally have impaired insulin clearance and hyperinsulinaemia, which can contribute to insulin resistance through insulin receptor downregulation.[5] Thiazolidinediones (TZDs) are strong insulin sensitizers because they bind to nuclear peroxisome proliferator-activated receptor gamma (PPARγ).[6] Thus, TZDs may be particularly useful in patients with T2DM and cirrhosis. Troglitazone, the first approved TZD, was withdrawn because it demonstrated serious hepatic reactions; however, the ensuing surveys of rosiglitazone and pioglitazone did not identify evidence of hepatotoxicity.[7] Furthermore, we still need to consider the risks of weight gain and heart failure after TZD use.[6]

Several clinical trials have evaluated the effect of TZD use in patients with nonalcoholic steatohepatitis and revealed that TZDs could attenuate hepatic inflammation and even fibrosis.[8,9] TZDs may be able to prevent cirrhosis development or progression.[10] However, no clinical studies have focused on the effectiveness of TZD use in patients with T2DM and cirrhosis. Therefore, we conducted this retrospective cohort study to investigate the long-term outcomes of TZD use in these patients.