Effectiveness and side effects of thiazolidinediones for type 2 diabetes

To the Editor: It was with interest that we read the recent article on real-life experience with thiazolidinediones by Hussein et al.1 The authors noted the absence of severe liver toxicity with the newer agents, rosiglitazone and pioglitazone, in contrast to troglitazone, which was withdrawn because of cases of hepatic failure.2 However, the sample was too small to conclude that these thiazolidinediones (TZDs) carry no hepatic risk, and they endorsed the current Pharmaceutical Benefits Scheme recommendations that liver function tests (LFTs) be monitored every 2 months. We have collected similar clinic data showing that the development of significant abnormalities in results of LFTs with TZD therapy is uncommon, and in fact, there are often improvements in LFT findings.

We reviewed the files of 166 patients with type 2 diabetes treated with TZDs between 1 August 2000 and 30 November 2002, with the aim of assessing their long-term effect on LFT results. Therapy was discontinued within 3 months in 26 patients. The reasons were non-compliance (7), therapy ineffective (8), weight gain (5), dyspnoea (1), peripheral oedema (1), malaise (1), dizziness (1), angio-oedema (1), and pre-existing LFT abnormality (1). We analysed data on the remaining 140 patients (see Box) treated for a mean of 188 ± 4 days with either pioglitazone (109 patients) or rosiglitazone (31 patients).

All LFT results improved significantly (Box). At baseline, 90 patients had abnormal findings on LFTs. These findings normalised in 43 of these patients (including one with steatohepatitis proven on biopsy); improved in 29 patients; and were unchanged in nine patients. LFT findings deteriorated in nine patients, leading to cessation of therapy in two. Most patients with normal LFT results at baseline experienced improvements of these parameters within the normal range. Three patients developed new abnormalities in their LFT findings, and therapy was stopped in one patient, leading to resolution of LFT abnormalitites. Changes in glycohaemoglobin (HbA1c) levels correlated positively with changes in activity of alkaline phosphatase (correlation coefficient [r], 0.33; P < 0.01), aspartate aminotransferase (r, 0.27; P < 0.01) and alanine aminotransferase (r, 0.29; P < 0.01).

Our findings support those of Hussein et al, that TZD therapy is usually stopped for reasons other than hepatic dysfunction. In contradistinction to early concerns about their hepatic safety, the improvements in LFT findings seen in our patients suggest that TZDs may even benefit hepatic function. In patients with diabetes, abnormal findings on LFTs are often attributed to fatty liver, which predisposes to steatohepatitis. TZDs may well alleviate or prevent steatohepatitis,3 thereby providing benefits beyond that of improved glycaemic control, and mild abnormalities in LFTs should not discourage their use in patients with diabetes.