Pioglitazone even at low dosage improves NAFLD in type 2 diabetes: clinical and pathophysiological insights from a subgroup of the TOSCA.IT randomised trial

Aims: Non-Alcoholic Fatty Liver Disease (NAFLD) and type 2 diabetes (T2D) share pathophysiological mechanisms and possible therapeutic strategies. We evaluated the effects of 1-year treatment with pioglitazone or sulphonylureas on indirect indices of NAFLD in people with T2D and the role of insulin-resistance and glucotoxicity in determining these effects. Methods: Patients with T2D (n = 195) aged 50–75 years, poorly controlled with metformin 2 g/day, were randomly allocated to add-on pioglitazone (n = 98) or sulphonylureas (n = 97) within the TOSCA.IT trial. Plasma insulin, glucose, and liver enzymes were measured at baseline and after 1-year. Indirect indices of NAFLD (Liver Fat Equation [LFE], Hepatic Steatosis Index [HSI], and Index of NASH [ION]), and insulin resistance (HOMA-IR, Visceral Adiposity Index [VAI] and adipose tissue Insulin Resistance [ADIPO-IR]) were calculated. Results: Indices of NAFLD improved after pioglitazone, but not after sulphonylureas; differences between changes (1-year minus baseline) were respectively: -1.76 ± 3.84 vs. 0.28 ± 3.75 for LFE; -1.35 ± 2.78 vs. -0.27 ± 2.63 for HSI; -9.75 ± 43 vs. 3.24 ± 31 for ION; p < 0.05 for all. Indices of insulin resistance decreased after pioglitazone, but not after sulphonylureas: -0.95 ± 4.57 vs. 0.37 ± 3.34 for HOMA-IR, p = 0.032; -1.25 ± 4.11 vs. 1.36 ± 5.43 for ADIPO-IR, p = 0.001; -0.53 ± 1.88 vs. 0.03 ± 2.36 for VAI, p = 0.074. Changes in NAFLD indices were similar with different doses of pioglitazone (15, 30, or 45 mg/day), and were independent of blood glucose control. Conclusions: One-year treatment with pioglitazone even at low dosage significantly improved liver steatosis and inflammation, systemic and adipose tissue insulin resistance in patients with T2D. The beneficial effects of pioglitazone on NAFLD were independent of blood glucose control.