Insulin and other antidiabetic drugs and hepatocellular carcinoma risk: A nested case-control study based on Italian healthcare utilization databases

Purpose: Insulin and other antidiabetic drugs may modulate hepatocellular carcinoma (HCC) risk in diabetics. Methods: We have analyzed the role of various antidiabetic drugs on HCC in a nested case-control study using the healthcare utilization databases of the Lombardy Region in Italy. This included 190 diabetic subjects with a hospital discharge reporting a diagnosis of malignant HCC and 3772 diabetic control subjects matched to each case on sex, age, date at cohort entry, and duration of follow-up. Results: Increased risks of HCC were found for use of insulin (odds ratio [OR]=3.73, 95% confidence interval [CI] 2.52-5.51), sulfonylureas (OR=1.39, 95%CI 0.98-1.99), and repaglinide (OR=2.12, 95%CI 1.38-3.26), while a reduced risk was found for use of metformin (OR=0.57, 95%CI 0.41-0.79). The risk of HCC increased with increasing duration of insulin use (OR=2.52 for <1year, 5.41 for 1-2 years, and 6.01 for ≥2years; p for trend<0.001), while no clear pattern with duration was observed for sulfonylureas, repaglinide, and metformin. Conclusion: Our study supports the evidence that patients with diabetes using metformin, and possibly other antidiabetic drugs that increase insulin sensibility, have a reduced risk of HCC, while those using insulin or drugs that increase circulating insulin, such as insulin secretagogues, have an increased risk. Whether these associations are causal, or influenced by different severity of diabetes and/or possible residual bias or misclassification, is still open to discussion.