Troglitazone was an oral hypoglycemic medication which generated over $2 billion in sales in the late 1990s. However, it caused at least 90 cases of acute liver failure, 70 of which resulted in death or liver transplantation. After 3 years on the market, it was withdrawn. Fortunately, other thiazolidinediones (TZDs) including pioglitazone and rosiglitazone do not seem to have the same propensity for liver failure and remain available for use. Even when patients present with advanced liver disease or cirrhosis, diabetic medications are not contraindicated. However, given certain changes in physiology or metabolism, medications should be dosed cautiously (Table 7.1). For example, sulfonylureas may not be able to overcome insulin resistance and defects in insulin secretion seen in patients with cirrhosis from alcohol abuse [38–40]; therefore, a different medication should be selected in this situation.

There are instances where steroids are necessary to treat autoimmune hepatobiliary disease despite the presence of diabetes. For example, steroids are frequently necessary for achieving remission in active autoimmune hepatitis despite comorbid diabetes. Control of glucocorticoid-induced hyperglycemia is important as even short-term hyperglycemia is associated with elevated inflammatory markers and endothelial dysfunction in patients with and without diabetes [41, 42], as well as an increased risk of cardiovascular complications [41, 43]. When possible, patients should be treated with budesonide instead of prednisone to minimize systemic effects. In non-cirrhotic patients, budesonide undergoes significant first-pass metabolism [44, 45], thereby reducing the risk of systemic steroid toxicity [44, 46]. In cirrhotic patients, budesonide is contraindicated due to portal systemic shunting and abnormal hepatic metabolism [44, 47]. These changes result in attenuated first-pass extraction, reduced therapeutic efficacy, and systemic steroid side effects.

When steroids must be used in the setting of diabetes, the dose and duration of steroids should be minimized. Patients also need to optimize glycemic control through adjustments or additions to their medications. In patients without cirrhosis, sulfonylureas, metformin, TZDs, and insulin have been used [41]. These would also be reasonable in cirrhotic patients with the caveats discussed previously. If the decision has been made to use insulin, neutral protamine Hagedorn (NPH) insulin is often a good choice given the similarities in pharmacodynamics profile between NPH and prednisone/prednisolone.

Although the relationship may not be intuitive, diabetes is intimately connected with a variety of hepatobiliary conditions including chronic HCV, acute liver failure, hemochromatosis, and diseases of the biliary tract. Diabetes is often associated with more frequent adverse outcomes and should be managed aggressively. Fortunately, even in the setting of advanced cirrhosis, our usual armamentarium of diabetic medications can be used safely and effectively.