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Hepatotoxicity in the Diabetic Population

Posted Oct 03 2008 11:31am
Diabetes is associated with clinical complications such as cardiopathy, nephropathy, and retinopathy .

Until now, the link between risk of hepatic failure and diabetic condition was unclear.

However, hepatotoxicity of antidiabetic drugs emerged as a common clinical complication.

Antidiabetic drugs with reported cases of hepatotoxicity include sulfonylureas, alpha-glucosidase inhibitors, biguanides, and thiazolidinediones.

Drug-induced hepatotoxicity has been reported occasionally with second-generation sulfonylureas. Second-generation sulfonylureas include glipizide, glibenclamide and glimepiride.

For alpha-glucosidase inhibitors, the most well-known of this class is acarbose. It is minimally absorbed in unchanged form after oral administration, therefore, this drug is widely believed to be safe. However, there were cases of severe hepatotoxicity reported for acarbose.

Biguanides (metformin) is widely used for the treatment of type 2 diabetes. A serious but rare side effect, lactic acidosis, is caused because of its interference with mitochondrial oxidative processes. For hepatotoxicity, only one or two cases reported so far.

Thiazolidinediones (TZDs, also known as glitazones) are insulin sensitizers now widely used for the treatment of type 2 diabetes. Three TZDs are being used in clinical practice: troglitazone, pioglitazone, and rosiglitazone.

Troglitazone is a peroxisome proliferators–activated receptor gamma agonist that enhances insulin sensitivity. Within one year after its widespread use, individual cases of liver injury and failure were reported. The mounting evidence for the idiosyncratic hepatotoxicity of troglitazone in the following years led to its withdrawal from the market in 2000.

Since then, efforts have been made to make clear the mechanism of troglitazone-induced hepatotoxicity. A number of hypotheses were deduced to explain troglitazone-induced cell injury, including the formation and accumulation of toxic metabolites, mitochondrial dysfunction and oxidant stress, inhibition of the bile salt transporter and bile acid toxicity, and the induction of apoptosis.

After the withdrawal of troglitazone due to hepatotoxicity, only pioglitazone and rosiglitazone can be used for the treatment of patients with type 2 diabetes. Fortunately, these two drugs in the TZD class have a much safety profile for hepatotoxicity.

Well, antidiabetic drugs are to be taken for long term, for life. For this reason, diabetic patients that are taking drug therapies should be monitored regularly. Although till now, antidiabetic drugs are still relatively 'liver-friendly', recent epidemiological studies suggested that patients with diabetes are twice as likely to suffer hepatic failure compared to patients who do not have diabetes. Increased incidences of hepatotoxicity have been observed in patients with diabetes receiving drug therapies.

We are not sure what is the mechanism or the predisposing factors for the hepatotoxicity in diabetic patients with drug therapies.

It is recommended that diabetic patients with drug therapies should have their liver function tests (LFT) regular (perhaps annually, or twice per year).

[Source: U.S. Pharmacist]
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