Possible mechanism of contraindication to acarbose in type 2 diabetic patients with renal failure

In Taiwan, 25.7% of dialysis patients have diabetes mellitus and more than 39.8% of patients with type-2 diabetes have microalbuminuria. Despite of this fact, 93.3% of type-2 diabetes patients are treated with oral anti-diabetic drugs (OADs), leading to great interest in relative drug metabolic disturbance caused by nephropathy. The prescribing rate in Taiwan for acarbose rose from 0.02% in 1997 to 4.1% in 2003 (P < 0.0001). However, the safety of using acarbose has frequently been ignored in diabetic patients with nephropathy. In healthy volunteers with normal renal function, only 1.7% of an oral dose of acarbose was absorbed as an original compound. However, approximately 35% of the ingested dosage marked with ¹⁴C was recovered in urine, indicating that its metabolites have been absorbed. In populations with renal impairment (creatinine clearance < 25 ml/min), the values of the peak plasma concentration and the mean steady-state area under the curve (AUC) of acarbose increased by five and six times normal values, respectively. Although there currently does not exist evidence that acarbose is toxic to the kidney, acarbose and its metabolites very likely accumulate in the patients with renal impairment, causing ill-defined iatrogenic risks. In related clinical trials, significant increases in transaminases were found in 3.8-15% of patients treated with acarbose. However, the latent period of acarbose induced hepatoxicity may last up to weeks or months after ingestion and without any allergic reactions. Therefore, the mechanism of acarbose induced hepatoxicity, caused by the original compound or its metabolites, may be due to metabolic idiosyncrasy. Although there are no available clinical trial data or case reports of hepatotoxicity in the patients with renal impairment, it is reasonable to be aware of accumulation of the drug and its metabolites in particular, in such patients, as well as those with high incidence of liver abnormalities. The use of acarbose is therefore contraindicated in patients with severe renal failure. Lower dosage and enzyme monitoring are recommended for those who must be treated with acarbose.