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In a recent review about the use of incretin-based therapies in patients with chronic liver disease and the hepatic safety of this new class of antidiabetic agents, the overall liver safety of dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) was considered as reassuring. More particularly, the review mentioned that "no hepatotoxicity has been reported in the development programme of alogliptin'' [1]. This conclusion, based upon an extensive review published in 2010 [2], has been challenged in a recent letter to the Editor based on three sets of arguments [3]: (1) a subsequent analysis of available data with alogliptin by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA); (2) rare case reports of liver injury in patients treated with alogliptin leading to special warning from the FDA; and (3) a numerical imbalance in the rate of patients with alanine aminotransferase (ALT) elevations treated with alogliptin versus placebo in the large Examination of Cardiovascular Outcomes with Alogliptin Versus Standard of Care (EXAMINE) trial [4]. However, all these data need a careful assessment and may also be challenged.
A recent review of safety of alogliptin confirmed that this DPP-4 inhibitor is generally well tolerated. In 13 controlled trials, adverse events were similar in all treatment arms; no specific discussion of hepatotoxicity or elevated ALT levels was mentioned [5]. Since the approval of alogliptin, a number of new studies have been completed, including the cardiovascular outcome trial EXAMINE [4] and a long-term durability study. Table 1A shows updated integrated results of the ALT enzymes dataset from all controlled phase 2/3 studies, including the latter two recent trials (2012 FDA Resubmission Dataset: Controlled Phase 2 and 3 Study Group). With this...