Safety of DPP-IV inhibitors
Overall, the DPP-4 inhibitors as a class appear to be well tolerated, and rates of adverse effects have been low, and generally not different from rates observed during placebo. Retrospective analyses of data from the clinical programmes of sitagliptin, vildagliptin, saxagliptin and linagliptin do not appear to indicate any increased cardiovascular risk with the DPP-4 inhibitors relative to comparators, but large prospective trials (including up to 12,000 patients), designed specifically to evaluate the effect of DPP-4 inhibitors on cardiovascular outcomes are ongoing/planned (TECHOS (sitagliptin), EXAMINE (alogliptin), CAROLINA (linagliptin), SAVOR-TIMI 53 (saxagliptin). There has also been some debate over whether incretin-based therapies, including the DPP-4 inhibitors, are associated with elevated risk of pancreatitis. This does not seem to be borne out by the pooled safety analyses or retrospective analyses of large healthcare data bases. Continued vigilance and longer term reports are still needed to confirm these observations.
Small differences between the different DPP-4 inhibitors have been seen from preclinical safety studies and observations made during the course of the clinical trial programmes. Thus, vildagliptin and saxagliptin have been reported to be associated with adverse skin toxicology in preclinical studies (monkeys). However, this may be a finding which is specific to monkeys, as it has not been observed in other preclinical species, and importantly, there have been no reports of skin problems in the clinical trials with any of the inhibitors. At the time of initial registration of vildagliptin (in the European Union), a meta-analysis of the clinical trial data revealed that the 100 mg once-daily dose was associated with small numerical elevations in liver transaminases compared to placebo or 50 mg given twice-daily. For this reason, the recommended therapeutic dose was changed to 50 mg twice-daily, with the recommendation that liver function tests to be performed before initiation and at three monthly intervals for the first year of treatment and periodically thereafter. Subsequently, the trend for increases (greater than three times the upper limit of normal) in liver enzymes was confirmed in the larger pooled safety analysis, but notably, this was not associated with any increased incidence of actual hepatic adverse events. Nevertheless, liver function tests are still recommended and vildagliptin is not approved for use in patients with hepatic insufficiency.