Safety and tolerability of sitagliptin in patients with type 2 diabetes: a pooled analysis

<p>Abstract</p> <p>Background</p> <p>Sitagliptin, a highly selective dipeptidyl peptidase-4 inhibitor, is the first in a new class of oral antihyperglycemic agents (AHAs) for the treatment of patients with type 2 diabetes. Type 2 diabetes is a life-long disease requiring chronic treatment and management. Therefore, robust assessment of the long-term safety and tolerability of newer therapeutic agents is of importance. The purpose of this analysis was to assess the safety and tolerability of sitagliptin by pooling 12 large, double-blind, Phase IIb and III studies up to 2 years in duration. Methods: This analysis included 6139 patients with type 2 diabetes receiving either sitagliptin 100 mg/day (N = 3415) or a comparator agent (placebo or an active comparator) (N = 2724; non-exposed group). The 12 studies from which this pooled population was drawn represent the double-blind, randomized, Phase IIB and III studies that included patients treated with the clinical dose of sitagliptin (100 mg/day) for at least 18 weeks up to 2 years and that were available in a single safety database as of November 2007. These 12 studies assessed sitagliptin as monotherapy, initial combination therapy with metformin, or add-on combination therapy with other oral AHAs (metformin, pioglitazone, sulfonylurea, sulfonylurea + metformin, or metformin + rosiglitazone). Patients in the non-exposed group were taking placebo, pioglitazone, metformin, sulfonylurea, sulfonylurea + metformin, or metformin + rosiglitazone. This safety analysis used patient-level data from each study to evaluate clinical and laboratory adverse experiences.</p> <p>Results</p> <p>For clinical adverse experiences, the incidence rates of adverse experiences overall, serious adverse experiences, and discontinuations due to adverse experiences were similar in the sitagliptin and non-exposed groups. The incidence rates of specific adverse experiences were also generally similar in the two groups, with the exception of an increased incidence rate of hypoglycemia observed in the non-exposed group. The incidence rates of drug-related adverse experiences overall and discontinuations due to drug-related adverse experiences were higher in the non-exposed group, primarily due to the increased incidence rate of hypoglycemia in this group. For cardiac- and ischemia-related adverse experiences (including serious events), there were no meaningful between-group differences. No meaningful differences between groups in laboratory adverse experiences, either summary measures or specific adverse experiences, were observed.</p> <p>Conclusion</p> <p>In patients with type 2 diabetes, sitagliptin 100 mg/day was well tolerated in clinical trials up to 2 years in duration.</p

Fetal polymorphisms at the ABCB1-transporter gene locus are associated with susceptibility to non-syndromic oral cleft malformations

ATP-binding cassette (ABC) proteins in the placenta regulate fetal exposure to xenobiotics. We hypothesized that functional polymorphisms in ABC genes influence risk for non-syndromic oral clefts (NSOC). Both family-based and case–control studies were undertaken to evaluate the association of nine potentially functional single-nucleotide polymorphisms within four ABC genes with risk of NSOC. Peripheral blood DNA from a total of 150 NSOC case-parent trios from Singapore and Taiwan were genotyped, as was cord blood DNA from 189 normal Chinese neonates used as controls. In trios, significant association was observed between the ABCB1 single-nucleotide polymorphisms and NSOC (P<0.05). Only ABCB1 rs1128503 retained significant association after Bonferroni correction (odds ratio (OR)=2.04; 95% confidence interval (CI)=1.42–2.98), while rs2032582 and rs1045642 showed nominal significance. Association with rs1128503 was replicated in a case–control analysis comparing NSOC probands with controls (OR=1.58; 95% CI=1.12–2.23). A comparison between the mothers of probands and controls showed no evidence of association, suggesting NSOC risk is determined by fetal and not maternal ABCB1 genotype. The two studies produced a combined OR of 1.79 (95% CI=1.38–2.30). The T-allele at rs1128503 was associated with higher risk. This study thus provides evidence that potentially functional polymorphisms in fetal ABCB1 modulate risk for NSOC, presumably through suboptimal exclusion of xenobiotics at the fetal–maternal interface