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IntroductionThe objective of this study was to assess the effect of sitagliptin on insulin dose in patients with inadequately controlled type 2 diabetes who titrate basal insulin to a target fasting glucose level after initiating sitagliptin.MethodsThis was a multicenter, randomized, double-blind, placebo-controlled, 24-week clinical trial in which treatment with sitagliptin 100 mg/day or placebo was administered concurrently with insulin glargine titration, targeting a fasting glucose of 4.0–5.6 mmol/L (72–100 mg/dL). The trial randomized 660 patients with type 2 diabetes and inadequate glycemic control on insulin, with or without metformin (≥1500 mg/day) or sulfonylurea, for ≥10 weeks. Patients could remain on metformin but not sulfonylurea after randomization.ResultsThe increase from baseline in the daily dose of insulin was less in the sitagliptin group (N = 329) compared to placebo (N = 329) (between group difference = −4.7 IU [95% confidence interval [CI] −8.3, −1.2]; p = 0.009). Patients in the sitagliptin group had lower glycated hemoglobin (HbA1c) levels after 24 weeks (between-group difference of −0.4% [95% CI −0.6, −0.3; −4.9 mmol/mol (95% CI −6.6, −3.2)]; p < 0.001), and more patients in the sitagliptin group reached the HbA1c goal of <7.0% (53 mmol/mol), with a between-group difference of 17.3% (95% CI 10.4%, 24.1%; p < 0.001). Fewer patients in the sitagliptin group experienced an adverse event of hypoglycemia (between-group difference = −15.5%, p < 0.001).ConclusionAdministration of sitagliptin prior to intensive titration of basal insulin glargine reduces the insulin dose requirement while providing superior glycemic control and less hypoglycemia, compared to an insulin-only regimen.FundingMerck & Co., Inc., Kenilworth, NJ, USA.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-015-0105-3) contains supplementary material, which is available to authorized users.

The development of the structure-activity studies leading to the discovery of anacetrapib is described. These studies focused on varying the substitution of the oxazolidinone ring of the 5-aryloxazolidinone system. Specifically, it was found that substitution of the 4-position with a methyl group with the cis-stereochemistry relative to the 5-aryl group afforded compounds with increased cholesteryl ester transfer protein (CETP) inhibition potency and a robust in vivo effect on increasing HDL-C levels in transgenic mice expressing cynomolgus monkey CETP.

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