Objective To assess the efficacy and safety of DPP‐4 inhibition with sitagliptin in youth with type 2 diabetes (T2D). Study Design This was a 54‐week, double‐blind, randomized, controlled clinical trial evaluating the safety and efficacy of DPP‐4 inhibition with sitagliptin 100 mg once daily as initial oral therapy in youth with T2D. The 190 participants, aged 10–17 years, had HbA1c 6.5%–10% (7.0%–10% if on insulin). All were negative for pancreatic autoantibodies and overweight/obese at screening or diagnosis. The trial was placebo controlled for the first 20 weeks, after which metformin replaced placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 20. Results Treatment groups were well balanced at baseline (mean ± SD HbA1c = 7.5% ± 1.0, BMI percentile = 97.1% ± 6.8, age = 14.0 years ± 2.0 [57.4% <15], 60.5% female). At Week 20, least squares mean changes from baseline in HbA1c were −0.01% (sitagliptin) and 0.18% (placebo); between‐group difference (95% CI) = −0.19% (−0.68, 0.30), p = 0.448. At Week 54, the changes in HbA1c were 0.45% (sitagliptin) and −0.11 (placebo/metformin). There were no notable between‐group differences in the adverse event profiles through Week 54. Conclusions DPP‐4 inhibition with sitagliptin did not provide significant improvement in glycemic control. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01485614; EudraCT: 2011‐002528‐42)
Objective To assess the efficacy and safety of sitagliptin in youth with type 2 diabetes (T2D) inadequately controlled with metformin ± insulin. Study Design Data were pooled from two 54‐week, double‐blind, randomized, placebo‐controlled studies of sitagliptin 100 mg daily or placebo added onto treatment of 10‐ to 17‐year‐old youth with T2D and inadequate glycemic control on metformin ± insulin. Participants (N = 220 randomized and treated) had HbA1c 6.5%–10% (7.0%–10% if on insulin), were overweight/obese at screening or diagnosis and negative for pancreatic autoantibodies. The primary endpoint was change from baseline in HbA1c at Week 20. Results Treatment groups were well balanced at baseline (mean HbA1c = 8.0%, BMI = 30.9 kg/m2, age = 14.4 years [44.5% <15], 65.9% female). The dose of background metformin was >1500 mg/day for 71.8% of participants; 15.0% of participants were on insulin therapy. At Week 20, LS mean changes from baseline (95% CI) in HbA1c for sitagliptin/metformin and placebo/metformin were −0.58% (−0.94, −0.22) and −0.09% (−0.43, 0.26), respectively; difference = −0.49% (−0.90, −0.09), p = 0.018; at Week 54 the LS mean (95% CI) changes were 0.35% (−0.48, 1.19) and 0.73% (−0.08, 1.54), respectively. No meaningful differences between the adverse event profiles of the treatment groups emerged through Week 54. Conclusions These results do not suggest that addition of sitagliptin to metformin provides durable improvement in glycemic control in youth with T2D. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (http://clinicaltrials.gov: NCT01472367, NCT01760447; EudraCT: 2011‐002529‐23/2014‐003583‐20, 2012‐004035‐23).
MK-0431-P083, a multinational, 54-week, phase III study of the DPP-4 inhibitor sitagliptin (SITA) as initial oral therapy in patients 10-17 years of age with T2D, was initiated in 2012 and completed enrollment in 2018. A total of 201 patients with T2D who were either drug-naïve or on insulin alone at study entry were randomized and treated. Baseline characteristics of this population were summarized in a preliminary analysis and are presented below. Mean age was 14.0 ± 2.0 years, ∼58% were <15 years of age, and ∼61% were female. The majority (∼53%) were White, 14.9% were Asian, 5.5% were Black, and ∼19% were multiracial, with ∼37% describing themselves as Hispanic. The mean duration of diabetes was 0.7 ± 1.2 years, with ∼17% of participants having a duration ≥1 year. Approximately 11% of participants were on insulin at study entry. Mean BMI was 32.2 ± 7.7 kg.m-2, mean waist circumference was 100.9 ± 17.5 cm, and mean systolic and diastolic BP were 115.5 ± 10.6 mm Hg and 70.5 ± 8.5 mm Hg, respectively. Mean A1C was 7.5 ± 1.0%, and mean FPG 138.3 ± 45.2 mg/dL. Mean triglycerides were 137.4 ± 73.8 mg/dL and mean eGFR (calculated using the MDRD formula) was 200.4 ± 61.1 mL.min-1/1.73 m2. Mean ALT and AST levels were 27.3 ± 18.4 IU/L and 21.6 ± 9.8 IU/L, respectively. Among females, ∼71% had Tanner IV-V breast development, and among males, ∼63% had Tanner IV-V testicular development. These baseline data show that most participants in this study were drug-naïve, with a relatively short duration of T2D, and were predominantly female, White, and sexually mature. They were significantly obese, with central adiposity. Except for race, the demographic and anthropometric characteristics and the A1C and FPG of the participants in this global study are consistent with previous reports of patients predominantly from the United States. In addition, these baseline data confirm reports of glomerular hyperfiltration in pediatric patients with T2D. Disclosure M.Y. Jalaludin: Advisory Panel; Self; Novo Nordisk Inc. Research Support; Self; Merck Sharp & Dohme Corp., Novo Nordisk Inc. R. Garcia: None. R.S. Newfield: Research Support; Self; Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Eli Lilly and Company, University of California and Rady Children's Hospital, San Diego. C.A. Rosario: None. Y. Samoilova: None. N. Shehadeh: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi-Aventis. Speaker's Bureau; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp. Y. Zhang: Employee; Self; Merck Sharp & Dohme Corp. L.W. Scherer: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. C.K. Saha: Research Support; Self; Indiana University School of Medicine. S.S. Engel: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc. K.D. Kaufman: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. R. Shankar: Employee; Spouse/Partner; AstraZeneca. Employee; Self; Merck & Co., Inc. Employee; Spouse/Partner; NGM Biopharmaceuticals. Funding Merck & Co., Inc.
Approved antihyperglycemic therapies for pediatric patients with T2D are currently limited to metformin (MET) and insulin. SITA is being evaluated in 3 studies in patients 10-17 years of age with T2D: SITA as initial oral therapy, MK-0431 P083; SITA as add-on to MET administered as a fixed dose combination (FDC), MK-0431A P170; and SITA as add-on to MET extended-release administered as a FDC of SITA and MET XR, MK-0431A XR P289. The studies, conducted to fulfill post-marketing requirements, and a Pediatric Investigation Plan (EU), were initiated between 2011 and 2013; enrollment completed in 2018. Study protocols were amended since initiation to accommodate regulatory agency requirements, reduce patient burden related to study conduct, and improve patient accrual. Major amendments to the protocols, their rationales, and their impacts are summarized (Table) and demonstrate the flexibility that may be required to enroll such studies. The impact on enrollment of 2 amendments common to all 3 studies were quantifiable. Of patients randomized after approval of an amendment that broadened the A1C entry criterion (from lower limit of 7.0% to 6.5%), ∼34% in P083, ∼20% in P170 and ∼20% in P289 had a baseline A1C between 6.5% and 6.9%. Of patients randomized after approval of an amendment to include patients on background insulin, 11% of patients in P083, 22% in P170, and 19% in P289 enrolled on background insulin. Disclosure R. Shankar: Employee; Spouse/Partner; AstraZeneca. Employee; Self; Merck & Co., Inc. Employee; Spouse/Partner; NGM Biopharmaceuticals. V.P. Pozharskaya: Employee; Self; Merck & Co., Inc. K. Leight: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. R.S. Newfield: Research Support; Self; Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Eli Lilly and Company, University of California and Rady Children's Hospital, San Diego. A. Deeb: None. R. Garcia: None. C.A. Rosario: None. C.K. Saha: Research Support; Self; Indiana University School of Medicine. N. Shehadeh: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi-Aventis. Speaker's Bureau; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp. Y. Samoilova: None. S.S. Engel: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. M.Y. Jalaludin: Advisory Panel; Self; Novo Nordisk Inc. Research Support; Self; Merck Sharp & Dohme Corp., Novo Nordisk Inc. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc. K.D. Kaufman: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. Funding Merck & Co., Inc.
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