Single- and Multiple-Dose Pharmacokinetics of Gefapixant (MK-7264), a P2X3 Receptor Antagonist, in Healthy Adults.

Gefapixant (MK-7264, RO4926219, AF-219) is a first-in-class P2X3 antagonists being developed to treat refractory or unexplained chronic cough. The initial single- and multiple-dose safety, tolerability, and pharmacokinetics of gefapixant at doses ranging from 7.5 to 1800 mg were assessed in four clinical trials. Following single-dose administration of 10-450 mg, the pharmacokinetic (PK) profile of gefapixant in plasma and urine demonstrated low inter-subject variability and a dose-proportional exposure. Following administration of multiple doses twice daily, the plasma exposures were dose-proportional at doses ranging from 7.5 to 50 mg and less than dose-proportional at doses ranging from 100 to 1800 mg. The time to mean peak drug concentration ranged from 2 to 3 h post-dose, and steady state was achieved by 7 days after dosing, with an accumulation ratio of approximately 2, comparing data from day 1 to steady state. The mean apparent terminal half-life ranged from 8.2 to 9.6 h. Gefapixant was primarily excreted unmodified in urine. Gefapixant was well tolerated following single-dose administration up to 1800 mg and multiple doses up to 1800 mg twice daily; there were no serious adverse events (AEs) reported. The most common AE reported was dysgeusia. The PK profile supports a twice-daily dosing regimen.

Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor.

BACKGROUND: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low density lipoprotein-cholesterol, but despite nearly 2 decades of effort, an oral inhibitor of PCSK9 is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable to small-molecule drug design. METHODS: Novel mRNA display screening technology was used to identify lead chemical matter, which was then optimized by applying structure-based drug design enabled by novel synthetic chemistry to identify macrocyclic peptide (MK-0616) with exquisite potency and selectivity for PCSK9. Following completion of nonclinical safety studies, MK-0616 was administered to healthy adult participants in a single rising-dose Phase 1 clinical trial designed to evaluate its safety, pharmacokinetics, and pharmacodynamics. In a multiple-dose trial in participants taking statins, MK-0616 was administered once daily for 14 days to characterize the safety, pharmacokinetics, and pharmacodynamics (change in low density lipoprotein cholesterol). RESULTS: MK-0616 displayed high affinity (Ki = 5pM) for PCSK9 in vitro and sufficient safety and oral bioavailability preclinically to enable advancement into the clinic. In Phase 1 clinical studies in healthy adults, single oral doses of MK-0616 were associated with >93% geometric mean reduction (95% CI, 84-103) of free, unbound plasma PCSK9; in participants on statin therapy, multiple-oral-dose regimens provided a maximum 61% geometric mean reduction (95% CI, 43-85) in low density lipoprotein cholesterol from baseline after 14 days of once-daily dosing of 20 mg MK-0616. CONCLUSIONS: This work validates the use of mRNA display technology for identification of novel oral therapeutic agents, exemplified by the identification of an oral PCSK9 inhibitor, which has the potential to be a highly effective cholesterol lowering therapy for patients in need.

Efficacy and safety of ipragliflozin in Japanese patients with type 2 diabetes and inadequate glycaemic control on sitagliptin.

AIMS: To assess the efficacy, safety and tolerability of ipragliflozin 50 mg once daily added to sitagliptin 50 mg once daily monotherapy in Japanese patients with type 2 diabetes (T2D). MATERIALS AND METHODS: The results of two clinical trials are reported. In both trials, patients had glycated haemoglobin (HbA1c) levels of 7.0% to 10.0% on sitagliptin 50 mg once daily 2 weeks prior to addition of ipragliflozin or placebo. In one trial (Trial 843), patients were randomized 1:1 to addition of blinded ipragliflozin 50 mg once daily (n = 73) or placebo (n = 70) for 24 weeks; the primary endpoint was efficacy (change in HbA1c at Week 24). In the other trial (Trial 849), open-label ipragliflozin 50 mg once daily was added for 52 weeks (n = 77); the primary objective was to assess safety/tolerability. RESULTS: In Trial 843, baseline characteristics were similar between groups (mean age 60.5 years, HbA1c 8.0%); after 24 weeks, adding ipragliflozin provided significantly greater reduction in HbA1c compared to placebo: least squares mean difference -0.77% (95% confidence interval -0.98, -0.57; P <0.001). In Trial 843, the incidences of adverse events (AEs) overall and prespecified AEs of clinical interest (symptomatic hypoglycaemia, urinary tract infection, genital infection, hypovolaemia, and polyuria/pollakiuria) were similar between groups. In Trial 849, specific AEs with incidence ≥5% were nasopharyngitis, pollakiuria, back pain, thirst, constipation, influenza and arthralgia; drug-related AEs reported in ≥2 patients were pollakiuria, thirst and constipation. CONCLUSIONS: Ipragliflozin 50 mg once daily added on to sitagliptin 50 mg once daily monotherapy provided significant improvement in glycaemic control and was generally well tolerated in Japanese patients with T2D. ClinicalTrials.gov: NCT02577003, NCT02564211.

A randomized, placebo-controlled trial to assess the efficacy and safety of sitagliptin in Japanese patients with type 2 diabetes and inadequate glycaemic control on ipragliflozin.

AIMS: To investigate the efficacy, safety and tolerability of sitagliptin 50 mg once daily added to ipragliflozin 50 mg once daily monotherapy in Japanese patients with type 2 diabetes (T2D). MATERIALS AND METHODS: Japanese patients with T2D and glycated haemoglobin (HbA1c) 7.0% to 10.0% while treated with ipragliflozin 50 mg once daily were randomized 1:1 to additional treatment with sitagliptin 50 mg once daily (N = 70) or matching placebo (N = 71) for 24 weeks. The primary efficacy endpoint was change in HbA1c at Week 24. Secondary efficacy endpoints were changes in 2-hour post-meal glucose (PMG), total PMG 0- to 2-hour area under the curve (AUC0-2h ), and fasting plasma glucose (FPG). RESULTS: Baseline characteristics were similar in the two groups (mean age 55.5 years, mean baseline HbA1c 8.0%). After 24 weeks, the addition of sitagliptin provided significantly greater reduction in HbA1c compared to placebo (least squares [LS] mean difference -0.83% [95% confidence interval -1.05, -0.62]; P <0.001). Significant reductions were also observed in all secondary endpoints: LS mean differences from placebo in changes in 2-hour PMG, total PMG AUC0-2h , and FPG were -42.5 mg/dL, -67.0 mg·h/dL and -11.2 mg/dL, respectively (all P <0.001). The incidence of adverse events (AEs) overall and incidence of predefined AEs of clinical interest (symptomatic hypoglycaemia, urinary tract infection, genital infection, hypovolaemia and polyuria/pollakiuria) were similar in the two groups. CONCLUSIONS: In Japanese patients with T2D, sitagliptin 50 mg once daily added to ipragliflozin 50 mg once daily monotherapy provided significant improvement in glycaemic control and was generally well tolerated. ClinicalTrials.gov: NCT02577016.

A randomized, placebo-controlled study to evaluate the efficacy and safety of adding omarigliptin to insulin therapy in Japanese patients with type 2 diabetes and inadequate glycaemic control.

AIM: To evaluate the efficacy and safety of adding the once-weekly oral dipeptidyl peptidase-4 inhibitor omarigliptin to treatment of Japanese patients with type 2 diabetes and inadequate glycaemic control on insulin monotherapy. MATERIALS AND METHODS: In a 52-week clinical trial, Japanese patients on insulin monotherapy were randomized to once-weekly omarigliptin 25 mg (N = 123) or placebo (N = 61) for a 16-week, double-blind, placebo-controlled period. After Week 16, patients continued or switched to omarigliptin for a 36-week open-label period. RESULTS: From a mean baseline of approximately 8.8%, the Week 16 least squares mean changes in HbA1c were -0.61% (omarigliptin) and 0.29% (placebo); the between-group difference was -0.90% (p < .001). At Week 52, the mean change from baseline in HbA1c was -0.57% in both the group on omarigliptin for 52 weeks and the group on omarigliptin for 36 weeks (switched from placebo at Week 16). During the first 16 weeks of treatment, the incidences of adverse events (AEs), serious AEs, drug-related AEs and discontinuation from trial medication because of an AE were similar in both groups. A slight increase in incidence of symptomatic hypoglycaemia was observed in the omarigliptin group (n = 13 [10.6%]) compared with placebo (n = 4 [6.6%]). No severe hypoglycaemia was reported during the study. No new safety signals emerged with treatment beyond Week 16 through Week 52. CONCLUSION: The addition of once-weekly omarigliptin to insulin therapy for up to 52 weeks was generally well tolerated and provided clinically meaningful improvement in glycaemic control throughout the trial period. ClinicalTrials.gov: NCT02906709.

Efficacy and Safety of Sitagliptin Compared with Dapagliflozin in People ≥ 65 Years Old with Type 2 Diabetes and Mild Renal Insufficiency.

INTRODUCTION: Older patients with type 2 diabetes (T2D) are at increased risk of diabetic nephropathy and mild renal insufficiency. This analysis compared the anti-hyperglycemic efficacy and safety of sitagliptin with dapagliflozin in patients ≥ 65 years of age with T2D and mild renal insufficiency. METHODS: This was a post hoc analysis of data from 410 patients ≥ 65 years old who participated in a 24-week, randomized, double-blind clinical trial (CompoSIT-R [comparison of sitagliptin with dapagliflozin in mild renal impairment]; NCT02532855) in T2D patients with mild renal insufficiency and on metformin ± a sulfonylurea; the primary efficacy end point was change in HbA1c at week 24. RESULTS: Treatment groups were well balanced at baseline (mean HbA1c = 7.7/7.7% and eGFR = 79/76 ml/min/1.73 m2 for sitagliptin/dapagliflozin). At week 24, LS mean (95% CI) change in HbA1c and percentage of patients with HbA1c < 7% were greater with sitagliptin, - 0.48% and 41%, respectively, compared with dapagliflozin, - 0.36% and 28%; between-group differences = - 0.12% (- 0.36, 0.01) and 12.8% (3.3, 22.2) for change in HbA1c and percentage with HbA1c < 7%, respectively. The sitagliptin group had greater reductions in PPG end points, while the dapagliflozin group had greater reductions in FPG. Treatments were generally well tolerated. There were fewer drug-related adverse events (AEs) with sitagliptin than with dapagliflozin but AE profiles were otherwise similar. CONCLUSIONS: In patients ≥ 65 years of age with T2D and mild renal insufficiency with inadequate glycemic control on metformin ± sulfonylurea, treatment with sitagliptin for 24 weeks resulted in improvement in HbA1c relative to treatment with dapagliflozin that is consistent with that previously observed in the overall population. Both treatments were generally well tolerated.

Double-blind, randomized clinical trial assessing the efficacy and safety of early initiation of sitagliptin during metformin uptitration in the treatment of patients with type 2 diabetes: The CompoSIT-M study.

AIMS: To characterize the glycaemic efficacy and safety of initiation of the dipeptidyl peptidase-4 inhibitor sitagliptin during metformin dose escalation in people with type 2 diabetes (T2D) not at glycated haemoglobin (HbA1c) goal on a sub-maximal dose of metformin. MATERIALS AND METHODS: Study participants with HbA1c ≥58 mmol/mol and ≤97 mmol/mol (≥7.5% and ≤11.0%) while on 1000 mg/d metformin were randomized to sitagliptin 100 mg once daily or placebo. All were to uptitrate metformin to 2000 mg/d. A longitudinal data analysis model was used to test the primary hypothesis that sitagliptin is superior to placebo when initiated during uptitration of metformin in reducing HbA1c at week 20. [ClinicalTrials.gov Identifier: NCT02791490, EudraCT: 2015-004224-59] RESULTS: A total of 458 participants (mean HbA1c 71.1 mmol/mol [8.7%], T2D duration 6.3 years) were treated. After 20 weeks, the least squares (LS) mean changes from baseline in HbA1c were -12.1 mmol/mol (-14.0, -10.1) (-1.10% [-1.28, -0.93]) and -7.6 mmol/mol (-9.6, -5.6) (-0.69% [-0.88, -0.51]) with sitagliptin and placebo, respectively; the between-group difference in LS mean changes from baseline HbA1c was -4.5 mmol/mol (-6.5, -2.5) (-0.41% [-0.59, -0.23]); P < 0.001. The likelihood of having HbA1c <53 mmol/mol (<7.0%) at week 20 was higher in the sitagliptin group than in the placebo group in the overall population (relative risk 1.7, P = 0.002) and in those with a baseline HbA1c ≥69 mmol/mol (≥8.5%) (relative risk 2.4, P = 0.026). There were no notable differences between groups with regard to adverse events overall, hypoglycaemia events, changes in body weight or other safety variables. CONCLUSION: In participants not at HbA1c goal on a sub-maximal dose of metformin, addition of sitagliptin at the time of metformin dose uptitration improved glycaemic response and HbA1c goal attainment, with similar safety and tolerability, compared to metformin uptitration alone.

Efficacy and safety of sitagliptin added to treatment of patients with type 2 diabetes inadequately controlled with premixed insulin.

To improve understanding of the safety and efficacy of adding sitagliptin to treatment of patients with type 2 diabetes taking premixed insulin, data from patients using premixed insulin ± metformin (screening HbA1c ≥7.5% and ≤11%) in either of two clinical trials in which sitagliptin 100 mg once-daily or placebo was added to various formulations of insulin treatment, were analysed. In both trials, insulin doses were to remain stable throughout the 24-week trial period. At week 24, the between-group difference (sitagliptin - placebo) in the least squares mean (95% confidence intervals) change from baseline in HbA1c in patients using premixed insulin was -0.43% (-0.58, -0.28), P <0.001. Adverse events were generally similar between the treatment groups. The incidence of symptomatic hypoglycaemia was slightly higher with sitagliptin, and the incidence of hypoglycaemia requiring medical attention was slightly higher with placebo; in both cases the difference was not statistically significant. The data from this pooled analysis confirm the utility of sitagliptin used in combination with premixed insulin in patients with type 2 diabetes.

Double-blind, randomized clinical trial comparing the efficacy and safety of continuing or discontinuing the dipeptidyl peptidase-4 inhibitor sitagliptin when initiating insulin glargine therapy in patients with type 2 diabetes: The CompoSIT-I Study.

AIMS: To compare the effects of continuing versus discontinuing sitagliptin when initiating and intensively titrating insulin glargine. MATERIALS AND METHODS: Eligible patients had inadequately controlled type 2 diabetes on metformin (≥1500 mg/d) in combination with a dipeptidyl peptidase-4 (DPP-4) inhibitor and/or a sulphonylurea. Those on metformin + sitagliptin were directly randomized; all others were switched to metformin + sitagliptin (discontinuing other DPP-4 inhibitors and sulphonylureas) and stabilized during a run-in period. At randomization, patients were allocated to continuing sitagliptin or discontinuing sitagliptin, with both groups initiating insulin glargine and titrating to a target fasting glucose of 4.0 to 5.6 mmol/L. RESULTS: A total of 743 participants (mean glycated haemoglobin [HbA1c] 72.6 mmol/mol [8.8%], disease duration 10.8 years), were treated. After 30 weeks, the mean HbA1c and least squares (LS) mean change from baseline in HbA1c were 51.4 mmol/mol (6.85%) and -20.5 mmol/mol (-1.88%) in the sitagliptin group and 56.4 mmol/mol (7.31%) and -15.5 mmol/mol (-1.42%) in the placebo group; the difference in LS mean changes from baseline HbA1c was -5.0 mmol/mol (-0.46%; P < 0.001). The percentage of participants with HbA1c <53 mmol/mol (<7.0%) was higher (54% vs. 35%) and the mean daily insulin dose was lower (53 vs. 61 units) in the sitagliptin group. Despite lower HbA1c, event rates and incidences of hypoglycaemia were not higher in the sitagliptin group. Adverse events overall and changes from baseline in body weight were similar between the two treatment groups. CONCLUSION: When initiating insulin glargine therapy, continuation of sitagliptin, compared with discontinuation, resulted in a clinically meaningful greater reduction in HbA1c without an increase in hypoglycaemia. ClinicalTrials.gov Identifier: NCT02738879.

A randomized clinical trial of the efficacy and safety of sitagliptin compared with dapagliflozin in patients with type 2 diabetes mellitus and mild renal insufficiency: The CompoSIT-R study.

AIM: To compare the efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin with the sodium-glucose transporter-2 inhibitor dapagliflozin in patients with type 2 diabetes and mild renal insufficiency. MATERIALS AND METHODS: Patients with HbA1c ≥7.0 to ≤9.5% (≥53 to ≤80 mmol/mol) and estimated glomerular filtration rate ≥60 to <90 mL/min/1.73m2 on metformin (≥1500 mg/d) ± sulfonylurea were randomized to sitagliptin 100 mg (n = 307) or dapagliflozin 5 mg titrated to 10 mg (n = 306) once daily for 24 weeks. A longitudinal data analysis model was used to test the primary hypothesis that sitagliptin is non-inferior to dapagliflozin in reducing HbA1c at Week 24, with superiority to be tested if non-inferiority is met. ClinicalTrials.gov NCT02532855. RESULTS: Baseline mean HbA1c (% [mmol/mol]) was 7.7 (60.9) and 7.8 (61.2), and mean eGFR (mL/min/1.73m2 ) was 79.4 and 76.9 for the sitagliptin and dapagliflozin groups, respectively. After 24 weeks, the between-group difference in least squares mean (95% CI) changes from baseline in HbA1c was -0.15% (-0.26, -0.04) (-1.67 mmol/mol [-2.86, -0.48]), P = 0.006, meeting the prespecified criteria for declaring both non-inferiority and superiority of sitagliptin versus dapagliflozin. The HbA1c goal of <7% (<53 mmol/mol) was met by 43% (sitagliptin) and 27% (dapagliflozin) of patients. No meaningful between-group difference was observed in a pre-specified analysis of 2-hour incremental postprandial glucose excursion. A review of adverse events (AEs) was notable for a lower incidence of drug-related AEs with sitagliptin compared with dapagliflozin. CONCLUSIONS: In patients with type 2 diabetes, mild renal insufficiency and inadequate glycaemic control on metformin ± sulfonylurea, sitagliptin treatment resulted in greater improvement in glycaemic control compared with dapagliflozin and was generally well tolerated.

Efficacy and Safety of Sitagliptin in Hispanic/Latino Patients with Type 2 Diabetes: A Pooled Analysis from Ten Randomized, Placebo-Controlled Phase 3 Clinical Trials.

INTRODUCTION: To assess the efficacy and safety profile of the dipeptidyl-peptidase-4 inhibitor sitagliptin in a population of self-identified Hispanic/Latino patients with type 2 diabetes. METHODS: Data were pooled from ten randomized, double-blind studies in which subjects were treated with sitagliptin 100 mg/day (as mono- or combination therapy) or placebo, and used to evaluate the glycemic efficacy, safety, and tolerability of sitagliptin compared with placebo after 24 weeks of treatment. RESULTS: A total of 804 Hispanic/Latino patients were included in the analysis. Baseline characteristics in the treatment groups were similar (mean baseline HbA1c of approximately 8.5%). The LS mean HbA1c changes from baseline were - 0.94% with sitagliptin and - 0.32% with placebo, and the between-group difference was - 0.62%, p < 0.001. After 24 weeks of treatment, 35% and 18% of subjects were at the HbA1c goal of < 7% in the sitagliptin and placebo groups, respectively. Body weight increased slightly in both treatment groups. Incidences of adverse events of hypoglycemia were similar and low (1.9% and 1.4% for sitagliptin and placebo, respectively) in both groups in studies in which insulin or sulfonylurea were not used and were similar (9% and 11% for sitagliptin and placebo, respectively) when all studies were included. Overall safety and tolerability of treatment with sitagliptin and placebo were similar. No clinically meaningful differences between the safety profile of sitagliptin in the Hispanic/Latino population analyzed here and broader populations previously evaluated were observed. CONCLUSION: In this pooled analysis of sitagliptin therapy vs placebo in Hispanic/Latino patients, sitagliptin provided significant improvement in glycemic control and was generally well tolerated. FUNDING: Merck & Co., Inc., Kenilworth, NJ, USA.

Characteristics of Elderly Patients Initiating Sitagliptin or Non-DPP-4-Inhibitor Oral Antihyperglycemic Agents: Analysis of a Cross-Sectional US Claims Database.

INTRODUCTION: Previous analyses concluded that patients initiating treatment with sitagliptin are older and have more comorbidities than patients initiating treatment with other oral antihyperglycemic agents (OAHAs). However, these studies focused on the general population or subjects ≤ 65 years of age. We sought to compare differences in baseline characteristics of elderly patients (≥ 65 years of age) with T2DM initiating sitagliptin vs. non-DPP-4 inhibitor (non-DPP-4i) OAHA in the MarketScan® Medicare Supplemental Database. METHODS: Relevant patients were identified in the MarketScan® Medicare Supplemental Database and categorized according to the complexity of their antihyperglycemic treatment: initiating monotherapy, escalating to dual combination therapy, or escalating to triple combination therapy. Within each category, the comparison between patients initiating use of sitagliptin or non-DPP-4i OAHA was made within three age groups: 65-74, 75-84, and ≥ 85 years. Gender and comorbidity recorded within the 12 months prior to the index date (date of initiation/escalation of treatment) were assessed as baseline characteristics in each group. Between-treatment group differences in each covariate were compared using standardized differences. RESULTS: Patients with T2DM who initiated treatment with sitagliptin tended to be older and were more likely to have a pre-treatment history of arrhythmia, congestive heart failure, peripheral vascular disease, renal failure, and stroke than those initiating non-DPP-4i OAHAs, with the most pronounced differences observed between patients initiating monotherapy in all three age groups. As treatment complexity advanced to dual combination therapy, the differences were attenuated and mostly observed in the 75-84 and ≥ 85 age groups. In patients aged 65-74 years initiating triple therapy, no differences were observed between groups. CONCLUSION: Patients ≥ 65 years with T2DM initiating sitagliptin tend to be older and have more comorbidities than those prescribed other classes of OAHA. Appropriate adjustment is required to minimize the impact of potential confounding and channeling bias in any comparative analyses including users of sitagliptin. FUNDING: Merck & Co., Inc., Kenilworth, NJ, USA.

A randomized, double-blind trial evaluating the efficacy and safety of monotherapy with the once-weekly dipeptidyl peptidase-4 inhibitor omarigliptin in people with type 2 diabetes.

AIMS: To assess the efficacy and safety of once-weekly omarigliptin as monotherapy in people with type 2 diabetes mellitus (T2DM). METHODS: People with T2DM not on glucose-lowering medications, or who were washed off monotherapy or low-dose dual therapy, were randomized double-blind to omarigliptin 25 mg (n=165) or matching omarigliptin placebo (n=164) for 24 weeks, followed by a 30-week period to assess continuing efficacy and safety longer-term of omarigliptin during which metformin was added to the placebo group and metformin placebo to the omarigliptin group. RESULTS: From a mean baseline HbA1c of 8.0-8.1%, the least squares mean (95% CI) change from baseline in HbA1c at week 24 (primary endpoint) was -0.49% (-0.73, -0.24) in the omarigliptin group and -0.10% (-0.34, 0.14) in the placebo group, for a between-group difference of -0.39% (-0.59, -0.19) (p<.001). Protocol deviation in use of metformin by 38 of 252 (15%) people whose samples were available for evaluation probably attenuated glycemic efficacy results, as suggested by the LS mean difference -0.53% (-0.75, -0.32) after censoring of such participants. At 24 and 54 weeks, the incidences of adverse events (AEs) were similar in the omarigliptin and placebo groups. During 54 weeks there were no AEs of symptomatic hypoglycemia in the omarigliptin group and 5 AEs in the placebo group. Over 54 weeks, a majority of the omarigliptin treatment had a persistent reduction in HbA1c, remaining rescue-free. CONCLUSIONS: In people with T2DM, omarigliptin monotherapy improved glycemic control over 54 weeks and was generally well tolerated with a low risk of hypoglycemia. ClinicalTrials.gov Identifier: NCT01717313. EudraCT Number: 2012-003626-24.

A randomized, placebo-controlled clinical trial evaluating the safety and efficacy of the once-weekly DPP-4 inhibitor omarigliptin in patients with type 2 diabetes mellitus inadequately controlled by glimepiride and metformin.

BACKGROUND: Type 2 diabetes (T2D) is a progressive disease that often requires a patient to use multiple antihyperglycemic agents to achieve glycemic control with disease progression. Omarigliptin is a once-weekly dipeptidyl peptidase-4 inhibitor. The purpose of this trial was to assess the efficacy and safety of adding omarigliptin to the treatment regimen of patients with T2D inadequately controlled by dual therapy with metformin and glimepiride. METHODS: Patients with T2D and HbA1c ≥7.5% and ≤10.5% while on metformin (≥1500 mg/day) and glimepiride (≥4 mg/day) were randomized to omarigliptin 25 mg once-weekly (N = 154) or placebo (N = 153) for 24 weeks. The primary objective was to assess whether omarigliptin was superior to placebo in reducing HbA1c at Week 24. Secondary objectives were to assess the effects of omarigliptin vs. placebo on FPG and the proportion of subjects attaining HbA1c goals of <7% and <6.5%. RESULTS: From a mean baseline HbA1c of 8.5% (omarigliptin) and 8.6% (placebo), the least squares (LS) mean change from baseline in HbA1c at Week 24 was -0.67% in the omarigliptin group and -0.06% in the placebo group, with a between-group difference (95% CI) of -0.61% (-0.85, -0.38). Treatment with omarigliptin resulted in a significantly greater reduction in FPG relative to placebo (LS mean difference [95% CI] -0.9 mmol/L [-1.4, -0.4]; p < 0.001). The proportion of patients achieving glycemic goals of <7.0% and <6.5% was higher in the omarigliptin group relative to the placebo group. The overall incidences of adverse events (AEs), serious AEs, drug-related AEs and discontinuations were generally similar between treatment groups. The incidence of symptomatic hypoglycemia was 10.5% in the omarigliptin group and 8.5% in the placebo group. Relative to baseline, omarigliptin and placebo treatments were associated with LS mean changes in body weight of -0.1 kg and -0.9 kg, respectively. CONCLUSION: In patients with T2D and inadequate glycemic control on dual therapy with metformin and glimepiride, compared with placebo, once-weekly omarigliptin provided greater improvement in glycemic control and was generally well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01704261 , EudraCT Number: 2012-002612-10. Trial Registration Date: October 8, 2012.

Use of Prohibited Medication, a Potentially Overlooked Confounder in Clinical Trials: Omarigliptin (Once-weekly DPP-4 Inhibitor) Monotherapy Trial in 18- to 45-year-olds.

PURPOSE: The objective of this clinical trial was to assess the efficacy and safety of omarigliptin monotherapy in young adult patients with type 2 diabetes mellitus (T2DM). Unexpected efficacy results in this trial led to a series of investigations that identified the use of prohibited medication by a substantial number of trial patients. METHODS: Patients with T2DM who were ≥18 to <45 years of age and either drug-naive or not on an antihyperglycemic agent for ≥12 weeks with inadequate glycemic control were randomized in a double-blind manner to receive omarigliptin 25 mg once weekly (n = 102) or placebo once weekly (n = 101) for 24 weeks. The objectives of the trial were to assess the effect of treatment with omarigliptin on glycemic parameters, including levels of glycosylated hemoglobin (HbA1c), 2-hour postmeal glucose, and fasting plasma glucose, and to assess the safety and tolerability of omarigliptin. Additional investigations into trial conduct included the measurement of drug levels for omarigliptin and metformin in blood samples collected for future biomedical research, available for approximately one half of the patients. FINDINGS: The mean age of trial participants was 39.2 years, approximately 60% were male, mean body mass index was 32.5 kg/m2, and mean duration of diabetes was 3.1 years. The mean baseline HbA1c value was 7.9% in the omarigliptin group and 8.1% in the placebo group. After 24 weeks, the least squares mean change (95% CI) in HbA1c value from baseline was -0.33% (-0.60 to -0.06) in the omarigliptin group and -0.45% (-0.72 to -0.18) in the placebo group, with a between-group difference of 0.12% (-0.26 to 0.49; P = 0.535). Similarly, no between-group difference was observed for the other glycemic parameters (2-hour postmeal glucose and fasting plasma glucose levels). No issues were identified in drug allocation, dispensing or supply, patient compliance with trial medication, sample handling or analysis, or site trial conduct that explained the observed results. Measurement of drug levels from future biomedical research samples uncovered the use, with no investigator knowledge, of an antihyperglycemic agent that was prohibited by the protocol (ie, metformin) by 42.4% (39 of 92) of patients. Metformin was used by more patients in the placebo group (57% [25 of 44]) than in the omarigliptin group (29% [14 of 48]). IMPLICATIONS: The use of prohibited metformin in a trial of a dipeptidyl peptidase-4 inhibitor, omarigliptin, introduced a confounding factor that invalidated the results of the trial. This behavior may have been encouraged in the trial by protocol-specified self-monitoring of blood glucose levels. Use of prohibited medication may be an underappreciated confounder in clinical trial research. TRIAL REGISTRATIONS: MK-3102-028 (US); ClinicalTrials.gov identifier, NCT01814748; EudraCT number, 2012-004303-12 (EU).

A randomized, placebo-controlled study of the cardiovascular safety of the once-weekly DPP-4 inhibitor omarigliptin in patients with type 2 diabetes mellitus.

BACKGROUND: Omarigliptin is a once-weekly (q.w.) oral DPP-4 inhibitor that is approved for the treatment of patients with type 2 diabetes mellitus (T2DM) in Japan. To support approval of omarigliptin in the United States, the clinical development program included a cardiovascular (CV) safety study. Subsequently, a business decision was made not to submit a marketing application for omarigliptin in the United States, and the CV safety study was terminated. Herein we report an analysis of data from that early-terminated study. METHODS: In this randomized, double-blind study, 4202 patients with T2DM and established CV disease were assigned to either omarigliptin 25 mg q.w. or matching placebo in addition to their existing diabetes therapy. A Cox proportional hazards model was used to summarize the primary endpoint of time to first major adverse CV event (MACE, the composite of CV death, nonfatal myocardial infarction, and nonfatal stroke) and the analysis of first event of hospitalization for heart failure (hHF). RESULTS: The median follow-up was approximately 96 weeks (range 1.1-178.6 weeks). The primary MACE outcome occurred in 114/2092 patients in the omarigliptin group (5.45%; 2.96/100 patient-years) and 114/2100 patients in the placebo group (5.43%; 2.97/100 patient-years), with a hazard ratio (HR) of 1.00 (95% confidence interval [CI] 0.77, 1.29). The hHF outcome occurred in 20/2092 patients in the omarigliptin group (0.96%; 0.51/100 patient-years) and 33/2100 patients in the placebo group (1.57%; 0.85/100 patient-years), with an HR of 0.60 (95% CI 0.35, 1.05). After 142 weeks, the least-squares mean difference (omarigliptin vs. placebo) in glycated hemoglobin levels was -0.3% (95% CI -0.46, -0.14). The numbers of patients with adverse events, serious adverse events or discontinued from study medication due to adverse events were similar in the omarigliptin and placebo groups. CONCLUSIONS: In this CV safety study of patients with T2DM and established CV disease, omarigliptin did not increase the risk of MACE or hHF and was generally well tolerated. Trial registration ClinicalTrials.gov: NCT01703208. Registered 05 October 2012.

A Randomized, Placebo-Controlled Trial Evaluating the Safety and Efficacy of Adding Omarigliptin to Antihyperglycemic Therapies in Japanese Patients with Type 2 Diabetes and Inadequate Glycemic Control.

INTRODUCTION: Daily dipeptidyl peptidase-4 (DPP-4) inhibitors are commonly used with other orally administered antihyperglycemic agents (AHA), as combination therapy, to treat Japanese patients with type 2 diabetes. When combination therapy is indicated, use of a once-weekly (q.w.) orally administered DPP-4 inhibitor might be an appropriate therapeutic option for some patients. METHODS: A 52-week trial was conducted to assess the safety and tolerability (primary objectives) and glycemic efficacy (secondary objectives) of the q.w. DPP-4 inhibitor omarigliptin as add-on therapy to five different classes of orally administered AHA [sulfonylurea (SU), glinide (GL), biguanide (BG), thiazolidinedione (TZD), or α-glucosidase inhibitor (AGI)] commonly used in Japan and having different mechanisms of drug action from DPP-4 inhibitors. The trial consisted of an initial 24-week double-blind, placebo-controlled period during which patients (stratified by background AHA) were randomized to omarigliptin 25 mg q.w. or placebo, followed by a 28-week open-label period during which patients on placebo were switched to omarigliptin. RESULTS: After 24 weeks, the percentages of patients with adverse events (AEs), serious AEs, drug-related AEs, AEs of symptomatic hypoglycemia, or who discontinued from trial medication because of an AE were generally similar in the omarigliptin and placebo groups, in all background AHA strata and in the overall population. From a mean baseline HbA1c of approximately 8.0%, the placebo-adjusted least-squares mean changes from baseline ranged from -0.80% (AGI stratum) to -1.16% (TZD stratum); p < 0.001 for all background AHA strata. During the open-label period, no safety signals emerged with longer-term treatment. At week 52, the change from baseline in HbA1c in the omarigliptin/omarigliptin group was similar to that of the placebo/omarigliptin group. CONCLUSIONS: Addition of once-weekly omarigliptin to AHA therapy with an SU, GL, BG, TZD, or AGI for up to 52 weeks was generally safe and well tolerated, and provided persistent efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01697592. FUNDING: MSD K.K., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

A randomized, double-blind, non-inferiority trial evaluating the efficacy and safety of omarigliptin, a once-weekly DPP-4 inhibitor, or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy.

OBJECTIVE: To evaluate the efficacy and safety of adding the once-weekly DPP-4 inhibitor omarigliptin or the sulfonylurea glimepiride to the treatment regimen of patients with type 2 diabetes (T2DM) and inadequate glycemic control on metformin monotherapy. METHODS: Patients with T2DM and HbA1c ≥6.5% to ≤9.0% while on a stable dose of metformin (≥1500 mg/day) were randomized to omarigliptin 25 mg once-weekly (n = 376) or glimepiride up to 6 mg once daily (n = 375) for 54 weeks. The primary hypothesis was that omarigliptin is non-inferior to glimepiride in reducing HbA1c at week 54. RESULTS: The mean baseline HbA1c was 7.5% in the omarigliptin group and 7.4% in the glimepiride group. After 54 weeks, the least squares (LS) mean change from baseline in HbA1c was -0.30% in the omarigliptin group and -0.48% in the glimepiride group, with a between-group difference (95% CI) of 0.18% (0.06, 0.30), which met the pre-specified criterion for declaring non-inferiority. The incidence of symptomatic hypoglycemia was 5.3% in the omarigliptin group and 26.7% in the glimepiride group. With the exception of hypoglycemia, the incidences of adverse events and discontinuations were similar between treatment groups. Relative to baseline, omarigliptin was associated with a mean weight loss (-0.4 kg) and glimepiride a mean weight gain (+1.5 kg). CONCLUSIONS: After 54 weeks, as add-on therapy to metformin, once-weekly omarigliptin was generally well tolerated and non-inferior to glimepiride in improving glycemic control, with a lower incidence of hypoglycemia and with weight loss vs weight gain.

A randomised, double-blind, trial of the safety and efficacy of omarigliptin (a once-weekly DPP-4 inhibitor) in subjects with type 2 diabetes and renal impairment.

AIMS: To assess the safety and efficacy of omarigliptin in subjects with type 2 diabetes mellitus (T2DM) and chronic renal impairment (RI). METHODS: Patients with T2DM with moderate RI (estimated glomerular filtration rate [eGFR] ≥30 to <60 mL/min/1.73 m2 ) (N=114), severe RI (eGFR <30 mL/min/1.73 m2 ) (N=55) or end-stage renal disease on dialysis (N=44), who were either not on an antihyperglycaemic agent therapy for at least 12 weeks at screening, washed-off of oral antihyperglycaemic agent monotherapy or low-dose dual combination therapy, or on insulin monotherapy, with baseline glycated haemoglobin (HbA1c) of 6.5%-10.0% were randomised to omarigliptin or to placebo for 24 weeks (primary end-point) followed by a 30-week period with subjects on placebo switched to blinded glipizide (if not on insulin). RESULTS: After 24 weeks, from a mean baseline HbA1c of 8.4% in the omarigliptin group and 8.3% in the placebo group, the least squares mean (95% CI) change from baseline in HbA1c in the overall population (all renal strata combined) was -0.77% (-1.00 to -0.54) in the omarigliptin group and -0.44% (-0.67 to -0.21) in the placebo group; between-group difference of -0.33% (-0.63 to -0.02); P=0.035. After 24 weeks, the incidences of subjects with symptomatic hypoglycaemia, one or more adverse event (AE), drug-related AE, serious AE and discontinuation due to an AE were similar in the omarigliptin and placebo groups. CONCLUSIONS: In this study in subjects with T2DM and RI, relative to placebo, omarigliptin provided clinically meaningful reductions in HbA1c, had a similar incidence of symptomatic hypoglycaemia and was generally well tolerated.

A randomized, placebo- and sitagliptin-controlled trial of the safety and efficacy of omarigliptin, a once-weekly dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes.

AIMS: To assess the safety and efficacy of omarigliptin in Japanese patients with type 2 diabetes (T2D). METHODS: In a 24-week double-blind trial, 414 patients with T2D were randomized to omarigliptin 25 mg once weekly, sitagliptin 50 mg once daily or placebo. The double-blind period was followed by a 28-week open-label extension during which all patients received omarigliptin 25 mg once weekly. Efficacy endpoints were glycated haemoglobin (HbA1c), 2-hour postprandial glucose (PPG) and fasting plasma glucose (FPG) levels. RESULTS: After 24 weeks, the least squares (LS) mean change from baseline in HbA1c was -0.66% for omarigliptin, -0.65% for sitagliptin and 0.13% for placebo. The difference in LS mean for omarigliptin vs placebo was -0.80% ( P < .001). The difference in LS mean for omarigliptin vs sitagliptin was -0.02% (95% confidence interval -0.15, 0.12), which met the criterion for non-inferiority to sitagliptin. Both active treatments provided significant reductions in FPG and 2-hour PPG compared with placebo (P < .001). Over the 24-week double-blind period, there were no clinically meaningful differences in the incidence rates of adverse events among the treatment groups. There was 1 episode of symptomatic hypoglycaemia in the sitagliptin group and none in the omarigliptin or placebo groups. In the 28-week open-label period, omarigliptin provided persistent improvements in glycaemic control without notable change in safety profile compared with the double-blind period. Omarigliptin had no meaningful effect on body weight. CONCLUSIONS: In Japanese patients with T2D, omarigliptin 25 mg once weekly provided significant glucose-lowering compared with placebo and was non-inferior to sitagliptin 50 mg once daily. Omarigliptin was generally well tolerated for up to 52 weeks.