Once-weekly Dipeptidyl Peptidase-4 Inhibitor Research Articles

Efficacy and Safety of Omarigliptin, a Novel Once-Weekly Dipeptidyl Peptidase-4 Inhibitor, in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

No recent meta-analysis has holistically analyzed and summarized the efficacy and safety of omarigliptin in type 2 diabetes mellitus (T2DM). We conducted a meta-analysis to address this knowledge gap. Electronic databases were searched to identify randomized controlled trials (RCTs) that included patients with T2DM who received omarigliptin in the intervention arm. The control arm consisted of either a placebo (passive control group [PCG]) or an active comparator (active control group [ACG]). The primary outcome assessed was changes in hemoglobin A1c (HbA1c), while secondary outcomes included variations in glucose levels, achievement of glycemic targets, adverse events (AEs), and hypoglycemic events. From 332 initially screened articles, data from 16 RCTs involving 8,804 subjects were analyzed. Omarigliptin demonstrated superiority over placebo in reducing HbA1c levels (mean difference, -0.58%; 95% confidence interval, -0.75 to -0.40; P<0.00001; I2=91%). Additionally, omarigliptin outperformed placebo in lowering fasting plasma glucose, 2-hour postprandial glucose, and in the percentage of participants achieving HbA1c levels below 7.0% and 6.5%. The glycemic efficacy of omarigliptin was similar to that of the ACG across all measures. Although the omarigliptin group experienced a higher incidence of hypoglycemic events compared to the PCG, the overall AEs, serious AEs, hypoglycemia, and severe hypoglycemia were comparable between the omarigliptin and control groups (PCG and ACG). Omarigliptin has a favorable glycemic efficacy and safety profile for managing T2DM.

Efficacy of omarigliptin, once-weekly dipeptidyl peptidase-4 inhibitor, in patients with type 2 diabetes.

BACKGROUNDOmarigliptin is one of several once-weekly dipeptidyl peptidase-4 inhibitors (DPP-4is). Despite the high frequency of switching from various daily DPP-4is to omarigliptin in actual clinical practice, data regarding its efficacy in patients with type 2 diabetes (T2D) after switching are limited.AIMTo analyze the efficacy of omarigliptin in Japanese patients with T2D who had previously received treatment with other glucose-lowering agents.METHODSForty-nine T2D patients treated for the first time with omarigliptin were recruited retrospectively and divided into four groups defined as either add-on or switched from daily DPP-4is: switched from linagliptin, switched from sitagliptin, and switched from vildagliptin. During a 3-mo follow-up, the clinical parameters among these groups were assessed and compared, with the impact of the switch on glycemic variability as measured by continuous glucose monitoring also being evaluated in the switched groups.RESULTSHemoglobin A1c levels saw a significant decrease of -0.32% ± 0.41% in the add-on group (P = 0.002). However, the other groups’ variables depended on the pre-switch daily DPP-4i: switched from linagliptin, -0.05% ± 0.22%; switched from sitagliptin, -0.17% ± 0.33%; and switched from vildagliptin, 0.45% ± 0.42%, which saw significant worsening (P = 0.0007). Multivariate logistic regression analysis revealed that switching from vildagliptin to omarigliptin was independently associated with worsening glycemic control (P = 0.0013). The mean and standard deviation of sensor glucose value, the mean amplitude of glycemic excursions, and the mean of daily difference significantly improved when switching the patient from either linagliptin or sitagliptin to omarigliptin. However, in patients switched from vildagliptin, not only did the glucose variability indices see no improvements, the mean of daily difference even underwent significant worsening.CONCLUSIONAdministering omarigliptin as add-on therapy or switching to it from sitagliptin and linagliptin, but not vildagliptin, improves glycemic control and thus should help in decision making when selecting DPP-4is for T2D patients.

Effects of omarigliptin on glucose variability and oxidative stress in type 2 diabetes patients: A prospective study

AimsTo date, no clinical studies have compared once-weekly dipeptidyl peptidase 4 (DPP-4) inhibitors with once-daily DPP-4 inhibitors in terms of glucose variability (GV) and oxidative stress (OS). MethodsThirty-six patients with type 2 diabetes mellitus (T2DM) treated with once-daily DPP-4 inhibitors for at least 12 weeks were randomized to either continue once-daily DPP-4 inhibitors or receive omarigliptin, a once-weekly DPP-4 inhibitor, for 24 weeks. The primary end points were changes in the diacron-reactive oxygen metabolite (d-ROMs) test, a marker of OS, and GV using flash glucose monitoring. The secondary end point was changes in the diabetes treatment satisfaction questionnaire (DTSQ) scores. ResultsThere were no significant group differences in d-ROMs and DTSQ scores after 24 weeks of treatments. However, omarigliptin was superior to once-daily DPP-4 inhibitors in controlling fasting plasma glucose (FPG) and time in range (TIR). Although FPG and TIR were unchanged at 24 weeks after switching to omarigliptin, these parameters increased in the group receiving maintenance therapy with once-daily DPP-4 inhibitors. No statistically significant changes in hemoglobin A1c were observed between the two groups. ConclusionsOur findings suggest that switching from once-daily DPP-4 inhibitors to omarigliptin may be efficacious for maintaining FPG and TIR in T2DM patients.

Treatment preference for weekly versus daily DPP-4 inhibitors in patients with type 2 diabetes mellitus: outcomes from the TRINITY trial

Objective: To examine patient preference for treatment with the oral once-weekly dipeptidyl peptidase-4 inhibitor (DPP-4i), trelagliptin, and oral once-daily DPP-4i, alogliptin, administered for 8 weeks each in patients with type 2 diabetes mellitus prescribed a daily DPP-4i.Methods: In this randomized, open-label, two-way crossover study, patients received trelagliptin followed by alogliptin (T-A group) or alogliptin followed by trelagliptin (A-T group), for 8 weeks each (NCT03231709, JapicCTI-173662). Treatment preference was assessed using a standardized questionnaire in the overall population and by baseline characteristics. Other outcomes included patient satisfaction with diabetes treatment (assessed using the Diabetes Treatment Satisfaction Questionnaire [DTSQ]), hemoglobin A1c (HbA1c) levels after 8 weeks of treatment with each agent, and safety.Results: Sixty patients from two clinical sites were randomized 1:1 to T-A and A-T groups (each n = 30); baseline characteristics were similar between groups. After 16 weeks of treatment, 51.7% of patients preferred treatment with alogliptin compared with 30.0% selecting trelagliptin (p = .014); preference for alogliptin was consistently greater than for trelagliptin in the secondary analyses by baseline characteristics. DTSQ score and HbA1c levels were similar between treatments after 8 weeks of therapy. Both treatments demonstrated favorable safety and tolerability profiles.Conclusions: Patients expressed a significantly greater treatment preference for once-daily alogliptin than once-weekly trelagliptin, although patient satisfaction and HbA1c levels were similar across treatments. The decision to administer a once-weekly or once-daily DPP-4i is likely to depend on patient preference, patient-physician discussions, and treatment practices of the prescribing physician.Trial registration: ClinicalTrials.gov identifier: NCT03231709.

The efficacy and safety of once-weekly DPP-4 inhibitor omarigliptin in patients with type 2 diabetes mellitus: A systemic review and meta-analysis.

Background:The efficacy and safety of once-weekly dipeptidyl peptidase-4 inhibitor (DPP-4i) omarigliptin as monotherapy or add on to other antihyperglycemic agents (AHAs) in patients with type 2 diabetes mellitus (T2DM) is unclear.Methods:PubMed, EMBASE, Cochrane library, and ClinicalTrials.gov were searched from the inception to January 24, 2018. Randomized controlled trials comparing omarigliptin with placebo or other AHAs in T2DM patients were included in our meta-analysis. Risk ratio (RR) and mean difference (MD) were used to evaluate the outcomes.Results:Totally, 11 trials involving 8276 patients were satisfied with our inclusion criteria. Compared with control group, omarigliptin was associated with a significantly stronger reduction in hemoglobin A1c (HbA1c) (MD 0.38%, 95% confidence interval [CI] [0.18, 0.58], P = .0002) and fasting plasma glucose (MD 0.48 mmol/L, 95% CI [0.14 mmol/L, 0.82 mmol/L], P = .006). Omarigliptin increased the number of participants who achieved HbA1c < 7.0% compared with control group (RR 2.03, 95% CI [1.38, 2.98], P = .0003). No significant difference was found in the aspect of adverse events (RR 1.00, 95% CI [0.97, 1.03], P = .99), serious adverse events (RR 1.02, 95% CI [0.91, 1.13], P = .75), hypoglycemic events (RR 0.86, 95% CI [0.48, 1.54], P = .61) between omarigliptin and control group. Omarigliptin has a homologous efficacy and safety background to other AHAs according to the results of subgroup analysis.Conclusions:This review revealed that omarigliptin had a favorable efficacy and safety as monotherapy or add on to other AHAs in treating T2DM patients. It is a superior choice for T2DM patients who have a poor adherence to daily AHAs.

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

BackgroundType 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.MethodsPatients 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%.ResultsFrom 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.ConclusionIn 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 registrationClinicalTrials.gov: NCT01704261, EudraCT Number: 2012-002612-10. Trial Registration Date: October 8, 2012.

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

AimsTo assess the efficacy and safety of once-weekly omarigliptin as monotherapy in people with type 2 diabetes mellitus (T2DM). MethodsPeople 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. ResultsFrom 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. ConclusionsIn 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.

Safety evaluation of trelagliptin in the treatment of Japanese type 2 diabetes mellitus patients

ABSTRACTIntroduction: Trelagliptin is a novel, long-acting dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM) in japan. The safety and efficacy of trelagliptin has been evaluated in three published clinical trials to date: one phase II and two phase III studies. As trelagliptin only requires dosing once per week, this new agent has the potential to improve compliance and subsequently, glycaemic control, in patients with T2DM.Areas covered: This article reviews the available safety data for trelagliptin from published clinical trials, and evaluates the published safety profile relative to competitor once-daily and once-weekly DPP-4 inhibitors.Expert opinion: Clinical trial data to date suggest that trelagliptin is a safe and efficacious medication with a similar safety profile to once-daily DPP-4 inhibitors, and to the once-weekly DPP-4 inhibitor, omarigliptin. Trelagliptin is well tolerated when given alone, and in combination with other anti-diabetic medications. An advantage of trelagliptin over existing once-daily DPP-4 inhibitors is the decrease of dosing frequency, rather than once-daily. No specific, serious adverse events have been reported for trelagliptin in published clinical trials, making it an attractive alternative to other DPP-4 inhibitors.

A randomized clinical trial evaluating the efficacy and safety of the once-weekly dipeptidyl peptidase-4 inhibitor omarigliptin in patients with type 2 diabetes inadequately controlled on metformin monotherapy

Objective: To examine the efficacy and safety of the once-weekly (q.w.) dipeptidyl peptidase-4 inhibitor, omarigliptin, in patients with type 2 diabetes (T2DM) and inadequate glycemic control on metformin monotherapy.Methods: In a randomized, double-blind trial, patients with T2DM on a stable dose of metformin monotherapy (≥1500 mg/day) with glycated hemoglobin (HbA1c) of 7.0–10.5% were randomized to omarigliptin 25 mg q.w. or matching placebo (n = 201 in both) for 24 weeks (primary timepoint) followed by an additional 80-week treatment period.Results: At week 24, from a mean baseline HbA1c of 8.0–8.1%, the least squares (LS) mean (95% CI) change from baseline in HbA1c (primary end-point) was –0.54% (–0.69%, –0.40%) in the omarigliptin group and 0.00% (–0.14%, 0.15%) in the placebo group, for a between-group difference of –0.55% (–0.75%, –0.34%); p < .001. Between-group differences (LS mean 95% CI) for the secondary end-points of 2-h post-meal glucose and fasting plasma glucose (omarigliptin vs placebo) were –0.8 mmol/L (–1.4, –0.2) (p = .011) and –0.5 mmol/L (–0.9, –0.1) (p = .010), respectively. At week 24, the incidences of symptomatic hypoglycemia and subjects with one or more adverse event (AE), serious AEs, and discontinuations due to an AE were similar in the omarigliptin and placebo groups. Over 104 weeks, omarigliptin treatment provided a clinically meaningful reduction in HbA1c.Conclusions: In patients with T2DM, adding omarigliptin 25 mg q.w. to metformin monotherapy improved glycemic control over 104 weeks and was generally welltolerated with a low risk of hypoglycemia.

Single and multiple dose pharmacokinetics and pharmacodynamics of omarigliptin, a novel, once-weekly dipeptidyl peptidase-4 inhibitor, in healthy Japanese men.

Aims/IntroductionOmarigliptin is a novel, potent, long‐acting oral dipeptidyl peptidase‐4 inhibitor being developed as a once‐weekly (q.w.) treatment for type 2 diabetes mellitus patients, with 25 mg and 12.5 mg tablets recently being approved as market formulations in Japan.Materials and MethodsThis was a two‐part, double‐blind, randomized, placebo‐controlled study in healthy Japanese men to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of omarigliptin after single dose (5–100 mg) and multiple dose (1–50 mg q.w. for 3 weeks) administration.ResultsOmarigliptin was rapidly absorbed with a time to maximum concentration of 0.5–4 h. The pharmacokinetic profile was biphasic with a long terminal half‐life >100 h. The area under the concentration–time curve from 0 to 168 h, maximum concentration and the concentration at 168 h post‐dose increased dose‐dependently after 3 weeks of once‐weekly dosing for doses ranging 1–50 mg, with accumulation ratios ranging 1.03–1.35 and 0.87–1.36 for the area under the concentration–time curve from 0 to 168 h and maximum concentration, respectively. Plasma dipeptidyl peptidase‐4 inhibition levels 1 week post‐dose increased with dose, ranging 79.2–94.0% after 5–100 mg single dose administration and 51.3–90.2% after 1–50 mg multiple once‐weekly dose administration. Administration with food did not meaningfully alter the pharmacokinetics of omarigliptin. Omarigliptin was generally well tolerated, with no hypoglycemia being reported.ConclusionThe results of the present study in healthy Japanese men showed that omarigliptin was well tolerated and had a pharmacokinetic and dipeptidyl peptidase‐4 inhibition profile that supports once‐weekly dosing in Japanese patients with type 2 diabetes mellitus.

First novel once-weekly DPP-4 inhibitor, trelagliptin, for the treatment of type 2 diabetes mellitus

Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors are weight neutral and well tolerated, and provide better glycaemic control for a longer period compared to conventional therapies. Despite the fact that various drugs are available, glycaemic control remains suboptimal in approximately half of patients with type 2 diabetes mellitus; one of the major reasons for low medication adherence.Areas covered: A novel DPP-4 inhibitor, trelagliptin, was approved in Japan in March 2015, and is the first once-weekly oral antidiabetic agent in the world. In this review, current issues concerning medication adherence for the treatment of diabetes are discussed followed by a summary of the characteristics and future expectations of trelagliptin, by reviewing the recent phase I, II, and III clinical studies of trelagliptin.Expert opinion: Trelagliptin has demonstrated superiority to placebo and non-inferiority to alogliptin, indicating its efficacy and tolerance in Japanese patients. Trelagliptin is expected to improve adherence and prevent complications. Due to the convenient dosing regimen, it is expected to be widely used in the clinical setting. A large-scale long-term study will help further confirm its long-term efficacy and safety, patients’ satisfaction, and medication adherence.

SYR-472, a novel once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor, in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial

In patients with type 2 diabetes, improving adherence to medication is important in order to maintain favourable glycaemic control during long-term treatment and, thus, prevent the onset or aggravation of complications. SYR-472 is a novel once-weekly oral DPP-4 inhibitor for type 2 diabetes, which could be a treatment option when clinicians seek to improve medication adherence by reducing the number of required administrations. In this study, we assessed the efficacy and safety of SYR-472 in patients with type 2 diabetes. In this phase 2, multicentre, randomised, double-blind, parallel-group, placebo-controlled, dose-ranging study, we included Japanese patients with inadequately controlled type 2 diabetes despite diet and exercise treatment. Patients were randomly assigned (allocation ratio 1:1:1:1:1:1) to receive either placebo or SYR-472 at five different doses (12·5 mg, 25 mg, 50 mg, 100 mg, or 200 mg). Randomisation was done with a permuted block schedule. All investigators and patients were unaware of the treatment assignment. Treatment drug was given orally once weekly for 12 weeks. The primary efficacy variable was the change in HbA1c concentration from baseline to the end of treatment. This study has been registered at the Japan Pharmaceutical Information Center (JAPIC) Clinical Trials Information: Japic CTI-090899. 322 patients were randomly assigned to receive placebo (55 patients) or SYR-472 at 12·5 mg (54 patients), 25 mg (52 patients), 50 mg (51 patients), 100 mg (55 patients) or 200 mg (55 patients). The least square (LS) mean change in HbA1c concentration from baseline was 0·35% (SE 0·068; -20 mmol/mol) for the placebo group, -0·37% (0·068; -28 mmol/mol) for the 12·5 mg group, -0·32% (0·070; -27 mmol/mol) for the 25 mg group, -0·42% (0·070; -28 mmol/mol) for the 50 mg group, -0·54% (0·068; -29 mmol/mol) for the 100 mg group, and -0·55% (0·069; -30 mmol/mol) for the 200 mg group. In general, HbA1c concentration decreased in a dose-dependent manner (trend test using contrast coefficients p<0·0001) and the reduction was significantly greater for all SYR-472 doses (p<0·0001 for each group) than for placebo. The incidence of treatment-emergent adverse events in each SYR-472 group was similar to that in the placebo group. The most common adverse event was nasopharyngitis in all groups. No episodes of hypoglycaemia defined by investigator occurred with any treatment during the study. Once-weekly SYR-472 treatment produced clinically and statistically significant improvements in glycaemic control in patients with type 2 diabetes. It was well tolerated and might be a new treatment option for patients with this disease. Takeda Pharmaceutical Company Limited.