Saxagliptin: A Clinical Review in the Treatment of Type 2 Diabetes Mellitus

Kania, Deanna; Gonzalvo, Jasmine D.; Weber, Zachary A.

doi:10.1016/j.clinthera.2011.06.016

Cited by 48 publications

(21 citation statements)

References 60 publications

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“…the base study appear to be generally comparable to those reported in studies of the presently marketed daily DPP-4 inhibitors (2)(3)(4)(5)(6). In the case of 2-h PMG, the incorporation of a study design in which the MTT was always performed at trough (day 7) supports the concept that the degree of DPP-4 inhibition observed at trough with the 25-mg dose is sufficient for maximal clinical efficacy.…”

Section: Discussionsupporting

confidence: 74%

Safety and Efficacy of Omarigliptin (MK-3102), a Novel Once-Weekly DPP-4 Inhibitor for the Treatment of Patients With Type 2 Diabetes

et al. 2015

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OBJECTIVEThis study was conducted to determine the optimal dose of omarigliptin, a onceweekly (q.w.) dipeptidyl peptidase IV (DPP-4) inhibitor, for the treatment of patients with type 2 diabetes and evaluate the long-term safety of that dose. RESEARCH DESIGN AND METHODSIn a multicenter, double-blind, 12-week, dose-range finding study, 685 oral antihyperglycemic agent-naïve or washed-out subjects with type 2 diabetes were randomized to one of five once-weekly doses of omarigliptin (0.25 mg, 1 mg, 3 mg, 10 mg, or 25 mg) or placebo. The primary efficacy end point was change from baseline in HbA 1c , and secondary end points were 2-h postmeal glucose (PMG) and fasting plasma glucose (FPG). Analysis included all patients who received at least one dose of the study medication. Subjects who completed the base study were eligible to enter a 66-week extension study. RESULTSOnce-weekly treatment for 12 weeks with omarigliptin provided dose-related reductions in HbA 1c , 2-h PMG, and FPG. At week 12, the omarigliptin 25-mg dose provided the greatest glycemic efficacy. The placebo-adjusted least-squares mean reductions from baseline in HbA 1c , 2-h PMG, and FPG were 20.72% (27.8 mmol/mol), 22.5, and 21.3 mmol/L, respectively (all P < 0.001). The incidence of adverse events was similar across dose groups, with a low incidence of symptomatic hypoglycemia and no effect on body weight. Omarigliptin was generally well-tolerated throughout the base and extension studies. CONCLUSIONSOmarigliptin 25 mg q.w., compared with placebo, provided significant glucose lowering and was generally well tolerated for up to 78 weeks in patients with type 2 diabetes.Dipeptidyl peptidase IV (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes by prolonging the half-life of incretin peptides, which stimulate insulin secretion and decrease glucagon release in a glucose-dependent manner (1). Studies with daily DPP-4 inhibitors have demonstrated a good efficacy, safety, and tolerability profile as monotherapy and as an add-on to other antihyperglycemic agents (AHAs) (2-6). Omarigliptin (MK-3102) is a potent, selective, oral DPP-4 inhibitor with a half-life that supports once-weekly dosing (7). Availability of a once-weekly administered oral

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Section: Discussionsupporting

confidence: 74%

Safety and Efficacy of Omarigliptin (MK-3102), a Novel Once-Weekly DPP-4 Inhibitor for the Treatment of Patients With Type 2 Diabetes

et al. 2015

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“…14 DPPIV inhibitors include sitagliptin and saxaglitin. 15,16 Alogliptin is in late stages of development, as are several other DPPIV agents. Both GLP1 agonists and DPPIV inhibitors lower glucose and decrease A 1C levels.…”

Section: Article See P 2338mentioning

confidence: 99%

The Incretin Axis in Cardiovascular Disease

Plutzky¹

2011

Circulation

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“…It was specifically designed for enhanced potency and selectivity and to provide extended inhibition of the DPP4 enzyme (Augeri et al, 2005). The ability of saxagliptin to affect reductions in glycosylated hemoglobin (HbA 1C ) and fasting plasma glucose in type 2 diabetes patients has been demonstrated in multiple Phase III clinical trials, both as a single agent and in combination regimens with metformin, a sulfonylurea or a thiazolidinedione (Kania et al, 2011). The most commonly used clinical dose of saxagliptin in adults is 5 mg, once daily (United States prescribing information for Onglyza, http://www.packageinserts.bms.com/pi/pi_onglyza.pdf).…”

Section: Introductionmentioning

confidence: 99%

Characterization of the In Vitro and In Vivo Metabolism and Disposition and Cytochrome P450 Inhibition/Induction Profile of Saxagliptin in Human

Boulton²,

Barros³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Saxagliptin is a potent dipeptidyl peptidase-4 inhibitor approved for the treatment of type 2 diabetes mellitus. The pharmacokinetics and disposition of [ 14 C]saxagliptin were investigated in healthy male subjects after a single 50-mg (91.5 Ci) oral dose. Saxagliptin was rapidly absorbed (T max , 0.5 h). Unchanged saxagliptin and 5-hydroxy saxagliptin (M2), a major, active metabolite, were the prominent drug-related components in the plasma, together accounting for most of the circulating radioactivity. Approximately 97% of the administered radioactivity was recovered in the excreta within 7 days postdose, of which 74.9% was eliminated in the urine and 22.1% was excreted in the feces. The parent compound and M2 represented 24.0 and 44.1%, respectively, of the radioactivity recovered in the urine and feces combined. Taken together, the excretion data suggest that saxagliptin was well absorbed and was subsequently cleared by both urinary excretion and metabolism; the formation of M2 was the major metabolic pathway. Additional minor metabolic pathways included hydroxylation at other positions and glucuronide or sulfate conjugation. Cytochrome P450 (P450) enzymes CYP3A4 and CYP3A5 metabolized saxagliptin and formed M2. Kinetic experiments indicated that the catalytic efficiency (V max /K m ) for CYP3A4 was approximately 4-fold higher than that for CYP3A5. Therefore, it is unlikely that variability in expression levels of CYP3A5 due to genetic polymorphism will impact clearance of saxagliptin. Saxagliptin and M2 each showed little potential to inhibit or induce important P450 enzymes, suggesting that saxagliptin is unlikely to affect the metabolic clearance of coadministered drugs that are substrates for these enzymes.

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Saxagliptin: A Clinical Review in the Treatment of Type 2 Diabetes Mellitus

Cited by 48 publications

References 60 publications

Safety and Efficacy of Omarigliptin (MK-3102), a Novel Once-Weekly DPP-4 Inhibitor for the Treatment of Patients With Type 2 Diabetes

Safety and Efficacy of Omarigliptin (MK-3102), a Novel Once-Weekly DPP-4 Inhibitor for the Treatment of Patients With Type 2 Diabetes

The Incretin Axis in Cardiovascular Disease

Characterization of the In Vitro and In Vivo Metabolism and Disposition and Cytochrome P450 Inhibition/Induction Profile of Saxagliptin in Human

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