Bioequivalence of Sitagliptin/Metformin Fixed-Dose Combination Tablets and Concomitant Administration of Sitagliptin and Metformin in Healthy Adult Subjects

Migoya, Elizabeth; Miller, Jutta; Gutiérrez, María Elena; Wang, Zheng; Johnson‐Levonas, Amy O.; Liu, Qi; Matthews, Catherine Z.; Wagner, John A.; Gottesdiener, Keith

doi:10.2165/11538410-000000000-00000

Cited by 5 publications

(9 citation statements)

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“…On the basis of the ideal efficacy of DPP‐4 inhibitors and metformin combination therapy, pharmaceutical companies have developed a fixed‐dose combination (FDC) of the two classes of antidiabetic drugs. Bioequivalence studies have shown that the bioequivalence, safety and efficacy profile of co‐administration of DPP‐4 inhibitors and metformin can be extended to the FDC and extended‐release FDC tablets . The changes from baseline HbA1c and FPG were greater in patients treated with the DPP‐4 inhibitors/metformin FDC than in those treated with metformin monotherapy .…”

Section: Efficacy and Safety Of Dpp‐4 Inhibitors And Metformin Combinmentioning

confidence: 99%

Combination therapy of dipeptidyl peptidase‐4 inhibitors and metformin in type 2 diabetes: rationale and evidence

Liu

Hong

2013

Diabetes Obesity Metabolism

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The main pathogenesis of type 2 diabetes mellitus (T2DM) includes insulin resistance and pancreatic islet dysfunction. Metformin, which attenuates insulin resistance, has been recommended as the first-line antidiabetic medication. Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel oral hypoglycaemic agents that protect glucagon-like peptide-1 (GLP-1) from degradation, maintain the bioactivity of endogenous GLP-1, and thus improve islet dysfunction. Results from clinical trials have shown that the combination therapy of DPP-4 inhibitors and metformin [as an add-on, an initial combination or a fixed-dose combination (FDC)] provides excellent efficacy and safety in patients with T2DM. Moreover, recent studies have suggested that metformin enhances the biological effect of GLP-1 by increasing GLP-1 secretion, suppressing activity of DPP-4 and upregulating the expression of GLP-1 receptor in pancreatic β-cells. Conversely, DPP-4 inhibitors have a favourable effect on insulin sensitivity in patients with T2DM. Therefore, the combination of DPP-4 inhibitors and metformin provides an additive or even synergistic effect on metabolic control in patients with T2DM. This article provides an overview of clinical evidence and discusses the rationale for the combination therapy of DPP-4 inhibitors and metformin.

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Section: Efficacy and Safety Of Dpp‐4 Inhibitors And Metformin Combinmentioning

confidence: 99%

Combination therapy of dipeptidyl peptidase‐4 inhibitors and metformin in type 2 diabetes: rationale and evidence

Liu

Hong

2013

Diabetes Obesity Metabolism

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“…Two randomized, open-label studies conducted by Chang et al 33 and Migoya et al 34 in the years 2012 and 2010 states that FDCs of dapagliflozin and metformin and of sitagliptin and metformin are bioequivalent to the concomitant doses administered as individual components.…”

Section: Resultsmentioning

confidence: 99%

“…However, there are some limitations for FDCs such as difficulty in dose titration and stability problems between the drugs leading to incompatibilities. Study design, intervention, outcomes, and safety of FDC use in T2DM was shown in Table II,3, 5, 10, 12, 14, 16, 18, 23, 30, 31 and bioavailability of FDCs is shown in Table III 33, 34Table IIStudies reporting the use of FDCs in T2DM patients.AuthorType of studyInterventionOutcomesSafetyVed et al 3 (2016)N = 400, open label, prospective, nonrandomized, multicenter, observational study, 3 monthsVildagliptin (50 mg) + metformin (500, 850, 1000 mg) as FDCMean value for FBG, PPG, and HbA 1c were significantly reduced after treatmentNot reported in this studyRombopoulos et al 18 (2014)N = 366, multicenter, observational study, 26 weeksVildagliptin (50 mg) + metformin (850 mg) as FDCIt resulted in a greater reduction in HbA 1c compared with free-dose combination; the patients with FDC were more compliant than with free doseNot reported in this studyLewin et al 23 (2013)N = 273, phase III, randomized, double- blind, parallel group, 52 weeksEmpagliflozin (25, 10 mg) + linagliptin (5 mg) as FDCReduction in HbA 1c was significantly greater with FDC compared with individual componentsThe incidence of ADRs such as UTI, genital infection, were more with empagliflozin 25 mg + linagliptin 10 mg compared with the other compared with the other group but were tolerable with medicationWang et al 5 (2012)N = 233, randomized, double-blind, parallel group, 16 weeksAcarbose (50 mg) + metformin (500 mg) TDS as FDCThe combination significantly reduced FBS, HbA 1c , and PPPG with superior efficacy compared with monotherapyNo hypoglycemia was reported.…”

Section: Resultsmentioning

confidence: 99%

Safety, Efficacy, and Bioavailability of Fixed-Dose Combinations in Type 2 Diabetes Mellitus: A Systematic Updated Review

Vijayakumar

Jayram

Cheekireddy

et al. 2017

Current Therapeutic Research

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PurposeType 2 diabetes mellitus (T2DM) is a multifactorial disease characterized by insulin resistance. As time progresses, monotherapy often does not provide effective glycemic control, generating the need for an add-on therapy. Hence, multiple oral hypoglycemic agents formulated as a single-dose form called fixed-dose combinations (FDCs) play an essential role in glycemic control. The purpose of this systematic review is to appraise the recently published evidence on the safety, efficacy, and bioavailability of FDCs.MethodsA comprehensive literature search of PUBMED, Scopus, ScienceDirect.com, ProQuest, SpringerLink, clintrials.gov, Embase, and EBSCO using the key words FDCs, combination therapy, T2DM management, and add-on therapy was conducted. Studies on the safety profile/tolerability, efficacy, and bioavailability of various FDCs of oral hypoglycemic agents were preferred.FindingsThe systematic review of all the publications suggests that FDCs of oral hypoglycemic agents (OHAs) significantly reduce HbA1c and fasting plasma glucose values, thereby efficiently reducing hyperglycemia in patients in whom monotherapy fails. FDCs are the bioequivalent of the concomitant drugs administered as individual components. Improved adherence to FDCs and the absence of serious adverse drug reactions compared with dual therapy play an important role in decreasing the incidence of hyperglycemia in patients with T2DM.ImplicationsFrom this updated review, it was found that metformin was the most widely used component of FDCs with other OHAs. Studies on the safety and efficacy of newly approved OHAs such as sodium glucose cotransporter inhibitors were limited. An increasing number of randomized trials on the safety and efficacy of newly emerging FDCs suggests that they would be better treatment options for T2DM patients.

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“…In a randomized, open-label, 2-part, 2-period crossover study, bioequivalence between FDC and coadministration of corresponding doses of sitagliptin and metformin was established in 48 nondiabetic subjects supporting the efficacy and safety of fixed dose combination treatment. 46 In a placebo-controlled, multipledose, crossover trial in 13 patients with type 2 diabetes, steady state pharmacokinetics of sitagliptin and metformin were not altered by their coadministration, and no drug-related adverse effects were reported. 47 Currently, there are no trials comparing the effect of FDC of sitagliptin and metformin on patient compliance although it might be expected that treatment with an FDC could improve patient compliance compared with treatment with separate agents.…”

Section: Pharmacokinetic and Pharmacodynamic Profile And Adverse Drugmentioning

confidence: 98%

“…FDC tablets are available in doses of 50 mg sitagliptin + 500 mg metformin or 50 mg sitagliptin + 1000 mg metformin. In a randomized, open-label, 2-part, 2-period crossover study, bioequivalence between FDC and coadministration of corresponding doses of sitagliptin and metformin was established in 48 nondiabetic subjects supporting the efficacy and safety of fixed dose combination treatment 46. In a placebo-controlled, multipledose, crossover trial in 13 patients with type 2 diabetes, steady state pharmacokinetics of sitagliptin and metformin were not altered by their coadministration, and no drug-related adverse effects were reported 47.…”

Section: Pharmacokinetic and Pharmacodynamic Profile And Adverse Drugmentioning

confidence: 99%

Safety and Efficacy of Sitagliptin-Metformin in Fixed Combination for the Treatment of Type 2 Diabetes Mellitus

Ballav

Gough

2013

Clin Med Insights Endocrinol Diabetes

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The biguanide, metformin, is considered first-line treatment for type 2 diabetes. Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor acts through the incretin pathway and has a glucose dependent mode of action. The complementary hypoglycemic properties of these drugs make fixed dose combination treatment an attractive prospect. Evidence from recent clinical trials suggests a beneficial effect of the combination on efficacy, demonstrated by significant improvement of hemoglobin A1c (HbA1c), fasting and postprandial glucose levels. The fixed dose combination is likely to have greater patient tolerability compared with monotherapy with either agent because of low rates of hypoglycemia, weight neutrality, and lower rates of side effects. High acquisition cost and paucity of long-term safety data are, however, potential barriers to their wider use. An overview of the pharmacology and clinical outcomes from recent trials of the metformin-sitagliptin combination and how the combination could fit into the type 2 diabetes treatment algorithm is presented in this review.

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Bioequivalence of Sitagliptin/Metformin Fixed-Dose Combination Tablets and Concomitant Administration of Sitagliptin and Metformin in Healthy Adult Subjects

Cited by 5 publications

References 0 publications

Combination therapy of dipeptidyl peptidase‐4 inhibitors and metformin in type 2 diabetes: rationale and evidence

Combination therapy of dipeptidyl peptidase‐4 inhibitors and metformin in type 2 diabetes: rationale and evidence

Safety, Efficacy, and Bioavailability of Fixed-Dose Combinations in Type 2 Diabetes Mellitus: A Systematic Updated Review

Safety and Efficacy of Sitagliptin-Metformin in Fixed Combination for the Treatment of Type 2 Diabetes Mellitus

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