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

Overview

Journal Curr Ther Res Clin Exp

Specialty Pharmacology

Date 2017 Aug 2

PMID 28761573

Citations 11

Authors

Thangavel Mahalingam Vijayakumar

Jayasutha Jayram

Vishnu Meghana Cheekireddy

Dasari Himaja

Yalamanchili Dharma Teja

Damodharan Narayanasamy

Affiliations

Soon will be listed here.

Abstract

Purpose: Type 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.

Methods: A 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.

Findings: The systematic review of all the publications suggests that FDCs of oral hypoglycemic agents (OHAs) significantly reduce HbA 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.

Implications: From 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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References

Gonzalez-Ortiz M, Guerrero-Romero J, Violante-Ortiz R, Wacher-Rodarte N, Martinez-Abundis E, Aguilar-Salinas C . Efficacy of glimepiride/metformin combination versus glibenclamide/metformin in patients with uncontrolled type 2 diabetes mellitus. J Diabetes Complications. 2008; 23(6):376-9. DOI: 10.1016/j.jdiacomp.2008.09.002. View

Balu S, Simko R, Quimbo R, Cziraky M . Impact of fixed-dose and multi-pill combination dyslipidemia therapies on medication adherence and the economic burden of sub-optimal adherence. Curr Med Res Opin. 2009; 25(11):2765-75. DOI: 10.1185/03007990903297741. View

Boulton D, Chang M, Griffen S, Kitaura C, Lubin S, Pollack A . Fed and Fasted Single-dose Assessment of Bioequivalence of Dapagliflozin and Metformin Extended-release Fixed-dose Combination Tablets Relative to Single-component Dapagliflozin and Metformin Extended-release Tablets in Healthy Subjects. Clin Ther. 2015; 38(1):99-109. DOI: 10.1016/j.clinthera.2015.11.010. View

Hoelscher D, Chu P, Lyness W . Fixed-dose combination tablet of repaglinide and metformin is bioequivalent to concomitantly administered individual tablets of repaglinide and metformin : randomized, single-blind, three-period crossover study in healthy subjects. Clin Drug Investig. 2008; 28(9):573-82. DOI: 10.2165/00044011-200828090-00004. View

Valensi P, de Pouvourville G, Benard N, Chanut-Vogel C, Kempf C, Eymard E . Treatment maintenance duration of dual therapy with metformin and sitagliptin in type 2 diabetes: The ODYSSEE observational study. Diabetes Metab. 2015; 41(3):231-8. DOI: 10.1016/j.diabet.2015.03.007. View

Vanderpoel D, Hussein M, Watson-Heidari T, Perry A . Adherence to a fixed-dose combination of rosiglitazone maleate/metformin hydrochloride in subjects with type 2 diabetes mellitus: a retrospective database analysis. Clin Ther. 2005; 26(12):2066-75. DOI: 10.1016/j.clinthera.2004.12.018. View

Ved P, Shah S . Evaluation of vildagliptin and fixed dose combination of vildagliptin and metformin on glycemic control and insulin dose over 3 months in patients with type 2 diabetes mellitus. Indian J Endocrinol Metab. 2012; 16 Suppl 1:S110-3. PMC: 3354946. DOI: 10.4103/2230-8210.94258. View

Barner J . Adherence to oral antidiabetic agents with pioglitazone and metformin: comparison of fixed-dose combination therapy with monotherapy and loose-dose combination therapy. Clin Ther. 2011; 33(9):1281-8. DOI: 10.1016/j.clinthera.2011.07.016. View

Saboo B, Reddy G, Juneja S, Kedia A, Manjrekar P, Rathod R . Effectiveness and safety of fixed dose combination of acarbose/metformin in Indian Type 2 diabetes patients: Results from observational GLOBE Study. Indian J Endocrinol Metab. 2015; 19(1):129-35. PMC: 4287757. DOI: 10.4103/2230-8210.146868. View

10.

Park S, Lee H, Oh J, Lim K, Jang I, Kim J . A fixed-dose combination tablet of gemigliptin and metformin sustained release has comparable pharmacodynamic, pharmacokinetic, and tolerability profiles to separate tablets in healthy subjects. Drug Des Devel Ther. 2015; 9:729-36. PMC: 4324327. DOI: 10.2147/DDDT.S75980. View

11.

Migoya E, Miller J, Gutierrez M, Zheng W, Johnson-Levonas A, Liu Q . Bioequivalence of sitagliptin/metformin fixed-dose combination tablets and concomitant administration of sitagliptin and metformin in healthy adult subjects: a randomized, open-label, crossover study. Clin Drug Investig. 2010; 30(12):855-66. DOI: 10.1007/BF03256914. View

12.

Rombopoulos G, Hatzikou M, Athanasiadis A, Elisaf M . Treatment Compliance with Fixed-Dose Combination of Vildagliptin/Metformin in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Metformin Monotherapy: A 24-Week Observational Study. Int J Endocrinol. 2015; 2015:251485. PMC: 4452314. DOI: 10.1155/2015/251485. View

13.

Lewin A, DeFronzo R, Patel S, Liu D, Kaste R, Woerle H . Initial combination of empagliflozin and linagliptin in subjects with type 2 diabetes. Diabetes Care. 2015; 38(3):394-402. DOI: 10.2337/dc14-2365. View

14.

Goldstein B, Feinglos M, Lunceford J, Johnson J, Williams-Herman D . Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007; 30(8):1979-87. DOI: 10.2337/dc07-0627. View

15.

Chien H, Chang C, Chu N, Hsieh S, Huang Y, Lee I . Effect of glyburide-metformin combination tablet in patients with type 2 diabetes. J Chin Med Assoc. 2007; 70(11):473-80. DOI: 10.1016/S1726-4901(08)70044-3. View

16.

Wang J, Huang C, Hung Y, Kwok C, Sun J, Pei D . Acarbose plus metformin fixed-dose combination outperforms acarbose monotherapy for type 2 diabetes. Diabetes Res Clin Pract. 2013; 102(1):16-24. DOI: 10.1016/j.diabres.2013.08.001. View

17.

Bailey C, Bagdonas A, Rubes J, McMorn S, Donaldson J, Biswas N . Rosiglitazone/metformin fixed-dose combination compared with uptitrated metformin alone in type 2 diabetes mellitus: a 24-week, multicenter, randomized, double-blind, parallel-group study. Clin Ther. 2005; 27(10):1548-61. DOI: 10.1016/j.clinthera.2005.10.012. View

18.

Gu N, Kim B, Rhim H, Chung J, Kim J, Shin H . Comparison of the bioavailability and tolerability of fixed-dose combination glimepiride/metformin 2/500-mg tablets versus separate tablets: A single-dose, randomized-sequence, open-label, two-period crossover study in healthy Korean volunteers. Clin Ther. 2010; 32(7):1408-18. DOI: 10.1016/j.clinthera.2010.07.012. View

19.

Jung J, Kim J, Kim S, Kim T, Lee S, Ko J . Pharmacokinetics of a fixed-dose combination of mitiglinide and metformin versus concurrent administration of individual formulations in healthy subjects: a randomized, open-label, two-treatment, two-period, two-sequence, single-dose, crossover study. Clin Drug Investig. 2012; 32(12):799-804. DOI: 10.1007/s40261-012-0012-6. View

20.

Shin K, Kim S, Yoon S, Cho J, Jang I, Shin S . Pharmacokinetic comparison of a new sustained-release formulation of glimepiride/metformin 1/500 mg combination tablet and a sustained-release formulation of glimepiride/metformin 2/500 mg combination tablet in healthy Korean male volunteers: a.... Clin Ther. 2011; 33(11):1809-18. DOI: 10.1016/j.clinthera.2011.10.003. View