Combination therapy with once-weekly glucagon like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a case series
Background: National treatment guidelines recommend glucagon-like peptide receptor agonists (GLP-1 RAs) as add-on therapy to oral agents. However, GLP-1 RAs in combination with dipeptidyl peptidase-4 (DPP-4) inhibitors is not recommended due to a lack of evidence.
Objective: This case series aims to describe the efficacy and safety of once-weekly GLP-1 RAs administered concomitantly with DPP-4 inhibitors in patients with type 2 diabetes.
Methods: A retrospective chart review of electronic medical records at a free health clinic was conducted between July 2014 and September 2016. Patients 18 years and older with type 2 diabetes were included if they received concomitant DPP-4 inhibitor and once-weekly GLP-1 RA therapy with at least one glycated hemoglobin A1c (HbA1c) measurement within three to six months of starting the combination. The primary and secondary outcomes included change in HbA1c and weight, and patient reported adverse events.
Results: Out of forty-three patients that received combination DPP-4 inhibitor plus GLP-1 RA therapy, only eighteen received once-weekly GLP-1 RA. At 3 months, the median (IQR) HbA1c and weight change was -0.8% (-4.3 to 2%) and -0.4kg (-4.2 to 5.8 kg) respectively. No patients reached an HbA1c below 7% and only three patients (17%) reached a HbA1c less than 8%. Patient reported adverse effects included gastrointestinal disturbances (28%), hypoglycemic symptoms (17%), and injection site reactions (0.6%).
Conclusions: Concomitant use of once-weekly GLP-1 RAs and DPP-4 inhibitors provides only modest improvement in glycemic control with minimal weight loss benefits, which is similar to monotherapy with either agent. The combination is unlikely to provide synergistic effects and is not cost effective. These data support the current recommendations against use of combined incretin therapy.
Maruthur NM, Tseng E, Hutfless S, Wilson LM, Suarez-Cuervo C, Berger Z, Chu Y, Iyoha E, Segal JB, Bolen S. Diabetes Medications as Monotherapy or metformin-Based Cominbation Therapy for Type 2 Diabetes: a Systematic Review and Meta-analysis. Ann Intern Med. 2016;164(11):740-751. https://doi.org/10.7326/M15-2650
American Diabetes Association standards of medical care in diabetes 2019. Diabetes Care 2019; 42 (Supplement 1):S1-S187.
Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, Dagogo-Jack S, DeFronzo RA, Einhorn D, Fonseca VA, Garber JR, Garvey WT, Grunberger G, Handelsman Y, Hirsch IB, Jellinger PS, McGill JB, Mechanick JI, Rosenblit PD, Umpierrez GE. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm - 2019 executive summary. Endocr Pract. 2019;25(1):69-100. https://doi.org/10.4158/CS-2018-0535
Nauck MA, Vardarli I, Deacon CF, Holst JJ, Meier JJ. Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down?. Diabetologia. 2011;54(1):10-18. https://doi.org/10.1007/s00125-010-1896-4
Nauck M. Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab. 2016;18(3):203-216. https://doi.org/10.1111/dom.12591
Herman GA, Bergman A, Stevens C, Kotey P, Yi B, Zhao P, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006;91(11):4612-4619. https://doi.org/10.1210/jc.2006-1009
Lee YS, Jun HS. Anti-diabetic actions of glucagon-like peptide-1 on pancreatic beta-cells. Metabolism. 2014;63(1):9-19. https://doi.org/10.1016/j.metabol.2013.09.010
Karagiannis T, Liakos A, Bekiari E, Athanasiadou E, Paschos P, Vasilakou D, Mainou M, Rika M, Boura P, Matthews DR, Tsapas A. Efficacy and safety of once-weekly glucagon-like peptide 1 receptor agonists for the management of type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2015;17(11):1065-1074. https://doi.org/10.1111/dom.12541
Violante R, Oliveira JH, Yoon KH, Reed VA, Yu MB, Bachmann OP, Lüdemann J, Chan JY. A randomized non-inferiority study comparing the addition of exenatide twice daily to sitagliptin or switching from sitagliptin to exenatide twice daily in patients with type 2 diabetes experiencing inadequate glycaemic control on metformin and sitagliptin. Diabet Med. 2012;29(11):e417-e424. https://doi.org/10.1111/j.1464-5491.2012.03624.x
Patel MB, Elmore LK, Edgerton LP, Whalin LM. Combination exenatide–sitagliptin therapy used with glipizide in a patient with type 2 diabetes mellitus. Am J Health Syst Pharm. 2012;69(12):1044-1048. https://doi.org/10.2146/ajhp110567
Iyer NS, Drake III AJ, West RL, Mendez CE, Tanenberg RJ. Case report of acute necrotizing pancreatitis associated with combination treatment of sitagliptin and exenatide. Endocr Pract. 2012;18(1):e10-e13. https://doi.org/10.4158/EP11264.CR
Nauck MA, Dipl MK, Baranov O, Deacon CF, Holst JJ. Addition of a dipeptidyl peptidase-4 inhibitor, sitagliptin, to ongoing therapy with the glucagon-like peptide-1 receptor agonist liraglutide: A randomized controlled trial in patients with type 2 diabetes. Diabetes Obes Metab. 2017;19(2):200-207. https://doi.org/10.1111/dom.12802
Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017. Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services; 2017.
Amylin Pharmaceuticals Inc. Bydureon (exenatide extended release) package insert. San Diego, CA; 2012.
GlaxoSmithKline LLC. Tanzeum (albiglutide) package insert. Wilmington, DE; 2014.
The authors hereby transfer, assign or otherwise convey to Pharmacy Practice (1) the right to grant permission to republish or reprint the stated material, in whole or in part, without a fee; (2) the right to print or epublish copies for free distribution or sale; and (3) the right to republish the stated material in any format (electronic or printed). In addition, the undersigned affirms that the article described above has not previously been published, in whole or part, is not subject to copyright or other rights except by the author(s), and has not been submitted for publication elsewhere, except as communicated in writing to Pharmacy Practice with this document.
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License (CC-BY-NC-ND) that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
Author Self-Archiving Policy
Pharmacy Practice permits and encourages authors to post and archive the final PDFs of their respective articles submitted to the journal on personal websites or institutional repositories after publication, while providing bibliographic details that credit its publication in this journal.