Type 2 Diabetes Therapy Intensification: Part II: GLP-1 Agonist Adverse Effects and Fixed-Ratio Combinations
Risks and benefits of GLP-1RAs should be considered when intensifying therapy for patients with type 2 diabetes.
Adverse Effects of GLP-1RAs
The primarily adverse effects of GLP-1RAs are gastrointestinal and consist of nausea, vomiting, and diarrhea.9,13 Up to half of patients taking a GLP-1RA may experience nausea, which typically resolves within the first week and rarely leads to treatment discontinuation.9 Some patients develop upper respiratory infection or injection-site reactions.6,10
In long-term studies of GLP-1RAs, discontinuation rates resulting from adverse events ranged from 4% to 21%.6 Some cases of pancreatitis have been reported with GLP-1RA use, but causality has not been established.9 In addition to class effects, each GLP-1RA has a unique safety profile, which must be weighed when choosing between them.
A meta-analysis of trials that added a GLP-1RA or an RAI to basal insulin found both approaches produced similar rates of symptomatic or severe hypoglycemia. However, patients taking a GLP-1RA with basal insulin were more likely to reach a target HbA1c <7.0% without experiencing symptomatic hypoglycemia than patients taking an RAI.14
Of the 2 FDA-approved fixed-ratio combinations, 1 pairs basal insulin with lixisenatide, and the other pairs it with liraglutide.1 A meta-analysis of trials that combined any GLP-1RA with basal insulin, including fixed-ratio combinations, found no significant difference in HbA1c outcomes among GLP-1RA/basal insulin regimens, basal-plus regimens, or basal-bolus regimens.8 However, the once-daily fixed-ratio combinations were better than insulin up-titration or basal insulin plus placebo at reducing HbA1c levels, with no increase in hypoglycemia and less weight gain.8
Many patients with type 2 diabetes require basal insulin with disease progression. When basal insulin no longer provides adequate glucose control, an RAI or a GLP-1RA may be used to intensify basal insulin therapy. Adherence is essential for optimizing glucose control (both HbA1c and postprandial glucose targets). Adherence is also critical for reducing the risk for diabetes complications, including adverse cardiovascular outcomes. The reduced incidence of weight gain and hypoglycemia with GLP-1RAs make them an appealing alternative to RAIs for patients unable to achieve HbA1c targets with basal insulin.
Treatment cost, patient preferences, and the patient's clinical picture are all important considerations when intensifying therapy after basal insulin failure. Studies are needed to identify biomarkers or patient factors that predict who is most likely to respond to a GLP-1RA vs RAI.
- American Diabetes Association. Pharmacologic approaches to glycemic treatment. Diabetes Care. 2017;40(Suppl 1):S64-S74. doi:10.2337/dc17-S011
- Raccah D, Bretzel RG, Owens D, Riddle M. When basal insulin therapy in type 2 diabetes mellitus is not enough--what next? Diabetes Metab Res Rev. 2007;23(4):257-264. doi:10.1002/dmrr.733
- Raccah D, Lin J, Wang E, et al. Once-daily prandial lixisenatide versus once-daily rapid-acting insulin in patients with type 2 diabetes mellitus insufficiently controlled with basal insulin: analysis of data from five randomized, controlled trials. J Diabetes Complications. 2014;28(1):40-44. doi:10.1016/j.jdiacomp.2013
- Raccah D. Basal insulin treatment intensification in patients with type 2 diabetes mellitus: a comprehensive systematic review of current options. Diabetes Metab. 2017;43(2):110-124. doi:10.1016/j.diabet.2016.11.007
- Giorgino F, Bonadonna RC, Gentile S, Vettor R, Pozzilli P. Treatment intensification in patients with inadequate glycemic control on basal insulin: rationale and clinical evidence for the use of short-acting and other glucagon-like peptide-1 receptor agonists. Diabetes Metab Res Rev. 2016;32(6):497-511. doi:10.1002/dmrr.2775
- Courtney H, Nayar R, Rajeswaran C, Jandhyala R. Long-term management of type 2 diabetes with glucagon-like peptide-1 receptor agonists. Diabetes Metab Syndr Obes. 2017;10:79-87. doi:10.2147/DMSO.S126763
- Darmon P, Raccah D. Options for intensification of basal insulin in type 2 diabetes: premeal insulin or short-acting GLP-1 receptor agonists? Diabetes Metab. 2015;41(6 Suppl 1):6S21-6S27. doi:10.1016/S1262-3636(16)30005-2
- Maiorino MI, Chiodini P, Bellastella G, Capuano A, Esposito K, Giugliano D. Insulin and glucagon-like peptide 1 receptor agonist combination therapy in type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetes Care. 2017;40(4):614-624. doi:10.2337/dc16-1957
- Anderson SL, Trujillo JM. Lixisenatide in type 2 diabetes: latest evidence and clinical usefulness. Ther Adv Chronic Dis. 2016;7(1):4-17. doi:10.1177/2040622315609312
- Rosenstock J, Fonseca VA , Gross JL, et al. Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Diabetes Care. 2014;37(8):2317-2325. doi:10.2337/dc14-0001
- Pozzilli P, Norwood P, Jodar E, et al. Placebo-controlled, randomized trial of the addition of once-weekly glucagon-like peptide-1 receptor agonist dulaglutide to titrated daily insulin glargine in patients with type 2 diabetes (AWARD-9) [published online March 14, 2017]. Diabetes Obes Metab. doi:10.1111/dom.12937
- Jendle J, Testa MA, Martin S, Jiang H, Milicevic Z. Continuous glucose monitoring in patients with type 2 diabetes treated with glucagon-like peptide-1 receptor agonist dulaglutide in combination with prandial insulin lispro: an AWARD-4 substudy. Diabetes Obes Metab. 2016;18(10):999-1005. doi:10.1111/dom.12705
- Porcellati F, Lucidi P, Bolli GB, Fanelli CG. GLP-1 RAs as compared to prandial insulin after failure of basal insulin in type 2 diabetes: lessons from the 4B and Get-Goal DUO2 trials. Diabetes Metab. 2015;41(6 Suppl 1):6S16-6S20. doi:10.1016/S1262-3636(16)30004-0
- Wysham CH, Lin J, Kuritzky L. Safety and efficacy of a glucagon-like peptide-1 receptor agonist added to basal insulin therapy versus basal insulin with or without a rapid-acting insulin in patients with type 2 diabetes: results of a meta-analysis. Postgrad Med. 2017;15:1-10. doi:10.1080/00325481.2017.1297669