Type 2 Diabetes Therapy Intensification: Part I: Insulin vs GLP-1 Agonists

Short-Acting GLP-1RAs

Short-acting GLP-1RAs appear to achieve glucose control primarily through reductions in postprandial gluclose.4 Controlling postprandial glucose contributes to overall HbA1 levels.5 Lixisenatide is a short-acting GLP-1RA evaluated as intensification of basal insulin in the Get-Goal series of randomized, controlled, phase 3 clinical trials.9 Comparators varied between the lixisenatide trials and included placebo, RAI, or another GLP-1RA.4,9

Data showed once-daily lixisenatide was noninferior to RAI given once daily or three times daily at reducing HbA1c levels. Lixisenatide was superior to RAI add-on therapy at achieving weight reduction.9 In a meta-analysis of 5 trials comparing lixisenatide vs RAI, 29% of patients taking lixisenatide achieved the composite end point of an HbA1c <7%, no weight gain, and no incidents of hypoglycemia compared with 15% of patients taking an RAI (P =.0046).4

Exenatide was the first FDA-approved GLP-1RA.6 Several trials looked at twice-daily exenatide as an add-on to basal insulin in patients with an HbA1c >8%. Similar to lixisenatide in the Get-Goal trials, exenatide was noninferior to a basal-plus regimen and contributed to greater weight loss.4 Exenatide was also associated with greater reductions in fasting plasma glucose than the RAI.4 Studies have not compared exenatide with lixisenatide in patients using basal insulin, but a head-to-head comparison of both GLP-1RAs in patients taking oral metformin reported similar efficacy outcomes.9

Long-Acting GLP-1RAs

Long-acting GLP-1RAs predominantly affect fasting plasma glucose levels.4 However, at least 1 study of long-acting liraglutide showed it also reduced postprandial glucose levels from baseline.4 A systematic analysis of studies that added liraglutide to basal insulin for patients with an HbA1c >7.5% concluded that once-daily liraglutide reduced the HbA1c more than insulin up-titration or a basal-plus regimen.4 The mean decrease in HbA1c across the trials ranged from –0.6% to −1.9%.4 Liraglutide was also associated with significantly more weight loss than a basal-plus regimen. Other studies have shown liraglutide to be noninferior to RAI at reducing HbA1c.4

Albiglutide is another long-acting GLP-1RA. It was compared with a basal-bolus regimen in people who had suboptimal HbA1c levels despite basal insulin use.10 Albiglutide was administered once weekly, whereas the RAI was injected 3 times daily.10 After 26 weeks, albiglutide was noninferior to the RAI at reducing the HbA1c.10 Albiglutide contributed to weight loss, whereas the RAI caused weight gain. No cases of severe hypoglycemia occurred with albiglutide vs 2 cases in RAI users.

In early 2017, the FDA expanded indications for the GLP-1RA dulaglutide to include coadministration with basal insulin based partly on results from the phase 3 AWARD-9 trial (ClinicalTrials.gov identifier: NCT02152371). AWARD-9 compared weekly dulaglutide vs placebo as intensification for basal insulin.11 At 28 weeks, the dulaglutide group had significantly greater mean reductions in HbA1c and significantly more weight loss, and required significantly smaller increases in basal insulin dose.11 A phase 3 trial that compared dulaglutide with RAI in patients taking basal insulin observed similar decreases in glucose levels with both therapies.12 Patients taking dulaglutide experienced more stable glucose levels during the 1-year trial.

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  1. American Diabetes Association. Pharmacologic approaches to glycemic treatment. Diabetes Care. 2017;40(Suppl 1):S64-S74. doi:10.2337/dc17-S011
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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