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Clinical Considerations for the Use of GLP-1 Agonists Post Lung Transplantation


Robin Klasek, PharmD
Rklasek@houstonmethodist.org

Kyle Dawson, PharmD, MBA, BCPS
KLDawson@HoustonMethodist.org
Houston Methodist
Houston, TX, USA



Hyperglycemia post transplantation is a relatively common complication, either due to pre-existing diabetes or new-onset diabetes after transplant (NODAT). The estimated rates of NODAT 12 months post-transplant are 28-30% in heart transplant and 6-45% for lung transplants [1-3]. This article aims to discuss pharmacotherapy considerations for a newer class of incretin mimetics, the glucagon-like peptide-1 (GLP-1) agonists, used in the management of hyperglycemia in thoracic transplant patients with focus on risk vs. benefit in lung transplant recipients.

Exposure to immunosuppressive agents, such as glucocorticoids and calcineurin inhibitors, in combination with other risk factors including older age, obesity (BMI>30), and frequent acute rejection episodes requiring treatment with high-dose steroids further increase the risk of NODAT. NODAT is associated with an increased risk of rejection, infections, and cardiovascular complications [4]. Many patients will require pharmacotherapy to manage hyperglycemia post transplantation, and this often includes insulin. Incretin mimetics, one of the latest additions to the armamentarium for the treatment of hyperglycemia and NODAT, are now available as an addition to insulin therapy to lower insulin requirements or as monotherapy in place of insulin [5]. Currently five agents in the GLP-1 agonist pharmacological class are available worldwide; albiglutide, dulaglutide, exenatide, liraglutide and lixisenatide. All five agents are peptides that need to be administrated by subcutaneous injection in various frequencies ranging from twice daily immediate release exenatide to once weekly albiglutide, dulaglutide and extended release exenatide.

GLP-1 agonists are less likely to cause hypoglycemia as a monotherapy than insulin or sulfonylureas, but they have similar rates of hypoglycemia when combined with these agents. GLP-1 agonists mimic the physiological profile of insulin by enhancing glucose-dependent insulin release and inhibiting secretion of glucagon [6]. GLP-1 agonists reportedly lower A1C levels in non-transplant individuals by up to 2% and promote weight loss of as much as 4 kg in 24-32 week-long trials [7]. In addition to lowering A1C and promoting weight loss, GLP-1 agonists also promote satiety in the central nervous system and slow down gastric emptying by relaxing the proximal stomach and inhibiting both antral and duodenal motility [8-12]. In healthy subjects, GLP-1 agonist use causes increased retention of solids in the distal stomach at 100 minutes from 29% to 58% and frequently produced gastroparesis, without regards to its dose [13].

Gastroparesis is a complication of lung transplantation, with a prevalence of 6-24% [14,15]. It is thought to be attributed to intraoperative vagal nerve damage, pharmacological agents, and preexisting lung disease [16]. Gastroparesis may play a significant role in Bronchiolitis Obliterans Syndrome (BOS) through an exacerbating effect on gastroesophageal reflux disease (GERD) leading to microaspiration and secondary activation of the innate immune system [17]. Bronchiolitis Obliterans Syndrome is a common cause of mortality and morbidity in lung transplantation, with a five-year patient survival from onset of 30-40% [18].

To our knowledge, no data on the use of GLP-1 agonists and gastroparesis complications in lung transplantation have been published at present. GLP-1 agonists increase the risk of gastroparesis in healthy individuals and we can reasonably expect this to affect some thoracic transplant patients as well. Given the role that gastroparesis may play in the development of serious, long-term sequelae, caution should be exercised with this new class of agents. As these agents gain popularity, prescribers should be aware of the side-effect profile before their initiation in lung transplant recipients and consider possible risks vs. benefits of therapy. ■

Disclosure Statement: The authors have no conflicts of interest to disclose.


References:

  1. Bedanova H, Ondrasek J, Cerny J et al. Impact of diabetes mellitus on survival rates after heart transplantation. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2009;153:283-287.
  2. Ye X,KuoHT, SampaioMS, Jiang Y et al. Risk factors for development of new-onset diabetes mellitus in adult heart transplant recipients. Transplantation 2010;89:1526-1532.
  3. Silverborn M, Jeppsson A, MÃ¥rtensson G et al. Newonset cardiovascular risk factors in lung transplant recipients. J Heart Lung Transplant 2005;24:1536-1543.
  4. Hjelmesaeth J, Hartmann A, Leivestad T et al. The impact of early diagnosed new-onset post-transplantation diabetes mellitus on survival and major cardiac events. Kidney Int 2006;69:588-595.
  5. Lane JT, Dagogo-Jack S. Approach to the Patient with New-Onset Diabetes after Transplant (NODAT). Clin Endocrinol Metab 2011;96(11):3289-3297.
  6. Nauck MA, Vilsboll T, Baptist, G. Incretin-Based Therapies. Diabetes Care 2009;32(2):S223-S231.
  7. Trujillo JM, Nuffer W, Ellis SL. GLP-1 receptor agonists: a review of head-to-head clinical studies. Ther Adv Endocrinal Metab 2015;6(1)19-28.
  8. Flint A, Raben A, Astrup A et al. Glucagon-like peptide-1 promotes satiety and suppresses energy intake in humans. J Clin Invest 1998;101:515-520.
  9. Zander M, Madsbad S, Madsen JL et al. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 2002;359:824-830.
  10. Delgado-Aros S, Kim DY, Burton DD et al. Effect of GLP-1 on gastric volume, emptying, maximum volume ingested, and postprandial symptoms in humans. Am J Physiol Gastrointest Liver Physiol 2002;282:G424-G431.
  11. Schirra J, Wank U, Arnold R et al. Effects of glucagon-like peptide-1(7-36)amide on motility and sensation of the proximal stomach in humans. Gut 2002;50:341-348
  12. Schirra J, Houck P, Wank U et al. Effects of glucagon-like peptide-1(7-36)amide on antro-pyloro-duodenal motility in the interdigestive state and with duodenal lipid perfusion in humans. Gut 2000;46:622-631.
  13. Little TJ, Pilichiewicz AN, Russo A et al. Effects of Intravenous Glucagon-Like Peptide-1 on Gastric Emptying and Intragastric Distribution in Healthy Subjects: Relationships with Postprandial Glycemic and Insulinemic Responses. The Journal of Clinical Endocrinology & Metabolism 2006;91(5):1916-1923.
  14. Berkowitz N, Schulman LL, Mcgregor C et al. Gastroparesis after lung transplantation. Potential role in postoperative respiratory complication. Chest 1995;108:1602-7.
  15. Subroto P, Escareno CE, Clancy K et al. Gastrointestinal Complications After Lung Transplantatio. J Heart Lung Transplant 2009;25(5)475-479.
  16. Raviv Y, D'Ovidio F, Pierra A et al. Prevalence of gastroparesis before and after lung transplantation and its association with lung allograft outcomes. Clin Transplant 2012;26:133-142.
  17. Swanstrom LL. Management of patients with gastroesophageal reflux disease and esophageal or gastric dysmotility. J Gastrointest Surg 2001;5:448-50.
  18. Valentine VG, Robbins RC, Berry GJ et al. Actuarial survival of heart-lung and bilateral sequential lung transplant recipients with obliterative bronchiolitis. J Heart Lung Transplant 1996:15:371-83



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