GLP-1 Receptor Agonists: Where do these non-insulin injectables, and newly approved oral option, fit in for the treatment of Type 2 Diabetes Mellitus?

GLP-1 Receptor Agonists:

Where do these non-insulin injectables, and newly approved oral option, fit in for the treatment of Type 2 Diabetes Mellitus?

By: Cedrice Davis, MD

Advances in treatment options for Diabetes have expanded over the last decade. While first-line therapy for the treatment of Diabetes has remained Metformin and comprehensive lifestyle modifications, several professional organizations, including the American Diabetes Association1, American College of Cardiology2, American Heart Association3, and American College of Clinical Endocrinologists4, have updated their guidelines to reflect a wider playing field for 2nd line options. Glucagon Like Peptide – 1 Receptor Agonists (GCP-1 RA) is one of those options.

Despite guideline updates, utilization of GLP-1 RA in the primary care setting remains relatively low.5 As an outpatient family physician with an office that participates in diabetes clinical research trials, I think it is important that we take a look at why this class of medicines should be part of the primary care physician’s armamentarium in the fight to control this disease.

GLP-1 is a member of the incretin family of glucoregulatory hormones.  It is secreted in response to food ingestion. GLP-1 RA therapies attempt to correct the dysregulation/dysfunction of normal physiology that contributes to the diabetes disease state.  GLP-1 RAs impact several core defects present in type 2 diabetes.6Background:

How do GLP-1 RA work?6

  1. Glucose-dependent increase in insulin secretion from pancreas. It does so by stimulating the beta cells of the pancreas in the setting of a glucose load.
  2. Glucose-dependent decrease of glucagon secretion from the liver. In Diabetes, the hormone glucagon is oversecreted causing an unwanted release of glucose from the liver. The suppression of the glucagon results in a welcomed decrease of glucose from the liver.
  3. Increased satiety resulting in a suppressed appetite. This occurs via receptors in the central nervous system.
  4. Delayed gastric emptying. This results in lower postprandial glucose levels.
  5. Protection of 𝛽-cell mass (demonstrated in animal models).

GLP-1 RA Products Available:

There is currently one newly approved oral GLP-1 RA and six injectable GLP-1 RAs available in the U.S. Dulaglutide (Trulicity), exenatide (Bydureon), exenatide (Byetta), liraglutide (Victoza), lixisenatide (Adlyxin), and semaglutide injectable (Ozempic) and now semaglutide oral (Rybelsus). (Click on brand name for link to product information)

Expected Clinical Outcomes:6,7,8

A1C reduction: 0.8-1.8%

Body weight reduction: 2-14 lbs

Efficacy and safety between GLP-1RAs vary. All have demonstrated cardiovascular safety, but liraglutide has an FDA approved indication to prevent CVD in high risk patients. Other GLP1 RAs are currently under FDA review for a CVD prevention indication (e.g., dulaglutide, semaglutide).

Cost:

Out of pocket expense for the patient will vary depending on insurance coverage.  Most manufacturers offer copay assistance for commercially insured patients and financial assistance for low income patients.

Tolerability: 6,7,9

GLP-1 RAs are generally well tolerated, with nausea and vomiting being the most common adverse event.  It is important to inform patients initiating GLP-1 RA therapy that this may occur initially, but it is usually transient and is typically mild to moderate in nature. If nausea is bothersome, the patient may be advised to eat smaller meals and avoid spicy or high-fat meals.  For patients already on the GLP-1 RA that experience nausea and vomiting with dose titration, consider decreasing back to the last tolerated dose for 1 week before repeating the incremental dosing steps.  The ADA standards of care note that renal dosing adjustments are required for exenatide and lixisenatide.1   Injection site reactions have also been reported.

What about GLP-1 RA and risk of pancreatitis? 9,10

Type 2 diabetes is a risk factor for development of acute pancreatitis, and studies of patients treated with GLP-1 RAs have reported that pancreatitis may occur more frequently with these medications, but results have been mixed. According to the PIs of all GLP-1 RAs, if pancreatitis is suspected, these drugs should be discontinued, and if acute pancreatitis is confirmed, they should not be restarted. The FDA and the European Medicines Agency (EMA) have agreed that assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer, as expressed in some scientific literature and in the media, are inconsistent with current data; however, the FDA and the EMA have not reached a final conclusion regarding such a causal relationship.

What about GLP-1 RA and risk of thyroid tumors? 6,7

In rodent models, GLP-1RAs have been linked to the release of calcitonin, and the potential formation of thyroid tumors, but there is no evidence of a causal relationship between GLP-1 RAs and thyroid tumors in humans. Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome is contraindicated according to the FDA PI for the long acting GLP-1 RAs dulaglutide, liraglutide, semaglutide and exenatide once weekly.

COMING SOON: 11

Different delivery systems for GLP-1 RAs are being investigated. Oral Semaglutide (Rybelsus) was approved by the FDA on September 20, 2019 and is now available in pharmacies. Other oral options are also being investigated as well as an implantable osmotic pump…. stay tuned!

References:

  1. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2019. Diabetes Care 2019;42(Suppl. 1): S1-S193. https://doi.org/10.2337/dc19-S009
  2. Das SR, et al. 2018 ACC expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a report of the American College of Cardiology Task Force on expert consensus decision pathways [published online November 26, 2018]. J Am Coll Cardiol. https://doi.org/10.1016/j.jacc.2018.09.020
  3. Arnett DK, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol 2019 Mar 17; [e-pub]. https://doi.org/10.1016/j.jacc.2019.03.010
  4. Alan J. Garber, et al. 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. Endocrine Practice: January 2019, Vol. 25, No. 1, pp. 69-100. https://doi.org/10.4158/EP151126.CS
  5. Raval, A. D., et al. National Trends in Diabetes Medication Use in the United States: 2008 to 2015. Journal of Pharmacy Practice.2018. https://doi.org/10.1177/0897190018815048
  6. Drucker DJ. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab.2018 Apr 3;27(4):740-756. https://doi.org/10.1016/j.cmet.2018.03.001
  7. Hinnen, D., et al. Glucagon-like peptide 1 receptor agonists for type 2 diabetes. Diabetes Spectr, 30 (3) 2017;202-210. https://doi.org/10.2337/ds16-0026
  8. Pratley RE, et al. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol 2018;6:275–86. https://doi.org/10.1016/S2213-8587(18)30024-X
  9. Thomsen RW, et al. Incretin-based therapy and risk of acute pancreatitis: a nationwide population-based case-control study. Diabetes Care 2015;38:1089–1098. https://doi.org/10.2337/dc13-2983
  10. Egan AG, et al. Pancreatic safety of incretin-based drugs—FDA and EMA assessment.New England Journal of Medicine. 2014;370(9):794-797. https://doi.org/1056/NEJMp1314078
  11. Meier, J.J., et al. Incretin-based therapies: where will we be 50 years from now? Diabetologia. 2015;58: 1745. https://doi.org/10.1007/s00125-015-3608-6