Going GLP-1Authors: James Rhodes, PharmD Candidate 2019,
UMKC School of Pharmacy
Amanda Stahnke, PharmD, BCACP:
UMKC School of Pharmacy/Kansas City
VA Medical Center
Since the first-in-class approval in 2005, there have been more glucagon-like peptide-1 (GLP-1) receptor agonists approved for type 2 diabetes mellitus (T2DM) than any other noninsulin monotherapy agent.1 These agents provide clinicians more options in the diabetes armamentarium to individualize their patients’ regimens to meet individualized short-term and long-term goals. According the American Diabetes Association, a GLP-1 may be added if noninsulin monotherapy failed to help patients reach their A1c target.2 Alternatively, practitioners may also need an additional agent for glycemic control after basal insulin has been maximized. Should a clinician decide to use a GLP-1, it is important to know how either short-acting (SA-GLP-1) or long-acting (LA-GLP-1) agonist subgroups can help a patient reach their goals, with an understanding of each agent’s pharmacokinetic profiles and clinical trial data.
An Incretin Introduction3GLP-1 is a physiologic regulator of appetite and caloric intake. These gut-derived agents also manage glucose control by influencing hyperglycemic insulin secretion, euglycemic glucagon inhibition, anoretic effects, and slowing gastric emptying. Mechanistic discovery of GLP-1s began after gastrointestinal secretion was identified to induce pancreatic insulin release after eating carbohydrates and fats. Also known as the incretin effect, dietary caloric intake has been identified to secrete GLP-1 from intestinal cells, thus contributing to glucose-dependent pancreatic insulin release. This process becomes impaired in individuals with T2DM,4 further disrupting glucose homeostasis which leads to uncontrolled hyperglycemia. Endogenous GLP-1 plays a significant role in augmenting these insulin secretions, which has led to the development of exogenous GLP-1 agents resistant to degradation by dipeptidyl peptidase 4 (DPP4).
Short-Acting GLP-1sUse of SA-GLP1s have been shown to reduce hyperglycemia and glucose excursions in the postprandial state.3 There are two SA-GLP-1s currently approved for glycemic control in adults with T2DM: exenatide (Byetta™) and lixisenatide (Adlyxin™). These exogenous GLP-1 agents have N-terminal modifications to provide half-lives between 2-6 hours.5,6 These agents slow intestinal absorption of nutrients and reduce postprandial hyperglycemia by reducing the rate of gastric emptying into the duodenum; providing a suitable alternative to bolus insulin in combination with basal insulin to reduce postprandial glycemic excursions and incidences of hypoglycemia. However, this notable short-acting therapeutic property requires special considerations for additional medications for patients. For oral medications which the efficacy is concentration-dependent (i.e. antibiotics or oral contraceptives), it is recommended to take these at least 1 hour prior to SA-GLP-1 administration. If such medications are advised to be taken with food, these medications should be administered at a different meal than the SA-GLP-1.5,6
Long-Acting GLP-1sSubgroup LA-GLP-1s notably reduce basal hyperglycemia for greater than 24 hours due to the prolonged pharmacokinetics. There are five LA-GLP-1’s currently authorized for clinical use as an adjunct to diet and exercise in adults with T2DM: exenatide XR (Bydureon™), liraglutide (Victoza™ & Saxenda™), dulaglutide (Trulicity™), and newly approved semaglutide (Ozempic™). Each active agent possesses unique chemical modifications to sustain half-lives longer than 12 hours,7-11 which would allow for once daily or weekly administrations. These modifications include albumin-binding (liraglutide3, semaglutide11), immunoglobulin-binding (dulaglutide3), or encapsulation of slow-release polymicrosperes (exenatide XR3). Consistent therapeutic drug levels induce hyperglycemic insulin release from the pancreas. However, such concentrations also lead to prolonged activation and tachyphylaxis of the GI tract receptors,3 consequently having a less pronounced effect on gastric motility compared to SA-GLP-1s. Nevertheless, the clinical outcomes of LA-GLP-1s have been superior regarding the control of basal hyperglycemia3 over SA-GLP-1 counterparts.
Cardiovascular Outcomes of LA-GLP-1sThere have been two LA-GLP-1 agents identified to reduce long-term cardiovascular (CV) risk as evidenced by the LEADER12 (liraglutide) and SUSTAIN-613 (semaglutide) trials (Appendix A). These trials were designed as time-to-event analyses of a primary composite endpoint of CV death, nonfatal myocardial infarction, or nonfatal stroke in participants with T2DM and established CV disease. Liraglutide and semaglutide both significantly decreased the incidence of the primary composite endpoint versus placebo. A subgroup analysis of the LEADER trial revealed significant interactions favoring patients with reduced renal function (CrCl < 60 mL/min/1.73 m2; p = 0.01) and established CVD (≥ 50 years of age and established CVD; p = 0.04), but no significant interactions were identified for the SUSTAIN-6 trial. Neither agent showed benefit regarding secondary heart failure outcomes.12,13
An Added Benefit by Subtracting WeightWeight reduction is also a common outcome attributed to delayed gastric emptying and suppressing appetite centers in the brain. Although weight loss has been observed as a significant secondary measure for most GLP-1 clinical studies, the SCALE14trial was statistically powered to determine liraglutide’s effect on weight loss (Appendix A). Obese T2DM participants received either liraglutide 3mg, 1.8mg, or placebo comparator over 56 weeks to measure three coprimary endpoints: relative change in body weight, reduction in 5% or more from baseline body weight, and reduction in more than 10% of body weight from baseline. Weight loss was significantly greater with liraglutide (3.0mg) and liraglutide (1.8mg) than the matching placebos for all three co-primary endpoints.14
Considering a Place in TherapyIn the absence of precautions5-11 (e.g. gallbladder disease, acute pancreatitis) and contraindications7-11 (e.g. personal or familial history of thyroid cancer), injectable GLP-1s are useful agents in glucose-lowering strategies as second line option after metformin, if weight gain is a concern or as a third line agent, particularly in combination with metformin and basal insulin. GLP-1s are also offered in fixed-combinations with basal insulin to reduce daily injections. The adverse effects7-11 are primarily gastrointestinal such as nausea, vomiting, and diarrhea but hypoglycemia is still possible when used in combination with other agents. When deciding between GLP-1s, either SA or LA-GLP-1 are acceptable; dosing convenience may give preference for the latter subclass. An additional consideration may also be room temperature stability of GLP-1s as times vary significantly (Appendix A) and proper refrigeration may not always be widely accessible. While these antidiabetic agents may be considered effective for individuals with T2DM, they do so at the expense of higher rates of gastrointestinal side effects and cost. Therefore, it is important to discuss these potential barriers with patients prior to starting GLP-1 treatment.
1. U.S. Department of Health and Human Services. Food & Drug Administration (FDA). (2017). FDA-Approved Diabetes Medicines. Retrieved from https://www.fda.gov/forpatients/illness/diabetes/ucm408682.htm2. American Diabetes Association (ADA). 8. Pharmacologic Approaches to Glycemic Treatment. Diabetes Care. 2018; 41(Suppl. 1): S73-S85.
3. Meier JJ. GLP-1 receptor agonists for individualized treatment for type 2 diabetes mellitus. Nat. Rev. Endocrinol. 2012; 8: 728-742.
4. Madsbad S. The role of glucagon-like peptide-1 impairment in obesity and potential therapeutic implications. Diabetes, Obesity, and Metabolism. 2014; 16: 9-21.
5. Byetta (exenatide) injection [package insert]. AstraZeneca Pharmaceuticals LP. Wilmington, DE; 2015.
6. Adlyxin (lixisenatide) injection [package insert]. Sanofi-Aventis US LLC. Bridgewater, NJ; 2016.
7. Bydureon (exenatide extended-release) injectable suspension [package insert]. AstraZeneca Pharmaceuticals LP. Wilmington, DE; 2017.
8. Victoza (liraglutide) injection [package insert]. Novo Nordisk A/S. Bagsvaerd, Denmark; 2017.
9. Saxenda (liraglutide [rDNA origin] injection) [package insert]. Novo Nordisk A/S. Bagsvaerd, Denmark; 2017.
10. Trulicity (dulaglutide) injection [package insert]. Eli Lilly and Company. Indianapolis, IN; 2017.
11. Ozempic (semaglutide) injection [package insert]. Novo Nordisk A/S. Bagsvaerd, Denmark; 2017.
12. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine. 2016, 375(4): 311-322.
13. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New England Journal of Medicine. 2016; 375: 1834-1844.
14. Davies MJ, Bergenstal R, Bode B, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes. Journals of American Medical Association. 2015; 314(7): 687-699.