GLUCAGON LIKE PEPTIDE (GLP) 1 AGONISTS FOR THE TREATMENT OF TYPE 2 DIABETES, WEIGHT CONTROL AND CARDIOVASCULAR PROTECTION. Patricia Garnica MS, ANP-BC, CDE, CDTC Inpatient Diabetes Nurse Practitioner North Shore University Hospital Department of Medicine Division of Endocrinology Manhasset, N.Y. DISCLOSURE TO PARTICIPANTS No Conflict of Interest (COI) and Financial Relationship to Disclose No Endorsement of Products No Off Label Use LEARNING OBJECTIVES Attendees will be able to recognize the physiological effect of Glucagon like Peptide (GLP) 1 in glycemic homeostasis and how this effect is altered on patients with type 2 diabetes. Attendees will be able to identify the available pharmacological preparations of GLP 1 agonists including their action, indications and how they can be prescribed to specific patients needs and preferences. Attendees will be able to identify the most common side effects, adverse events and contraindications of GLP 1 agonists. 1
Insulin Resistance: The Core Defect in Type 2 Diabetes, Presented by Barry J. Goldstein, MD, PhD.(Medscape, 2018) INSULIN 2
DUAL IMPAIRMENT IN T2 DIABETES 1.Impaired insulin action (insulin resistance) 2. Impaired β cell function (Functional effect in insulin secretion) Insulin Resistance: The Core Defect in Type 2 Diabetes, Presented by Barry J. Goldstein, MD, PhD.(Medscape, 2018) HYPERGLYCEMIA CAUSES Defronzo et al. Diabetes Care 2013 3
OVERWEIGHT AND OBESITY Fat has very important effects on metabolism and cardiovascular health People collect fat in their visceral compartment as they age Visceral adipose tissue has a high rate of lipolysis Fat tissue releases fatty acids into the blood steam Fatty acids block the promotion of glucose uptake into muscle Fatty acids enhance gluconeogenesis in the liver HYPERGLYCEMIA CARDIOVASCULAR RISK FACTORS Higher triglyceride levels Higher systolic blood pressure Lower HDL levels WHAT IS GLUCAGON LIKE PEPTIDE (GLP) 1? It is an incretin which is a gut derived hormone that is released by the L cells in the distal parts of the intestines in response to nutrient ingestion stimulating insulin secretion in response to meals. The are two gut derivate incretin hormones: glucagon like peptide 1 (GLP 1) and glucose dependent insulinotropic polypeptide (GIP). The main meal components that act as potent stimulants of GLP 1 secretion are glucose and triacylglycerol but fructose and some proteins are also effective. GLP 1 decreases blood glucose levels by increasing insulin production after a meal. Slows the rate of absorption of nutrients into the blood stream by reducing gastric emptying and by this action reduce food intake Inhibits glucagon release from the alpha cells of the islets of Langerhans. 4
INCRETINE PHYSIOLOGICAL EFFECT OF GLUCAGON LIKE PEPTIDE (GLP) 1 IN GLYCEMIC HOMEOSTASIS In healthy individuals, oral ingestion of nutrients stimulates secretion of multiple gut hormones involved in regulating digestion, motility and metabolism, including insulin. The gut hormones GIP and GLP 1 are secreted from the intestinal K and L cells within minutes of food ingestion Together they account for up to 70% of insulin secretory responses after nutrient ingestion GLP 1 IN PEOPLE WITH TYPE 2 DIABETES The incretin hormone glucagon like peptide 1 (GLP 1) might be reduced in some people with T2Diabetes specially those with obesity, older age and those with higher levels of glucagon in the blood. More studies are needed to conclude that ALL patients with T2DM had reduced GLP 1 production. Some studies had shown that the use of Metformin increases the natural release of GLP 1 Pharmacological doses/concentrations of GLP 1 can compensate for the inability of diabetic β cells to respond to the main incretin hormone glucose dependent insulinotropic polypeptide. Nauck, et al. Diabetologia. 2011, 54(1);10 18. 5
GLUCOSE LOWERING ACTION OF GLP 1 RECEPTOR AGONISTS Use of native GLP 1 is limited by its very short half life and rapid degradation.glp 1 receptor agonists are resistant to degradation making them more therapeutic Mimic the effects of the incretin hormone GLP 1 which is excreted from the intestine when eating. Enhance glucose dependent insulin secretion release from the pancreatic islets. Inhibit inappropriate post meal glucagon release. Reduce food intake (increase satiety feeling, slow gastric emptying). Diabetes, Obesity and Metabolism. 2016; 18(3): 203 216 GLP 1 AGONISTS BENEFITS Can reduce A1C (by 0.8 1.6%) Can reduce body weight (by 1 3 kg) Decrease free fatty acids concentrations Reduce blood pressure and lipid levels. Protect beta cells against cytokine induced apoptosis and in s0me studies improves β call mass Can be added to Metformin/TZD as a second agent on patients that want to avoid weight gain or hypoglycemia. In some cases they can be as effective on achieving glycemic control as insulin therapy Diabetes, Obesity and Metabolism. 2016; 18(3): 203 216 Diabetes Spectrum 2017 Aug; 30(3): 202 210. Prasad Reddy, L & Isaacs, D. Drugs in context. 2015; 4:212283. GLP 1 AGONISTS THERAPEUTIC ACTION http://spectrum.diabetesjournals.org/content/30/3/202 6
GLUCAGON LIKE PEPTIDE 1 (GLP 1) AGONIST. SIDE EFFECTS Gastrointestinal: diarrhea, nausea, and vomiting. Adverse reactions Albiglutide Dulaglutide Liraglutide Exenatide QW Exenatide BID N Albiglutide N=923, % Placebo N=468, % Dulaglutid Dulaglutide e 0.75 mg 1.5 mg N=834, % N=836, % Placebo Liraglutide Exenatide N=568, N=497, % N=248, % % Exenatide N=963, % Placebo N=483, % Diarrhea 13.1 10.5 8.9 12.6 6.7 17.1 10.9 13 6 Nausea 11.1 9.6 12.4 21.1 5.3 28.4 11.3 44 18 Vomiting 4.2 2.6 6.0 12.7 2.3 10.9 NA 13 4 Injection site reaction or nodules 10.5 2.1 0.5 0.5 0 NA 10.5 NA NA GLUCAGON LIKE PEPTIDE 1 (GLP 1) AGONIST: CONTRAINDICATIONS Any one with the following history: Acute pancreatitis Pancreatic cancer Thyroid C cell hyperplasia, adenomas Medullary Thyroid carcinoma Multiple neoplasia syndrome type 2 (MEN2) Gastroparesis Caution on patients with liver or kidney disease Prasad Reddy, L & Isaacs, D. Drugs in context. 2015; 4:212283. GLUCAGON LIKE PEPTIDE 1 (GLP 1) BASED THERAPIES (NON INSULIN INJECTABLES) exenatide (Byetta ) 2005 liraglutide (Victoza,Saxenda ) 2010 lixisenatide (Adlyxin, Lyxumia ) 2016 exenatide (Bydureon ) 2012 weekly albiglutide (Tanzeum ) 2014 Weekly dulaglutide (Trulicity )2014 weekly semaglutide (Ozempic ) 2017 Weekly 7
SHORT ACTING GLP1 RECEPTOR AGONIST EXENATIDE (BYETTA ) This 39 amino acid synthetic peptide is based on exendin 4 from the lizard Heloderma suspectum (Gila monster), sharing 53% homology with human GLP 1 It binds to the pancreatic GLP 1 receptor and has many of the glucoregulatory properties of human GLP 1 such as enhances glucose dependent insulin secretion, suppresses postprandial glucagon secretion, slows gastric emptying and reduces caloric intake. Some studies have shown that exenatide also increases pancreatic β cell mass and improves β cell function Give BID 60 minutes prior to breakfast and dinner. Half life is 2.4 hours Start dose is 5mcg sq bid for one month and then if tolerated increase to 10mcg bid Uccellatore et al. Diabetes ther. 2015; 6(3): 239 256 Byetta for Heath Care Professionals 2016 SHORT ACTING GLP1 RECEPTOR AGONIST LIRAGLUTIDE (VICTOZA,SAXENDA ) It is a human GLP 1 analog in which lysine 34 is substituted with arginine, and lysine 26 has a C16 acyl chain attached. The above modifications improve the absorption and extend the half life compared to native GLP 1 Give once a day. Half life is 13 h Liraglutide should be initiated at a dose of 0.6 mg once daily for 1 week and then titrated to 1.2 mg daily. If the 1.2 mg dose does not achieve glycemic goals, it can be increased to 1.8 mg daily. Initial dose of 0.6 mg is ineffective for glycemic control, and is only initiated to maximize patient tolerance to the potential gastrointestinal effects of the medication Studies had shown improves fasting BG levels better than BID exenatide Uccellatore et al. Diabetes ther. 2015; 6(3): 239 256 SHORT ACTING GLP1 RECEPTOR AGONIST LIXISENATIDE (ADLYXIN, LYXUMIA ) It is a synthetic peptide derived from the exendin 4 hormone. It is made up of 44 amino acids and includes six lysine residues at the C terminal end of the molecule to prevent degradation of the peptide increasing the peptide s time in circulation. Starting dose of 50 mcg/ml strength for 2 weeks for titration and 100 mcg/ml strength for maintenance dose. Lixisenatide has a half life of 1.5 3 hours and given as a once daily injection It has a positive effect on both the first phase and second phase insulin response, providing reductions in both fasting and postprandial glucose concentrations. A study comparing it to Liraglutide showed better post prandial glycemic control but lesser effect on fasting blood glucose. Prasad Reddy, L & Isaacs, D. Drugs in context. 2015; 4:212283. Lixisenatide: Division Director Review FDA 2016. 8
LONG ACTING GLP1 RECEPTOR AGONIST EXENATIDE (BYDUREON ) The first once weekly diabetes treatment 2 mg subcutaneously once every 7 days (weekly). The dose can be administered at any time of day, with or without meals. The day of weekly administration can be changed if necessary as long as the last dose was administered 3 or more days before the new day of administration. Bydureon is made up of biodegradable microspheres that provide a controlled release of exenatide throughout the week. Uccellatore et al. Diabetes ther.2015; 6(3): 239 256 Bydureon for health care professionals. 2018 LONG ACTING GLP1 RECEPTOR AGONIST EXENATIDE (BYDUREON ) The initial presentation of BYDUREON in 2012 was of four single dose trays with vials requiring constitution to obtain a final concentration of 2 mg In 2014, the FDA approved a prefilled single use pen injector, eliminating the need for the patient to transfer the medication between a vial and syringe during the self injection process. In 2017, the FDA approved Bydureon Bcise single dose autoinjector device. In 2018, the FDA approved Bydureon (exenatide extended release) for injectable suspension as an add on therapy to basal insulin in adults with type 2 diabetes (T2D) with inadequate glycemic control. Uccellatore et al. Diabetes ther. 2015; 6(3): 239 256 Prasad Reddy, L & Isaacs, D. Drugs in context. 2015; 4:212283. LONG ACTING GLP1 RECEPTOR AGONIST EXENATIDE (BYDUREON ) https://ndclist.com/ndc/0310 6520 https://ndclist.com/ndc/0310 6520 https://www.bydureon.com/using bcise/how to use bydureon bcise.html 9
LONG ACTING GLP1 RECEPTOR AGONIST ALBIGLUTIDE (TANZEUM ) It is a dimer of two copies of 30 amino acid fused to human albumin, and a single amino acid substitution (glycine to alanine) in vivo, resulting in a half life of approximately 5 days Comparison data between albiglutide and lispro insulin in HARMONY 6 trial suggest that this long acting GLP 1 RA is a valid alternative to lispro insulin in add on basal insulin. In the HARMONY 7 clinical trial, it was demonstrated that liraglutide at a dose of 0.6 mg titrated to 1.8 mg was more effective than albiglutide (at a dose of 30 mg titrated to 50 mg), but with less frequent gastrointestinal adverse events albiglutide may be an alternative option in patients who cannot tolerate shorteracting GLP 1 receptor agents due to adverse effects Prasad Reddy, L & Isaacs, D. Drugs in context. 2015; 4:212283. LONG ACTING GLP1 RECEPTOR AGONIST DULAGLUTIDE (TRULICITY ) It has modified amino acid sequences that resist DPP 4 degradation, as well as the large size of the molecule, reducing renal clearance Administered as a 0.75 mg injection which can be titrated to 1.5 mg once weekly to achieve glycemic targets. Therapeutic concentrations are achieved faster when compared to other weekly GLP 1 receptor agonists, within 1 3 days versus 2 4 weeks after administration Dulaglutide is available in two dosage forms, a prefilled pen syringe ready for injection and a solution for injection that requires reconstitution by the patient prior to administration In the AWARD 2 study, dulaglutide at doses of 0.75 mg once weekly and 1.5 mg weekly resulted in a larger reduction in hemoglobin A1C compared to insulin glargine titrated to a goal fasting blood glucose level of <100 mg/dl Prasad Reddy, L & Isaacs, D. Drugs in context. 2015; 4:212283. LONG ACTING GLP1 RECEPTOR AGONIST SEMAGLUTIDE (OZEMPIC ) Has 94% sequence homology to native GLP 1 Start at 0.25 mg once weekly. After 4 weeks, increase the dose to 0.5 mg once weekly. If after at least 4 weeks additional glycemic control is needed, increase to 1 mg once weekly increased risk for diabetic retinopathy complications was noted on semaglutide trial while medication was improving glycemic control. Benefit risk needs to be evaluated and this agent should be avoided on people with baseline retinopathy. More studies need to be done since the DCCT study showed the same effect on patients with thigh glycemic control. OZEMPIC (semaglutide) injection, for subcutaneous use. Prescribing information. Ozempic (semaglutide) Injection FDA 2017. 10
BASAL AND GLP 1 AGONISTS MIX 2016 Basal insulin glargine plus lixisenatide (Soliqua 100/33 ) Basal insulin degludec plus liraglutide (Xultophy 100/3.6 ) GLP 1 AGONISTS DIFFERENCES Clinical application of GLP 1 Receptor Agonists. J Korean Diabetes. 2015 Dec; 16(4): 252 259 COMPARISON OF SHORT ACTING VERSUS LONG ACTING GLP 1 AGONISTS Clinical application of GLP 1 Receptor Agonists. J Korean Diabetes. 2015 Dec; 16(4): 252 259 11
WEIGHT LOSS OUTCOMES FOR GLP 1 AGONISTS CARDIOVASCULAR OUTCOMES OF GLP 1 AGONISTS. A systematic review and meta analysis of trials of GLP 1 receptor agonists versus placebo assessed a primary outcome including, but not limited to, cardiovascular mortality, non fatal myocardial infarction, and non fatal stroke. Four trials of cardiovascular outcomes of GLP 1 receptor agonists were identified: ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN 6 (semaglutide), and EXSCEL (extended release exenatide) Findings included 10% relative risk reduction (RRR) in the three point major adverse cardiovascular event primary outcome, a 13% RRR in cardiovascular mortality, and a 12% relative risk reduction in all cause No significant effect of GLP 1 receptor agonists was identified on fatal and non fatal myocardial infarction, fatal and non fatal stroke, hospital admission for unstable angina, or hospital admission for heart failure Bethel et al. The Lancet: Diabetes and endocrinology 2018, 6(2):105 113 MULTIPLE CAUSES OF HYPERGLYCEMIA 12
REFERENCES A clinical review of GLP 1 receptor agonists: efficacy and safety in diabetes and beyond. Drugs in context. 2015; 4:212283. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4509428/ Byetta for Heath Care Professionals 2016. https://www.byettahcp.com/dosing andadministration.html Bydureon for health care professionals. https://www.bydureonhcp.com/ Cardiovascular outcomes with glucagon like peptide 1 receptor agonists in patients with type 2 diabetes: a meta analysis. The Lancet: Diabetes and endocrinology 2018, 6(2):105 113 https://www.thelancet.com/journals/landia/article/piis2213 8587(17)30412 6/fulltext Clinical application of GLP 1 Receptor Agonists. J Korean Diabetes. 2015 Dec; 16(4): 252 259 https://synapse.koreamed.org/doix.php?id=10.4093/jkd.2015.16.4.252&vmode=pubreader Comparison Review of Short Acting and Long Acting Glucagon like Peptide 1 Receptor Agonists. Diabetes therapeutics. 2015; 6(3): 239 256 https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4575308/ Glucagon Like Peptide 1 Receptor Agonists for Type 2 Diabetes. Diabetes Spectrum 2017 Aug; 30(3): 202 210. http://spectrum.diabetesjournals.org/content/30/3/202 REFERENCES Incretin therapies: highlighting common features and differences in the modes of action of glucagon like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors. Diabetes, Obesity and Metabolism. 2016; 18(3): 203 216 https://onlinelibrary.wiley.com/doi/full/10.1111/dom.12591 Lixisenatide: Division Director Review FDA 2016. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208471orig1s000sumr.pdf Ozempic (semaglutide) Injection FDA 2017. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637orig1s000toc.cfm OZEMPIC (semaglutide) injection, for subcutaneous use https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl.pdf Secretion of glucagon like peptide 1 (GLP 1) in type 2 diabetes: what is up, what is down? Diabetologia. 2011, 54(1);10 18. https://link.springer.com/article/10.1007%2fs00125 010 1896 4 Q&A 13