Incredible Incretins Abby Frye, PharmD, BCACP

Incredible Incretins Abby Frye, PharmD, BCACP Objectives & Disclosures Review the pathophysiology of T2DM and the impact of the incretin system Describe the defining characteristics of the available glucagonlike peptide-1 (GLP-1) receptor agonists, including their impact on glycemic control, weight and blood pressure, as well as their safety profiles including hypoglycemic risk Analyze the available evidence regarding the cardiovascular effects of the GLP-1 receptor agonists Identify the role(s) of GLP-1 receptor agonist therapy in the treatment algorithm for T2DM Disclosures: None 2 Assessment Questions 1. GLP-1 is an endogenous incretin with which of the following glucoregulatory actions? A. Stimulation of glucose-dependent insulin secretion B. Reduction of glucagon secretion C. Retardation of gastric emptying D. All of the above 3 1

Assessment Questions 2. Compared to rapid-acting insulin, the GLP-1 agonists have all the following advantages, EXCEPT? A. A lower risk of hypoglycemia B. A potential for weight loss, even when added to insulin C. Fewer side effects D. Fewer dose adjustments/less frequent injections 4 Assessment Questions 3. Which currently available GLP-1 agonist has been associated with a reduction in ASCVD in a highrisk cohort? A. Liraglutide (Victoza) B. Exenatide (Byetta, Bydureon) C. Albiglutide (Tanzeum) D. Dulaglutiide (Trulicity) 5 Assessment Questions 4. GLP-1 agonists are an appropriate second-line option (after metformin) for patients with T2DM A. True B. False C. It depends on patient-specific characteristics 6 2

THE PATHOPHYSIOLOGIC ROLE OF INCRETINS 7 The Ominous Octet Diabetes. 2009;58:773-795. 8 GLP-1 Appetite Gastric emptying Insulin secretion Glucagon secretion Cardioprotection Cardiac function Weight loss Glucose production 9 3

THE GLP-1 RECEPTOR AGONISTS albiglutide dulaglutide exenatide liraglutide lixisenatide 10 Exenatide BID (Byetta ) FDA approval: 2005 T ½ = 2.4 hours Dosing schedule: twice-a-day, 30-60 minutes before breakfast and dinner How supplied: pre-filled, multi-dose pen device Cost: ~$700-800/month Byetta [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2015. Cost information: Goodrx.com [accessed 4/2017] 11 Lixisenatide (Adlyxin ) FDA approval: 2016 T ½ = 3 hours Dosing schedule: once daily, within one hour of the first meal of the day How supplied: pre-filled, multi-dose pen device Cost: $600/month Adlyxin [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2016. Cost information: Goodrx.com [accessed 4/2017] 12 4

Liraglutide (Victoza ) FDA approval: 2010 T ½ = 13 hours Dosing schedule: once daily without regard to meals How supplied: pre-filled, multi-dose pen device Cost: ~$800-900/month Victoza [package insert]. Princeton, NJ: Novo Nordisk Inc; 2010. Cost information: Goodrx.com [accessed 4/2017] 13 Albiglutide (Tanzeum ) FDA approval: 2014 T ½ = 5 days Dosing schedule: once weekly How supplied: pre-filled, single-dose pen device that requires reconstitution Cost: ~$600/month Tanzeum [package insert]. Wilmington, DE: GlaxoSmithKline LLC; 2016. Cost information: Goodrx.com [accessed 4/2017] 14 Dulaglutide (Trulicity ) FDA approval: 2014 T ½ = 5 days Dosing schedule: once weekly How supplied: pre-filled, single-dose pen device Cost: $750-850/month Trulicity [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014. Cost information: Goodrx.com [accessed 4/2017] 15 5

Exenatide QW (Bydureon ) FDA approval: 2012 Pharmacokinetics: Absorption: from microspheres x 10 weeks after injection Tmax: initial peak, 2 weeks; steady state, 6-7 weeks Dosing schedule: once weekly How supplied: Pre-filled, single-dose pen a single-dose tray that both require reconstitution Cost: ~$700-800/month Bydureon [package insert]. San Diego, CA: Amylin Pharmaceuticals, Inc.; 2012. Cost information: Goodrx.com [accessed 4/2017] 16 AGENT (BRAND ) INITIAL DOSE MAX DOSE DOSAGE FORM (QUANTITY) RENAL ADJ? SPECIAL CONSIDERATIONS Exenatide (Byetta ) 5mcg SC BID 10mcg BID 5 mcg (1 pen) 10 mcg (1 pen) Yes Timing with meals Lixisenatide (Adlyxin ) 10 mcg SC daily 20 mcg daily 10 mcg (2 pens) 20 mcg (2 pens) Yes Timing with meals Liraglutide (Victoza ) 0.6mg SC daily 1.8mg daily 18mg/3ml (2-pak) 18mg/3ml (3-pak) No Also FDA approved for weight loss (Saxenda ) Albiglutide (Tanzeum ) 30mg SC weekly 50mg weekly 30mg (4 pens) 50mg (4 pens) No Requires mixing Dulaglutide (Trulicity ) 0.75mg SC weekly 1.5mg weekly 0.75 mg (4 pens) 1.5mg (4 pens) No Auto-injector Exenatide QW (Bydureon ) 2mg SC weekly 2mg weekly 2mg (4 vials) 2mg (4 pens) Yes Both kit & pen require mixing 17 Insulin glargine/lixisenatide (Soliqua 100/33) FDA approval: 2016 Dosing schedule: once daily, within one hour of the first meal of the day How supplied: Pre-filled, multi-dose pen device which can deliver doses ranging from 15 units (15 units insulin glargine/5mcg lixisenatide) to 60 units (60 units insulin glargine/20 mcg lixisenatide) Cost: ~$650/month Soliqua 100/33 [package insert]. Bridgewater, NJ: Sanofi-aventis, U.S. LLC.; 2016. Cost information: Goodrx.com [accessed 4/2017] 18 6

Insulin degludec/liraglutide (Xultophy 100/3.6) FDA approval: 2016 Dosing schedule: once daily How supplied: Pre-filled, multi-dose pen device which can deliver doses ranging from 10 units (10 units insulin degludec/0.36 mg liraglutide) to 50 units (50 units insulin degludec/1.8 mg liraglutide) Cost: ~$950-1000/month Soliqua 100/33 [package insert]. Bridgewater, NJ: Sanofi-aventis, U.S. LLC.; 2016. Cost information: Goodrx.com [accessed 4/2017] 19 Important Contraindications/Warnings Contraindicated in patients with a personal or family history of medullary thyroid carcinoma Contraindicated in patients with a history of multiple endocrine neoplasia syndrome type 2 Consider avoiding use in patients with history of pancreatitis or gastroparesis 20 Head-to-Head Clinical Trials 21 7

Study Design Active Comparators DURATION-1 n=295 30 weeks LEAD-6 n=464 26 weeks DURATION-5 n=252 24 weeks DURATION-6 n=911 26 weeks GetGoal-X n=634 24 weeks HARMONY-7 n=841 32 weeks AWARD-1 n=978 26 weeks AWARD-6 n=599 26 weeks Ther Adv EndrocrinolMetab2015;6(1):19-28. Exenatide 10 mcg BID Exenatide 2 mg QW Exenatide 10 mcg BID Liraglutide 1.8 mg daily Exenatide 10 mcg BID Exenatide 2 mg QW Exenatide 2 mg QW Liraglutide 1.8 mg daily Lixisenatide 20 mcg daily Exenatide 10 mcg BID Albiglutide 50 mg QW Liraglutide 1.8 mg daily Dulaglutide 1.5 mg QW Dulaglutide 0.75 mg QW Exenatide 10 mcg BID Dulaglutide 1.5 mg QW Liraglutide 1.8 mg daily 22 Change in A1C A1C: 1% - 1.5% Liraglutide ~ Dulaglutide > Exenatide QW > Exenatide BID ~ Lixisenatide ~ Albiglutide Ther Adv EndrocrinolMetab2015;6(1):19-28. 23 Change in Weight weight: 1-4 kg Liraglutide ~ Exenatide BID > Exenatide QW, Lixisenatide, Albiglutide, Dulaglutide Ther Adv EndrocrinolMetab2015;6(1):19-28. 24 8

Adverse Effects Nausea/vomiting: Twice daily > Once-daily > Weekly formulations Injection site reactions: Exenatide QW > Other weekly formulations > daily/twice-daily formulations Hypoglycemia: Similar and low rates across trials Major hypoglycemia: 0%-1.2% The only patients with major hypoglycemia were also on a sulfonylurea Minor hypoglycemia: significantly higher risk in patients on a sulfonylurea Upper respiratory tract infections: unclear mechanism, but consistently reported across trials Ther Adv EndrocrinolMetab2015;6(1):19-28. 25 GLP-1 RA + Insulin 26 Adding a GLP-1 RA to Insulin Study GLP-1 agonist Population Duration Yoon et al., 2009 Exenatide BID Nayak et al., 2010 Buse et al., 2011 Lind et al., 2012 Lane et al., 2011 Seino et al., 2012 Diabetes Care. 2013;36(2):S226-S232. Exenatide BID Exenatide BID v. Placebo Liraglutide or Exenatide Liraglutide Lixisenatide v. placebo N=188, ~70% had T2DM for > 10 years N=57 obese patients, mean duration of DM ~11 years n=261, mean duration of DM ~ 12 years N=61 (40 added LIR, 21 added EXE) N=15, mean daily basal insulin dose 192 ± 77 units N=311, Asian population A1C: Change from baseline (%) 27 months -0.54 12 months -0.1 30 weeks -1.74 (LIR) -1.04 (placebo) 7 months -1 12 weeks -1.4 24 weeks -0.77 (LIX) +0.11 (placebo) 27 9

Design Buse, et al: Use of Exenatide BID with Lantus Intervention 30-week, randomized, double-blind, placebo-controlled trial Exenatide BID v. placebo in patients on glargine ± orals Glargine dose was titrated to target fasting glucose < 100mg/dL based on treat-to-target algorithm Population N=261 mean age ~59yo, 75-80% white, BMI = 33, A1C ~ 8.4%, duration of DM ~ 12yrs Pre-study DM Meds: Baseline glargine dose = 47-49 units/day metformin and/or pioglitazone Ann Intern Med 2011; 154: 103-112 28 Buse, et al: Use of Exenatide BID with Lantus Change in A1C Lantus + Placebo: -1.04% Lantus + ExBID: -1.74% Ann Intern Med 2011; 154: 103-112 29 Buse, et al: Use of Exenatide BID with Lantus Safety Results Quantity of hypoglycemic events did not differ between ExBID & placebo (25% v. 29%) ExBID associated with significantly more nausea, diarrhea, vomiting, headache, constipation More exenatide-treated patients withdrew due to adverse events (13% v. 1%, p<0.010) Serious adverse events were similar between groups; no renal failure, pancreatitis, or cancer were observed Ann Intern Med 2011; 154: 103-112 30 10

Design DeVries, et al: Liraglutide ± Detemir 26-week, randomized, open-label, parallel-group trial Intervention First, LIR (1.8mg/day) was added to metformin in 987 patients with uncontrolled T2DM on metformin ±SFU After a 12-week run-in, patients with persistently uncontrolled DM (n=323) were randomized to insulin detemir v. placebo. 498 patients (~50%) achieved target A1C < 7% during run-in period During the randomization period, insulin detemir was titrated to target fasting CBG values of 73-108 mg/dl Population N=323 (with A1C 7% after run-in) mean age ~57yo, BMI = 34, A1C ~ 8.3% (at baseline) and 7.6% (after run-in), duration of DM ~ 8.5yrs Diabetes Care. 2012;35(7):1446-54. 31 DeVries, et al: Liraglutide ± Detemir A1C 0.5% w/ addition of insulin detemir Diabetes Care. 2012;35(7):1446-54. 43% of insulin detemir recipients achieved the <7% A1C target, compared with 17% continuing treatment with metformin + liraglutide 32 DeVries, et al: Liraglutide ± Detemir Safety Results No major hypoglycemia during randomized period, but significantly more minor hypoglycemia with the addition of insulin detemir. The significant weight loss achieved in run-in phase (~3kg) was maintained with addition of detemir. 2 cases of pancreatitis were reported (one acute and one chronic) Diabetes Care. 2012;35(7):1446-54. 33 11

Adding a GLP-1 RA to Insulin: Insulin Dose Reduction Study GLP-1 agonist Insulin dose: Change from baseline Yoon et al., 2009 Nayak et al., 2010 Buse et al., 2011 Exenatide BID Exenatide BID Exenatide BID v. Placebo 14.8% total daily dose [prandial insulin - 55.7%, basal insulin unchanged] 144 units/day 55 units/day; 25% off insulin after 3 months +13 units/day +20 units/day Lind et al., 2012 Liraglutide or Exenatide 91.1 units/day 52.2 units/day Lane et al., 2011 Liraglutide 28% Seino et al., 2012 Lixisenatide v. placebo 1.39 units/day 0.11 units/day 34 Adding a GLP-1 RA to Insulin: Body Weight 35 GLP-1 RA vs. Bolus insulin Study Duration Active Comparators Rosenstock et al., 2014 Diamont et al., 2014 26 weeks Albiglutide QW v. insulin lispro TID 30 weeks Exenatide v. insulin lispro TID A1C (%) -0.82-0.66-1.13-1.10 weight -0.73kg +0.81kg -2.5kg +2.1kg Adverse effects 15.8% hypo (0 severe), more GI side effects 29.9% hypo (2 severe) 30% hypo (2 severe), more GI side effects 41% hypo (7 severe) Diabetes Care. 2014;37:2317-2325. Diabetes Care. 2014;37:2763-2773 36 12

GLP-1 RA + Insulin Several prospective and retrospective trials have demonstrated that adding a GLP-1 agonist to insulin (and vice versa) is associated with improvements in glycemic control and body weight, with a low incidence of hypoglycemia In patients already receiving insulin therapy, the addition of a GLP-1 agonist typically allows reduction in insulin dose 37 THE CARDIOVASCULAR EFFECTS OF GLP-1 AGONISTS 38 Cardiovascular Outcomes Trials Agent (Brand ) Cardiovascular Outcome Trial Exenatide (Byetta ) -- Lixisenatide (Adlyxin ) ELIXA (published 2015) Liraglutide (Victoza ) LEADER (published 2016) Albiglutide (Tanzeum ) (expected May 2019) Dulaglutide (Trulicity ) REWIND (expected April 2019) Exenatide ER (Bydureon ) EXSCEL (expected April 2018) 39 13

ELIXA Lixisenatide (Adlyxin ) 20 mcg/day v. placebo in 6068 patients with T2DM, who had had an acute coronary event (i.e., MI or unstable angina) within the previous 180 days. Glycemic control was managed according to local guidelines Median follow-up: 2.1 years Baseline characteristics: mean age 60 years, 70% male, 75% white mean A1C 7.6%, mean duration of DM ~ 9 years 22% had history of a prior MI, 67% had history of PCI N EnglJ Med. 2015; 373:2247-57. 40 ELIXA Primary Composite Outcome Lixisenatide Placebo Hazard Ratio NNT 13.4% 13.2% 1.02 (0389-1.17); p<0.001 for NI, p = 0.81 for superiority CV death 5.1% 5.2% 0.98 (0.78-1.22); p=0.85 NS Nonfatal MI 8.9% 8.6% 1.03 (0.87-1.022); p=0.71 NS Nonfatal stroke 2.2% 2.0% 1.12 (0.79-1.58); p=0.54 NS Unstable angina 0.4% 0.3% 1.11 (0.47-2.62), p=0.81 NS Death from any cause NS 7.0% 7.4% 0.94 (0.78-1.13); p=0.50 NS HF Hospitalizations 4.0% 4.2% 0.96 (0.75-1.23); p=0.75 NS N EnglJ Med. 2015; 373:2247-57. 41 ELIXA Other results: After 12 weeks, change in A1C was greater in the lixisenatide group (-0.6% v. -0.2%, p<0.001), and across all visits, the lixisenatide treated patients had a lower average A1C (A1C difference: -0.27%, p<0.001) Lixisenatide was also associated with a modest weight difference of -0.7 kg GI events were the most common adverse events Lixisenatide was not associated with an increase in pancreatic events: Pancreatitis: 5 cases in lixisenatide group, 8 in placebo group Pancreatic Cancer: 3 cases in lixisenatide group, 9 in placebo N EnglJ Med. 2015; 373:2247-57. 42 14

LEADER Liraglutide (Victoza ) 1.8 mg/day v. placebo in 9340 patients with T2DM, aged 50 years with at least one co-morbid CV condition (CHD, CVD, PVD, CKD, CHF) or 60 years with one CV risk factor Median follow-up: 3.8 years Baseline characteristics: mean age 64 years, 64% male, 81.3% had established CVD or CKD mean A1C 8.7%, mean duration of DM 12.8 years >90% on antihypertensive therapy, 72% on statin 68% on ASA or other platelet aggregation inhibitor N Engl J Med 2016;375:311-22. 43 LEADER Primary Composite Outcome Liraglutide Placebo Hazard Ratio NNT 13.0% 14.9% 0.87 (0.78-0.97); p = 0.01 53 CV death 4.7% 6.0% 0.78 (0.66-0.93); p=0.007 77 Nonfatal MI 6.0% 6.8% 0.88 (0.75-1.03); p=0.11 NS Nonfatal stroke 3.4% 3.8% 0.89 (0.72-1.11); p=0.30 NS Death from any cause 8.2% 9.6% 0.85 (0.74-0.97); p=0.02 72 HF Hospitalizations 4.7% 5.3% 0.87 (0.73-1.05); p=0.14 NS Microvascular Outcomes N Engl J Med 2016;375:311-22. 7.6% 8.9% 0.84 (0.73-0.97); p=0.02 77 44 LEADER Other results: A1C difference (after 36 months): -0.40% (95% CI, -0.45 to -0.34) Severe hypoglycemia was more common in placebo group 2.4% vs. 3.3%; RR 0.69 (0.51-0.93); p=0.02 Discontinuation due to adverse effects was more common with liraglutide 9.5% v. 7.3%, p<0.001 nausea, vomiting, diarrhea, abdominal pain, decreased appetite No significant difference in pancreatitis or neoplasm, but liraglutide treatment was associated with more acute gallstone disease (3.1% v. 1.9%) and more injection site reactions (0.7% v. 0.3%). N Engl J Med 2016;375:311-22. 45 15

New Guideline Recommendation In patients with long-standing suboptimally controlled T2DM and established ASCVD, empagliflozin or liraglutide should be considered as they have been shown to reduce CV and all-cause mortality when added to standard care. Diabetes Care. 2017;40:S1-S135. 46 POTENTIAL PLACE(S) IN THERAPY FOR GLP-1 RAS 47 Diabetes Care. 2017;40:S1-S135. 48 16

Diabetes Care. 2017;40:S1-S135. 49 Guideline-based Recommendations: 1. Consider initiating a GLP-1 receptor agonist in patients who have not achieved goal A1C despite optimal oral therapy May be preferable in patients for whom hypoglycemia and weight loss are primary concerns, or in the setting of established ASCVD (Liraglutide) Factors to consider: cost/coverage, safety & tolerability, convenience, reduction in A1C required Diabetes Care. 2017;40:S1-S135. 50 Guideline-based Recommendations: 2. Consider initiating a GLP-1 receptor agonist in patients who have not achieved goal A1C despite optimal basal insulin therapy Potential Benefits: less risk of hypoglycemia and weight gain as compared to prandial insulin, easier dose titration Factors to consider: reduction in A1C required, safety & tolerability, cost/coverage, convenience Diabetes Care. 2017;40:S1-S135. 51 17

Guideline-based Recommendations: 3. Consider initiating liraglutide or empagliflozin in patients with long-standing suboptimally controlled T2DM and established ASCVD, as they have been shown to reduce CV and allcause mortality when added to standard care. Diabetes Care. 2017;40:S1-S135. 52 Additional practice-based recommendations: Consider initiating a GLP-1 receptor agonist in the following patient-types: Patients who are unwilling/unable to be adherent to multiple daily injections or multiple daily blood glucose checks precluding safe/optimal use of bolus insulin Patients on high doses of basal-bolus insulin with persistently poor or suboptimal glycemic control Patients on basal-bolus insulin with frequent episodes of hypoglycemia or persistently variable glycemic control despite close follow-up and dose adjustments 53 Assessment Questions 1. GLP-1 is an endogenous incretin with which of the following glucoregulatory actions? A. Stimulation of glucose-dependent insulin secretion B. Reduction of glucagon secretion C. Retardation of gastric emptying D. All of the above 54 18

Assessment Questions 2. Compared to rapid-acting insulin, the GLP-1 agonists have all the following advantages, EXCEPT? A. A lower risk of hypoglycemia B. A potential for weight loss, even when added to insulin C. Fewer side effects D. Fewer dose adjustments/less frequent injections 55 Assessment Questions 3. Which currently available GLP-1 agonist has been associated with a reduction in ASCVD in a highrisk cohort? A. Liraglutide (Victoza) B. Exenatide (Byetta, Bydureon) C. Albiglutide (Tanzeum) D. Dulaglutiide (Trulicity) 56 Assessment Questions 4. GLP-1 agonists are an appropriate second-line option (after metformin) for patients with T2DM A. True B. False C. It depends on patient-specific characteristics 57 19

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