2/17/2020 ILDIKO LINGVAY, MD, MPH, MSCS UT SOUTHWESTERN MEDICAL CENTER, DALLAS, TX Disclosures Speakers Bureau none Research Funding Novo Nordisk, Merck, Pfizer, Mylan, Gan & Lee, Novartis, GI Dynamics Consulting/Advising/ Novo Nordisk, Sanofi, Eli Lilly, Boeringer-Ingelheim, Astra Steering Committee Zeneca, Intarcia, Valeritas, TARGETPharma, Mannkind, Janssen 1
2/17/2020 Timeline of Glucose Lowering Medications in USA glargine U300 degludec FiAsp basaglar liraglutide ertugliflozin 19 linagliptin semaglutide 18 exenatide weekly Number of medications & classes 17 empagliflozin sitagliptin inhaled insulin 16 colesevelam albiglutide 15 saxagliptin 12 dapagliflozin 14 bromocriptine aspart dulaglutide 45 >70 13 glimepiride glulisine Distinct metformin 12 detemir glargine acarbose exexatide 11 Agents Products nateglinide pramlintide Classes lispro 10 miglitol 9 Human insulin: 8 troglitazone Regular, NPH & U500 repaglinide 7 rosiglitazone 6 glipizide, glyburide 1 st gen. SU pioglitazone 5 4 NPH insulin 3 Ultralente, Lente & PZI insulin Semilente insulin 2 Iletin insulin 1 1920 1930 1940 1950 1980 1990 1995 2000 2005 2010 2015 2020 Goals of Treatment I. Metformin Davies et al, Diabetes Care 2019 II. Co-existing comorbidities/complications (ASCVD/ HF/ CKD) III. Glycemic control Weight control Hypoglycemia Cost 2
2/17/2020 Goals of Treatment Prevent/Manage Prevent/Manage Prevent/Manage Prevent/Manage Maintain/improve Macrovascular Microvascular Quality of Life Disease Disease Asymptomatic Tight glycemic (and BP) control Prevent acute complications Targeted interventions Other SOC (Statins/ β -blockers/ACEI…) Manageable side effects Targeted interventions Anti-VEGF therapy Practical GLP-1 RAs (retinopathy, DME) Route SGLT2 inh SGLT2 inhibitors Frequency of administration (nephropathy) Cost Co-manage weight Davies et al, Diabetes Care 2019 3
2/17/2020 GLP-1 Receptor Agonists (GLP-1 RA) The Incretin Effect • GLP-1 * N = 6; Mean (SE); * P 0.05 • GIP 2.0 Oral Glucose * • PYY Intravenous Glucose * C-peptide (nmol/L) 1.5 • Cholecystokinine * Incretin Effect * • Oxyntomodulin * 1.0 • VIP * • Secretin 0.5 • Ghrelin • … 0.0 0 60 120 180 Time (min) Nauck MA. J Clin Endocrinol Metab . 1986;63:492-498 4
2/17/2020 GLP-1 RAs: Metabolic Actions Saraiva FK. Cardiovascular Diabetology. 2014;13:142 GLP-1 RA Class Agent Brand Name Half Life Route Frequency Exenatide Byetta 2.4 hrs SQ Twice Daily Lixisenatide Adlyxin* 3 hrs SQ Daily Duration of Action Liraglutide Victoza 13 hrs SQ Daily Albiglutide Tanzeum* 5 Days SQ Weekly Dulaglutide Trulicity 5 Days SQ Weekly Exenatide Bydureon/ Bcise 7-14 Days SQ Weekly Semaglutide Ozempic 7 Days SQ Weekly Semaglutide Rybelsus 7 Days PO Daily *no longer marketed 5
2/17/2020 GLP-1 RAs in T2D: HbA 1c Nauck et al. 3 Kapitza et al. 1 * HARMONY-7 1 SUSTAIN-3 4 SUSTAIN-7 5 SUSTAIN-10 6† DURATION-1 1 DURATION-5 1 Ji et al. 1 GetGoal-X 1 AWARD-1 2 AWARD-6 1 LEAD-6 1 DURATION-6 1 DURATION-1 DURATION-5 Ji et al GetGoal-X AWARD-1 AWARD-6 LEAD-6 DURATION-6 Nauck et al Kapitza et al HARMONY-7 SUSTAIN 3 SUSTAIN 7 SUSTAIN 10 0 Baseline 8.3 8.3 8.5 8.4 8.7 8.7 8.0 8.0 8.1 8.1 8.1 8.1 8.2 8.1 8.4 8.5 8.4 8.4 7.4 7.2 8.2 8.2 8.4 8.3 8.2 8.2 8.2 8.3 HbA 1c -0.3 • Long acting agents more effective than short acting -0.5 Change from baseline in HbA 1c (%) -0.5 • GLP-1 RA class has the greatest glucose lowering efficacy -0.8 -0.8 -0.8 (similar to insulin) -0.9 -0.9 -1 -1 -1 -1 -1 -1.1 -1.1 -1.2 -1.3 -1.4 -1.4 -1.4 -1.4 -1.5 -1.5 -1.5 -1.5 -1.5 -1.6 -1.7 -1.8 -1.8 -1.9 -2 Exenatide 10 µg BID Liraglutide 1.8 mg OD Albiglutide 50 mg QW Semaglutide 1.0 mg QW -2.5 Exenatide 2 mg QW Lixisenatide 20 µg OD Dulaglutide 1.5 mg QW *Liraglutide 0.6–1.8 mg, lixisenatide 10–20 µg; † liraglutide 1.2 mg. 1. Madsbad S. Diabetes Obes and Metab 2016;18(4):317–32; 2. Trujillo M, et al. Ther Adv Endocrinol Metab 2015;6(1)19–28; 3. Nauck M, et al. Diabetes Care 2016:39(9):1501–9; 4. Ahmann AJ et al. Diabetes Care 2018;41:258–66; 5. Pratley RE et al. Lancet Diabetes Endocrinol 2018;6:275–86; 6. Capehorn M et al. Diabetes UK Annual Conference 2019;P439. “Equivalent” Doses Amongst GLP-1 RA Glycemic effect †Equivalency based on clinical trials and expert opinion. Almandoz et al. Clinical Diabetes, in press 6
2/17/2020 Oral semaglutide (GLP-1 RA) vs sitagliptin (DPP IV inh): Hypoglycemia by SU background Proportion of participants • GLP-1 RAs have low risk of hypoglycemia HbA 1c change from baseline experiencing a hypoglycemic event (%) over 78 weeks • glucose-dependent mechanism of action Week 26 Week 78 0.0 • Hypoglycemia risk increased when co-administered with SU or INS 0 10 20 30 40 50 from baseline (%) HbA 1c change -0.4 11.8 -0.6 -0.6 Metformin -0.7 14.2 -0.8 only -0.8 15.5 -0.8 † -1.0 11.3 -1.1 * -1.2 * -1.3 Semaglutide 3 mg 33.2 Metformin * Semaglutide 7 mg 33.6 + SU Semaglutide 14 mg 42.3 -1.6 Sitagliptin 100 mg 38.5 PIONEER 3, JAMA. 2019:2942 GLP-1 RAs in T2D: weight DURATION-1 1 DURATION-5 1 Ji et al. 1 Nauck et al. 3 Kapitza et al. 1 * HARMONY-7 1 SUSTAIN-3 4 SUSTAIN-7 5 SUSTAIN-10 6† GetGoal-X 1 AWARD-1 2 AWARD-6 1 LEAD-6 1 DURATION-6 1 DURATION-1 DURATION-5 Ji et al GetGoal-X AWARD-1 AWARD-6 LEAD-6 DURATION-6 Nauck et al Kapitza et al HARMONY-7 SUSTAIN 3 SUSTAIN 7 SUSTAIN 10 0 Baseline BW 102 102 97 94 70 70 94 96 96 97 94 94 93 93 91 91 102 101 93 91 93 92 96 95 96 93 97 97 -0.6 -1 GLP-1 RA class has by far the greatest weight lowering effect -1.1 Change from baseline in BW (kg) -1.3 -1.4 -1.6 -1.6 -2 -1.9 -1.9 -2.2 Sema>lira>dula>exenatide>lixisenatide -2.3 -2.4 -2.5 -2.7 -3 -2.9 -2.9 -3 -3 -3.2 -3.6 -3.6 -3.6 -3.7 -3.7 -4 -4 -4.3 -5 -5.6 -6 -5.8 -6.5 -7 Albiglutide 50 mg QW Semaglutide 1.0 mg QW Exenatide 10 µg BID Liraglutide 1.8 mg OD Exenatide 2 mg QW Lixisenatide 20 µg OD Dulaglutide 1.5 mg QW BID, twice daily; BW, body weight; GLP-1 RA, glucagon-like peptide-1 receptor agonist; OD, once daily; QW, once a week; T2D, type 2 diabetes. *Liraglutide 0.6–1.8 mg, lixisenatide 10–20 µg; † liraglutide 1.2 mg. 1. Madsbad S. Diabetes Obes and Metab 2016;18(4):317–32; 2. Trujillo M, et al. Ther Adv Endocrinol Metab 2015;6(1)19–28; 3. Nauck M, et al. Diabetes Care 2016:39(9):1501–9; 4. Ahmann AJ et al. Diabetes Care 2018;41:258–66; 5. Pratley RE et al. Lancet Diabetes Endocrinol 2018;6:275–86; 6. Capehorn M et al. Diabetes UK Annual Conference 2019;P439. 7
2/17/2020 Davies et al, Diabetes Care 2019 Davies et al, Diabetes Care 2019 8
2/17/2020 CV Composite in Prespecified Subgroups Gerstein et al, REWIND, Lancet 2019: 121 9
2/17/2020 GLP-1 RA: Potential Mechanisms for CVD Benefit Drucker DJ. Cell Metab. 2016;24:15-30. Rakipovski et al. JACC Basic Transl Sci 2018; 3: 844-857 10
2/17/2020 Davies et al, Diabetes Care 2019 GLP-1 RA & Heart Failure Study Hospitalization for Heart Failure HR (CI) ELIXA 0.96 (0.75, 1.23) LEADER 0.87 (0.73, 1.05) SUSTAIN-6 1.11 (0.71, 1.61) 0.94 (0.78, 1.13) EXSCEL 0.86 (0.48, 1.55) PIONEER 6 0.83 (0.77, 1.12) REWIND 0.5 1 1.5 HR approx. 0.81 HARMONY Favors GLP-1 RA Favors placebo 11
2/17/2020 Renal Composite Outcome New Macroalbuminuria, 30% fall in eGFR, or Renal Replacement Rx Gerstein et al, REWIND, Lancet 2019: 121 Sustained eGFR Decline ≥ 30, 40 & 50% ≥ 30% Decline Sustained eGFR HR 0.89 (0.78, 1.01) 0.066 decline ≥ 30% Sustained eGFR ≥ 40% Decline HR 0.70 (0.57, 0.85) 0.0004 decline ≥ 40% Sustained eGFR ≥ 50% Decline HR 0.56 (0.41, 0.76) 0.0002 decline ≥ 50% Sensitivity Analyses Gerstein et al, REWIND, Lancet 2019: 121 12
2/17/2020 GLP-1 RA Side Effects • GI issues (up to 40%): • Mitigating actions: • Decrease intake • Nausea • Only eat if hungry • Vomiting • Eat slowly • Increase fiber content • Heartburn • Reassurance (resolves over time) • Diarrhea • OTC remedies (ginger, preggy pops, etc) • Slow (back down) titration • Constipation • Cramping • Good to know: • Medullary Thyroid Carcinoma • Retinopathy • Pancreatitis • Cholelithiasis Oral Semaglutide: first oral GLP-1 RA • SNAC causes a local increase of pH leading to higher solubility and protection from proteolytic degradation • The effect is fully reversible • Approximately 1% of semaglutide is absorbed, the rest is degraded in the GI tract • Maximum concentration after po intake: 1 hr • Half-life: 1 weeks Steady state: 4-5 weeks • ≈5 wks to be eliminated after last dose • • Dosing conditions: SNAC: Sodium N-(8-(2-hydroxybenzoyl) amino) caprylate • Fasting for 6 hrs - a small fatty acid derivative • Small amount of water only No intake for MINIMUM 30 minutes • Buckley ST et al. Sci Transl Med 2018 13
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