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New Medications on the Horizon Diana Isaacs Andrew Bzowyckyj

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New Medications on the Horizon Diana Isaacs Andrew Bzowyckyj 7/31/2019 New Medications on the Horizon Diana Isaacs PharmD, BCPS, BC-ADM, CDE Clinical Pharmacy Specialist Cleveland Clinic Diabetes Center Cleveland, OH Andrew Bzowyckyj PharmD, BCPS, CDE Associate Professor Pacific University Oregon School of Pharmacy Hillsboro, OR 1 7/31/2019 Disclosure to Participants • Notice of Requirements For Successful Completion – Please refer to learning goals and objectives – Learners must attend the full activity and complete the evaluation in order to claim continuing education credit/hours • Conflict of Interest (COI) and Financial Relationship Disclosures: – Presenter: Diana Isaacs, PharmD, BCPS, BC-ADM, CDE – Advisory Board: Sanofi; Becton, Dickinson & Co. – Presenter: Andrew Bzowyckyj, PharmD, BCPS, CDE – No COI/Financial Relationship to disclose • Non-Endorsement of Products: – Accredited status does not imply endorsement by AADE, ANCC, ACPE or CDR of any commercial products displayed in conjunction with this educational activity • Off-Label Use: – Participants will be notified by speakers to any product used for a purpose other than for which it was approved by the Food and Drug Administration. Session Objectives • Describe new agents approved and in the pipeline for type 1 and type 2 diabetes. • Compare and contrast new diabetes medications and formulations to what was previously available. • Discuss factors to consider when adding these new medications for specific patient populations. Drug Selection Factors Mechanism of Risk of Cost Action Hypoglycemia Impact on Route of Adverse Effects Glucose Administration Effects on Patient CV Benefits Weight Preferences ADA. Standards of Care. Diabetes Care 2019;42(Suppl. 1):S90–S10 2 7/31/2019 How many medication classes are available to treat diabetes? Drug Options for Diabetes • Biguanide • Sodium glucose cotransporter- • Sulfonylureas 2 (SGLT-2) inhibitors • Meglitinides • Bile acid sequestrant • Thiazolidinediones (TZD’s) • Dopamine-2-agonist • Dipeptidylpeptidase-4 (DPP- • Amylin mimetic 4) inhibitors • Alpha-glucosidase inhibitors • Glucagon-like-peptide-1 • Insulin (GLP-1) receptor agonists • Glucagon What’s New? • Oral semaglutide • Insulin devices • GLP/GIP dual agonist • Insulin formulations • Glucagon receptor • Ultra‐rapid antagonist • Generic • Sotagliflozin • Glucagon 3 7/31/2019 GLP-1 Receptor Agonists GLP-1 Receptor Agonist Mechanism 11 GLP-1 Receptor Agonist Comparison GLP‐1 RA Dosing Administration Pen Device Dulaglutide 0.75mg SC weekly, may increase to 1.5mg SC Without regard to meals Single use, needle never seen (Trulicity) weekly if needed after 1 month Exenatide IR 5mcg SC BID, may increase to 10mcg SC BID if Within 60 minutes before morning Multi use, attach needle (Byetta) needed after 1 month and evening meals Exenatide ER 2mg SC weekly Without regard to meals Single use, needle never seen (Bydureon) Liraglutide* 0.6mg SC daily x 1 week, then 1.2mg SC daily; May Without regard to meals Multi use, attach needle (Victoza) increase to 1.8mg SC if needed after 1 week Lixisenatide 10mcg SC daily x 14 days, then increase to 20mcg Within 60 minutes before morning Multi use, attach needle (Adlyxin) SC daily meal 0.25mg SC weekly x 4 weeks, then 0.5mg SC Multi use, attach needle (comes with Semaglutide Without regard to meals weekly; May increase to 1 mg SC weekly if needed device) (Ozempic) after 4 weeks * Liraglutide FDA‐approved to reduce the risk of major adverse cardiovascular events (cardiovascular death, MI, stroke) in adults with type 2 diabetes and established CVD Clinical Resource, Comparison of GLP‐1 Agonists. Pharmacist’s Letter/Prescriber’s Letter. January 2017 4 7/31/2019 GLP-1 Receptor Agonist Devices 5mcg or 10mcg pen 0.5mg, 1 pen/month 1.2mg, 2 pens/month 1 pen/month 1mg, 2 pen/month Requires Rx for needles 1.8mg, 3 pens/month (Comes with needles Requires Rx for needles 2mg pen Contains 14 doses (20mcg) 0.75mg or 1.5mg pens 4 pens/month 2 pens/month 4 pens/month Shake 15 seconds Requires Rx for needles Never see needle Never see needle Oral Semaglutide • Barriers to GLP-1 oral absorption: – Degradation by gastrointestinal enzymes – pH induced conformational changes – Limited protein permeability of the intestinal membrane • Semaglutide co-formulated with sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC), an absorption enhancer • Absorbed in stomach where SNAC causes a localized increase in pH, leading to higher solubility and protection against proteolytic degradation • Phase 3 PIONEER (Peptide InnOvatioN for Early diabEtes tReatment) studies • Submitted to the FDA in early 2019 with priority review voucher Granhall et al. Clin Pharmacokinet. 2019 Jun;58(6):781‐791. Oral Semaglutide – PIONEER 1 (n=703) Placebo 3 mg 7 mg 14 mg Parameter N=175 N=175 N=175 N=178 A1C ‐0.1% ‐0.8% ‐1.3% ‐1.5% A1C < 7 34% 59% 72% 80% (Baseline 8%) Weight ‐1.5 kg ‐1.7 kg (NS) ‐2.5 kg (NS) ‐4.1 kg (Baseline 88 kg) • Oral tablet administered once daily; 30 minutes before first meal • Advantages: long half-life; lower molecular weight; high potency; molecular stability • NS: Not statistically-significant 15 Aroda VR, et al. Diabetes 2018;67(Suppl 1): https://doi.org/10.2337/db18-2-LB. 5 7/31/2019 PIONEER 3: Compared to DPP4 Inhibitor • RCT comparing oral semaglutide to sitagliptin (N=1864) • Primary endpoint: change in A1C • Baseline A1C=8.3%, BMI=32.5 Bain SC et al. Diabetes Obes Metab. 2019 Mar;21(3):499‐508. PIONEER 6: CV Outcomes • RCT comparing oral semaglutide 14mg vs placebo, N=3183 adults • Primary outcome: first occurrence of CV death, non-fatal MI, non-fatal stroke • Median follow-up: 16 months • Demonstrated non-inferiority of major CV events (MACE) – Overall MACE (HR 0.79 favoring semaglutide, P<0.05) – CV death reduction (HR 0.49, P=0.03) – All cause mortality (HR 0.49, p=0.008) • Novo applied for CV indication based on PIONEER 6 and SUSTAIN-6 https://www.novonordisk.com/media/news‐details.2226789.html. Accessed 5/30/19 17 Bain SC et al. Diabetes Obes Metab. 2019 Mar;21(3):499‐508. Semaglutide is different from other GLP-1 agonists because: A. An oral formulation is currently in development B. It is available as a once‐monthly injection C. It requires a prescription for pen needles D. The pen needle is never visible to the patient 6 7/31/2019 GLP-1/GIP Dual Agonist GLP-1/GIP Dual Agonist GLP‐1: Glucagon‐like peptide‐1 GIP: Glucose‐dependent Insulinotropic Polypeptide Prog Biophys Mol Biol. 2011;107(2):248‐56. Glucose-dependent Insulinotropic Polypeptide • Can increase glucagon AND insulin – Glucose‐dependent – Dose‐dependent • Responsible for majority of insulinotropic effect • Therapeutic utility diminished in hyperglycemia • Role in regulating body weight? Mol Metab. 2018;18:3‐14. 7 7/31/2019 Tirzepatide (LY3298176) • Once weekly subcutaneous injection – Peak concentration within 24‐48 hours – Half‐life approximately 5 days • High affinity for GIP AND GLP-1 receptors Mol Metab. 2018;18:3‐14. Tirzepatide (LY3298176) A1C Reduction by Dose A1C Reduction By Duration Baseline A1C ~ 8%; n=318 Lancet. 2018;392:2180‐93. Tirzepatide (LY3298176) Total Weight Loss % of Weight Lost Baseline weight ~ 91.5 kg; BMI ~32.6; n=318 Lancet. 2018;392:2180‐93. 8 7/31/2019 Tirzepatide (LY3298176) Drop out rate:17.6% 15.4% 14.5% 13.7% 34.0% 14.8% Lancet. 2018;392:2180‐93. Glucagon Receptor Antagonist(s) Glucagon-Receptor Antagonist(s) • Mechanism of Action: – Prevent glycogenolysis & hepatic glucose production • Limited by adverse effects: – Increased liver enzymes – Increased hepatic fat fraction – Increased BP (?) FASEB J. 2019;33(1 Supp):514.5 9 7/31/2019 Sodium Glucose co-Transporter (SGLT) Inhibitors Sotagliflozin (Zynquista) • Dual SGLT1/SGLT2 inhibitor: – SGLT1: small intestine – SGLT2: nephron (proximal convoluted tubules) • Hypothesis: – SGLT2 inhibition leads to SGLT1 upregulation – Decrease post‐prandial glucoses & suppress glucagon Sims H, et al. Diabet Med. 2018;35(8):1037‐48. Frandsen et al. Lancet Diabetes Endocrinol. 2016;4(9):766‐80. Sotagliflozin: inTandem Trials (T1DM) Trial N Trial Population Efficacy 46 years; 91% white A1C change vs. placebo: inTandem 1 A1C ~ 7.57%; BMI ~ 29 kg/m2 793 200 mg: ‐0.36% (p<0.001) (USA) Insulin pump: 60% 400 mg: ‐0.41% (p<0.001) Sota 200 or 400 vs. PBO x 52 weeks 41 years; 96% white A1C change vs placebo: inTandem 2 A1C: ~7.8%; BMI: ~ 30 kg/m2 782 200 mg: ‐0.37% (p<0.001) (Europe) Insulin pump: 25% 400 mg: ‐0.35% (p<0.001) Sota 200 or 400 vs. PBO x 52 weeks 43 years; 88.4% white Percent achieving A1c < 7% with no inTandem 3 A1C ~8.2%; BMI: ~ 28 kg/m2 severe hypoglycemia or DKA 1402 (Global) Insulin pump: 40% Sota: 28.6% vs. PBO: 15.2% (p<0.001) Sota 400 mg vs PBO x 24 weeks NNT: 8 people x 6 months Buse JB, et al. Diabetes Care 2018 Sep; 41(9): 1970‐1980. Danne Tm et al, Diabetes Care 2018 Sep; 41(9): 1981‐1990. Garg SK, et al. N Engl J Med 2017;377:2337‐48. 10 7/31/2019 Sotagliflozin & DKA: inTandem Trials Trial N PBO Sota NNH Sota NNH 200 mg (vs. 200 mg) 400 mg (vs. 400 mg) inTandem 1 793 0.4% 3.4% 33 4.2% 26 (USA) inTandem 2 782 0% 2.3% 43 3.4% 29 (Europe) inTandem 3 1402 0.6% N/A N/A 3.0% 41 (Global) Buse JB, et al. Diabetes Care 2018 Sep; 41(9): 1970‐1980. Danne Tm et al, Diabetes Care 2018 Sep; 41(9): 1981‐1990. Garg SK, et al. N Engl J Med 2017;377:2337‐48. Updates: SGLT Use in T1DM • Dapagliflozin submitted to EU • Sotagliflozin submitted to EU and and FDA FDA – EMA recommended approval for use – Jan 2019: FDA advisory committee in T1DM who meet certain criteria: voted 8‐8 if benefits outweigh risks • Adjunct to insulin therapy – Mar 2019: FDA issues Complete • BMI > 27kg/m2 Response Letter (not approved) • Supplemental ketone monitoring – Feb 2019: EU approved with same • Additional patient selection criteria criteria as dapagliflozin • Patient Alert Card • Ipragliflozin approved for use in – Waiting on decision from FDA T1DM in Japan Mitigating DKA Risk – STICH Protocol ST • STop SGLT Inhibitor I • Inject bolus insulin C • Consume 30 grams carbohydrates H • Hydrate with water Diabetes Technol Ther 2018;20:571‐5.
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