I have no financial incentives or conflicts of interest to disclose for this presentation.

Transcription

1 Jacob Lenzmeier, PharmD Resident Pharmacist-CentraCare Health November 9, I have no financial incentives or conflicts of interest to disclose for this presentation. 2 1

2 Review the mechanism of action, dosing, efficacy and safety of the new classes of diabetes medications including: Sodium-glucose co-transporter 2 (SGLT2) inhibitors New basal insulins Basal Insulin/Glucagon-like peptide 1 (GLP-1) agonists Identifying patients who would benefit from these agents and patients who may not be appropriate. Review implications of copay assistance programs Briefly review a patient case and discuss treatment options 3 Diabetes Care. 2016;39:

3 Dapagliflozin (Farxiga), empagliflozin (Jardiance) and canagliflozin (Invokana) Mechanism of Action: -Inhibit SGLT2 in the proximal nephron lowering threshold for glucose reabsorption from ~180mg/dL to ~75-90mg/dL 5 Dosing: Starting dose of 100mg once daily in the morning, titrate as tolerated Monitoring: blood pressure, self-monitoring blood glucose targets, adverse effects as listed below, foot examinations Efficacy: Hemoglobin A1C lowering of ~ % Adverse Effects: Urinary tract infection (females 7-8%, males 6%) Genital mycotic infection (females 6%, males 3%) Hypotension Rise in LDL (3%) Weight loss ~2-3kg Bone mineral loss/bone fracture (8%) Cost/How Supplied: 100mg tablets and 300mg tablets (~$510/month) 6 3

4 4 May 16, 2017 Food and Drug Administration issued safety warning regarding risk of amputations and canagliflozin. Frequent foot examinations encouraged Look for risk factors - Prior amputation -Neuropathy - Peripheral vascular disease - Diabetic foot infection 7 5 Study examined cardiovascular events in patients on canagliflozin vs. placebo Patients were either >30 years old with symptomatic cardiovascular disease or >50 years old with at least 2 risk factors for cardiovascular disease 14% relative risk reduction of death from cardiovascular cause, nonfatal myocardial infarction, nonfatal stroke 8 4

5 Dosing: Starting dose of 5mg once daily in the morning, titrate as tolerated Monitoring: blood pressure, self-monitoring blood glucose targets, adverse effects as listed below Efficacy: Hemoglobin A1C lowering of ~ % Adverse Effects: Urinary tract infection (females 7-8%, males 6%) Genital mycotic infection (females 6%, males 3%) Hypotension Rise in LDL (3%) Weight loss ~2-3kg Bone mineral loss/bone fracture (8%) Cost/How Supplied: 5mg tablets and 10mg tablets (~$480/month) 9 Dosing: Starting dose is 10mg once daily in the morning, titrate as tolerated Monitoring: Blood pressure, self-monitoring blood glucose targets, adverse effects as listed below Efficacy: Hemoglobin A1C lowering of ~ % Adverse Effects: Urinary tract infections (females 18%, males 4%) Genital mycotic infections (females 5-6%, males 2-3%) Hypotension Rise in LDL (4%) Weight loss ~2-3kg Cost/How Supplied: 10mg tablets and 25mg tablets (~$500/month) 10 5

6 8 Study examined cardiovascular death of patients on empagliflozin compared to standard of care Patients already had established cardiovascular disease (prior myocardial infarction, unstable angina, coronary artery disease with or without stents, prior stroke, occlusive peripheral vascular disease, etc.) 38% relative risk reduction in cardiovascular death, nonfatal myocardial infarction and nonfatal stroke 11 Diabetes Care. 2016;39:

7 Insulin is like the key that opens the door for glucose to be removed from the bloodstream and utilized in the tissues 13 Ultra-long acting basal insulin produced by Novo Nordisk ~42 hours of action at steady state Dosing conversion from other basal insulins is 1:1 Available as a pen in U-100 and U-200 strengths U-200 dosed in 2 unit increments 14 7

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9 Patient Adherence Ultra-long duration of action Anytime of the day dosing Minimal day-to-day variability Improved Safety Hypoglycemia 17 Concentrated formulation of insulin glargine (Lantus) Available only as a pen in U-300 strength Lower volume required for same dose of basal insulin 18 9

10 19 Generics Chemically identical to brand name product Do not require additional testing for regulatory approval Therapeutic substitution allowed Must wait until brand drug patent expires Biosimilars Highly similar to brand name product Require preclinical and clinical trials prior to approval Must apply for therapeutic substitution designation May become available before brand drug patent expires 20 10

11 Product Total Units per Box Estimated Cost Tresiba U pen box 1500 units ~$460 Tresiba U pen box 1800 units ~$560 Toujeo* U pen box 1350 units ~$405 Toujeo* U pen box 2250 units ~$675 Basaglar U pen box 1500 units ~$380 Lantus U pen box 1500 units ~$445 Levemir U pen box 1500 units ~$480 *Toujeo = 1.5 milliliters per pen 21 Diabetes Care. 2016;39:

12 11 LEADER trial evaluating cardiovascular outcomes Patients either: >50 years old with established cardiovascular disease or >60 with at least 1 known risk factor present. Randomized to receive maximum tolerated liraglutide or placebo alongside standard of care. 13% relative risk reduction of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke 23 Basal insulin and glucagon-like peptide 1 (GLP-1) agonist combinations 1. Insulin degludec and liraglutide (Xultophy) = 100 U mg/1ml - Made by Novo Nordisk 2. Insulin glargine and lixisenatide (Soliqua) = 100 U + 33 mcg/1ml - Made by Sanofi 24 12

13 Indication: Type II Diabetes, inadequately controlled on one of the following: 1) Basal insulin alone 2) GLP-1 agonist alone 3) 2 oral antidiabetic medications Dosing Initial Titration Maximum Insulin glargine/lixisenatide (Soliqua) 15 units insulin glargine/5mcg lixisenatide 2-4 unit adjustments weekly until reach desired goals 60 units insulin glargine/20mcg lixisenatide Insulin degludec/liraglutide (Xultophy) 16 units insulin degludec/0.58 mg liraglutide 2-4 unit adjustments every 3-4 days until reach desired glucose goals 50 units insulin degludec/1.8mg liraglutide 25 Insulin glargine/lixisenatide: LixiLan-O Trial 1,170 patients on maximally tolerated metformin ( 1500mg/day) with or without other oral agents included Randomized to either insulin glargine, lixisenatide or the combination product daily for 30 weeks 26 13

14 Efficacy Average baseline A1C 8.1% 1) insulin glargine 6.8% 2) lixisenatide 7.3% 3) combination injection 6.5% Safety/Adverse effects Average change in body weight 1) insulin glargine +1.1kg 2) lixisenatide -2.3kg 3) combination injection -0.3kg Percentage of patients reaching goal of <7% 1) insulin glargine 59% 2) lixisenatide 33% 3) combination injection 74% Symptomatic hypoglycemia (FPG 70) 1) insulin glargine 23.6% 2) lixisenatide 6.4% 3) combination injection 25.6% 27 Series of DUAL trials evaluating insulin degludec/liraglutide combination as compared to liraglutide alone as well as various basal insulins DUAL III compared combination drug to liraglutide DUAL IV compared combination drug to insulin glargine 28 14

15 Efficacy Average baseline A1C 7.8% 1) liraglutide 7.4% 2) combination injection 6.5% Safety/Adverse effects Average change in body weight 1) liraglutide -0.8kg 3) combination injection +2kg Percentage of patients reaching goal of <7% 1) liraglutide 30% 2) combination injection 75% Confirmed hypoglycemia (BG 56mg/dL) 1) liraglutide 2.8% 2) combination injection 32% 29 Efficacy Average baseline A1C 8.3% 1) insulin glargine 7.1% 2) combination injection 6.6% Percentage of patients reaching goal of <7% 1) insulin glargine 46% 2) combination injection 68% Safety/Adverse effects Average change in body weight 1) insulin glargine +1.8kg 2) combination injection -1.3kg Symptomatic hypoglycemia (FPG 70) 1) insulin glargine 49.1% 2) combination injection 28.4% 30 15

16 Benefits Patient adherence Increased tolerability Challenges Dosing ranges are limited Titration challenges Cost per box of 5 pens Insulin glargine/lixisenatide (Soliqua) Insulin degludec/liraglutide (Xultophy) ~$650 ~$ How does it work Discount or cover the out-of-pocket expense for the patient Things to keep in mind Government funded insurance plans are excluded Applied in addition to insurance Funded by the drug manufacturer Products prescribed are often nonformulary Read the fine print! 32 16

17 67 year old male referred to you for diabetes management Past Medical History: Diabetes Mellitus Type II Hypertension Hyperlipidemia Myocardial Infarction 2 years ago Gout Social History No tobacco use, drinks 2-3 beers a few nights per week. Occasionally falls asleep before giving his insulin. No trouble affording his meds currently. Current Medications Metformin 1000mg BID Lantus 15 units at bedtime Lisinopril/HCTZ 20/12.5mg daily Atorvastatin 40mg daily Metoprolol succinate 50mg daily Allopurinol 100mg daily Aspirin 81mg daily Laboratory Data Ht/Wt: 70 inches and 270 lbs A1C= 8.3% BP today = 135/78 Pulse today = 72 Lipids: LDL=105, HDL=55, TG=165, TC= Schwartz SS, Epstein S, Corkey BE, et al. A Unified Pathophysiological Construct of Diabetes and its Complications. Trends Endocrinol Metab. 2017;28(9): David L. Joffe, BSPharm, CDE, FACA. SGLT2 Inhibitors: A New Class of Diabetes Medications. Diabetes In Control. Published September 29, Invokana [package insert]. Janssen Pharmaceuticals, Inc., Titusville, NJ. Revised July, FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). May 16, Accessed October 6, Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(7): Farxiga [package insert]. AstraZeneca pharmaceuticals LP. Wilmington, DE. Revised October, Jardiance [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc.; Ridgefield, CT. Revised December, Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):

18 9. Wysham C, Bhargava A, Chaykin L, et al. Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 2 Diabetes: The SWITCH 2 Randomized Clinical Trial. Jama. 2017;318(1): Morse, Michael A. Examine Biosimilars. Genetech USA, Inc. Accessed Oct Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4): Rosenstock J, Aronson R, Grunberger G, et al. Benefits of LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide, Versus Insulin Glargine and Lixisenatide Monocomponents in Type 2 Diabetes Inadequately Controlled on Oral Agents: The LixiLan-O Randomized Trial. Diabetes Care. 2016;39(11): Linjawi S, Bode BW, Chaykin LB, et al. The Efficacy of IDegLira (Insulin Degludec/Liraglutide Combination) in Adults with Type 2 Diabetes Inadequately Controlled with a GLP-1 Receptor Agonist and Oral Therapy: DUAL III Randomized Clinical Trial. Diabetes Ther. 2017;8(1): Lingvay I, Perez Manghi F, Garcia-Hernandez P, et al. Effect of Insulin Glargine Up-titration vs Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients With Uncontrolled Type 2 Diabetes: The DUAL V Randomized Clinical Trial. Jama. 2016;315(9):