Navigating New Diabetes Meds https://diatribe.org/fda-approves-admelog-first-biosimilar-mealtime-insulin Diana Isaacs, PharmD, BCPS, BC-ADM, CDE Clinical Pharmacy Specialist/ CGM Program Coordinator Cleveland Clinic Diabetes Center

Learning Objectives Discuss new medication options for diabetes. Compare and contrast new diabetes medications and formulations to what was previously available. Outline when to use new medications for specific patient populations.

Disclosures Diana Isaacs has nothing to disclose.

How many medication classes are available to treat diabetes?

Drug Options for Diabetes Sodium glucose cotransporter-2 (SGLT-2) inhibitors Bile acid sequestrants Dopamine-2-agonist Amylin mimetic Alpha-glucosidase inhibitors Insulin Glucagon Biguanide Sulfonylureas Meglitinides Thiazolidinediones (TZD’s) Dipeptidylpeptidase-4 (DPP-4) inhibitors Glucagon-like-peptide-1 (GLP-1) receptor agonists

New Drugs New Devices Semaglutide (Ozempic®) Ertugliflozin (Steglatro®) Ultra rapid-acting insulin aspart (Fiasp®) Insulin lispro follow-on biologic (Admelog®) New Devices Exenatide ER (Bydureon BCise®) Insulin lispro (Humalog Junior Kwikpen®) Insulin glargine U-300 (Toujeo Max Solostar®)

Drugs in the Pipeline Insulin glargine follow-on biologic (Lusduna Nexvue®) Oral semaglutide Sotagliflozin Dual SGLT1/SGLT2 inhibitor For this talk, we will first discuss GLP-1 agonists including the new semaglutide, oral formulation and Bcise pen, then SGLT-2 inhibitors including ertugliflozin and sotagliflozin, and then insulins.

Semaglutide (Ozempic®) GLP-1 receptor agonist (FDA Approved 12/2017) ↑ Insulin secretion (glucose dependent) ↓ Glucagon secretion (glucose dependent) Slows gastric emptying ↑ Satiety ↓ weight loss Established cardiovascular safety and trend toward benefit Warnings: higher rates of retinopathy 3% semaglutide compared to 1.8% placebo Usual GLP-1 RA warnings Thyroid C-cell tumors Pancreatitis GI effects: N/V/D Injection site reactions https://diatribe.org/a1c-lowering-and-weight-loss-once-weekly-convenience-get-ozempic-pharmacy-near-you Established cardiovascular safety and trends toward benefit in sustain 6 trial. Couldn’t go for CV indication yet b/c they had to first prove non-inferiority. Current trial underway to show superiority and get a CV indication like liraglutide. ADA Standards of Care 2018. Semaglutide prescribing information. Available at: http://www.novo-pi.com/ozempic.pdf. Accessed 4/11/18.

SUSTAIN Trials Trials N Duration Background Comparator Primary Endpoint SUSTAIN-1 388 30 weeks Monotherapy Placebo A1C SUSTAIN-2 1231 56 weeks Add on OADs Sitagliptin SUSTAIN-3 813 Exenatide ER SUSTAIN-4 1089 Insulin glargine SUSTAIN-5 397 Add on basal insulin +/-metformin SUSTAIN-6 3297 104 weeks Add on standard of care MACE SUSTAIN-7 1201 40 weeks Metformin Dulaglutide https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM580461.pdf. Accessed 4/11/18. Pratley RE et al. Lancet Diabetes Endocrinol. 2018 Apr;6(4):275-286

SUSTAIN Trial A1C Changes https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM580461.pdf. Accessed 4/11/18.

SUSTAIN Trial Weight Changes https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM580461.pdf. Accessed 4/11/18.

Semaglutide vs. Dulaglutide Pratley RE et al. Lancet Diabetes Endocrinol. 2018 Apr;6(4):275-286

Oral Semaglutide Formulated with an absorption enhancer Phase 2 trial Tablets are absorbed in the stomach, causes a localized increase in pH, leading to higher solubility and protection against proteolytic degradation Phase 2 trial Randomized, parallel-group, dosage-finding, 26-weeks (N=632 with T2DM +/- metformin) Primary outcome: change in A1C, various doses (2.5mg, 5mg 10mg 20mg, 40mg once daily) vs placebo and sc semaglutide Change in A1C: -0.7% (2.5mg) to -1.9% (40mg) and sc semaglutide (-1.6%) vs. placebo (-0.3%) Change in body weight: -2.1 kg (2.5mg) to -6.9 kg (40mg) and sc semaglutide(-6.4 kg) vs placebo (-1.2 kg) Mild to moderate GI events were most common https://diatribe.org/promising-early-study-results-first-glp-1-pill-type-2-diabetes http://www.ajmc.com/newsroom/novo-nordisk-announces-phase-3a-trial-results-for-oral-semaglutide https://globenewswire.com/news-release/2018/02/22/1379640/0/en/Novo-Nordisk-successfully-completes-the-first-phase-3a-trial-PIONEER-1-with-oral-semaglutide.html Davies M, Pieber TR, Hartoft-Nielsen ML, Hansen OKH, Jabbour S, Rosenstock J. Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial. JAMA. 2017;318(15):1460-1470. Participants also had to be fasting when they took the medication (although not for a defined amount of time) and had to wait another 30 minutes afterward before eating.  The PIONEER phase 3a clinical development programme for oral semaglutide is a global development programme with an expected enrolment of more than 9,000 people with type 2 diabetes across 10 clinical trials, which all are expected to complete in 2018. The first oral GLP-1 analog, using semaglutide in a tablet co-formulated with the absorption enhancer sodium N-[8 (2-hydroxylbenzoyl) amino] caprylate (SNAC), Semaglutide tablets are absorbed in the stomach, where SNAC causes a localized increase in pH, leading to higher solubility and protection against proteolytic degradation. Semaglutide is believed to be absorbed via the transcellular route http://www.ajmc.com/newsroom/novo-nordisk-announces-phase-3a-trial-results-for-oral-semaglutide. Accesed 4/11/18. Davies M et al. . JAMA. 2017;318(15):1460-1470.

Oral Semaglutode (Cont) Phase 3a trial: PIONEER 1 (9 more trials expected this year) Randomized, placebo controlled, 26 weeks (N=703) to investigate efficacy and safety of 3 mg, 7 mg, 14 mg doses Change in A1C of 0.8% (3mg), 1.3%(7mg), 1.5% (14mg), and weight loss of 1.7kg (3mg), 2.5kg (7mg), and 4.1kg (14mg) compared with 0.1% A1C reduction and 1.5kg weight loss (placebo) Nausea most common AE: 5% -16% in semaglutide groups May potentially be submitted to the FDA in 2019

Test Your Knowledge: Which of the following is a difference between semaglutide and dulaglutide? Greater A1C lowering in clinical trials with dulaglutide compared to semaglutide. Greater rates of retinopathy observed with dulaglutide compared to semaglutide. Semaglutide is dosed once daily compared to dulaglutide which is dosed once weekly. More weight loss in clinical trials with semaglutide compared to dulaglutide. d

Exenatide ER Has Come a Long Way 2010: Initial kit required reconstitution 2014: Moved to a pen device Large needle Tap 80 times 1 time disposable pen https://diatribe.org/fda-approves-bydureon-bcise-new-autoinjector-launch-early-2018 Bcise: shake for 15 seconds 2017: Simpler pen, never see needle Shake 15 seconds 1 time disposable pen

GLP-1 RA Comparison GLP-1 RA Dosing Administration Pen Device Dulaglutide 0.75mg SC weekly; May further increase to 1.5mg SC weekly if needed Without regard to meals Single use, needle never seen Exenatide IR 5mcg SC BID, After 1 month may increase to 10mcg BID if needed Within 60 minutes before morning and evening meals Multi use, attach needle Exenatide ER 2mg weekly Single use, large needle, not seen with BCise pen Liraglutide 0.6mg SC daily x 1 week, then 1.2mg SC daily; May further increase to 1.8mg SC if needed after 1 week Lixisenatide 10mcg SC daily x 14 days, then increase to 20mcg SC daily Within 60 minutes before morning meal Semaglutide 0.25mg SC weekly x 4 weeks, then 0.5mg SC weekly; May increase to 1.0mg SC weekly if needed after 4 weeks Multi use, attach needle (comes with device) Clinical Resource, Comparison of GLP-1 Agonists. Pharmacist’s Letter/Prescriber’s Letter. January 2017.

Ertugliflozin (Steglatro®) FDA approved 12/2017 VERTIS MONO trial 26 week double blind, placebo controlled (N=461) Ertugliflozin 5mg and 15mg daily reduced A1C by -0.99% and -1.16% and weight by -1.76kg and -2.16kg, respectively (placebo-adjusted) Higher rates of genital mycotic infections VERTIS program 9 phase 3 trials with 12,600 adults with T2DM Lower limb amputation concern: 0.2% ertugliflozin 5mg, 0.5% ertugliflozin 15mg, 0.1% placebo CV outcome trials underway Combination options Seglujan (sitagliptin/ertugliflozin) Segluromet (metformin/ertugliflozin) https://diatribe.org/latest-diabetes-drugs-less-hypoglycemia-more-weight-loss Expected to be chepaer than other SGLT-2 inhibitors. No significant impact on BP. Vertis cv to assess cv impact https://diatribe.org/latest-diabetes-drugs-less-hypoglycemia-more-weight-loss. Accessed 4/11/18 Terra SG et al. Diabetes Obes Metab. 2017;19:721–728.

SGLT-2 Inhibitor Comparison Drug Dosing Use Not Recommended Canagliflozin* 100mg-300mg QAM eGFR 45-59: 100 mg daily max eGFR <45ml/min Dapagliflozin 5-10mg QAM eGFR <60ml/min Empagliflozin* 10-25 mg QAM Ertugliflozin 5-15mg QAM All are containdicated when egfr<30 Canagliflozin  300 mg (~$465) Dapagliflozin 10 mg (~$465) Empagliflozin 25 mg (~$465) Ertugliflozin 15 mg (~$270 Established CV benefit in clinical trials Micromedex® 2.0, (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com/ (cited: 4/11/18).

Sotagliflozin Dual SGLT1/SGLT2 inhibitor InTandem3 trial SGLT2 inhibition impairs renal glucose reabsorption SGLT1 impairs renal glucose absorption, impairs intestinal glucose absorption, and stimulates GLP-1 and polypeptide YY InTandem3 trial Randomized, double-blind, placebo-controlled trial in T1DM over 24 weeks (n=1402) Primary endpoint: A1C<7% with no episodes of severe hypoglycemia or DKA Sotagliflozin 400mg daily (200 of 699 patients [28.6%] vs. Placebo 107 of 703 [15.2%], P<0.001) achieved the primary endpoint The least-squares mean change from baseline was significantly greater in the sotagliflozin group: A1C, (-0.46%), weight (-2.98 kg), SBP(-3.5 mm Hg) DKA was higher with sotagliflozin: (3.0% vs. 0.6%) and higher in patients on insulin pumps NDA submitted to the FDA and EMA EMA: european medicine agency. Dapgliflozin also submitted to eMA Garg SK et al. N Engl J Med. 2017 Dec 14;377(24):2337-2348 https://diatribe.org/two-pills-type-1-diabetes-under-us-and-european-review. Accessed 4/11/18. .

Test Your Knowledge Which of the following is a newly FDA approved SGLT-2 inhibitor? Sotagliflozin Ertugliflozin Semaglutide Fiasp

Choice of Basal Insulin NPH Levemir Glargine U-300 Delgludec U-100 Glargine U-100 Degludec U-200

Choice of Bolus Insulin Aspart Lispro U-100 Glulisine Inhaled U-200 Regular Ultra-rapid Aspart

Fast-Acting Insulin Aspart FDA Approved 9/2017 Insulin aspart formulation with niacinamide (vitamin B3) and L-arginine (stabilizer) Faster absorption Quicker onset Available as 10mL vial or Flextouch pen Niche: type 1 diabetes, insulin pumps? Early lispro Ultra rapid acting lispro: LY90014 https://diatribe.org/fiasp-faster-mealtime-insulin-now-available-us-pharmacies. Accessed 5/22/18. Fiasp package insert. Available at: http://www.novo-pi.com/fiasp.pdf . Accessed 5/22/18

Fast-Acting Insulin Aspart Inject at start of meal up to 20 min after Duration of action 10% shorter vs insulin aspart Not as fast as inhaled insulin Fiasp begins lowering glucose in 15-20 minutes, has a peak glucose-lowering effect in about 1.5-2 hours, and returns to baseline glucose-lowering within 5-7 hours after dosing. (L-arginine and niacinamide) have been added, L-arginine serving as a stabilising agent, while niacinamide being responsible for accelerated initial absorption after subcutaneous administratio Russell-Jones D et al. Diabetes Care. 2017 Jul;40(7):943-950

Test Your Knowledge Which of the following patients would be most appropriate for ultra-rapid acting insulin aspart (Fiasp®)? Newly diagnosed patient with type 2 diabetes 45 year old patient with type 1 diabetes and gastroparesis 25 year old patient with type 1 diabetes on insulin pump 30 year old patient with type 1 diabetes on hybrid-closed loop insulin pump

New Follow-on Biologic Insulins Insulin lispro (Admelog®) produced by Sanofi Available in vials and solostar pens Approximately 15% cheaper than Humalog® Insulin glargine U-100 (Lusduna Nexvue®) produced by Merck This would be the 3rd insulin glargine U-100 formulation Lawsuit with Sanofi has put final FDA approval on hold Cost is usually 15-30% less than brand name. Lusduna in lawsuit, so not approved yet. Lantus produced by Sanofi Humalog produced by Lilly https://diatribe.org/fda-tentatively-approves-basal-insulin-lusduna-nexvue. Accessed 4/10/18. https://diatribe.org/fda-approves-admelog-first-biosimilar-mealtime-insulin. Accessed 4/10/18.

Max Solostar Pen Approved For insulin glargine U-300 (Toujeo®) Holds 900 units/pen, 2 pens/box Up to 160 units/injection Expected availability: Summer/2018 http://www.news.sanofi.us/2018-03-27-FDA-approves-Toujeo-R-Max-SoloStar-R

Insulin Lispro ½ Unit Pen Junior Kwikpen Disposable pen option for patients that need ½ unit increments of rapid-acting insulin Contains 300 units/pen Max dose/injection is 30 units Aspart has a version, but is not disposable and requires refilling with cartridges http://uspl.lilly.com/humalog/humalog.html#ug3

Rapid-Acting Insulin Comparison Property Insulin Lispro Humalog® (U-100/U-200) Admelog® Insulin Aspart Novolog® Ultra-Rapid Aspart (Fiasp®) Insulin Glulisine Apidra® Inhaled Insulin Afrezza® Onset 15-30 min 10-20 min 15-20 min 25 min 12-15 min Duration of Action 3-6.5 hours 3-5 hours 4-5.3 hours 160 min Meal Timing SC up to 15 min before or immediately after meal SC 5-10 min before meals SC at start of meal or 20 min after starting meal SC within 15 min before or 20 min after starting meal Inhaled at beginning of meal Units per pen 300 units in 3mL 600 units in 3mL NA Max units injected/dose 60 units 80 units 4,8,12 unit cartridges Pens/box 5 2 Available as vial? Yes No Expiration 28 days 3 days Clinical Resource, Comparison of Insulins. Pharmacist’s Letter/Prescriber’s Letter. December 2017. Clinical Resource, Comparison of Insulins. Pharmacist’s Letter/Prescriber’s Letter. December 2017

Long-Acting Insulin Comparison Property Glargine (U-300) Toujeo® Glargine (U-100) Lantus® Basaglar® Degludec (U-100) Tresiba® (U-200) Levemir (Detemir®) Concentration 300 units/mL 100 units/mL 200 units/mL Duration of Action 24-36 hours 24 hours > 42 hours Up to 24 hours Units per pen 450 units in 1.5mL OR 900 units in 3mL 300 units in 3mL 300 units in 3mL 600 units in 3mL Max units injected/dose 80 units in 1.5mL pen 160 units in 3mL pen 80 units 160 units Dial 1 unit/2 units 1 unit 2 units Pen or Vial? Pen Pen/vial Basaglar: pen only Expiration 42 days 28 days 56 days Clinical Resource, Comparison of Insulins. Pharmacist’s Letter/Prescriber’s Letter. December 2017.

Clinical Pearls Semaglutide Ertugliflozin Sotagliflozin Superior to current GLP-1 agonists More weight loss/A1C lowering Oral version on the horizon Ertugliflozin A “me too” drug Sotagliflozin Novel mechanism of action On the horizon for type 1 diabetes

Clinical Pearls Biologic insulins Reduced costs, may be preferable on formularies Ultra rapid insulin aspart Slightly faster Potential niches: type 1 diabetes, insulin pumps New devices offer easier injection (exenatide ER) and flexibility for insulin dosing (Junior kwikpen)

Summary There are many options for diabetes treatment as well as new drugs and devices on the horizon Areas of particular growth are GLP-1 agonists, SGLT-2 inhibitors and follow-on biologic insulins Patient populations that may particularly benefit from these new therapies are obese patients (semaglutide), patients with type 1 diabetes (sotagliflozin, junior kwikpen , ultra rapid aspart ) and patients on insulin that would like cost savings (follow-on biologics) Discuss new medication options for diabetes. Compare and contrast new diabetes medications and formulation to what was previously available. Outline when to use new medications for specific patient populations.