Cara Liday, PharmD, CDE Associate Professor, Idaho State University Clinical Pharmacist and CDE, InterMountain Medical Center Pocatello, ID The planners and presenter have disclosed no conflict of interest, including no relevant financial relationships with any commercial interests pertaining to this activity. Learning Objectives Pharmacists, nurses, prescribers Describe new and emerging therapies for the treatment of diabetes mellitus List the potential pros and cons of new and emerging therapies Discuss the potential implications of these therapies on clinical practice Learning Objectives Technicians List the brand and generic names of medications for the treatment of diabetes Describe important dispensing points for each of new classes of medications List two disadvantages of these new agents compared with older agents for the treatment of diabetes Glycemic Goals of Therapy ADA guidelines AACE/ACE guidelines ADA guidelines A1c goal is <7% A1c goal for the individual patient is as close to normal (<6.5%) as possible without significant hypoglycemia AACE/ACE guidelines 6.5% w/o serious illness and low hypoglycemic risk 6.5% w/serious illness and at risk for hypoglycemia 2015/2016 1

ADA: Antihyperglycemic therapy in type 2 diabetes: general recommendations Insulin The old, the new, and the upcoming American Diabetes Association Dia Care 2016;39:S52-S59 2016 by American Diabetes Association Insulin Types Insulin Types Inhaled rapid acting: human insulin (Afrezza ) Onset 10 mins, peak 15-30 min, duration 3 hrs Rapid acting: lispro (Humalog ), aspart (Novolog ), glulisine(apidra ) Onset 10-15 min, peak 1 hr, duration 3-5 hr Short acting: regular- humulin R, novolin R Onset 30-60 min, peak 2-4 hr, duration 6-8 hr Intermediate acting: NPH (cloudy)- humulin N, novolin N Onset 2-4 hr, peak 4-10 hr, duration 10-18 hr Long acting: detemir (Levemir ), glargine (Lantus Tujeo ), degludec (Tresiba ) Lantus onset 2 hr, no peak, duration 22-24 hr Levemir onset 3 hr, peak 6-8 hr?, duration 6-23 and variable with dose Insulin Characteristics Combinations: 50/50* 50% NPH 50% R 70/30* 70% NPH 30% R Humalog mix 75/25 75% LPS 25% lispro Humalog mix 50/50 50% LPS 50% lispro Novolog mix 70/30 70% APS 30% aspart Insulin Preparations Rapid acting insulin (aspart, lispro, glulisine, inhaled) Onset very quick; duration shortest Dosed prior to meals to provide bolus Correction doses for highs Short acting insulin (Regular; R) Humulin/Novolin R Onset later than rapid; longer duration Dosed prior to meals for bolus Correction of highs *Humulin,Novolin, ReliOn /Novolin All mixes are cloudy (excluding Ryzodeg ) 2

Insulin Preparations Intermediate acting (NPH;N) Humulin/Novolin N Onset later Duration average 12 hours (variable) Large peak Basal insulin (BID) Long acting (glargine, detemir, degludec) Onset couple hours Duration longest (around 18-42 hours) Basal insulin Insulin Preparations Intermediate with short/rapid Pre-mixed/split-mixed/dual-acting Novolog mix 70/30 Humalog 75/25 or 50/50 Humulin or Novolin 70/30 or 50/50 Dosed BID Rapid or short for B & D Intermediate for lunch and basal Insulin glargine (Toujeo ) 300 units/ml glargine preparation Non-inferior to glargine (Lantus ) Onset 6 hours; minimal peak Duration up to 36 hrs 450 units per pen 1-80 unit dose; actual dose in window Need higher doses for effect Lantus/Levemir 20-30% more effective If converting to Toujeo increase dose 20% Insulin degludec (Tresiba ) Basal (long-acting) insulin Approved September 2015 Onset 1 hour; half life >25 hours Duration 42 hours Steady state in 3 days No accumulation **No peak Actual dose in window Insulin degludec (Tresiba ) 100 units/ml 1-80 unit doses 300 units/pen 200 units/ml 2-160 unit doses 2 unit dose increments 600 units/pen Stable 8 weeks at room temperature Stable 8 weeks opened refrigerated Flex touch: no dose button extension and very low injection force 3

Insulin degludec/aspart 70/30 (Ryzodeg ) Molecules remain structurally separate Dosed QD to BID Type 2 > type 1 diabetes Type 2 diabetes: once daily with largest meal; progress to BID **Clear mixture Insulin lispro (Humalog 200 u/ml KwikPen ) Same insulin contained in Humalog and Humalog mixes Concentrated 200 u/ml 1-60 unit doses Actual dose shown in window 600 units/pen U-500 Regular insulin 500 units/ml of Regular insulin For extremely insulin resistant patients Onset similar to Regular (30-60 mins) Duration similar to NPH (10-16 hours) Typically used BID to TID 20 ml vials = 10,000 units Dosed by units (insulin syringe) Use smallest insulin syringe possible Dosed by volume (tuberculin syringe) 1 unit = 0.002 ml Regular insulin (U-500 KwikPen ) Available April 2016 Use if > 200 units/day insulin 1500 units/pen 5 unit increment doses Actual dose in window 300 unit max injection Insulin Human Inhalation Powder (Afrezza ) Onset 10 minutes Duration 3 hours 4, 8, 12 unit cartridges Round up if between doses Contraindicated with lung disease, current or recent smoking (<6 months) Spirometry prior to starting, 6 months, then annually with or without symptoms Adverse effects: cough, throat pain/irriation, headache 4

Insulin Human Inhalation Powder (Afrezza ) Insulin Human Inhalation Powder (Afrezza ) Insulin Human Inhalation Powder (Afrezza ) New device every 15 days Glucagon-like peptide-1 (GLP-1) agonists Incretin Effect Incretin Hormones INtestinal secretion of INsulin Released from GI tract in response to meal Two predominant incretin hormones: GIP (glucose-dependent insulinotropic peptide) GLP-1 (glucagon-like peptide) Both augment glucose-stimulated insulin release 5

GLP-1 Effects GLP-1 Agonists Type 2 diabetes Subcutaneous injectables Rare hypoglycemia unless concomitant sulfonylurea or insulin use AEs: nausea, weight loss, headache, diarrhea or constipation, pancreatitis, thyroid cancer Once weekly: may take multiple doses for steady state A1c reduction of 1.0%-1.5% GLP-1 agonist general education Inject into arms, abdomen, thighs Hold injection for 5-10 seconds Change needle & rotate site every injection Store pens in use at room temperature; unopened pens under refrigeration Adverse effects and s/s of pancreatitis Nausea should resolve over time Specific education for each device *Refer to package inserts and individual websites for written and video education Exenatide (Bydureon, Byetta ) Byetta Twice daily 30-60 minutes prior to meals * More effect on post-prandial glucose 5mcg or 10mcg pens (1 per month) Bydureon 2 mg once weekly Pen or single-dose tray Requires mixing; inject immediately Raised bump for 3-6 weeks; 0.25-2 cm 6

Liraglutide (Victoza ) Once daily SQ injection Anytime of day 0.6mg, 1.2 mg, 1.8 mg dose options One pen available Titrate dose up weekly 3 pens/month at max dose Liraglutide (Saxenda ) Albiglutide (Tanzeum ) 0.6,1.2,1.8, 2.4, and 3.0 mg doses One pen option Initiate 0.6 mg daily and increase at weekly intervals to 3 mg dose Same medication in Victoza Approved for treatment of obesity Rare hypoglycemia 30 mg and 50 mg pens Initiate 30 mg once weekly; increase to 50 mg Efficacy data not as robust No dose adjustments down to GFR of 15 Requires mixing Dulaglutide (Trulicity ) 0.75 to 1.5 mg once weekly Initiate 0.75 and increase as needed for control No mixing required! *Inject immediately once needle attached; within 8 hours if not attached 7

Upcoming therapies Lixisenatide (Lyxumia in Europe) GLP-1 agonist NDA accepted for review by FDA Sept 29, 2015 Lixilan (Lyxumia/Lantus combination) Submitted to FDA December 2015 Biosimilar glargine FDA approved Basaglar August 2014 Patent dispute regarding SoloStar pen: Lilly must wait until Dec 2016 Abasaglar in other countries 15-20% cheaper Upcoming therapies Liraglutide/degludec (Xultophy ) Type 2 diabetes 3 ml per pen One dose step contains 1 unit of insulin degludec and 0.036 mg of liraglutide Recommended starting dose is 10 dose steps (10 units insulin degludec/ 0.36 mg liraglutide) Maximum dose is 50 dose steps (50 units degludec/ 1.8 mg liraglutide) SGLT-2 Inhibitors Glucuretics Sodium Glucose Transporter 2 is major cotransporter involved in glucose reabsorption in the kidney Inhibitors block reabsorption of filtered glucose in the kidneys = glucosuria Reduced plasma glucose and caloric loss Type 2 diabetes A1c reduction 0.7%-1.0% SGLT2 Inhibitors Canagliflozin (Invokana ) Dapagliflozin (Farxiga ) Empagliflozin (Jardiance ) Once daily oral dosing Recent data with empagliflozin and reductions in CV outcomes/mortality Benefits: weight loss and reduced BP 8

SGLT2 Inhibitors Rare hypoglycemia unless concomitant sulfonylurea or insulin use Adverse effects: genital yeast infections, urinary tract infections, polyuria, volume depletion, increase in LDL, fractures?, bladder cancer? Increased risk of DKA (often euglycemic) Reduction in plasma glucose without increased insulin requirement After Metformin. Agents chosen based on: Cost/coverage A1c reduction needed Adverse effects Specifically weight gain and hypoglycemia Patient acceptance Concomitant disease states, i.e. kidney dysfunction, etc. Questions? References https://www.aace.com/publications/algorithm http://care.diabetesjournals.org/content/39/supplement_1/s52.f ull.pdf+html http://www.toujeo.com https://www.tresiba.com http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/203 313lbl.pdf http://www.humalog.com/humalog-u200-kwikpen.aspx http://humulin.com/index.aspx http://www.humulinhcp.com/ http://www.afrezza.com http://www.bydureon.com https://www.victoza.com https://www.saxenda.com References http://www.tanzeum.com http://www.trulicity.com http://www.drugs.com/nda/lyxumia_150929.html https://globenewswire.com/news- release/2015/12/23/797792/0/en/zealand-announces-that- Sanofi-has-submitted-LixiLan-for-regulatory-review-in-the- US-triggering-a-USD-20-million-milestone-payment.html http://www.fda.gov/newsevents/newsroom/pressannounce ments/ucm477734.htm https://www.medicines.org.uk/emc/medicine/29493 Facts and Comparisons online Lexicomp online 9