GROWING OUR FUTURE IN DIABETES CARE: WHERE ARE WE NOW AND WHERE ARE WE GOING?

Ashley Firm, Pharm.D. Lindsey Meston, Pharm.D. Disclosure

Neither Dr. Firm nor Dr. Meston have anything to disclosure concerning possible financial or personal relationships with commercial entities (or their competitors) mentioned in this presentation. Objectives

■ Summarize key differences and updates to guidelines related to the care of diabetic patients, especially updates in the 2018 American Diabetes Association Standard of Medical Care in Diabetes ■ Select most appropriate treatment regimens for sample patients based on diabetic presentation and co-morbid conditions ■ Evaluate new products to the market for the treatment of diabetes, including place in therapy, pros and cons of use, major adverse effects, and other pertinent pharmacokinetic and pharmacodynamic properties. SOC-36238233

Socrative Join Code Which of the following correctly pairs a basal insulin and GLP1-RA coformulation?

A. Insulin glargine- semaglutide B. Insulin determir- dulaglutide C. Insulin degludec- liraglutide Which new agent was accepted by the FDA for regulatory filing as a dual inhibitor of SGLT-2 in the treatment of type 1 diabetes?

A. Sotagliflozin B. Empagliflozin C. Dapagliflozin D. Canagliflozin Under the ADA Standards of Care 2018, a patient with a history of a myocardial infarction would be recommended for which class of medication in addition to metformin? A. Thiazolidinediones B. Sulfonylureas C. Sodium Glucose Co-Transporter 2 Inhibitor D. Alpha Glucosidase Inhibitor Under the updated guidelines of the American Association of Clinical Endocrinologists, a patient failing to achieve A1C goal with metformin would be most appropriately treated with a medication from which class?

A. Glucagon-like Peptide 1 Receptor Agonist B. Meglitinides C. Bolus insulin D. Amylin Analog Diabetes in America

■ According to the CDC, more than 30 million Americans have diabetes – 1 in 4 don’t even know – Total direct and indirect cost is more than $240 billion/year – Seventh leading cause of death in the United States in 2015

■ According to the American Diabetes Association, 1 in 3 Americans has prediabetes – That's more than 84 million Americans! – 90% of these patients do not know their risk

https://www.cdc.gov/diabetes/basics/quick-facts.html National Diabetes Statistics Report, 2017 Diabetes in America ■ In the last 20 years, the number of diagnosed cases of diabetes has tripled as the population has aged

CDC's Division of Diabetes Translation. United States Diabetes Surveillance System. http://www.cdc.gov/diabetes/data Diabetes in America

Sotagliflozin Dapagliflozin/metformin Lixisenatide *Pending approval 10/2014 7/2016 2019 dapagliflozin/saxagliptin empagliflozin/metformin 2/2017 8/2015

Insulin degludec/liraglutide Empagliflozin/linagliptin Insulin glargine/lizisenatide 2/2015 11/2016 Semaglutide Ertugliflozin Insulin degludec Ertugliflozin/metformin Insulin degludec/insulin aspart Ertugliflozin/sitagliptin 9/2015 12/2017 NEW MEDICATIONS NEW INDICATIONS ■ Regular Insulin U-500 Pen

■ Insulin Lispro U-200 Pen Insulin and Insulin Changes ■ Insulin Glargine U-300 Pen

■ Insulin Degludec (Tresiba) Regular Insulin U-500 Pen ■ Class – Regular Insulin (Humulin-R) ■ Delivery Method – Kwikpen – U-500 syringes ■ Clinical Pearls – Useful for severely insulin-resistant patients requiring >200 units/day – Contains both basal and prandial properties ■ Can be used as monotherapy ■ Requires 2-3 injections per day – Can reduce insulin volume by 80% compared to U-100 Regular Insulin U-500

Vial and Syringe Pen ■ Syringe calibrated for 500U/1ML ■ Dial doses in increments of 5 units ■ No conversion needed ■ No conversion needed ■ Reduced risk for dosing errors ■ Reduced risk for dosing errors ■ Use with 20ml vial ■ Ease of administration with pens ■ 1500 units/3 ml pen, 2 pens per box

https://www.humulin.com/hcp/delivery-options.aspx#u-500-kwikpen Insulin Lispro U-200 Pen

■ Class – Rapid Acting Insulin (Humalog) ■ Delivery Method – 200 units/1ml pen, can dial doses in 1-unit increments – Max dose per injection is 60 units – Box contains 2 x 3ml pens ■ Clinical Pearls – Rapid-acting meal time insulin given 15 minutes before a meal – One-half the volume of U-100 insulins – Consider switching when meal time insulin needs >20 units/meal – No dosing conversion needed from U-100 to U-200

https://www.humalog.com/hcp/humalog-u200/ Insulin Lispro Junior Pen

■ Class – Rapid acting insulin (Humalog Junior) ■ Delivery Method – Insulin lispro pen device delivering 0.5-unit increments! ■ Clinical Pearls – Self- contained delivery unit only requiring an additional pen needle – Can dial between 0.5 units and 30 units per injection

https://www.humalog.com/hcp/humalog-u100-and-junior-kwikpen/#junior_kwikpen Insulin Lispro U-100

■ Class - Rapid-acting insulin (Admelog) ▪ "Follow on" to Humalog ■ Delivery Method - Available in Solostar or vial ▪ Discard open insulin after 28 days ■ Clinical Pearls - Identical amino acid sequence to Eli Lilly insulin lispro leading to similar PK profile - 1:1 dosing conversion from other insulin lispro products - ADE: similar to other rapid acting insulins- hypoglycemia, hypokalemia, lipodystrophy Insulin Aspart U-100

■ Class – Rapid-acting insulin (Fiasp) ■ Delivery Method – Available in Flextouch or vial ▪ Max 80 units per injection with pen ▪ Discard open insulin after 28 days ■ Clinical Pearls – Insulin aspart with two excipients allowing ultra-rapid acting characteristics ▪ Enters blood stream in ~2.5 minutes ▪ Can be taken with start of meal or within 20 minutes of starting – 1:1 dosing conversion from other rapid acting insulin products – Not approved for pediatric population – ADE: similar to other rapid acting insulins- hypoglycemia, hypokalemia, lipodystophy Insulin Glargine U-300 Pen

■ Class – Basal insulin (Toujeo Max Solostar) ■ Delivery Method – Same insulin glargine U-300 in original pen device – Pen device has changed to hold 900 units of insulin per pen – Packages as 2 x 3ml pens – Dose 2-160 units per injection ■ Clinical Pearls – Insulin glargine U-100 to U-300 conversion- 1:1 – 42-day expiration after opening, removal from refrigeration Insulin Degludec ■ Class – Basal Insulin (Tresiba) ■ Delivery Method – Available as U-100 or U-200 insulin pens ■ Clinical Pearls – Unique PK: T ½ 25 hours ■ Provides 42-hour coverage ■ Allows for a more flexible dosing schedule – 1:1 dose conversion from other basal or intermediate insulins – Insulin naïve patients: start with 10 units nightly

DEVOTE Trial

■ Non-inferiority safety outcomes trial in risk of major cardiovascular events (MACE) with insulin degludec U-100 compared to insulin glargine U-100 ■ Treat to target study design of 7600+ patients with inadequately controlled diabetes and atherosclerotic cardiovascular disease ■ Primary endpoint: time to first MACE – 8.5% in degludec group vs 9.3% in glargine group ■ Secondary confirmatory endpoint: number and incidence of severe hypoglycemic events Insulin degludec/ insulin aspart

■ Class – basal insulin/ rapid acting insulin combination (Ryzodeg) ■ Delivery Method – Available in Flextouch pens – 0.7 units insulin degludec and 0.3 units insulin aspart in each 1 unit of insulin ■ Clinical Pearls – Unlike other mix insulins, solution should be clear and cloudless – Titrate to goal basal dosing- may need to supplement bolus doses ■ Place in Therapy (PiT): reduce needle sticks by combining injections ■ Samaglutide New Non-insulin ■ Lixisenatide Therapies ■ Sotagliflozin ■ Ertugliflozin Semaglutide injection

■ Class – Glucagon-like peptide-1 receptor agonist (Ozempic) ■ Delivery Method – Different pens for 0.25 and 0.5mg doses vs 1mg doses – Dosing ■ 0.25mg SQ weekly x 4 weeks ■ Week 5: Increase to 0.5mg SQ weekly ■ Week 9: May increase to 1mg SQ weekly ■ Clinical Pearls – Take missed dose if remember within 5 days – Adverse Drug Effects (ADE): Nausea, vomiting, diarrhea, abdominal pain, constipation – Warnings: possible thyroid tmors, including cancer Semaglutide injection

■ Semaglutide outperformed dulaglutide in head-to-head A1C lowering (SUSTAIN 7) – 40 weeks, randomized, open-label, active control of 1201 adults – Semaglutide 0.5mg vs dulaglutide 0.75mg ■ A1C lowered 1.4% vs 1.1% (baseline 8.2 vs 8.3) – Semaglutide 1mg vs dulaglutide 1.5mg ■ A1C lowered 1.6% vs 1.3% (baseline 8.2) ■ Semaglutide outperfomed sitagliptan and exenatide extended release in head-to-head A1C lowering (SUSTAIN 2 & SUSTAIN 3) Semaglutide Injection

■ Semaglutide was evaluated for CV safety in a 2-year cardiovascular outcomes trial (CVOT) ■ SUSTAIN 6- 104 week, randomized, multinational, multicenter, double blind, placebo controlled, parallel group, noninferiority, CV safety trial of 3297 adults – Randomized 1:1:1:1 to semaglutide 0.5mg or 1 mg or plaecbo 0.5 or 1mg – All received Diabetes and cardiovascular standards of care – Primary endpoint: first occurance of MACE ■ Standard of care: 8.9% ■ Semaglutide: 6.6% ■ No additional clinical studies establishing reduction in MACE Lixisenatide Injection

■ Class – GLP-1 Receptor Antagonist (Adlyxin in US, Lyxumia in EU) ■ Delivery Method – Dosing: Starter pack of 10 mcg SQ daily for 14 days then increase to 20 mcg SQ daily (Starter pack contains one 10mcg pen and one 20mcg pen) – Maintenance pack contains two 20mcg pens ■ Clinical Pearls – MACE: no reduction shown – Similar ADE and warnings to other members of the class Sotagliflozin

■ FDA has accepted regulatory filing with a target action date of March 2019 ■ Class – Oral dual inhibitor of SGLT-1 and SGLT-2 (Zynquista) ■ SGLT-2 found in proximal tubule of the nephron ■ SGLT-1 found in the small intestines regulating uptake of glucose ■ Treatment of Type 1 Diabetics ■ Anticipated dosing: 200mcg or 400mcg daily ■ In Tandem 1 trial- double blind, phase 3 trial comparing optimized insulin to optimized insulin + sotagliflozin Sotagliflozin

■ In Tandem 1 trial- double blind, phase 3 trial comparing optimized insulin to optimized insulin + sotagliflozin – Randomized 1:1:1 to placebo, 200mcg, 400mcg – Primary endpoint: lowering A1C – Placebo: 0.08%, 200mcg: 0.43%, 400mcg 0.49% – Lower incidence of hypoglycemia requiring treatment in active arms compared to usual insulin optimized group – Slighltly increased risk of diabetic keotacidosis Ertugliflozin

■ Class – SGLT2 Inhibitor (Steglatro) ■ Dosing – Starting dose 5mg daily, can increased to 15mg if needed ■ Clinical Pearls – ADE: female genital mycotic infections, small increased risk of lower limb amputations (also noted with canagiflozin) – CVOT data expected late 2019-2020 SGLT2 + DPP IV Inhibitors ■ Dapagliflozin/saxagliptin (Qtern) Non-insulin – 10mg/5mg tablets Combination ■ Empagliflozin/linagliptin (Glyxambi) – 10mg/5mg or 25mg/5mg tablets Products ■ Ertugliflozin/sitagliptin (Steglujan) – 5mg/100mg or 15mg/100mg tablets SGLT2 + metformin ■ Empagliflozin/metformin (Synjardy) Non-insulin – 5mg/500mg, 5mg/1000mg, 12.5mg/500mg or 12.5mg/1000mg tablets Combination ■ Dapaglifozin/ metformin ER (Xigduo XR) Products – 5/1000mg tablets ■ Ertugliflozin/metformin (Segluromet) – 2.5mg/500mg, 2.5mg/1000mg, 7.5mg/500mg or 7.5mg/1000mg tablets Insulin Glargine/ Lixisenatide

■ Class – Basal insulin/ GLP-1 Receptor Antagonist (Soliqua) ■ Delivery Method – 100 units glargine/ 1ml & 33mcg lixisenatide / 1ml – 1 unit of glargine contains 0.33mcg of lixisenatide ■ Dosing – If currently only <30 units basal insulin- start 15 units SQ daily – If currently >30 units basal insulin- start 30 units SQ daily – Titrate by 2-4 units weekly Insulin Degludec/ Liraglutide

■ Class – Basal insulin, GLP-1RA combination (Xyltophy) ■ Delivery Method – 100 units degludec and 3.6 mg liraglutide per mL ■ 3mL prefilled pen, each dosing increment 1 unit degludec/0.036 mg liraglutide ■ Dosing – Start all patients at 16 units daily and titrate + 2 units every 3-4 days based on fasting glucose Insulin Glargine/ Lixisenatide

■ Efficacy – A1c reduction from 8.1% to 6.9% at week 30 – Mean final dose: titrated to 46.7 units daily – Compared to 7.5% with glargine alone ■ Safety – ADE were no different than individual agents – Overall weight loss observed despite addition of insulin Insulin Degludec/ Liraglutide

■ DUAL Trials- 26 weeks with four arms – DUAL II- insulin degludec + liraglutide + metformin ■ A1c lowered from 8.7% to 6.9% – DUAL V- insulin degludec + liraglutide + metformin ■ A1c lowered from 8.4% to 6.6% – DUAL VII- insulin degludec + liraglutide + metformin ■ A1c lowered from 8.2% to 6.7% – DUAL III- insulin degludec + liraglutide + metformin + pio + SU ■ A1c lowered from 7.8% to 6.4% DUAL V- insulin degludec + liraglutide + metformin

■ 26-week, randomized, parallel, open-label, treat-to-target trial in adult patients with type 2 diabetes inadequately controlled on insulin glargine + metformin were compared to degludec + liraglutide + metformin – A1c of treatment arm reduced from 8.4% to 6.7% – Usual care arm reduced from 8.2% to 7.0% ■ Patients required 38% less insulin in treatment arm – Less hypoglycemia with zero incidents of severe hypoglycemia ■ Reduction in body weight DUAL VII- insulin degludec + liraglutide + metformin

■ A 26-week, randomized, parallel, open-label, treat-to-target trial in adult patients with type 2 diabetes inadequately controlled on insulin glargine + metformin were compared to addition of bolus insulin or conversion to degludec + liraglutide – Similar A1C lowering in both arms from 8.2% to 6.7% ■ Treatment arm required 52% less insulin – 89% lower rate of hypoglycemia in treatment arm ■ Weight loss compared to weight gain ■ Once daily injection compared to up to 5 daily injections with basal-bolus Continuous Glucose Monitoring (CGM)

■ Tiny sensor inserted under the skin to read blood glucose levels and communicates to a reader – Typically worn on the abdomen or arm ■ Several brands in the market place – Freestyle libre: communicates with dedicated reader ■ Sensor replaced every 10 days ■ Coming soon! 14 day sensors – Dex Com 6: communicates with apple or android smart devices ■ Sensor replaced every 10 days ■ Limitations of use ■ Janet is a 57 yo female with a three-year history of diabetes type 2 in addition to a five-year history of hypertension and Janet, 57 dyslipidemia. Her current medications include metformin 1000mg po BID, lisinopril 20mg po QD, and atorvastatin 40mg po QD. She was also started on liraglutide four months ago and titrated to 1.8mg daily with good tolerance. Janet is currently unhappy with her daily injection even though she has experienced a decrease in A1C to 6.8% and weight loss. What options can we recommend to Janet to help maintain her good glycemic control with better patient satisfaction? GUIDELINE UPDATES American Diabetes Association 2018 Update

▪ Cardiovascular disease and diabetes ▪ Recent cardiovascular outcomes trial (CVOT) data prompted updates to type 2 diabetes management

▪ People with atherosclerotic cardiovascular disease (ASCVD) should consider an agent proven to reduce major adverse cardiovascular events and/or cardiovascular mortality

▪ The algorithm for antihyperglycemic treatment was updated to incorporate the new ASCVD recommendation

Diabetes Care Volume 41, Supplement 1, Jan 2018 Diabetes Care Volume 41, Supplement 1, Jan 2018

American Diabetes Association 2018 Update

■ Hypertension ▪ Most patients with diabetes and hypertension should target a systolic blood pressure goal of <140 mmHg and a diastolic blood pressure goal of <90 mmHg

▪ Lower systolic and diastolic blood pressure targets (ex. 130/80 mmHg) may be appropriate for individuals at high risk of cardiovascular disease, if they can be achieved without undue treatment burden

▪ Analysis of ACCORD BP, ADVANCE BP, HOT, and SPRINT trials included for support

▪ Encouraged home monitoring of blood pressure by patient

Diabetes Care Volume 41, Supplement 1, Jan 2018 American Diabetes Association 2018 Update

■ Individualization ▪ Verbiage to take into consideration the potential limitations in A1c during diagnosis and to consider alternative methods of diagnosis if discrepancy is found

▪ Updated recommendations emphasize that testing for prediabetes and type 2 diabetes should be considered in children and adolescents younger than 18 years of age who are overweight or have additional risk factors

▪ Recommendation for awareness of social determinants of health (financials, access, community support) when determining drug therapy options

▪ Inclusion of technology-based methods and individual and group settings for delivery of diabetes self-management education and support

▪ Lowered the recommended age for continuous glucose monitoring for type 1 diabetes starting at age 18 (previous recommendations were for ages 25 and older)

Diabetes Care Volume 41, Supplement 1, Jan 2018

AACE/ACE Diabetes Management Algorithm

■ Revisions include noting glucose-lowering medications for type 2 diabetes that have proven benefits in mitigating atherosclerotic CVD – Emphasis on liraglutide’s FDA approval for prevention of MACE events – Emphasis on empagliflozin’s FDA approval to reduce CV mortality – Emphasis on canagliflozin being shown to reduce MACE events

■ Discussion of a complication-centric model for managing patients who are overweight/obese

ACC/AHA Hypertension Guideline Update

■ Updated definition of hypertension, with classification of “elevated” blood pressure

J Am Coll Cardiol. Sep 2017, 23976; DOI: 10.1016/j.jacc.2017.07.745 Jonathan ■ Jonathan is a 62-year-old male with a 10 year history of poorly controlled diabetes with an A1C averaging 9.5-10% on metformin 1000mg po BID and linagliptin 5mg po QD. He recently has become more concerned with gaining control of his glucose after he was rushed to the ED with a myocardial infarction in which he received two stents. He was discharged from the hospital on all appropriate post-MI medications and is presenting to your diabetes clinic for diabetes education and pharmacotherapy management. Jonathan

■ What other information would you like on Jonathan? ■ Prior to the latest ADA update, what would ADA guidelines recommend as next step in therapy? ■ How has the update ADA changed your recommendation? ■ Prior to AACE consensus statement, what would AACE recommend as next step in therapy? ■ How has the consensus statement changed your recommendation? CLINICAL SERVICE OPPORTUNITIES Diabetes Self-Management Education and Support

■ Education classes geared towards giving patients the tools to manage their diabetes effectively ■ Pharmacy must undergo accreditation through either AADE or ADA – Varying accreditation requirements – Must undergo accreditation renewals and audits ■ Billing structure – First year: 1 hour of individual education and up to 9 hours of group education ■ You don't use it you lose it! – After first year, two hours of individual education ■ Billing codes – G0108: individual, billed per 30 minutes – G0109: group session, billed per 30 minutes Diabetes Prevention Program

■ Lifestyle change program focused on sustainable, significant improvements in nutrition and activity ■ Apply for recognition through CDC ■ Become a certified trainer – Various training sessions offered throughout the state – Facilitate sessions using CDC-approved curriculum ■ Bill up to 12 months of group-style education – Attendance and performance-based payment Pennsylvania Pharmacist Care Network (PPCN)

■ Network of pharmacists and pharmacies that provide enhanced clinical services to their patient population with the united goal of improving patient outcomes ■ Billable opportunities – Medication reviews for insurer groups – Follow-up on disease state management GROWING OUR FUTURE IN DIABETES CARE: WHERE ARE WE NOW AND WHERE ARE WE GOING?

Ashley Firm, Pharm.D. Lindsey Meston, Pharm.D. Which of the following correctly pairs a basal insulin and GLP1-RA coformulation?

A. Insulin glargine- semaglutide B. Insulin determir- dulaglutide C. Insulin degludec- liraglutide Which of the following correctly pairs a basal insulin and GLP1-RA coformulation?

A. Insulin glargine- semaglutide B. Insulin determir- dulaglutide C. Insulin degludec- liraglutide Which new agent was accepted by the FDA for regulatory filing as a dual inhibitor of SGLT-2 in the treatment of type 1 diabetes?

A. Sotagliflozin B. Empagliflozin C. Dapagliflozin D. Canagliflozin Which new agent was accepted by the FDA for regulatory filing as a dual inhibitor of SGLT-2 in the treatment of type 1 diabetes?

A. Sotagliflozin B. Empagliflozin C. Dapagliflozin D. Canagliflozin Under the ADA Standards of Care 2018, a patient with a history of a myocardial infarction would be recommended for which class of medication in addition to metformin? A. Thiazolidinediones B. Sulfonylureas C. Sodium Glucose Co-Transporter 2 Inhibitor D. Alpha Glucosidase Inhibitor Under the ADA Standards of Care 2018, a patient with a history of a myocardial infarction would be recommended for which class of medication in addition to metformin? A. Thiazolidinediones B. Sulfonylureas C. Sodium Glucose Co-Transporter 2 Inhibitor D. Alpha Glucosidase Inhibitor Under the updated guidelines of the American Association of Clinical Endocrinologists, a patient failing to achieve A1C goal with metformin would be most appropriately treated with a medication from which class?

A. Glucagon-like Peptide 1 Receptor Agonist B. Meglitinides C. Bolus insulin D. Amylin Analog Under the updated guidelines of the American Association of Clinical Endocrinologists, a patient failing to achieve A1C goal with metformin would be most appropriately treated with a medication from which class?

A. Glucagon-like Peptide 1 Receptor Agonist B. Meglitinides C. Bolus insulin D. Amylin Analog