Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes.

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1 Learning Objectives Understand and appropriately individualize treatments based on evidencebased guideline recommendations across the continuum of care in patients with T2DM Key = Clinical Pearl Identify and address both patient and clinician barriers to using injectable therapies in patients with T2DM in an effort to easily adopt therapy, increase medication adherence, and improve overall outcomes Utilize a pathophysiologic approach to intensify therapy with the combination of GLP-1 RAs and basal insulin in patients not achieving glycemic control, including the use of fixed-dose combinations to improve adherence Importance of Glycemic Control UKPDS Individualizing HbA1c Targets for Patients with T2DM ACCORD and VADT suggested increased risk from intensive glycemic control in high risk patients 12% 14% 21% 19% For Every 1% Reduction in HbA1C 37% 16% 43% 14% 21% ACCORD, ADVANCE, and VADT found NO significant reduction in adverse CV outcomes with intensive glycemic control in patients with more advanced T2DM Stratton IM et al. BMJ. 2;321: Diabetes Care 218 Jan; 41 (Supplement 1): S55-S64.

2 ADA Framework for Considering Glycemic Goals in Older Adults with Diabetes Patient Characteristics/Health Status Rationale Reasonable HbA1c Goal Healthy (few coexisting chronic illnesses, intact cognitive and functional status) Complex/intermediate (multiple coexisting chronic illnesses* or 2+ instrumental ADL impairments or mild-to-moderate cognitive impairment) Very complex/poor health (LTC or end-stage chronic illnesses** or moderate-to-severe cognitive impairment or 2+ ADL dependencies) Adapted from ADA. Diabetes Care. 218: 41(1):21, Table Longer remaining life expectancy Intermediate remaining life expectancy, high treatment burden, hypoglycemia vulnerability, fall risk Limited remaining life expectancy makes benefit uncertain <7.5% <8.% <8.5% *Coexisting chronic illnesses are conditions serious enough to require medications or lifestyle management. **The presence of a single end-stage chronic illness may cause significant symptoms or impairment of functional status and significantly reduce life expectancy. Patient-Centered Care Improves: Patient care Cost Patient knowledge Shared decision making Adapted from Oshima Lee E, Emanuel EJ. N Engl J Med. 213;368(1):6-8; Wilson SR, et al. Am J Respir Crit Care Med. 21;181(6): Patient outcomes Adherence AACE/ACE Glycemic Control Algorithm AACE/ACE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM. AACE/ACE. Garber AJ, et al. Endocr Pract. 218;24(1): ADA Treatment Recommendations A1C is less than 9%, consider monotherapy A1C is greater than or equal to 9%, consider dual therapy A1C is 1%, blood glucose is 3 mg/dl, or a patient is markedly symptomatic consider combination injectable therapy Monotherapy Lifestyle Management + Metformin Initiate metformin therapy if no contraindications A1C at target after 3 months of monotherapy? Monitor A1C every 3-6 Assess medication-taking behavior months Consider Dual therapy Dual Therapy Lifestyle Management + Metformin + Additional Agent ASCVD? Add agent proven to reduce major adverse CV events and/or CV mortality Combination Injectable Therapy Adapted from ADA. Diabetes Care. 218: 41(1):S Add second agent after consideration of drug-specific effects and patient factors A1C at target after 3 Monitor A1C every 3-6 Assess medication-taking behavior months of dual therapy? months Consider Triple therapy Triple Therapy Lifestyle Management + Metformin + Two Additional Agents Add a third agent based on drug-specific effects and patient factors A1C at target after 3 months of triple therapy? Monitor A1C every 3-6 months Assess medication-taking behavior Consider Combination Injectable therapy

3 Patient Case of Uncontrolled T2DM Patient Case of Uncontrolled T2DM John is a 6-year-old man diagnosed with T2DM six years ago. Medical history: Surgical History: He feels well and expresses no concerns at today s routine office visit. T2DM 6 years HTN Lasik Appendectomy John, age 6 He is compliant with his current medications He checks his FPG sometimes and reports a range of mg/dl He tries to exercise 2-3 times a week but has trouble finding the time John, age 6 Hyperlipidemia Obesity BPH Social History: Denies tobacco ~2 drinks/week Patient Case of Uncontrolled T2DM Patient Case of Uncontrolled T2DM John, age 6 Medications: Metformin 1 mg BID Glimepiride 4 mg QD Lisinopril 4 mg QD Metoprolol 1 mg BID Atorvastatin 4 mg QD Tamsulosin.4 mg QD Aspirin 81 mg QD John, age 6 Vitals: Temp 98.7 F HR 56 bpm RR 16 BP 13/84 mmhg Ht 72 inches Wt 25 lbs BMI 34 kg/m² WC 45 inches Allergies: NKDA

4 Relevant Labs (fasting) HbA1c 8.8% Fasting Plasma Glucose 185 mg/dl Limitations of Oral Antidiabetic Medications Many patients fail to achieve glycemic goals with initial monotherapy¹ John, age 6 LDL HDL BUN 12 mg/dl 45 mg/dl 2 mg/dl Of those who do achieve their goals, few consistently maintain these targets over three years due to lack of durability¹ Creatinine 1.4 mg/dl egfr 5 ml/min/1.73m² What s Next? In when oral therapy fails, is contraindicated, or is not recommended such with elevated entry HbA1c patients often require injectable therapies to help achieve glycemic control 1,2 1. McColloch DK. Accessed Apr 5 217; 2. ADA. Diabetes Care. Jan 217; 4(Suppl 1); 3. Garber AJ, et al. Endocr Pract. 217; 23(2): AACE/ACE Glycemic Control Algorithm AACE/ACE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM. AACE/ACE. Garber AJ, et al. Endocr Pract. 218;24(1): ADA Treatment Recommendations A1C is less than 9%, consider monotherapy A1C is greater than or equal to 9%, consider dual therapy A1C is 1%, blood glucose is 3 mg/dl, or a patient is markedly symptomatic consider combination injectable therapy Monotherapy Lifestyle Management + Metformin Initiate metformin therapy if no contraindications A1C at target after 3 months of monotherapy? Monitor A1C every 3-6 Assess medication-taking behavior months Consider Dual therapy Dual Therapy Lifestyle Management + Metformin + Additional Agent ASCVD? Add agent proven to reduce major adverse CV events and/or CV mortality Combination Injectable Therapy Adapted from ADA. Diabetes Care. 218: 41(1):S Add second agent after consideration of drug-specific effects and patient factors A1C at target after 3 Monitor A1C every 3-6 Assess medication-taking behavior months of dual therapy? months Consider Triple therapy Triple Therapy Lifestyle Management + Metformin + Two Additional Agents Add a third agent based on drug-specific effects and patient factors A1C at target after 3 months of triple therapy? Monitor A1C every 3-6 months Assess medication-taking behavior Consider Combination Injectable therapy

5 Patient Barriers to Injectable Therapy Overcoming Patient Barriers to Injection Perceptions of hypoglycemia Associated with poor outcomes/ diabetic complications Associated with failure Ascertain and acknowledge the patient s fears Simple regimen (once daily) Convenience and accuracy -pens Concerns about restricted, burdensome lifestyle Believe that it portends worsening disease Have patient demonstrate injection in office Educate on lifestyle modifications/diabetes educator Allow patients to self-titrate medication Customize treatment plan for each patient Cultural taboos Cost Injection pain/phobia Provide written instructions Injectable medication as a solution, not a threat To overcome concerns of weight gain, combo basal insulin and GLP-1 RA ADA. Diabetes Care. Jan 217; 4(Suppl 1). Karter AJ, et al. Diabetes Care. 21; 33(4): Funnell MM. Clinical Diabetes. 27;25(1):36-38; Peyrot M, et al. Primary Care Diabetes. 21;4(Suppl 1):S11-S18; Unger J. Diabetes Metab Syndr Obes. 211;4: ; Zisman A, et al. ADA Scientific Sessions. San Diego, CA P. Clinician Barriers to Injectable Therapy Time constraints Lack of support/resources Perceived inadequacy of blood glucose monitoring Fear of poor patient adherence Actual patient non-adherence Concern about adverse events from insulin such as hypoglycemia Lack of knowledge of guidelines and injectable medication options/use/mechanism of action/benefits Pathophysiology of T2DM Progressive β cell failure Elevated post prandial glucose (PPG) Subsequent rise in fasting plasma glucose (FPG) Glucose overproduction in the liver during basal state Impaired suppression of hepatic glucose production by insulin Impaired glucose uptake in the muscle after carbohydrate ingestion Smith RJ, et al. J Clin Endocrinol Metab. 21;95(4): Frei A, et al. Cardiovasc Diabetol. 21;9:23. Martin D, et al. Pediatr Diabetes. 212;13 Suppl16:2-28. DeFronzo RA, et al. Diabetes Care. 213;36 Suppl 2:S

6 The Physiologic Insulin Profile Basal Insulin / MoA Serum insulin (mu/l) Mealtime insulin excursions Rapid rise; short duration Smooth, steady basal insulin profile Suppresses hepatic glucose secretion Accounts for approx. 4-5% of total daily insulin requirements Keeps plasma glucose stable in absence of food Breakfast Lunch Dinner 4 8 Adapted from Kruszynska Y, et al. Diabetologia. 1987;3:16. Advantages of Basal Insulin Basal Insulins Long acting Basal Insulin Type Onset Peak Duration of Action (h) Variability Once daily Flat biologic profile with minimal peaks Intermediate-acting Human NPH 1-2 h 4-12 h 1-24 h Greater Insulin glargine (U-1) (Lantus, Basaglar) Long-acting analogs Insulin detemir (Levemir) h 1.1 h No pronounced peak No pronounced peak 7.6 to >24 Less 6 to >24 Less Lower risk of hypoglycemia, especially nocturnal Ultra-long-acting analogs Insulin glargine U-3 (Toujeo) Insulin degludec (U-1/U-2) (Tresiba) Less variability = Less hypoglycemia 6 h Nearly peakless >36 h Minimal 3-9 min Nearly peakless >42 Minimal Hirsch IB. N Engl J Med. 25;352(2): Meneghini L. et al. Diabetes Obes Metab. 27;9(6): PL Detail-Document, Comparison of Insulins and Injectable Diabetes Meds. Pharmacist s Letter/Prescriber s Letter. March 215; PDR.net. Accessed Jan 26, 218; PDR.net. Accessed Jan 26, 218; Tresiba package insert. Accessed Jan 3, 218. Fiasp package insert. Accessed Jan 26, 218; Monami M, et al. Diabetes Res Clin Pract. 28;81(2): ; Marso SP et al. N Engl J Med 217;377:

7 Insulin Initiation AACE/ACE ADA Initiate Basal Insulin Usually with metformin ± other noninsulin agent Start: 1 U/day or.1-.2 U/kg/day Adjust: 1-15% or 2-4 units once or twice weekly to reach FBG target For hypo: Determine & address cause; if no clear reason for hypo dose by 4 units or 1-2% Monitoring HbA1c every 3 months Check FPG daily Check PPG 2 hrs after meals if concern for PPG elevations AACE/ACE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM. AACE/ACE. Garber AJ, et al. Endocr Pract. 218;24(1): Adapted form ADA. Diabetes Care. 218: 41(1):S Patient Case of Uncontrolled T2DM John s Weekly BG Log John, age 6 Metformin 1 mg BID Glimepiride 4 mg QD Glargine 6 units John was initiated on basal insulin six months ago. The dose of insulin glargine was titrated up to 6 U/day. HbA1C = 7.4% FPG range mg/dl PPG range 18-3mg/dL What would you recommend NEXT? Time of Day Saturday Sunday Monday Tuesday Wednesday Thursday Friday Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Breakfast Lunch Dinner Bedtime On two occasions in the afternoon when feeling weak and hungry, John checked his BG and it was <7 mg/dl (62 and 67 mg/dl)

8 Hypoglycemia and Medication Adherence ADA / Insulin Algorithm If A1C not controlled, consider combination injectable therapy Add 1 rapid-acting insulin injection before largest meal Start: 4 units,.1 U/kg, or 1% basal dose. If A1C <8%, consider basal by same amount Adjust: dose by 1-2 units or 1-15% once or twice weekly until SMBG target reached For hypo: Determine and address cause; if no clear reason for hypo, corresponding dose by 2-4 units or 1-2% Add GLP-1RA If not tolerated or A1C target not reached, change to 2 injection insulin regimen If goals not met, consider changing to alternative insulin regimen Change to premixed insulin twice daily (before breakfast and supper) Start: Divide current basal dose into 2/3 am, 1/3 PM or ½ am, ½ PM Adjust: dose by 1-2 units or 1-15% once or twice weekly until SMBG target reached For hypo: Determine and address cause; if no clear reason for hypo, corresponding dose by 2-4 units or 1-2% Hajós TR. Diabetes Care. 214;37(1): Gonder-Frederick LA. Diabet Med. 213;3(5): Adapted from ADA. Diabetes Care. 218: 41(1):S Leveraging the Incretin Effect of GLP-1 Central nervous system Promotes satiety and reduction of appetite GLP-1 Receptor Agonists Excess glucose production Liver: glucagon reduces hepatic glucose output Glucagon excess α-cell glucagon secretion post-meal Impaired beta-cell function Enhances glucose-dependent insulin secretion and β-cell functional mass Stomach Regulates gastric emptying Flint A, et al. J Clin Invest. 1998;11(3): Larsson H, et al. Acta Physiol Scand. 1997;16(4): Nauck MA, et al. Diabetologia. 1996;39(12): Drucker DJ. Diabetes. 1998;47(2):

9 FDA Approved GLP-1 RAs GLP-1 RAs Added to Metformin Medication Exenatide BID Lixisenatide Liraglutide Exenatide QW Trade name Duration Adverse Events Dosing Byetta Adlyxin Victoza Bydurion Short-acting Long-acting Nausea, vomiting, dyspepsia Nausea, vomiting, diarrhea, headache Nausea, vomiting, diarrhea, headache, dyspepsia, fatigue Nausea, diarrhea, headache, dyspepsia, vomiting Dulaglutide Trulicity Nausea, diarrhea, vomiting Semaglutide Ozempic Nausea, vomiting, diarrhea, constipation, abdominal pain Start 5 mcg twice daily (1 h before morning and evening meals), may increase to 1 mcg after 1 mo Start 1 mcg daily (1 h before 1 st meal of day), may increase to 2 mcg daily after 14 d Start.6 mg once daily, may increase to 1.2 mg after 1 wk. Max dose 1.8 mg daily 2 mg once wk Start.75 mg once weekly, may increase to 1.5 mg once wk Start.25 mg once wk, may increase to.5 mg once wk. Max dose 1 mg wk Δ HbA1c,% EXE BID EXE QW PLB LIRA 1.8 mg PLB LIXI EXE BID -1 P< P = NI DULA 1.5 DULA.75 mg mg -.71 P<.1 SITA -.32 SEMA.5 DULA.75 SEMA 1 mg mg mg DULA 1.5 mg Byetta. Summary of Product Characteristics; 2. Lyxumia. Summary of Product Characteristics; 3. Victoza. Summary of Product Characteristics; 4. Marbury T et al. Diabetes 214;63(Suppl.1):A26(11-P); 5. Kapitza C et al. J Clin Pharm 215;55:497 54; 6. Barrington et al. Diabetes Obes Metab 211;13: ; 7. Fineman M et al. Clin Pharmacokinet 211;5:65 74; 8. Ozempic prescribing information; 9. Trulicity prescribing information. P<.1 P< NI = non-inferior P<.1 DeFronzo RA, et al. Diabetes Care. 25;28(8):192-11; (2) Bergenstal RM, et al. Lancet. 21;376: (3) Nauck M, et al. Diabetes Care. 29;32(1):84-9. (4) Ahren B, et al. Diabetes Care. 214;37(8): (5) Weinstock RS, et al. Diabetes Obes Metab 215; 17:849. (6) Rosenstock J. Diabetes Care. 213 Oct;36(1): (7) Pratley R, et al. Lancet Diabetes Endocrinol GLP-1 RAs: Comparative Change in Weight Advantages of GLP-1 RAs Baseline Weight avg 95 LEAD-6 Duration-1 Duration-6 AWARD-1 AWARD-6 LIRA-LIXI SUSTAIN-7 Change in Weight (kg) p= p=.89 p=.1 Buse JB et al. Lancet. 29;374:39 47 (LEAD-6); Drucker DJ et al. Lancet. 28;372:124 5 (DURATION-1); (3) Buse JB et al. Lancet. 213;381: (DURATION-6); Pratley RE et al. Lancet Diabetes Endocrinol. 214;2: (Harmony-7); Wysham C et al. Diabetes Care. 214;37(8): (AWARD-1); Dungan KM et al. Lancet. 214; 384(9951): (AWARD-6). Nauck M et al. Diabetes Care. 216 Sep;39(9):151-9; Pratley R, et al. Lancet Diabetes Endocrinol. 218 (SUSTAIN 7) p= p< p< p<.1 Liraglutide 1.8 mg Exenatide 1 µg BID Exenatide 2 mg QW Dulaglutide 1.5 mg Lixisenatide Semaglutide 1. mg Lower HbA1c (1-2%)¹ Lower rates of Hypoglycemia Weight loss (2-5 kg)¹ Decreased post-prandial glucose (more with short-acting agents)¹ Decrease cardiovascular risk factors (blood pressure, lipids, hs-crp) Drucker DJ, Nauck MA. Lancet. 26;368(9548): ; Baggio LL, Drucker DJ. Gastroenterology. 27;132(6): ; American Diabetes Association. Diabetes Care. 215;38(suppl MA.. 1):S41-S48.

10 Cardiovascular Benefit of GLP-1 RAs Lixisenatide (ELIXA) and exenatide (EXSEL) showed no adverse CV outcomes Liraglutide (LEADER) and Semaglutide (SUSTAIN-6) showed CV benefit Albiglutide (Harmony Outcomes) showed CV benefit Not being marketed in the US Dulaglutide (REWIND) ongoing trial Pfeffer MA, et al. N Engl J Med. 215;373: cardiovascular-safety.html; Accessed January 17, 217. Marso SP, et al. N Engl J Med. 216;375(4): Marso SP, et al. N Engl J Med. 216;375(19): , Hernandez, A, et al. Lancet. Oct 2, 218. DOI: GLP-1 Contraindications and Warnings Warning/ contraindication Do not use if history of MTC or MEN2 History of pancreatitis Increased risk of hypoglycemia with secretagogues/ insulin Serious Hypersensitivity Exenatide BID (Byetta) Consider other agents Exenatide QW (Bydureon) Liraglutide (Victoza) Lixisenatide (Adlyxin) Dulaglutide (Trulicity) Semaglutide (Ozempic) X X X X Consider other agents Consider other agents Consider other agents Consider other agents Consider other agents X X X X X X X X X X X X Do not use if X X X severe GI disease MEN2, multiple endocrine neoplasia syndrome type 2; MTC, medullary thyroid carcinoma; GI, gastrointestinal Lixisenatide 5. Albiglutide 6) Dulaglutide 7. semaglutide Avoiding Nausea with GLP-1 RAs Renal Dosing of GLP-1 RAs Educate on meal size, eating pace, and dose timing relative to meals Short-acting GLP-1 RAs should be taken within 6 minutes before morning and evening meals Avoid taking a GLP-1 RA close to a large or high fat meal, as this may cause nausea Use incremental dose titration, particularly with shorter-acting agents Renal Status Mild impairment (CrCl 5-8 ml/min) Moderate impairment (CrCl 3-5 ml/min) Severe impairment (CrCl <3 ml/min) ESRD Exenatide BID (Byetta) Exenatide QW (Bydureon) No adjustment or recommendation Use caution when initiating or escalating doses Use with caution Should not be used Liraglutide (Victoza) No dose adjustment Use caution when initiating or escalating doses Semaglutide & Dulaglutide (Ozempic & Trulicity) No dose adjustment Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions Lixisenatide (Adlyxin) Use caution but no dose adjustment Renal transplant Use with caution Ellero C, et al. Diabet Med. 21;27(1): Adapted from prescribing information for Byetta, Bydureon, Victoza, Ozempic, Trulicity, Adlyxin.

11 Selecting the Ideal GLP-1 RA PPG Effect of Short- and Long-Acting GLP-1 RAs The selection of GLP-1 RA depends on individual pharmacokinetics/pharmacodynamics of each agent Long acting GLP 1 RAs dulaglutide, liraglutide, exenatide QW, semaglutide Have a preferential effect on lowering FPG Short acting agents lixisenatide and exenatide BID Have a preferential effect on lowering PPG Mean Change from Pre-Meal Plasma Glucose, mg/dl Liraglutide (Baseline) Lixisenatide (Baseline) Liraglutide (Day 28) Lixisenatide (Day 28) Meal GLP-1 RA Time Post Administration Holst JJ, Vilsbøll T. Diabetes Obes Metab. 213;15(1):3-14. Kapitza C, et al. Diabetes Obes Metab. 213;15(7): Patient Case of Uncontrolled T2DM John, age 6 HbA1c = 7.4% FPG = mg/dl PPG = 18 3mg/dL Metformin 1 mg BID Glargine 6 units Because John has elevated PPG, a short-acting GLP-1 RA is the best choice. John is receptive to adding a GLP-1 RA but asks if he really needs to also continue on the basal insulin as he is reluctant to have another daily injection Complementary Action Addresses Underlying Pathophysiologic Defects in T2DM 5 6% HbA1c goal attained Simple to initiate Modest weight gain Hypoglycemia risk lower than NPH Decreases FPG and nocturnal hypoglycemia Basal Insulin GLP 1 RAs 4 6% HbA1c goal attained Simple to initiate Weight loss No increase in hypoglycemia Decreases PPG (short acting) Little S, et al. Diabetes Technol Ther. 211:13(suppl 1):S53-S64; Cohen ND, et al. Med J Australia. 213;199(4): ; Carris NW, et al. Drugs. 214;74(18):

12 Approved Fixed-Ratio GLP-1 RA/Basal Insulin Formulations Drug Brand Name Insulin to GLP 1 RA Ratio Supplied As Insulin Glargine/Lixisenatide Soliqua 1 Unit/.33 mcg 3 ml prefilled pen 1/33 (iglarlixi) Insulin Degludec/Liraglutide 1/3.6 (ideglira) Xultophy 1 Unit/.36 mg 3 ml prefilled pen Less Frequent Injection = Improved Adherence Persistence With GLP-1 RA at 1 Year, % Once-daily injection 73 UK 64 Twice-daily injection Germany Accessed December 18, Accessed December18, Wilke T, et al. Diabetes Ther. 216;7:15-124; Garber AJ. Lancet Diabetes Endocrinol. 214;2: ; Kirkman MS, et al. Diabetes Care. 215;38: Effects of Lixisenatide, iglarlixi, and Glargine on Glucose Levels Difference (mg/dl) 95% CI Mean (95% CI) Change From Baseline (mg/dl) iglarlixi (n=468) FPG (-7.6,.7) (-4.5, -3.3) -59. Glargine (n=466) -27. Lixi (n=233) iglarlixi (n=468) Glargine affects FPG, Lixisenatide affects PPG Rosenstock J, Aronson R, Grunberger G, et al. Diabetes Care. 216;39(11): hr PPG Excursions (-45., -31.9) (8.1, 24.8) -3.2 Glargine (n=466) Lixi (n=233) iglarlixi in Insulin-Naive Patients with T2DM HbA1c (%) * iglarlixi 1/33 (n=469) 75% of patients achieved an HbA1c < 7% 32% of patients who achieved an HbA1c < 7% had no symptomatic hypoglycemia and did not gain weight Change From Baseline at Week 3 Glargine (n=467) *p<.1; p<.5; p<.1 compared with Glar/Lixi 1/33; PPG changes are mean for all three meals. Rosenstock J, Aronson R, Grunberger G, et al. Diabetes Care. 216;39(11): * Lixisenatide (n=234) Baseline Week 3 59% of patients achieved an HbA1c < 7% 19% of patients who achieved an HbA1c < 7% had no symptomatic hypoglycemia and did not gain weight 33% of patients achieved an HbA1c < 7%

13 iglarlixi Trials: Changes in Weight ideglira in Insulin Naive Patients With T2DM Change From Baseline at Week 26 Weight Change, kg Insulin-Naive Patients with T2DM iglarlixi 1/33 Glargine Lixisenatide P <.1 Weight Change, kg Patients with T2DM Not Controlled with Basal Insulin iglarlixi 1/ Glargine.7 % HbA1c ideglira 1/3.6 (n=833) 81% of patients achieved an HbA1c < 7% Degludec (n=413) 65% of patients achieved an HbA1c < 7% Liraglutide (n=414) 6% of patients achieved an HbA1c < 7% Baseline Week 3 Rosenstock J, Aronson R, Grunberger G, et al. Diabetes Care. 216;39(11): ; Aroda VR, et al. Diabetes Care. 216;39(11): Gough SC, et al. Lancet Diabetes Endocrinol. 214;2(11): ideglira in Insulin Naive Patients with T2DM Changes in Weight Initiating GLP-1 RA/Basal Insulin Therapy Weight Change, kg Insulin Naive Patients with T2DM ideglira 1/3.6 Degludec Liraglutide Weight Change, kg Patients with T2DM Not Controlled by Insulin ideglira 1/3.6 Degludec First: Down-titrate basal insulin dose Gough SC, et al. Lancet Diabetes Endocrinol. 214;2(11):

14 Initiating Insulin iglarlixi (Xultophy) Therapy Titrating iglarlixi (Xultophy) Pen Ratio of iglarlixi in 3 ml prefilled pen is 1 Unit/.33 mcg (1/33) The lowest possible dose of iglarlixi is 15 Units/5 mcg (for patients inadequately controlled on < 3 Units of basal insulin, insulin naive patients, or patients not controlled on lixisenatide) 3 Units/1 mcg starting dose for patients inadequately controlled on 3-6 Units of insulin daily Dose should be given 1 hour prior to 1 st meal of the day If FPG is above target, increase 2U every week If FPG is below target, decrease 2U every week Maximum dose is 6 U/2 mcg Accessed December 18, Accessed December 18, 217. Initiating Insulin ideglira (Soliqua) Therapy Titrating Insulin ideglira (Soliqua) Pen Ratio of ideglira in 3 ml prefilled pen is 1 Unit/.36 mg Recommended starting dose is 16 Units/.58 mg Regardless of whether patient was previously on insulin (even though the lowest possible dose is 1 Units/.36 mg) Regardless of the patients previous basal insulin dose If FPG is above target, increase 2 Units every 3-4 days If FPG is below target, decrease 2 Units every 3-4 days Maximum dose is 5 Units/1.8 mg Accessed December 18, Accessed December 18, 217.

15 Patient Case of Uncontrolled T2DM John returns after three months on 45 Units / 15 mcg of iglarlixi. John, age 6 Metformin 1 mg BID iglarlixi 45 U/ 15 mcg HbA1c = 6.6%. FPG = mg/dl PPG = mg/dl HbA1c = 6.6%. PPG = mg/dl. No hypoglycemic episodes. He has lost another 2 lbs and feels great.