Activity Overview

In this Webinar, experts in endocrinology and primary care present clinical evidence and answer participant questions regarding intensification with -like -1 receptor agonists (GLP-1 RAs) in the treatment of type 2 diabetes mellitus, pharmacologic differences among available GLP-1 RAs, and strategies to address barriers that may delay the initiation of insulin therapy. Target Audience

This activity is intended for family practice physicians, general practice physicians, internal medicine physicians, nurse practitioners, physician assistants, pharmacists, and endocrinologists.

1 Accreditation / Designation Statements

Med-IQ is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Med-IQ designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Med-IQ is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. 1.0 contact hour (0.1 CEU) of credit for pharmacists. ACPE #0476-0000-17-001-L01-P. This knowledge-based activity is designed for all pharmacists.

Accreditation / Designation Statements

AAPA accepts certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 1.0 hour of Category I credit for completing this program.

Nurses, nurse practitioners, and other healthcare professionals who successfully complete the activity will receive a Statement of Participation indicating the maximum credits available.

2 Disclosure Policy

Med-IQ requires any person in a position to control the content of an educational activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines “relevant financial relationships” as those in any amount occurring within the past 12 months, including those of a spouse/life partner, that could create a conflict of interest (COI). Individuals who refuse to disclose will not be permitted to contribute to this CME activity in any way. Med-IQ has policies in place that will identify and resolve COIs prior to this educational activity. Med-IQ also requires faculty to disclose discussions of investigational products or unlabeled/unapproved uses of drugs or devices regulated by the US Food and Drug Administration.

Disclosure Statement

The content of this activity has been peer reviewed and has been approved for compliance. The faculty and contributors have indicated the following financial relationships, which have been resolved through an established COI resolution process, and have stated that these reported relationships will not have any impact on their ability to give an unbiased presentation.

3 Disclosure Statements

Vivian Fonseca, MD, FRCP Consulting fees/advisory boards: AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Novo Nordisk, -aventis U.S. Inc., Takeda Pharmaceuticals North America, Inc.

Davida Kruger, MSN, APN-BC, BC-ADM Consulting fees/advisory boards: Abbott Laboratories, Dexcom, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Novo Nordisk, Sanofi-aventis U.S. Inc. Ownership interest (stocks/stock options – excluding mutual funds): Dexcom, Inc. Other (speakers bureau): Abbott Laboratories, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Dexcom, Inc., Janssen Pharmaceuticals, Lilly USA, LLC, Novo Nordisk, Valeritas, Inc.

The peer reviewers and other activity planners have no financial relationships to disclose.

Acknowledgment of Commercial Support This activity is supported by an educational grant from Sanofi US.

Copyright © 2017 Med-IQ®. All rights reserved.

4 Instructions to Receive Credit

To receive credit, read the introductory CME/CPE material, watch the Webinar, complete the post-survey, evaluation, and attestation online. To evaluate this activity, claim credit, and download your certificate, please visit: www.med-iq.com/a1035 and click on the “Credit” button.

Contact Information For questions or comments about this activity, please contact Med-IQ.

Call (toll-free) 866 858 7434 E-mail [email protected]

Please visit us online at www.Med-IQ.com for additional activities provided by Med-IQ®.

5 Learning Objectives

Upon completion, participants should be able to: • Describe the benefits and limitations of using an insulin/GLP-1 receptor agonist strategy for improving glycemic control and minimizing diabetes- related complications • Apply clinical evidence to choose treatment regimens that address the physiology of basal and prandial glycemic control • Outline strategies for overcoming patient and clinician barriers to the initiation or intensification of insulin therapy

Faculty

Vivian Fonseca, MD, FRCP Professor of Medicine Chief, Section of Endocrinology Tullis-Tulane Alumni Chair in Diabetes Tulane University New Orleans, LA

Davida Kruger, MSN, APN-BC, BC-ADM Certified Nurse Practitioner Division of Endocrinology, Diabetes, Bone and Mineral Disease Henry Ford Health System Detroit, MI

6 Activity Planners

Stephanie Larson, PhD Clinical Content Manager Med-IQ Baltimore, MD

Amy Sison Director of Continuing Medical Education Med-IQ Baltimore, MD

ADA and AACE Glycemic Targets

• HbA1C target should be Glycemic Control Targets individualized based on a Test ADA AACE number of factors including: HbA1C <7% ≤ 6.5% –Age FPG 80-130 mg/dL < 110 mg/dL – Life expectancy < 180 mg/dL < 140 mg/dL PPG (measured within (2-hour value) – Comorbidities 1-2 hours after the – Duration of diabetes start of a meal) – Risk of hypoglycemia – Patient motivation – Patient adherence

ADA. Diabetes Care. 2017;40:S48-56; Garber AJ, et al. Endocr Pract. 2016;22:84-113; Handelsman Y, et al. Endocr Pract. 2015;21:1-87.

7 HbA1C Levels in Patients With Diabetes

• Many patients with diabetes have HbA1C levels above the ADA- Total US Population recommended target of 7% With Diabetes • As T2DM progresses, maintaining 48% glycemic control becomes more HbA1C > 7% difficult and often requires insulin therapy 22% HbA1C > 8%

Ali MK, et al. N Engl J Med. 2013;368:1613-24; Kahn SE, et al. Lancet. 2014;383:1068-83; Casagrande SS, et al. Diabetes Care. 2013;36:2271-9; Maiorino MI, et al. Diabetes Care. 2017;40:614-24.

Decline in -Cell Function With Diabetes Progression 100

75

50

IGT Postprandial T2DM T2DM

-Cell Function, % 25 hyperglycemia phase I phase III  T2DM phase II 0 -12 -10 -6 -2 0 2 6 10 14 Years From Diagnosis

Dashed line shows extrapolation forward and backward from years 0 to 6 based on HOMA data from UKPDS.

Lebovitz H. Clin Chem. 1999;45:1339-53; UKPDS Group. Diabetes. 1995;44:1249-58.

8 T2DM

• T2DM is a complex, chronic disease characterized by multiple pathophysiologic abnormalities • Most classes of drugs have multiple sites of action, leading to increased antihyperglycemic efficacy • Combinations of oral and injectable therapies may be needed in T2DM patients to normalize glucose homeostasis, even those who are initially well controlled on monotherapy

Ferrannini E, et al. Eur Heart J. 2015;36:2288-96; ADA. Diabetes Care. 2017;40:S11-24.

Pathophysiologic Targets of T2DM Therapies

GLP-1 RA, DPP4-i, Insulin, SU TZD Pancreatic β-cells Adipocytes GLP-1 RA, ↓ Insulin release ↑ Lipolysis DPP4-i AGi, Pancreatic α-cells Intestine GLP-1 RA ↑ Glucagon secretion ↓ Incretin effect Hyperglycemia Liver ↑ Glucose production Kidneys Insulin, TZD, Glucose reabsorption MET, GLP-1 RA, DPP4-i Brain Muscle Neurotransmitter ↓ Glucose uptake SGLT2-i dysfunction Insulin, GLP-1 RA TZD

Ferrannini E, et al. Eur Heart J. 2015;36:2288-96.

9 ADA 2017 Guidelines for the Management of T2DM

Start With Monotherapy Unless: HbA1C ≥ 9%, consider Dual Therapy should be started at HbA1C ≥ 10%, BG ≥ 300 mg/dL, or patient is markedly symptomatic, consider Combination Injectable Therapy diagnosis unless there are If HbA1C target Monotherapy: Metformin contraindications not achieved Efficacy Hypoglycemia risk Weight Side effects after ~3 months, proceed to High Low Neutral/loss GI/lactic acidosis 2-drug Dual Therapy: Metformin + combination Basal insulin DPP4-i GLP-1 RA SGLT2-i SU TZD GLP-1 RA or basal insulin should be Efficacy Highest Intermediate High Intermediate High High considered early in the course of Hypoglycemia risk High Low Low Low Moderate Low therapy Weight Gain Neutral Loss Loss Gain Gain Side effects Hypoglycemia Rare GI GUI, dehydration, fxs Hypoglycemia Edema, HF, fxs If HbA1C target not achieved Triple Therapy: Metformin + after Basal insulin + DPP4-i or GLP-1 RA or SGLT2-i or TZD DPP4-i + basal insulin or SGLT2-i or SU or TZD ~3 months, proceed to GLP-1 RA + basal insulin or SGLT2-i or SU or TZD SGLT2-i + basal insulin or DPP4-i or GLP-1 RA or SU or TZD 3-drug SU + basal insulin or DPP4-i or GLP-1 RA or SGLT2-i or TZD TZD + basal insulin or DPP4-i or GLP-1 RA or SGLT2-i or SU combination

• If HbA1C target not achieved after ~3 months, and patient is on (1) oral , move to basal insulin or GLP-1 RA, (2) GLP-1 RA, add basal insulin, or 3) optimally titrated insulin, add GLP-1 RA or mealtime insulin.

ADA. Diabetes Care. 2017;40:S64-74.

Basal Insulin and GLP-1 RAs: Barriers to Intensification Strategies • Provider barriers – Delay in initiating insulin therapy in patients with T2DM – Limited knowledge of GLP-1 RAs and how to choose among available GLP-1 RA therapies – Lack of experience with dose titration • Patient barriers – Reluctance to accept an insulin-based strategy for glycemic control • Self-blame/feeling of failure • Belief that insulin therapy is complicated • Fear of injections

Peyrot M, et al. Diabetes Care. 2005;28:2673-9; Peyrot M, et al. Diabetologia. 2003;46:A89; Polonsky WH, et al. Diabetes Care. 2005;28:2543-5.

10 DAWN Study: Provider Barriers

• The DAWN study examined provider and patient attitudes toward insulin therapy – US physicians are significantly more likely to delay insulin therapy than physicians in other countries (P < .05 or P < .001 for all comparisons), except India and Japan – Only approximately 50% of MDs and RNs believe that insulin has a positive effect on care

Peyrot M, et al. Diabetes Care. 2005;28:2673-9.

Polling Question 1: Initiating Insulin Therapy

I prefer to delay the initiation of insulin until it is absolutely necessary.

a. Strongly agree b. Agree c. Disagree d. Strongly disagree e. N/A

11 DAWN Study: Delaying Insulin Therapy Is Common in the US

“I prefer to delay the initiation of insulin until it is absolutely necessary”

47% 34% 68%

50% Nurse 42% Specialist physician

Overall US 59% General practitioner

0 20406080100 Percent of Respondents

Peyrot M, et al. Diabetes Care. 2005;28:2673-9.

Self-Reported Comfort Level for Managing Diabetes by Professional Category

80 Very comfortable 70 Somewhat comfortable 60 Somewhat uncomfortable Very uncomfortable 50 Unanswered 40 30 20

Number of Participants 10 0 General Specialty PGY3 PGY2 PGY1 Nurse Nurse Nurse faculty faculty resident resident resident > 10 yrs 6-10 yrs < 5 yrs Professional Category

Derr RL, et al. Diabetes Spectrum. 2007;20:177-85.

12 Patient Barriers

• The DAWN study demonstrated that in patients with T2DM who were not on insulin (n = 2,061): – 57% had anxiety about initiating insulin therapy – US patients were more likely to report a lower belief in insulin efficacya and self-blameb for insulin therapy than patients from any other country • A separate study of 708 patients with T2DM who were not on insulin found that: – 28% were unwilling to administer insulin even if prescribed – < 25% were “very willing” to begin insulin therapy

a Significant difference from Germany (P < .001), India (P < .01), Japan (P < .001), Scandinavia (P < .05), and Peyrot M, et al. Diabetologia. 2003;46:A89; Spain (P < .001). Peyrot M, et al. Diabetes Care. 2005;28:2673-9; b Significant difference from Australia, Germany, India, and the Netherlands (all P < .001). Polonsky WH, et al. Diabetes Care. 2005;28:2543-5.

Psychological Barriers to Insulin Therapy

• For many patients, initiating insulin therapy represents a failure in self-care – 48% of patients believed they were to blame for not following physician instructions • Other barriers to insulin use include: – Fear of injections – Belief that insulin use is complicated – Fear of loss of independence or a change in lifestyle – Stigma attached to needle use

Peyrot M, et al. Diabetologia. 2003;46:A89; Peyrot M, et al. Diabetes Care. 2005;28:2673-9.

13 Barriers to Initiating Insulin Therapy Among Privately Insured Patients—New Jersey, 2010

Risks/benefits not well explained

Inadequate health literacy

Side effects of injection

Hypoglycemia Initiated (n = 100) Doubt ability to adjust dose Did not initiate (n = 69)

Negative social impact

Negative job impact

Too painful

0 102030405060 Patients With T2DMa With Moderate to Extreme Concerns, %

Statistically significant factors influencing insulin use from a survey of 169 privately insured, insulin- naïve patients with poorly controlled T2DM; P < .05, not adherent vs adherent for all factors shown. aPercentages of omitted responses not shown. Karter AJ, et al. Diabetes Care. 2010;33:733-5.

Insulin Initiation Improves Quality of Life in T2DM

QOL P < .05

Physical complaints

Social worries

Worries about future P < .05 6 months after insulin initiation Before insulin initiation Fear of hypoglycemia P < .01

Dietary restrictions

P < .05 Daily struggles

0 20406080100 QOL Scorea

Results from 42 insulin-naïve older (mean age, 68.4 years) German adults with T2DM who initiated insulin with a structured diabetes education program. aHigher scores indicate better QOL. Braun A, et al. Patient Educ Couns. 2008;73:50-9.

14 Assessing and Addressing Common Patient Concerns • Many patients fear: – Needles – Painful injections – Hypoglycemia – Weight gain – Adverse effects on lifestyle – Loss of personal freedom and independence – Complications caused by insulin – Effects on relationships with family and friends • Additionally, patients may believe that taking insulin means their diabetes has gotten worse or may think that needing insulin indicates a personal failure

Funnell MM, et al. Diabetes Educ. 2004;30:274-80.

Patient Engagement: Assessment Questions • What is your greatest concern about your diabetes? • What is the hardest thing for you in taking care of your diabetes? • How satisfied are you with your current therapy for diabetes? • How satisfied are you with your current level of glucose control? • What do you need to know to consider insulin therapy? • What is your biggest fear about insulin? • What problems do you think you will encounter? • What do you see as the most negative? • What do you see as the most positive? • What support do you have to overcome barriers? • Are you willing to start insulin? If not, what would cause/help you to start taking insulin?

Funnell MM, et al. Diabetes Educ. 2004;30:274-80.

15 Overcoming Patients’ Fear of Injection

• Perform “dry run” injection – Insert needle without injecting any drug • Administer the first injection in the office • Use the smallest needle possible • Present injection as a relatively painless process – Injection is into fatty tissue, not muscle (like an intramuscular vaccine) • Discuss injection technique – Injection devices are quick and easy to use – Have a pen available for demonstration

Kruger DF, et al. Diabetes Metab Syndr Obes. 2015;8:49-56.

Polling Question 2: Insulin Intensification Strategy

When a patient on basal insulin therapy is not achieving glycemic goals, which of the following is your preferred strategy for intensifying therapy?

a. Add a GLP-1 RA b. Add oral noninsulin therapy c. Add prandial insulin d. Titrate insulin e. Other

16 Therapeutic Options in Patients Not Achieving Glycemic Goals With Basal Insulin

Initiate Basal Insulin Usually with metformin +/- other noninsulin agent

If HbA1C not controlled, consider combination injectable therapy

Add 1 rapid-acting Add GLP-1 RA Change to premixed insulin insulin injection If not tolerated or HbA1C target twice daily (before before largest meal not reached, change to 2-injection breakfast and supper) insulin regimen If HbA1C not controlled, If HbA1C not controlled, If goals not met, consider changing advance to 3-injection advance to basal-bolus to alternative insulin regimen insulin regimen

Add ≥ 2 rapid-acting Change to premixed analog insulin injections before If goals not met, consider changing insulin 3 times daily meals (“basal-bolus”) to alternative insulin regimen (breakfast, lunch, supper)

ADA. Diabetes Care. 2017;40:S64-74.

Postprandial Hyperglycemia Persists After Basal Insulin Therapy

220 • 164 patients with baseline HbA1C > 7% (n = 44) HbA1C > 7.5% in 3-month HbA1C  7% (n = 120) 200 intensified forced titration program 180

• Mealtime hyperglycemia 160 persists after 3 months of intensive treatment 140 Glucose, mg/dL 120

100 6 8 10 12 14 16 18 20 22 24 Time, hours

Woerle HJ, et al. Diabetes Res Clin Pract. 2007;78:280-5.

17 When to Stop Titrating Basal Insulin and Consider Prandial Control Options for T2DM Patients

The individual is not meeting glycemic targets on basal insulin and:

FPG with Elevated Further HbA1C still not basal insulin is HbA1C despite increases in at goal with within target normal FPG basal insulin 0.5 units/kg/day range, but PPG with basal result in of basal insulin is persistently insulin hypoglycemia above goal

Inzucchi S, et al. Diabetes Care. 2012;35:1364-79; Davidson MB, et al. Endocr Pract. 2011;17:395-403.

Aggressive Basal Dose Titration May Increase Severe Hypoglycemia Without Improving HbA1C

Mean basal insulin dose, units/day

Mean HbA1C, % events/patient-year

Severe hypoglycemia, events/patient-year 0.13 Hypoglycemia, 0.15 0.08 Severe 0.05 0.1 0.03 0.02 0.05 0 78.1 80 74.9 9

69.6 Mean HbA1C,% 59.2 62.2 60 8 7.4 7.4 7.3

7.6 7.5

units/day 40 7

Mean Insulin Dose,Mean Insulin 0 6 120 110 100 90 80 FPG Goal, mg/dL 24-week randomized study, N = 4,824. Tanenberg RJ, et al. Diabetologia. 2006;55:A135.

18 When to Consider Combination Injectable Therapy for T2DM Patients Using Basal Insulin

Insulin is titrated to an Injectable Intensification with insulin acceptable FPG target therapy (prandial or premixed) (OR basal insulin dose options is > 0.5 units/kg/day) OR AND Intensification with HbA1C remains above GLP-1 RA target

ADA. Diabetes Care. 2017;40:S64-74.

Basal Insulin and GLP-1 RAs: Benefits • GLP-1 RAs increase insulin secretion in a glucose-dependent manner, suppress glucagon secretion, and delay gastric emptying through their activation of the GLP-1 receptor • GLP-1 RA therapies effectively control glycemia and are not associated with weight gain or hypoglycemia • Improvements in cardiovascular markers including blood pressure, triglycerides, and low-density lipoprotein cholesterol are also associated with GLP-1 RA therapy

Balena R, et al. Diabetes Obes Metab. 2013;15:485-502.

19 Benefits of Adding a GLP-1 RA to Basal Insulin vs Adding Prandial Insulin

Intensification with insulin (prandial or premixed) • More injections Insulin is titrated to an • Increased risk of hypoglycemia Injectable acceptable FPG target • Increased body weight therapy (OR basal insulin dose • Increased SMBG options is > 0.5 units/kg/day) Intensification with GLP-1 RA AND • Fewer injections HbA1C remains • Complementary pharmacologic profile to insulin, above target especially with short-acting agents • Lower risk of hypoglycemia (vs insulin) • Decreased body weight • Less SMBG (vs insulin) • Large postprandial benefit, especially with short- acting agents

ADA. Diabetes Care. 2017;40:S64-74; Ahluwalia R, et al. Diabetes Ther. 2011;2:146-61; Inzucchi SE, et al. Diabetes Care. 2012;35:1364-79; Carris NW, et al. Drugs. 2014;74:2141-52.

GLP-1 RAs Improve Glycemic Control in Patients With T2DM

P = NS P < .001 P = NS P = NS P = .010 P = .0039 P = NS P < .0001 P < .0001 90 84 81 80 78 77 69 70 65 61 60 59 60 57 58 50 49 50 45

40 35 30 30 25

20 14 Percentage Achieving Percentage Achieving HbA1C < 7% 10

0 vs BBT* Exenatide vs FRC vs BBT vs BBT Exenatide QW vs vs BBT Liraglutide FRC Liraglutide vs placebo* vsvs glargineGLAR exenatide BID vsvs degludec DEG placebo GLP-1 RA Comparator

Diamant M, et al. Diabetes Care. 2014;37:2763-73; Mathieu C, et al. Diabetes Obes Metab. 2014;16:636-44; Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2:885-93; Rosenstock J, et al. Diabetologia. 2014;57:abstr 241; Blonde L, et al. Lancet. 2015;385:2057-66; Buse JB, et al. Ann Intern Med. 2011;154:103-12; Ahmann A, et al. Diab Obes Metab. 2015;17:1056-64; Drucker DJ, et al. Lancet. 2008;372:1240-50; Rosenstock J, et al. Diabetes Care. 2014;37:2317-25.

20 GLP-1 RAs Improve Glycemia and Are Associated With Weight Loss and Reduced Insulin Dose • 7 RCTs and 15 clinical practice or observational studies including ≥ 30 patients with T2DM

10 130 150

130 9 120 110

8 90

HbA1C, % HbA1C, 110 70

7 kg Weight, Body Insulin Dose, units Insulin Dose, 50

6 100 30 Baseline Endpoint Baseline Endpoint Baseline Endpoint

GLP-1 RA added to insulin Insulin added to GLP-1 RA GLP-1 RA + insulin (sequence not specified)

Each line represents a study. Balena R, et al. Diabetes Obes Metab. 2013;15:485-502.

Head-to-Head Trials of GLP-1 RAs: Efficacy and Weight

LEAD-1 DURATION-5 DURATION-6 HARMONY 7 1 Noninferiority vs LIRA not met 0 -1 -0.8 -0.9 -0.8 -1.1 -1.3 -1.0 HbA1C, % HbA1C, -2 -1.6 -1.5 ∆ P < .05 P < .05 P < .05 P = .08 0 -0.6 -2 -1.4 -2.3 -2.7 -2.2 BW, kg BW, -2.9 -3.2 ∆ -4 -3.6 P < .05 P < .05 EXN BID 10 mcg • Occurrence of GI adverse effects is generally lower with longer-acting LIRA 1.8 mg agents (LIRA and EXN QW vs EXN BIDa; EXN QW and ALBI vs LIRA) EXN QW 2.0 mg • Injection-site reactions are more common with EXN QW and ALBI ALBI 50 mg aNausea rates initially similar for LIRA vs EXN BID, but rates Buse JB, et al. Lancet. 2009;374:39-47; Blevins T, et al. J Clin Endocrinol Metab. 2011;96:1301-10; were lower with LIRA (8%) vs EXN BID (16%) by week 6. Buse JB, et al. Lancet. 2013;381:117-24; Pratley R, et al. Lancet Diabetes Endocrinol. 2014;2:289-97.

21 GLP-1 RAs Significantly Lower PPG Levels 13 12

11 10 9 8 P < .001

Glucose, mmol/L P < .001 7 P < .001 P < .01 P < .001 P < .01 6 Pre 2 hr post Pre 2 hr post Pre 2 hr post 0300 h Morning Meal Midday Meal Evening Meal

Glargine + placebo, baseline Glargine + exenatide, baseline Glargine + placebo, week 30 Glargine + exenatide, week 30 Balena R, et al. Diabetes Obes Metab. 2013;15:485-502.

Polling Question 3: GLP-1 RA Selection

In your practice, what is your GLP-1 RA dosing frequency preference?

a. I prefer to prescribe a GLP-1 RA that is taken once daily b. I prefer to prescribe a GLP-1 RA that is taken once weekly c. I prefer to prescribe a GLP-1 RA that is taken twice daily d. N/A, I have no preference

22 Choosing the Appropriate GLP-1 RA to Achieve Patient Treatment Goals • GLP-1 RA biomedical factors – Targeting of FPG vs PPG – Duration of action – Body weight reduction – Severity of side effects • Patient psychosocial factors – Comfort with injections – Frequency of contact with healthcare provider – Meal pattern – Adherence

Kalra S. Diabetes Ther. 2014;5:333-40.

Comparison of Short-Acting vs Long-Acting GLP-1 RAs

Short-Acting GLP-1 RAs Long-Acting GLP-1 RAs Exenatide Lixisenatide Albiglutide Dulaglutide Exenatide-ER Liraglutide Half-life 2.4 hours 2-4 hours 6-7 days 5 days 2 weeks 13 hours Dosing Twice daily Once daily Once weekly Once weekly Once weekly Once daily Control of HbA1C Effective Control of FPG Suitable More suitable Control of PPG More suitable Suitable Body weight reduction 1-5 kg 2-5 kg Directly observed therapy Not feasible Feasible Injection-site reactions Rare Common; seldom for liraglutide GI symptoms More common Less common Increase in pulse rate Less common More common

Kalra S. Diabetes Ther. 2014;5:333-40; Pinelli NR, et al. Ann Pharmacother. 2011;45:850-60; ADA. Diabetes Care. 2017;40:S64-74; Anderson SL, et al. Ther Adv Chronic Dis. 2016;7:4-17; Murphy CE. Ann Pharmacother. 2012;46:812-21; Meier JJ. Nat Rev Endocrinol. 2012;8:728-42.

23 Changes in HbA1C Values in Head-to-Head GLP-1 RA Clinical Trials

Duration-1 Lead-6 Duration-5 Duration-6 GetGoal-X Harmony-7 Award-1 Award-6 0 -0.2

-0.4 Exenatide BID Exenatide QW -0.6 Liraglutide Lixisenatide -0.8 Albiglutide Dulaglutide 1.5 mg -1 P = NSa P = .846b * Dulaglutide 0.75 mg -1.2 P < .0001

-1.4 d

Change in HbA1C, % P = NS P = .02 P < .001c -1.6 d P < .0001 P = NS -1.8

-2 P < .0025

P values are for statistical superiority unless otherwise noted as noninferiority. aNoninferiority P value not reported (95% CI, 0.033-0.297, meeting predefined noninferiority margin). bNoninferiority P value (not meeting predefined noninferiority margin). cP value for both doses of dulaglutide vs exenatide BID. dNoninferiority P value < .0001 (meeting predefined noninferiority margin). Trujillo JM, et al. Ther Adv Endocrinol Metabl. 2015;6:19-28.

Changes in Weight in Head-to-Head GLP-1 RA Clinical Trials

Duration-1 Lead-6 Duration-5 Duration-6 GetGoal-X Harmony-7 Award-1 Award-6 0.2

-0.3

-0.8 Exenatide BID Exenatide QW -1.3 P < .001b,c Liraglutide P < .001b,c Lixisenatide -1.8 Albiglutide Dulaglutide 1.5 mg -2.3 P < .0001 Dulaglutide 0.75 mg P = NS -2.8 Change inkg Weight, -3.3 P = NS

-3.8 P = .0005 P = .011 P = NS P = NRa -4.3

P values are for statistical superiority unless otherwise noted as noninferiority. aP value not reported for weight difference of 1.02 kg (95% CI, 0.456-1.581). bP value vs dulaglutide 0.75 mg. cP value not significant between dulaglutide 1.5 mg vs exenatide BID. Trujillo JM, et al. Ther Adv Endocrinol Metabl. 2015;6:19-28.

24 FDA-Approved Basal Insulin/GLP-1 RA FRCs

• Two FRCs currently available – /liraglutide – /lixisenatide • Benefits – Better efficacy than either component given alone – Improved FPG and PPG levels – Lower rates of hypoglycemia and weight gain vs insulin monotherapy – Slow uptitration reduces GI effects vs GLP-1 RA alone – Simplified regimen may increase patient adherence • Limitations – Nausea remains problematic – Dose titration is required

Rosenstock J, et al. Diabetes Care. 2016;39:2026-35; Aroda VR, et al. Diabetes Care. 2016;39:1972-80; Gough S, et al. Lancet Diabetes Endocrinol. 2014;2:885-9; Buse JB, et al. Diabetes Care. 2014;37:2926-33.

Insulin Degludec/Liraglutide Phase 3 Clinical Trials

Dual I Dual II Dual III Dual IV Dual V Trial Number 3697 (pivotal) 3912 (pivotal) 3851 3951 3952 Objective IDegLira vs IDeg vs lira IDegLira vs IDeg IDegLira vs GLP-1 RA IDegLira vs IDegLira vs insulin (3-arm factorial study) with dose cap alone placebo glargine HbA1C entry criteria 7%-10% 7.5%-10% 7%-9% 7%-9% 7%-10% Blinding Open Blind Open Blind Open Control Active Active Active Placebo Active (IDeg and lira) (IDeg) (exenatide and lira) (glargine) Duration 26 weeks + 26 weeks 26 weeks 26 weeks 26 weeks 26-week extension Background therapy MET ±PIO MET MET ±SU ±PIO MET ±SU MET Randomization ratio 2:1:1 1:1 2:1 2:1 1:1 (IDegLira:IDeg:lira) Population Add on to OAD Previous insulin users Previous GLP-1 Add on to OAD Previous insulin Insulin naïve analog users Insulin naïve users Hypothesis test Noninferiority to IDeg and Superiority Superiority Superiority Noninferiority superiority to lira

IDeg = insulin degludec; IDegLira = insulin degludec and liraglutide; lira = Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2:885-93; Buse JB, et al. liraglutide. Diabetes Care. 2014;37:2926-33; Linjawi S, et al. Diabetes Ther. 2017;8:101-14; MET ≥ 1,500 mg/day or maximum tolerated dose; PIO ≥ 30 mg/day; SU at 1/2 Rodbard HW, et al. Diabet Med. 2017;34:189-96; Lingvay I, et al. JAMA. 2016;315:898- max of approved dose. 907; Gough SC, et al. Diabetes Obes Metab. 2015;17:965-73.

25 DUAL I: Insulin Degludec/Liraglutide vs Degludec vs Liraglutide • Degludec/liraglutide FRC 8.5 Liraglutide (n = 414) significantly reduces HbA1C Degludec (n = 413) and body weight vs degludec 8.0 Degludec/liraglutide FRC (n = 833) and liraglutide given alone (all P < .0001) 7.5 • Rates of hypoglycemia lower 7.0 7.0% HbA1C, % HbA1C, with degludec/liraglutide FRC 6.9% vs degludec alone 6.5 6.4%

0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time, weeks

Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2:885-93.

DUAL I: Rates of Nausea Over Time

12

10 Insulin degludec/liraglutide 8 Insulin degludec Liraglutide 6

4

2 Percentage of Patients Percentage of 0 0 4 8 12 16 20 24 26 Time, weeks

Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2:885-93.

26 DUAL III: Insulin Degludec/Liraglutide vs Unchanged GLP-1 RA

• Degludec/liraglutide FRC HBA1C Over Time 8.0 significantly reduces HbA1C vs unchanged 7.5 7.4% GLP-1 RA (P < .001) • FRC associated with 7.0 6.4% significant increase in 6.5 weight vs GLP-1 RA (P < % HbA1C, 6.0 Insulin degludec/liraglutide (n = 292) .001) Unchanged GLP-1 RA (n = 146) 0.05.5 -202468101214161820222426 Time, weeks

Linjawi S, et al. Diabetes Ther. 2017;8:101-14.

DUAL IV: Insulin Degludec/Liraglutide vs Placebo • Degludec/liraglutide FRC 8.5 significantly reduces HbA1C 8.0 over time vs placebo (treatment difference, 1.02%; 7.5 7.4% P < .0001) 7.0 • Greater reduction in mean 9- HbA1C, % HbA1C, 6.5 point SMBG profile with FRC 6.4% 6.0 Insulin degludec/liraglutide (n = 289) vs placebo (treatment Placebo (n = 146) difference, 1.55 mmol/L; 0.05.5 P < .001) -202468101214161820222426 Time, weeks

Rodbard HW, et al. Diabet Med. 2017;34:189-96.

27 Insulin Glargine/Lixisenatide vs Glargine

8.5 Glargine + Glargine lixisenatide

8.0 Glargine (n = 162) SE, % SE, % Glargine + lixisenatide (n = 161) ± 7.5

7.0

6.5 6.5% 6.3% LS Mean HbA1C Change, %

HbA1C MeanHbA1C Change 6.0 Sc 0 8 12 24 24 P = .0130 Time, weeks LS mean difference glargine/lixisenatide vs glargine = -0.17% (95% CI, -0.312 to -0.037)

Rosenstock J, et al. EASD 2014. Vienna, Austria. Abstract 241.

Get Goal Duo-2: Lixisenatide Plus Basal Insulin vs Insulin Glulisine (Basal-Plus or Basal-Bolus)

Insulin glargine ± metformin Insulin glargine ± lixisenatide QD OR insulin glulisine ±metformin QD OR insulin glulisine TID

10.0 86 2 Lixisenatide QD + insulin glargine

Lixisenatide QD + mmol/mol HbA1C, SE ± Mean Insulin glulisine QD + insulin glargine insulin glargine (n = 297) Insulin glulisine TID + insulin glargine 9.5 Insulin glulisine QD + 80 1.4 (0.3) insulin glargine (n = 298) 1 1.0 (0.3) 9.0 Insulin glulisine TID + 75 insulin glargine (n = 295) 8.5 8.5% 69 0 8.0 7.9% 64

7.8% -0.6 (0.3) 7.5 7.8% 7.2% 58 7.7% 7.2% kg Weight, Body -1 Mean ± SE HbA1C, % 7.0 53 Mean ± SE Change in 7.0% 6.5 48 -2 -16 -12 -8 -4 0 4 8 12 16 20 24 Week 2 6 8 12 20 26 26 Screening Baseline 26 Baseline (LOCF) Time, weeks (LOCF) Time, weeks • Patients receiving lixisenatide were twice as likely to achieve HbA1C < 7% without weight gain or documented symptomatic hypoglycemia Rosenstock J, et al. Diabetes Care. 2016;39:1318-28.

28 Insulin Glargine/Lixisenatide vs Lixisenatide vs Glargine A 0.0 8.5 iGlarLixi 69

iGlar mmol/mol HbA1C, SE ± Mean -0.2 Lixi 8.0 64 -0.4 -0.6 7.5 58 -0.8 -0.85

7.3% -1.0 7.0 53 -1.2 6.8% -1.3 Mean ± SE HbA1C, % 6.5 48 -1.4 6.5% LS Mean Change in HbA1C, HbA1C, Change in % LS Mean -1.6 iGlarLixi -1.6 iGlar 6.0 42 Lixi S BL 8 12 20 30 30 -1.8 P < .0001 (LOCF) Time, weeks P < .0001

Rosenstock J, et al. Diabetes Care. 2016;39:2026-35.

Insulin Glargine/Lixisenatide vs Lixisenatide vs Glargine

0 0 240 13 -3.2 LS Mean Change in 2-Hour PPG -20 -1 220 Change in 7-Point SE Mean ± -41.7 [-0.2] 12 [-2.3] -2 -58.1 Excursion, mmol/L Baseline -40 200 11 [-3.2] -3 mmol/L SMBG, -60 180 10 -38.4* -4 -80 9 95% CI, -45.0 to -31.9 160

-5 mg/dL [-2.1*]

-100 Change in 8 -6 Mean ± SE 140

[95% CI, -2.5 to -1.8] 7-Point SMBG, -120 P < .0001 7 Excursion, mg/dL -7 Week 30 120 iGlarLixi 6 -140 -16.4* -8 100 95% CI, 8.1 to 24.8 iGlar LS Mean Change in 2-Hour PPG 2-HourChange in LS Mean [+0.9*] Lixi 5 -160 -9 80 [95% CI, 0.4 to 1.4] Pre- 2 hours Pre- 2 hours Pre- 2 hours Bedtime -180 -10 breakfast post- lunch post- dinner post- iGlarLixi breakfast lunch dinner iGlar Lixi

Rosenstock J, et al. Diabetes Care. 2016;39:2026-35.

29 Basal Insulin/GLP-1 RA FRCs

• Insulin degludec/liraglutide 100/3.6 – 1 dose step = 1 unit of insulin degludec + 0.036 mg of liraglutide – 16 dose steps = 16 units of degludec + 0.6 mg of liraglutide – 32 dose steps = 32 units of degludec + 1.2 mg of liraglutide – 50 dose steps = 50 units of degludec + 1.8 mg of liraglutide

• Insulin glargine/lixisenatide 100/33 – 15 units of insulin glargine + 5 mcg lixisenatide – 30 units of glargine + 10 mcg lixisenatide – 60 units of glargine + 20 mcg of lixisenatide

Prescribing information for individual agents.

Basal Insulin/GLP-1 RA FRCs: Dosing and Titration

Product Starting Dose Dose Range Titration Every 3 to 4 days Lowest dose: Insulin degludec/ Above target: + 2 units 16 units/0.58 mg 10 units/0.36 mg liraglutide 100/3.6 Within target: 0 units Max dose: 50 units/1.8 mg Below target: -2 units 15 units/5 mcg Weekly (if < 30 units basal Lowest dose: Above target: + 2 units Insulin glargine/ insulin or lixisenatide) 15 units/5 mcg Within target: 0 units lixisenatide 100/33 30 units/10 mcg Max dose: (if 30-60 units 60 units/20 mcg Below target: -2 units basal insulin)

Prescribing information for individual agents.

30 Safety Considerations: GLP-1 RAs

Albiglutide Dulaglutide Exenatide BID Exenatide QW Liraglutide Lixisenatide Thyroid C-cell tumors in preclinical studies; do not use if personal or family history of XX X X MTC or MEN2 Prior severe hypersensitivity to agent XX X X X Discontinue if pancreatitis is suspected XXX XXX Not recommended for patients with preexisting or severe GI XX X X disease Use caution in patients with X X X renal impairment (Not recommended (Not recommended (Not recommended XXin patients with in patients with X in patients with severe renal severe renal end-stage renal impairment impairment disease [eGFR [CrCl < 30 mL/min]) [CrCl < 30 mL/min]) < 15 mL/min]) Adverse events: GI (nausea, diarrhea, vomiting), XXX XXX injection-site irritation

Prescribing information for individual agents.

Conclusions

• Basal insulin and GLP-1 RAs have different and complementary mechanisms of action that result in the improvement of both FPG and PPG control • Clinical trials demonstrate the efficacy of a basal insulin/GLP-1 RA combination in the management of T2DM • FRCs allow greater ease of use of a basal insulin/GLP-1 RA combination in one injection • Addressing patient concerns about injections and discussing the efficacy of combination insulin and GLP-1 RA therapy can help mitigate barriers to injectable treatment for T2DM

31 Question/Answer Session With Faculty

Please continue on with the activity to complete the post-survey and receive the instructions to claim CME/CPE credit.

© 2017 Unless otherwise indicated, photographed subjects who appear within the content of this activity or on artwork associated with this activity are models; they are not actual patients or doctors.

32 Abbreviations and Acronyms

AACE = American Association of Clinical Endocrinologists LOCF = last observation carried forward ADA = American Diabetes Association LS = least squares AGi = alpha‐glucosidase inhibitor MEN2 = multiple endocrine neoplasia type 2 BBT = basal insulin glargine, bolus , and metformin therapy MET = metformin BG = blood glucose MTC = medullary thyroid carcinoma BID = twice daily OAD = oral antidiabetic drug BW = body weight PIO = CrCl = creatinine clearance PPG = postprandial glucose DDP4‐i = dipeptidyl‐peptidase 4 inhibitor QD = daily eGFR = estimated glomerular filtration rate QOL = quality of life ER = extended release QW = once weekly FDA = Food and Drug Administration RA = receptor agonist FPG = fasting plasma glucose RCT = randomized controlled trial FRC = fixed‐ratio combination SE = standard error fxs = fractures SGLT2‐i = sodium‐glucose cotransporter 2 inhibitor GI = gastrointestinal SMBG = self‐monitoring of blood glucose GLP‐1 = glucagon‐like peptide‐1 SMPG = self‐monitoring of plasma glucose GUI = genitourinary infections SU = HbA1C = hemoglobin A1C T2DM = type 2 diabetes mellitus HF = heart failure TID = three times daily HOMA = homeostasis model assessment TZD = IGT = impaired glucose tolerance UKPDS = United Kingdom Prospective Diabetes Study US = United States

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