in the participant guide, please see important safety information, including boxed warning about...

In the Participant Guide, please see Important Safety Information, including Boxed Warning about possible thyroid tumors including thyroid cancer, the Full Prescribing Information, and Medication Guide.

This program is sponsored by and the speaker is presenting on behalf of Lilly USA, LLC.

It is being presented consistent with FDA guidelines and is not approved for continuing education credit.

1


The goal of this program is to review information pertinent to the topic and answer your questions.

For questions that directly relate to this topic and/or are consistent with product labeling, I will respond during the program. For all other questions, I will be glad to talk with you individually at the conclusion of the program.

2

Trulicity: A case study

in treating adult patients

with type 2 diabetes

WELCOME

3In the Participant Guide, please see Important Safety Information, including Boxed Warning about possible thyroid tumors including thyroid cancer, the Full Prescribing Information, and Medication Guide.

DG96638 06/2015 ©Lilly USA, LLC 2015. All rights reserved.


Indication

Trulicity™ (dulaglutide) is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) that is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitations of Use

• Not recommended as first-line therapy for patients inadequately controlled on diet and exercise because of the uncertain relevance of rodent C-cell tumor findings to humans. Prescribe only if potential benefits outweigh potential risks.

• Has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapy.

• Not for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. Not a substitute for insulin.

• Has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis. Not for patients with pre‐existing severe gastrointestinal disease.

• Has not been studied in combination with basal insulin.

4

Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015.


WARNING: RISK OF THYROID C-CELL TUMORS

In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure. It is unknown whether Trulicity causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined.

Trulicity is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with use of Trulicity and inform them of symptoms of thyroid tumors (eg, mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Trulicity.

Important Safety Information—Boxed Warning

5



Important Safety Information (continued)

Trulicity is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2, and in patients with a prior serious hypersensitivity reaction to dulaglutide or any of the product components.

Risk of Thyroid C-cell Tumors: Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 RA use in humans. If serum calcitonin is measured and found to be elevated or thyroid nodules are noted on physical examination or neck imaging, the patient should be further evaluated.

Pancreatitis: Has been reported in clinical trials. Observe patients for signs and symptoms including persistent severe abdominal pain. If pancreatitis is suspected, discontinue Trulicity promptly. Do not restart if pancreatitis is confirmed. Consider other antidiabetic therapies in patients with a history of pancreatitis.

Hypoglycemia: The risk of hypoglycemia is increased when Trulicity is used in combination with insulin secretagogues (eg, sulfonylureas) or insulin. Patients may require a lower dose of the sulfonylurea or insulin to reduce the risk of hypoglycemia.

6



Pathogenesis of type 2 diabetes

• The pathogenesis of diabetes is multifactorial

• Insulin resistance in muscle and liver and β-cell failure represent the core pathophysiologic defectsin type 2 diabetes

• In addition to the fat cell, the GI tract, the α-cell, kidneys, and brain all play important roles in developing glucose intolerance

7

GI = gastrointestinal.

Defronzo RA. Diabetes. 2009;58(4):773-795.

Hyperglycemia

Decreased incretin effect

Islet α-cell

Increased glucagon secretion

Increased hepatic glucose production

Increased lipolysis

Increased glucose

reabsorption

Decreased glucose uptakeNeurotransmitter

dysfunction

Decreased insulin secretion


American Diabetes Association/EASD and AACE: Recommend reviewing treatment ~3 months

8

treatment whenA1C goal not reached

Modify Maintaintreatment when

A1C goal is reached

AACE = American Association of Clinical Endocrinologists.

1. Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364-1379. 2. AACE/ACE Diabetes Guidelines, Endocr Pract. 2015;21(Suppl 1):1-87. 3. Inzucchi SE, et al. Diabetes Care. 2015;38(1):140-149.

Treatment guidelines recommend assessing patient progressin reaching goal approximately every 3 months and then1-3:


Patients are reluctant to initiate injectable therapies1-3

9

1. Joy SV. Diabetes Educ. 2008;34(suppl 3):54S-59S. 2. Öst LG. Behav Res Ther. 1991;29(4):323-332. 3. Rubin RR, et al. Diabetes Educ. 2009;35(6):1014-1022. 4. Korytkowski M. Int J Obesity. 2002;26(suppl 3):S18-S24. 5. Karter AJ, et al. Diabetes Care. 2010;33(4):733-735.

Patient beliefs

surrounding injectable therapies

Lifestyle burdens4,5

Indication of disease progression1,4

Feelings of failure and guilt for not adhering to previous treatment1,4

Fearful and anxious about injections1,3 • Fear of needles3 • Fear of painful injections3,5


Once-weekly Trulicity™: the molecule• A recombinant GLP-1 Fc fusion protein linking a human GLP-1 peptide analog

and a variant of a human IgG4-Fc fragment result in a 63-kDa molecule1 that met the following development goals2,3

10

Fc = fragment crystallization; IgG = immunoglobulin G. 1. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015. 2. Data on File. Eli Lilly and Company; 2014, TRU20140919A. 3. Umpierrez G, et al. Diabetes Obes Metab. 2011;13(5):418-425. 4. Trulicity [Instructions for Use]. Indianapolis, IN: Lilly USA, LLC; 2014.

– Once-weekly dosing1

• Extended plasma half-life (~5 days)

• Minimal renal clearance1

– Does not require reconstitution4

– Low immunogenicity1,2

• Percentage of patients who developed Trulicity antidrug antibodies in clinical studies was 1.6%1

GLP-1 analog

Linker

Modified IgG4-Fc domain



Hypersensitivity Reactions: Systemic reactions were observed in patients receiving Trulicity in clinical trials. Instruct patients who experience symptoms to discontinue Trulicity and promptly seek medical advice.

Renal Impairment: In patients treated with GLP-1 RAs, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, sometimes requiring hemodialysis. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. In patients with renal impairment, use caution when initiating or escalating doses of Trulicity and monitor renal function in patients experiencing severe adverse gastrointestinal reactions.

Severe Gastrointestinal Disease: Use of Trulicity may be associated with gastrointestinal adverse reactions, sometimes severe. Trulicity has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.

11


12

Meet Jim*Treatment considerations

Busy man in his

mid‐50s

Diabetes duration: 7 years

Currently on dual OAM

Takes small steps to manage diabetes

Frustrated he is not achieving diabetes

goals

Last visit A1C: 8.2%Goal A1C:

7.0%

Time to add therapy but…

He is reluctant to

move to injectable therapy

Family and career keep him going

Case study

Jim*

*Hypothetical patient. OAM = oral antihyperglycemic medication.Trulicity is not indicated for weight loss. Weight change was a secondary endpoint in clinical trials.



• Efficacy• Hypoglycemia• Weight• Major adverse reaction(s)• Cost

Add a DPP-4

inhibitor

Add a GLP-1 RA

Addinsulin

Given these considerations, what therapy might you add?

13

DPP-4 = dipeptidyl peptidase-4.


Once-weekly Trulicity compared to Januvia® (sitagliptin): AWARD-5Design: 104‐week, randomized, placebo‐controlled, double‐blind phase 3 study of adult patients with type 2 diabetes

Primary outcome measure: Noninferiority of Trulicity 1.5 mg to Januvia 100 mg on A1C change from baseline at 52 weeks

14

All patients underwent a metformin run-in period that lasted up to 11 weeks and continued throughout the study; other oral antihyperglycemic medications were discontinued. During a dose-finding portion of the study, seven doses of Trulicity were evaluated along with sitagliptin and placebo. Trulicity 1.5 mg and 0.75 mg were selected for further evaluation and those patients assigned to the doses and comparators continued forward in the study.

Recommended starting dose is 0.75 mg. Dose can be increased to 1.5 mg for additional glycemic control.

-11 0 52 104 108

Januvia 100 mg

Trulicity 1.5 mg

Januvia 100 mgPlacebo

Trulicity 0.75 mg

Me

tfo

rmin

Sa

fety

fo

llo

w-u

p

Treatment period Follow-upLead-in

Weeks

Trulicity (mg)0.250.50

1.0

2.03.0

Dose finding Primary time point Final time point

26

AWARD = Assessment of Weekly AdministRation of LY2189265 in Diabetes.

Nauck M, et al. Diabetes Care. 2014;37(8):2149-2158.

Diabetes Duration Years (Mean)

7

7

7

7


Trulicity showed superior A1C reduction* vs Januvia®1-3

15

†Multiplicity-adjusted 1-sided P value .001, for superiority of Trulicity compared to Januvia. Analysis of covariance using last observation carried forward (LOCF).

1. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015. 2. Data on file, Lilly USA, LLC. TRU20150203B. 3. Data on file, Lilly USA, LLC. TRU20150203A. 4. Dungan et al. Lancet. 2014;384:1349-1357.

Trulicity (0.75 mg)(n=281; Baseline A1C: 8.2%)

Januvia® (100 mg)(n=273; Baseline A1C: 8.0%)


-0.4

-0.2

0

-0.6

-1.6

-1.4

-1.2

-0.8

-1.0

Week 52

-0.4

-0.9†

-1.1†M

ean

A1

C c

hang

e fr

om b

asel

ine

(%)

Select Important Safety Information: Counsel patients regarding the risk of medullary thyroid carcinoma with Trulicity and the symptoms of thyroid tumors (eg, a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Patients with elevated serum calcitonin (if measured) and patients with thyroid nodules noted on physical examination or neck imaging should be referred to an endocrinologist for further evaluation.

Data represent least-squares (LS) mean ± standard error (SE).

*In clinical studies, the range of A1C reduction from baseline was 0.7% to 1.6% for the 0.75 mg dose and 0.8% to 1.6% for the 1.5 mg dose. 1,4

The most commonly reported treatment-emergent adverse events were gastrointestinal-related.1


Trulicity 1.5 mg helped 59% of patients, and Trulicity 0.75 mg helped 49% of patients achieve A1C 7%1,2

16

1. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015. 2. Data on file, Lilly USA, LLC. TRU20150203A. 3. Dungan KM et al. Lancet. 2014;384:1349-1357. 4. Umpierrez G. et al. Diabetes Care. 2014;37:2168-2176. 5. Giorgino F, et al. Presented at: American Diabetes Association Conference; San Francisco, CA: June 13-17, 2014. 6. Jendle J, et al. Presented at: American Diabetes Association Conference; San Francisco, CA; June 13-17, 2014.

100

60

70

80

90

40

0

10

20

30

50 49%*

52 weeks

59%*

33%

Select Important Safety Information: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Trulicity or any other antidiabetic drug.



Januvia® (100 mg)(n=273; Baseline A1C: 8.0%)

Pat

ient

s ac

hiev

ing

A1

C

7.0%

(%

)

In clinical studies, the percentage of patients achieving A1C 7% ranged from 37% to 69% for 0.75 mg and 53% to 78% for 1.5 mg.1,3-6

Data presented are secondary endpoints.

*P<0.001 Trulicity compared to Januvia.1


Once-weekly Trulicity showed weight reduction compared to Januvia® at 52 weeks1-3

17

1. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015. 2. Data on file, Lilly USA, LLC. TRU20141010A. 3. Data on file, Lilly USA, LLC. TRU20150203A.

Trulicity (1.5 mg)(n=279; Baseline Weight: 190.7 lb)

Trulicity (0.75 mg)(n=281; Baseline Weight: 188.5 lb)

Januvia (100 mg)(n=273; Baseline Weight: 189.2 lb)

Mea

n w

eig

ht c

hang

e fr

om b

asel

ine

(lb)

Select Important Safety Information: Pancreatitis has been reported in clinical trials. Observe patients for signs and symptoms including persistent severe abdominal pain. If pancreatitis is suspected discontinue Trulicity promptly. Do not restart if pancreatitis is confirmed. Consider other antidiabetic therapies in patients with a history of pancreatitis.

-10

0

-9

-8

-7

-6

-5

-4

-3

-2

-1

Data represent LS mean ± SE.

-6.0-6.8

-3.3

Trulicity is not indicated for weight loss. In AWARD studies 1-5, weight change was a secondary endpoint. Mean weight change was -6.8 lb to -2.0 lb at the 1.5 mg dose and -6.0 lb to +0.4 lb at the 0.75 mg dose.1


Incidence of hypoglycemia*

18

Documented symptomatic 1.1% 2.6% 5.6%

Severe hypoglycemia† 0 0 0

Trulicity 1.5 mg (n=304)

Trulicity™ 0.75 mg (n=302)

Placebo(n=177)

In a head-to-head study with Januvia

Add-on to metformin (26 weeks)

Select Important Safety Information: The risk of hypoglycemia is increased when Trulicity is used in combination with insulin secretagogues (eg, sulfonylureas) or insulin. Patients may require a lower dose of sulfonylurea or insulin to reduce the risk of hypoglycemia.

*For study description, see slide 14.


Documented symptomatic hypoglycemia was defined as 70 mg/dL glucose threshold. †Severe hypoglycemia is defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.


7


7

Trulicity 1.5 mg compared to Victoza® (liraglutide) 1.8 mg: AWARD-6

19

Design: 26‐week, randomized, open‐label comparator phase 3 study of adult patients with type 2 diabetes

Primary outcome measure: Noninferiority of Trulicity 1.5 mg vs Victoza 1.8 mg on A1C change from baseline at 26 weeks


Victoza 1.8 mg once daily + metformin

Trulicity 1.5 mg once weekly + metformin

-2 0 2 26 30

Met

form

in

Victoza titration period

Treatment periodLead-in

Randomization

Saf

ety

follo

w-u

p

Follow-up

Week

Final time point

Dungan KM, et al. Lancet. 2014;384(9951):1349-1357.


Trulicity 1.5 mg demonstrated comparable A1C reduction to Victoza® 1.8 mg at 26 weeks1

20

Consistent with product labeling, patients randomized to Victoza started at 0.6 mg/day in week 1, then were up-titrated to 1.2 mg/day in week 2 and to 1.8 mg/day in week 3.*American Diabetes Association recommended target goal. Treatment should be individualized.4 MMRM = mixed models, repeated measures.


Victoza (1.8 mg)(n=300; Baseline A1C: 8.1%)

LS m

ean

A1

C (

%)

±SE

8.2

8.0

7.8

7.4

7.2

7.0

6.8

6.6

6.4

7.6

Week 0 Week 8 Week 26Week 12

-1.42-1.36

Primary objective was noninferiority vs Victoza 1.8 mg at 26 weeks; MMRM analysis. Primary objective met: P.0001. Secondary endpoint of superiority was not met.

85% fewerinjections2

*

Recommended starting dose of Trulicity is 0.75 mg. Dose can be increased to 1.5 mg for additional glycemic control. In clinical studies the range of A1C reduction from baseline was 0.7% to 1.6% for the 0.75 mg dose and 0.8% to 1.6% for the 1.5 mg dose. 1,3

Select Important Safety Information: Use of Trulicity may be associated with gastrointestinal adverse reactions, sometimes severe. Trulicity has not been studied in and is not recommended for patients with a history of severe gastrointestinal disease (eg, severe gastroparesis).

1. Dungan KM, et al. Lancet. 2014;384(9951):1349-1357. 2. Data on file, Lilly USA, LLC. TRU20140919B. 3. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015. 4. American Diabetes Association. Diabetes Care 2015;38(Suppl. 1):S1-S93.

Most common side effects were gastrointestinal. They were nausea, diarrhea, vomiting, and dyspepsia.


Trulicity 1.5 mg helped 68% of patients achieve A1C 7% at 26 weeks1

21

Select Important Safety Information: Systemic hypersensitivity reactions were observed in patients receiving Trulicity in clinical trials. Instruct patients who experience symptoms to discontinue Trulicity and promptly seek medical advice.

Per

cen

tag

e o

f pa

tient

s ac

hiev

ing

A1C

7%

100

60

70

80

90

40

0

10

20

30

50

68%68%


Victoza® (1.8 mg)(n=300; Baseline A1C: 8.1%)

Recommended starting dose of Trulicity is 0.75 mg. Dose can be increased to 1.5 mg. In clinical studies, the percentage of patients achieving A1C 7% ranged from 37% to 69% for 0.75 mg and 53% to 78% for 1.5 mg.1-5

Consistent with product labeling, patients randomized to Victoza started at 0.6 mg/day in week 1, then were up-titrated to 1.2 mg/day in week 2 and to 1.8 mg/day in week 3.

1. Dungan KM, et al. Lancet. 2014;384(9951):1349-1357. 2. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015. 3. Umpierrez G. et al. Diabetes Care. 2014;37:2168-2176. 4. Giorgino F, et al. Presented at: American Diabetes Association Conference; San Francisco, CA: June 13-17, 2014. 5. Jendle J, et al. Presented at: American Diabetes Association Conference; San Francisco, CA; June 13-17, 2014.

Data presented are secondary endpoints.

Most common side effects were gastrointestinal. They were nausea, diarrhea, vomiting, and dyspepsia.


Once-weekly Trulicity 1.5 mg showed weight reduction at 26 weeks1

22

Consistent with product labeling, patients randomized to Victoza started at 0.6 mg/day in week 1, then were up-titrated to 1.2 mg/day in week 2 and to 1.8 mg/day in week 3.

1. Dungan KM, et al. Lancet. 2014;384(9951):1349-1357. 2. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015.

Trulicity (1.5 mg)(n=299; Baseline weight: 206.8 lb)

Victoza® (1.8 mg)(n=300; Baseline weight: 208.1 lb)

-10

0

-9

-8

-7

-6

-5

-4

-3

-2

-1

Mea

n w

eig

ht c

hang

e fr

om b

asel

ine

(lb)


Select Important Safety Information: There have been postmarketing reports of acute renal failure and worsening of chronic renal failure, sometimes requiring hemodialysis, in patients treated with GLP‐1 receptor agonists. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. In patients with renal impairment, use caution when initiating or escalating doses of Trulicity and monitor renal function in patients experiencing severe adverse gastrointestinal reactions.

-7.96

-6.39


Weight change was a secondary endpoint



23


Total hypoglycemia 6% 9%

Total hypoglycemia: Events/patient/year 0.5 0.3

Severe hypoglycemia† 0 0


Victoza 1.8 mg (n=300)

In a head-to-head study with Victoza® 1.8 mg Add-on to metformin (26 weeks)


Dungan KM, et al. Lancet. 2014;384(9951):1349-1357.

Documented symptomatic hypoglycemia was defined as 70 mg/dL glucose threshold. †Severe hypoglycemia is defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.

Setting expectations and starting once-weekly Trulicity



Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Trulicity or any other antidiabetic drug.

The most common adverse reactions reported in 5% of Trulicity-treated patients in placebo-controlled trials (placebo, Trulicity 0.75 mg, and Trulicity 1.5 mg) were nausea (5.3%, 12.4%, 21.1%), diarrhea (6.7%, 8.9%, 12.6%), vomiting (2.3%, 6.0%, 12.7%), abdominal pain (4.9%, 6.5%, 9.4%), decreased appetite (1.6%, 4.9%, 8.6%), dyspepsia (2.3%, 4.1%, 5.8%), and fatigue (2.6%, 4.2%, 5.6%).

Gastric emptying is slowed by Trulicity, which may impact absorption of concomitantly administered oral medications. Use caution when oral medications are used with Trulicity. Drug levels of oral medications with a narrow therapeutic index should be adequately monitored when concomitantly administered with Trulicity. In clinical pharmacology studies, Trulicity did not affect the absorption of the tested, orally administered medications to a clinically relevant degree.

25



Trulicity reduced fasting glucose levels1-3

26

104-week, randomized, placebo-controlled, double-blind phase 3 study of adult patients with type 2 diabetes treated with metformin 1500 mg. Primary objective was to demonstrate noninferiority of Trulicity 1.5 mg vs Januvia on A1C change from baseline at 52 weeks (-1.1% vs -0.4%, respectively; difference of -0.7%; 95% CI [-0.9, -0.5]; multiplicity-adjusted 1-sided alpha level of 0.025 for noninferiority with 0.25% margin; analysis of covariance using last observation carried forward); primary objective met

Select Important Safety Information: Use of Trulicity may be associated with gastrointestinal adverse reactions, sometimes severe. Trulicity has not been studied in and is not recommended for patients with a history of severe gastrointestinal disease (eg, severe gastroparesis).

FP

G c

han

ge f

rom

ba

selin

e (m

g/dL

, L

S m

ean

± S

E)

10

-30

-20

0

-50

0 4 8 26 522Weeks

-40

A

12 39

-10

Trulicity (1.5 mg)(n=279; Baseline FPG: 173 mg/dL)

Trulicity (0.75 mg)(n=281; Baseline FPG: 174 mg/dL)

Placebo(n=139; Baseline FPG: 179 mg/dL)

Januvia® (100mg)(n=273; Baseline FPG: 171 mg/dL)

Data presented are secondary endpoints. Placebo was replaced with Januvia after26 weeks to keep blinding.

FPG = fasting plasma glucose. 1. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015. 2. Data on file, Lilly USA, LLC. TRU20150130A. 3. Data on file, Lilly USA, LLC. TRU20150203A.


Trulicity reduced 2-hour postprandial glucose levels1,2

27

1. Data on file, Lilly USA, LLC. TRU20140912F. 2. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015.

Pla

ceb

o-ad

just

ed L

S m

ean

chan

ge

from

ba

selin

e in

PP

G (

mg/

dL)

Trulicity (0.75 mg) (n=11)

Trulicity (1.5 mg)(n=9)

-20

-10

0

-30

-70

-60

-40

-50-39.8

-59.5

Select Important Safety Information: Trulicity slows gastric emptying, which may impact absorption of concomitantly administered oral medications. Use caution when oral medications are administered with Trulicity. Monitor drug levels of oral medications with a narrow therapeutic index when concomitantly administered. In clinical pharmacology studies, Trulicity did not affect the absorption of the tested, orally administered medications to a clinically relevant degree.

6-week, multicenter, parallel-design, double-blind, part-randomized, placebo-controlled, multiple-dose, phase 1 study in patients 65 years old with type 2 diabetes treated with oral antihyperglycemic medications except sulfonylureas, disaccharidase inhibitors, and meglitinides. Study arms included placebo (n=8); Trulicity 0.5 mg (n=9), not a marketed dose; Trulicity 0.75 mg (n=11); and Trulicity 1.5 mg (n=9). Primary objective was to evaluate the safety and tolerability of Trulicity 0.5 mg, 0.75 mg, and 1.5 mg for 6 weeks; mixed effect linear model; primary objective met. Data presented are secondary endpoints and show change in 2-hour postprandial plasma glucose concentration 48 hours after the first dose of Trulicity.

PPG = postprandial glucose.


Adverse reactions in placebo-controlled studies through 26 weeks, reported in 5% of Trulicity-treated patients

28


Nausea (%) 5.3 12.4 21.1

Vomiting (%)* 2.3 6.0 12.7

Diarrhea (%)* 6.7 8.9 12.6

Abdominal pain (%)* 4.9 6.5 9.4

Decreased appetite (%) 1.6 4.9 8.6

Dyspepsia (%) 2.3 4.1 5.8

Fatigue (%)* 2.6 4.2 5.6*Adverse reaction term represents 1 preferred MedDRA terms, clustered under a single, common term.Note: Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction.

Trulicity 1.5 mg(N=834)

Trulicity 0.75 mg(N=836)

Placebo(N=568)

Adverse reaction (through 26 weeks)

Select Important Safety Information: Pancreatitis has been reported in clinical trials. Observe patients for signs and symptoms including persistent severe abdominal pain. If pancreatitis is suspected discontinue Trulicity promptly. Do not restart if pancreatitis is confirmed. Consider other antidiabetic therapies in patients with a history of pancreatitis.


Common side effects your patient may experience

29


Select Important Safety Information: There have been postmarketing reports of acute renal failure and worsening of chronic renal failure, sometimes requiring hemodialysis, in patients treated with GLP-1 receptor agonists. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. In patients with renal impairment, use caution when initiating or escalating doses of Trulicity and monitor renal function in patients experiencing severe adverse gastrointestinal reactions.

The most common adverse reactions in clinical trials were GI in nature

32% for 0.75 mg

41% for 1.5 mg

21% for placebo

GI events were usually reported as mild or moderate

93% for 0.75 mg

90% for 1.5 mg

N/A

Discontinuation rates due to GI adverse reactions

1.3% for 0.75 mg

3.5% for 1.5 mg

0.2% for placebo

Use of Trulicity may be associated with gastrointestinal adverse reactions, sometimes severe. Trulicity has not been studied in and is not recommended for patients with a history of severe gastrointestinal disease (eg, severe gastroparesis).


1. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015. 2. Dungan KM et al. Lancet. 2014;384:1349-1357. 3. Umpierrez G. et al. Diabetes Care. 2014;37:2168-2176. 4. Giorgino F, et al. Presented at: American Diabetes Association Conference; San Francisco, CA: June 13-17, 2014. 5. Jendle J, et al. Presented at: American Diabetes Association Conference; San Francisco, CA; June 13-17, 2014.

When patients need additional A1C control, consider adding Trulicity along with diet and exercise

30

Trulicity offers your patients1

• Once-weekly dosing

• The Trulicity pen

• Proven glycemic control*

*In clinical studies, the range of A1C reduction from baseline was 0.7% to 1.6% for the 0.75 mg dose and0.8% to 1.6% for the 1.5 mg dose; the percentage of patients achieving A1C 7% ranged from 37% to 69% for 0.75 mg and 53% to 78% for 1.5 mg.1-5


Select Important Safety Information: Trulicity is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2.


Designed with your patients in mind1-3

31

Trulicity offers

• Once-weekly dosing

• No reconstitution required

• Hidden 29-gauge needle4

• No need to dial a dose

1. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015. 2. Trulicity [Instructions for Use]. Indianapolis, IN: Lilly USA, LLC; 2014. 3. Glaesner W, et al. Diabetes Metab Res Rev. 2010;26(4):287-296. 4. Data on file, Lilly USA, LLC. TRU20140918A. 5. Data on file, Lilly USA, LLC. TRU20140910L.

Please see Instructions for Use included with the pen.

In a study of 128 patients, caregivers, and healthcare providers, most people agreed the Trulicity pen was overall easy to use.5

Easy to use

94%Select Important Safety Information: Safety and effectiveness of Trulicity have not been established in pediatric patients. It is not recommended for use in patients younger than 18 years.


0.75 mg dose[NDC: 0002-1433-80]

Recommended starting dose

1.5 mg dose[NDC: 0002-1434-80]

Should your patientneed more glycemic control

Prescribing once-weekly Trulicity

There are 2 efficacious doses available• The recommended starting dosage of

Trulicity is 0.75 mg once a week• For patients requiring additional glycemic

control, the dosage may be increasedto 1.5 mg once a week

32


Select Important Safety Information: There are no adequate and well-controlled studies of Trulicity in pregnant women. Use only if the potential benefit outweighs potential risk to the fetus. It is not known whether Trulicity is excreted in human milk. A decision should be made whether to discontinue nursing or to discontinue Trulicity, taking into account the importance of the drug to the mother.



Pregnancy: There are no adequate and well-controlled studies of Trulicity in pregnant women. Use only if potential benefit outweighs potential risk to fetus.

Nursing Mothers: It is not known whether Trulicity is excreted in human milk. A decision should be made whether to discontinue nursing or to discontinue Trulicity, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of Trulicity have not been established and use is not recommended in patients less than 18 years of age.

Please see accompanying Participant Guide for Prescribing Information, including Boxed Warning about possible thyroid tumors including thyroid cancer, and Medication Guide.

Please see Instructions for Use included with the pen.

DG HCP ISI 20APR2015

33


Byetta® is a registered trademark of the AstraZeneca group of companies. Januvia® is a registered trademark of Merck & Co., Inc. Lantus® is a registered trademark of sanofi-aventis U.S. LLC. Trulicity™ is a trademark owned or licensed by Eli Lilly and Company, its subsidiaries or affiliates. Trulicity is available by prescription only. Victoza® is a registered trademark of Novo Nordisk A/S.

THANK YOU

34In the Participant Guide, please see Important Safety Information, including Boxed Warning about possible thyroid tumors including thyroid cancer, the Full Prescribing Information, and Medication Guide.

Appendix: overview of efficacy


Clinical trial program

36

*Titrated to FPG target of 100 mg/dL.Met = metformin; Pio = pioglitazone; SU = sulfonylurea; BG = blood glucose.

Active Comparator

Metformin(1500-2000 mg)

Januvia® (sitagliptin) 100 mg/d

Victoza®

(liraglutide) 1.8 mg/d Byetta®

(exenatide) 10 mcg BIDLantus®

(insulin glargine)Lantus

Background therapy None (monotherapy)

Met 1500 mg (titrated over

11-week lead-in)Met 1500 mg Met + Pio (maximally

tolerated doses)Met + SU (maximally

tolerated doses)Prandial insulin lispro

(titrated to BGtargets) ± met

Primary objective

Noninferiority of Trulicity 1.5 mg vs metformin on A1C change from

baseline at 26 weeks

Noninferiority of highest selected dose vs Januvia on A1C change from baseline at

52 weeks

Noninferiority of Trulicity 1.5 mg vs Victoza on A1C change

from baseline at 26 weeks

Superiority of Trulicity 1.5 mg vs placebo on A1C change


Noninferiority of Trulicity 1.5 mg vs Lantus* on A1C change


Noninferiority of Trulicity 1.5 mg vs Lantus* on A1C change


Study design Randomized, double-blind study

Randomized, placebo-controlled, double-blind study

Randomized, open-label

comparator study

Randomized, placebo-controlled

study with open-label assignments to Byetta or blinded assignment to Trulicity or placebo

Randomized, open-label comparator

study (double-blind with respect to Trulicity

dose assignment)

Randomized, open-label comparator

study (double-blind with respect to Trulicity

dose assignment)

Trial AWARD-31

(N=807) AWARD-51

(N=972)AWARD-62

(N=599)AWARD-11

(N=976)AWARD-21

(N=807)AWARD-41

(N=884)

Monotherapy

2-drug combinations Insulin3-drug combinations

1. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015. 2. Dungan KM, et al. Lancet. 2014;384(9951):1349-1357.


Select Important Safety Information: Systemic hypersensitivity reactions were observed in patients receiving Trulicity in clinical trials. Instruct patients who experience symptoms to discontinue Trulicity and promptly seek medical advice.

A1C reduction across trials at primary endpoint

37

1. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015. 2. Data on file, Lilly USA, LLC. TRU20150203A. 3. Data on file, Lilly USA, LLC. TRU20150203B. 4. Dungan KM, et al. Lancet. 2014;384:1349-1357. 5. Wysham C, et al. Diabetes Care. 2014;37:2159-2167. 6. Giorgino F, et al. Presented at: American Diabetes Association Conference; San Francisco, CA: June 13-17, 2014. 7. Data on file, Lilly USA, LLC. TRU20140912A. 8. Data on file, Lilly USA, LLC. TRU20150313A.

A1C

cha

nge

from

bas

elin

e (%

)

0

-1.8

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

-1.10

-0.39

-0.87

-1.51

-1.30

-0.99

-0.46

-1.08

-0.76

-0.63

Data represent LS mean±SE



Byetta (10 mcg BID)(n=276; Baseline A1C: 8.1%)

Placebo(n=141; Baseline A1C: 8.1%)



Lantus (n=262; Baseline A1C: 8.1%)

-1.42-1.36


Victoza (1.8 mg) (n=300; Baseline A1C: 8.1%)



Januvia (100 mg)(n=273; Baseline A1C: 8.0%)

Compared to Januvia®1-

3


Compared to Byetta®1,5

Add-on to metforminand pioglitazone

(26 weeks)

Compared to Lantus®1,6,7,8

Add-on to metformin and glimepiride

(52 weeks)

Compared to Victoza®4


*In clinical studies, the range of A1C reduction from baseline was 0.7% to 1.6% for the 0.75 mg dose and 0.8% to 1.6% for the 1.5 mg dose. 1,4


Patients may have the opportunity to lose weight while taking Trulicity to lower their A1C1

38

Trulicity is not indicated for weight loss. In AWARD studies 1-5, weight change was a secondary endpoint. Mean weight change was -6.8 lb to -2.0 lb at the 1.5 mg dose and -6.0 lb to +0.4 lb at the 0.75 mg dose1

Compared to Januvia®1-3


Compared to Byetta®1,5

Add-on to metformin and pioglitazone (26 weeks)

Compared to Lantus®1,6-8

Add-on to metformin and glimepiride (52 weeks)

Trulicity (1.5 mg)(n=279; Baseline weight:190.7 lb)

Trulicity (0.75 mg)(n=281; Baseline weight:188.5 lb)

Januvia (100 mg)(n=273; Baseline weight:189.2 lb)



Lantus(n=262; Baseline weight: 193.1 lb)

4

-10

0123

-9-8-7-6-5-4-3-2-1

Mea

n w

eigh

t cha

nge

from

bas

elin

e (lb

)



Byetta (10 mcg BID)(n=276; Baseline weight: 214.7 lb)

Placebo(n=141; Baseline weight: 207.5 lb)


Compared to Victoza®4



Victoza (1.8 mg)(n=300; Baseline weight: 208.1 lb)

-3.3

-6.8-6.0

-6.39

-7.96

-2.9

+0.4

-2.4

+2.6

-4.2-2.9

+3.1

Data represent LS mean±SE.

1. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015. 2. Data on file, Lilly USA, LLC. TRU20141010A. 3. Data on file, Lilly USA, LLC. TRU20150203A. 4. Dungan KM, et al. Lancet. 2014;384(9951):1349-1357. 5. Wysham C, et al. Diabetes Care. 2014;37(8):2159-2167. 6. Giorgino F, et al. Presented at: American Diabetes Association Conference; San Francisco, CA: June 13-17, 2014.7. Data on file, Lilly USA, LLC. TRU20140912B. 8. Data on file, Lilly USA, LLC. TRU20150313A.

Back-up slides


Epidemiology and burden of diabetes in the US

40

1. Centers for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014. 2. ADA. Diabetes by the Numbers. http://www.stopdiabetes.com/get-the-facts/diabetes-by-the-numbers.html. Updated October 24, 2014. Accessed May 5, 2015.

$245 BILLION IN 20121

29.1 MILLION OR ~1 IN 11 PEOPLE OF ALL AGES1DIABETES

AFFECTS

ESTIMATED COSTS

• Diagnosed: 21.0 million- 1.7 million 20 years of age newly diagnosed

in 2012- In adults, type 2 diabetes accounts for

~90-95% of all diagnosed cases of diabetes• Undiagnosed: 8.1 million

• Direct medical costs: $176 billion• Indirect societal costs: $69 billion

EVERY

19 SECONDS SOMEONE

isDIAGNOSED

WITHDIABETES2


American Diabetes Association/EASD general therapy recommendations in type 2 diabetes*

41

Trulicity™ has not been studied in combination with basal insulin.

HbA1C = glycated hemoglobin; DPP-4-i = dipeptidyl peptidase-4 inhibitor; EASD = European Association for the Study of Diabetes; fxs = fractures; GU = genito-urinary infections; HF = heart failure; SU = sulfonylurea; TZD = thiazolidinedione.

Inzucchi SE, et al. Diabetes Care. 2015;38(1):140-149.

Dual therapy

EfficacyHypo riskWeightSide effectsCosts

highmoderate riskgainhypoglycemialow

highlow riskgain edema, HF, fxslow

intermediatelow riskneutralrarehigh

Thiazolidinedione DPP-4 inhibitorSulfonylurea

Healthy eating, weight control, increased physical activity, and diabetes education

If HbA1C target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference—choice dependent on a variety of patient- and disease-specific factors):

Metformin Metformin Metformin

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference—choice dependent on a variety of patient- and disease-specific factors)::

or or or or

orororor

ororor

TZDDPP-4-i

GLP-1-RA

Insulin

SU

DPP-4-i

GLP-1-RA

Insulin

SU

Insulin

If HbA1C target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables; (2) on GLP-1-RA, add basal insulin; or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGLT2-i:

Basal insulin + or

Monotherapy

EfficacyHypo riskWeightSide effectsCosts

Triple therapy

Combination injectable therapy

TZD

Sulfonylurea

MetforminMetformin

Thiazolidinedione

Metformin

DPP-4 inhibitor

highlow risklossGIhigh

GLP-1 receptor agonist

Metformin

oror

TZD

SU

Insulin

Metformin

GLP-1 receptor agonist

intermediatelow risklossGU, dehydrationhigh

SGLT2 inhibitor

Metformin

ororor

Metformin

SGLT2 inhibitor

highesthigh riskgainhypoglycemiavariable

Insulin (basal)

Metformin

ororor

DPP-4-i

TZD

GLP-1-RA

Metformin

Insulin (basal)

SU

TZD

DPP-4-i

Insulin

GLP-1-RAMealtime insulin

Metformin+

SGLT2-i SGLT2-i SGLT2-i SGLT2-i

Metformin

highlow riskneutral / lossGI / lactic acidosislow

*Adapted from Inzucchi SE, et al. Diabetes Care. 2015;38(1):140-149.

+ + + + + +

+ + + + + +

+ + + + + +


Individualizing treatment goals in type 2 diabetes*

42

This approach is not designed to be applied rigidly but to be used as a broad construct to help guide clinical decisions.*Adapted from Inzucchi SE, et al. Diabetes Care. 2015;38(1):140-149.Inzucchi SE, et al. Diabetes Care. 2015;38(1):140-149.

Usually not modifiable

Low High

Risks potentially associated with hypoglycemia and other drug adverse effects

Disease duration

Life expectancy

Important comorbidities

Established vascular complications

Resources and support system

Newly diagnosed Long-standing

Long Short

Absent Severe

Absent Severe

Readily available

Less motivated, nonadherent, poor self-care capacities

Limited

Highly motivated, adherent, excellent self-care capacities

Less stringent

More stringent

HbA1c

7%

Potentially modifiable

Patient attitude and expected treatment efforts

PATIENT/DISEASE FEATURES

few/mild

few/mild



9

9

9

Once-weekly Trulicity compared to Lantus® (insulin glargine): AWARD-21

43

Design: 78‐week, randomized, open‐label comparator phase 3 study (double‐blind with respect to Trulicity dose assignment) of adult patients with type 2 diabetes

Primary outcome measure: A1C change from baseline at 52 weeks

Recommended starting dose is 0.75 mg. Dose can be increased to 1.5 mg for additional glycemic control. In clinical studies, the range of A1C reduction from baseline was 0.7% to 1.6% for the 0.75 mg dose and 0.8% to 1.6% for the 1.5 mg dose. 2,3

Insulin glargine

Trulicity 0.75 mg

Trulicity 1.5 mgM

etfo

rmin

+

gli

mep

irid

e

-12-10 0 78 82

Saf

ety

fo

llo

w-u

p

Treatment period Follow-upLead-inScreening

Weeks

Final time pointPrimary time pointRandomization

52

1. Giorgino F, et al. Presented at: American Diabetes Association Conference; San Francisco, CA: June 13-17, 2014. 2. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015. 3. Dungan KM, et al. Lancet. 2014;384(9951):1349-1357.


Once-weekly Trulicity demonstrated A1C reduction from baseline in a study compared to Lantus®1

44

-0.4

-0.2

-0.6

-1.4

-1.2

-0.8

-1.0

-1.1

-0.8

-0.6

Lantus (n=262; Baseline A1C: 8.1%)

Trulicity (0.75 mg) (n=272; Baseline A1C: 8.1%)

Trulicity (1.5 mg) (n=273; Baseline A1C: 8.2%)

0.0

Mea

n ch

ange

in A

1C (

%)

1. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015. 2. Dungan KM, et al. Lancet. 2014;384:1349-1357.

Select Important Safety Information: Safety and effectiveness of Trulicity have not been established in pediatric patients. It is not recommended for use in patients younger than 18 years.

Recommended starting dose is 0.75 mg. Dose can be increased to 1.5 mg. In clinical studies, the range of A1C reduction from baseline was 0.7% to 1.6% for the 0.75 mg dose and 0.8% to 1.6% for the 1.5 mg dose.1,2



1. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015. 2. Data on file, Lilly USA, LLC. TRU20140912B. 3. Data on file, Lilly USA, LLC. TRU20150313A.



Lantus(n=262; Baseline weight: 193.1 lb)

4

0

1

2

3

-7

-6

-5

-4

-3

-2

-1M

ean

we

ight

cha

nge

from

bas

elin

e (l

b)


Once-weekly Trulicity showed weight reduction compared to Lantus® at 52 weeks1-3

45


+3.1

-2.9-4.2





Documented symptomatic (events/patient/year) 3.02 1.67 1.67

Severe hypoglycemia†, n (%) 2 (0.8) 0 (0.0) 2 (0.7)

Trulicity 1.5 mg (n=273)


Lantus (n=262)

In a head-to-head study with Lantus®1-2

Add-on to metformin + glimepiride (52 weeks)

1. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015. CA. 2. Data on file, Lilly USA, LLC. TRU20140915B. 3. Dungan KM, et al. Lancet. 2014;384:1349-1357.

Documented symptomatic hypoglycemia was defined as 70 mg/dL glucose threshold.†Severe hypoglycemia is defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.

Trulicity is not indicated for weight loss. Recommended starting dose is 0.75 mg. Dose can be increased to 1.5 mg. In clinical studies, the range of A1C reduction from baseline was 0.7% to 1.6% for the 0.75 mg dose and 0.8% to 1.6% for the 1.5 mg dose.1,3

32



Getting your patients started on once-weekly Trulicity

Get your patients off to a good start with the Trulicity sample pack. The pack includes:

• A savings card to help eligible commercially covered patients save money (pay as little as $25*) on their prescription

• Educational information so your patients have support once they are home and preparing for their first dose

• Two sample pens for your patients’ first two weeks on Trulicity

47

*For each of your patient’s first 26 prescriptions, Lilly pays up to $150 per month depending on insurance coverage. Only for those who do not receive government reimbursement for their prescriptions. Other terms and restrictions apply.

Your patients should be aware of the safety and efficacy information for the product and be trained on proper injection technique.

in the participant guide, please see important safety information, including boxed warning about...

Documents

thyroid cancer

possible thyroid tumors

prescribing information

rodent thyroid ccell

important safety information

medication guide

participant guide

information pertinent