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1

AgendaAgenda

Insights into the Physiologic Action of the GLP‐1 RAsAdrian Vella, MD

New Safety Data and Ongoing Cardiovascular TrialsAnne L. Peters, MD

Patient Preferences and Novel Regimens Incorporating GLP‐1 RAs With InsulinIncorporating GLP 1 RAs With InsulinSam Dagogo‐Jack, MD, MBBS, FRCP

These slides are for informational purpose only and should not be reproduced.

2

FacultyFaculty

PROGRAM DIRECTORSilvio E. Inzucchi, MDProfessor of Medicine

PROGRAM FACULTYAnne L. Peters, MDDi t USC Cli i l Di b t PProfessor of Medicine

Clinical Director, Section of EndocrinologyMedical Director, Yale Diabetes CenterYale School of MedicineNew Haven, CT

PROGRAM FACULTYSam Dagogo‐Jack, MD, MBBS, FRCPA. C. Mullins Chair in Translational Research

Director, USC Clinical Diabetes ProgramProfessor, Keck School of Medicine of USCLos Angeles, CA

Adrian Vella, MDProfessor of MedicineDivision of EndocrinologyMayo Clinic and FoundationRochester, MN

Professor of Medicine and DirectorDivision of Endocrinology,

Diabetes and MetabolismDirector, Clinical Research CenterThe University of Tennessee

Health Science CenterMemphis, TN

Rochester, MN

Accreditation StatementAccreditation Statement

The Endocrine Society is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Endocrine Society has achieved Accreditation with Commendation.

The Endocrine Society designates this liveThe Endocrine Society designates this live activity for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.


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Learning ObjectivesLearning Objectives

At the conclusion of this activity, participants should be better able to:

Evaluate the most recent evidence when considering use of a GLP‐1 RA as part of a T2DM treatment plan

Review updated safety data for the GLP‐1 RA drug class

Discuss the nonglycemic effects of GLP‐1 RAs, g y ,including their positive impact on weight and cardiovascular risk factors

Describe the optimal use of GLP‐1 RAs in the context of practice‐based clinical scenarios

DisclosuresDisclosures

The following faculty reported relevant financial relationships:

Sam Dagogo‐Jack, MD, MBBS, FRCP: Principal Investigator, AstraZeneca, Boehringer Ingelheim, Novo Nordisk; Consultant: Merck & Co., Novo Nordisk

Silvio E. Inzucchi, MD: Scientific Board Member, Boehringer Ingelheim, Eisai, Lexicon Pharmaceuticals, Inc.; Speaker, AstraZeneca; Research Support, Takeda

Anne L. Peters, MD: Advisory Board Member, Abbott Lab, Amgen, AstraZeneca, Eli Lilly & Co., Janssen Pharmaceuticals, Lexicon Pharmaceuticals, Inc., Medtronic, MiniMed, Novo Nordisk, Sanofi, Takeda; Speaker, Bristol‐Myers Squibb, Novo Nordisk; Investigator,Medtronic, MiniMed, Janssen Pharmaceuticals

Adrian Vella, MD: Consultant, Genentech, Inc., Sanofi; Research Funding, BioKier, Novartis

The following SPC member who reviewed content for this activity reported relevantThe following SPC member who reviewed content for this activity reported relevant financial relationships:

Anton Luger, MD: Advisory Board Member, Investigator, and Speaker, Novo Nordisk; Advisory Board Member and Speaker, AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Ipsen, Merck, Novartis, Pfizer, Reckitt Benckiser, Sharp & Dohme, Takeda; Investigator, Roche

Endocrine Society and Haymarket Medical Education staff associated with the development of content for this activity reported no relevant financial relationships.


1

Adrian Vella MD

What’s New With What’s New With GLPGLP‐‐1 Receptor Agonists?1 Receptor Agonists?

Adrian Vella, MDProfessor of Medicine

Division of EndocrinologyMayo Clinic and Foundation

Rochester, MN

Physiology of GLPPhysiology of GLP‐‐11

Glucagon‐like peptide‐1 (GLP‐1) is an incretin hormone secreted by the gut in response to nutrientsnutrients

– Appears in the plasma within minutes of food ingestion;is rapidly degraded by dipeptidyl peptidase‐4 (DPP‐4)

– Actions include:

Enhancement of insulin secretion

S i f l tiSuppression of glucagon secretion

Slowing of gastric emptying

Reduction in food intake


2

GLPGLP‐‐1 Corrects Several of the Metabolic 1 Corrects Several of the Metabolic Defects Seen in Patients With T2DMDefects Seen in Patients With T2DM

Defects in Type 2Defects in Type 2 EffectsEffects of GLPof GLP‐‐11

Insulin secretion ↓ ↑

Glucagon secretion ↑ or↔ ↓

Islet insulin content ↓ ↑ (in vitro)

Food intake Excessive ↓

Gastric emptying ↑ or↔ ↓

Glucose effectiveness ↓ ––

Insulin action ↓ ––

Route of Glucose Administration Route of Glucose Administration Affects Plasma Insulin LevelsAffects Plasma Insulin Levels

Blood GlucoseBlood Glucose Plasma InsulinPlasma Insulin300300 Intravenous GlucoseIntravenous Glucose 300300

200200

100100

Glucose m

g/100 mL

Glucose m

g/100 mL

Intrajejunal GlucoseIntrajejunal Glucose

200200

100100

Insulin

Insulin

μμU/m

LU/m

L

McIntyre N, et al. Lancet. 1964;2:20‐21.

0000 3030 6060 9090 120120Time in MinutesTime in Minutes

0000 3030 6060 9090 120120Time in MinutesTime in Minutes

Intrajejunal glucose infusion results in greater plasma insulin and lower blood glucose levels than intravenous glucose infusion, suggesting that the gut influences insulin secretion.


3

GLPGLP‐‐1 Affects Secretion of 1 Affects Secretion of Pancreatic HormonesPancreatic Hormones

GLPGLP‐‐1 (71 (7‐‐36 amide)36 amide) PlaceboPlacebo

150150

200200

Plasma G

Plasma G

1212

mmol/L)

mmol/L)

1010

88 2020

00

5050

100100

Glucose (m

g/dL)Glucose (m

g/dL)

Plasma Glucose (

Plasma Glucose (

‐‐6060

88

66

44

22

0000 6060 120120 180180 240240 300300 360360

P P < 0.0001< 0.0001

** ** ** ** ** ** ** ** **

2020

Glucagon (pmol/L)

Glucagon (pmol/L)

‐‐6060

1515

1010

55

00

00 6060 120120 180180 240240 300300 360360

P P = 0.26= 0.26

**** ** ** **

300300

mol/L)

mol/L) 250250

2002003030

4040

5050

InsuliInsuli

****** **

**

Nauck MA, et al. Diabetologia. 1993;36:741‐744.

Intravenous infusion of GLP‐1 (7‐36 amide) in patients with poorly‐controlled T2DM results in normalization of fasting plasma glucose.

6060 00 6060 120120 180180 240240 300300 360360

Insulin

(pm

Insulin

(pm

‐‐6060

150150

100100

5050

0000 6060 120120 180180 240240 300300 360360

00

1010

3030 in (mU/L)

in (mU/L)

2020

P P < 0.0001< 0.0001

Time in Minutes

GLPGLP‐‐1 Increases Gastric Volume in Healthy 1 Increases Gastric Volume in Healthy Individuals But Not in Diabetic Patients Individuals But Not in Diabetic Patients

With Vagal NeuropathyWith Vagal Neuropathy

HealthHealth DiabetesDiabetesGLPGLP‐‐11PlaceboPlacebo

PP 0 0090 009700700

astric Volum

e (m

L)astric Volum

e (m

L) 600600

500500

400400

300300

200200 P P = 0.005= 0.005

P P = 0.009= 0.009

P P = 0.3= 0.3

Delgado Aros S, et al. Neurogastroenterol Motil. 2003;15:435‐443.

Intravenous GLP‐1 infusion did not increase gastric volume in diabetics with vagal neuropathy, suggesting GLP‐1's effects on stomach volume are vagally mediated.

Ga

Ga

100100

00Fasting Fasting ChangeChange

Postprandial Postprandial ChangeChange

Fasting Fasting ChangeChange

Postprandial Postprandial ChangeChange

P P = 0.5= 0.5


4

Measurement of Gastric AccommodationMeasurement of Gastric Accommodation

Delgado Aros S, et al. Neurogastroenterol Motil. 2003;15:435‐443.

Images of the stomach Images of the stomach were acquired by single were acquired by single photon emission computed tomography (SPECT)photon emission computed tomography (SPECT)

The CNSThe CNSIntegrates Appetite SignalsIntegrates Appetite Signals

AP =AP = area postremapostrema

ME =ME = median eminence

NTS =NTS = nucleus tractus solitarius

ARC =ARC = arcuate nucleus

Chaudhri OB, et al. Annu Rev Physiol. 2008;70:239‐255.


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Circumventricular Organs May Play a Role Circumventricular Organs May Play a Role in Sensing GLPin Sensing GLP‐‐1 and Other Hormones 1 and Other Hormones

Controlling Energy HomeostasisControlling Energy Homeostasis

AdipoAdipoR1/R2R1/R2

CTACTA‐‐RAMP3RAMP3 AT1AAT1A CCKCCK‐‐11 GHSRGHSR

GLPGLP‐‐1R1R

GLPGLP‐‐1R1R

Y1/Y1/Y2/Y5Y2/Y5 V1V1

R R R R R R R

P P P

Ph Ph Ph Ph Ph Ph

R R R R R R R

P P

APAP

NTSNTS

SFOSFO

Ph Ph Ph Ph Ph Ph

Hoyda TD, et al. Int J Obes (Lond). 2009;33 (suppl 1):S16‐S21.

AP = area postrema; NTS = nucleus tractus solitarius; SFO = subfornical organ.

The circumventricular organs are a specialized group of CNS structures, which are not protected by the blood‐brain barrier. They may play an important role in blood‐brain communications and regulation of energy balance.

l)l)

900900800800700700

******** ** **

GLPGLP‐‐1 Regulates Food Intake and the 1 Regulates Food Intake and the Rate of Gastric EmptyingRate of Gastric Emptying

1.001.00

tying

tying SalineSaline

ExendinExendin‐‐9,399,39.75.75

1.001.00

tying

tying

.75.75

EXEEXEEX9EX9‐‐39 + EXE39 + EXE

PlaceboPlacebo

Intake (kcal

Intake (kcal

60060050050040040030030020020010010000 `̀ `̀ `̀

LeanLean ObeseObese T2DMT2DM

Gastric Empt

Gastric Empt

00

MinMin

,,

.50.50

.25.25

00

3030 6060 9090 120120 150150 180180 210210 240240 270270

Gastric Empt

Gastric Empt

00

MinMin

SalineSalineExendinExendin‐‐9,399,39

.50.50

.25.25

00

3030 6060 9090 120120 150150 180180 210210 240240 270270

Intravenous administration of exenatide decreases food intake. GLP‐1 receptor blockade with exendin (9‐39), a competitive antagonist of GLP‐1, blocks this effect

Exendin (9‐39) significantly increases the rate of gastric emptying in the first 45 minutes after food ingestion In patients post‐Roux‐en‐Y gastric bypass but not healthy controls

Van Bloemendaal, et al. Diabetes. 2014;63:4186‐4196.Shah M, et al. Diabetes. 2014;63:483‐493.


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GLPGLP‐‐1 Receptor1 Receptor

Continuous exogenous administration

GLPGLP‐‐1 (7,36)1 (7,36) GLPGLP‐‐1 (9,36)1 (9,36)

DPPDPP‐‐44

ACTIVE HORMONE

Inhibition

INACTIVE HORMONE

DPPDPP 44 Inhibition

ExendinExendin‐‐4 (7,39)4 (7,39) ExendinExendin‐‐4 (9,39)4 (9,39)

Use of GLP‐1 analogue with resistance to DPP‐4

GLPGLP‐‐1 RAs: Approved and in Development1 RAs: Approved and in Development

Marketed Marketed NameName CompanyCompany Year ApprovedYear Approved AdministrationAdministration

ExenatideExenatide Short‐acting Byetta AstraZeneca 2005 BID

ExenatideExenatide Long‐acting Bydureon AstraZeneca 2012 QWK

LiraglutideLiraglutide Long‐acting Victoza Novo Nordisk 2010 QD

LixisenatideLixisenatide Short‐acting Lyxumia SanofiEMA approval 2013FDA submission pending

QD

AlbiglutideAlbiglutide Long‐acting Tanzeum GSK 2014 QWK

DulaglutideDulaglutide Long‐acting Trulicity Eli Lilly 2014 QWK

Long‐acting plus EMA approval 2014IDegLiraIDegLira

Long acting plus ultralong‐acting basal insulin

Xultophy Novo NordiskEMA approval 2014FDA submission pending

QD

SemaglutideSemaglutide Long‐acting Novo Nordisk Phase III development QWK

ITCA 650ITCA 650Continuoussubcutaneous delivery system for exenatide

Intarcia Phase III development Continuous

TaspoglutideTaspoglutide Long‐acting Roche Development suspended QWK


7

Pharmacokinetics of ShortPharmacokinetics of Short‐‐ vs vs LongLong‐‐Acting GLPActing GLP‐‐1 RAs1 RAs

Short‐acting GLP‐1 RAs have strong effects on postprandial glucose, likely due to delays in gastric emptying

Long‐acting GLP‐1 RAs produce more consistent activation of the GLP‐1 receptor

Long‐acting GLP‐1 RAs maintain some postprandial activity but better controlpostprandial activity, but better control fasting plasma glucose levels leading to greater overall reductions in A1C

Pharmacokinetics of ShortPharmacokinetics of Short‐‐ vs vs LongLong‐‐Acting GLPActing GLP‐‐1 RAs 1 RAs (cont’d)(cont’d)

Exenatide BIDExenatide BID Exenatide Once WeeklyExenatide Once Weekly1616

se (m

mol/L)

se (m

mol/L)

1515141413131212

1616

ose (m

mol/L)

ose (m

mol/L)

1515141413131212

BaselineBaselineWeek 14Week 14


Time (Min)Time (Min)

Postpran

dial Glucos

Postpran

dial Glucos

‐‐3030

1212111110109988776655

00 3030 6060 9090 120120 150150 180180 210210 240240 270270 300300Time (Min)Time (Min)

Postpran

dial Gluco

Postpran

dial Gluco

‐‐3030

111110109988776655

00 3030 6060 9090 120120 150150 180180 210210 240240 270270 300300

400400

Mean (SD)

Mean (SD)

e pg/m

Le pg/m

L

350350

300300

250250Week 14Week 14

400400

Mean (SD)

Mean (SD)

e pg/m

Le pg/m

L

350350

300300

250250Week 14Week 14

Fineman MS, et al. Diabetes Obes Metab. 2012;14:675‐688.

Exenatide BID results in greater reductions in postprandial plasma glucose than exenatide QWK despite lower geometric mean plasma concentrations.


Geo

metric M

Geo

metric M

Exen

atide

Exen

atide

‐‐3030

200200

150150

100100

5050

5500 3030 6060 9090 120120 150150 180180 210210 240240 270270 300300

Week 14Week 14


Geo

metric M

Geo

metric M

Exen

atide

Exen

atide

‐‐3030

200200

150150

100100

5050

5500 3030 6060 9090 120120 150150 180180 210210 240240 270270 300300

Week 14Week 14


8

Postprandial Pharmacokinetics of Postprandial Pharmacokinetics of ShortShort‐‐ vsvs LongLong‐‐Acting GLPActing GLP‐‐1 RAs1 RAs

(mmol/L)

1414

1313BaselineBaselineWeek 26Week 26


LiraglutideLiraglutide ExenatideExenatide

easured Plasma Glucose (

1212

1111

1010

99

88

Buse JB, et al. Lancet. 2009;374:39‐47.

Exenatide BID reduced postprandial plasma glucose more than did liraglutide (self‐measured with 7‐point plasma glucose profiles) after breakfast and dinner.

BeforeBreakfast

Breakfast + 90 Min

BeforeLunch

Lunch + 90 Min

BeforeDinner

Dinner + 90 Min

Bedtime

Self‐Me

77

66

Pharmacokinetics of ShortPharmacokinetics of Short‐‐ vs vs LongLong‐‐Acting GLPActing GLP‐‐1 RAs1 RAs

Lixisenatide produced greater reductions in postbreakfast glucose

1515

1414

Lixisenatide (Baseline)Lixisenatide (Baseline)Lixisenatide (Day 28Lixisenatide (Day 28Liraglutide (Baseline)Liraglutide (Baseline)postbreakfast glucose

levels than liraglutide

Fasting plasma glucose levels were lower in patients who received liraglutide

Remember: the action of GLP‐1RAs is 2‐fold:(1) i l t f ti

Plasma Glucose (m

mol/L)

Plasma Glucose (m

mol/L)

1313

1212

1111

1010

99

88

77

66

Liraglutide (Baseline)Liraglutide (Baseline)Liraglutide (Day 28)Liraglutide (Day 28)

(1) islet function(2) gastric emptying

Kapitza C, et al. Diabetes Obes Metab. 2013;15:642‐649.

55550.50.5 1.51.5 2.52.5 3.53.5 4.54.5 6.56.5 8.58.5 10.510.5 12.512.5 14.514.5 2424

Time After Study Drug Administration (h)Time After Study Drug Administration (h)


9

AcuteAcute IntermittentIntermittentl b

‐30 min 4 h 23.5 h 28 h

Intermittent GLPIntermittent GLP‐‐1R Stimulation 1R Stimulation Slows Gastric EmptyingSlows Gastric Emptying

100100

8080

%)

%)

AcuteAcutePlaceboPlaceboIntermittentIntermittent400400 * #

50005000

aa *Acute Acute GLPGLP‐‐11

Scintigraphy

IntermittentIntermittentGLPGLP‐‐11

Scintigraphy

Placebo

Placebo ProlongedProlongedGLPGLP‐‐11

‐30 min 4 h 23.5 h 28 h

Regimen A

Regimen B

642 kcalmeal

642 kcalmeal

8080

6060

4040

2020gastric Re

tention (

gastric Re

tention ( ProlongedProlonged

Postpran

dial Glycemia

Postpran

dial Glycemia

(mmol/L AUC

(mmol/L AUC 6

060))

350350

300300

250250

200200

150150

100100

5050

00

Postpran

dial In

sulin

emia

Postpran

dial In

sulin

emia

(mU/L AUC

(mU/L AUC 1

80180))

00

4500450040004000350035003000300025002500200020001500150010001000500500

Placebo

Scintigraphy

GLPGLP‐‐11

Scintigraphy

GLPGLP‐‐11Regimen B

642 kcalmeal

642 kcalmeal

Umapathysivam MM, et al. Diabetes. 2014;63:785‐790.

642 kcal meal642 kcal mealTime (min)Time (min)

2020

0000 3030 6060 9090 120120 150150 180180 210210 240240

Intrag

Intrag

IV InfusionIV Infusion IV InfusionIV Infusion

Both ShortBoth Short‐‐ and Longand Long‐‐Acting Acting GLPGLP‐‐1 RAs Cause Weight Loss1 RAs Cause Weight Loss

00

(SEM

)(SEM

)eline (kg)

eline (kg)

22

Baseline: 99.7 (1.1) kgBaseline: 99.7 (1.1) kg 9898

9696

LiraglutideLiraglutideExenatideExenatide

Weight, M

ean

Weight, M

ean

Chan

ge From Bas

Chan

ge From Bas

WeeksWeeks

‐‐22

‐‐44

‐‐6600 2626 5252 7878 104104

00

9494

9292

0000

8888

868622 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424 2626

Body

Weight (kg)

Body

Weight (kg)

Time in WeeksTime in Weeks

81% of patients lost weight with exenatide BID treatment (mean weight loss = 3.6 kg)

Weight loss was similar with exenatide BID and liraglutide treatment

Buse JB, et al. Clin Ther. 2007;29:139‐153.Buse JB et al. Lancet. 2009;374:39‐47.



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GLPGLP‐‐1 RAs Are Associated With 1 RAs Are Associated With Weight Loss*Weight Loss*

*Meta‐analysis of change in body weight after at least 20 weeks of treatment

Vilsboll T, et al. BMJ. 2012;344:d7771.

ConclusionsConclusions

GLP‐1 RAs have GI as well as islet effects

B th ti i t t t ff t t di lBoth actions interact to affect postprandial glycemia

The relative contribution of these effects might change over time

The duration of GLP‐1 receptor stimulationThe duration of GLP 1 receptor stimulation might affect the contribution of these effects to the net effect on glycemia (and weight)


1

Addressing the Common ConcernsAddressing the Common ConcernsAddressing the Common Concerns Addressing the Common Concerns Regarding the Use of GLPRegarding the Use of GLP‐‐1 RAs: 1 RAs: Recent Safety Data and New Recent Safety Data and New

Cardiovascular TrialsCardiovascular Trials

Anne L. Peters, MDDirector, USC Clinical Diabetes Program

Professor, Keck School of Medicine of USCLos Angeles, CA

GLPGLP‐‐1 RAs: Common Safety Concerns1 RAs: Common Safety Concerns

Tolerability

G t i t ti l (GI) id ff t ( )– Gastrointestinal (GI) side effects (eg, nausea)

– Injection‐site reactions

Safety

– Hypoglycemia

– Cardiovascular (CV) outcomes

– Medullary thyroid carcinoma (MTC)

– Acute pancreatitis


2

Total Proportion of Patients Experiencing Total Proportion of Patients Experiencing Nausea Varies by TherapyNausea Varies by Therapy

Exenatide BIDExenatide BID Exenatide QWKExenatide QWK LiraglutideLiraglutide DulaglutideDulaglutide AlbiglutideAlbiglutide

4040

Patien

ts W

ith

Patien

ts W

ith

Nau

sea (%

)Nau

sea (%

) 3030

2020

1010

00

**

**** **

Buse JB, et al. Lancet. 2009;374:39‐47.Drucker DJ, et al. Lancet. 2008;372:1240‐1250.Blevins T, et al. J Clin Endocrinol Metab. 2011;96:1301‐1310.Wysham C, et al. Diabetes Care. 2014;37:2159‐2167.Buse JB, et al. Lancet. 2013;381:117‐124.Dungan KM, et al. Lancet. 2014;384:1349‐1357.Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289‐297.

Nausea Is Transient and Decreases More Rapidly in Nausea Is Transient and Decreases More Rapidly in Patients Taking LongPatients Taking Long‐‐Acting GLPActing GLP‐‐1 RAs1 RAs

LEADLEAD‐‐6:6:Patients with nausea over time (liraglutide QD vs exenatide BID)Patients with nausea over time (liraglutide QD vs exenatide BID)

2020

Patien

ts (%

)Patien

ts (%

)

1818

1616

1414

1212

1010

88

66

Liraglutide 1Liraglutide 1‐‐8 mg once a day8 mg once a dayExenatide 10 Exenatide 10 μμg twice a dayg twice a day

PP 0 00010 0001

Buse JB, et al. Lancet. 2009;374:39‐47.Buse JB, et al. Lancet. 2013;381:117‐124.

66

44

22

0000 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424 2626


P P < 0.0001< 0.0001


3

Nausea Is Transient and Decreases More Rapidly in Nausea Is Transient and Decreases More Rapidly in Patients Taking LongPatients Taking Long‐‐Acting GLPActing GLP‐‐1 RAs 1 RAs (cont’d)(cont’d)

DURATIONDURATION‐‐6: 6: Patients with nausea and vomiting over time (exenatide QWK vs liraglutide QD)Patients with nausea and vomiting over time (exenatide QWK vs liraglutide QD)

Exenatide once weekly (n = 461)Exenatide once weekly (n = 461)Li l tid d il ( 450)Li l tid d il ( 450)

1515Liraglutide once daily (n = 450)Liraglutide once daily (n = 450)

Patien

ts W

ith

Patien

ts W

ith

Nau

sea (%

)Nau

sea (%

)

1010

55

00

th

th

%)

%)

1515 Exenatide once weekly (n = 461)Exenatide once weekly (n = 461)Liraglutide once daily (n = 450)Liraglutide once daily (n = 450)

Buse JB, et al. Lancet. 2009;374:39‐47.Buse JB, et al. Lancet. 2013;381:117‐124.

Patien

ts W

itPatien

ts W

itVo

miting (%

Vomiting (% 1010

55

0000‐‐22 22‐‐44 44‐‐66 66‐‐88 88‐‐1010 1010‐‐1212 1212‐‐1414 1414‐‐1616 1616‐‐1818 1818‐‐2020 2020‐‐2222 2222‐‐2424 2424‐‐2626 > 26> 26


InjectionInjection‐‐Site ReactionsSite Reactions

ExenatideExenatide QWKQWK ExenatideExenatide BIDBID LiraglutideLiraglutide

23 gauge 29‐32 gauge 29‐32 gaugeNeedle size 23 gauge(0.64 mm)

29‐32 gauge(0.24‐0.34 mm)

29‐32 gauge(0.24‐0.34 mm)

Injection site reactions

~10‐15% of patients <2% <2%

Meier JJ. Nat Rev Endocrinol. 2012;8:728‐742.


4

GLPGLP‐‐1 RAs and Hypoglycemia1 RAs and Hypoglycemia

Warnings and PrecautionsWarnings and PrecautionsC id l i h d f h i li i liConsider lowering the dose of the insulin secretagogue or insulin to reduce the risk of hypoglycemia

NonsulfonylureaNonsulfonylurea BackgroundBackground Sulfonylurea BackgroundSulfonylurea Background

Exenatide QWKExenatide QWK ExenatideExenatide BIDBID Exenatide QWKExenatide QWK ExenatideExenatide BIDBID

Percentage of patients with at least 1 episode of hypoglycemia

Drucker DJ, et al. Lancet. 2008;372:1240‐1250.

QQN = 93N = 93 N = 93N = 93

QQN = 55N = 55 N = 54N = 54

MajorMajor 0 0 0 0

MinorMinor 0 1 (1.1) 8 (14.5) 8 (15.4)

Hypoglycemia Rates With GLPHypoglycemia Rates With GLP‐‐1 RAs 1 RAs Combined With Insulin/MetforminCombined With Insulin/Metformin

Diamant M, et al. Lancet Diabetes Endocrinol. 2014;2:464‐473.


5

Contrasting Action of Native GLPContrasting Action of Native GLP‐‐1, GLP1, GLP‐‐1R Agonists, 1R Agonists, DPPDPP‐‐4 Inhibitors, and GLP4 Inhibitors, and GLP‐‐1 (91 (9‐‐36) on the 36) on the

Cardiovascular System and Cardiovascular Risk FactorsCardiovascular System and Cardiovascular Risk Factors

GLPGLP‐‐1R 1R AgonistsAgonists GLPGLP‐‐11

DPPDPP‐‐4 4 InhibitorsInhibitors

GLPGLP‐‐1 1 (9(9‐‐36)36)

LV functionLV function Increased Increased Increased Increased

Heart rateHeart rate Increased Increased No effect No effect

Coronary flowCoronary flow No effect Increased No effect Increased

Infarct sizeInfarct size Decreased Decreased Decreased Decreased

Body weightBody weight Decreased Decreased No effect No effect

Blood pressureBlood pressure Decreased Decreased No effect/decreased ND

Ussher JR, et al. Circ Res. 2014;114:1788‐1803.

DPP‐4, dipeptidyl peptidase‐4; GLP‐1R, glucagon‐like peptide‐1 (GLP‐1) receptor; LV, left ventricular; ND, not determined.

Incretin Mimetics Do Not Increase Risk Incretin Mimetics Do Not Increase Risk of Congestive Heart Failure of Congestive Heart Failure

Current Current ExposureExposure

Case Case Subjects Subjects ((n n = 1118)= 1118)

ControlControlSubjectsSubjects(n = 17,626)(n = 17,626)

CrudeCrudeOROR

(95% CI)(95% CI)

Adjusted Adjusted OROR

(95% CI)(95% CI)

≥ 2 oral antidiabetic drugs, n (%) 267 (23.9) 4198 (23.8) 1.00 (Reference) 1.00 (Reference)

Incretin‐based drugs, n (%) 64 (5.7) 923 (5.2) 0.98 (0.73‐1.33) 0.85 (0.62‐1.16)

DPP‐4 inhibitors 54 (4.8) 808 (4.6) 0.96 (0.70‐1.32) 0.88 (0.63‐1.22)

GLP‐1 analogs 10 (0.9) 115 (0.7) 1.18 (0.59‐2.39) 0.67 (0.32‐1.42)

Duration of incretin‐based drug use, n (%)

P trend = 0.39

Yu OH, et al. Diabetes Care. 2015;38:277‐284.

1‐83 days 25 (2.2) 310 (1.8) 1.18 (0.74‐1.89) 1.01 (0.62‐1.63)

84‐265 days 18 (1.6) 299 (1.7) 0.86 (0.51‐1.44) 0.79 (0.46‐1.36)

> 265 days 21 (1.9) 314 (1.8) 0.92 (0.56‐1.50) 0.75 (0.45‐1.25)


6

Ongoing/Recent Cardiovascular Ongoing/Recent Cardiovascular Outcomes TrialsOutcomes Trials

TrialTrial(Sponsor)(Sponsor) Study DrugStudy Drug

PrimaryPrimaryOutcomeOutcome

PatientsPatients(n)(n) TimelineTimeline

ELIXA(Sanofi)

Lixisenatide20 mg QD MACE ~ 6000 Jun 2010 – Dec 2014

LEADER (Novo Nordisk)

Liraglutide1.8 mg QD MACE ~ 9000 Aug 2010 – Oct 2015

SUSTAIN 6(Novo Nordisk)

Semaglutide0.5 or 1.0 mg QWK

MACE ~ 3000 Feb 2013 – Jan 2016

EXSCEL Exenatide MACE ~ 14 000 Jun 2010 – Dec 2017(AstraZeneca) 2.0 mg QWK MACE 14,000 Jun 2010 – Dec 2017

REWIND(Eli Lilly)

Dulaglutide1.5 mg QWK MACE ~ 95,00 Jul 2011 – Apr 2019

MACE, major adverse cardiovascular events.

ClinicalTrials.gov: NCT01147250, NCT01179048, NCT01720446, NCT01144338, NCT01394952.

Risk of Thyroid CancerRisk of Thyroid Cancer

ContraindicationsContraindications

Patients with a personal or family history of MTCh l l d l d ( )

Thyroid C‐cell tumors have been observed in rodents exposed to GLP‐1 RAs at clinically relevant dosesIt is unknown whether GLP 1 RAs cause thyroid C cell tumors including MTC

Patients with multiple endocrine neoplasia syndrome (MEN 2)

Warnings and PrecautionsWarnings and PrecautionsCounsel patients regarding the risk of MTC and symptoms of thyroid tumors

It is unknown whether GLP‐1 RAs cause thyroid C‐cell tumors, including MTC, in humansIt is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate the potential risk of MTC, and such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid diseasePatients with thyroid nodules noted on physical examination or neck imaging obtained for other reasons should be referred to an endocrinologist for further evaluation


7

Risk of Thyroid CancerRisk of Thyroid Cancer

Gallo M. J Endocrinol Invest. 2013;36:140‐145.

Cases of Acute Pancreatitis Have Been Reported Cases of Acute Pancreatitis Have Been Reported But Relationship to GLPBut Relationship to GLP‐‐1 RAs Is Unclear1 RAs Is Unclear

Several analyses of health care claims data demonstrated no increased risk of pancreatitis ith GLP 1 RAwith GLP‐1 RA use

Controversial analysis of FDA Adverse Events Reporting Database showed increased risk of pancreatitis with GLP‐1 RA use

W iW i d P tid P tiWarningsWarnings and Precautionsand Precautions

Discontinue promptly if pancreatitis is suspected

Do not restart if pancreatitis is confirmed

Consider other antidiabetic therapies in patients with a history of pancreatitis


8

Number of subjects with reports (A) and number of adverse events Number of subjects with reports (A) and number of adverse events (B) reported to the FDA Adverse Event Reporting System between (B) reported to the FDA Adverse Event Reporting System between 2004 and 2010 for different glucose2004 and 2010 for different glucose‐‐lowering medications including lowering medications including

exenatideexenatide (green lines) and sitagliptin (blue lines).(green lines) and sitagliptin (blue lines).

Michael A. Nauck, and Nele Friedrich Dia Care 2013;36:S245‐S252.

Large Database Studies Suggest Large Database Studies Suggest No Increase in Risk of PancreatitisNo Increase in Risk of Pancreatitis

GLPGLP‐‐1 Receptor Agonist1 Receptor Agonist DPPDPP‐‐4 Inhibitor4 Inhibitor

43

2

1.5

1.0

.5

ds Ratio fo

r Pancreatitis

(±95% CI)

43

2

1.5

1.0

.5

ds Ratio fo

r Pancreatitis

(±95% CI)

Nauck MA, et al. Diabetes Care. 2013 ;36(suppl 2):S245‐S252.

0

0dd 0

0dd


9

GLPGLP‐‐1 RA Pancreatitis Data 20141 RA Pancreatitis Data 2014

Country/Ref Type of Database N FindingsItaly, Lancet DiabEndo. 2:111-115,

Administrative database from

282,429 pts T2DM; 1003 cases

Use of incretins not associated with increased

2014 Piedmont pancreatitis vs 4012 controls

risk of pancreatitis

Indiana, Pharmacoepidemiology & Drug Safety. 23:234-9, 2014

Large observational database

1.2 million pts, 7992 on sita (245 cases) and 3552 on exenatide(96 cases)

No relationship between use of GLP-1 based therapies and pancreatitis

United Kingdom,Diabetologia.

Population based cohort study

20,748 new incretinusers vs 51,712 users

Rates panc: 1.45 per 1,000 pts/yr incretins vsDiabetologia.

57:1320-4, 2014cohort study users vs 51,712 users

of SU’s1,000 pts/yr incretins vs1.47 for SU’s. Adjusted HR = 1.0

International, BMJ. 348:g2780, 2014

Pooled Phase IIItrial data

GLP-1 38 cases/17,775 PYO’s vs9/5,863 PYO’s

Non-significant trend to pancreatitis. Pooled event rates 2.1 and 1.5 per 1,000 PYOs (OR 1.39, CI 0.67, 2.88)


GI symptoms such as nausea are the most common adverse event seen with GLP‐1 RAs

– Nausea tends to be transient, varies according to therapy, and decreases more rapidly with long‐acting formulations

Risk of hypoglycemia is low

– Increases when used in combination with insulin secretagogues or insulin

It is currently unknown whether GLP‐1 RAs cause thyroid C‐cell tumors, including MTC, in humans

– Counsel patients regarding the risk of MTC and symptoms of thyroid tumors


10

Conclusions Conclusions ((cont’dcont’d))

Controversial analysis of FDA Adverse Events Reporting Database showed increased risk of pancreatitis with GLP‐1 RA use

– However, multiple analyses of health care claims data demonstrated no increased risk

Retrospective analysis shows no increased risk for major adverse CV events with GLP1‐risk for major adverse CV events with GLP1RAs

– In response to an FDA requirement, several long‐term trials examining CV outcomes with GLP‐1 RAs have been established


1

Patient Preferences andPatient Preferences and

Sam Dagogo‐Jack, MD, FRCPA C M lli Ch i i T l i l R h

Patient Preferences and Patient Preferences and Novel Regimens Incorporating Novel Regimens Incorporating

GLPGLP‐‐1 RAs and Insulin1 RAs and Insulin

A. C. Mullins Chair in Translational ResearchProfessor of Medicine and Director

Division of Endocrinology, Diabetes and Metabolism

Director, Clinical Research CenterThe University of Tennessee

Health Science CenterMemphis, TN


2

Patient’s PerspectivePatient’s Perspective

Efficacy:Efficacy: Preference for glucose control over avoiding minor hypoglycemic events

f d d d h hlRoute:Route: Preference towards drug administration highly associated with previous experience with injectable diabetes medicine

Adverse events: Adverse events: “Avoiding a 3‐kg weight gain is important but not superior to avoiding hypoglycemic events”

Cost:Cost: Patient willingness to pay (WTP): US $28 ‐ $205/mo

von Arx LB, et al. Patient. 2014;7:283‐300. Gelhorn HL, et al. Diabetes Obes Metab. 2013;15:802‐809.


The ability of a drug to lower glucose levels plays a decisive role in the choice between alternative treatments Future research should develop questionnaire designs to foster shared decision making in clinical practice or drug development

WTP for Pharmaceutical WTP for Pharmaceutical Diabetes TreatmentDiabetes Treatment

Efficacy

WTP t di f ll i liWTP among studies of all insulin users

– $28/mo for having a 2hrPG of 9.4 mmol/L

– $36/mo for having optimal BG 2‐6 days/wk

WTP in studies with ~ 50% insulin users

von Arx LB, et al. Patient. 2014;7:283‐300; Guimaraes C, et al. Diabetes Technol Ther. 2009;11:567‐573. Lloyd A, et al. Clin Ther. 2011;33:1258‐1267. Jendle J, et al. Curr Med Res Opin. 2010;26:917‐923.

WTP in studies with 50% insulin users

– $146/mo for optimal FPG

– $205/mo for a 1% HbA1c reduction


3

Patient WTP for Pharmaceutical Patient WTP for Pharmaceutical Diabetes TreatmentDiabetes Treatment

Adverse events and mode of treatmentWTP for adverse events– Highest ($124 ‐ $220/mo) for avoiding nausea

– $45 ‐ $94/mo for avoiding hypoglycemia

– $72 ‐ $94/mo for avoiding night‐time events

– WTP reported for weight control: $58 ‐ $76/mo

WTP for mode of treatment

von Arx LB, et al. Patient. 2014;7:283‐300; Guimaraes C, et al. Diabetes Technol Ther. 2009;11:567‐573. Lloyd A, et al. Clin Ther. 2011;33:1258‐1267. Jendle J, et al. Curr Med Res Opin. 2010;26:917‐923.

– $86 for meal‐independent injections (prandial experience $117/none $65)

– Inhaled administration: $62 ‐ $215/mo

– Oral drug administration $50 ‐ $108/mo

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

Metformin high low risk neutral/loss GI / lactic acidosis low

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- & disease-specific factors):

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Thi lidi DPP 4 Insulin (basal)GLP 1 tS lf l SGLT2

Metformin +

Mono- therapy

Efficacy* Hypo risk Weight Side effects Costs

Dual

ADAADA‐‐EASD Position Statement: EASD Position Statement: 2015 2015 UpdateUpdate

Dual

high low risk gain edema, HF, fxs low

Thiazolidine- dione

intermediate low risk neutral rare

high

DPP-4inhibitor

highest high risk gain hypoglycemia variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Sulfonylurea +

TZD

Thiazolidine-dione +

SU TZD

high low risk loss GI high

GLP-1 receptoragonist

Sulfonylurea

high moderate risk gain hypoglycemia low

SGLT2inhibitor intermediate low risk loss GU, dehydration high

SU

GLP-1 receptor agonist +

SGLT-2 Inhibitor +

SU

Metformin +

Dual therapy†�

Efficacy* Hypo risk Weight Side effects Costs

Triple therapy

DPP-4 Inhibitor +

SU

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- & disease-specific factors):

Insulin (basal) +

Dualtherapy

Tripletherapy

Basal Insulin +

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

DPP-4-i

GLP-1-RA

Insulin§

DPP-4-i or

or

or

GLP-1-RA

TZD

Insulin§

TZD

Insulin§

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

or

or

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i

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 SGL T2-i:

Metformin + Combination

injectable therapy‡�

GLP-1-RA Mealtime Insulin

Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

Combinationinjectabletherapy


4

What Do You Do When 2 or More What Do You Do When 2 or More Oral Agents Fail to Control T2DM?Oral Agents Fail to Control T2DM?

Add 3rd/4th OHAAdd 3rd/4th OHA

Choices:


Add Add basal insulin basal insulin injectioninjection

Add incretin injectionAdd incretin injection

Exenatide Exenatide vs vs Insulin Glargine in Patients Insulin Glargine in Patients With Suboptimally With Suboptimally Controlled Type 2 Controlled Type 2 Diabetes: A Randomized Diabetes: A Randomized TrialTrial

82 sites

13 countries

Robert J. Heine, MD, PhD; Luc F. Van Gaal, MD; Don Johns, PhD; Michael J. Mihm, PhD; Mario H. Widel, MS; and Robert G. Brodows, MD, for the GWAA Study Group

Heine RJ, et al. Ann Intern Med. 2005;143:559‐569.

13 countries

551 patients

Background SU + metformin


5

Exenatide BID vs Glargine: Exenatide BID vs Glargine: Effects on HbA1c and WeightEffects on HbA1c and Weight

obin A

obin A

1c1cl (%)

l (%)

8.58.58.08.07.57.57 07 0

Exenatide group Exenatide group (n(n = 275)= 275)Insulin glargine Insulin glargine group (n = 260)group (n = 260)

Hem

oglo

Hem

oglo

Level

Level 7.07.0

6.56.5

00

00 1212 2626WeeksWeeks

Exenatide group, nExenatide group, nInsulin glargine group, nInsulin glargine group, n

275275260260

244244249249

229229243243

2211inin ht

(kg)

ht (kg) Exenatide group Exenatide group

(n(n = 275)= 275)Insulin glargineInsulin glargine


00

00‐‐11‐‐22‐‐33

Chan

ge

Chan

ge

Body

Weigh

Body

Weigh

22 44 00 1212 1818 2626WeeksWeeks

Exenatide group, nExenatide group, nInsulin glargine group, nInsulin glargine group, n

281281267267

277277266266

275275261261

261261253253

245245251251

235235246246

231231244244

** **** ** **

**

Insulin glargine Insulin glargine group (n = 260)group (n = 260)

Exenatide vs Glargine Exenatide vs Glargine Added to Oral Agents Added to Oral Agents

Insulin Insulin GlargineGlargineExenatideExenatide

14 BaselineWeek 26

14 BaselineWeek 26

BG (m

mol/L)

Pre‐

6

8

10

12Week 26

Pre‐ Pre‐ 3 AM144 mg/dL

126mg/dL

6

8

10

12

Pre‐ Pre‐ 3 AMPre‐

Week 26

ITT population; mean ± SE.


PreBreakfast

PreLunch

PreDinner

3 AM

MDG (mg/dL) Exenatide: 146 ± 2 Glargine: 144 ± 2 HbA1c: ‐1.11%

PreLunch

PreDinner

3 AMPreBreakfast


6

HbA1c and Body Weight During HbA1c and Body Weight During the Comparative Studythe Comparative Study

Start End Change

12 0 120 0 90 7 92 7 90 012.0

HBA

1c(%

Units‐m

mol/m

ol)

10.0

8.0

6.0

4.0

2.0

0.0

‐2.0

86

64

42

20

‐22

9.0

7.1

9.1

7.3

120.0

Body

Weight (kg)

100.0

80.0

60.0

40.0

20.0

0.0

‐2.0

2.0†

‐3.0

90.7 92.7 90.0 87.0

D’Alessio D, et al. Diabetes Obes Metab. 2015;17:170‐178.

*P = 0.019; †P < 0.001 compared with liraglutide.

H

‐4.0 ‐44 ‐1.9* ‐1.8

Glargine Liraglutide

Comparative Study

‐4.0

Glargine Liraglutide

Comparative Study


7

DURATIONDDiabetes therapy UUtilization: RResearching changes in AA1c, weight,

and other factors TThrough IIntervention with exenatide ONONce‐Weekly

Change in HbA1c and FSG After Change in HbA1c and FSG After 26 Wks Across Baseline HbA1c Quartiles26 Wks Across Baseline HbA1c Quartiles

0.0

‐0.8

‐0.5‐1.0‐1.5‐2.0‐2.5

nge in HbA

1Cm Baseline

1st 1st QuarterQuarter

2nd 2nd QuarterQuarter

3rd 3rd QuarterQuarter

4th 4th QuarterQuarter

BaselineBaseline HbA1C (%):HbA1C (%): 7.17.1 7.17.1 7.77.7 7.87.8 8.48.4 8.58.5 9.99.9 9.89.8

N:N: 5555 4949 5454 5959 5959 5959 6060 5353

‐0.6

‐1.2‐0.9

‐1.3 ‐1.3

0.0

‐1.3

‐1.0‐2.0‐3.0‐4.0‐5.0

ge in FPG

From

ine (m

mol/L)





BaselineBaseline FSG (mmol/L)FSG (mmol/L) 8.28.2 8.08.0 9.29.2 9.09.0 9.99.9 10.110.1 12.112.111.711.7

N:N: 5151 4747 5353 5555 5757 5454 5252 5151

‐1.6 ‐2.1 ‐2.0‐2.0 2 7

Buse JB, et al. Diabetes Obes Metab. 2015;17:145‐151.

‐3.0‐3.5‐4.0

Chan Fro

‐2.3

‐2.1

End of trialEnd of trialHbA1C (%):HbA1C (%): 6.46.4 6.66.6 6.66.6 6.86.8 7.17.1 7.17.1 7.57.5 7.77.7

Exenatide OW

Glargine

‐6.0‐7.0‐8.0

Chan

gBa

sel ‐2.7

‐3.2‐4,2

End of trialEnd of trialFSG (mmol/L):FSG (mmol/L): 6.96.9 6.56.5 7.17.1 7.07.0 7.97.9 7.47.4 8.98.9 7.57.5

Exenatide OW

Glargine

LEADLLiraglutide EEffect and AAction in DDiabetes

Change in HbA1c and FSG after Change in HbA1c and FSG after 26 Wks Across Baseline HbA1c Quartiles 26 Wks Across Baseline HbA1c Quartiles ((cont’dcont’d ))

0.0

‐0.9

‐0.5‐1.0‐1.5‐2.0‐2.5

nge in HbA

1Cm Baseline





BaselineBaseline HbA1C (%):HbA1C (%): 7.27.2 7.17.1 7.97.9 7.97.9 8.58.5 8.68.6 9.59.5 9.49.4

N:N: 6161 6363 5555 6969 4949 4444 5959 4949

‐0.5

‐1.1

‐0.9

‐1.4‐1.2

‐1 5

0.0

‐1.3

‐1.0‐‐2.0‐‐3.0‐4.0‐5.0

ge in FPG

From

ine (m

mol/L)





BaselineBaseline FSG (mmol/L)FSG (mmol/L) 7.97.9 8.08.0 8.58.5 8.98.9 9.49.4 9.29.2 10.810.8 10.710.7

N:N: 6262 6363 5555 6969 4848 4444 6060 5050

‐0.9

‐1.1

‐1.8‐1.3 ‐1.4

‐2.1 ‐2.7

‐3.0‐3.5‐4.0

Chan Fro

‐1.8

‐1.5

End of trialEnd of trialHbA1C (%):HbA1C (%): 6.36.3 6.66.6 6.86.8 7.07.0 7.27.2 7.47.4 7.77.7 7.97.9

Liraglutide

Glargine

‐6.0‐7.0‐8.0

Chan

gBa

sel

End of trialEnd of trialFSG (mmol/L):FSG (mmol/L): 6.66.6 7.17.1 7.47.4 7.17.1 8.18.1 7.77.7 8.78.7 8.08.0

Liraglutide

Glargine

Buse JB, et al. Diabetes Obes Metab. 2015;17:145‐151.


8

What Do You Do When 2 or More What Do You Do When 2 or More Oral Agents Fail to Control T2DM?Oral Agents Fail to Control T2DM?


Choices:




GLPGLP‐‐1 RA + Basal Insulin Meta1 RA + Basal Insulin Meta‐‐Analysis: Effects on HbA1cAnalysis: Effects on HbA1cWeightedWeighted mean difference (95% CI)mean difference (95% CI) WeightWeight

Buse et al (2011) ‐0.70 (‐0.72 to ‐0.68) 7.44%

DeVries et al (2012) ‐0.43 (‐0.68 to ‐0.18) 6.27%

Li et al (2012) ‐0.13 (‐0.32 to 0.06) 6.67%

Seino et al (L‐Asia; 2012) ‐0.88 (‐0.93 to ‐0.83) 7.38%

Riddle et al (Duo‐1;2013) ‐0.30 (‐0.58 to ‐0.02) 5.99%

Riddle et al (L; 2013) ‐0.30 (‐0.58 to ‐0.02) 6.00%

Diamant et al (2014) ‐0.03 (‐0.17 to 0.11) 7.03%

Lane et al (2014) ‐0.26 (‐0.52 to 0.00) 6.15%

Mathieu et al (2014) ‐0.35 (‐0.48 to ‐0.22) 7.06%

Rosenstock et al (2014) ‐0.16 (‐0.33 to 0.01) 6.86%

Shao et al (2014) ‐0.11 (‐0.23 to 0.01) 7.15%

Wit et al (2014) ‐0.78 (‐1.10 to ‐0.46) 5.64%

Ahmann et al (2014) ‐1.19 (‐1.36 to ‐1.02) 6.86%

Rosenstock et al (LixiLan; 2014) ‐0.20 (‐0.40 to ‐0.00) 6.65%

Seino et al (LIRA‐ADD2INSULIN; 2014) ‐0.80 (‐0.96 to ‐0.64) 6.87%

‐1 1‐0.5 ‐1 0.5

Overall (IOverall (I2 2 = 96.6%, = 96.6%, P P < 0.0001)< 0.0001) ‐‐0.44% (0.44% (‐‐0.60 to 0.60 to ‐‐0.29)0.29) 100%100%

Eng C, et al. Lancet. 2014; 384:2228‐2234.

Diamant et al (2014) ‐0.03 (‐0.17 to 0.11) 32.25%

Rosenstock et al (2014) ‐0.16 (0.33 to 0.01) 22.50%

Shao (2014) ‐0.11 (‐0.23 to 0.01) 42.25%

Favors GLP‐1 + basal insulin Favors basal‐bolus insulin

‐0.3

Favours GLP‐1 + basal insulin Favours basal‐bolus insulin

0.3‐0.1 0 0.5‐0.2 0.1

Overall (IOverall (I2 2 = 98.7%, = 98.7%, P P < 0.47)< 0.47) ‐‐5.66 (5.66 (‐‐9.80 to 9.80 to ‐‐1.51)1.51) 100%100%


9

GLPGLP‐‐1 RA 1 RA + + Basal Insulin Basal Insulin MetaMeta‐‐AnalysisAnalysis: : Effects on Effects on BodyWeightBodyWeight

Overall (p<0.0001) -3.22 kg (-4.90 to -1.54)

Eng C, et al. Lancet. 2014; 384:2228‐2234.

Body WeightBody Weight

-5.66 kg (-9.80 to -1.51) Overall (p<0.0001)

What Do You Do When Basal Insulin What Do You Do When Basal Insulin Added to Added to OHA OHA Fails?Fails?

Start BasalStart Basal‐‐BolusBolus

Choices:

Start BasalStart Basal BolusBolus

Consider SplitConsider Split‐‐MixMix



10

Comparison of Adding Comparison of Adding LiraglutideLiraglutide vsvsa Single Daily Dose of Insulin a Single Daily Dose of Insulin AspartAspart to to Insulin Insulin DegludecDegludec in Subjects With T2DMin Subjects With T2DM

Subjects completing a 104‐week trial on insulin degludec (IDeg) OD + metformin with HbA1c ≥ 7 0% were randomized to≥ 7.0% were randomized to:

IDeg + Lira (n = 88, mean HbA1c: 7.7%) or

IDeg + IAsp (n = 89, mean HbA1c: 7.7%)

Metformin continued in both groups

Assessed after 26 weeks

Mathieu C, et al. Diabetes Obes Metab. 2014;16:636‐644.

Assessed after 26 weeks

Subjects completing 104 weeks with HbA1C < 7.0% continued IDeg + metformin in a third, nonrandomized arm (n = 236)

Comparison of Adding Comparison of Adding LiraglutideLiraglutide vs vs a Single Daily Dose of Insulin a Single Daily Dose of Insulin AspartAspart to to Insulin Insulin DegludecDegludec in Subjects With T2DMin Subjects With T2DM

IDeg + Lira (n = 88)

IDeg(n = 236)

IDeg + IAsp(n = 89)

IDeg + Lira (n = 88)

IDeg + IAsp(n = 89)

IDeg(n = 236)

9.09.0

8.58.58.08.0

7.57.57.07.0

6.56.56.06.0

5.55.50.00.0 00

35353939434347475151555559596363676771717575

HbA

HbA

1c1c(%

)(%

)

HbA

HbA

1c1c (mmol/m

ol)(m

mol/m

ol)

55

Chan

ge in

Weight

Chan

ge in

Weight

From

Baseline (kg)

From

Baseline (kg)

4433221100‐‐11‐‐22‐‐33‐‐44

1111997755

11‐‐11‐‐33‐‐55‐‐77‐‐99

33 (lb)(lb)

Mathieu C, et al. Diabetes Obes Metab. 2014;16:636‐644.

00 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424 262600


44 99


11

Efficacy and Safety of aEfficacy and Safety of a FixedFixed‐‐Ratio CombinationRatio CombinationEfficacy and Safety of a Efficacy and Safety of a FixedFixed‐‐Ratio Combination Ratio Combination of Insulin of Insulin DegludecDegludec and Liraglutide and Liraglutide Compared to Compared to

Each of Its Components Given Alone: Each of Its Components Given Alone: Results of a Phase 3, Randomised, Results of a Phase 3, Randomised, 2626‐‐Week, TreatWeek, Treat‐‐toto‐‐Target Trial in Target Trial in

InsulinInsulin‐‐Naïve Patients With Type 2 Diabetes.Naïve Patients With Type 2 Diabetes.(Clinicaltrials gov identifier: NCT01336023)

Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2:885‐893.

(Clinicaltrials.gov identifier: NCT01336023)

Trial DesignTrial Design

Patients with T2DM Statistical

comparisonsIDegIDeg ODOD ++ metforminmetformin ±± pioglitazonepioglitazone (n = 414(n = 414))

IDegLiraIDegLira OD + metformin OD + metformin ±± pioglitazonepioglitazone (n = 834)(n = 834)

(n = 1663)

26 weeks

Randomized 2:1:1Open‐label

comparisons

Liraglutide OD (1.8 mg) Liraglutide OD (1.8 mg) + metformin + metformin ±± pioglitazonepioglitazone (n = 415(n = 415) )

IDegIDeg OD OD metformin metformin ±± pioglitazonepioglitazone (n 414(n 414))

Inclusion criteria

Start doseStart dose Max. doseMax. dose

IDegIDeg 10 units Not specified

0

• T2DM• Insulin naïve, treated with metformin ± pioglitazone

• HbA1c 7.0%‐10.0%• BMI ≤40 kg/m2

• Age ≥ 18 years*

*Singapore, age ≥ 21 years.

BMI, body mass index; lira, liraglutide; OD, once daily.

gg p

LiraLira 0.6 mg 1.8 mg

IDegLiraIDegLira10 dose steps(10 units IDeg/0.36 mg Lira)

50 dose steps(50 units IDeg/1.8 mg Lira)

Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2:885‐893.


12

HbAHbA1c1c Over TimeOver Time

75

69IDeg (n=413)Liraglutide (n=414)

IDegLira (n=833)8.5

9.0

HbA

1c (%

)

64

58

53

48

HbA

1c (mmol/m

ol)

IDegLira (n 833)

6.5

7.0

7.5

8.0

8.5

Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2:885‐893.d

*P < 0.0001 vs IDegand vs liraglutide

∆∆HbHbAA1c1c EOTEOT

‐1.28% 7.0%

‐1.44% 6.9%

‐1.91%* 6.4%Time in Weeks

42

05.5

6.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26

g)

Change in Body Weight Over TimeChange in Body Weight Over Time

6

8

IDeg (n=413)Liraglutide (n=414)

IDegLira (n=833)

hange in Bod

y Weigh

t (kg

−2.22 kg P < 0.0001

2.44 kgP < 0.0001

‐4

‐2

0

2

4IDegLira (n 833)

Ch


‐8

‐6

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Time in Weeks


13

Confirmed Confirmed HypoglycemiaHypoglycemia

tien

t1.4

1.2 6.9%

HbA1c

R t ti 0 68

IDeg (n = 412)Liraglutide (n = 412)

IDegLira (n = 825)

umulative Even

ts per Pa

1.0

0.8

0.6

0.4

6.4%

Rate ratio: 7.61P < 0.0001

Rate ratio: 0.68P = 0.0023

Time in Weeks

Mean C

0 2 4 6 8 10 12 14 16 18 20 22 24 26

0.2

0.0

7.0%


Approach to Management Approach to Management of Hyperglycemiaof Hyperglycemia

HbA1c 7%

ADA. Diabetes Care. 2015;38(suppl 1) Adapted from Ismail‐Beigi et al. Ann Intern Med. 2011;154:554‐555.


14

Approach to Management Approach to Management of Hyperglycemiaof Hyperglycemia

ADA. Diabetes Care. 2015;38(suppl 1); Adapted from Ismail‐Beigi et al. Ann Intern Med. 2011;154:554‐555.

What Do You Do When 2 or More Oral What Do You Do When 2 or More Oral Agents Fail to Control T2DM?Agents Fail to Control T2DM?


Choices:





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