EST 18 PCU Track 1 Session 3 pmiCME GLP-1 RA

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

11:15 AM - 12:30 PM

The Expanding Role of GLP-1 Receptor Agonists in the Changing Landscape of T2DMSPEAKERSJohn E. Anderson, MDJessica R. Castle, MD

Disclosures

► John E. Anderson, MD: Advisory Board for Abbott; AstraZeneca; Boehringer Ingelheim Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; Lilly; Merck & Co., Inc.; and Sanofi US. Services Provided for Promotional Purposes (not for CME/CE) for Janssen Pharmaceuticals, Inc.; Lilly; and Sanofi US. Speaker's Bureau for AstraZeneca; Boehringer Ingelheim Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; Lilly; and Sanofi US.

► Jessica R. Castle, MD: No financial relationships to disclose.

The following relationships exist related to this presentation:

Off-Label/Investigational Discussion► In accordance with pmiCME policy, faculty have been asked to disclose discussion of

unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.

This session is supported by an independent educational grant from Lilly .

30.3 million Americans (9.3% of US population) have diabetes

92 million Americans have pre-diabetes (increased from 79 million in 2010)

1 in 3 adults will have T2DM in 2050

90% of all diabetes management occurs within the primary care setting

(1) Unger J. Diabetes Management in Primary Care, 2nd ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2012.

WHY BOTHER ATTENDING YET ANOTHER DIABETES LECTURE?

The World is Changing!

► Tendency is to intensify therapy based on sampling availability rather than pathogenetic targets

► Concern of possible AEs of newer agents► Currently 257 drug combinations can be used to manage patient with T2DM► As therapy is intensified, patients experience an increase risk of weight gain, hypoglycemia and

even mortality

T2DM SIGNIFICANTLY REDUCES LIFE EXPECTANCY

(1) Emerging Risk Factors Collaboration. JAMA. 2015;314:52–60. (2) World Heart Federation. http://www.world-heart-federation.org/fileadmin/user_upload/documents/Fact_sheets/2012/PressBackgrounderApril2012RiskFactors.pdf. Accessed August 10, 2017.

-6.7 years

-11.2 years

-15.7 years

T2DMT2DMHistory of MI T2DM

History of MIHistory of Stroke


Even

ts p

er 1

0,00

0 ov

eral

lad

ult p

opul

atio

n

Gregg et al. N Engl J Med 2014;370:1514–23

DIABETES-RELATED COMPLICATIONS IN THE USACUTE MYOCARDIAL INFARCTION AND STROKE

Overall population

Population with diabetesOverall population

Acute myocardial infarctionStroke

1990 1995 2000 2005 20100

150

125

25

100

75

50

Age-

adju

sted

Rel

ativ

e R

isk

Body mass index (BMI) (kg/m2)

Men

Women

<22 <23 23-23.9

24-24.9

25-26.9

27-28.9

29-30.9

31-32.9

33-34.9

35+

1.02.91.0

4.31.0

5.01.5

8.12.2

15.8

4.4

27.6

40.3

54.0

93.2

6.7 11.6

21.3

42.1

0

25

50

75

100

(1) Chan JM, et al. Diabetes Care. 1994;17:961-969. (2) Colditz GA, et al. Ann Intern Med. 1995;122:481-486.

RELATIONSHIP BETWEEN BMI AND RISK OF T2DM

BILL – 67 YEARS OLD

FAMILY HISTORYMother (died age 71): T2DM, CVD, hypercholesterolemiaFather (died age 75): T2DM, diverticulosis, hypercholesterolemia

MEDICAL HISTORYT2DM x 6 yrsHTN x 7 yrs

MEDICATIONSMetformin 1000 mg BIDGlimepiride 8 mg QDLisinopril 30 mg QDAtorvastatin 40 mg QD

VITALSHeight: 5’ 11”Weight: 205 lbsBMI: 32 kg/m2

BP: 130/82 mm Hg

LABSFPG: 102 mg/dLPPG average: 150 mg/dLHbA1c: 7.7%LDL: 89 mg/dL

HDL: 51 mg/dLTG: 97 mg/dLeGFR: 96 mL/min/1.73 m2

INITIAL VISIT

2018 ADA STANDARDS OF MEDICAL CARE IN DIABETES

American Diabetes Association Diabetes Care 2018;41:S73-S85

HbA1c goal <7%

Monitor for hypoglycemia

Prevent weight gain


HYPERGLYCEMIA

Pancreas Insulin secretionGlucagon secretion

Liver Hepatic

glucose secretion

Muscle andadipose tissueGlucose uptake

CNSDelayed satiety

Neurotransmitter dysfunction

KidneyGlucose reabsorption

Adipose tissueLipolysis

PATHOPHYSIOLOGIC MECHANISMS IN HYPERGLYCEMIA OF T2DM

GutDiminished incretin

effect Altered intestinal glucose absorption

2018 ADA STANDARDS OF MEDICAL CARE IN DIABETES

American Diabetes Association Diabetes Care 2018;41:S73-S85

2018 ADA/EASD CONSENSUS REPORTNO ASCVD OR HF/CKD | NEED TO MINIMIZE HYPOGLYCEMIA

Davies MJ, et al. Consensus ADA and EASD Report. Diabetes Care 2018, on-line

Metformin +

Lifestyle

Metformin +

Lifestyle

Metformin +

Lifestyle

ORSGLT2i GLP-

1 RADPP-

4i OR

ORGLP-1

RA TZDDPP-4i O

R

ORSGLT2i TZD

ORSGLT2i TZDDPP-4iDPP-4i

GLP-1 RA

GLP-1 RA

SGLT2iSGLT2i

TZDTZD

If HbA1c above target




• Choose later generation of SU with lower risk of hypoglycemia

• Consider basal insulin with lower risk of hypoglycemia

• Choose later generation of SU with lower risk of hypoglycemia

• Consider basal insulin with lower risk of hypoglycemia

Consider the addition of SU or basal insulin

If HbA1c above

target…

Continue with addition

of other agents

If HbA1c still above

target….

2018 ADA/EASD CONSENSUS REPORTNO ASCVD OR HF/CKD | NEED TO MINIMIZE WEIGHT GAIN OR PROMOTE WEIGHT LOSS

*With good weight loss efficacy


GLP-1 RA*

SGLT2i

GLP-1 RA*

SGLT2i


• PREFERABLYDPP-4i (if not on GLP-1 RA) based on weight neutrality

If triple therapy required or SGLT2i and/or GLP-1 RA not tolerated or

contraindicated use regimen with lowest

risk of wt gain• PREFERABLY

DPP-4i (if not on GLP-1 RA) based on weight neutrality

If triple therapy required or SGLT2i and/or GLP-1 RA not tolerated or

contraindicated use regimen with lowest

risk of wt gain

EITH

ER/O

REI

THER

/OR

GLP-1 RA*GLP-1 RA* SGLT2iSGLT2i

EITH

ER/O

R

GLP-1 RA* SGLT2i



• SU• TZD• Basal insulin

If DPP-4i not tolerated or

contraindicated or patient already on

GLP-1 RA, cautiously add…

• SU• TZD• Basal insulin

If DPP-4i not tolerated or

contraindicated or patient already on

GLP-1 RA, cautiously add…

Metformin +

Lifestyle

Metformin +

Lifestyle

Metformin +

Lifestyle


2018 ADA/EASD CONSENSUS REPORTNO ASCVD OR HF/CKD | COST EFFECTIVE


Metformin +

Lifestyle

Metformin +

Lifestyle

Metformin +

Lifestyle

SU

TZD SU

TZD



OR

Insulin therapy basal

insulin with lowest

acquisition cost

Consider DPP-4i OR SGLT2i with

lowest acquisition

cost


Garber, AJ, et al. Endocr Pract.2018.

2018 AACE/ACE COMPREHENSIVE T2DM MANAGEMENT ALGORITHM

Entry HbA1c < 7.5%

MonotherapyMetforminGLP-1 RASGLT2iDPP-4iTZDAGISU/GLN

Hie

rarc

hy o

f usa

ge

Triple TherapyGLP-1 RASGLT2iTZDBasal InsulinDPP-4iColesevelamBromocriptine QRAGISU/GLN

Metformin +

Hie

rarc

hy o

f usa

ge Metformin +

If not at goal in 3 moIf not at goal in 3 mo

Hie

rarc

hy o

f usa

ge

Entry HbA1c ≥ 7.5%

Dual TherapyGLP-1 RASGLT2iDPP-4iTZDBasal InsulinColesevelamBromocriptine QRAGISU/GLN

Metformin +

If not at goal in 3 moIf not at goal in 3 moIf not at goal in 3 mo, use or

intensify insulin therapy (refer to Insulin Algorithm)

If not at goal in 3 mo, use or intensify insulin therapy (refer to Insulin Algorithm)

Entry HbA1c > 9.0%Symptoms

YES NODualOR

Triple therapy

Insulin ± other agents



Metformin + Lifestyle

PROFILES OF ANTIDIABETIC DRUGS

Garber AJ, et al. Endocr Pract. 2018 Jan;24(1):91-120.

Few AEs or possible benefits

Likelihood of AEs

Use with caution

Time (min)

IR In

sulin

(mU

/L)

nmol/L

0.6

0.5

0.40.3

0.2

0.1

0

80

60

40

20

018060 1200

T2DM(n=14)

Control subjects (n=8)

Time (min)

IR In

sulin

(mU

/L)

nmol/ L

0.6

0.5

0.40.3

0.2

0.1

0

80

60

40

20

018060 1200

IncretinEffect

The Incretin Effect Is Diminished in T2DM

Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.


Courtesy of Primary Care Network and Jeff Unger, MD

GLP-1 SECRETED FROM THE L-CELLS OF GUT IN RESPONSE TOCARBOHYDRATE STIMULUS

(1) Baggio L, et al. Gastroenterology. 2007;132:2131-2157. (2) DeFronzo RA, et al. Curr Med Res Opin. 2008;24:2943-2952. (3) Inzucchi SE, et al. Diabetes Care. 2015;38:140-149.

DPP-4 INHIBITORS AND GLP-1 RASINCREASE GLP-1 ACTIVITY IN DIFFERENT WAYS

< 2 min DPP-4 inhibitors increase GLP-1 by preventing

degradation

GLP-1 RAs act like GLP-1 but are not readily

degraded by DPP-4Active GLP-1

DPP-4

Inactive GLP-1

(1) Baggio L, et al. Gastroenterology. 2007;132:2131-2157. (2) DeFronzo RA, et al. Curr Med Res Opin. 2008;24:2943-2952. (3) Inzucchi SE, et al. Diabetes Care. 2015;38:140-149.

DPP-4 INHIBITORS AND GLP-1 RAS INCREASE GLP-1 ACTIVITY INDIFFERENT WAYS

► GLP-1 activity is higher with GLP-1 RAs (≈ 9 ×baseline) vs DPP-4 inhibitors (≈ 2 × baseline)

► Both classes mediate glucose-dependent changes▪ Increase insulin▪ Decrease glucagon

► GLP-1 RAs also…▪ Slow gastric emptying▪ Increase satiety

Add GLP-1 analogues with longer half-life:Injectables

Incretin effect is impaired in T2DM

Natural GLP-1/GIP have extremely short half-lives

Block DPP-4, the enzyme that degrades GLP-1:

Oral agents ► Sitagliptin► Saxagliptin► Linagliptin► Alogliptin

Drucker. Curr Pharm Des. 2001;7(14):1399-1412. Drucker. Mol Endocrinol. 2003;17(2):161-171.

INCRETIN THERAPIES TO TREAT T2DM

Exendin-4 Based:► Exenatide► Exenatide QW► Lixisenatide

Human GLP-1 based:► Liraglutide► Dulaglutide► Semaglutide


CANDIDATES FOR GLP-1 RA THERAPY

(1) Garber AJ, et al. Endocr Pract. 2018 Jan;24(1):91-120. (2) American Diabetes Association Diabetes Care 2018;41:S73-S85

☑Add-on therapy for patients who do not achieve their HbA1c target after 3 months of metformin therapy1

☑ In combination with metformin (and/or another oral agent*) when:1,2

▪ Weight loss or avoidance of hypoglycemia is a primary consideration

▪ The HbA1c level is close to target (within 1-1.5%)

▪ Cost or injection therapy are not major barriers

☑1st-line therapy as an alternative to metformin in patients who cannot tolerate or are contraindicated for metformin

*Use with DPP-4 inhibitors is NOT RECOMMENDED

due to similar mechanisms and lack of additional therapeutic

benefit

ANTIDIABETIC AGENTS: EFFECT ON WEIGHT

(1) ADA. Diabetes Care. 2017;40(suppl 1):S1-S135. (2) Garber AJ, et al. Endocr Pract. 2017;23:207-238. (3) Zhong X, et al. Diabetes Res Clin Pract. 2015;109:451-460.

Agent Weight ChangeMetformin Slight loss

Sulfonylureas Gain

TZDs Gain

DPP-4 inhibitors Neutral

SGLT2 inhibitors Loss

GLP-1 RAs Loss

Basal insulin Gain

HYPOGLYCEMIC RISK WITH ANTIDIABETIC AGENTS

(1) ADA. Diabetes Care. 2017;40(suppl 1):S1-S135. (2) Garber AJ, et al. Endocr Pract. 2017;23:207-238.

Agent Risk of HypoglycemiaMetformin NeutralSulfonylureas High

TZDs Neutral

DPP-4 inhibitors LowSGLT2 inhibitors Low

GLP-1 RAs Neutral*Insulin High* Increased risk if used in combination with sulfonylureas or insulin

Zoungas S, et al. N Engl J Med. 2010;363:1410-1418.

FREQUENCY OF ADVERSE OUTCOMES IN PATIENTS WITH T2DM EXPERIENCINGSEVERE HYPOGLYCEMIA

25

No.

of A

dver

se O

utco

mes

Severe Hypoglycemia to Event (months)

20

15

10

5

00-12 13-24 25-36 37-48

Macrovascular eventMicrovascular eventDeath from any causeCV deathNon-CV death

The median time from an episode of severe hypoglycemia until death in T2DM is ≤ 1.05 years!

The median time from an episode of severe hypoglycemia until death in T2DM is ≤ 1.05 years!

Conclusion − severe hypoglycemia is associated with a higher risk of mortalityConclusion − severe hypoglycemia is associated with a higher risk of mortality


(1) Hajós TR. Diabetes Care. 2014;37(1):102–108. (2) Gonder-Frederick LA. Diabet Med. 2013;30(5):603–609.

HYPOGLYCEMIA DECREASES ADHERENCE

Single hypoglycemic event

Fear of hypoglycemia

Patient chooses to keep his/her blood glucose levels in a higher range to minimize the likelihood of hypoglycemia

Medication adherence

BILL – 67 YEARS OLD

▪ You discuss with Bill the benefits and risks of starting a GLP-1 RA

▪ Bill expresses some concern about having to stick himself with a needle and the amount of injections that are required

What are some strategies to improve Bill’s buy-in with GLP-1 RAs to ultimately increase adherence to treatment?

“Drugs don’t work in patients who don’t take

them”

- C. Everett Koop, MD (Surgeon General)

Lindenfeld J, Jessup M. Eur J Heart Fail. 2017 Nov;19(11):1412-1413

NON-ADHERENCE

45% adherence rates amongst patients with T2DM

1/3 of all initial prescriptions for glucose lowering agents are unfilled

30% risk of hospitalization at the lowest level of adherence (1-19 % vs. 13 % at the highest adherence quintile (80-100 % at 12 months)

Non-adherence increases the likelihood of long-term complications, more frequent hospitalizations and higher

health care costs(1) Curkendall SM, et al. Curr Med Res Opin. 2013;29:1275–1286. (2) Fischer MA, et al. J Gen Intern Med 2010; 25:284-290

ADHERENCE TO PRESCRIBED MEDICATION


► Discussions between patients and clinicians related to risk:benefit ratio is critical.

► Choose therapies which reduce risk of hypoglycemia and weight gain (hypoglycemia risk increases with duration of disease and age of patient)

► Hypoglycemia increases risk of mortality

► Consider use of drugs which may improve CV outcomes (death from MI, nonfatal MI, stroke, CHF) - and/or renal disease progression

► Decisions which are “patient-centered” are likely to improve clinical outcomes

► Injection therapies are NOT threatening and could improve ß-cell mass and function - THIS IS A GOOD THING!

Garcia-Perez LE, et al. Diabetes Ther. 2013;4:175–194

IMPROVING PATIENT ADHERENCE

Mody R, et al. Diabetes Jul 2018, 67 (Supplement 1) 1264-P.

LESS FREQUENT INJECTION = IMPROVED ADHERENCE

67%

51% 51%60%

38%

62%

PDC, mean(SD) in %

Adherence (%) Patients whodiscontinuedtherapy (%)

67%

51% 51%51%

32%

71%

PDC, mean(SD) in %

Adherence (%) Patients whodiscontinuedtherapy (%)

Dulaglutide Liraglutide Exenatide QW

PATIENT PRIORITIES FOR INJECTABLE AGENTS

Boegelund M, et al. Diabetes. 2015;64(suppl 1):A349 [abstract 1341-P].

4

1

2

3

4

5Will

ingn

ess

to P

ayW

illin

gnes

s to

Pay

Greater glycemic efficacy

Low risk of hypoglycemia

Weight loss (2-3 kg)

Avoid mixing (resuspension)

Fewer daily injections

Holst JJ, Vilsbøll T. Diabetes Obes Metab. 2013;15(1):3-14.

HOW TO SELECT GLP-1 RAS

PREFERENTIAL EFFECT ON…LONG-ACTING GLP-1 RAS DulaglutideLiraglutideExenatide QWSemaglutide

FASTINGPLASMA GLUCOSE

SHORT-ACTING GLP-1 RAS LixisenatideExenatide BID

POST-PRANDIALPLASMA GLUCOSE


Medication Adverse Events Dosing

Shor

t-act

ing

Exenatide BID Nausea, vomiting, dyspepsia Start 5 mcg twice daily (1 hour before morning and evening meals), may increase to 10 mcg after 1 month

Lixisenatide Nausea, vomiting, diarrhea, headache

Start 10 mcg daily (1 h before 1st meal of day), may increase to 20 mcg daily after 14 days

Long

-act

ing

Liraglutide Nausea, vomiting, diarrhea, headache, dyspepsia, fatigue

Start 0.6 mg once daily, may increase to 1.2 mg after 1 week. Max dose 1.8 mg daily

Exenatide QW Nausea, diarrhea, headache, dyspepsia, vomiting 2 mg once weekly

Dulaglutide Nausea, diarrhea, vomiting Start 0.75 mg once weekly, may increase to 1.5 mg once weekly

Semaglutide Nausea, vomiting, diarrhea, constipation, abdominal pain

Start 0.25 mg once weekly, may increase to 0.5 mg once weekly. Max dose 1 mg per week

1. Byetta. Summary of Product Characteristics; 2. Lyxumia. Summary of Product Characteristics; 3. Victoza. Summary of Product Characteristics; 4. Marbury T et al. Diabetes 2014;63(Suppl.1):A260(1010-P); 5. Kapitza C et al. J Clin Pharm 2015;55:497–504; 6. Barrington et al. Diabetes Obes Metab 2011;13:434–438; 7. PI Tanzeum 8. Fineman M et al. Clin Pharmacokinet 2011;50:65–74; Ozempic prescribing information; Trulicity prescribing information.

FDA APPROVED GLP-1 RAS

*Albiglutide to be discontinued July 2018

-0.78

-1.5

0.08

-1

0.1

-0.79-0.96 -0.99

-0.71

-0.32

-1.5

-1.1

-1.8

-1.4

-2

-1.5

-1

-0.5

0

0.5

EXEBID

EXEQW PLB

LIRA1.8 mg PLB LIXI

EXEBID

DULA1.5 mg

DULA0.75mg SITA

SEMA0.5 mg

DULA0.75mg

SEMA1 mg

DULA1.5 mg

EFFICACY OF GLP-1 RAS ADDED TO METFORMIN

ΔH

bA1c

,%

P<0.001

P<0.01 P = NI P<0.001

P<0.0001P<0.0001

NI = non-inferior

(1) DeFronzo RA, et al. Diabetes Care. 2005;28(8):1092-1100; (2) Bergenstal RM, et al. Lancet. 2010;376:431-439. (3) Nauck M, et al. Diabetes Care. 2009;32(1):84-90. (4) Ahren B, et al. Diabetes Care. 2014;37(8):2141-2148. (5) Weinstock RS, et al. Diabetes Obes Metab 2015; 17:849. (6) Rosenstock J. Diabetes Care. 2013 Oct;36(10):2945-2951. (7) Pratley R, et al. Lancet Diabetes Endocrinol. 2018.

-1.25% -1.26% -1.33%

-1.09%

-1.50%

-1.30%

-1.08%

-0.63%

-1.60%

-1.40%

-1.20%

-1.00%

-0.80%

-0.60%

-0.40%

-0.20%

0.00%

ExenatideBID

Insulinglargine Liraglutide

Insulinglargine

ExenatideQW

Insulinglargine Dulaglutide

Insulinglargine

EFFICACY OF GLP-1 RAS VS BASAL INSULIN

ΔH

bA1c

,%

(1) Davies MJ, et al. Diabetes Obes Metab. 2009;11:1153-1162. (2) Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055. (3) Diamant M, et al. Lancet. 2010;375:2234-2243.(4) Giorgino R, et al. Diabetes Care. 2015;38:2241-2249.

-3.24 -3.7-2.68

-1.53

-2.9

-4.3

-3-2.87-3.6 -3.57

-0.99

-3.61 -3.7

-6.5

LEAD-6 DURATION-1 DURATION-6 AWARD-1 AWARD-6 LIRA-LIXI SUSTAIN-7

p=0.0001

Baseline 93.1 93.0 102.0 102.0 90.9 91.7 96.0 97.0 94.4 93.8 102 101 Average 95Weight(kg)

Cha

nge

in W

eigh

t (kg

)

p=0.089

p=0.474

p<0.01p<0.01

p=0.022

GLP-1 RAS CAN LEAD TO WEIGHT LOSS

(1) Buse JB et al. Lancet. 2009;374:39–47 (LEAD-6). (2) Drucker DJ et al. Lancet. 2008;372:1240–50 (DURATION-1); (3) Buse JB et al. Lancet. 2013;381:117–24 (DURATION-6). (4) Wysham C et al. Diabetes Care. 2014;37(8):2159–67 (AWARD-1). (5) Dungan KM et al. Lancet. 2014; 384(9951):1349–1357 (AWARD-6). (6) Nauck M et al. Diabetes Care. 2016 Sep;39(9):1501-9. (7) Pratley R, et al. Lancet Diabetes Endocrinol. 2018 (SUSTAIN 7).

Liraglutide 1.8 mg

Exenatide 10 µg BID

Exenatide 2 mg QW

Dulaglutide 1.5 mg Semaglutide 1.0 mg

Lixisenatide

p<0.0001


AVOIDING NAUSEA WITH GLP-1 RAS

Ellero C, et al. Diabet Med. 2010;27(10):1168-1173.

Educate on meal size, eating pace, and dose timing relative to meals

• Short-acting GLP-1 RAs should be taken within 60 minutes before morning and evening meals

• Do not eat beyond point of satietyUse incremental dose titration, particularly with shorter-acting

agents

ACUTE PANCREATITIS WITH GLP-1 RAS

Egan AG, et al. N Engl J Med. 2014 Feb 27;370(9):794-7.

Pancreatitis risk is 1.5 to 3-fold higher in individuals with diabetes

PRECAUTIONS• Cases have been reported• Consider treatments other than GLP-1 RAs in patients with

history of pancreatitis

RECOMMENDATIONS

• Ask about pancreatitis history• Educate patients, monitor for signs and symptoms

• Discontinue promptly if pancreatitis symptoms occur • If acute pancreatitis is confirmed, do not restart GLP-1 RA

• Report cases of pancreatitis to www.fda.gov/medwatch

After independent evaluation of > 80 K patients by FDA and EMA, no causal relationship between any incretin product and pancreatitis has been established

RISK OF PANCREATIC AND MEDULLARY ANDTHYROID CANCERS WITH GLP-1 RAS

(1) Knudsen LB, et al. Endocrinology. 2010;151:1473-1486; (2) MacConell L, et al. Diabetes Metab Syndr Obes. 2015;8:241-253; (3) Jendle J, et al. Diabetes Metab Res Rev. 2016 Apr 21. [Epub ahead of print]; (4) Pfeffer MA, et al. N Engl J Med. 2015;373:2247-2257; (5) Marso SP, et al. N Engl J Med. 2016 Jun 13. (6) Guo X, et al. Clin Drug Investig. 2016 Mar 15. (7) Azoulay L, et al. BMJ. 2016;352:i581

Pancreatic Cancer

Medullary Thyroid Cancer► Long-term exposure to GLP-1 RAs in rodents, but not monkeys or humans, has

been associated with thyroid C-cell hyperplasia and tumors► Long-acting GLP-1 RAs contraindicated in patients with a personal or family history

of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2

► Pooled analysis showed no increased risk of thyroid cancer

No evidence of increased risk

GLP-1 RA USE WITH RENAL IMPAIRMENT

Adapted from prescribing information for Byetta, Bydureon, Victoza, Ozempic, Trulicity, Adlyxin

Renal Status Exenatide BID

Exenatide QW Liraglutide Semaglutide,

Dulaglutide Lixisenatide

Mild impairment(CrCl 50-80 mL/min)

No adjustment or recommendation

No dose adjustment

Use caution when initiating or

escalating doses

No dose adjustment

Monitor renal function in

patients with renal impairment

reporting severe adverse

gastrointestinal reactions

Moderate impairment(CrCl 30-50 mL/min)

Use caution when initiating or escalating

doses

Use with caution

Severe impairment(CrCl < 30 mL/min)

Should not be usedESRD

Use caution but no dose adjustment

Renal transplant Use with caution


Warning/contraindication

Exenatide BID

Exenatide QW Liraglutide Lixisenatide Dulaglutide Semaglutide

Do not use if history of MTC or MEN2 X X X X

History of pancreatitis Consider other agents Risk of hypoglycemia with secretagogues/ insulin

X X X X X X

Serious Hypersensitivity X X X X X X

Do not use if severe GI disease X X X

GLP-1 CONTRAINDICATIONS AND WARNINGS

0.

0.65

1.3

1.95

2.6

3.25

CV death All-cause mortality

Haz

ard

ratio

(95%

CI)

(dia

bete

s vs

. no

diab

etes

)

CVD IS THE LEADING CAUSE OF DEATH IN PEOPLE WITH T2D

Mortality risk associated with diabetes (n=820,900)1

0

7

40 50 60 70 80 90Age (years)

Year

s of

life

lost 6

543210

76543210

Men

40 50 60 70 80 900Age (years)

Women Non-vascular deathsVascular deaths

Years of life lost in people with diabetes* compared with non-diabetes peers1

RESULTS OF CVOTS FOR GLP-1 RAS

Lixisenatide1 Liraglutide2 Exenatide QW3 Semaglutide4

*MACE Neutral (13%) Neutral (26%)CV

Death (22%) Neutral

Death (Any Cause) (15%) Neutral

Non-Fatal Stroke (39%)

Hospitalization for HF Neutral

*MACE = Death From CV Causes, Nonfatal MI, or Nonfatal Stroke (+/- hospitalization for unstable angina)

(1) Pfeffer M. N Engl J Med. 2015 Dec 3;373(23):2247-57 (2) Marso SP. N Engl J Med. 2016 Sep 16; 375:311-322 (3) Holman RR et al. N Engl J Med. 2017 Sep 14. (4) Marso SP, et al. N Engl J Med. 2016;375(19):1834-1844.

2018 ADA/EASD CONSENSUS REPORTIF ASCVD OR HF/CKD PREDOMINATES


EITH

ER/O

REI

THER

/OR

GLP-1 RA w/ proven

CVD benefit

GLP-1 RA w/ proven

CVD benefit

SGLT2i w/ proven CVD

benefit (if eGFR adequate)


benefit (if eGFR adequate)EI

THER

/OR

GLP-1 RA w/ proven

CVD benefit


benefit (if eGFR adequate)

• Consider adding the other class w/ proven CVD benefit

• DPP-4i (not saxagliptin) in the setting of HF (if not on GLP-1 RA)

• Basal insulin• SU

Avoid TZD in the setting of HFChoose agents demonstrating CV safety

• Consider adding the other class w/ proven CVD benefit

• DPP-4i (not saxagliptin) in the setting of HF (if not on GLP-1 RA)

• Basal insulin• SU

Avoid TZD in the setting of HFChoose agents demonstrating CV safety

• Consider adding the other class (GLP-1 RA and/or SGLT2i) w/ proven CVD benefit

• DPP-4i if not GLP-1 RA• Basal insulin• TZD• SU

If further intensification is required/ patient is now unable to tolerate GLP-1 RA

and/or SGLT2i, choose agents demonstrating CV safety

• Consider adding the other class (GLP-1 RA and/or SGLT2i) w/ proven CVD benefit

• DPP-4i if not GLP-1 RA• Basal insulin• TZD• SU

If further intensification is required/ patient is now unable to tolerate GLP-1 RA

and/or SGLT2i, choose agents demonstrating CV safety

Metformin +

Lifestyle

Metformin +

Lifestyle

Metformin +

Lifestyle

ASCVD

OR

OR

PreferredSGLT2i w/ evidence of reducing HF and/or CKD

progression in CVOTs if EGFR

adequate

If SGLT2i not tolerated/

contraindicated/if eGFR less than

adequate add GLP-1 RA w/ proven CVD

benefit




benefitO

R

PreferredSGLT2i w/ evidence of reducing HF and/or CKD

progression in CVOTs if EGFR

adequate




benefit

HF or CKD




SUMMARY

► Long-acting GLP-1 RAs preferred due to patient convenience► Reduction in HbA1c is greater with the longer-acting GLP-1 RAs► Avoid combination therapy with GLP-1 RAs and DPP-4 inhibitors as

there are no proven additive glucose-lowering effects► The risk of hypoglycemia is small with GLP-1 RAs (as compared to

insulin, sulfonylureas, glinides)► Select GLP-1 RAs with consideration of renal impairment creatinine /

eGFR► Consider selection of GLP-1 RAs based on comparative effectiveness

to reduce glycemia and weight, as well as impact on CV risk

EST 18 PCU Track 1 Session 3 pmiCME GLP-1 RA

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