Session 10: Drugs

GLP-1 receptor agonists

Dr. Manel Mata

La Mina Primary Health Care Centre. Barcelona. Catalonian Institute of Health.

Grup DAP_Cat, Barcelona Research Support Unit. IDIAP-Jordi Gol. CIBERDEM. RedGDPS (Spanish Network of Primary Care Groups for the Study of Diabetes)

Session 10: Drugs

GLP-1 receptor agonists

Dr. Manel Mata

Conflict of interest disclosure:

Honoraria from AstraZeneca, GlaxoSmithKline, Eli Lilly, Novo Nordisk and Sanofi for the participation in advisory boards and lectures about the treatment of diabetes.

Session 10: DrugsGLP-1 receptor agonists

Agenda

- Mechanism of action and benefits - GLP-1ra in the algorithms- GLP-1ra as alternative to basal insulin- GLP-1ra as alternative to prandial insulin added to basal insulin- Adverse Effects. Cardiovascular and pancreatic safety- Key factors when choosing a GLP-1ra- Messages to take home

The ‘ideal’ drug for type 2 diabetes

• Safe • Efficacious• Durable control• Well‐tolerated• Low risk of hypoglycaemia• Weight neutral or weight loss• Reduction of long term complications

Metformin isthe recommended

first line agent

GLP-1ra are a goodoption in the second

and third steps

GLP-1 is released by the small intestine after meal ingestion and enhances glucose-stimulated insulin secretion (incretin action )

Kerr Saraiva F & Sposito AC. Cardiovasc Diabetol. 2014;13(142)

Pleiotropic effects of GLP-1 and GLP-1ra

Kerr Saraiva F & Sposito AC. Cardiovasc Diabetol. 2014;13(142)

GLP-1ra different effects based on the duration of their action in the receptor

Exenatide BIDLixisenatide

DulaglutideExenatide LAR

AlbiglutideLiraglutide

Madsbad S. Diabetes Obes Metab. 2016;18(4):317-32

BrandName

InjectionFrequency

UsualDose

Clinical Trial Program

Exenatide BID Byetta® Twice daily 10 μg AMIGOLixisenatide Lyxumia® Once daily 20 mg GetGoalLiraglutide Victoza® Once daily 1.2-1.8 mg LEADERExenatide LAR Bydureon® Once weekly 2 mg DURATIONAlbiglutide Eperzan® Once weekly 50 mg HARMONYDulaglutide Trulicity® Once weekly 1.5 mg AWARD

GLP-1 receptor agonists

Favorable effects Adverse effects

HbA1c Nausea

Weight Diarrhea

Satiety Vomiting

Blood Pressure Heart Rate

No Hypoglycaemia Pancreatitis

Neutral or CVD Pancreas cancer (?)

GLP-1ra in the algorithm

of T2DM treatment

Need for personalized care: the benefits versus risks of diabetes therapy must be

assessed for each patient

Based on:

Preferences, needs andvalues of the patient

Shared decisions

Resources and support

ADA/EASD Position StatementA patient-centered approach

Patients’ preferences related to the effects of T2DM treatmentMonthly willingess to pay in Denmark

Bøgelund M et al. Curr Med Res Opin 2011;27(11):2175-83

N=270

WTP forBeneficialAttributes

WTP to avoid detrimental

attributes

45-50% of T2DM patients are obese 50-75% of T2DM patients have metabolic syndrome

GlitazonesGlinides

SulfonylureasInsulin

GlitazonesGlinides

SulfonylureasInsulinMetformin

AGiDPP-4i

MetforminAGi

DPP-4iGLP-1raSGLT-2iGLP-1raSGLT-2i

Weight and antidiabetic drugs

The consequences of hypoglycaemia

Cardiovascularcomplications3

Weight gain due to defensive eating5

Coma3

Increased risk of car accident6

Hospitalisation costs4

Loss of consciousness3

Increased risk of seizures3

Death2,3

Increased risk of dementia1

1Whitmer RA, et al. JAMA. 2009;301:1565–1572; 2Bonds DE, et al. BMJ. 2010;340:b4909; 3Barnett AH. Curr Med Res Opin. 2010;26:1333–1342; 4Jönsson L, et al. Value Health. 2006;9:193–198;

5Foley JE, Jordan J. Vasc Health Risk Manag. 2010;6:541–548; 6Cox DJ. Am J Med Sci. 2013;345:263-5; 7McEwan P, et al. Diabetes Obes Metab. 2010;12:431–436.

Reduced quality of life7

Hypoglycaemia

BenefitsHbA1c reduction

Reduced complications

SafetyHypoglycaemia

Weight gainSpecific adverse effectsLong-term side effects

Cost

T2DM treatment choiceRisks vs Benefits

0 € 500 € 1.000 € 1.500 € 2.000 €

Metformina

Sulfonilureas

Repaglinida

Inh. α-Glucosidases

Pioglitazona

IDPP-4

ISGLT-2

ArGLP-1

Annual cost of antidiabetic drugs in Spain

Evolution of new antidiabetic drugsin Catalunya (Spain) from 2007 to 2013

4,9 5,2 5,5 5,6 5,6 5,8 5,7

0,6

3,3

6,910

1213,2

3,9 4 3,7 3,2 2,61,5 1,2

0,1 0,4 0,5 0,7 0,9

-5

0

5

10

15

2007 2008 2009 2010 2011 2012 2013

%patients

DPP4i

Glinides

Glitazones

GLP1ra

2014

GLP-1ra in the 2015 Nice guideline

Second Intensification of drug treatment(triple therapy)

GLP-1ra in the 2015 Nice guideline

Stop if no efficacy (HbA1c+weight loss)

GLP1ra vs oral antidiabetic drugs

GLP-1ra vs DPP4i in patients treated with Metformin

–1.6

–1.5

–1.0

–0.5

1. Bergenstal et al. Lancet. 2010;376:431–4392. Pratley et al. Int J Clin Pract. 2011;65:397–407.3. Nauck M et al. Lancet 2014; 384 (9951): 1349-574. Ahrén B, et al. Diabetes Care 2014; 37(8):2141-8

0

Weight (kg): -2.3 -0.8 -3.0 -1.2 -3.0 -1.5 -1.2 -0.9 Hypos (%) : 2.0 1.5 5.0 5.0 10.2 4.8 3 1.7

∆m

ean

HbA

1c fr

om b

asel

ine

(%)

‐1.5

Exe 1/w

Exenatide LAR vs Sitagliptin1

Sita1/d

‐0.9

Dula 1.51/w

‐1.1

Dulaglutidevs Sitagliptin3

Sita1/d

‐0.4

Lira 1.8 1/d

Liraglutide vsSitagliptin2

‐1.5

‐0.9

Sita1/d

Albiglutide vsSitagliptin4

‐0.6

‐0.3

Sita1/d

Albi1/w

GLP1ra vs basal insulin

GLP-1ra vs basal insulin in patients treated with Met SU

–1.6

–1.2

–0.8

–0.4

1. Russell-Jones D et al. Diabetologia 2009; 52:2046-55.2. Diamant M et a. Diabetes Care. 2012; 35(4):683-9.3 Weissman PN, et al. Diabetologia 2014;57:2475-844. Georgino F et al. Diabetes Care. 2015;38(12):2241-9.

0

Weight (kg): -1.8 +1.6 -2.1 +2.4 -1.1 +2.6 -1.9 +1.4 Hypos (%): 27 29 36 56 17 27 54 69

∆m

ean

HbA

1c fr

om b

asel

ine

(%)

‐1.3

Daily Liraglutide1

LEAD 5 Lira Glargine

‐1.1

Weekly Albiglutide3

HARMONY 4 Albi Glargine

Weekly Exenatide2

DURATION 3 Exe Glargine

Weekly Dulaglutide4

AWARD 2 Dula Glargine

‐0.9

‐0.6

–1.4

‐1.2

‐1.0

‐0.7‐0.8

DURATION-3: 79% of patients treated with Once Weekly Exenatide lost weight and reduced HbA1c vs 31% with Glargine

Exenatida semanal

Insulina glargina

Wei

ght c

hang

e fr

om b

asel

ine

(kg)

HbA1c (%) change from baseline

16

12

8

4

0

−4

−8

−12

−16−6 −4 −2 0 2 4 6

79%31%

0%5%

4%1%

16%63%

Modified ITT population, N=448.Diamant M, et al. Lancet. 2010;375:2234-2243.

GLP1ra vs prandial insulinin patients on basal insulin

ConsiderGLP1 ra

GLP-1ra vs prandial insulin in patients on basal insulin

–1.6

–1.2

–0.8

–0.4

1. Diamant M, et al, . Diabetes Care. 2014;37(10):2763-732. Rosenstock J et al. Diabetes Care 2014; 37(8):2317-253. Mathieu C et al. Diabetes Obes Metab. 2014;16(7):636-444. Rosenstock J et al. Poster ADA 2015; Boston, USA

0

Weight (kg): -2.5 +2.1 -0.7 +0.8 -2.8 +0.9 -0.6 +1.4 Major hypos : 2.1 5.2 1.0 2.1 1.0 8.2 0 0

∆m

ean

HbA

1c fr

om b

asel

ine

(%)

‐1.13

EXE 2/d

Daily Exenatidevs Lispro1

Lispro 3/d

‐1.10

LIRA 1/d

‐0.74

Liraglutidevs Aspart3

Aspart1/d

‐0.39

ALBI 1/sem

Albiglutidevs Lispro2

‐0.82

‐0.66

Lispro 3/d

Lixisenatidevs Glulisine4

‐0.6‐0.7

Glulisine3/d

LIXI 1/d

GLP-1ra

Gastrointestinal Adverse EffectsPancreatitis and pancreas cancer

Cardiovascular Safety

GLP1ra Adverse Effects

Adverse reactions

Albiglutide

Placebo

Dulaglutide1.5

Placebo

Liraglutide1.8

Placebo

ExenatideLAR

Placebo

Lixisenatide

Placebo

Diarrhea 13.1 10.5 12.6 6.7 17.1 3 13 0 9 3Nausea 11.1 9.6 21.1 5.3 28.4 5.3 27 15 23 4Vomiting 4.2 2.6 12.7 2.3 11 2.3 0 0 7 0Injection‐site reactions

10.5 2.1 0.5 0 2 0 10.5 0 4.6 0

Heart rateincrease(bpm)

+1‐2 Ref +2‐3 Ref +1‐2 Ref 0 Ref 0 Ref

No increase in hypoglycaemiasSmall increase in pancreatitis Risk of pancreas cancer (?)

Incretins and PancreatitisMeta-analysis

55 Randomized trials (N=33,350)0.11% vs 0.11% (OR 1.11; 0.57 to 2.17)

5 Observational studies (N=320,289)0.47% vs 0.47% (OR 0.98; 0.69 to 1.38)

1.11 (0.57 to 2.17)

Li L et al. BMJ. BMJ 2014;348:g2366 doi: 10.1136/bmj.g2366 (Published 14 April 2014)

ConclusionsThe available evidence suggests that the incidence of pancreatitis among patients using incretins is low and that the drugs do not increase the risk of pancreatitis.

Egan AG et al. NEJM 2014; 370(9) Pub Online 27 february 2014

Both agencies agree that assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer, as expressed recently in thescientific literature and in the media, are inconsistent withthe current data.

Although the totality of the data that have been reviewedprovides reassurance, pancreatitis will continue to beconsidered a risk associated with these drugs until more data are available; both agencies continue to investigatethis safety signal.

http://professional.diabetes.org/Presentations_Details.aspx?session=4740

Primary endpoint

Number at riskPlaceboLixisenatide

Cum

ulat

ive

inci

denc

e (%

)

Months30343034

27612788

16001584

515528

1928

0 12 24 36 480

5

10

15

20

25

30

HR (95% CI): 1.017 (0.886, 1.168)

PlaceboLixisenatide

ELIXA: Lixisenatide vs placebo in 6.060 T2DM with a recent coronary event*, mean follow‐up 2 years. 

Secondary VariableHeart Failure Hospitalization

RR 0,96

* AMI or Unestable Angina in the previous 180 days

29/4/16: Novo Nordisk announces that Semaglutide reduces CVD

4/3/16: Novo Nordisk announces that Liraglutide reduces CVD

GLP1ra choice based on:

Head to Head studies?Efficacy

Tolerability

Patient convenience?Frequency of injection

Device

Review of head-to-head comparisons of GLP-1ra Effects on HbA1c

Madsbad S. Diabetes Obes Metab. 2016;18(4):317-32

HbA1c reduction

Liraglutide ****Dulaglutide ****Exenatide OW ***Exenatide BID **Lixisenatide **Albiglutide **

Review of head-to-head comparisons of GLP-1ra Effects on Weight

Madsbad S. Diabetes Obes Metab. 2016;18(4):317-32

Weight reduction

Liraglutide ****Dulaglutide ***Exenatide OW ***Exenatide BID ***Lixisenatide ***Albiglutide *

GLP1ra Adverse effects in 

Head to Head studies

Trujillo JM et al. Ther Adv Endocrinol Metab. 2015 Feb;6(1):19-28

Gastrointestinal AE

Exenatide BID ****Liraglutide ****Dulaglutide ****Exenatide OW ***Lixisenatide **Albiglutide *

EperzanTM

Daily GLP‐1ra

Exenatide BID, Byetta®

Liraglutide,  Victoza®

Lixisenatide,  Lyxumia®

Weekly GLP‐1ra

Exenatide LAR, Bydureon®

Albiglutide,  Eperzan®

Dulaglutide, Trulicity®

How to select a GLP-1ra?

Use in clinical practice should be customized for individual patients, based on clinical profile and patient preferences

HbA1c reduction

Weightloss

Postprandial effect

GI effects

Sitereactions

Frequencyinjection

Device

Exenatide BID ++ ++ +++ ++ + BID +++Lixisenatide ++ ++ +++ ++ + OD +++Liraglutide +++ ++++ + +++ + OD +++Exenatide LAR +++ +++ + +++ +++ OW +Albiglutide + + + + ++ OW ++Dulaglutide +++ +++ + +++ + OW ++++

• GLP‐1ra reduce HbA1c, weight, blood pressure and probably cardiovascular events, but are of limited use in primary care mainly because of its high cost

• GLP‐1ra are preferable in the second and third steps of treatment in obese patients as an alternative to basal or prandial insulin with fewer injections,     no need of blood glucose monitoring or dose adjustments

• Adverse gastrointestinal effects (mainly nausea) are frequent but are usually well tolerated and improve spontaneously after several weeks.  Don’t use them in patients with history of pancreatitis, gastroparesia or severe renal failure

• GLP‐1ra use in clinical practice should be customized to individual patients, based on their clinical profile and patients preferences

Messages to take home

Thanks for your attentionmanelmatacases@gmail.com

CV Outcome trials in Type 2 Diabetes 1

2012 2013 2014 2015 2016 2017 2018 2019 2020

DPP4

GLP1

ORIGINInsulin glargineSanofi (6/´12)

SGLT2 EXSCELExenatide LARAmylin (3/’17)

SAVOR TIMI 53 Saxagliptin

AZ/BMS (6/’13)

EXAMINEAlogliptin

Takeda (12/’13)

CANVAS (interim)Canagliflozin J&J

200 events (subm: 1/’12) 

CAROLINA Linagliptin

BI/Lilly (9/’18)

C‐SCADE 8 EmpagliflozinBI/Lilly (3/’18)

LEADERLiraglutideNovo (1/’16)

TECOSSitagliptin

Merck (12/’14)

ELIXALixisenatideSanofi (5/’14)

REWINDDulaglutideLilly (4/’19)

FREEDOM‐CVO ITCA650  

Servier (7/’17)

Insulin

SUSTAIN 6SemaglutideNovo (1/’16)

DECLAREDapagliflozin

BMS/AZ (04/’19)

CANVAS (final) Canagliflozin500 events J&J (/4‘17)

MK‐3102‐018Omarigliptin

MercK (12/’20)

EMPA‐REG OUTCOME

EmpagliflozinBI/Lilly (8/’15)

‐‐ErtugliflozinMSD (04/’20)

Cardiac effects of GLP-1 and GLP-1ra

Ussher JR, Drucker DJ Circ Res. 2014;114(11):1788‐803

Bergenstal et al. Lancet. 2010;376:431–439. Pratley et al. Int J Clin Pract. 2011;65:397–407.

GLP1ra vs. DPP4i: HbA1c and weight changes

Weight (kg)-0.8 -2.3 -1.2 -2.8 -3.0

aEfficacy data through week 26 in the safety population using an LOCF analysis

Albiglutide (N=246)

Mea

n (S

D) H

bA1c

(%)

Sitagliptina (N=240)

4

8,58,07,57,0

6,0

Weeks

9,0

6,5

0 1 2 3 20 268 12 16

Mean (SD

) HbA

1c mm

ol/mol

75

69

63

57

51

45

Number of patients at each point:Albiglutide 246 242 242 242 242 242 Sitagliptin 234 236 236 236 236 236

HbA1c,a % Albiglutide SitagliptinModel‐adjusted LS mean change from baseline 0.83 0.52

Treatment difference (albiglutide vs. sitagliptin) (CI 95%)P value for superiority

0.32 (0.49, 0.15)0.0003

Harmony 8: Albiglutide vs Sitagliptin in Renal Impaired

a Based on analysis of covariance (ANCOVA)

Model-Adjusteda Change From Baseline in HbA1cAt Week 26 by Severity of Renal Impairment (ITT-LOCF)

Albiglutide

Sitagliptin

Mea

nC

hang

e Fr

om

Bas

elin

e in

HbA

1c, %

Mild60-89

0,2

0,4

0,6

1,2

Moderate30-59

Severe15-29 , mL/min/1.73 m2

0,0

0,8

1,0

n =125

0,800,67

n =122

n =98

0,83

n =99

0,31

n =19

1,08

n =15

0,61

Leiter LA, et al. Diabetes Care 2014;37:2723-30Adapted from Leiter LA, et al. Diabetes Care 2014;37:2723-30 [Supplement]]

Dulaglutide vs sitagliptin vs placeboAWARD-5 trial:1098 T2DM patients on metformin, 52 weeks

HbA1c WeightDU 1.5 -1.22 -3.03DU 0.75 -1.01 -2.60Sita -0.61 -1.53Placebo +0.03 -1.50

Nauck M, et al. Diabetes Care. 2014;37(8):2149-58.

††P , 0.001, superiority vs. sitagliptin; ‡‡P , 0.001, superiority vs. placebo; #, *P , 0.05 vs.sitagliptin and placebo, respectively; ##, **P , 0.001 vs. sitagliptin and placebo, respectively.

AE Lira Gla*

Any hypo 27.4% 28.9%Major hypo 6 0Diarrhoea 10.0% 1.3%Nausea 13.9% 1.3%*Mean daily dose: 24 UI/day

LEAD-5; N=581, 26 weeksHbA1c

Weight

Lira -1.8

Gla +1.6

Lira -1.3

Gla -1.1

Triple therapyGLP-1 RA vs Basal insulin

Russell-Jones D, et al. Diabetologia. 2009;52:2046–55.

AE ExeW Gla*

Hypos** 12% 40%Hypos*** 36% 56%Diarrhoea 12% 6%Nausea 15% 1%* Mean daily dose: 35 UI/d** Symptomatic in patients on Met*** Symptomatic in patients on SU+Met

DURATION-3; N=415, 84 weeks

HbA1c

Weight

Exe -2.1

Gla +2.4

Exe -1.2

Gla -1.0

Triple therapyGLP-1 RA vs Basal insulin

Diamant M, et al. Diabetes Care. 2012;35(4):683–9.

8.4

HbA

1c%

7.47.67.88.08.2

0 4 89 12 16 20 24 28 36 48 52

Albiglutide (N =496) Glargine* (N =239)

0 4 8 12 16 20 24 36 48 5293

94

95

96

97

98

Wei

ght

KG +1,57

-1,06

-0,67-0,79

Weissman PN, et al. Diabetologia 2014;57:2475-84*Mean daily dose: 30UI

Glar Albi Hypos 27,4% 17,5%Nausea 3,7% 9,9%

Triple therapyGLP1ra vs Insulin

Difference: 0.11 (-0.04, 0.27)P no inferiority (margin 0.3)= 0.0086

P superiority = 0.1463

-2.61

Dulaglutide vs insulin Glargine (AWARD 2) add-on to Metformin ± glimepiride, 78 weeks

Georgino F et al. Diabetes Care. 2015;38(12):2241-9.

Dula 1.5 Glargina*

Hypos 54.4% 69.1%Major Hipos 2 2Diarrhea 10.6% 5.7%Nausea 15.4% 1.5%* Mean daily dose: 29 UI

-0.59 -0.62 -0.90

HbA1c

+1.44

-1.33 -1.87

Weight

N=810, 78 weeksGlargine, Dulaglutide 0.75 and 150 mg

Trujillo JM et al. Ther Adv Endocrinol Metab 2015; 6(1):19-28

Review of head-to-head comparisons of GLP-1ra Effects on HbA1c

Trujillo JM et al. Ther Adv Endocrinol Metab 2015; 6(1):19-28

Review of head-to-head comparisons of GLP-1ra Effects on Weight