session 10: drugs glp-1 receptor agonists...glp-1ra different effects based on the duration of their...
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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 [email protected]
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