This document discusses glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and compares them to other diabetes medications. It provides an overview of GLP-1 RAs, noting they are more effective at lowering A1C than other classes but also carry a lower risk of hypoglycemia. The document compares specific GLP-1 RAs such as liraglutide, exenatide, and lixisenatide, noting they differ in terms of amino acid homology to human GLP-1 and risk of antibody formation. DPP-4 inhibitors are also discussed and shown to result in lower GLP-1 levels than exogenous GLP-1 analog administration.

1. DM-Type 2
Role of GLP-1 RA
Mohammad Daoud, MD
Consultant Endocrinologist –ABIM Certified
KAMC – Jeddah

2. DM and GLP-1 RA
Objectives
What do we know about DM?
GLP 1 RA : Overview & Head to Head
GLP-1 RA and Guidelines
Take home messages

3. What Do We Know About ?
-DM
-DM Medications

4. Type 2 Diabetes Prevalence
MI, myocardial infarction.
1. IDF Diabetes Atlas 6th Edition 2014 http://www.idf.org/diabetesatlas; 2. The Emerging Risk Factors Collaboration.
JAMA. 2015;314(1):52-60.
4
This will rise to
592 million by 20351
Disease status
at baseline
Hazard ratio
(95% Cl)a
Diabetes, stroke, and MI 6.9 (5.7, 8.3)
Stroke and MI 3.5 (3.1, 4.0)
Diabetes and stroke 3.8 (3.5, 4.2)
Diabetes and MI 3.7 (3.3, 4.1)
MI 2.0 (1.9, 2.2)
Stroke 2.1 (2.0, 2.2)
Diabetes 1.9 (1.8, 2.0)
None 1.0 (Ref)
Globally, 387 million people are
living with diabetes1 All-cause mortality by disease status of
participants at baseline2
Hazard ratio
(95% CI)
1.0 2.0 4.0 8.0 16.0

5. Type 2 diabetes is NOT a mild disease
Diabetic
Retinopathy
Leading cause
of blindness
in working age
adults1
Diabetic
Nephropathy
Leading cause of
end-stage renal disease2
Cardiovascular
Disease
Stroke
2 to 4 fold increase
in
cardiovascular
mortality and stroke3
Diabetic
Neuropathy
Leading cause of
non-traumatic lower
extremity
amputations5
8/10 diabetic patients
die from CV events4
1 Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99–S102. 2Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94–
S98.
3 Kannel WB, et al. Am Heart J 1990; 120:672–676. 4Gray RP & Yudkin JS. In Textbook of Diabetes 1997.
5Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78–S79.
Mild Type 2 Diabetes ?

6. Over time, glycaemic control deteriorates
*Diet initially then sulphonylureas, insulin and/or metformin if FPG>15 mmol/L
†ADA clinical practice recommendations. UKPDS 34, n=1704
UKPDS 34. Lancet 1998:352:854–65; Kahn et al. (ADOPT). N Engl J Med 2006;355:2427–43
6.2% – upper limit of normal range
Conventional*
Glibenclamide
Metformin
Insulin
UKPDS
MedianHbA1c(%)
6.0
7.0
8.0
9.0
Years from randomisation
2 4 6 8 100
7.5
8.5
6.5
Recommended
treatment
target <7.0%†
ADOPT Glibenclamide
Metformin
Rosiglitazone
8.0
6.0
7.5
7.0
6.5
Time (years)
0 2 3 4 51

7. *
HbA1c<8.0%
(<64 mmol/mol)
Achievement of the ABC Goals has improved, but remains suboptimal among adults with diabetes
Stark Casagrande S et al. Diabetes Care. 2013;36(8):2271-2279.
ABC, haemoglobin A1c, BP, blood pressure; HbA1c, glycosylated haemoglobin; LDL, low-density lipoprotein;
NHANES, National Health and Nutrition Examination Survey.
Prevalence of meeting ABC goals among adults aged ≥20 years with diagnosed diabetes, NHANES 1988–2010. Estimates are age- and sex-standardised to the 2007–2010 diabetic
NHANES population. *p<0.01, estimates are compared with those of 2007–2010. †p<0.05, estimates are compared with those of 2007–2010.
90
80
70
60
50
40
30
20
10
0
Adultswithdiabetes(%)
HbA1c<7.0%
(<53 mmol/mol)
HbA1c <7.0%
BP <130/80 mmHg,
and LDL <2.6 mmol/L
1988−1994 1999−2002 2003−2006 2007−2010
*
*
*
*
†
NHANES (2007-2010)

8. Hypoglycemia in Recent Major Clinical Trials
• After the results became available, hypoglycemia was
identified as an area of concern in 3 recent major clinical trials
in which intensive glucose control was compared with
standard glucose control:
– ACCORD1
– VADT2
– ADVANCE3
8
ACCORD=Action to Control Cardiovascular Risk in Diabetes; ADVANCE=Action in Diabetes and Vascular Disease: Preterax and Diamicron MR
Controlled Evaluation; VADT=Veterans Affairs Diabetes Trial.
1. ACCORD Study Group et al. N Engl J Med. 2008;358:2545–2559.
2. Duckworth W et al. N Engl J Med. 2009;360:129–139.
3. ADVANCE Collaborative Group et al. N Engl J Med. 2008;358:2560–2572.

9. Anti-diabetic treatment options for T2DM
DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT2, sodium glucose co-transporter-2; T2DM, type 2 diabetes
mellitus
Sulphonylureas
Metformin
Thiazolidinediones
1960s 1970s 1980s 1990s1950s 2000s 2010s
Human
insulin
GLP-1 receptor
agonists
DPP-4 inhibitors
SGLT-2
inhibitors

10. SU TZD DPP-4i GLP-1RA
Insulin
(Basal)
Physiologi
cal
action(s)
↑ Insulin
secretion
↑ Insulin
sensitivity
↑ Insulin
secretion†
↓ Glucagon
secretion†
↑ Insulin
secretion†
↓ Glucagon
secretion†
Slows gastric
emptying
↑ satiety
↑ Glucose
disposal
↓ Hepatic
glucose
production
Efficacy
(↓HbA1c)
High High
Intermedia
te
High Highest
Hypoglyca
emia risk
Moderate Low Low Low High
Weight
effect ↑ ↑ ↔ ↓ ↑
Major side
effects
Hypoglycae
mia
Oedema
Heart
failure
Bone
fractures
Rare GI
Hypoglycae
mia
Beyond Metformin: Pros/Cons
*Limited comparative data are available; †Glucose dependent.
DPP-4i, dipeptidyl peptidase-4 inhibitor; GI, gastrointestinal; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycosylated haemoglobin; SU, sulphonylurea; TZD, thiazolidinedione; ↑,
increase; ↓, decrease; ↔, neutral.
Adapted from Inzucchi SE et al. Diabetologia 2012;55:1577–1596.

14. Incretins
Basics to Remember

15. Reduced Incretin Effect inType 2
Diabetic Patients
0
20
40
60
80
INSULIN(mU/L)
0 30 60 90 120 150 180
TIME (min)
Control Subjects
Intravenous Glucose
Oral Glucose
*
* *
** * *
0
20
40
60
80
INSULIN(mU/L)
0 30 60 90 120 150 180
TIME (min)
Type 2 Diabetic Patients
*
*
*
Nauck M, et al. Diabetologia. 1986;29:46-52.
Incretin
effect

16. Elevated glucagon levels in patients with T2DM
T2DM, type 2 diabetes mellitus
T2DM patients, n=54; Normal subjects, n=33.
Toft-Nielson MB et al. J Clin Endocrinol Metab 2001;86:3717–3723
P<0.001
Postprandial Glucagon
0 60 120 180 240
25
PlasmaGlucagon(pmol/l)
Minutes
T2DM patients
Normal subjects
20
15
10
5
0
Fasting Glucagon

17. Pancreas
Stomach
Cardiovascular
system
Brain
Liver
Adapted from Baggio, Drucker. Gastroenterol 2007;132:2131–57
Blood pressure
Satiety
Gastric
emptying
Glucose
production
Glucose-dependent
insulin secretion
Insulin synthesis
Glucose-dependent
glucagon secretion
GLP-1: Incretin hormone with multiple
physiologic effects
β
β
α
β
α
L-cells secrete GLP-1
 degraded by DPP-4
GLP-1
Intestine

18. N=10 patients with type 2 diabetes. Patients were studied on two occasions. A regular meal and drug
schedule was allowed for one day between the experiments with GLP-1 and placebo.
*p<0.05 GLP-1 vs. placebo
Adapted from Nauck MA et al Diabetologia 1993;36:741–744.
Effects of GLP-1 on Insulin and Glucagon
Shown to Be Glucose Dependent in Type 2 Diabetes
With hyperglycemia
GLP-1 stimulated insulin
and suppressed glucagon.
Glucose
(mmol/L)
Glucagon
(pmol/L)
Time (minutes)
250
200
150
100
50
15.0
12.5
10.0
7.5
5.0
20
15
10
5
0 60 120 180 240
Placebo
GLP-1 infusion
Insulin
(pmol/L)
*
*
* * *
*
*
*
* *
* * *
*
* * * *
*
When glucose levels
approached normal,
insulin levels
declined
and glucagon was no
longer suppressed.
Infusion

19. • Belongs to the group of incretin
hormones
• Produced by L-cells in distal gut (and
neurons in hypothalamus)
• Native GLP-1 is a 31 amino acid
polypeptide
• Cleaved from pro-glucagon
• Degraded by the enzyme DPP-4
(T1/2= 1.5-2.1 min)
Role of GLP-1
DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1
Baggio L, Drucker J. Gastroenterol 2007; 132: 2131–57
Proteolytic inactivation
by DPP-4
7
37
9
His Ala Thr Thr SerPheGlu Gly Asp
Val
Ser
SerTyrLeuGluGlyAlaAla GlnLys
Phe
Glu
Ile Ala Trp Leu GlyVal Gly ArgLys

20. Therapeutic Strategies to Enhance
Incretin Action
DPP-4 inhibitors (Incretin enhancers)
Purpose: Prevent degradation of endogenously
released incretin hormones to elevate plasma
levels of the active incretins
DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1.
1. Deacon C et al. Diabetes. 1995;44:1126–1131.
2. Brubaker PL. Trends Endocrinol Metab. 2007;18(6):240–245.

21. Therapeutic Strategies to Enhance
Incretin Action1,2
• GLP-1 agonists
(GLP-1 receptor activators; Incretin Mimetics)
Purpose: Raise agonist plasma concentrations into the
pharmacologic range
– DPP-4- Resistant GLP-1 mimetics
– GLP-1 Analogues with delayed absorption
DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1.
1. Deacon C et al. Diabetes. 1995;44:1126–1131.
2. Brubaker PL. Trends Endocrinol Metab. 2007;18(6):240–245.

23. 97% amino acid
homology to
human GLP-1
53% amino acid
homology to human GLP-1
1. Victoza. Summary of Product Characteristics; 2. Byetta. Summary of Product Characteristics; 3. Lyxumia. Summary of
Product Characteristics. Christensen et al. Idrugs. 2009;12:503–513; Ratner et al. Diabet Med. 2010;27:1024–1032.
Native human GLP-1
Liraglutide
Exenatide
GLP-1RAs Are Not All the Same
LysLysLysLys LysLys
Lixisenatide
50% amino acid
homology to human GLP-1
GLP-1, glucagon-like peptide-1; GLP-1RAs, glucagon-like peptide-1 receptor agonists.
0
20
40
60
80
Liraglutide Exenatide Lyxumia
Percentageofpatientswith
positiveantibodystatus
69.83
382
8.61

24. Glaesner W et al. Diabetes Metab Res Rev 2010;26:287‒296
GLP-1RAs Are Not All the Same
GLP-1, glucagon-like peptide-1; GLP-1RAs, glucagon-like peptide-1 receptor agonists.
Dulaglutide
GLP-1
peptide
analogues
Linker
peptide
Modified IgG4 Fc
domain
Albiglutide
Human
Albumin
Human GLP-1
peptide
analogue 1
Human GLP-1
peptide
analogue 2
Alanine 8 -> glycine

25. Antibody formation is higher for exendin-4-derived agonists
NR, not reported
1. Victoza. Summary of Product Characteristics; 2. Byetta. Summary of Product Characteristics; 3. Lyxumia. Summary of Product Characteristics; 4. Pratley RE et al. Lancet Diabetes Endocrinol
2014;2:289–297; 5. Dungan KM et al. Lancet 2014; 384:1349–1357
8.6
69.8
3.7
0
10
20
30
40
50
60
70
80
90
100
Liraglutide Exenatide Lixisenatide Albiglutide Dulaglutide Semaglutide
Patientswithpositive
antibodystatus(%)
NR
1 2 3 4 5

26. DPP-4 inhibitors result in lower levels of GLP-1 than exogenous
administration of a GLP-1 analogue
GLP-1 RA Liraglutide DPP-4 inhibitor Vildagliptin
Time (h)
30
60
90
120
8 1612 20 24
0
GLP-1(pmol/L)
Liraglutide dose
Time (h)
30
60
90
120
8 1612 20 24
0
GLP-1(pmol/L)
Vildagliptin dose
Adapted from: Degn et al. Diabetes 2004;53:1187–94; Mari et al. J Clin Endocrinol Metab
2005;90:4888–94
*GLP-1 levels for liraglutide calculated as 1.5% free liraglutide

27. GLP-1 RA : Head to Head

28. GLP-1 as a therapeutic target
Liraglutide
Exenatide
BID
Liraglutide Exenatide
OW
LixisenatideExenatide BID
Exenatide
OW
Lixisenatide &
Albiglutide
submitted for
FDA review
Albiglutide
submitted for
EMA review
Dulaglutide
EMA submission
expected
Dulaglutide
FDA submission
expected
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

29. Additional physiological benefits are observed at pharmacological
levels of GLP-1
DPP-4is, dipeptidyl peptidase-4 inhibitors; GLP-1, glucagon-like peptide 1; GLP-1RAs, glucagon-like peptide 1 receptor agonists
Adapted from Holst et al.1
1. Holst JJ et al. Trends Mol Med 2008;14:161–168; 2. Flint A et al. Adv Ther 2011;28:213–226
 Gastric
emptying
Physiological
GLP-1 levels
Pharmacological
GLP-1 levels
GLP-1 effects
IncreasingplasmaGLP-1
concentrations
GLP-1RAs
DPP-4is
Insulin
 Glucagon
=  Plasma glucose2
 Appetite
 Food intake
= Weight loss2

32. –0.2
LEAD trials with Liraglutide:
Reductions in HbA1c
*Significant vs. comparator
Marre et al. Diabetic Medicine 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90
(LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care
2009;32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:2046-2055 (LEAD-5); Buse et al.
Lancet 2009;374 (9683):39–47 (LEAD-6)
ChangeinHbA1c(%)
0.0
–0.4
–0.6
–0.8
–1.0
–1.2
–1.4
SU
combination
(LEAD-1)
Met
combination
(LEAD-2)
Met + TZD
combination
(LEAD-4)
Met + SU
combination
(LEAD-5)
–1.6
–1.3
–1.5–1.5
Monotherapy
(LEAD-3)
51% 43%
–1.4–1.3
–1.6
–1.2
–1.5
–1.3
Met ± SU
combination
(LEAD-6)
–1.1–1.1
–0.9
–0.8
–1.1
–0.5
Exenatide
Glimepiride
Rosiglitazone
Glargine
Glimepiride
Placebo
–0.8
Liraglutide 1.8 mgLiraglutide 1.2 mg
*
*
*
* * *
*
*

33. Percentage of patients reaching ADA targets when adding
Liraglutide
***p<0.0001 **p<0.001; *p<0.05 vs. comparator; patients reaching HbA1c ADA targets for overall population
(LEAD-4,-5) add-on to diet and exercise failure (LEAD-3); or add-on to monotherapy (LEAD-2,-1)
Marre et al. Diabetic Med 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81
(LEAD-3); Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:2046–55 (LEAD-5); Buse et al. Lancet
2009; 374:39–47 (LEAD-6)

34. Meta-analysis: early use of Liraglutide achieved a greater
change in HbA1c than late use
Garber et al. Diabetes 2011;60(Suppl. 1):967-P
-1.38
-0.82
-1.55
-1.18
-0.46
0.09
-1.8
-1.6
-1.4
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
0.2ChangeinHbA1c(%)
Early
Diabetes duration: 6 years
(≤1 OAD)
Late
Diabetes duration: 9 years
(2 OADs)
p=0.0010
p=0.0027
p<0.0001
Liraglutide 1.2 mg
Liraglutide 1.8 mg
Placebo
OAD, oral antidiabetic drug
Analysis includes data from LEAD-1–6 and the Lira vs. DPP-4i study

35. Changeinbodyweight
(kg)
0.0
-0.5
-1.0
-1.5
-2.0 -1.8-2.0
51%43%
-2.5
-2.8
-2.5
-3.0
-3.2
-3.5
2.5
2.0
1.5
1.0
0.5
-0.2
Exenatide
-2.9
Placebo
Glimepiride
Rosiglitazone
Glargine
Glimepiride
+1.1
+1.6
+0.6
+1.0
+2.1
Liraglutide 1.8 mg *Significant vs. comparator
SU
combination
(LEAD-1)
Met
combination
(LEAD-2)
Met + TZD
combination
(LEAD-4)
Met + SU
combination
(LEAD-5)
Monotherapy
(LEAD-3)
Met ± SU
combination
(LEAD-6)
-2.1
-2.6
0.3
-1.0
*
*
*
*
*
*
* *
Liraglutide 1.2 mg
Marre et al. Diabetic Medicine 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et
al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones et al.
Diabetologia 2009;52:2046-2055 (LEAD-5); Buse et al. Lancet 2009;374 (9683):39–47 (LEAD-6)
*
LEAD trials with Liraglutide:
Weight reductions

36. Real-life data: ABCD nationwide liraglutide audit
Ryder et al. Diabetologia 2012;55 (suppl 1):S330 (Abstr 801)
Mean HbA1c was adjusted for baseline HbA1c, ethnicity, gender, age and number of OADs ; p=0.894 for effect of
baseline BMI. All patients received liraglutide 1.2 mg
BMI, body mass index; OADs, oral antidiabetic drugs
50‒54.9
n=33
0.0
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2
-1.4
-1.6
ChangeinHbA1c(%)
25‒29.9
n=37
30‒34.9
n=161
35‒39.9
n=204
40‒44.9
n=123
45‒49.9
n=76
Baseline BMI category (kg/m2) Baseline BMI category (kg/m2)
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
-3.5
-4.5
-4.0
-5.0
Changeinweight(kg)
25‒29.9
n=34
35‒39.9
n=182
30‒34.9
n=153
40‒44.9
n=119
50‒54.9
n=29
45‒49.9
n=71
Body weight reduction from
baseline
HbA1c reduction from baseline

37. When used to treat type 2 diabetes liraglutide
consistently reduces SBP
ChangeinSBP(mmHg)
SU
combination
LEAD-1
Met
combination
LEAD-2
Met + TZD
combination
LEAD-4
Met + SU
combination
LEAD-5
Mono-
therapy
LEAD-31
–5
–6
–7
–4
–3
–2
–1
0
–2.8
–2.6
–2.8
–6.7
Liraglutide 1.8 mgLiraglutide 1.2 mg
–5.6
–4.0
–2.3
–2.1
–3.6
*
*
*
*
*
*
Met ± SU
combination
LEAD-6
–2.5
–2.0
–0.7
0.4 0.5
–0.9
Glimepiride
Glimepiride
Rosiglitazone
Glargine
Exenatide
–1.1
Placebo
*Significant vs. comparator
Marre et al. Diabetic Medicine 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90
(LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care
2009;32:1224–30 (LEAD-4); Buse et al. Lancet 2009;374 (9683):39–47 (LEAD-6); Colagiuri et al.

38. -0.17
-0.08
-0.28
0.24
0.17
-0.09
-0.06
-0.19
0.00
0.07
-0.22
-0.05
-0.09
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
0.3
Changefrombaseline(mmol/l)
Liraglutide 1.8 mg
N=1496
Rosiglitazone
N=219
Glimepiride
N=467
Glargine
N=225
Exenatide
N=210
Sitagliptin
N=201
Liraglutide effect on fasting lipid levels
LEAD 1–6: meta-analysis
*p<0.05; **p<0.01; ***p<0.0001; all vs baseline; † is used instead of * to indicate a significant increase from baseline
LDL-C, low-density lipoprotein cholesterol; T2DM, type 2 diabetes
Fonseca VA et al. International Diabetes Federation 21st World Diabetes Congress, 4–8 December 2011, Dubai, UAE
***
***
**
***
††
††
LDL-CTotal cholesterol Triglyceride
**

39. Subjectsreachingendpoint(%)
Adapted from Zinman et al. Diabetes Obes Metab 2011;in press
*
***
Liraglutide
1.8 mg
(n=1513)
Liraglutide
1.2 mg
(n=1077)
Exenatide
(n=186)
Sitagliptin
(n=210)
SU
(n=447)
TZD
(n=226)
Insulin
glargine
(n=226)
Placebo
(n=505)
*
***
*
*
*
*** *
***
**
*p<0.0001 vs. liraglutide 1.8 mg; **p<0.001 vs. liraglutide 1.8 mg; ***p<0.0001 vs. liraglutide 1.2 mg
HbA1c<7.0% + no weight gain + no hypos
• A meta-analysis showed significantly more subjects achieved this triple
composite endpoint with liraglutide than comparators
Composite Endpoint: Meta-analysis
HbA1c <7.0%, No Weight Gain, No Hypoglycaemia

40. GLP-1RA comparative studies: Change in HbA1c
BID, twice a day; ETD, estimated treatment difference; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycosylated haemoglobin;
OD, once daily; OW, once weekly
Buse JB et al. Lancet 2009;374:39–47 (LEAD-6); Buse JB et al. Lancet 2013;381:117–24 (DURATION-6); Pratley RE et al. Lancet Diabetes Endocrinol 2014;2:289–97 (HARMONY-7); Dungan KM
et al. Lancet 2014;384:1349–1357 (AWARD-6)
-1.6
-1.4
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
LEAD-6 DURATION-6 Harmony-7 AWARD-6
ChangeinHbA1c(%)
p<0.0001
p=0.085
LEAD-6 DURATION-6 HARMONY-7
Baseline HbA1c: 8.2% 8.1% 8.2% 8.2%8.5%8.4%
p=0.002
AWARD-6
8.1% 8.1%
Liraglutide 1.8 mg OD Exenatide 10 µg BID Exenatide 2 mg OW
Albiglutide 50 mg OW Dulaglutide 1.5 mg
ETD (95% CI) = –0.06 (–0.19, 0.07),
p<0.0001 for non inferiority vs. liraglutide

41. GLP-1RA comparative studies: Body weight
BID, twice a day; GLP-1RA, glucagon-like peptide-1 receptor agonist; OD, once daily; OW, once weekly
Buse JB et al. Lancet 2009;374:39–47 (LEAD-6); Buse JB et al. Lancet 2013;381:117–24 (DURATION-6); Pratley RE et al. Lancet Diabetes Endocrinol 2014;2:289–97 (HARMONY-7); Dungan KM
et al. Lancet 2014;384:1349–1357 (AWARD-6)
Baseline body
weight (kg):
–3.2
–3.6
–2.2
-3.6
–2.9
–2.7
–0.6
-2.9
-4.0
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
LEAD-6 DURATION-6 Harmony-7 AWARD-6
Changeinbodyweight(kg)
p<0.001
p=0.22
93.1 93.0 90.991.1
LEAD-6 DURATION-6 HARMONY-7 AWARD-6
93.894.4
p<0.01
Liraglutide 1.8 mg OD Exenatide 10 µg BID Exenatide 2 mg OW
Albiglutide 50 mg OW Dulaglutide 1.5 mg
p<0.0001
91.792.8

42. GLP-1 RA : Safety

44. Contraindicated in patients with :
-Personal or family history of Medullary Thyroid Carcinoma
(MTC)
-Multiple Endocrine Neoplasia type 2 (MEN-2);
(MTC is part of it + PHPTH + Pheo…)

45. S

46. Most frequent side effects for GLP-1RAs
• Headache
• Gastrointestinal disorders
- Nausea
- Diarrhoea
- Vomiting
- Dyspepsia
- Anorexia
• Injection site reactions
GI-side effects are most pronounced in the initial treatment phase
and decrease in most patients during continuous treatment.
GI, gastrointestinal; GLP-1RAs, glucagon-like peptide-1 receptor agonists.
1. Victoza. Summary of Product Characteristics; 2. Byetta. Summary of Product Characteristics; 3. Lyxumia. Summary of
Product Characteristics; 4. Pratley et al. Int J Clin Pract. 2011;65:397–407
Proportion of subjects with nausea by week
and treatment4
Liraglutide 1.2 mg
Liraglutide 1.8 mg
Sitagliptin 100 mg
Patientsexperiencingnausea
(%)
Time (weeks)
0
2
4
6
8
10
12
14
16
0 4 8 12 16 20 24 28 32 36 40 44 48 52

47. Safety : Pancreas

49. GLP-1 RA and Guidelines

50. 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
+
high
low risk
gain
edema, HF, fxs
low
Thiazolidine-
dione
intermediate
low risk
neutral
rare
high
DPP-4
inhibitor
highest
high risk
gain
hypoglycemia
variable
Insulin (basal)
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Basal Insulin +
Sulfonylurea
+
TZD
DPP-4-i
GLP-1-RA
Insulin§
or
or
or
or
Thiazolidine-
dione
+
SU
DPP-4-i
GLP-1-RA
Insulin§
TZD
DPP-4-ior
or
or GLP-1-RA
high
low risk
loss
GI
high
GLP-1 receptor
agonist
Sulfonylurea
high
moderate risk
gain
hypoglycemia
low
SGLT2
inhibitor
intermediate
low risk
loss
GU, dehydration
high
SU
TZD
Insulin§
GLP-1 receptor
agonist
+
SGLT-2
Inhibitor
+
SU
TZD
Insulin§
Metformin
+
Metformin
+
or
or
or
or
SGLT2-i
or
or
or
SGLT2-i
Mono-
therapy
Efficacy*
Hypo risk
Weight
Side effects
Costs
Dual
therapy†
Efficacy*
Hypo risk
Weight
Side effects
Costs
Triple
therapy
or
or
DPP-4
Inhibitor
+
SU
TZD
Insulin§
SGLT2-i
or
or
or
SGLT2-i
or
DPP-4-i
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):
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-RAMealtime Insulin
Insulin (basal)
+
Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-
ADA 2015

51. 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
+
high
low risk
gain
edema, HF, fxs
low
Thiazolidine-
dione
intermediate
low risk
neutral
rare
high
DPP-4
inhibitor
highest
high risk
gain
hypoglycemia
variable
Insulin (basal)
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Basal Insulin +
Sulfonylurea
+
TZD
DPP-4-i
GLP-1-RA
Insulin§
or
or
or
or
Thiazolidine-
dione
+
SU
DPP-4-i
GLP-1-RA
Insulin§
TZD
DPP-4-i
GLP-1-RA
high
low risk
loss
GI
high
GLP-1 receptor
agonist
Sulfonylurea
high
moderate risk
gain
hypoglycemia
low
SGLT2
inhibitor
intermediate
low risk
loss
GU, dehydration
high
SU
TZD
Insulin§
GLP-1 receptor
agonist
+
SGLT-2
Inhibitor
+
SU
TZD
Insulin§
Metformin
+
Metformin
+
or
or
or
or
SGLT2-i
or
or
or
SGLT2-i
Mono-
therapy
Efficacy*
Hypo risk
Weight
Side effects
Costs
Dual
therapy†
Efficacy*
Hypo risk
Weight
Side effects
Costs
Triple
therapy
or
or
DPP-4
Inhibitor
+
SU
TZD
Insulin§
SGLT2-i
or
or
or
SGLT2-i
or
DPP-4-i
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):
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-RAMealtime Insulin
or
or
or
Insulin (basal)
+
Avoidance of Hypoglycemia
Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-
ADA 2015

52. 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
+
high
low risk
gain
edema, HF, fxs
low
Thiazolidine-
dione
intermediate
low risk
neutral
rare
high
DPP-4
inhibitor
highest
high risk
gain
hypoglycemia
variable
Insulin (basal)
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Basal Insulin +
Sulfonylurea
+
TZD
DPP-4-i
GLP-1-RA
Insulin§
or
or
or
or
Thiazolidine-
dione
+
SU
DPP-4-i
GLP-1-RA
Insulin§
TZD
DPP-4-i
GLP-1-RA
high
low risk
loss
GI
high
GLP-1 receptor
agonist
Sulfonylurea
high
moderate risk
gain
hypoglycemia
low
SGLT2
inhibitor
intermediate
low risk
loss
GU, dehydration
high
SU
TZD
Insulin§
GLP-1 receptor
agonist
+
SGLT-2
Inhibitor
+
SU
TZD
Insulin§
Metformin
+
Metformin
+
or
or
or
or
SGLT2-i
or
or
or
SGLT2-i
Mono-
therapy
Efficacy*
Hypo risk
Weight
Side effects
Costs
Dual
therapy†
Efficacy*
Hypo risk
Weight
Side effects
Costs
Triple
therapy
or
or
DPP-4
Inhibitor
+
SU
TZD
Insulin§
SGLT2-i
or
or
or
SGLT2-i
or
DPP-4-i
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):
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-RAMealtime Insulin
Insulin (basal)
+
or
or
or
Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-
Avoidance of Weight Gain
ADA 2015

55. GLP-1 RA: Other Novel Uses

57. Basal insulin added to GLP-1 receptor agonist: LIRA-DETEMIR
study design
MET, metformin; SU, sulphonylurea
DeVries JH et al. Diabetes Care 2012;35:1446–1454
Patients with sub-
optimal control on
MET  SU
Addition of
liraglutide
1.8 mg to MET
Continue MET + liraglutide 1.8 mg
(Observational group)
Main study n=498; extension n=461
Continue MET + liraglutide 1.8 mg
(Control group)
Main study n=161; extension n=122
Addition of insulin detemir to
MET + liraglutide
Main study n=162; extension n=140
Open-label
randomisation (1:1)
Main study
26 weeks
Extension
26 weeks
39%
61%
12-week
run-in phase
HbA1c <7%
HbA1c ≥7%

58. Addition of insulin detemir to liraglutide:
Change in HbA1c (%)
Mean (2SE); data are LOCF
Last observation before intensification is included as LOCF in the initial treatment group; ANCOVA on FAS LOCF for difference in randomised phase
ANCOVA, analysis of covariance; FAS, full analysis set; HbA1c, glycosylated haemoglobin; IDet, insulin detemir; LOCF, last observation carried forward;
SE, standard error
Rosenstock J et al. J Diabetes Complications 2013;27:492–500
Time (weeks)
Run-in phase Randomised phase (Weeks 0 to 52)
–0.50
+0.01
p<0.0001
8.5
8.0
7.5
7.0
6.5
6.0
HbA1c(%)
−12 −8 −4 0 4 8 12 16 20 24 28 32 36 40 44 48 52
Liraglutide 1.8 mg
Liraglutide 1.8 mg + IDet
Observational liraglutide 1.8 mg

59. Addition of insulin detemir to liraglutide:
Mean change in body weight
Mean (2SE); data are LOCF
Last observation before intensification is included as LOCF in the initial treatment group; ANCOVA on FAS LOCF for difference in randomised phase
ANCOVA, analysis of covariance; FAS, full analysis set; IDet, insulin detemir; LOCF, last observation carried forward; SE, standard error
Rosenstock J et al. J Diabetes Complications 2013;27:492–500
-1.02
-0.05
p=0.04
-12 -8 -4 0 4 8 12 16 20 24 32 36 40 44 48 52
Run-in phase Randomised phase (Weeks 0 to 52)
28
0
-1
-2
-3
-4
-5
-6
Changeinbodyweight(kg)
Liraglutide 1.8 mg
Liraglutide 1.8 mg + IDet
Observational liraglutide 1.8 mg
Time (weeks)

60. Observational liraglutide 1.8 mg Liraglutide 1.8 mg Liraglutide 1.8 mg + IDet
Addition of insulin detemir to liraglutide:
Subjects meeting targets at week 52
Data for the randomised groups are estimates from logistic regression analyses for the FAS LOCF. Data for the observational group are for the FAS LOCF; logistic regression analyses were not
performed. Patients in the extension IDet-intensified group are included in their initial treatment groups until they received IDet
AACE, American Association of Clinical Endocrinologists; ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes
Rosenstock J et al. J Diabetes Complications 2013;27:492–500
Patientsreachingtarget(%)
72.7
0
10
20
30
40
50
60
70
80
90
0
10
20
30
40
50
60
70
80
90
p<0.0001
p<0.0001
ADA/EASD: HbA1c <7.0% AACE: HbA1c ≤6.5%
Patientsreachingtarget(%)

61. Incretin Therapy
Inpatient –Non ICU setting
For patients who are treated with diet only , oral agents or on low dose
insulin (<0.4 u/kg)
Use of DPP4 Inhibitors + corrective doses
Or
Use of DPP4 Inhibitors + Basal insulin 0.15-0.25 u/kg
Or
GLP-1 RA + Corrective doses
Pilot studies

62. Incretin Therapy
Inpatient –ICU setting
IV infusion of GLP-1 RA + Corrective doses
Lower insulin doses adjustments
Improved LV function after acute MI / CHF patients
SC Exenatide 5-10 mcg bid vs IV insulin in Pediatric burn patient
IV Exenatide infusion :ICU patients
0.05 mg /min bolus? then 0.025 for 24-48 hrs
Lowered risk of hypoglycemia by 50%
Pilot studies

63. To Conclude…

64. Safety …First
Get the maximum benefit
 Early and Strict but Safe
 Avoid hypoglycemia and Wight gain
 Tailor proper Rx and Targets
 Don’t forget other CV Risks

65. GLP-1 RA
GLP-1 RA based therapy is noteworthy for association with low
hypoglycemic risk and weight loss while effective HbA1c drop
Large-scale clinical trials are in progress to clarify the CV safety
and efficacy of the incretin-based therapies in T2DM patients

66. Liraglutide
A once-daily GLP-1 analogue that consistently and significantly
reduced HbA1c by ≥1% (–1.0 to –1.6%)
Significantly lowered body weight up to –3.6 kg and
(sustained up to 2 years)
Has a low risk of hypoglycaemia and generally
well-tolerated, with transient GI side effects

67. Do It Right
Safety
Patient
Disease
Comorbidities
Treatment