- GLP-1 receptor agonists are recommended as first-line treatment after metformin for type 2 diabetes due to their ability to reduce weight and cardiovascular risk factors like lipids and blood pressure while improving glycemic control with a low risk of hypoglycemia. Early initiation of GLP-1 agonists may help preserve beta-cell function by reducing glucotoxicity and increasing beta-cell mass. Exenatide was the first incretin mimetic and works similarly to natural GLP-1 but is resistant to degradation, allowing twice-daily dosing. Newer long-acting GLP-1 agonists only require once weekly or daily dosing. Nausea is a common side effect but usually mild and intermittent

1. Role of Early Initiation of Glucagon
Like Peptide _1 Receptor (GLP_1 Agonist)
Agonist
in
Management of DM2/OBESITY
CARDIO-METABOLIC RISK REDUCTION
DR./ADEL ELNAGGAR
Endocrinologist
Dr.Erfan & Bagedo General Hospital

2. DIABETES SPOT LIGHTS
Glp_1 R Agonist
guidelines
Mechanism of
action/types/clinical outcomes
(initiation benefits)
Summary/Home message

3. :
A GROUP OF DISEASES
Characterized By High Levels Of Blood Glucose
Resulting From Defects In Insulin Production,
Insulin Action, Or Both
Diabetes Mellitus :
Metabolic Disorders
Cardio-metabolic Disorders
Complex Metabolic Disorders
Characterized By Hyperglycemia Due To An Absolute Or Relative
Lack Of Insulin
Or To A Cellular Resistance To Insulin

8. SAUDI ARABIA
1 IN 4

9. Failure of stop diabetes!!
Why??
(LACK OF DIABETES PYRAMID
STRATEGIES):
BASE: Early detection; diagnosis &
prevention Programs (Health
Education).
BODY: Proper scientific socio-
economic Management (Qualified
Health Care Providers).
TOP: Delay or prevent Diabetic
Complications (Reduce Morbidity &
Mortality).

12. Pre-Diabetes
•Impaired fasting glucose (IFG)
•FPG 100-125mg/dL
•Impaired glucose tolerance (IGT)
•PPBG 140-199mg/dL
•HbA1c 6-6.5%

14. INSULIN RESISTANCE
METABOLIC SYNDROME
&
ADULT OBESITY
Central obesity (waist circumference)
IGT or IFG
High lipid profile
LDL-HDL/CHOLESTEROL/TRIGLYCERIDES
HIGH BP more than 130/90

15. Every 1% reduction in HbA1c
can reduce long-term
DIABETES COMPLICATIONS1
*p<0.0001
1. Adapted from Stratton IM et al. BMJ 2000;321:405–412.
37%
21%
14%
Microvascular
complications*
Deaths related
to diabetes*
Myocardial
infarction*

16. Benefits of weight neutral/reduction
regimens in management of
type 2 diabetes
1. Anderson and Konz. Obes Res 2001;9(Suppl. 4):326S–334S
2. Anderson et al. J Am Coll Nutr 2003;22:331–9
BP, blood pressure; CV, cardiovascular; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-
density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides

17. MANAGEMENT OF DM-2
METFORMIN
DPP4
PIOGLTAZONES
GLP1 ANALOUGES
SGLT2 INHIBITORS
SUs
INSULINs
PANCREATIC TRANSPLANTION
STEM CELLS
METABOLIC SURGERIES
Lower risk of
hypoglycemia
Higher risk of hypoglycemia
Curative
procedures

19. INTERNATIONAL DIABETES FEDERATION (IDF)
2005 and 2011/12
AMERICAN GUIDELINES (ADA)
2006, 2008, 2009, 2012, 2015, 2016 ???
EUROPEAN GUIDELINES (EASD)
2006, 2008, 2009, 2012, 2015
NATIONAL GUIDELINES (KSA –EGYPT)
WE LIVE IN A WORLD OF GUIDELINES
FOR MANAGING T2DM
AACE/ACE GUIDELINES
2009, 2013, 2015

20. GUIDANCE Study 7,597 T2DM patients
Gap exists between
checking HbA1c and achieving target HbA1c <7%
Stone MA et al. Diabetes Care. 2013 ; 36: 2628-38
Percent

21. Barriers to Diabetes Care
Clinical Practice
Therapeutic Regimen
(poly-pharmacy/complex)
Disease Process
Patient Adherence

22. 7
6
Diagnosis +5 yrs +10 yrs + 15 yrs
9
8
Diet +
Metformin
Treatment ApproachesHbA1C%
Failure based treatment
of symptoms approach
HbA1C < 7% approach
Campbell. Br J Cardiol 2000; 7: 625-31
Clinical Practice
OHA 3 INSULIN
COMPLEX
INSULIN

23. INCRETINS
Incretins are gut-derived hormones,
released in response food intake (mainly
glucose and fat).
They exert a wide range of effects,
including stimulation of pancreatic
insulin secretion in a glucose-dependent
manner and play an important role in the
local gastrointestinal and whole-body
physiology

24. Two gut-hormones were found to
mediate the “incretin effect”
Glucagon Like Peptide _1 (GLP-1)
secreted from the K-cells in the
duodenum and jejunum
Glucose-dependent Insulinotropic
Polypeptide (GIP)
secreted from the L-cells of the
distal ileum and colon and

27. Both incretins
are rapidly deactivated
by an enzyme called
Di_Peptidyl Peptidase_4
(DPP4).

34. Types Of Glp_1 Agonists
Exenatide
short acting twice daily
Liraglutide:
Another GLP-1 analog with longer half-life,
similar to exenatide with once-daily injection.
Diabetes Care. 2007;30:1608-1610
Long acting exenatide:
Highly effective with once weekly injection.
Diabetes Care. 2007;30:1487-1493
Incretin mimetics

35. Exenatide
• The first incretin-related therapy
available for patients with type 2
diabetes.
• Naturally occurring peptide from the
saliva of the Gila Monster.
• Has an approximate 50% amino acid
similar with GLP-1.
• Binds to GLP-1 receptors and behaves
as GLP-1.

36. Gila Monster

37. Incretin mimetics
Exenatide
• Resistant to DPP-4 inactivation.
Following injection,
• it is measurably present in plasma
for up to 10 hours.
• Suitable for twice a day
administration by subcutaneous
injection.
Regul Pept. 2004;117:77-88.
Am J Health Syst Pharm. 2005;62:173-181.

38. Nausea With
Exenatide
• was seen uniformly across the
clinical trials, although most
episodes were mild-to-moderate in
intensity and generally intermittent.
• more frequent at the initiation of
treatment and decreased over the
course of several weeks.

39. Risk/benefits assessment
Role of Early initiation of:
Glp-1
or
Insulin
Or both
As regard b-cell function

40. §

41. Turner et al. Br Med J 1976;1:1252–4; Owens. Diabetes Technol Ther 2013;15:776–85; Unger & Zhou. Diabetes 2001;50:S118–21
Overcoming glucotoxicity with early
insulin initiation facilitates beta-cell
rest

42. But
Insulin considered as
A …………??
For both * patients* doctors

43. LETHAL
WEAPON

45. ADA. Diabetes Care 2014;37:S14–80
*Usually basal; ADA, American Diabetes Association; DPP-4i, dipeptidyl peptidase-4 inhibitor; Fx; bone fractures; GI,
gastrointestinal; GLP-A RA, glucagon-like peptide-1 receptor agonist; HF; heart failure; SU, sulphonylurea; TZD,
thiazolidinedione
ADA 2014 – guidelines for managing hyperglycaemia

51. Antihyperglycaemic therapy in type 2
diabetes : add-on therapy to metformin
Inzucchi SE et al. Diabetes Care 2015;38:140-149
Metformin

52. CHOICES MODULES OF THERAPIES FOR MANAGEMENT
OF TYPE 2 DM
4 RIGHTS MODULE

53. Glp_1 agonists
• Highly recommended by guidelines as first
line after metformin
• Weight reduction / cv risk reduction / lipid
improvement / systolic BP reduction /
increase insulin sensitivity
• Improve gluceamic control by early initiation
• Increase b-cell mass
• Low risk hypoglycemia
• Neausea / GIT upset

55. Me
At home

56. Institute of Medicine Report, November 2010
Thank you
DR./ ADEL EL NAGGAR