- GLP-1 agonists like liraglutide and lixisenatide are used to treat type 2 diabetes by mimicking the effects of the incretin hormone GLP-1. They work by stimulating insulin secretion, suppressing glucagon secretion, slowing gastric emptying, and reducing food intake. - Liraglutide is 97% homologous to human GLP-1 with an added fatty acid chain. It has a half-life of 11-13 hours and is effective at reducing HbA1c and body weight but can cause gastrointestinal side effects. - Lixisenatide is derived from exendin-4 and has a half-life of 2-3 hours.

1. GLP-1 Agonis
(Liraglutide & Lixisenatide)
PPDS Farmakologi Klinik
Pembimbing :
Prof. dr. Slamet Suyono Sp.PD-KEMD

2. Role of Incretin in
Glucose Homeostasis
IN-CRET-IN
INtestine seCRETion INsulin
Definition: gut derived factors that increase
glucose stimulated insulin secretion
Two hormones: (1) glucagon-like peptide-1 (GLP-1)
(2) glucose-dependent insulinotropic
polypeptide (GIP)
Creutzfeldt Diabetologia 28: 5645 1985

4. GLP-1 and GIP Are Incretin Hormones
GLP-1 GIP
 Released from L cells in
ileum and colon1,2
 Stimulates insulin from
beta cells in a glucose-
dependent manner1
 Inhibits gastric
emptying1,2
 Reduces food intake and
body weight2
 Inhibits glucagon
secretion from
alpha cells in a glucose-
dependent manner1
 Deficient in type 2
diabetes
 Released from K cells in
duodenum1,2
 Stimulates insulin from
beta cells in a glucose-
dependent manner1
 Minimal effects on gastric
emptying2
 No significant effects on
body weight2
 Does not appear to inhibit
glucagon secretion from
alpha cells1,2
 Normal levels but
decreased responsiveness
in type 2 diabetes
1.Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.
2.Drucker DJ. Diabetes Care. 2003;26:2929–2940.

5. GLP1 & GIP play a role in the regulation of glucose control
Incretins have very mportant role in diabteic patient

6. Release of
active incretins
GLP-1 and GIP  Blood glucose
in fasting and
postprandial
states
Ingestion
of food
 Glucagon
(GLP-1)
 Hepatic
glucose
production
GI tract
DPP-4
enzyme
Inactive
GLP-1
X
(DPP-4
inhibitor)
 Insulin
(GLP-1and
GIP)
Glucose-
dependent
Glucose
dependent
Pancreas
Inactive
GIP
Beta cells
Alpha cells
 Glucose
uptake by
peripheral
tissue
GLP-1 agonis

8. GLP-1 Agonis
 Exenatide
 Disetujui oleh FDA pada tahun 2005
sebagai kombinasi terapi dan sebagai
monoterapi disetujui pada tahun 2009
 Liraglutide
 Disetujui oleh FDA pada tahun 2010
 Lixisenatide
 Disetujui oleh FDA pada tanggal 19
Februari 2013

9. Liraglutide
• 97% homolog dgn GLP-1 manusia
• Substitusi lys dgn arg pada asam amino ke -34
• Penambahan rantai samping asam lemak C-16 (ɣ-
glutamic acid)

10. Farmakokinetik
 Liraglutide diberikan inj subcutan
 ≥ 98% terikat dengan protein
plasma
 t1/2 11-13 jam
 Metabolisme liraglutide ≈
metabolisme protein  ≠ organ
spesifik
 Feses 5% & urin 6%

11. EFIKASI LIRAGLUTIDE

13. Efek Samping & Kontraindikasi
 Efek Samping
 Gastrointestinal (mual,muntah, diare)
 Hipoglikemia
 Pankreatitis akut
 Kontraindikasi
 Karsinoma medulla tiroid
 Kanker tiroid
 multiple endocrine neoplasia syndrome
type 2.

14. Regimen Dosis

15. Lixisenatide
 Merupakan sintetik dari exendin-4
yang mengalami delesi satu residu
prolin dan penambahan 6 residu lys
pada atom C-terminal

16. Farmakokinetik
 Lixisenatide diberikan scr inj
subkutan
 tmax 1 - 3.5 jam
 t1/2 2-3 jam
 55% terikat dengan protein plasma
 Afinitas ikatan dengan reseptor
GLP-1 4x> kuat dibandingkan GLP-
1 endogen

17. Efikasi Lixisenatide sebagai
monoterapi (GetGoal-Mono)
 HbA1c
 lixisenatide -0.85 ± 0.12 % vs plasebo
-0.19 ± 0.12 %
 Glukosa Post-Prandial
 -98.46 ± 9.9 mg/dL pada kelompok
lixisenatide vs -11.7 ± 10.08 mg/dL
pada kelompok plasebo
 Glukosa puasa
 -16.02 ± 4.5 mg/dL pada kelompok
lixisenatide vs 3.42 ± 4.68 mg/dL pada
kelompok plasebo

18. Lixisenatide vs Exenatide
(GetGoal-X)
 HbA1c
 LS mean HbA11c reduction -0.79% for
lixisenatide vs -0.96% for exenatide
 Fasting plasma glucose
 174.6 ± 36.0 to 151.2 ± 36.0 mg/dL
dengan lixisenatide
 174.6 ± 41.4 to 147.6 ± 37.8 mg/dL
dengan exenatide
 Body weight
 LS mean body weight reduction was -2.96
kg for lixisenatide vs with -3.98 kg for
exenatide

19. Efikasi Lixisenatide vs Liraglutide
 Post-prandial glucose
 -12,6 mmol/L vs -4.0 mmol/L
 Fasting glucose
 -0.3 mmol/L vs -1.3 mmol/L
 HbA1c
 7.2%  6.9 % (Lixisenatide)
 7.4%  6.9% (Liraglutide)
 Body weight
 -1.6 kg vs -2.4 kg

20. Efek Samping & Kontraindikasi
 Efek samping
 Gastrointestinal (mual, muntah)
 Hipoglikemia
 Kontraindikasi
o Pankreatitis akut
o Gastroparesis berat
o Gangguan ginjal

21. Regimen dosis
 Lixisenatide diberikan secara injeksi
subkutan
 Dosis awal diberikan 10 mcg sekali
sehari selama 14 hari dilanjutkan
dengan dosis maintenance 20 mcg
pada hari ke-15.

22. Sediaan

23. Terima Kasih