Liraglutide in Type 2 Diabetes

management
Wismandari Wisnu

Division of Metabolic Endocrine

Department of Internal Medicine
Faculty of Medicine Universitas Indonesia
RSUP Nasional Cipto Mangunkusumo
Jakarta, Indonesia
2018
IDF Atlas 2015 IDF Atlas 2017

7 6
 3

Type 2 diabetes is a progressive disease

Progression of Type 2 Diabetes

Insulin resistance
Hepatic glucose
production
Insulin level

Beta-cell function

4–7 years Postprandial

glucose
Fasting plasma
glucose

Development of Microvascular Complications

Development of Macrovascular Complications
Impaired Glucose Tolerance Diabetes
Diabetes Diagnosis

Conceptual representation adapted from Ramlo-Halsted BA, Edelman SV. Prim Care 1999;26(4):771–789. © 1999 Elsevier
 Majority of Type 2 DM patients in Asia Pacific fail to
achieve glycemic control (HbA1c < 7.0%)
Australia Thailand Singapore India Indonesia
(St Vincent’s1) (Diab Registry2) (Diabcare3) (DEDICOM4) (Diabcare5)

30.0% 30.2% 33.0% 37.8% 32.1%
37.8
70.0% 69.8% 67.0% 62.2% 62.2 67.9%

Hong Kong China S. Korea Malaysia

(Diab Registry6) (Diabcare7) (KNHANES8) (DiabCare9)

HbA1c at or
39.7% 41.1% 43.5% 22.0%
below target
58.9% 56.5% HbA1c above target
60.3% 78.0%

1.Bryant W, et al. MJA 2006;185:305–9. 2. Kosachunhanun N, et al. J Med Assoc Thai 2006;89:S66–S71. 3. Lee WRW, et al. Singapore Med J 2001;42:501–7. 4. Nagpal J &
Bhartia A. Diabetes Care 2006;29:2341–8. 5. Soewondo P, et al. Med J Indoes 2010;19(4):235–44. 6. Tong PCY, et al. Diab Res Clin Pract 2008;82:346–352. 7. Pan C, et al.
Curr Med Res Opin 2009;25:39–45. 8. Choi YJ, et al. Diabetes Care 2009;32:2016–20. 9. Mafauzy M, et al. Med J Malaysia 2011;66(2):175–81 .
Diabetes Mellitus
Type 2 patients in
Indonesia do not
achieve target
HbA1c (<7%)

Soewondo P. Med J Indones 2010;19(4):235-244

 ‘Conventional’ therapies increase the risk of
weight gain and hypoglycaemia
Weight gain during UKPDS Hypoglycaemia during ADOPT2,3

Subjects with hypoglycaemia** (%)

(up to 8 kg in 12 years)1
45
8
40
Insulin
Change in weight (kg)

7 39
35
6
30
5 25
4 SU*
20
3 15
Conventional
2 treatment: 10
diet initially then 12
1 SUs, insulin 5 10
Metformin and/or metformin
0 0
0 3 6 9 12 Rosiglitazone Metformin SU*
Time (years)
*SU = glibenclamide/glyburide; **patients self-reporting (unconfirmed) hypoglycaemia

1. UKPDS 34. Lancet 1998:352:854–65; 2. Riddle et al. Diabetes Care 2003;26:3080;3. Kahn et al. N Engl J Med 2006;355:2427–43
 Evolution of type 2 DM management
REDUCE….

HbA1c HbA1c CV risk

• The lower the • The lower the • BP
better better • LDL
• But w/o hypos and • Glycemic, but use
weight gain agents with proven
safety and efficacy

Til 2008 2008-….. 2017 !

 Anti-hyperglycaemic medication in the last 90 years12 in 25
years SGLT-2 inhibitors
Exenatide LAR
Saxagliptin/Linagliptin
Sitagliptin/Vildagliptin
Exenatide/Liraglutide
Pramlintide
5 in 70 Insulin Detemir
years Insulin Aspart
Insulin Glargine
Glinide
Glitazone (Pioglitazone)
Insulin Lispro
Acarbose
Human Insulin
Metformin
Sulfonylureas
Animal Insulin

LAR, long-acting release; SGLT-2, sodium-glucose cotransporter-2. Adapted from: Schernthaner G. Internist 2012;53:1399–1410
 The structure of native human GLP-1 and liraglutide

• Liraglutide shares 97% amino acid identity with

human GLP-11,2
Native human GLP-11 Liraglutide1
C-16 fatty acid
(palmitoyl)
His Ala Glu Gly Thr Phe Thr Ser Asp His Ala Glu Gly Thr Phe Thr Ser Asp
Val Val

Ser Glu Ser

Lys Ala Ala Gln Gly Glu Leu Tyr Ser Lys Ala Ala Gln Gly Glu Leu Tyr Ser
Glu Glu

Phe Phe
Ile Ala Trp Leu Val Lys Gly Arg Gly Ile Ala Trp Leu Val Arg Gly Arg Gly

GLP-1, glucagon-like peptide-1

1. Knudsen LB et al. J Med Chem 2000;43:1664–1669; 2. Degn KB et al. Diabetes 2004;53:1187–1194

GLP-1 actions in peripheral tissues

Drucker D.J in Cell Metabolism 3, 153–165, 2006

 Additional physiological benefits are observed at
pharmacological levels of GLP-1
Pharmacological GLP-1
levels
Increasing Plasma GLP-1 Concentrations

GLP-1RAs
 Appetite
 Food intake
= Weight loss2
 Gastric
emptying

Physiological
GLP-1 levels DPP-4is
 Insulin
 Glucagon
=  Plasma glucose2

GLP-1 effects
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
Algoritma Pengelolaan DM Tipe-2 di Indonesia, KONSENSUS PERKENI 2015
MODIFIKASI
MODIFIKASIGAYA
GAYAHIDUP
HIDUPSEHAT
SEHAT

HbA1C <7.5% HbA1C >7.5% HbA1C >9.0%

Gejala (-) Gejala (+)
Monoterapi* dengan salah Kombinasi 2 obat* dengan Kombinasi 2 obat
satu dibawah ini mekanisme yang berbeda Insulin ± obat lain
Kombinasi 3 obat Kombinasi 3 obat
- Metformin Agonis GLP1
Metformin atau obat lini pertema -
- Agonis GLP1 Penghambat - Agonis GLP1 -

Metformin atau obat lini pertema

- Penghambat DPP4 Penghambat -
DPP4 - Tiazolidindion DPP4
- Penghambat - Penghambat - Tiazolidindion

2 Obat lini kedua

yang lain

SGLT2 ** - Penghambat
glukosidase

yang lain
- Insulin basal SGLT2 **
alfa Mulai intensifikasi insulin
- SU / Glinid - Insulin basal
- Penghambat
- Kolesevelam** - SU / Glinid
SGLT2 ** - Bromokriptin - Kolesevelam**
- Tiazolidindion QR - Bromokriptin
- Sulfonilurea - Penghambat QR
Keterangan:
- Glinid glukosidase - Penghambat
Jika HbA1C belum * Obat yang terdaftar, pemilihan dan penggunaannya
mencapai <7% alfa glukosidase disarankan mempertimbangkan faktor keuntungan,
Jika HbA1C belum
dalam 3 bulan, mencapai <7% dalam 3 alfa kerugian dan ketersediaan sesuai tabel 11.
Jika HbA1C belum mencapai
tambahkan obat ke- bulan, tambahkan obat ke- <7% dalam 3 bulan, mulai ** Kolesevelam belum tersedia di Indonesia dan
2 (kombinasi 2 3 (kombinasi 3 obat) terapi insulin atau intensifikasi Bromokriptin QR umumnya digunakan pada terapi
obat) terapi insulin tumor hipofisis
PERKENI, 2015
 ADA Guideline 2018: Pharmacological approaches to Glycemic Treatment
Table 8.1-Drug-specific and patient factors to consider when selecting antihyperglycemic treatment in adults with type
2 diabetes
Efficacy Hypo- Weight CV effects Renal effects
glycemia change
ASCVD CHF CKD progression
Metformin High No Neutral Potential benefit Neutral Neutral

SGLT-2 inhibitor Intermediate No Loss Benefit: Benefit: Benefit:

Canaglifozin, Canagliflozin Canagliflozin
Empaglifozin Empaglifozin Empaglifozin

GLP-1 RAs High No Loss Benefit: Liraglutide Neutral Benefit:

Liraglutide
Neutral:
Lixitenatide, exenatide
extended release

DPP-4 inhibitor Intermediate No Neutral Neutral Potential risk: Neutral

Saxagliptin, alogliptin
Thiazolidinediones High No Gain Potential Benefit: Increased risk Neutral
Pioglitazone

Sulphonylureas (2nd High Yes Gain Neutral Neutral Neutral

gen)

Insulins Highest Yes Gain Neutral Neutral Neutral

A new table was added (Table 8.1) to summarize the drug-specific and patient factors of antihyperglycemic agents including CV and renal effects of drugs with additional considerations.
*See ref. 31 for description of efficacy. †FDA approved for CVD benefit
CKD, chronic kidney disease; CVD, cardiovascular disease; DKA, diabetic ketoacidosis; DKD, diabetic kidney disease; NASH, nonalcoholic steatohepatitis;RAs, receptor agonists; SQ,
subcutaneous; T2DM, type 2 diabetes
Diabetes Care 2018;41(Suppl. 1):S1–S155