CTRPM

Centre for Translational Research

and Precision Medicine

01-11-2022

Potensi Penerapan (Farmako) Genomik

pada Pengelolaan Diabetes Melitus:
Program Biomedical & Genome Science Initiatives (BGSI)
Dicky L. Tahapary
Hub Diabetes
Instalasi Laboratorium Penelitian Translational dan Kedokteran Presisi
RSUPN Dr. Cipto Mangunkusumo
Diabetes Mellitus CTRPM
Centre for Translational Research
and Precision Medicine

a chronic disease in which the pancreas not being able to produce insulin
or the body being unable to use insulin effectively which then leads to hyperglycaemia,
complications, reduced quality of life and increased mortality.

1 out of 10
Indonesian Adults
~ 20 Million People With Diabetes in Indonesia

~86% undiagnosed
~70% uncontrolled
~ 25% less than 45 years old

High proportion of diabetes complications

Diabetes Mellitus
Riskesdas 2018, DiabCare 2012 2
 Diabetes Complications in Indonesia CTRPM
Centre for Translational Research
and Precision Medicine

70%
~50% 59,1%
60%
With active case finding
50%

40%
32,4%
29,1%
30%
22,8%
20% 14,5%
12,4%
10%

0%
Any recorded Any recorded Any recorded Any recorded eye Erectile Peripheral
foot renal cardiovascular complications dysfunction neuropathy
complications complications complications

DiabCare Indonesia 2012, n = 1967

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 Direct Medical Cost of Diabetes in Indonesia
Poor glycemic control may cause life-threatening complications that will cost a lot of money:

CARDIOVASCULAR
DISEASE
RENAL FAILURE

Hidayat B, Ramadani R, Rudijanto A, Soewondo P, Suastika K, Siu Ng J. Direct Medical Cost of Type 2 Diabetes Mellitus and Its Associated Complications in Indonesia. Value in Health Regional Issues. 2022;28:82-89.
Soewondo et al. The DiabCare Asia 2008 study – Outcomes on control and complications of type 2 diabetic patients in Indonesia. The DiabCare Asia 2008 study. 2010. 19(4);235-244

* Berdasarkan Diabcare 2008. Studi non-intervensi, potong lintang, merekrut 1832 pasien dari pusat kesehatan sekunder dan tersier di Indonesia.
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 Advanced-Stage -
Model Layanan Berkelanjutan
DIABETES Diabetes Melitus
RS Pengampu Paripurna
(With End-Stage + Advanced Management
Faskes Tersier Complications) (Personalised Medicine)
RSUP (RS Pengampu Utama)

Mid-Stage - DIABETES
(With Complications) + Management of
Faskes Sekunder Complications
RSUD (RS Madya dan Dasar)
Private Hospital*
Early Stage - DIABETES + Medications
(Without Complications) + Screening for complications
Faskes Primer (AI-based)
Puskesmas
Private Clinic* PREDIABETES Intensive Lifestyle
Intervention

Komunitas INSULIN RESISTANCE Risk Factors Screening

Universitas (Family History of Diabetes, Obesity, Hypertension, Dyslipidemia, etc)
Tempat Kerja
Area Publik
Population At Risk Health Promotion
Posbindu PTM
“One Health” & Tech Support (DTO)
Facilities & Human Resources
 Biomedical and Genome Science Initiative (BGSi)
is Indonesia's first national integrated biomedical initiative established
to leap Indonesia into the era of precision medicine
by integrating genomics capacity into health services.

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https://bgsi.kemkes.go.id
 CTRPM
Centre for Translational Research
and Precision Medicine

Genetic Factors of Diabetes

95%

1-5%
Genetics for Type 2 Diabetes Mellitus CTRPM
Centre for Translational Research
and Precision Medicine

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Genetics for Type 2 Diabetes Mellitus CTRPM
Centre for Translational Research
and Precision Medicine

Genetic Risk Prediction for T2DM

• Genetic variants associated with T2DM each have small impact on risk
(typically OR<1,2) compared to monogenic diabetes (OR>10)

• Polygenic risk scores for T2DM incorporated thousands of genetic markers

• Risk of diabetes conferred to individuals with T2DM polygenic risk scores in

top 1% remains significantly lower than that conferred by the rare variants
causing monogenic diabetes

• Environmental factors still play a major role in the development of diabetes

Mahajan Nat genet. 2018;50(11):1505

Khera AV. Nat genet 2018;50(9):1219

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Genetics for Type 2 Diabetes Mellitus

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Genetics for T2DM CTRPM
Centre for Translational Research
and Precision Medicine

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Novel T2DM Phenotype CTRPM
Centre for Translational Research
and Precision Medicine

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Ahlqvist E. Subtype of type 2 diabetes determined from clinical parameters. Diabetes. 2020.
Novel T2DM Phenotype CTRPM
Centre for Translational Research
and Precision Medicine

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Ahlqvist E. Subtype of type 2 diabetes determined from clinical parameters. Diabetes. 2020.
Genetics for Type 2 Diabetes Mellitus CTRPM
Centre for Translational Research
and Precision Medicine

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Precision Medicine in Diabetes CTRPM
Centre for Translational Research
and Precision Medicine

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Precision Medicine in Diabetes CTRPM
Centre for Translational Research
and Precision Medicine

Precision diabetes medicine

has found a firm foothold in the diagnosis and treatment of monogenic diabetes,

while the application of precision medicine to other types of diabetes is at this time
aspirational, rather than standard of care.

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Precision Medicine in Diabetes CTRPM
Centre for Translational Research
and Precision Medicine

Monogenic Diabetes
Formerly MODY

• Heterogeneous disorder characterized by:

• Diabetes at young age (usually <25 y.o)

• Automosomal dominant transmission

• Lack of autoantibodies

• Several genetic abnormalities have been identified

Balasubramanyam. Classifica1on of diabetes melitus and gene1c diabe1c syndromes. Uptodate. 2021.

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Early Onset Diabetes CTRPM
Centre for Translational Research
and Precision Medicine

1 out of 4
Indonesian Diabetes Patients
Age <45 years old

~ 5 millions people
Increased
Lower Working productivity economic
burden

Higher Risk of Complications

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Early Onset Diabetes CTRPM
Centre for Translational Research
and Precision Medicine
Diabetes diagnosed <40 years of age

Faster Greater risk of

Diagnosis β-cell decline complications
Dilemma: & &
Monogenic vs Polygenic Progression to Mortality
treatment failure

Importance of Genetic Testing

Dianna et al. Young-onset Type 2 diabetes mellitus-implications for 19

morbidity and mortality. 2020
Importance of Genetic Testing for CTRPM
Centre for Translational Research

Early-Onset Diabetes in Indonesia and Precision Medicine

Not all individuals with diabetes

Diagnosis Dilemma: respond to therapies the same way
Genetic testing
Monogenic vs Polygenic Treatment Gap in
help to Indonesia
Mutations in HNF4A or HNF1A are
Faster β-cell decline & sensitive to Sulfonylurea differentiate
Genetic Kit not
Progression to treatment Type, Therapeutic available
failure GCK mutations do not require specific approaches, &
anti-diabetic medication Diabetes genetic
Prognosis services not available
Greater risk of
complications & of diabetes
Not all individuals with diabetes
Mortality
develop chronic complications

Dianna et al. Young-onset Type 2 diabetes mellitus-implications for Kwak et al. Clinical Whole Exome Sequencing in Early Onset Diabetes 20
morbidity and mortality. 2020 Patients. 2016
State of the art CTRPM
Centre for Translational Research
and Precision Medicine

Improved Improved
DIAGNOSIS RISK STRATIFICATION
Complications and Treatment Response

Genomic, Associated to
epigenomic and functional diabetic patient’s clinical
testing manifestations

Risk Stratification and Personalized Treatment

to Improve Quality of Care

SDG: reducing premature death from NCDs, including diabetes

State of the art CTRPM
Centre for Translational Research
and Precision Medicine

Comprehensive Diabetes Evaluation - Electronic Diabetes Registry – Biobank - Bioinformatics

Clinical B
i
Biobank o
i
n
Personalized
f Diagnosis & Treatment
Laboratory o
r
Risk to Improve
Registry
m Stratification Quality of
Comprehensive
a Care
Imaging t
Diabetes
Evaluation i
c
Genomics, s
Epigenomic,Transcriptomics Omics
Proteomics, Metabolomics
 Conceptual Framework of Study Design
~1000 participants

Longitudinal Study* Genomics Study

Baseline – M 1-6-12-24
& functional analysis

First Degree Relatives

Healthy Control

Early-Onset Diabetes in Indonesia

Blood Sample
Socio-demographic Characteristics Urine, Saliva, Faecal*
Clinical Characteristics Biobank WGS
Targeted Genes
OUTCOMES
1. Diagnosis Accuracy
Start from RSCM & AHS UI

Bioinformatics
Study Location

• C-peptide/insulin
Registry
• Islet Cell autoantibodies
then expand

MODY Gene Kit

2. Risk of Complications Comprehensive Complications Risk Gene Kit
• Cardio-vascular Complications Diabetes
• Kidney Complications Evaluation &
Care
• Neurological Complications Personalized Treatment
• Eye Complications
• Liver Complications RCT: personalized vs standard of care
• Sexual Dysfunction Complications
• Other Complications
Sample Recruitment Process
Comprehensive Clinical Evaluation

Year 1
Start with RSCM
AHS-UI Jakarta

Year 2
4 Hospitals
(Advanced Diabetes Centre)

Year 3
4 Hospitals
(Advanced Diabetes Centre)

Year 4
4 Hospitals
(Advanced Diabetes Centre)

Registry
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 Biomedical and Genome Science Initiative (BGSi)
is Indonesia's first national integrated biomedical initiative established
to leap Indonesia into the era of precision medicine
by integrating genomics capacity into health services.

25
https://bgsi.kemkes.go.id
 CTRPM
Centre for Translational Research
and Precision Medicine

SUMMARY
Personalized Medicine for Diabetes in Indonesia
is currently still on its earliest phase

BGSI to start with early-onset diabetes:

high proportion monogenic diabetes, more progressive, high burden

Pharmacogenomics application in Indonesia:

more data needed
Indonesia should be involved in international diabetes drugs RCTs

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 CTRPM
Centre for Translational Research
and Precision Medicine

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