Pengelolaan Prediabetes di Faskes Primer

Pradana Soewondo
Division of Metabolism and Endocrinology, Department of Internal
Medicine FMUI / RSCM, Jakarta, Indonesia
 Faktor Risiko Penyakit Tidak Menular

Cancer NCDs
Diabetes
Chronic
Respiratory
Cardiovascular Diseases
Disease
Sco
pe

Increased weight, BP,

Clinical risk factors
sugar, cholesterol,
Physical inactivity Unhealthy Behavioral/
diets
Harmful use environmental risk
of alcohol
Tobacco use Air pollution
factors

Underlying
Social Trade & causes
Urbanization Globalisation
determinants marketing
Regional Targets for NCD Household air
pollution
50% reduction
in SFU for Essential NCD
Harmful use cooking medicines and
of alcohol
technologies
10%
80% coverage
reduction

Physical
Drug therapy &
inactivity
10%
25% reduction counseling
50% coverage
in NCD mortality
reduction

by 2025
Salt/sodium
intake Diabetes/obesity
30% 0% increase
reduction

Tobacco use Raised blood

30% pressure
reduction 25% reduction
 Apakah Pre-diabetes ?
Pre-diabetes suatu istilah untuk
menggambarkan konsentrasi glukosa darah
Impaired
atau HbA1c diatas normal tapi belum
Impaired
Glucose
Tolerance
Fasting Increased
HbA 1c
memenuhi kriteria diabetes ( Pedoman
Glucose
(IGT) (IFG) Pengelolaan & Pencegahan Pre-diabetes di
Indonesia 2019)

Kriteria diagnosa disglikemia 3

References:
1. National Institute of Diabetes and Digestive and Kidney Disease. Diagnosis of Diabetes and Prediabetes. http://www.niddk.nih.gov/health- . information/health-
topics/Diabetes/diagnosis-diabetes-prediabetes. Accessed Sept. 2015. 2. American Diabetes Association. Diabetes Care. 2013;36(S1):S11-S66. 3. Ryden L et al.
European Heart Journal.2013;34:3035–3087. 4. American Diabetes Association. Diabetes Care. 2015;38(1):S8-S16.
IDF Atlas 2017 : Indonesia

IDN/MULD/0319/0005 5
Mengapa Pre-diabetes Harus di
Intervensi ?
• Menyebabkan komplikasi

• Progresi menjadi Diabetes

• Mengobati Diabetes lebih mahal vs Pre-diabetes

 Sejak Awal Pre-diabetes
Risiko Komplikasi Makrovascular & Mikrovascular Telah Meningkat
complications
Macrovascular

Increased Increased Increased

 Macrovascular complications 13% 10% 6%
CVD CHD Stroke
Kidney disease Retinopathy

IGT 7.9%
 Data from the Diabetes Prevention
Program (DPP) study group : the
Newly diagnosed diabetes 12.6%
incidence of retinopathy:

 Percentage of patients with

CKD between 1992 & 2006:

Diagnosed undiagnosed prediabetes no-diabetes

diabetes diabetes
1.Huang Y,et al.BMJ. 2016 Nov 23;355:i5953. doi: 10.1136/bmj.i5953. 2.Plantinga LC,et al.Clin J Am Soc Nephrol. 2010 Apr;5(4):673-82.
3.Diabetes Prevention Program Research Group.Diabet Med. 2007 Feb;24(2):137-44.
 Pre-diabetes & Penyakit Makrovaskular
• Pre-diabetes banyak ditemui pada pasien dengan penyakit makrovaskular
termasuk : PJK, stroke & Gangguan Penyakit Arteri Perifer

Coronary artery disease CVD

Stroke

• 24 ％ with • 32-34 ％ with

prediabetes prediabetes
Prediabetes
Peripheral artery disease Chronic heart failure

• 26-28 ％ with • 40 ％ with

prediabetes prediabetes

Kleinherenbrink W, et al. Eur J Intern Med. 2018 Sep;55:6-11.

 Pre-diabetes - Diabetes tipe 2 : Suatu Proses Berkelanjutan

Natural history of Type 2 diabetes

Prediabetes diabetes
(IGT,IFG)

Glucose(mg/dl)
Postmeal glucose Fasting glucose

Sebelum terdiagnosa diabetes

• Terjadi peningkatan glukosa darah
puasa & postprandial secara
bermakna function(%) Insulin resistance
Relative

• Sensitivitas insulin menurun

Insulin level
• Fungsi sel beta menurun secara
cepat
β-cell function

Years

1.Gregg Simonson,et al.Diabetes Manage. (2011) 1(2), 175–189

2.Yang WY.et al. N Engl J Med. 2010 Mar 25;362(12)1090-1011.
 Risiko Terjadinya Diabetes1

Plasma Glucose
(mmol/L)

11  11.1

Risiko rata-rata untuk terjadinya diabetes tipe 2 Diabetes

IGT

• Jika Glukosa darah n: 0.7% per tahun 8

Diabetes
FPG  7.0 < 7.8
• IFG atau IGT : 5% atau 10% per tahun
2

IFG
Normal
• IFG & IGT : dua kali lipat terjadinya diabetes
Normal
0
FPG  6.1
dibandingkan IFG atau IGT1 Q -30 0 30 60 90 120 150 180
Minutes
Fasting OGTT

IFG: Impaired fasting glucose; IGT: Impaired glucose tolerance. Adapted from: The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus 3 and
Nathan DM et al. Diabetes Care. 2007.

References:
1. Aroda VR and Ratner R. Approach to the Patient with Prediabetes. J Clin Endocrinol Metab. 2008;93:3259–3265. 2. NICE Public Health Guidance. Preventing the
progression from pre-diabetes to type 2 diabetes in adults. Final scope. 3. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care.
1997;20:1183-1197.4. Nathan DM et al. Diabetes Care. 2007; 30(3):753-759.
 Konversi Prediabetes – Kohort Bogor
Insiden Konversi Pada Subjek Prediabetes
Regresif Normoglikemik Tetap Prediabetes Progres Diabetes Pada 371 subjek prediabetes, 5 tahun follow up,

Konversi Tahun Ke-5 42.05% 36.93% 21.02% 156 subjek regresivitas normoglikemik,
137 subjek tetap prediabetes,
Konversi Tahun Ke-3 40.16% 50.67% 9.16%
78 subjek progresivitas menjadi diabetes.

Insiden Konversi Pada Subjek Normoglikemik

Tidak Konversi Progres Prediabetes Progres Diabetes Pada 1300 subjek normoglikemik, 5 tahun follow up,
988 subjek tetap normoglikemik,
Konversi Tahun Ke-5 76.00% 21.62% 2.38%
281 subjek progresivitas prediabetes,
Konversi Tahun Ke-3 77.62% 21.46% 0.92%
31 subjek progresivitas diabetes.
 Nilai Prediksi TyG Index
Nilai Prediksi TyG index Terhadap Status Konversi Pada Subjek Prediabetes

Status Konversi 5 Tahun Cut off Point Sensitivitas Spesifisitas AUC CI 95%
Regresi Normoglikemik <4,51
83,9% 80,1% 0,913 0,875-0,943
Tidak Konversi 4,51 - 4,54
Progres Diabetes >4,54 80,8% 73,1% 0,858 0,807 - 0,900

Nilai Prediksi TyG index Terhadap Status Konversi Pada Subjek Normoglikemik

Status Konversi 5 Tahun Cut off Point Sensitivitas Spesifisitas AUC CI 95%
Tidak Konversi ≤4,43
Progres Prediabetes 4,44 - 4,47 80,1% 71,1% 0,834 0,812 - 0,854

Progres Diabetes >4,47 80,6% 80,8% 0,909 0,890 to 0,926

 Studi Daqing
65.8% Pasien Pre-diabetes Menjadi Diabetes dalam 6 Tahun
Jika Tanpa Intervensi

Control Da Qing Diabetes Prevention

100
Study in China ： TANPA
Intervention
Percentage of progression to type 2

90
80
intervensi , 65.8% pasien
menjadi diabetes dalam 6 tahun
70
diabetes (%)

60
50

40
6-year intervention hazard rate ratio:
30
0.49(95%CI 0.33-0.73) Tingkat progresi diabetes
20
20-year follow-up hazard rate ratio :
10 0.57(95%CI 0.41-0.81)
92.8% lebih dari 20 tahun
0
0 2 4 6 8 10 12 14 16 18 20
Years of follow-up
• A six-year clinical trial was conducted in daqing, China from 1986 to 1992 ,577 adults with impaired glucose tolerance were randomly assigned to either the control
group(n=138) or to one of three lifestyle intervention groups (diet, exercise, or diet plus exercise,n=438), After 6 years of lifestyle interventions, subjects were followed up
until 2008 , We aimed to assess whether intensive lifestyle interventions have a long-term effect on the risk of diabetes
Li G,et al.Lancet,2008,371:1783-1789.
 Pre-diabetes Merupakan Situasi Ideal untuk Intervensi

"
Pre-diabetes patients has been experienced severe beta cell decline
Lost up to 80% by the new diagnosis stage
resistance (disposition) index
40 "
30
insulin secretion/insulin

(△I/△G÷IR)

20

10

0 2-hour PG
0 <100 <120 <140 <160 <180 <200 <240 <280 <320 <360 <400 >400 (mg/dl)

NGT IGT T2DM

DeFronzo RA,et al.Diabetes Care. 2013 Aug;36 Suppl 2:S127-38. (ΔI/ΔG ÷ IR):the gold standard measure of β-cell function in vivo in man
 Pasien Pre-diabetes Harus Melakukan Intervensi
untuk Mengurangi Beban Keuangan

For pre-diabetes patients, lifestyle intervention ( diet + exercise ) or metformin treatment has cost-
effectiveness advantages

• Using an epidemiological modelling approach, we calculated the cost-effectiveness of screening to identify individuals with pre-diabetes,
followed up by treatment with a pharmaceutical or lifestyle intervention ， aimed to evaluate the costeffectiveness of a screening programme
for pre-diabetes, which was followed up by treatment with pharmaceutical interventions (acarbose, metformin, orlistat) or lifestyle interventions
(diet, exercise, diet and exercise)

Bertram MY, et al. Diabetologia. 2010 May;53(5):875-81. CER ： Median cost-effectiveness ratio ， DALY ： disability-adjusted life year
Dapatkah Diabetes Ditunda atau Dicegah ?
 Prediabetes & Komplikasi Dapat Dicegah
Intervensi pada pasien pre-
diabetes : dapat mencapai
remisi klinis & semakin cepat
intervensi, semakin baik
hasilnya
Intervensi dini dengan modifikasi gaya
hidup efektif dan harus dipromosikan
secara luas di komunitas
Efektivitas farmakoterapi juga telah
dikonfirmasi dalam banyak studi
Normalisasi homeostasis
glukosa pada populasi "pre-
diabetes" dapat menurunkan
penyakit kardiovaskular &
komplikasi kronis lainnya
Intervensi menjadi penting dan
berharga mempertimbangkan
semakin meningkatkannya kejadian
diabetes di dunia
 Pencegahan Diabetes Berkesinambungan adalah Sangat Penting
Dukungan dari Pembuat Kebijakan Sangat Penting

IDN/GLUX/0120/0002, Jan 2020

Golden SH, et al. Curr Diab Rep. 2017 Jul;17(7):51
 Pembuatan Guideline Pre-diabetes dengan Panduan Nilai Klinis

• As early as 2008, Europe and the United States developed a special pre-diabetes management
Guidelines ， while the Asia - Pacific region lacks a pre-diabetes management guide

2013
2007
-Guidelines for the treatment of
-ADA pre-diabetes consensus pre-diabetes

2008
2018-ADA Guidelines
-Guidelines for the treatment of pre-diabetes A pre-diabetes screening program
was clearly put forward

IDN/GLUX/0120/0002, Jan 2020

1.Xiao Xinhua. Journal of Practical Diabetes, 2008,4(4):3-4. 2.Guo yifang. Clinical metaphor,2010,25: 1937-1938. 3. Eur Heart J. 2013 Oct;34(39):3035-87. 4. ADA.Diabetes Care 2018;41(Suppl. 1):S13–S27.
 PREDIABETES
Indonesia Guideline 2019

Prediabetes Consensus 2019

Endorsed by PERSADIA/MoH/PERKENI
Launching on Nov 8, 2019
In Prapat North Sumatra, attended by ± 50 HCPs IDN/GLUX/0120/0002, Jan 2020
 Prediabetes: Metode Intervensi

shoulder

chest

Lifestyle Drug Others, such as bariatric

Intervention Intervention surgery
 Beberapa Studi Besar Memperlihatkan Diabetes tipe 2 Dapat Dicegah
dengan Perubahan Gaya Hidup

1997 2001 2002 2005 2006

China Diabetes Japanese
Da Qing Diabetes Finnish Diabetes Prevention Diabetes Indian Diabetes
Prevention Prevention Study2 Program Prevention Prevention
Outcome Study 1
Research3 Programme4 Programme5

42% 28.5%

58% 58%
67.4%

1.Pan XR, et al.Diabetes Care. 1997 Apr;20(4) ： 537-44.. 2.Tuomilehto J, et al. N Engl J Med. 2001 May 3;344(18)1343-50. 3.Knowler WC, et al.N Engl J Med. 2002 Feb 7;346(6)393-403.
4.Kosaka K, et al. Diabetes Res Clin Pract. 2005 Feb;67(2):152-62. 5. Ramachandran A et al. Diabetologia 2006;49_289–297.
 Keterbatasan Intervensi Gaya Hidup

100% Intensive lifestyle intervention control group

Low control rate

% of subjects
80%
60% 47%
43% • Less than 50% of
40% 26% 26% 25% patients success
20% 13% 11% 12%
achieving the goals of
Finland DPS 0%
WeightSeries1
reduction Fat intake <30% of Saturated-fat Fiber intake
the intervention by
>5% energy intake intake<10% of energy >15g/1000
one year according to
intake kcal treatment group

2 Standard lifestyle intervention + placebo

Efficiency decline

groups(per 100 people)

The crude incidence of
0 8
5.9
weight

diabetes in lifestyle
-2 6 4.8
-4 4
Intensive lifestyle intervention
-6 2
-8 0
Series1
DPP(2.8 year) DPPOS(15-years)
(n=3234) (n=1994)
Follow-up years
457
United States DPP 6000 2
4000 228
1
Expensive
expenses,
medical

2000 752
Direct

$*

0
Series1
Intensive lifestyle Standard lifestyle Standard lifestyle
intervention intervention intervention
+ metformin + placebo
 Prediabetes: Metode Intervensi

shoulder

chest

Lifestyle Drug Others, such as bariatric

Intervention Intervention surgery
 Efektivitas Obat Telah Terbukti tetapi Harus Dievaluasi secara Baik

Drug with evidence of diabetes prevention

• Metformin
• Thiazolidinediones Intervention assessment:
• α- glucosidase inhibitors • Practicality
• safety
• Clinical efficacy
• Pharmacoeconomics

Measures suitable for pre-diabetes:

——"Clinical efficacy+ Practical safety+Pharmacoeconomics "

Pour OR,et al.Clin Chem. 2011 Feb;57(2):215-20.

 Obat untuk Pencegahan Diabetes Yang Diinginkan

Efficacy Adiposity
• should equal or exceed the efficacy
• should induce weight loss or be
of lifestyle intervention
weight neutral

Mechanism(s) ideal Safety

• should repair the pathophysiologic
• should have minimal toxicity and
defects that underlie prediabetes drug require no safety monitoring
model
Glucoregulation Tolerability
• should normalize glucose metabolism • should be well tolerated, without GI or
other adverse effects

Durability Cost
• effects should outlast the period of
• should cost less than the least
medication exposure
expensive drug for diabetes treatment

Pour OR, et al. Clin Chem. 2011 Feb;57(2):215-20.

 Dari Bukti Ilmiah ke Klinis ：
Efektivitas Obat untuk Pencegahan Diabetes Telah Terbukti
Discussion on drug Doubts Safety and Controversial Benefits and go on
prevention practicality burden

Is drug intervention Tolbutamide/Nateglinide Rosiglitazone/ AGI Metformin

worth doing? Pioglitazone/insulin

1997 Limitations of 1982 2010 2006 2012 2009 2017 Experienced 2002-now
Da Qing: intensive Bedford NAVIGATOR DREAM ORIGIN Victory ACE DPP/DPPOS
2017 study:
Lifestyle lifestyle study : study: 2011 study: ABC study:
intervention interventions Tolbutamid Nateglinide ACT NOW positive Acarbose Metformin
Study:
does not can reduce
has residual e did not did not delay study: results, Voglibose
did not improve the risk and
risks reduce the diabetes osiglitazone/ rarely CVD
reduce the has
risk of IGT progression Pioglitazone used. outcomes Microvascul
risk of CVD
to diabetes and increased can reduce ar benefits
the risk of the risk,but
hypoglycemia have safety
burden

1.Barbara Westerhaus,et al.Prim Care Diabetes. 2011 Jul; 5(2) 73–80. 2. Chiasson JL, et al. Lancet. 2002 Jun 15;359(9323)2072-7. 3.Chiasson JL, et al. JAMA. 2003 Jul 23;290(4): 486-94. 4.DREAM Trial Investigators, et al. Lancet. 2006 Sep 23;368(9541): 1096-
105. 5.Kawamori R, et al.. Lancet. 2009 May 9;373(9675): 1607-14. 6. NAVIGATOR Study Group, et al. N Engl J Med. 2010 Apr 22;362(16): 1463-76. 7. DeFronzo RA, et al. N Engl J Med. 2011;364(12): 1104-15 8. Gerstein HC ,et al.N Engl J Med 2012;367:
319–328. 9.Asakura M, et al. Cardiovasc Drugs Ther. 2017 Aug;31(4): 401-411. 10.Holman RR, et al. Lancet Diabetes Endocrinol. 2017 Nov;5(11): 877-886. 11.Hemmingsen B, et al. Cochrane Database Syst Rev. 2017 May 10;5: CD012204.
12, Knowler WC, et al. N Engl J Med. 2002 Feb 7;346(6): 393-403 13.DPP.Lancet Diabetes Endocrinol. 2015 Nov; 3(11): 866–875.
 Intervensi Obat Dapat Menurunkan Risiko Kejadian Kardiovaskular pada
Pasien Pre-diabetes

Risk decreased
by

49%

HR=0.51,95CI,0.28-0.95
P=0.03

• International, multicenter double-blind, placebo-controlled, randomized trial, undertaken in hospitals in Canada, Germany, Austria, Norway, Denmark,
Sweden, Finland, Israel, and Spain ,1429 Patients with IGT were randomized to receive either placebo (n = 715) or 100 mg of acarbose 3 times a day (n =
714). ， The average follow-up was 3.3 years ， To evaluate the role of acarbose in preventing T2DM

Chiasson JL, et al. JAMA. 2003 Jul 23;290(4): 486-94.

 Intervensi dengan Metformin Menurunkan Beban Ekonomis Pasien

Pre-diabetes patients treated with metformin, with cost-effective advantages

a
Median cost-effectiveness ratio (CER); b Probability (%); DALYs, disability-adjusted life year

Bertram MY, et al. Diabetologia. 2010 May;53(5):875-81.

 Dari Perspektif Sosial,
Intervensi dengan Metformin Menurunkan Beban Ekonomi Total
• The cost of lifestyle modification from the societal perspective would have to be reduced in order to
match the cost-effectiveness of metformin intervention.

Type 2 diabetes Pre-diabetes/NGR

40,000
35163
35,000 32921 33232
economic cost ($)

30,000 28108
25867 26177
25,000
20,000
15,000
10,000
5,000
0
安慰剂
Placebo 2 型糖尿病
Lifestyle 糖尿病前期
modification/NGR
生活方式干预 二甲双胍
Metformin intervention
* Societal perspective = total direct medical cost+direct nonmedical cost+indirect cost.

• Cost effectiveness was analysed from 2010–2012 using a decision-based model to estimate the rates of getting diabetes, healthcare costs and
health-related quality of life. Cost per quality-adjusted life year (QALY) was estimated using costs relevant to the time horizon of the study from
Singapore. All costs are expressed in 2012 US dollars.

Png ME, et al. PLoS One. 2014 Sep 9;9(9):e107225.

 Sistim
Sistim Kesehatan Nasional
UPAYA KESEHATAN PERORANGAN UPAYA KESEHATAN MASYARAKAT
 private goods  public goods

- RS Umum/Khusus Pusat - Kemenkes

- RS Umum/Khusus Propinsi - Dinkes Propinsi
Strata-3
- RS Umum/Khusus Kota/Kab
- Dinkes Kota/Kab
- BP4, BKMM, Klinik/Praktek Dr. Spes Strata-2 - BP4, BKMM, BKOM
- Laboratorium Klinik

- Puskesmas
- Klinik/Praktek Dokter Umum Strata-1 - Puskesmas
- BP, BKIA, Praktek Bidan

- Posyandu, Polindes,
- UKBM: Posyandu, Polindes, Posbindu, dll
Posbindu, dll Masyarakat

Perorangan/Keluarga
 Prediabetes Process for Diagnosing

and screening Diagnosis Management Follow-up

Screening Blood tests Lifestyle interventions Annual Regular Check

-Routine health -Fasting Glucose -Reduced intake of simple sugars and fat - Blood Glucose monitoring
checkup -HbA1C -5 to 10% weight loss from baseline - Complications Screening
-Opportunistic -2-hrs OGTT - Refer to dietitians and health
-30 minutes of exercise 5 to 7 times per
screening for other week coach
diseases/symptoms
Pharmacological Empowerment
Therapy -Provide information about materials
available to achieve goals, such as
-Metformin
weight loss or physical activity log
-Acarbose
-Pioglitazone
Screening for Diabetes

Be proactive in an effort to improve outcomes

Find who might have risk factors
Ask patients to take the ADA
Diabetes Risk Test*
● Depending on results, invite
them into the office to be tested
● If diagnosed with diabetes/
prediabetes
 Assess and advise
 Follow-up
 Evaluate

* Available at: www.diabetes.org/risktest

Criteria for Screening for Prediabetes/Type 2
Diabetes in Asymptomatic Adult Individuals

DIABETES RISK FACTORS Consider testing (screening) all adults

●Physical
with a BMI* ≥25 kg/m2 and additional
inactivity
●First-degree
risk factors
relative with diabetes
●High-risk race/ethnicity  If no risk factors, consider
●Women who delivered a baby screening no later than age 45
weighing >9 lb or were diagnosed years
with GDM
●Hypertension (≥140/90 mmHg or If normal results, repeat testing
on therapy for hypertension) (screening) at ≥3-year intervals
●HDL-C<35 mg/dL and/or a  More frequently depending on
TG >250 mg/dL
initial test results and risk factors
●A1C ≥5.7%, IGT, or IFG on
previous testing  Test yearly if prediabetes
●Other clinical conditions associated
with insulin resistance, such as
severe obesity, acanthosis nigricans,
PCOS *At-risk BMI may be lower in some ethnic
groups
●History of CVD

Adapted from:
American Diabetes Association. Testing for Diabetes in Asymptomatic Patients. Diabetes Care.
2014;37(suppl 1):S17; Table 4
 Modifiable Risk Factors of
Diabetes/Prediabetes for CV Disease

Non-modifiable Modifiable

Age Physical inactivity

Race/Ethnicity Overweight/Obesity

Gender Hypertension

Family history Smoking

Abnormal lipid metabolism

High plasma glucose levels

American Diabetes Association. Diabetes Care. 2014:37:S14-80.

Management Strategies for Prediabetes

Treatment according to HbA1c Baseline

High A1c Baseline

Lifestyle therapy
+
Pharmacotherapy

Tuso P. Perm J. 2014 Summer;18:88–93

 Lifestyle Therapy for pre-diabetes Replacing
refined
carbohydrates
with wholegrain
foods

150 minutes of physical

Lifestyle activity per week
e.g. 30mins x 5 days Overall 7%
Therapy weight loss

Reducing the amount

• Initial target: 1-2 pound/week weight loss of saturated fat in
• Long-range goal: 7% loss of body weight the diet Maintain a
• Increase physical activity to ≥150 min/week healthy BMI
• Individualized medical nutrition therapy
• Provided by a registered dietitian
• Reduce caloric intake by 500-1000 kcal/day
• Reduce dietary fat
• Limit intake of sugar-sweetened beverages
• Dietary fiber intake of 14 grams/1000 kcal
• Whole grains are 50% of grain intake
• 5-7 servings of fruits and vegetables a day

1: DPP (Diabetes Prevention Program Research Group). Reduction in the incidence of type 2 diabetes with lifestyle intervention or
metformin. N Engl J Med. 2002;346:393-403.