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GLOBAL PROJECTIONS FOR THE DIABETES EPIDEMIC: 2003-2025 (Millions)
25.0 39.7 59%
10.4 19.7 88%
38.2 44.2 16%
1.1 1.7
59%
13.6 26.9 98%
World 2003 = 189 million 2025 = 324 million
Increase 72%
81.8 156.1 91%
18.2 35.9 97%
Amos et al. Diabet Med. 1997;14:S1-S85; Zimmet et al. Nature. 2001;414:782-787.
Diabetes Risk Factors – Age
– History of gestational diabetes
– Family history of diabetes
– Physical activity
– Weight relative to height
It is important to identify patients at the pre-diabetes stage to help prevent the development
of T2DM and the upcoming complications.
I. Type 1 diabetes* (ß-cell destruction, usually leading to absolute insulin deficiency)
A. Immune mediated
B. Idiopathic
II. Type 2 diabetes* (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance)
III. Other specific types
A. Genetic defects of ß-cell function
B. Genetic defects in insulin action
C. Diseases of the exocrine pancreas
D. Endocrinopathies
E. Drug- or chemical-induced
F. Infections
G. Uncommon forms of immune-mediated diabetes
H. Other genetic syndromes sometimes associated with diabetes
IV. Gestational diabetes mellitus (GDM)
Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus
[Diabetes Care 26:S5-S20, 2003]
• Absorb food • Produce incretin hormone to induce insulin release
• Produce insulin to increase glucose absorption • Produce glucagon, which is involved in glucose production during
fasting
• Store glucose in form of glycogen need insulin • Produce glucose from glycogen need glucagon
• Major site for glucose metabolism (70 – 80%) need insulin
• Site for deposition of excessive calories need insulin
Organs Involved in Blood Glucose Regulation Process
Cell Morphology in the Pancreas: β-Cell Disorders in T1DM
β-Cells (insulin)
α-Cells (glucagon)
• Autoimmune process/ unknown origin
• β-cell amount is very little/depleted
Normal T1DM
Adapted from Rhodes CJ. Science. 2005;307:380-4.
Pancreatic Islet Morphology: Structural Defects are Evident in T2DM
• Disorganized and misshaped • Marked reduction in
β-cell number • Amyloid plaques
Amyloid plaques
β-Cells (insulin)
α-Cells (glucagon)
Normal T2DM
Ramlo-Halsted B, et al. Prim Care 1999;26:771-89.
T2DM is a Progressive Disease Characterized by Insulin Resistance and Insulin Deficiency
Inherited/acquired factors Overweight, inactivity (inherited/acquired)
Gluco- lipotoxicity
Glucose uptake
Insulin resistance Insulin deficiency
Hyperglycemia
T2DM
FFA Glucose
production in the liver
Yki-Järvinen H. In: Textbook of Diabetes 1, third edition. Oxford, UK: Blackwell; 2003: p22.1−22.19.
Insulin Deficiency is Often Already Established when T2DM is Diagnosed
20
15
10
5
0
−10 −5 0 5 10 15 20 25 30 Years
Insulin level
Insulin resistance
β-cell failure
250 200 150 100 50 0 R
elat
ive β-
cell
func
tion
(%)
Fasting glucose
Postprandial glucose
Glu
cose
(m
mol
/l)
Clinical features MICROVASCULAR CHANGES
MACROVASCULAR CHANGES
DIAGNOSIS
Adapted from Rhodes CJ. Science. 2005;307:380-4.
Diabetes mellitus
adalah gangguan metabolik kronis, yang ditandai oleh peningkatan kadar gula darah:
Puasa ≥ 126 mg/dl atau 2 jam OGTT ≥ 200 mg/dl Sewaktu ≥ 200 mg/dl disertai gejala klinis klasik
• Screen for undiagnosed T2DM at the first prenatal visit in those with risk factors, using standard diagnostic criteria
• In pregnant women not previously known to have diabetes, screen for GDM at 24–28 weeks’ gestation, using a 75-g OGTT and specific diagnostic cut points
• Screen women with GDM for persistent diabetes at 6-12 weeks’postpartum, using a test other than A1C
• Women with a history of GDM should have lifelong screening for the development of diabetes or prediabetes at least every 3 years
• Women with a history of GDM found to have prediabetes should receive lifestyle interventions or metformin to prevent diabetes
ADA. III. Detection and Diagnosis of GDM. Diabetes Care 2012;35(suppl 1):S15.
Detection and Diagnosis of Gestational DM
PERKENI: Diabetes Prevention
High-risk population at < 30-year old • Family history of DM • Cardiovascular disorder • Overweight • Sedentary life style • Known IFG or IGT • Hypertension • Elevated triglyceride, low
HDL or both • History of Gestational DM • History of given birth
> 4000g • PCOS
• Medical Nutritional Therapy
• Physical activity
• Weight reduction
• If overweight, reduce body weight by 5-10%
• Physical exercise for 30 minutes, 5 times/week
• Not yet recommended
Early Detection Lifestyle Changes Pharmacology Therapy
Periodic Blood Glucose & Risk Factor
Monitoring • Hypertension
• Dyslipidemia
• Physical health
• Body weight control
• 2-hour OGTT is the most sensitive method for early detection and a recommended screening test procedure
Management
PERKENI: Early Detection
• High risk population at the age < 30 years old
OGTT is the most sensitive method for early detection and the recommended screening tool
Family history of diabetes Hypertension
Cardiovascular abnormalities Increase of TG/Decrease of HDL or both
Overweight History of Gestational Diabetes
Sedentary life History of delivering infant > 4000g
History of IFG or IGT PCOS
PERKENI: Standard Values of Random Blood Glucose and Fasting Blood Glucose for
Screening and Diagnosis of DM (mg/dL)
Non DM Uncertain DM DM
Random blood glucose level (mg/dL)
Venous plasma <100 100-199 ≥200
Capillary blood <90 90-199 ≥200
Fasting blood glucose level (mg/dL)
Venous plasma <100 100-125 ≥126
Capillary blood <90 90-99 ≥100
Note: For high-risk groups which show no abnormal results, the test should be done every year. For those aged > 45 years without other risk factors, screening can be done every 3 years.
PERKENI GUIDELINES 2011
Algoritme Pengelolaan DM Tipe 2 di Indonesia KONSENSUS PERKENI 2015
Modifikasi pola hidup sehat
HbA1c < 7.5%
Monoterapi* dengan salah satu obat di bawah ini
• Metformin
• Agonis GLP-1
• Penghambat DPP-IV
• Penghambat
Glukosidase Alfa
• Penghambat SGLT-2**
• Tiazolidindion
• Sulfonilurea
• Glinid
Jika HbAc1 > 6.4%
dalam 3 bulan tambahan
obat ke 2 (kombinasi 2
obat)
HbA1c ≥ 7.5%
Kombinasi 2 obat* dengan mekanisme kerja yang
berbeda
• Agonis GLP-1
• Penghambat DPP-IV
• Tiazolidindion
• Penghambat SGLT-2
• Insulin Basal
• SU/Glinid
• Kolsevelam**
• Bromokriptin-QR
• Penghambat
Glukosidase Alfa
Jika belum memenuhi
sasaran dalam 3 bulan,
masuk ke kombinasi 3 obat
Met
form
in a
tau
obat
lini
per
tam
a ya
ng la
in +
Kombinasi 3 obat
• Agonis GLP-1
• Penghambat DPP-IV
• Tiazolidindion
• Penghambat SGLT-2
• Insulin Basal
• Kolsevelam**
• Bromokriptin-QR
• Penghambat
Glukosidase Alfa
Jika belum memenuhi sasaran
dalam 3 bulan, mulai terapi insulin
atau intensifikasi terapi insulin
Met
form
in a
tau
obat
lini
per
tam
a ya
ng la
in +
Oba
t lin
i ked
ua +
Kombinasi 2 obat
Insulin ± obat jenis lain
Kombinasi 3 obat
HbA1c ≥ 9.0%
Gejala (-) Gejala (+)
Keterangan
*Obat yang terdaftar, pemilihan dan
penggunaannya disarankan mempertimbangkan
faktor keuntungan, kerugian biaya, dan
ketersediaan sesuai tabel 11
** Kolsevelam belum tersedia di Indonesia
Bromokriptin QR umumnya digunakan pada
terapi tumor hipofisis
Mulai atau intensifikasi Insulin
Konsensus Pengelolaan dan Pencegahan Diabetes Melitus Tipe 2 di Indonesia. 2015.
Target of Treatment Risk CVD (-) Risk CVD (+)
BMI (kg/m2) 18.5 – <23 18.5 – <23
Blood Glucose
• FPG (mg/dL) <100 <100
• Post Prandial BG (mg/dL) <140 <140
A1C (%) <7.0 <7.0
Blood Pressure <130/80 <130/80
Lipid
Total Cholesterol (mg/dL) <200 <200
Triglyceride (mg/dL) <150 <150
HDL Cholesterol (mg/dL) >40 / >50 >40 / >50
LDL Cholesterol (mg/dL) <100 <70
PERKENI GUIDELINES 2011
Organs Involved with Glucose Homeostasis
Liver Pancreas
Gut
Muscle
↓ Hyperglycemia
Holst JJ, Ørskov C. Diabetes. 2004;53:S197-S204. Lebovitz HE. Diabetes Rev. 1999;7:139-153.
Adipose
Kidneys
Brain
Metformin TZDs
Sulfonylureas Glinides, GLP-1RA DPP-4 Inhibitors
GLP-1RA Bromo-criptine
α-glucosidase inhibitors GLP-1RA, Colesevelam TZDs
Insulin
SGLT2 Inhibitors
Oral Diabetes Drugs in Indonesia
Class Generic Mg/tab Daily dose (mg)
Duration of action (hr)
Freq/day Time A1C
reduction FBG vs. PPG
Sulfonylureas
Glibinclamide 2.5-5 2.5-15 12-24 1-2 Before meals
1.5 FBG
Glipizid 5-10 5-20 12-16 1
Gliklazid 30,60,80 30-320 24 1-2
Glikuidon 30 30-120 6-8 2-3
Glimepiride 1,2,3,4 0.5-6 24 1
Glinid Repaglinid 1 1.5-6 3 1-1.5 Both
Nateglinid 120 360 3 0.5-0.8 PPG
TZD Pioglitazone 15-30 15-45 18-24 1 Indep of
meals 0.5-1.4 FBG
α-glucosidase inhibitor
Acarbose 50-100 100- 300
3 With 1st food
0.5-0.8 PPG
Oral Diabetes Drugs in Indonesia
Class Generic Mg/tab Daily dose (mg)
Duration of action (hr)
Freq/day Time A1C
reduction FBG vs.
PPG
Biguanides Metformin 500-850 500-3000 6-8 1-3 With or
after meals 1.5 FBG
Metformin XR 500-750 500-2000 24 1
DPP-IV inhibitors
Vildagliptin 50 50-100 12-24 1-2 Indep of meals
0.6-0.8 Both
Sitagliptin 25,50,100 25-100 24 1
Saxagliptin 5 5 24 1
Fixed dose combination drug
Metformin+ Glibenclamide
25-500/ 1.25-5
Glib max 20 mg/day
12-24 1-2 With or after meals
Glimepiride + metformin
1-2/ 250-500
2-4/ 500-1000
2
Pioglitazone+ metformin
15-30/ 500-850
Piog max 45 mg/day
18-24 1
Sitagliptin + metformin
50/ 500-1000
Sita max 100 mg/day
1
Vildagliptin + metformin
50/ 500-1000
Vilda max 100 mg/day
12-24 2
Insulin in Indonesia Sediaan Insulin Awal Kerja
(Onset) Puncak Kerja
(Peak) Lama Kerja (Duration) Kemasan
Insulin Prandial (Meal Related)
Insulin Short Acting
Reguler (Actrapid®, Humulin® R) 30-60 menit 30-90 menit 3-5 jam Vial, pen/cartridge
Insulin Analog Rapid Acting
Insulin Lispro (Humalog®) 5-15 menit 30-90 menit 3-5 jam Pen/cartridge
Insulin Glulisine (Apidra®) 5-15 menit 30-90 menit 3-5 jam Pen
Insulin Aspart (Novorapid®) 5-15 menit 30-90 menit 3-5 jam Pen, Vial
Insulin Intermediate Acting
NPH (Insulatard®, Humulin® N) 2-4 jam 4-10 jam 10-16 jam Vial, Pen/cartridge
Insulin Long Acting
Insulin Glargine (Lantus®) 2-4 jam No Peak 18-26 jam Pen
Insulin Detemir (Levemir®) 2-4 jam No Peak 22-24 jam Pen
Insulin Campuran
70% NPH 30% Reguler (Mixtard®, Humulin® 30/70) 30-60 menit Dual 10-16 jam Pen/cartridge
70% Insulin Aspart Protamin 30% Insulin Aspart (Novomix® 30) 10-20 menit Dual 15-18 jam Pen
75% Insulin Lispro Protamin 30% Insulin Lispro (HumalogMix® 25) 5-15 menit Dual 16-18 jam Pen/cartridge
Dyslipidemia in Indonesia
• International Diabetes Management Practices Study (IDMPS) – Study of 674 patients with T2DM
• 53.5% had dyslipidemia
– 44.5% were receiving treatment
• Demonstrated that the metabolic control of diabetes is not good enough to prevent complications
Current practice in the management of type 2 diabetes in Indonesia. Results from IDMPS. J Indon Med Assoc 2011
CLASSIFICATION
• Primary Dyslipidemia • Secondary Dyslipidemia
– Diabetes melitus – Hipothyroidism – Obstructive liver disease – Nephrotic Syndrome – Medication that could increase LDL and decrease HDL
such as: progestin, anabolic steroid, corticosteroid, beta-blocker
Abnormal Lipid Metabolism
Increased: • Triglycerides • Very-low-density
lipoprotein (VLDL) • LDL and small dense
LDL • Apolipoprotein B
Decreased: • HDL • Apolipoprotein A-I
American Diabetes Association. Diabetes Care. 2007;30:S4-41.
Major Risk Factors Affecting Lipid Goals
• Cigarette smoking
• Hypertension (≥140/90 mm Hg or on antihypertensive medication)
• Low HDL-C (<40 mg/dL)
• Family history of early heart disease
• Age (men ≥45 years; women ≥55 years)
Screening for Dyslipidemia
• Persons without diabetes
– Test at least every 5 years, starting at age 20, including adults with low-risk values
• Persons with diabetes
– In adults, test at least annually
– Lipoproteins: measure after initial BG control is achieved as hyperglycemia may alter results
Low HDL-C: Independent Predictor of CHD Risk, Even When LDL-C is Low
Ris
k of
CH
D
LDL-C (mg/dL) 100 160 220
25 45
85 65 0.0
1.0
2.0
3.0
Lowering Lipid Blood Level Accounted for >70% of CV Risk Reduction in Diabetes
Adapted from Gaede P, Pedersen O. Diabetes. 2004;53 (suppl 3):S39–S47.
0
20
40
60
80
Lipids
Perc
ent o
f Tot
al C
alcu
late
d Ri
sk R
educ
tion
in C
VD E
vent
s
HbA1c Blood Pressure
Steno-2 study
Multifactorial therapy in type 2 DM , to achieve : BP <130/80, HbA1c < 6.5%, total cholest < 175 mg/dL
The most of the CV benefit was attributable to the use of lipid-lowering therapy
Classes of Medications for Lipid Pharmacology
• Statins: Work by increasing hepatic LDL-C removal from the blood • Fibrates: Activate an enzyme that speeds the breakdown of
triglyceride-rich lipoproteins while also increasing HDL-C • Niacin: Reduces the livers ability to produce very low density
lipoprotein (VLDL) – When given at high doses, it can also increase HDL-C
• Resins: Bind to bile acids in the intestines and prevent their reabsorption, leading to increased hepatic LDL-C removal from the blood
• Cholesterol absorption inhibitors help lower LDL-C by reducing the amount of cholesterol absorbed in the intestines – Increases LDL receptor activity
Risk Management: Abnormal Lipids
• Lifestyle Modification – Increased physical activity
– Diet: reduced saturated fat, trans fat, and cholesterol
– Weight loss, if indicated
• Pharmacologic Treatment: – Primary goal is LDL lowering
– Without overt CVD: If >40, statin to achieve 30-40% LDL reduction
– With overt CVD: All patients, statin to achieve 30-40% LDL reduction
– Lowering TG and raising HDL with a fibrate is associated with fewer cardiovascular events in patients with clinical CVD, low HDL, and near-normal LDL
American Diabetes Association. Diabetes Care. 2007;30:S4-41.
American Diabetes Association: Standards of Care 2015 in people with Diabetes
American Diabetes Association. Diabetes Care 2015;38(Suppl. 1):S49–S57
Dyslipidemia Treatment Goal in ADA Standards of Care 2015 in people with Diabetes
• Combination therapy has been shown not to provide additional cardiovascular benefit above statin therapy alone and is not generally recommended
• With consideration for the new statin treatment
recommendations, the Standards of Care now provide the following lipid monitoring guidance: a screening lipid profile is reasonable at diabetes
diagnosis at an initial medical evaluation and/or at age 40 years and periodically thereafter.
American Diabetes Association. Diabetes Care 2015;38(Suppl. 1):S49–S57 American Diabetes Association. Diabetes Care. 2014:37, S14-80
TATA LAKSANA DISLIPIDEMIA TERAPI NON-FARMAKOLOGIS Aktifitas Fisik
o30 menit aktifitas intensitas sedang (menurunkan 4 – 7 kkal/menit), 4-6 kali seminggu
oAktifitas penguatan otot minimal 2 kali seminggu
Nutrisi oDiet rendah kalori oAsupan lemak jenuh, lemak trans dan
kolesterol dibatasi
Stop Merokok
TATA LAKSANA DISLIPIDEMIA Berdasarkan ATP III dan ACC/AHA 2013
Molekul Efek pada Lipid Efek Samping Kontra Indikasi
STATIN
LDL 18-55% HDL 5-15% TG 7-30%
Myopati, peningkatan enzim hati
Absolut : gangguan hati akut dan krnois Relatif : Penggunaan beberapa obat tertentu
BILE ACID SEQUESTRANT
LDL 15-30% HDL 3-5%
TG no change
Gangguan gastrointestinal, konstipasi, penurunan absorbsi obat lain
Absolute: dysbetalipoproteinemia TG > 400mg/dl Relatif: TG > 200 mg/dl
NICOTINIC ACID
LDL 5-25% HDL 15-35% TG 20-50%
Flushing, hiperglikemia, gangguan gastrointestinal, hepatotoxic
Absolute: Gangguan hati kronis, gout Relatif : diabetes, hiperurisemia, ulkus peptikum
FIBRATE LDL 18-55% HDL 5-15% TG 7-30%
Dispepsia, myopati, batu empedu
Absolut : gangguan ginjal dan hati yang berat
● Statin direkomendasikan sebagai pilihan utama pencegahan primer dan sekunder ● Obat lain dapat digunakan jika terdapat kontraindikasi statin
36
TATA LAKSANA DISLIPIDEMIA Rekomendasi Statin (Berdasarkan ACC/AHA 2013)
HIGH INTENSITY MODERATE INTENSITY LOW INTENSITY
Penurunan LDL-C ≥ 50% Penurunan LDL-C 30 – 50% Penurunan LDL-C < 30%
Atorvastatin 40 – 80 mg Rosuvastatin 20 – 40 mg
Atorvastatin 10 – 20 mg Rosuvastatin 5 – 10 mg Simvastatin 20 – 40 mg Pravastatin 40 – 80 mg
Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2 – 4 mg
Simvastatin 10 mg Pravastatin 10 – 20 mg
Lovastatin 20 mg Fluvastatin 20 – 40 mg
Pitavastatin 1 mg
ALUR ACC/AHA
Clinical evidence of ASCVD
Person with ASCVD (Group I)
Yes
< 75 y.o > 75 y.o
High Intensity Statin
Moderate Intensity Statin
No
Check LDL-C
LDL-C ≥ 190 mg/dl (Group II)
LDL-C 70 – 189 mg/dl, with DM, age 40-75 y.o
(Group III)
LDL-C 70 – 189 mg/dl with ASCVD or DM, 40 –
75 y.o (Group IV)
ASCVD Risk ASCVD Risk
< 7.5% < 7.5% ≥ 7.5% ≥ 7.5% High Intensity Statin
Moderate Intensity Statin
High Intensity Statin
Special Consideration
Moderate Intensity Statin
Stone NJ, et al. J Am Coll Cardiol 2013 Nov 7. Epub ahead of print
ASCVD, atherosclerotic cardiovascular disease CHD, coronary heart disease LDL-C, low-density lipoprotein-cholesterol
ACC/AHA Guidelines identify 4 statin benefit groups
Group 1
Clinical ASCVD
CHD, stroke, and peripheral arterial
disease, all of presumed atherosclerotic origin
Group 3
Diabetes mellitus
+ age of 40–75 years + LDL-C 70–189 mg/dL
(1.8–4.9 mmol/L)
Group 4
ASCVD risk ≥7.5%
No diabetes + age of 40–75 years
+ LDL-C 70–189 mg/dL (1.8–4.9 mmol/L)
Group 2
LDL-C ≥190 mg/dL (~5 mmol/L) Moderate/High
Intensity
Moderate/High Intensity
High Intensity
Moderate Intensity
Summary • Screening for risk factors for development of DM helps identify
patients early • T1DM & T2DM can be distinguished by age onset, weight, and
progression of signs and symptoms • Each have different underlying pathophysiology and thus require
different treatment and management strategies • There are several different classes of anti-hyperglycemia
medications available – Biguanides, sulfonylureas, thiazolidinediones, alpha-glucosidase
inhibitors, DPP-IV inhibitors and GLP-1 receptor agonists • Each class differs in their target site, pharmacology, efficacy and
safety profile • Treatment algorithms aid in choosing which medication to use for
each patient
Summary: Cardiometabolic Risk
• Assessing a patient’s cardiometabolic risk is important in the prevention of CVD and T2DM
• Dyslipidemia plays key role in the development of CVD especially with the presence of T2DM
• Identification of risk factors such as obesity, dyslipidemia and hypertension allow for the initiation of appropriate risk management strategies such as:
– Lifestyle modification
– Addition of pharmacologic agents in some clinical scenarios
Recommended