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.

2014

Diabetes is a Huge and Growing Problem…

2035

IDF Diabetes Atlas 2014

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