DIABETES

dr. Hermawan Susanto SpPD

Definition of Diabetes Mellitus

• Diabetes Mellitus is a disease marked

by high levels of sugar in the blood.

• Mellitus is Latin for “sweet as honey”.

EPIDEMIOLOGIC DATA of T2DM
 Classification of Diabetes

1. Type 1 diabetes
- β-cell destruction
2. Type 2 diabetes
-Progressive insulin secretory defect
3. Gestational Diabetes Mellitus (GDM)
4. Other specific types of diabetes
- Monogenic diabetes syndromes
- Diseases of the exocrine pancreas, e.g: cystic
fibrosis
- Drug- or chemical-induced diabetes
American Diabetes Association Standards of Medical Care in Diabetes.
Classification and diagnosis of diabetes. Diabetes Care 2017; 40 (Suppl. 1): S11-S24
Prevalence

• Type 1
– Type 1 diabetes develops if the body is
unable to produce any insulin.
– This type of diabetes usually appears
before the age of 40.
– Accounts for between 5 – 15% of all
people with diabetes.
Prevalence

• Type 2
– Type 2 diabetes develops when the body can still
make some insulin, but not enough, or when the
insulin that is produced does not work properly
(known as insulin resistance).
– This type of diabetes usually appears in people
over the age of 40.
– Type 2 diabetes is the most common of the two
main types and accounts for between 85 - 95% of
all people with diabetes.
Prevalence

• Gestational diabetes mellitus:

is a type of diabetes that arises during
pregnancy (usually during the second
or third trimester).
 Perjalanan penyakit DM T2 ditandai dengan
penurunan fungsi sel ß pankreas
100 Saat didiagnosis
?
Fungsi sel - (% dari normal HOMA)

80

60

Fungsi pankreas
40
= 50% dari normal

20

0
―10 ―8 ―6 ―4 ―2 0 2 4 6

Waktu (tahun)
HOMA=homeostasis model assessment.
UKPDS Group. Diabetes 1995;44:1249―58.
Adapted from Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21―5.
 PANCREAS
NORMAL

SEL OTOT

Insulin diumpamakan
Sebagai ANAK KUNCI

GULA

USUS
Tempat masuknya gula
di otot dan
Tempat bekerjanya
Pembuluh
Insulin di otot diumpakan
darah
Pintu dan lubang kunci
 PANCREAS
NORMAL

SEL OTOT

Insulin diumpamakan
Sebagai ANAK KUNCI

GULA

USUS
Tempat masuknya gula
di otot dan
Tempat bekerjanya
Pembuluh
Insulin di otot diumpakan
darah
Pintu dan lubang kunci
 PANCREAS
NORMAL

SEL OTOT

Insulin diumpamakan
Sebagai ANAK KUNCI

GULA

USUS
Tempat masuknya gula
di otot dan
Tempat bekerjanya
Pembuluh
Insulin di otot diumpakan
darah
Pintu dan lubang kunci
 PANCREAS
DM Tipe-1

SEL OTOT

Insulin diumpamakan
Sebagai ANAK KUNCI

GULA

USUS
Tempat masuknya gula
di otot dan
Tempat bekerjanya
Pembuluh
Insulin di otot diumpakan
darah
Pintu dan lubang kunci
 PANCREAS
DM Tipe-1

SEL OTOT

Insulin diumpamakan
Sebagai ANAK KUNCI

GULA

USUS
Tempat masuknya gula
di otot dan
Tempat bekerjanya
Pembuluh
Insulin di otot diumpakan
darah
Pintu dan lubang kunci
 PANCREAS
DM Tipe-1

SEL OTOT

Insulin diumpamakan
Sebagai ANAK KUNCI

GULA

USUS
Tempat masuknya gula
di otot dan
Tempat bekerjanya
Pembuluh
Insulin di otot diumpakan
darah
Pintu dan lubang kunci
 PANCREAS
DM Tipe-2

SEL OTOT

Insulin diumpamakan
Sebagai ANAK KUNCI

GULA

USUS
Tempat masuknya gula
di otot dan
Tempat bekerjanya
Pembuluh
Insulin di otot diumpakan
darah
Pintu dan lubang kunci
 PANCREAS
DM Tipe-2

SEL OTOT

Insulin diumpamakan
Sebagai ANAK KUNCI

GULA

USUS
Tempat masuknya gula
di otot dan
Tempat bekerjanya
Pembuluh
Insulin di otot diumpakan
darah
Pintu dan lubang kunci
 3
CRITERIA FOR THE DIAGNOSIS OF DIABETES-ADA 2019
STANDARDS of MEDICAL CARE in DIABETES-2019
Diabetes Care 39 (Suppl 1), S14, January 2017, Summarized : 2015-2019

1 FPG >126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at
least 8 h. *)
or
2 2-h PLASMA GLUCOSE >200 mg/dL (11.1 mmol/L) during an OGTT. The test
should be performed as described by the WHO, using a glucose load containing the
* ) in water.
equivalent of 75 g anhydrous glucose dissolved
or
3 A1C >6.5%. The test should be performed in a laboratory using a method that
in NGSP certified and standardized to the DCCT assay. )
*
or
4 In a PATIENT with CLASSIC SYMPTOMS of HYPERGLYCEMIA or
HYPERGLYCEMIC CRISIS, a RANDOM PLASMA GLUCOSE >200 mg/dL
(11.1 mmol/L)

* ) In the ABSENCE of UNEQUIVOCAL HYPERGLYCEMIA, RESULT SHOULD

BE CONFIRMED BY REPEAT TESTING.

DIABETES: A1C > 6.5% PRE-DIABETES: A1C 5.7 – 6.4%

 4
CATEGORIES OF INCREASED RISK FOR DIABETES(IRD
(IRD = Prediabetes*) : ADA-2019
= PREDIABETES*)
STANDARDS of MEDICAL CARE in DIABETES-2019
Diabetes Care 39 (Suppl1), S16, January 2019
(Summarized : 2016)

IFG = Impaired Fasting Glucose IGT = Impaired Glucose Tolerance

Normal Fasting Plasma Glucose (FPG) : < 100 mg/dL
1 FPG 100 mg/dL to 125 mg/dL : IFG – PRE DIABETES
or
2 2-h PG 140 mg/dL to 199 mg/dL in the 75 g OGTT : IGT – PRE
PRE
DIABETES or DIABETES
3 “PREDIABETES” is the term used for individuals with IFG and/or
IGT or
4 HbA1c 5.7 – 6.4% : IRD or PREDIABETES
* For all Three Tests, Risk is Continuous Extending below the Lower Limit of
the Range and Becoming Disproportionately Greater at Higher Ends of the
Range
ADA = American Diabetes Association
ASK-SDNC NORMAL A1C : < 5.7 %
Increased
Glucagon
Islet- cell
Decreased Glucose LIVER 5
Secretion Uptake
MUSCLE
Increased
2 3 4 HGP
(Hepatic Glucose Product)
TZDs
PANCREAS
MET
TZDs (PIPOD),
MET
TZDs INTESTINES
SU, GLP-1RA,
Decreased DPP4-i
Insulin Secretion 1 HYPERGLYCEMIA DPP4-i
5
GLP1-RA
Decreased
8 SGLT2-I
Islet-β cell Incretin Effect
BRAIN 7
TZDs
ADIPOSE
Neurotransmitter 6
Dysfunction KIDNEY Increased
THE OMINOUS OCTET Increased Lipolysis
(DeFronzo 2009, Provided : Tjokroprawiro 2015 - 2016) Glucose
Reabsorption
CURRENT AVAILABLE OADS AND NON-INSULIN INJECTABLES IN INDONESIA
1 METFORMIN 4 THIAZOLIDINEDIONES (TZDs)
2 SULFONYLUREAS (SUs) AND GLINIDES 5 DIPEPTIDYL PEPTIDASE-4 INHIBITORS (DPP4-Is): ORAL
3 ΑLPHA-GLUCOSIDASE INHIBITORS (AGIS) (DPP-4 INHIBITORS : DPP-4Is=INCRETINS)
PIPOD : Pioglitazone In Prevention Of DM 6 GLP-1 RA : SC INJECTION
(Xiang et al 2006) THE TRIUMVIRATE : PANCREAS, MUSCLE, LIVER
ASK-SDNC
 6

PRACTICAL TOOL FOR INSULIN RESISTANCE AND -CELL FUNCTION

(Mathews et al 1985, Falutz et al 2002, Summarized : Tjokroprawiro 2005-2016)

HOMA-R Fasting Insulin (U/mL) x FPG (mmol/L)

: (N: < 2.0)
Insulin Resistance 22.5

HOMA-B 20 x Fasting Insulin (U/mL)

: (N: 70–150%)
-Cell Function FPG (mmol/L) – 3.5

Clinical Use in Daily Practice 1 FOR RATIONALE TREATMENT

:
HOMA-R and HOMA-B 2 FOR FOLLOW-UP OF TREATMENT

ASK-SDNC
 COMPLICATION

ACUTE CHRONIC
COMPLICATION COMPLICATION

HYPOGLICEMIA

HYPERGLICEMIA

• KAD
• HHS
 86
KOMPLIKASI AKUT DIABETES MELLITUS
(Pengalaman Klinik : Tjokroprawiro 1993-2016)

1 HIPOGLIKEMIA : TRUE, REACTIVE

2 KETOASIDOSIS DIABETIK (KAD)

HHS : Hyperosmolar Hyperglycemic State
3 HHS / NKHC / NKHC : Non-Ketotic Hyperosmolar Coma
HONK HONK : Hiperosmoler Non Ketotik

4 KOMA ASIDOSIS ASAM LAKTAT (KAAL)

No. 2 dan No. 3 DISEBUT KRISIS HIPERGLIKEMIA

ASK-SDNC
ASK-SDNC
HIPOGLIKEMIA
Glukosa darah ≤ 70 mg/dl

10% dari pasien diabetes

Angka kematian 3-4% terutama pada manula

GEJALA NEUROGLYCOPENIC :
Penurunan daya ingat, mudah marah,
bingung, tingkah laku aneh,
kejang, koma
GEJALA ADRENERGIC SYMPTOMS :
Keringat dingin, berdebar , rasa lapar,
rasa mau pingsan, pandangan gelap,
sakit kepala, pusing, lemas
TERAPI HIPOGLIKEMIA
• Makan roti, pisang, permen
• Minum Teh Manis, Sirup
• Glukosa Infus
 89
Practical Guidelines : Treatment of Hypoglycemia with
Formula 3-2-1-1 for Pts with DM to Avoid “Honey Moon”
Phenomena
(Clinical Experiences : Tjokroprawiro 1996-2016)

GlLUCOSE Treatment of Hypoglycemia with GLUCOSE 40%

LEVEL FORMULA 3-2-1-1 1 VIAL: 25 mL
(mg/dL) with 10 g Glucose

< 30 mg/dL *) : I.V GLUCOSE 40%, BOLUS 3 VIALS FORMULA - 3

30-50 mg/dL *): I.V GLUCOSE 40%, BOLUS 2 VIALS FORMULA - 2
50-70 mg/dL *): I.V GLUCOSE 40%, BOLUS 1 VIAL FORMULA - 1
70-90 mg/dL **): I.V GLUCOSE 40%, BOLUS 1 VIAL FORMULA - 1
If 15 (fifteen) minutes After Treatment the Blood Glucose < 100 mg/dL,
I (one) VIAL IV Glucose Should be Repeated
*) True Hypoglycemia : The 4 (Four) Hormones CGCG may be
Secreted (Catecholamine, Glucagon, Cortisol, Growth hormone)
**) Reactive Hypoglycemia : If Plasma Glucose Rapidly to be
Lowered and Drops Steeply f.e. from 400 to 70-90 mg/dL
ASK-SDNC
 90

HYPERGLYCEMIC CRISES : from >250 to >600 mg/dl

(Clinical Experiences : Tjokroprawiro 1991-2016)

DKA (>250; Mostly >600) HHS~NKHC~HONK (>600)

Uncontrolled
The TRIAD The TETRALOGY
DM 1 Yes, 3 No
Glycemia, Ketonuria, (f.e. Glucose > 600 mg/dl) Glycemia, No History of DM,
Kussmaul’s Breathing No Ketonuria, No Kussmaul’s

FORMULA-DKA FORMULA FORMULA-DKA

2 4 18 24 Time 2 4 18 24 Time
–1 , x12 , 3 , x2
2 80 30 20 Fluid 2 80 30 20 Fluid
 PATHOGENESIS OF DKA AND HHS / NKHC / HONK 91

(ADA-2009; Kitabchi et al 2009; Provided :2009-2016)

ABSOLUTE INSULIN COUNTERREGULATORY RELATIVE INSULIN

DEFICIENCY HORMONES : CGCG *) DEFICIENCY

 LIPOLYSIS  Protein Synthesis  Proteolysis

Absent or Minimal
 Gluconeogenic Substrates Ketogenesis
 FFA to Liver

 GLUCOSE  GLUCONEOGENESIS  GLYCOGENOLYSIS

 KETOGENESIS UTILIZATION
HYPERGLYCEMIA
 Alkali Reserve
Glycosuria (Osmoticdiuresis)

S
Triacylglicerol Loos of Water and Electrolytes
HHS HONK
Decrease
DEHYDRATION HYPEROSMOLARITY
HYPERLIPIDEMIA Fluid Intake
IMPAIRED RENAL FUNCTION

HHS / NKHC / HONK

DKA
*) CGCG : Catecholamine Glucagon Cortisol Growth hormone
 92
DKA – ESSENTIALS OF DIAGNOSIS
(ADA-2009, Summarized : 2009-2016)

A The TRIAD of DKA

1 Glycemia (>250 mg)
2 Hyperketonemia (Serum and/or Urine)
3 Metabolic Acidosis (pH <7.30, Kussmaul’s Breathing)

B The SUPPORTING FINDINGS for Dx CRITERIA :

1 SERUM GLUCOSE >250 mg
2 ARTERIAL pH <7.3
3 SERUM BICARBONATE <18 meq/l
4 ANION GAP >10 [ Na – ( Cl + HCO3 )]
5 MODERATE KETONURIA or KETONEMIA
 93
TERAPI KETOASIDOSIS DIABETIK (KAD) - REVISI 2016
(Summarized and Illustrated : Tjokroprawiro 1991-2016)

1 REHIDRASI : NaCl 0.9% atau RL, 2 L / 2 jam pertama, lalu 80 tt/m

selama 4 jam, lalu 30 tt/m selama 18 jam (4-6 L/24 jam),
diteruskan sampai 24 jam berikutnya ( 20 tt/m) : FORMULA KAD : 2,4,18-24
2 IDRIV (NovoRapid ® ): 4 unit/jam i.v (FORMULA MINUS SATU)
FASE-I 3 INFUS KALIUM : 25 mEq (bila K+ = 3.0-3.5 mEq/l), 50 mEq (K+ = 2.5 - 3.0),
PER 24 JAM 75 mEq (bila K+ = 2.0-2.5), dan 25mEq /100cc/5j ( K+ < 2.0 )
4 INFUS : bila pH < 7.2 atau BIK <12 mEq/l : 50-100 mEq / 500ml / 24 jam
BIKARBONAT Bolus BIK 50 mEq / 10 menit diberikan bila pH < 7.0
dan sisanya (50 mEq) diberikan dengan drip selama 2 jam
5 ANTIBIOTIK : HARUS RASIONAL dengan DOSIS ADEKUAT
Glukosa Darah + 250 mg/dl atau Reduksi Urine + IDRIV : INSULIN DOSIS RENDAH INTRA VENA
1 MAINTENANCE NaCl
: 0.9% atau Pot. R (INS 4-8u), Maltosa 10% (INS 6-12u)
bergantian : 20 tt/m (Start Slow, Go Slow, Stop Slow)
FASE-II 2 KALIUM : p.e (bila K+ < 4 mEq/l), atau per os (air tomat/kaldu)
3 NovoRapid ® : 3 x 8-12 U sc (ingat : FORMULA KALI DUA)
4 MAKANAN LUNAK : KARBOHIDRAT KOMPLEKS PER ORAL

FORMULA : 2,4,18,24–Time ; FORMULA : 2,80,30,20–Fluid *)

F4 : 25 meq K+, dlm 100 ml RL, drip 5 jam

2 4 18 24 TIME
Koreksi HIPOKALEMIA gunakan FORMULA sbb : FORMULA KAD : 2 80 30 20 FLUID
HIPO K: F1, F2, F3, F4 (251005) *) ASK-SDNC
Hati hati pada pasien CKD dan GAGAL JANTUNG IDRIV AMAN pada kasus HIPOKALEMIA
TERAPI KAD

• Koreksi cairan
• Koreksi Kadar Gula
• Koreksi Penyebab dan Komplikasi
HHS (HYPERGLYCEMIC HYPEROSMOLAR STATE)

• A high level of blood glucose may interfere blood

circulation (level >600 mg/dl)
• Glucose uptake by the cells decreases, the glucose
passed from blood to urine  draws tremendous amounts
of fluid from body and produces dehydration
• Common in type 2 DM, especially who does not monitor
blood sugar, and who does not know have DM
• Trigger factors: high-dose steroid, diuretics, infection,
illness, stress or drinking excessive alcohol
Gejala HHS

• Excessive thirst
• Increased urination
• Weakness
• Leg cramps
• Confusion
• Rapid pulse
• Convulsions
• Coma
 94
HHS (HONK) – ESSENTIALS OF DIAGNOSIS
(ADA-2009, Kitabchi et al 2009, Tjokroprawiro 2009-2016)

1 Yes - Severe Hyperglycemia (>600 mg) TETRALOGY HONK :

2 No History of DM
3 1 Yes & 3 No
No Kussmaul’s Breathing
4 No Ketonuria or Ketonemia; Sometimes : Mild Ketonuria (Tjokroprawiro 2009)

5 No Metabolic Acidosis (pH >7.3)

6 Serum Bicarbonate >18 meq/l
7 Anion Gap <12
8 Serum Osmolality ≥ 325 mOsm/kg
Serum Glucose mg/dl
2 [ Measured Na (meq/l) ] + = > 325 mOsm/kg
18
Clinical Experiences (Tjokroprawiro 1991-2016), Clinical Dx of HHS
The TETRALOGY of HHS (HONK) : 1 Yes & 3 No
1 Yes : Glycemia >600 mg/dl
2 No : No History of DM HHS HONK
3 No : No Kussmaul’s Breathing
4 No : No Ketonuria or Ketonemia
Hyper Osmolar Non Ketotic
 95
PROTOCOL FOR DIAGNOSIS AND THERAPY OF HONK or HHS
(Summarized and Illustrated : Tjokroprawiro 1991-2016)

PATHOGENESIS CLINICAL DIAGNOSIS : 1 YES & 3 NO THERAPY

TETRALOGY SUPPORTING FINDINGS SIMILAR WITH DKA THERAPY

PRECIPITATING FACTORS
HONK :
1 Thiazide 1 YES & 3 NO 1 pH > 7.30 a PLASMA Na <150 mEq/l
2 Glucose Drinks 1 YES: Glycemia >600 mg/dl 2 Neurological Sign
3 Infection 2 NO: History of DM - 3 Prerenal Uremia NORMAL SALINE
4 Corticosteroid 3 NO: Kussmaul’s Breathing - 4 Mental Impairment
5 Beta Blocker 4 NO: Ketonuria - or + 5 Severe Dehydration b PLASMA Na >150 mEq/l
6 Phenytoin 6 Age : More than 60 Years Old
7 Cimetidine
8 Chlorpromazine TETRALOGY HHS (1 YES & 3 NO) : 1 H + 3 NO SOLUTION NaCL 0.45%

PATHOPHYSIOLOGY Glucose (mg/dl)

5 Osm/l = 2x (Na) + > 320
l Grossly Elevated Glucagon 18
l Relative Insulin Deficiency
l Sufficient Insulin to inhibit lipolysis
PENTALOGY HONK : 1 YES, 3 NO, Osmol/l > 320
HHS : HYPERGLYCEMIC HYPEROSMOLAR STATEH ONK : HYPEROSMOLAR NON KETOTIK
 TERAPI HHS

• Check blood glucose level (> 600mg/dL)

• Emergency treatment can correct the problem
within hours
• Give intravenous fluids to restore water to the
tissue
• Short acting insulin to help cells can uptake
glucose
• Without prompt treatment  can be fatal
 Komplikasi Kronik

ASK-SDNC
 OTAK

MATA

GIGI

Complications of Diabetes
 PARU

JANTUNG

LAMBUNG

KOMPLIKASI KRONIS DM
 GINJAL

ORGAN INTIM

SARAF TEPI &

PEMBULUH DARAH

KOMPLIKASI KRONIS DM
Saya DE tapi
Sudah minum obat
He..he..
Hati-hati kalau
Dekat saya….
 PARADIGMA PENGELOLAAN
DIABETES MELLITUS TIPE-2
PERUBAHAN MONOTERAPI KOMBINASI INSULIN,
GAYA HIDUP BEBERAPA MC DG ATAU TANPA
OBAT OBAT MINUM

POLA MAKAN
OLAH RAGA
SEHAT
ASK-SDNC
Recommendations: Glycemic Goals in Adults

• A reasonable A1C goal for many nonpregnant adults is

<7% (53 mmol/mol). A
• Consider more stringent goals (e.g. <6.5%) for select
patients if achievable without significant hypos or other
adverse effects. C
• Consider less stringent goals (e.g. <8%) for patients with
a history of severe hypoglycemia, limited life expectancy,
or other conditions that make <7% difficult to attain. B

American Diabetes Association Standards of Medical Care in Diabetes.

Glycemic targets. Diabetes Care 2017; 40 (Suppl. 1): S48-S56
A1C and CVD Outcomes

• DCCT: Trend toward lower risk of CVD events with

intensive control (T1D)
• EDIC: 57% reduction in risk of nonfatal MI, stroke, or
CVD death (T1D)
• UKPDS: nonsignificant reduction in CVD events (T2D).
• ACCORD, ADVANCE, VADT suggested no significant
reduction in CVD outcomes with intensive glycemic
control. (T2D)

American Diabetes Association Standards of Medical Care in Diabetes.

Glycemic targets. Diabetes Care 2017; 40 (Suppl. 1): S48-S56
 Approach to the Management of
Hyperglycemia
more A1C less
Patient/Disease Features stringent 7% stringent

Risk of hypoglycemia/drug adverse

effects low high

Disease Duration
newly diagnosed long-
standing
Life expectancy
long short
Relevant comorbidities
absent Few/mild severe
Established vascular complications
absent Few/mild severe

Patient attitude & expected

treatment efforts highly motivated, adherent, less motivated, nonadherent,
excellent self-care capabilities poor self-care capabilities

Resources & support system

readily available limited
American Diabetes Association Standards of Medical Care in Diabetes.
Glycemic targets. Diabetes Care 2017; 40 (Suppl. 1): S48-S56
 Glycemic Recommendations for Nonpregnant Adults
with Diabetes

A1C <7.0%*
(<53 mmol/mol)
Preprandial capillary 80–130 mg/dL*
plasma glucose (4.4–7.2 mmol/L)
Peak postprandial <180 mg/dL*
capillary plasma (<10.0 mmol/L)
glucose†
* Goals should be individualized.
† Postprandial glucose measurements should be made 1–2
hours after the beginning of the meal.

American Diabetes Association Standards of Medical Care in Diabetes.

Glycemic targets. Diabetes Care 2017; 40 (Suppl. 1): S48-S56
Pharmacologic Approaches
to
Glycemic Treatment
Recommendations: Pharmacologic Therapy
For T2DM

• Metformin, if not contraindicated and

if tolerated, is the preferred initial
pharmacologic agent for T2DM. A
• Consider insulin therapy (with or without
additional agents) in patients with newly
dx’d T2DM who are markedly symptomatic
and/or have elevated blood glucose levels
(>300 mg/dL) or A1C (>10%). E

American Diabetes Association Standards of Medical Care in Diabetes.

Approaches to glycemic treatment. Diabetes Care 2017; 40 (Suppl. 1): S64-S74
 Recommendations: Pharmacological Therapy
For T2DM

- If noninsulin monotherapy at maximal

tolerated dose does not achieve or
maintain the A1C target over 3 months,
add a second oral agent, a GLP-1
receptor agonist, or basal insulin. A
- Use a patient-centered approach to guide
choice of pharmacologic agents. E
- Don’t delay insulin initiation in patients not
achieving glycemic goals. B
American Diabetes Association Standards of Medical Care in Diabetes.
Approaches to glycemic treatment. Diabetes Care 2017; 40 (Suppl. 1): S64-S74
 7
ALGORITME PENGELOLAAN DMT2 DI INDONESIA KONSENSUS PERKENI 2015
MODIFIKASI POLA HIDUP SEHAT, Provided : 2016***

HbA1c < 7.5% HbA1c > 7.5% HbA1c > 9.0%

Gejala (-) Gejala (+)
Monoterapi* dengan Kombinasi 2 obat* dengan
Kombinasi 2 obat
salah satu dibawah ini mekanisme kerja yang berbeda
Insulin + Obat jenis lain
• Metformin • Agonis GLP-1 Kombinasi 3 obat*
Kombinasi 3 obat
Metformin atau obat lini pertama yang lain +

• Agonis GLP-1 • Penghambat • Agonis GLP-1

Metformin atau obat lini pertama yang lain +

• Penghambat DPP-IV
• Penghambat
DPP-IV • Tiazolidindion DPP-IV
• Penghambat • Penghambat • Tiazolidindion
Glikosidase Alfa SGLT-2 obat lini kedua +
• Penghambat
• Penghambat • Insulin basal SGLT-2 Mulai atau intensifikasi Insulin
SGLT-2 • SU/Glinid • Insulin basal ADA-2015 : A1C 7.5% ~ eAG 168
• Tiazolidindion
• Kolsevelam** • Kolsevelam** mg/dL ***
• Sulfonilurea
• Bromokriptin- • Bromokriptin-
ADA-2015 : A1C 9.0% ~ eAG 212
• Glinid QR*** QR*** mg/dL
• Penghambat Keterangan:
• Penghambat
Jika HbA1c > Glukosidase Glukosidase * Pemilihan obat yang terdapat di dalam daftar,
6.4% dalam 3 Alfa Alfa digunakan dengan mempertimbangkan faktor
bulan tambahkan Jika belum memenuhi keuntungan dan kerugian, biaya serta
obat ke 2 sasaran dalam 3 Jika belum memenuhi
ketersediaan.
(kombinasi 2 bulan, masuk ke sasaran dalam 3 bulan,
obat) mulai terapi insulin atau ** Menunjukkan obat yang tidak tersedia di
kombinasi 3 obat
intensifikasi terapi insulin Indonesia
*** Bromokriptin QR umumnya digunakan pada
eAG***
terapi tumor (estimated
hiposis Average Glucose)
ASK-SDNC
 8
GLYCEMIC CONTROL ALGORITHM : CONSENSUS AACE-
2016
eAG (estimated Average Glucose)* LIFESTYLE THERAPY Provided : 2016*
(Including Medically Assisted Weight Loss)
 9
ANTIHYPERGLYCEMIC THERAPY IN T2DM (ADA/EASD-
2015)
(Inzucchi et al - ADA, Nauck et al – EASD; Diabetes Care, Volume 38, January 2015)

HEALTHY EATING, WEIGHT CONTROL, INCREASED PHYSICAL ACTIVITY, AND DIABETES

INITIAL DRUG
EDUCATION
MONOTHERAPY METFORMIN
Efficacy (HbA1c) high
Hypoglycemia low risk
Weight neutral/loss
Side effects GI / lactic acidosis
Costs low
IF HBA1c TARGET NOT ACHIEVED AFTER ~3 MONTHS OF MONOTHERAPY, PROCEED TO TWO-DRUG COMBINATION (order
TWO DRUG not meant to denote any specific preference – choice dependent non a variety of patient-and disease-specific factors)
COMBINATIONSa METFORMIN METFORMIN METFORMIN METFORMIN METFORMIN METFORMIN
+ + + + + +
SULFONYLUREA THIAZOLIDINE- DPP-4 INHIBITOR SGLT2 inhibitor GLP-1 Receptor INSULIN (basal)
DIONE Agonist
Efficacy (HbA1c) high high intermediate intermediate highest
Hypoglycemia moderate risk low risk low risk low risk high high risk
gain neutral loss low risk gain
Weight gain
hypoglycemia rare GU, dehydration loss hypoglycemia
Major Side effects low
edema, HF,Fx’s
high high variable
high GI
Costs high
IF HBA 1c TARGET NOT ACHIEVED AFTER ~3 MONTHS OF DUAL THERAPY, PROCEED TO TWO-DRUG COMBINATION (order
not meant to denote any specific preference – choice dependent non a variety of patient-and disease-specific factors)
METFORMIN METFORMIN METFORMIN METFORMIN METFORMIN METFORMIN
+ + + + + +
THREE DRUG SULFONYLURE THIAZOLLDINEDION DPP-4 INHIBITOR SGLT2 inhibitor GLP-1 RECEPTOR INSULIN (basal)
E+ AGONIST
COMBINATIONS A+
TZD SU
+
SU
+
SU
+
SU
+
TZD
or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-1
or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or INSULIN or SGLT2-i
or GLP-1-RA or GLP-1-RA or INSULIN or INSULIN or GLP-1-RA
or INSULIN or INSULIN

If HbA 1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables; (2) on GLP-1-RA, add
MORE COMPLEX basal insulin; or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory npatients consider adding TZD or
INSULIN SGLT2-i:
Metformin
STRATEGIES +
Basal Insulin + Mealtime Insulin or GLP-1-RA
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 SASARAN PENGENDALIAN DIABETES

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 10
PENTALOGI TERAPI DIABETES MELLITUS
1 PENYULUHAN – EDUKASI TENTANG DIABETES MELLITUS
2 LATIHAN JASMANI
TERAPI NUTRISI MEDIK (TNM) : Nutrisi Oral – Enteral – Par
3
Enteral
4 TERAPI FARMAKOLOGIK
a. TABLET : OBAT ANTI DIABETES (OAD)
b. INSULIN :
• Native Human Insulin : Actrapid, Insulatard, Monotard, Mixtard
• Insulin Analogues : - Apidra, Novorapid, Humalog
- Novomix 70/30, Humalog Mix 75/25, Humalog Mix 50/50
- Lantus, Levemir

5 a. TRANSPLANTASI PANKREAS
• SEL BETA : Pusat Diabetes dan Nutrisi (Tikus : 1989)
• TOTAL : Pusat Diabetes dan Nutrisi (Anjing : 1991)
Transplantasi Pankreas pada Manusia : Sudah Berjalan Lancar di Luar Negeri
b. STEM CELL (SEL PUNCA)
 11
MAP OF ORAL ANTI DIABETES (OAD) IN DAILY PRACTICE
(Summarized : Tjokroprawiro 1996-2016)
1 SUs : Gliquidone, Glipizide, Gliclazide, Glibenclamide, Glimepiride
I INSULIN SECRETAGOGUES 2 NON-SUs (Metaglinides : Nateglinide, Repaglinide) 3 DPP-4 Inhibitors
4GLIMIN (new tetrahydrotriazine-containing class) : IMEGLIMIN (1500 mg twice/day) : Insulin,  Muscle glucose uptake,  HGP
5 GPR40 Agonist (TAK-875) : 50-200 mg once/day. The long-chain FAs amplify glucose-stimulated insulin secretion,  GLP-1
6 GPR119 Agonist 7 GPR120 Agonist 8 GPR142 Agonist : Insulinotropic and -cell Proliferation (ADA 2015)

II INSULIN SENSITIZERS (Rosi-*), Pio-, Neto-, Dar-glitazone)

1 THIAZOLIDINEDIONES (TZDs): Glitazone Class
2 NON-TZDs : *) Withdrawn
aGlitazar Class (Mura- *) , Raga-, Ima-, Tesa-, Saroglitazar**) : MRITS
**) A Novel dual PPAR / agonist approved in India for Tx Diabetic Hyper TG
b Non-Glitazar Class (Metaglidasen : Non Edema and Non Weight Gain)
3 BIGUANIDE : METFORMIN, METFORMIN XR (Glucophage XR), 3-Guanidinopropionic- 4 DLBS-3233 (Inlacin®)
Acid
5 Dopamine-2 Agonists (Bromocriptime) : Activates Dopaminergic Receptors (  Insulin Sensitivity & No Hypoglycemia, ?CVD Events)
6 DPP-4 Inhibitors Methazolamide
7 (ALT and Berberine
Weight Loss)
(Chinese
8 Herb) ***) : Insulin Sensitizer and Incretin Enhancer

III INTESTINAL ENZYME INHIBITORS 1 -Glucosidase Inhibitor (AGI): Acarbose

2 -Amylase Inhibitor (AMI): Tendamistase
IV INCRETIN-ENHANCERS Sita-, Vilda-, Saxa-, Lina- , Alo-, Dena-, Duto-, Melo-,
DPP-4 INHIBITORS
(Gliptin – Class) (13) Teneli-, Omari-, Gosogliptin, SYR-322, TA-666
FDC: empaglifozin + linagliptin
V FIXED DOSE COMBINATION (FDC) TYPES Xigduo XR (dapa + met XR) Invokamet® (cana + met)


Glucophage XR , Glucovance ®, Amaryl-M ®, Janumet ® , Galvusmet ®, Kombiglyze ®XR, Trajenta ®Duo ,

VI OTHER SPECIFIC (OS) TYPES 1 Sodium GLucose coActosmet
®
Transporter-2 (SGLT2)-Inhibitors Dapagliflozin (Farxiga ® 10 mg, FDA-
(17): ® 10mg, 25mg, Phase-III),2014),
Canagliflozin (Invokana ® 100mg, 300mg, FDA-filed), Empaglifozin (Jardiance Ipragliflozin: ASP1941, (Ph-III),
Tofogliflozin : CSG412 (Ph-III), Luseogliflozin TS-071 (Ph-II), Ertugliflozin: PF-04971729 (Ph-II), Sergliflozin (?), Remogliflozin (?), BI 44847
(Ph-II), LX-4211 (Ph-II), ISIS 388626 (Ph-I), YM-543, BI 10773, KGT-1681, AVE-2268, SAR7266 2 Glucokinase Activator (GKA): MTBL1, MK-0941.
3 Oxphos-Blocker 4 FBPase – Inhibitor 5 INCB13739 (11HSD1–inhibitor) 6 Berberine ***) : Rhizomacoptidis
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 57
PHARMACOKINETICS OF HUMAN INSULIN AND INSULIN ANALOGUES
(Summarized : Tjokroprawiro 2008-2016)

DURATION
ONSET OF PEAK OF
INSULIN PREPARATION ACTION ACTION (HRS)
OF ACTION
(HRS)
SHORT ACTING *) RAPID ACTING **)
Regular Human Insulin = RHI*) 30-60 mins 2-4 6-8
INSULIN GLULISINE : APIDRA **) 5-15 mins 1-2 3-4
Insulin Aspart : Novorapid **) 5-15 mins 1-2 3-4
Insulin Lispro : Humalog **)
 5-15 mins 1-2 3-4
INTERMEDIATE-ACTING
NPH 1-3 hrs 5-7 13-16
Lente 1-3 hrs 4-8 13-20
LONG-ACTING
INSULIN GLARGINE (LANTUS) 1-3 hrs No Peak 24
Detemir (Levemir) 1-3 hrs No Peak 24
Ultralente 2-4 hrs 8-14 22-24 hrs
Ultra-long-acting insulin DEGLUDEC : New Gen. Basal Ins. that forms Soloble Hexamers upon SC
inj.
PREMIXED = Biphasic
Insulin Lispro 75/25 (Humalog Mix25) 10 mins 1-4 10-20
Insulin Aspart 70/30 (Novomix30) 10 mins 1-4 16-20
Insulin Lispro 50/50 (Humalog Mix50) 15-30 min 0.5-3 14-24
 51
The 34 ENDOCARDIOMETABOLIC PROPERTIES OF INSULIN
(The Multitude of Insulin Effects)
(Summarized – Illustrated : Tjokroprawiro and Murtiwi 2009-2016)
25  Cell Cycle and Proliferation 1 GLYCEMIC CONTROL CARDIO-PROTECTION
2
and Diff. of Cell  GLUT-4 Synt. & Transl,  Glucose,  A1C (ANIMALS, HUMAN)

24  Uric Acid Clearance 3 ANTI-INFLAMMATION

 Uric Acid Formation 29  EPCs SURVIVAL IB, NFB, TNF,
(Avogaro et al 2011) ICAM-1, MCP-1, CRP
23  ANDROGEN :
 DHEAS,  ANDROSTENE-DIONE, 4 Egr : TF,  PAI-1,  Ap-1 ( MMPs)
27  HSP 70 / 72 / 90
 TESTO,  DH TESTOSTERONE 5 ANTI-ATHEROSCLEROSIS
(Wound Healing, Etc)
NADPH oxidase,  ROS,  IB,
22 RESTORE
30  CORTICOSTERON-DEPENDENT INSULIN  NFB ( ICAM, MCP, CRP)
LH, FSH, TESTOSTERON
RESISTANCE 6 PROFIBRINOLYSIS ( PAI-I)
21 MATURATION OF ADIPOCYTE
(mTORC1, CREB, C/ EBP, GPDH) 34 INSULIN PROPERTIES 7 VASODILATATION
( eNOS, iNOS,  NO)
20  LIPOLYSIS via HSL
34 Mt Biogenesis,  Oxidative Capacity,  ATP 8 ANTI-PLATELET ( c-AMP)
(Hormone Sensitive Lipase)
33Brain :  Appetite & Energy Expenditure 9 ANTI-THROMBOSIS
19  LIPOGENESIS via  LPL ( TISSUE FACTOR)
(Lipoprotein Lipase)
32 PLASMA ARGINASE ACTIVITY
10 ANTI-APOPTOSIS
18  PROTEIN SYNTHESIS (Heart, Brain,  Cell)
31 GLUCAGON SECRETION
17  FA &  AA to Ketoacids 11 ANTI-OXIDANT ( ROS)
 AA Transport 14 GROWTH DEVELOPMENT
HYPOTHETICAL WAY TO TUMOR 12  ADMA : PLASMA & END.
16  GLYCOGEN SYNTHESIS ( NO : RENOFIBROSIS)
VIA IGF1 – RECEPTOR ?
15 BONE ANABOLIC 13  RONS
28 ARTERIAL VASODILATOR
( OSTEOGENESIS) ( RENAL FIBROSIS)
(SKELETAL MUSCLE VASCULAR BEDS)

ASK-SDNC 26 VASPIN mRNA IS INCREASED WITH INSULIN INJECTION IN SEVERE INSULIN RESISTANCE
 33

Alm. Alm.
Askandar Tj. Soeharjono Hendromartono Ari Sutjahjo Agung Pranoto Sri Murtiwi Soebagijo Adi Sony Wibisono

The 11 CORE STAFFS of SDNC 1986 - 2015

PLUS 52 EXPERT MEMBERS FROM MULTIPLE DISCIPLINES
61st QUADRUPLE SDW – 25
SYMPOSIUM : PEPIC - 3
1 SUMETSU DIAPIC –: Will
WillBe
Be
2 MECARSU
3 SOBU
Jongky
Hendro
Hermina
Novida
Hermawan
Susanto
Rio
Wironegoro
Deasy
Ardiany
* EDUCATION
4 SDU * HEALTH SERVICE
OBELAR–MEETING EVERY TWO WEEKS
• NOS – 2 ...... Obesity, Biomolecular, Endothelium, Lipids, Atherosclerosis, Radicals
* INVESTIGATION:
WDF, GIANT, ISIS, Etc
OBELAR–MEETING Surabaya, 1 August 1986 – 1 August 2015

SURABAYA DIABETES AND NUTRITION CENTER (SDNC)

Dr. SOETOMO TEACHING HOSPITAL
FACULTY OF MEDICINE AIRLANGGA UNIVERSITY, SURABAYA
 • TERIMA KASIH

ANTI NEUROPATI

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