Pedoman Terapi pada

Diabetes Mellitus (DM)

Cahyo Wibisono N., dr., SpPD., FINASIM

Internal Medicine Department

Universitas Airlangga Teaching Hospital-Faculty of Medicine Airlangga
University
SURABAYA 1
 What is diabetes?
 Diabetes mellitus (DM) is a group of diseases
characterized by high levels of blood glucose resulting
from defects in insulin production, insulin action, or both.

 The term diabetes mellitus describes a metabolic

disorder of multiple aetiology characterized by chronic
hyperglycaemia with disturbances of carbohydrate, fat
and protein metabolism resulting from defects in insulin
secretion, insulin action, or both.

 The effects of diabetes mellitus include long–term

damage, dysfunction and failure of various organs.
Diagnosis of Diabetes Mellitus
Values of Diagnosis of Diabetes Mellitus
Diagnosis of Type 2 Diabetes
KONSENSUS: Pengelolaan Dan Pencegahan DM Type 2. 2015

Gula Darah Puasa** ≥ 126 mg/dl

or
2 jam post TTGO ≥ 200 mg/dl
or
Gejala klasik diabetes* & Gula darah sewaktu
≥ 200 mg/dl
or
HbA1c ≥ 6,5% (standardised assay***)
*Classical symptom of diabetes (polyuria, polydipsia, weight loss), only need 1 abnormal BG, otherwise need 2 x abnormal BG level on different days
**Fasting is defined as no caloric intake for at least 8 hours
***Standarized to National Glycohaemoglobin Standardization Program (NGSP)

Konsensus PERKENI. Pengelolaan dan Pencegahan Diabetes Melitus Tipe 2 di Indonesia. 2015
 DIAGNOSIS Post-meal BG
Glucose (mg/dL) 350
300 Fasting BG
250
200
150
100
50

250
Relative -cell

Insulin resistance
function (%)

200
150
100
50 -cell failure
Insulin
0 level
Obesity IGT Diabetes Uncontrolled
hyperglycaemia

Clinical MACROVASCULAR CHANGES

features
MICROVASCULAR CHANGES

Years -10 -5 0 5 10 15 20 25 30

The natural progression of type 2 diabetes

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Adapted from Type 2 Diabetes BASICS. International Diabetes Center; 2000.
 Hyperglycemia in Type 2 Diabetes
Inherited/acquired factors Overweight, inactivity
(inherited/acquired)

Insulin deficiency Insulin resistance

 FFA
 Glucose  Glucose production
Gluco- uptake in the liver
lipotoxicity

Hyperglycaemia

FFA=free fatty acid

Type 2 diabetes

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Adapted from Yki-Jarvinen H. Textbook of Diabetes 1, third edition; 2003
Management of Type 2 DM : Long-term Challenges

• Prevent microvascular - Glycemic control

complications
• Prevent macrovascular - Glycemic control
complications - Improve dyslipidemia
- Control blood pressure
- Control other risk factors
(smoking etc.)

• Prevent long-term
deterioration of
glucose homeostasis

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 UKPDS: progressive decline of
-cell function over time
100

80 Start of treatment
-cell function (%)

60

40

20 P < 0.0001

0
–10 –9 –8 –7 –6 –5 –4 –3 –2 –1 1 2 3 4 5 6
Time from diagnosis (years)
HOMA model, diet-treated (n = 376)

Adapted from Holman RR. Diabetes Res Clin Pract 1998;40(Suppl.):S21–S25. 9

 Management

Medical Nutrition
Physical activity
Therapy

Education

Oral anti diabetics

Monitoring
& Insulin

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 MAP OF ORAL ANTI DIABETES (OAD) IN DAILY PRACTICE
(Summarized : Tjokroprawiro 1996-2014)

I INSULIN SECRETAGOGUES - Sulphonylureas (Gen I, II, III: Glimepiride)

- Non-Sulphonylureas (Metaglinides : Nateglinide, Repaglinide)
II INSULIN SENSITIZERS
1 THIAZOLIDINEDIONES (TZDs): Glitazone Class (Rosi-*), Pio-, Neto-, Dar-glitazone)
2 NON-TZDs :
a Glitazar Class (Mura-*), Raga-, Ima-, Tesaglitazar) : MRIT *) Withdrawn
b Non-Glitazar Class (Metaglidasen : Non Edema and Non Weight Gain)
3 BIGUANIDE : - Metformin , Metformin XR (Glucophage® XR) , 3-Guanidinopropionic-Acid
4 DLBS-3233 (INLACIN®)

III INTESTINAL ENZYME INHIBITORS 1 -Glucosidase Inhibitor: Acarbose

2 -Amylase Inhibitor: Tendamistase

(Sita-, Vilda- , Saxa-, Alo-, Dena-, Duto-, Lina-

IV INCRETIN-ENHANCERS DPP-4 Inhibitors Melo-, Teneli-gliptin, SYR-322, TA-666)

V FIXED DOSE COMBINATION TYPES

VI OTHER SPECIFIC TYPES

1 Sodium GLucose co Transporter-2 (SGLT2)-Inhibitors: Dapagliflozin, Emfagliflozin , Canagliflozin,
Dapagliflozin, Seragliflozin, Remogliflozin, AVE-2268, KGT-1681, LX-4211, TS-033, YM-543
2 Glucokinase Activator (GKA): MTBL1, MK-0941 . 14
Incretins Based Therapy

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 Proof of a Gastrointestinal ‘Incretin Effect’: Different
Responses to Oral vs IV Glucose

Oral Glucose Tolerance Test and Matched IV Infusion

200 400
Plasma Glucose (mg/dL)

50 g Glucose

Plasma Insulin (pmol/L)

150 300

100 200

50 100

0 0
–30 0 30 60 90 120 150 180 210 –30 0 30 60 90 120 150 180 210
Time (min) Time (min)
N=6 Oral IV

IV=intravenous.
Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986; 63: 492–498.
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GLP-1 and GIP are Synthesized and Secreted from the
Gut in Response to Food Intake

L-cell
(ileum) ProGIP

Proglucagon

GLP-1 [7–37] GIP [1–42]

K-cell
GLP-1 [7–36 NH2] (jejunum)
GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1.
Adapted from Drucker DJ. Diabetes Care. 2003; 26: 2929–2940.
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Role of the Incretin System in Glucose Homeostasis

Incretins (GLP-1 and GIP) released

throughout the day

Caloric intake Enhanced incretin release

GI tract

DPP4 enzymes
rapidly degrade Effect of incretins
incretins
+ ­ Pancreas

Beta Alpha
Increased cells cells Decreased
insulin glucagon

Decreased
Increased glucose
glucose output
Muscle uptake by muscles Liver
by liver

Blood
glucose
DPP=dipeptidyl peptidase; GLP=glucagon-like peptide; homeostasis
GIP=gastric inhibitory peptide.

Adapted with permission from Drucker DJ et al. Cell Metab. 2006;3:153-165

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GLP-1: effects in humans

• Stimulates glucose-
After food ingestion… dependent insulin
secretion
• Suppresses glucagon
secretion
• Slows gastric emptying

• Leads to a reduction of
GLP-1 is secreted from food intake
L-cells of the jejunum
and ileum • Improves insulin sensitivity

Long-term effects
That in turn… in animal models:
• Increase of β-cell mass
and improved β-cell function
Drucker. Curr Pharmaceutical Design 7, 1399 – 1412, 2001.
Drucker. Diabetes Care 26: 2929-2940, 2003.
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Inhibition of DPP-4 Increases Active GLP-1

Meal

Intestinal
GLP-1 GLP-1 t½=1–2 min
release

Active
GLP-1

DPP-4

GLP-1
DPP-4 inactive
inhibitor (>80% of pool)
DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1.
Adapted from Rothenberg P, et al. Diabetes. 2000; 49 (Suppl 1): A39. Abstract 160-OR.
Adapted from Deacon CF, et al. Diabetes. 1995; 44: 1126–1131.
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 PHARMACOKINETICS OF HUMAN INSULIN AND INSULIN ANALOGUES
(Summarized : Tjokroprawiro 2008-2012)

ONSET OF PEAK OF ACTION DURATION OF

INSULIN PREPARATION ACTION (HRS) 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
Insulin Lispro 75/25 (Humalog Mix25) 10 mins 1-4 10-20
Insulin Aspart 70/30 (Novomix) 10 mins 1-4 16-20
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New position statement of the ADA and EASD on management of
hyperglycemia in type 2 diabetes (2015)

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 New position statement of the ADA and EASD :
Approach to starting and adjusting insulin in T2D (2015)

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 Recommendation for Glycemic Control, ADA 2015

Parameter Target
A1c <7%
Pre-prandial capilary plasma glucose 80-130 mg/dL
Peak prandial capillary plasma 180 mg/dL
glucose after 1-2 hour meal

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ADA Consensus Statement 2011
Thank You