Diabetes Comprehensive

T2DM Management

Hemi Sinorita
 Egregious Eleven: 11 known mediating pathways of hyperglycemia

1. Pancreas β-cells: β-Cell function β-Cell mass↓

8. Colon Insulin ↓ 7. Brain:

Abnormal-microbiota Appetite↑
GLP-1 secretion ↓ Morning
dopamine surge↓
2. Incretin effect ↓ 3. α-cell defect Sympathetic one↑
Insulin resistance
9. Immune
4. Adipose:lipolysis ↑
dysregulation/
Hyperglycemia 5. Muscle: glucose
inflammation
uptake ↓
10. Stomach/ small intestine 6. Liver: glucose
Rate of glucose absorption ↑ production ↑

11. Kidney: Glucose re-absorption ↑

Schwartz et al, 2017; Trends in Endocrinology & Metabolism, Month Year, Vol. xx, No. yy http://dx.doi.org/10.1016/j.tem.2017.05.005 1
Kelompok resiko tinggi
 Classification of Diabetes

Type 1 Type 2 Other specific Gestationa

type of diabetes l
due to other
Cells Progressive causes Diabetes
destruction insulin diagnosed
• Genetic defect on
leading to secretory cell function
during
defect on pregnancy
absolute • Genetic defects in
insulin background of insulin action
deficiency insulin • Disease of the
exocrine pancreas
resistance
• Drug or chemical
induced diabetes
Tes Laboratorium Darah untuk Diagnosis Diabetes dan Prediabetes.

PERKENI, 2021
 Kriteria Diagnosis Diabetes Melitus

• Pemeriksaan glukosa plasma puasa > 126

mg/dl. Puasa adalah kondisi tidak ada asupan
kalori minimal 8 jam
Atau
• Pemeriksaan glukosa plasma > 200 mg/dl
setelah TTGO dengan beban 75 gram glukosa.
Atau
• Pemeriksaan glukosa plasma sewaktu > 200
mg/dl dengan keluhan klasik atau krisis
hiperglikemia.
Atau
• Pemeriksaan HbA1C > 6,5% dengan PERKENI, 2021
menggunakan metode yang terstandarisasi oleh

POLIDIPSIA= BANYAK MINUM/HAUS

POLIFAGIA= BANYAK MAKAN/LAPAR

PENURUNAN BERAT BADAN

GEJALA TIDAK KLASIK DM
 Conduct 1st Blood Test

Clinical Test
(+) Classic Symptoms (-) Classical Symptoms

FBG
or
≥126 <126 FBG
or
≥126 100-125 <100
RBG ≥200 <200 RBG ≥200 140-199 <140

Repeat FBG or
RBG 2 Hour TTGO

Diabetes Mellitus IGT IFG Normal

Slide 9
Source: KONSENSUS: Pengelolaan Dan Pencegahan DM Type 2
 Conduct 2nd Blood Test (if required)
and Establish Diagnosis

Clinical Test
(+) Classic Symptoms (-) Classical Symptoms

FBG
or
≥126 <126 FBG
or
≥126 100-125 <100
RBG ≥200 <200 RBG ≥200 140-199 <140
Repeat FBG or
RBG
≥126 <126 2 Hour TTGO
≥200 <200
PPG ≥200 140-199 <140

Diabetes Mellitus IGT IFG Normal

Slide 10
Source: KONSENSUS: Pengelolaan Dan Pencegahan DM Type 2
Ibu rumah tangga usia 49 tahun
DM tipe 2 sejak tahun 2010.
TB 158cm, BB 70 kg.
Lingkar perut 110cm, TD 140/90 mmHg.
2 tahun ini pasien rutin kontrol dengan terapi
Glimeperide 2mg dan Metformin 1x500mg.

Pasien mengeluh BB sulit turun dan selama 2

tahun BB naik 5 kg. Glukosa darah naik turun
Jika terlambat makan kepala terasa pusing, pasien
sering merasa lapar.
 Prinsip Dasar Terapi Diabetes Mellitus
1 2 3

PENYULUHAN DIET AKTIFITAS FISIK

4 5

OBAT SMBG
ANTIDIABETES/INSULIN
 Materi edukasi di Pelayanan Kesehatan Primer
1. Perjalanan penyakit DM.
2. Pengendalian dan pemantauan DM berkelanjutan.
3. Penyulit DM dan risikonya.
4. Intervensi non-farmakologis dan farmakologis serta
target pengobatan.
5. Interaksi antara asupan makanan, aktivitas fisik, dan
OAD oral/insulin serta obat-obatan lain.
6. Cara pemantauan glukosa darah dan pemahaman
hasil glukosa darah atau urin mandiri (hanya jika
pemantauan glukosa darah mandiri tidak tersedia).
7. Mengenal gejala dan penanganan awal hipoglikemia.
8. Pentingnya latihan jasmani yang teratur.
9. Pentingnya perawatan kaki.
10. Cara mempergunakan fasilitas perawatan kesehatan
PERKENI, 2015
 Algorithm of Type 2 Diabetes management in Indonesia (PERKENI, 2021)
GOAL THERAPY : HbA1c <7% (Individualised)

HEALTHY LIFESTYLE MODIFICATION

Entry HbA1c <7.5% Entry HbA1c >7.5% Entry HbA1c >9%

MONOTHERAPY DUAL THERAPY SYMPTOMS

(combination of 2 drugs with TRIPLE THERAPY
Metformi different mechanism) (combination of 3 drugs with
NO YES
n different mechanism)

If HbA1c is M M S DUAL INSULIN

SU/Glinid SU/Glinid e SU/Glinid
not < 7% in 3 e e If THERAPY ±
months, t If HbA1c is not t c HbA1c Other
AG-I AG-i AG-I OR
proceed to f < 7% in 3 f o is not < Agents
DUAL o months, o n 7% in 3
TZD TZD TZD TRIPLE
THERAPY r proceed to r d months,
THERAPY
m m l proceed
DPP-4i DPP-4i TRIPLE DPP-4i
i THERAPY i i to ADD
n SGLT-2i (combination of n n OR
SGLT-2i SGLT-2i
o 3 drugs) o e INTENS
r r ADD OR INTENSIFY
GLP-1 Basal d Basal IFY
o Insulin o r Insulin INSULIN
RA Insulin
t t u Therapy
h GLP-1 RA h g GLP-1 RA
1. The selection and use of drugs consider drug cost, availability, effectiveness, cardiorenal benefits, safety profile, effects on body
e e s
r r
weight and patients' choice. f f
2. Management includes not only blood glucose, but also integrated management of other Cardio-Renal risk factors.
i i
r r
3. Some GLP-1 RA and SGLT-2i show benefits to patients with Atherosclerotic Cardiovascular Disease, Heart Failure, and
s s
Kidney Failure comorbidities. Both classes are suggested as options for patients with mentioned comorbidities / complications.
t t
l l
4. If the HbA1C cannot be checked, then the average blood glucose is used as a guide which is then converted to HbA1C
i i
n n
e e
d d
r r
u u
g g
 Diet pada Diabetes Melitus

1. Jumlah kalori
2. Jenis makanan
3. Jam makan

3-J
Pasien mengeluh BB sulit turun.
Selama 2 tahun BB naik 5 kg. Glukosa darah naik turun

Ibu rumah tangga usia 49 tahun, BB 70kg, TB 158cm

25 (wanita) x (90% x 158-100) - 5% (usia)

+ 30% (pekerjaan) - 20% (kurus) = 1356,75 kal
Sarapan= 271,35 kalori

TOTAL KALORI= 20% - 10% - 30% - 10% - 25% - 5%

 SARAPAN: 271,35 KALORI

1. Nasi 4 SDM = 100 kalori

Karbohidrat : 45 - 65% 2. Ayam goreng ½ ons = 140 kalori
3. Tahu bakar ½ potong = 40 kalori
Lemak : 20 - 25% 4. Plecing kangkung sambal mentah
Protein : 10 - 20% = 0 kalori
(PERKENI 2011)
 SELINGAN : 130 kalori

Jeruk 400 gram

Kalori 236 kkal

Lemak 10,2 g
Protein 11,8 g
Karbohidrat 23,8 g
 How you cook is important

100 gram jeruk

½ SDM minyak
Jenis makanan

Nilai Gizi (per porsi):

Energi : 664 kkal
Protein : 70 gram
Lemak : 15 gram
Karbohidrat : 70 gram
Jam makan
30 minutes of moderate-intensity exercise Physical activity
5 days of the week.
Training zone 50-70% (220 – age).
C= Continue - olahraga berkesinambungan
30 menit 5 kali seminggu
R= rytmic - berirama kontraksi-relaksasi
jogging, jalan kaki, bersepeda
I = intensity - olahraga dimulai ringan
P= progresif - berkembang/meningkat
E= endurance - ketahanan
 …those with DM should be encouraged to
reduce the amount of time spent being
sedentary (working at a computer, watching
TV) by breaking up bouts of sedentary
activity (>30 min) by briefly standing,
walking, or performing other light physical
activities (ADA 2019)
Asian Food Information Centre. 2010. Calorie Expenditures Through Exercise and Other Activities. Available from
http://www.afic.org/Burner.htm. Accessed 21 June 2010.
 Loss of Early- phase Insulin Secretion
in Type 2 Diabetes
Pattern of insulin secretion is altered early in type 2 diabetes

Type 2 diabetes
Normal 20g glucose
Plas120 20g Plas 120
glucose
ma100 ma 100
insu insu
lin 80 lin 80
(µU/ 60 (µU/ 60
ml) ml)
40 40
20 –30 0 30 60 90 20
–30 0 30 60 90
0 120
Time (minutes) 0 Time
120 (minutes)
Ward WK, et al. Diabetes Care 1984;7:491–502.
 Egregious Eleven: 11 known mediating pathways of hyperglycemia
1. Pancreas β-cells: β-Cell function β-Cell mass↓
8. Colon 7. Brain: Appetite↑
Abnormal-microbiota Insulin ↓ Morning dopamine
GLP-1 secretion ↓ surge↓
3. α-cell defect
Pre/probiotics DPP-4 Sympathetic tone↑
GLP-1 RAs ∗ GLP-1 RAs ∗
inhibitors GLP-1 RAs ∗
DPP-4 inhibitors Dopamine agonist-QR∗
Metformin
Pramlintide Appetite Suppressants∗
2. Incretin effect ↓
GLP-1 RAs ∗ DPP-4 inhibitor Insulin resistance
4. Adipose:lipolysis ↑
9. Immune dysregulation/ Hyperglycemia 5. Muscle: glucose uptake↓
inflammation 6. Liver:glucose production↑
DPP-4 inhibitors GLP-1 RAs∗ Metformin ∗
Anti-inflammatories Immune modulator
TZDs ∗
10. Stomach/ small intestine
11. Kidney: Glucose reabsorption↑
Rate of glucose absorption ↑
GLP-1 RAs∗ Pramlintide AGI SGLT2 inhibitors∗
Schwartz et al, 2017; Trends in Endocrinology & Metabolism, Month Year, Vol. xx, No. yy http://dx.doi.org/10.1016/j.tem.2017.05.005 1
 Oral Antidiabetes Medications
1. Sulfonylureas (glipizide, glybenclamide
gliclazide, glimepiride)
2. α-Glucosidase inhibitors (acarbose)
3. Biguanides (Metformin)
4. Thiazolidinediones (pioglitazone)
5. Meglitinides (Repaglinide and nateglinide)
6. DPP-4 inhibitors (sitagliptin, saxagliptin,
vildagliptin, linagliptin)
7. SGLT2 inhibitors (dapagliflozin and
canagliflozin)
 TZ
D
Increased Insulin
lipolysis resistance
Decreased glucose
uptake Metformin
TZD

Metformin
Excessive glucose
production
Lack of glucagon Excess glucose in the urine
suppression DPPIV SGLT2
FPG

Resistance to the action of insulin

 Carbohydrate resorption ACARBOSA

Prandial insulin GLINID

Incretin signaling DPPIV
Excess glucose in the urine SGLT2

Glucose load from meal

2hPG
-cell failure
 Slide 30

Metformin
850 mg-500 mg
Titration dose: 3 x 500 mg, 2 x 850
mg
Safety,
Contraindicatio
Efficacy* Tolerability Advantages
ns
and Adherence

• HbA1c : • Diarrhea • Renal Do not cause

and insufficiency hypoglycaemi
1-2% abdominal • Liver failure a when used as
discomfort • Heart failure mono-therapy
• FPG: • Latic • Severe Do not cause
40-70 acidosis if gastrointestinal weight gain;
improperly disease may contribute
mg/dl prescribed to weight loss

Krentz AJ, Bailey CJ. Drugs 2005;65:385–411.

 * Efficacy depends on existing blood glucose levels

Slide 31

Thiazolidinediones(PIOGLITAZONE)
Dose : 15-30 mg once daily
Safety,
Contraindicatio
Efficacy* Tolerability Advantages
ns
and Adherence
• HbA1c • Weight gain • Liver • Reduced
and edema
reduction disease, heart levels of
• Contraindica
of 0.5-1.5% ted in patients failure or LDL-
with abnormal history of heart cholesterol
• FPG liver function disease and
reduction • Warnings
• Pregnancy increased
of 20-55 regarding risk
of fractures and breast level of
mg/dl • May feeding HDL-
exacerbate or cholesterol
precipitate CHF
* Efficacy depends on existing blood glucose levels

Krentz AJ, Bailey CJ. Drugs 2005;65:385–411. Drug Class Review: Thiazolidinediones. Available at:
http://pharmacy.oregonstate.edu/drug_policy/pages/dur_board/reviews/articles/TZD_ClassReview.pdf . Rizzo M, et al. Expert Opin Pharmacother. 2008;9:2295–303.
 Slide 32
Carbohydrate
resorption Alpha glucosidase inhibitors
without (ACARBOSE)
3x50mg – 3x100mg dc
acarbose
with
acarbose

Duodenum Jejunum Ileum

Local
GLP-1 release

Efficacy* Safety, Tolerability and Adherence

• HbA1c reduction of 0.5-1% • Associated with flatulence,

• FPG reduction of 10-20 mg/dl diarrhea and abdominal discomfort
• PPG reduction of 40-50 mg/dl • As mono-therapy will not cause
hypoglycaemia
• Every meal is required, first bite.
* Efficacy depends on existing blood glucose levels
Krentz AJ, Bailey CJ. Drugs 2005;65:385–411. Nathan DM, et al. Diabetologia. 2009;52:17–30. Rosenstock J, et al. Diabetes Care. 2004;27:1265–70.
 Slide 33

Glinides
Efficacy* Safety, Tolerability and Adherence

• HbA1c reduction • Associated with weight gain.

of 0.5-1.5% • To be glucose dependent, is associated
• FPG reduction of with a much lower incidence of
20-60 mg/dl hypoglycemia.
• PPG reduction of • Taken just before or with meals, and
75-100 mg/dl the stimulation of the pancreas is limited
only to a brief time around meals.

* Efficacy depends on existing blood glucose levels

Krentz AJ, Bailey CJ. Drugs 2005;65:385–411. Nathan DM, et al. Diabetologia.
 GLP-1 has wide-ranging biological activity

↑ Neuroprotection
Brain

↑ Cardioprotection
Heart ↓ Appetite
↑ Cardiac function
Stomach

Intestine
↓ Gastric
emptying

Liver
GLP-1
↓ Glucose
production
↑ Insulin secretion
Insulin Pancreas
Muscle & Adipose tissue ↓ Glucagon secretion
sensitivity
↑ Glucose uptake ↑ Insulin biosynthesis
↑ Glucose storage ↑ -cell proliferation
↓ -cell apoptosis
Baggio & Drucker. Gastroenterol. 2007;132:2131–57.
 DPP-4 inhibitors
Increases and prolongs GLP-1
DPP-4 β-cells and GIP effects on β-cells
Food intake inhibitor
Glucose-dependent
insulin secretion
Stomach Pancreas
DPP-4

GI tract
Incretins α-cells Increases and prolongs
(GLP-1, GLP-1 effect on α-cells
GIP) Glucose-dependent
Intestine glucagon secretion
* GIP does not inhibit glucagon secretion by α-cells

DPP-4: dipetidyl peptidase-4; GI: gastrointestinal; GIP:glucose-dependent insulinotropic polypeptide; GLP-1: glucagon-like peptide

Drucker DJ et al. Nature 2006;368:1696–705. Idris I, et al. Diabetes Obes Metab 2007;9:153–65. Barnett A. Int J Clin Pract 2006;60:1454–70. Gallwitz B, et al.
Diabetes Obes Metab 2010;12:1–11.
 Slide 37

DPP-4 inhibitors
DPP-4 inhibitors
Efficacy* Safety, Tolerability and Adherence

• HbA1c reduction of • Generally well tolerated

0.5-1% • Low risk of hypoglycemia
• FPG reduction of 20 • Not associated with weight
gain
mg/dl
• Upper respiratory tract
• PPG reduction of 45-55 infection has been reported in
mg/dl clinical studies
• Most require only once daily
administration
* Efficacy depends on existing blood glucose levels

Ahrèn B. Expert Opin Emerg Drugs 2008;13:593–607. Gallwitz B, et al. Diabetes Obes Metab 2010;12:1–11. Amori RE, et al. JAMA 2007;298:194–206.
Saxagliptin, FDA’s Endocrinologic and Metabolic Drugs Advisory Committee Briefing Document for April 2009 Meeting: NDA 22-350. Available at:
http://www.fda.gov/OHRMS/DOCKETS/ac/09/briefing/2009-4422b1-02-Bristol.pdf. (accessed Nov 2010). Aschner P, et al. Diabetes Care 2006;29:2632–7.
Glucagon-like peptide-1 (GLP-1) receptor agonist.

Exenatide(administered twice daily)

Liraglutide and lixisenatide (administered once daily)
Dulaglutide and semaglutide (administered once weekly)
 Inhibits SGLT2 and removes excess glucose in
the urine independently of insulin
SGLT2
Reduced glucose
reabsorption

Proximal
tubule

Increased
Increasedurinary
urinary
SGLT2 excretion of of
excretion excess
excess
Glucose glucose
glucose (~70g/day,
(~70 g/day,
Glucose filtration correspondingtoto
corresponding
280280 kcal/day*1)
kcal/day*)

• By inhibiting SGLT2, removes glucose and associated

calories

*Increases urinary volume by only ~1 additional void/day (~375 mL/day) in a 12-week study of healthy subjects and patients with Type 2 diabetes.
FORXIGA®. Summary of product characteristics, 2015.
 Pasien rutin kontrol dengan
Typesterapi
of Insulin
Glimeperide 2mg dan Metformin 1x500mg.

DPP IV inhibitor, Acarbosa

Glinide, SGLT2 inhibitor
2HPG
-cell
failure
Insulin
resistance
FPG
Metformin
TZD, DPP IV inhibitor,
SGLT2 inhibitor
Sulfonylurea: glibenklamid, glimeperide
Ca++

SUR Voltage-
ATP- dependent Ca2+
sensitive K+ Depolarizatio channel
channel n
Ca2
↑
Islet +
ATP/A
MitochonDP transcriptio
n factors
dria Insulin
Pyruvate
Glucose-6- Nucleus
Glucokinase
Phosphate Secretory
Glucose granules
GLUT2
Glucose INCRETIN
 Slide 42

Sulphonylurea

Efficacy* Safety, Tolerability and Adherence

• HbA1c reduction • Associated with
of 1-2% hypoglycaemia and weight
gain.
• FPG reduction of • Precaution : long acting SU
40-70 (elderly, hepar-renal
mg/dl insuffisient, cardiovascular,
malnutrisi)

* Efficacy depends on existing blood glucose levels

Krentz AJ, Bailey CJ. Drugs 2005;65:385–411. Nathan DM, et al. Diabetologia. 2009;52:17–30. Rosenstock J, et al. Diabetes Care. 2004;27:1265–70.
Gejala Hipoglikemia

TMF, Health Quality Institute

Hipoglikemia ringan – sedang
kadar glukosa darah <70 mg/dl
pasien sadar bisa menelan
15-20g karbohidrat sederhana:
150-200 ml jus buah, 1-2 sdm gula dilarutkan dalam air
Ulang periksa glukosa darah 10-15 menit.
jika <70 mg/dl, ulang sampai 3 kali.
jika<70 mg/dl setelah 45 menit/3 siklus.
Hubungi dokter: 1mg of Glucagon IM
atau D10% infusi 100ml/1 jam.
jika>70 mg/dl, pasien membaik,
karbohidrat kompleks : 2 biskuit, 1 lembar roti tawar,
200-300ml susu , makan.
Monitoring glukosa darah 24 sd 48 jam.
 Oral Anti Diabetes

FPG

Sulphonylurea
Insulin
 The main principles that underlie combination therapy start with the
assessment of patient’s specific pathophysiology at the time of initiation of
therapy. Lebovitz. Joslin’s Diabetes Mellitus 4th Ed.

Pasien mengeluh BB sulit turun

selama 2 tahun BB naik 5 kg.

FPG
Insulin
SULFONILUREA - METFORMIN resistance
SINDROMA METABOLIK
4-Year Failure Rate With Combination OADS

n-2220; 4 yrs after initiation

Cook MN et al. Diabetes Care. 2005;28:995-1000.

 Algorithm of Type 2 Diabetes management in Indonesia (PERKENI, 2021)
GOAL THERAPY : HbA1c <7% (Individualised)

HEALTHY LIFESTYLE MODIFICATION

Entry HbA1c <7.5% Entry HbA1c >7.5% Entry HbA1c >9%

MONOTHERAPY DUAL THERAPY SYMPTOMS

(combination of 2 drugs with TRIPLE THERAPY
Metformi different mechanism) (combination of 3 drugs with
NO YES
n different mechanism)

If HbA1c is M M S DUAL INSULIN

SU/Glinid SU/Glinid SU/Glinid
not < 7% in 3 e e e If THERAPY ±
months, t If HbA1c is not t c HbA1c Other
AG-I AG-i f AG-I OR
proceed to f < 7% in 3 o is not < Agents
DUAL o months, o n 7% in 3
TZD TZD TZD TRIPLE
THERAPY r proceed to r d months,
THERAPY
m m l proceed
DPP-4i DPP-4i TRIPLE DPP-4i
i THERAPY i i to ADD
n SGLT-2i (combination of n n OR
SGLT-2i SGLT-2i
o 3 drugs) o e INTENS
r r ADD OR INTENSIFY
GLP-1 Basal d Basal IFY
o Insulin o r Insulin INSULIN
RA Insulin
t t u Therapy
h GLP-1 RA h g GLP-1 RA
1. The selection and use of drugs consider drug cost, availability, effectiveness, cardiorenal benefits, safety profile, effects on body
e e s
r r
weight and patients' choice. f f
2. Management includes not only blood glucose, but also integrated management of other Cardio-Renal risk factors.
i i
r r
3. Some GLP-1 RA and SGLT-2i show benefits to patients with Atherosclerotic Cardiovascular Disease, Heart Failure, and
s s
Kidney Failure comorbidities. Both classes are suggested as options for patients with mentioned comorbidities / complications.
t t
l l
4. If the HbA1C cannot be checked, then the average blood glucose is used as a guide which is then converted to HbA1C
i i
n n
e e
d d
r r
u u
g g
 Jenis Insulin

2hPG
GI
R
(m
g/
kg
/m
in)
BASAL INSULIN
PRE-MIX INSULIN
FAST-ACTING
INSULIN

FPG
0 4 8 12 16 20 24
Time (h)

Slide 49
• HbA1C >7,5% sudah menggunakan 1 atau 2 OAD
• HbA1C >9%
• Penurunan BB yang cepat
• Hiperglikemia berat dengan ketosis
• Krisis hiperglikemia
• Gagal kombinasi OAD dosis optimal
• Stres berat (infeksi sistemik, operasi mayor, AMI,
stroke)
• Kehamilan dengan DM/ DM gestasional tidak
terkendali dengan perencanaan makan
• Gangguan fungsi hati/ginjal berat
• Kontraindikasi atau alergi OAD
• Kondisi perioperatif sesuai indikasi
 http://3.bp.blogspot.com/-AfTbIRu5rOc/TsMh2vbsHPI/AAAAAAAAAJY/8xt-VBgzceU/s200/pen1.png
https://lh3.googleusercontent.com/proxy/NmApJTtaG8UD3gjoMWmHajST7bmlET-Gk8xh7PWo5qw88_4CMdIkHsD6NqMpJPBZnNll_8W6KyQD9D-
MWqZtLCiwsWopj7BU6Qfjl_Tcb0s6GOeozyEF5COOXf3cCOl9XmwMN18kZqMA
 A1C

1%

12% 14% 43%

37% 21%

Sltratlon IM et at. UKPDS35. BMJ 2000..321 (7258) 405-12.

ALHAMDULILLAH
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