DIABETES TREATMENT

CONTINUUM
PIT IDI WILAYAH KEPULAUAN RIAU

HOTEL PLANET HOLIDAY – BATAM

23-25 MARET 2017

 DEFINISI DIABETES

DIABETES MELITUS ADALAH PENYAKIT METABOLIK KRONIK PROGRESIF YANG DITANDAI DENGAN
HIPERGLIKEMIA AKIBAT KELAINAN PADA :

Sekresi hormon insulin

Aksi hormon insulin (resistensi)

Kombinasi keduanya
 DIABETES TIPE 2 MERUPAKAN PENYAKIT PROGRESIF

HOMA: homeostasis model assessment

Lebovitz. Diabetes Reviews 1999;7:139–53 (data are from the UKPDS population: UKPDS 16.
Diabetes 1995;44:1249–58)
 HIGH BLOOD GLUCOSE IS THE 3RD BIGGEST RISK FACTOR
CONTRIBUTOR TO CARDIO-VASCULAR
DEATHS GLOBALLY

Attributable deaths due to selected risk factors (000’)

WHO 2011. Global Atlas on CVD prevention and Control

 TYPE 2 DIABETES—INCREASED HBA1C ELEVATES
RISK OF COMPLICATIONS

Diabetes-related
complications included:
●Fatal or nonfatal myocardial
infarction, stroke, or
microvascular disease
●Amputation or death from
peripheral vascular disease
●Heart failure
●Cataract extraction

Stratton IM, et al. BMJ. 2000;321:405-412.

 DIABETES—A GROWING GLOBAL EPIDEMIC
Diabetes* worldwide prevalence, 2011: ~360 million1
2030 prevalence estimates : >550 million1

Of all cases
of diabetes,
90% are type 2
diabetes2

2030 prevalence1:
South East Asia: 121 million
Indonesia: 7,2 → 11,8 million

•All cases of diabetes, including type 1 and type 2 diabetes, and impaired glucose tolerance (IGT), in patients aged 20-79 years.
1. International Diabetes Federation. IDF Diabetes Atlas, 5th ed. Brussels, Belgium: International Diabetes Federation, 2011.

DIABETES* WORLDWIDE PREVALENCE ESTIMATES, 2030: >550 MILLION1

DIABETES IS DEVELOPING FAST IN INDONESIA

2007 2013
Diagnosed Diabetes 1.5% 2.1%

Undiagnosed Diabetes 4.2% 4.8%

Impaired Glucose Tolerance 10.2% 29.9%

More than 10 million people live with diabetes

RISKESDAS Survey 2007
in Indonesia in 2015
Laporan RISKESDAS 2013
WHY ARE WE SEEING SUCH AN INCREASE IN
THE NUMBER OF PEOPLE WITH TYPE 2
DIABETES WORLDWIDE ??

Unhealthy lifestyle Aging population rbanisation

Dietary changes Sedentary lifestyle

IDF Diabetes Atlas 2014
Cockram 2000. HKMJ; 6 (1): 43-52
Mohan 2007. Indian J Med Res; 125: 217-230
 TYPE 2 DIABETES—APPROXIMATELY ONE-HALF OF PATIENTS
ARE UNCONTROLLED

WONG ND, ET AL. PERSISTENT UNDERTREATMENT OF CARDIOVASCULAR RISK FACTORS AMONG SUBJECTS WITH TYPE 2 DIABETES IN THE UNITED STATES 2005-
2006. PRESENTED AT: AMERICAN DIABETES ASSOCIATION 70TH SCIENTIFIC SESSIONS; JUNE 25-29, 2010; ORLANDO, FL.
 GEJALA KLASIK DIABETES

Polyuria • Sering buang air kecil

Polyphagia • Sering makan

Polydipsia • Sering minum

Unexplained weight loss • Berat badan turun dengan

penyebab tidak diketahui
 DIAGNOSA DIABETES

• A1C ≥ 6,5%
ATAU
• KADAR GULA DARAH PUASA (GDP) ≥ 126 MG/DL
• PASIEN PUASA ≥ 8 JAM
ATAU
• KADAR GULA DARAH 2 JAM POST PRANDIAL (GD2PP) ≥ 200 MG/DL
ATAU
• GEJALA KLASIK DIABETES + KADAR GULA DARAH SEWAKTU (GDS) ≥ 200 MG/DL
 KLASIFIKASI DIABETES
• Diabetes tipe 1
• Defisiensi insulin absolut akibat rusaknya sel beta pankreas
• Diabetes tipe 2
• Defek sekresi hormon insulin
• Resistensi hormon insulin
• Diabetes gestasional
• Intoleransi glukosa yang pertama kali terdeteksi saat kehamilan
• Umumnya akan sembuh setelah persalinan
• Lainnya :
Drug- or chemical-induced, e.g steroids, treatment of HIV/AIDS or after organ transplantation
Genetic defects in beta cell function or in insulin action
Diseases of the exocrine pancreas (e.g. cystic fibrosis)
Diabetes Care 1997; 20: 1183-1197
 KOMPLIKASI DIABETES
• MAKROVASKULAR
• STROKE
• PENYAKIT JANTUNG

• MIKROVASKULAR
• RETINOPATI
• NEFROPATI
• NEUROPATI
 TERAPI DIABETES

• NON-FARMAKOLOGI (BUKAN OBAT)

• GAYA HIDUP SEHAT
• MAKAN MAKANAN YANG SEHAT & BERGIZI
• OLAHRAGA TERATUR

• FARMAKOLOGI (OBAT)
• ORAL
• INSULIN
 THE CORNERSTONES
OF DIABETES MANAGEMENT

• EDUCATION
• MEDICAL NUTRITION THERAPY
• EXERCISE
• PHARMACOLOGIC INTERVENTION (OHAs, INSULIN)
 ADA/EASD treatment algorithm

American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetes 2015. Diabetes Care 2015;38(Suppl. 1):S41–S48
Type 2 diabetes—controlling multiple
parameters is essential

Incremental reductions sustained

over time in HbA1c and other
parameters can benefit the
physical health of patients with
type 2 diabetes1-5

1. Stratton IM, et al. BMJ. 2000;321:405-412. 2. Pi-Sunyer FX. Postgrad Med. 2009;121(5):94-107. 3. Williamson DF, et al. Diabetes Care. 2000;23(10):1499-1504. 4.
Patel A. Lancet. 2007;370(9590):829-840. 5. Pyǒrälä K, et al. Diabetes Care. 1997;20(4):614-620.
 WHAT IS GOOD GLYCAEMIC CONTROL?

 Overall aim is to achieve glucose levels as close to normal as possible

 Minimise development and progression of microvascular and
macrovascular complications

ADA1 FPG HbA1c PPG

<130 mg/dL < 7.0 % <180 mg/dL

FPG HbA1c PPG

IDF2 <110 mg/dl
< 6.5 % <145 mg/dL

PERKENI3 FPG HbA1c PPG

<130 mg/dl < 7.0 % <180 mg/dl

1. American Diabetes Association Diabetes Care 2015;38 (Suppl 1):S8-S15

2. IDF Clinical Guidelines Task Force. International Diabetes Federation 2005. 3. Konsensus PERKENI 2015.
 Type 2 diabetes—LOWERING HbA1c reduces risk for macro-
and microvascular complications

Stratton IM et al. BMJ. 2000;321:405-412.

Type 2 diabetes—lowering BLOOD PRESURE reduces risk of
complications

P= 0.10
(95% CI -1 to 10%)
P= 0.42
(95% CI -10 to 20%)

P= 0.020
(95% CI 41 to 453)

P= 0.027 P< 0.0001

(95% CI 2 to 32%) (95% CI 15 to -27%)

Patel A et al; for the ADVANCE Collaborative Group. Lancet. 2007;370(9590):829-840.

 TERAPI NON-FARMAKOLOGI

2.5 million years 50 years

Karbohidrat
Kurangi Tambahkan

White sugar, Brown sugar, Buah, susu rendah lemak,

White bread, nasi putih kacang-kacangan, yogurt, roti
gandum, nasi merah
Protein
Kurangi Tambahkan

Sosis, daging olahan, udang, Ayam, ikan, tahu

daging merah
Lemak
Kurangi Tambahkan

Kelapa, mentega, kehu, Alpukat, kacang-kacangan,

lemak jenuh olive oil, lemak tidak jenuh
Type 2 diabetes—WEIGHT LOSS is associated with
decreased mortality

Weight loss of 1 to 9 lbs

is associated with
decreased mortality rates

Author/Editor: David F. Williamson. Copyright 2000 American Diabetes Association. From Diabetes Care, Vol. 23, 2000; 1499-1504.
Reproduced by permission of The American Diabetes Association.
Prospective analysis with a 12-year mortality follow-up (1959-1972) of 4,970 overweight people with diabetes.
 Olahraga Mampu Menurunkan HbA1c Secara Signifikan

Meta-analisis dari 14 penelitian

%
0.2
0.1 0,08%
Olahraga
0.0
Perubahan HbA1c

Tidak olahraga
-0.1
-0.2
-0.3
p<0.001
-0.4
-0.5
-0.6
-0.7 -0,66%
Source: Boule NG et al. Effects of exercise on glycemic control and body mass in T2 Diabetes: JAMA2001;
Boulé286:1218-27
NG, et al. JAMA 2001;286:1218-27.
 ORAL Antihyperglycaemic agents currently
available in Indonesia
 Metformin
 Sulfonylureas (SUs) and glinides
 α-glucosidase inhibitors (AGIs)
 Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors)
 Glucagon-like peptide-1 (GLP-1) agonists
 Thiazolidinediones (TZDs)
 Sodium glucose co-transporter 2 inhibitors (SGLT2-inhibitors)
INJECTION Antihyperglycaemic agents currently
available in Indonesia

 INSULIN

 LYRAGLUTIDE
 History of diabetes medications.

John R. White, Jr. Diabetes Spectr 2014;27:82-86

 ORAL Choice of agents in current use
Glipizide
Gliclazide
Glimepiride
Glibenclamide
Sulphonylureas Acarbose
Miglitol
Voglibose
Rosiglitazone
Metformin -glucosidase
Pioglitazone TZDs
inhibitors

Meglitinides
Repaglinide
Nateglinide
 Metformin
Mode of action
Metformin decreases hepatic glucose production and affects
insulin-mediated peripheral glucose uptake

Muscle Liver Intestine Adipose tissue

 Glucose uptake  Gluconeogenesis  Anaerobic glucose  Glucose uptake
 Glucose oxidation  Glycogenolysis metabolism  Glucose oxidation
 Glycogenesis  Oxidation of FA  ?Lower bowel- mediated
 Oxidation of FA

FA: Fatty Acids

Krentz AJ, Bailey CJ. Oral antidiabetic agents: current role in type 2 diabetes melitus. Drugs 2005;65:385–411.
Buse et al The Primary Glucose-Lowering Effect of Metformin Resides in the Gut, Not the Circulation. Diabetes Care. 2016
Feb;39(2):198-205
 Metformin
Clinical overview and contraindications
Metformin

Efficacy on glucose Safety, Tolerability and

Contraindications Advantages
levels Adherence

• HbA1c reduction of • Usually first choice • Renal insufficiency • Does not cause
1-2% (cut-offs vary) hypoglycaemia when
• Nausea, diarrhea and used as monotherapy
• FPG reduction of abdominal discomfort • Liver failure
40-70 mg/dl • Does not cause weight
• Heart failure gain; may contribute
• Severe gastrointestinal to weight loss
disease

1. Krentz AJ, Bailey CJ. Oral antidiabetic agents: current role in type 2 diabetes melitus. Drugs 2005; 65:385–411
2. KDOQI Diabetes Guideline: 2012 Update. Am J Kidney Dis. 2012;60(5):850-886
Metformin
Little glycaemic benefit evident with doses over 2 g/day

Fasting Plasma Glucose HbA1c

Garber AJ, Efficacy of metformin in type 2 Diabetes. Am J Med 1997;102:491-7.

 Sulfonylureas and Glinides
Mode of action ATP-sensitive
Pancreatic β-cell
potassium channel
• Sulfonylureas (SUs) and glinides
increase endogenous insulin Glucose Glycolysis ATP
secretion by binding to pancreatic
SUs /
uptake respiration
β-cells and triggering a cascade of glinides
intracellular events1–3 Glucokinase
• The mode of action of SUs and
glinides is similar, but stimulation
of insulin secretion is more rapid
and short-acting with glinides
• SU receptors are also found on
other cells, including the cardiac
myocytes
Insulin release Voltage-gated Ca2+
SU: sulfonylurea; GLUT: glucose transporter. calcium channel
1. Gallwitz B, Haring H-U. Diabetes Obes Metab 2010;12:1–11. 2. Schuit FC, et al. Diabetes 2001;50:1–11. 3. Krentz AJ, Bailey CJ.
Drugs 2005;65:385–411.
Sulfonylureas and Glinides
Clinical overview

Sulphonylureas Glinides

Efficacy on glucose Safety, Tolerability and Efficacy on glucose Safety, Tolerability and
levels Adherence levels Adherence

• HbA1c reduction of • Associated with • HbA1c reduction of • Associated with

1-2% hypoglycaemia and 0.5-1.5% hypoglycaemia and
weight gain weight gain
• FPG reduction of • FPG reduction of
40-70 mg/dl 20-60 mg/dl • Administration with
every meal is required
• PPG reduction of
75-100 mg/dl

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.
 Thiazolidinediones
Clinical overview
Thiazolidinediones

Efficacy on glucose levels Safety, Tolerability and Adherence Contraindications

• HbA1c reduction of 0.5- • Weight gain and oedema • Liver disease

1.5%
• Risk of bone fractures • Heart failure
• FPG reduction of 20-55
mg/dl • May exacerbate or precipitate • History of heart disease
congestive heart failure
• Pregnancy and
breastfeeding

* 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.
Sodium Glucose Co-transporter-2 inhibitors
(SGLT-2 inhibitors)
Mode of action
Glomerulus Proximal tubule Distal tubule Collecting duct

S1
Glucose
filtration
SGLT2 SGLT1 S3

90%
reabsorption
Glucose
reabsorption
Minimal
glucose
Loop of Henle excretion

Glucose reabsorbtion by the normal kidney, showing the site of action of sodium-glucose
co-transporter 2 inhibitors (SGLT2 inhibitors)

Fioretto P, Giaccari A dan Sesti G. Efficacy and safety of dapagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in diabetes mellitus. Diabetol 2015;14:142
 Acarbose delays carbohydrate absorption
Without acarbose With acarbose

Carbohydrate
Carbohydrate
absorption Jejunum
Jejunum

Ileum Ileum

Carbohydrate
absorption Without acarbose
With acarbose

Duodenum Jejunum Ileum

 Alpha glucosidase inhibitors
Mode of action

 Slow digestion and delay absorption of sucrose and starch

 Slow post-meal rise in blood glucose
 Do not cause hypoglycaemia when used as monotherapy

1. Gallwitz B, Haring H-U. Diabetes Obes Metab 2010;12:1–11. 2. Schuit FC, et al. Diabetes 2001;50:1–11. 3. Krentz
AJ, Bailey CJ. Drugs 2005;65:385–411.
 Alpha-glucosidase inhibitors
Clinical overview

Alpha-glucosidase inhibitors

Efficacy on glucose levels Safety, Tolerability and Adherence

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

abdominal discomfort
• FPG reduction of 10-20 mg/dl
• Administration with every meal is
• PPG reduction of 40-50 mg/dl required

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.
 DPP-4 inhibitors
Mode of action
Increases and prolongs GLP-1
DPP-4 β-cells and GIP effects on β-cells
Food intake inhibitor Glucose-dependent
insulin secretion
Stomach DPP-4 Pancreas Net effect:
blood glucose
GI tract Incretins (GLP-1, GIP) Increases and prolongs
α-cells GLP-1 effect on α-cells
Glucose-dependent
Intestine glucagon secretion
* GIP does not inhibit glucagon secretion by α-cells
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.
DPP-4 inhibitors
Clinical overview
DPP-4 inhibitors

Efficacy on glucose levels Safety, Tolerability and Adherence

• HbA1c reduction of 0.5-1% • Generally well tolerated

• FPG reduction of 20 mg/dl • Low risk of hypoglycaemia
• PPG reduction of 45-55 mg/dl • No weight gain
• Administration usually once daily
• Risk of upper respiratory tract infection

* 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.
 Incretins regulate glucose homeostasis
through effects on islet cell function

Ingestion
of food Glucose dependent
 Insulin Insulin
from beta cells increases
(GLP-1 and GIP) peripheral
glucose
GI tract Release of Pancreas uptake
incretin gut
hormones Beta cells Blood
Alpha cells glucose control
Active
GLP-1 and GIP
Increased insulin
and decreased
 Glucagon glucagon
from alpha cells reduce
(GLP-1) hepatic
Glucose dependent glucose output

Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:2653–2659; Zander M et al Lancet 2002;359:824–830; Ahrén B Curr Diab Rep
2003;3:365–372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.
 Blocking DPP-4 can improve incretin activity
and correct the insulin:glucagon ratio in T2DM
 Insulin
T2DM
Incretin
Further impaired
response Hyperglycemia
islet function
diminished

 Glucagon

DPP- 4 inhibitor
 Insulin

Incretin
Improved islet Improved
activity
function glycemic control
prolonged

 Glucagon

DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus

Adapted from Unger RH. Metabolism. 1974; 23: 581–593. Ahrén B. Curr Enzyme Inhib. 2005; 1: 65–73.
 Active GLP-1 is inactivated
by DPP-4
Meal

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

Active
GLP-1

DPP-4
Helps:
increase insulin release GLP-1
suppress glucagon release inactive
(>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.
 Inhibition of DPP-4 increases
active GLP-1
Meal

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

Active
GLP-1

DPP-4

Prolongs incretin activity

GLP-1
inactive
(>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.
 GLP-1 receptor agonist
Mode of action
Glucagon-like peptide-1 (GLP-1) agonists:
• Increase insulin release from the pancreatic β-cells
• Inhibit glucagon release from the pancreatic α-cells
• Delay gastric emptying

β-cells Glucose-dependent insulin secretion

Pancreas
GLP-1 agonist Net effect:
blood glucose

α-cell Glucagon secretion

GLP-1: glucagon-like peptide

1. Doyle ME, Egan JM. Mechanism of action of glucagon-like peptide 1 in the pancreas. Pharmacol Ther 2007;113(3):546–93.
GLP-1 receptor agonist
Clinical overview

GLP-1 Agonist

Efficacy on glucose levels Safety, Tolerability and Adherence

• HbA1c reduction of 1-2% • Moderate and transient nausea, vomiting and

diarrhoea
• FPG reduction of 6-12 mg/dl
• Low risk of hypoglycaemia
• PPG reduction of 6-18 mg/dl
• Often weight reduction
• Blood pressure reduction
• Avoid use in patients with history or family
history of medullary thyroid carcinoma

* Efficacy depends on existing blood glucose levels

Garber AJ. Diabetes Care 2011;34 (Suppl 2):S279–84. Moretto TJ, et al. Clin Ther 2008;30:1448–60. Drucker DJ. Cell
Metab 2006;3:153–65. Amori RE, et al. JAMA 2007;298:194–206.
 Kapan Insulin Diberikan ?

Gaya hidup + 1 OAD + 2 OAD + 3 OAD

INISIASI INSULIN

Adapted from Nathan DM, et al. Diabetes Care 2009; 31:193-203

 Insulin is the most effective glucose-lowering agent

Decrease in HbA1c: Potency of monotherapy

Nathan et al., Diabetes Care 2009;32:193-203.

 Fisiologi Sekresi Hormon Insulin
50 Insulin bolus/prandial
Serum insulin (mU/L)

40

30

20
Insulin basal
10

0
08.00 12.00 16.00 20.00 24.00 04.00 08.00
Waktu (jam)
Sarapan Makan siang Makan
malam
Kruszynska. Diabetologia 1987;30:16
 Insulin
Mode of action

Insulin

Insulin binds to the insulin receptors on the cell membranes of the

target cells in the liver, muscles and adipose tissue

Adipose
Liver Muscles
tissue

 Inhibits glucose production

 Promotes uptake,  Promotes uptake and
 Promotes glycogen formation utilization and storage of glucose
and glycogen storage storage of glucose
 Suppresses lipolysis
Types of insulin available in Indonesia

Human Insulin Analogue Insulin

 Types of insulin
Basal
analogue
GIR (mg/kg/min)
GIR (mg/kg/min)
0 4 8 12 16 20 24
Time (h)
Basal Insulin provides a
steady concentration of
insulin in the bloodstream
over 24 hours. Basal insulin
is commonly commenced at
a dose of 10 units once per
day1
1. Hompesch M. Diabetes Obes Metab 2006; 8:568; 2. Weyer et al. Diabetes Care 1997;10:1612–1614.;
Diabetes Care. 1998;21:1910–4
Premixed Rapid-acting
analogue analogue
GIR (mg/kg/min)
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Time (h) Time (h)
Premixed insulin is a
Rapid-acting insulin
mixture of rapid and
analogues are quickly
intermediate-acting insulin in
absorbed into the
a fixed combination to
bloodstream leading to rapid
provide coverage of prandial
onset of action and a shorter
and basal insulin
duration of action3
requirements2
3. Heinemann et al.
 Basal titration scheme
BASAL • Start with Basal Insulin 10 U daily with meal or before bedtime
INSULIN • Same injection time every day

Fasting blood glucose (mg/dl) Basal Insulin Titration

<70 mg/dl Reduce dosage with 2 units

70-130 mg/dl Maintain dosage

130-180 mg/dl Increase dosage 2 units per 3 days

>180 mg/dl Increase dosage 4 units per 3 days

Once titrated, continue to monitor HbA1c every 3 months

Adapted from PERKENI Insulin Guidelines. 2011

 How to optimise insulin treatment
Start with Basal Insulin
10 IU with meal or Basal Insulin Usually
before bedtime. Same with oral agents
injection time everyday

If glycaemic target is not reached,

titrate according to basal titration scheme

= Fasting glucose within target range, but A1c target is not reached within 2-3 months
 intensify insulin treatment
Premixed Insulin Basal with Prandial Basal-Bolus
Usually keep or Usually keep or Usually keep
Metformin metformin Metformin

Switch to Premixed twice- Add prandial starting Switch to Basal-Bolus,

daily. Start with equal basal with 4 U / day either start with 4 U each
dose, but give 50% per OD or BID and titrate meal (TID), and titrate
injection and titrate accordingly accordingly)
accordingly Adapted from PERKENI Insulin Guidelines. 2011
Insulin-independent pathways: SGLT system1-6
The role of the sodium-glucose cotransporter (SGLT)
system
in glucose regulation

1. DeFronzo RA. Med Clin N Am. 2004;88(4): 787-835. 2. Rahmoune H, et al. Diabetes. 2005;54:3427-3434. 3. Marsenic O. Am J Kidney Dis. 2009;53(5):875-883. 4. Brown GK.
J Inherit Metab Dis. 2000;23(3):237-246. 5. Vallon V, Sharma K. Curr Opin Nephrol Hypertens. 2010;19(5):425-431. 6. Wright EM, et al. J Intern Med. 2007;261(1):32-43.
SGLT and GLUT transporters facilitate insulin independent
reabsorption of filtered glucose in the proximal tubule
Tissue
S1 proximal
reabsorption
tubule lumen
(filtrate)
ATPase
SGLT2
SGLT 2 Glucos
e
• Low affinity
1 Na+
• High
GLUT 2
capacity

Tissue
reabsorption
S3 proximal
tubule lumen Glucos ATPase SGLT1
(filtrate) SGLT 1 e
2 Na+ • High affinity
• Low
GLUT 1
capacity

GLUT, glucose transporter; SGLT, sodium-glucose co-transporter.

Adapted from: Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18.

59
 Normal glucose homeostasis1,2
Net balance ~0 g/day
Glucose input ~250 g/day: Glucose uptake ~250 g/day:

• Dietary intake ~180 g/day • Brain ~125 g/day

• Glucose production ~70 g/day • Rest of the body ~125 g/day
• Gluconeogenesis
• Glycogenolysis
+ The kidney filters The kidney reabsorbs
−
circulating glucose and recirculates
glucose

Glucose filtered Glucose reabsorbed

~180 g/day ~180 g/day

1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18;

2. Gerich, JE. Diabetes Obes Metab 2000;2:345–50.
 In normal renal glucose handling, 90% of glucose is
reabsorbed by SGLT21–4

Majority of glucose is
reabsorbed by SGLT2
(90%)

Proximal tubule

Remaining
glucose is
SGLT2
Glucose reabsorbed by
Glucose filtration SGLT1 (10%)
Minimal to
no glucose
excretion

SGLT, sodium-glucose co-transporter 2.

Adapted from: 1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; 3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14–21;
4. Marsenic O. Am J Kidney Dis 2009;53:875–83.
 Glucose handling in Type 2 diabetes1,2

Glucose input >280 g/day: Glucose uptake >250 g/day:

• Dietary intake >180 g/day • Brain ~125 g/day

• Glucose production ~100 g/day • Rest of the body >125 g/day
• Gluconeogenesis*
• Glycogenolysis
+ Increased reabsorption
−
Average blood glucose
concentration 150 mg/dL and recirculation of
Kidney filters all glucose
circulating glucose

Glucose filtered Above the renal threshold for

~270 g/day glucose (~200 mg/dL), glucose is
excreted in the urine (glucosuria)

*Elevated glucose production in patients with Type 2 diabetes attributed to

hepatic and renal gluconeogenesis.2
1. Gerich JE. Diabet Med 2010;27:136–42;
2. Abdul-Ghani MA, DeFronzo RA. Endocr Pract 2008;14:782–90.
 FORXIGA inhibits SGLT2 and removes excess glucose in
the urine independently of insulin
SGLT2
Reduced glucose
reabsorption
FORXIGA

Proximal tubule

Increased urinary
Increased urinary
excretion of excess
excretion of excess
SGLT2
Glucose glucose
glucose (~70 g/day,
(~70 g/day,
Glucose filtration corresponding to
corresponding to
280kcal/day*
280 kcal/day*)1)
FORXIGA

• By inhibiting SGLT2, FORXIGA removes glucose and associated calories

• FORXIGA is >1400-times more selective for SGLT2 versus SGLT1

*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.
 Sodium Glucose Co-transporter 2 inhibitors
(SGLT-2 inhibitors/Dafagliflozin-FORXIGA)
Clinical overview

Sodium Glucose co-Transporter 2 inhibitors (SGLT2-inhibitors)

Efficacy on glucose
Adverse event Contraindications Advantages
levels
• HbA1c reduction of • Vulvovaginitis, balanitis and • Age ≥75 years • Reduce total body
1.3-1.8%1 related genital infections • Concomitant weight, blood
• Urinary tract infections pioglitazone treatment pressure1
• FPG reduction of • Haematocrit increase • Concomitant loop
23,4-28.8 mg/dl2-4 • Renal creatinine clearance diuretics treatment
decrease • Volume depletion
• Dyslipidaemia

.
1. Katz A, et al. Diabetes 2014;63(Suppl. 1):A284. 2. Henry R, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011
Abstract 307-OR. 2. Bailey CJ, et al. Lancet 2010;375:2223-33; Strojek K, et al. Diabetes Obes Metab 2011;13:928-38;
4. Rosenstock J, et al. Diabetes Care, Volume 35, July 2012
2.
 FORXIGA: For your patients who are uncontrolled on
metformin with sufficient renal function
FORXIGA as add on to
metformin delivers significant
and sustained reductions in:1,2
 PPG, FPG & HbA1c,
Wth ADDITIONAL Benefit
As FORXIGA has an Insulin Independent
Reduction1 : Pathway it may also be used to complement
other medications across the spectrum of
 Weight
disease3
 Blood pressure
 Waist Circumference

Early disease Advanced disease

FORXIGA is not indicated for the management of obesity or high blood pressure. 1 Weight change was a secondary endpoint in clinical trials. 1,2
1. FORXIGA®. Summary of product characteristics, 2014; 2. Bailey CJ, et al. Lancet 2010;375:2223–33; 3. Jabbour SA, et al. Diabetes Care 2014;37:740–50;
 FORXIGA: Safety and tolerability from a wide-ranging
clinical programme
• The safety of FORXIGA 10 mg was assessed in a pooled analysis of 13 placebo-controlled studies in
>2300 patients
Adverse reactions in placebo-controlled studies of FORXIGA (24-week data regardless of glycaemic rescue)
Very common Common* Uncommon†
System organ class
(1/10) (1/100 to <1/10) (1/1000 to <1/100)
Infections and infestations Vulvovaginitis, balanitis and Fungal infection
related genital infections‡
UTIs§
Metabolism and nutrition disorders Hypoglycaemia (when Volume depletion||
used with a SU or insulin) Thirst
Nervous system disorders Dizziness
GI disorders Constipation
Dry mouth
Musculoskeletal and connective Back pain
tissue disorders
Renal and urinary disorders Dysuria Nocturia
Polyuria¶ Renal impairment
Reproductive system and breast Vulvovaginal pruritus
disorders Pruritus genital
Investigations Haematocrit increased** Blood creatinine increased
Creatinine renal clearance Blood urea increased
decreased Weight decreased
Dyslipidaemia††

Footnotes are available in the slide notes.

GI, gastrointestinal; SU, sulphonylurea; UTI, urinary tract infection.
FORXIGA®. Summary of product characteristics, 2015.
 Clinical considerations when prescribing FORXIGA

• FORXIGA is not recommended in:

 Patients aged ≥75 years

 Patients treated concomitantly with pioglitazone

 Patients receiving loop diuretics
• FORXIGA is also not recommended for initiation of therapy in patients who are
volume depleted
 Temporary interruption of FORXIGA is recommended for patients who
develop volume depletion until the depletion is corrected
• Caution should be exercised in patients for whom a FORXIGA-induced drop
in blood pressure could pose a risk
• A lower dose of insulin or an insulin secretagogue may be required to reduce the
risk of hypoglycaemia when used in combination with FORXIGA

FORXIGA®. Summary of product characteristics, 2015.

 Algoritma Pengelolaan DM Tipe-2 di Indonesia, KONSENSUS
HbA1C <7.5%
Dalam 3 bulan
HbA1C > 7%
Monoterapi* dengan salah
satu dibawah ini
- Metformin
- Agonis GLP1
- Penghambat
SGLT2 *
- Penghambat
DPP- 4
- Penghambat
glukosidase alfa
- Tiazolidindion
- Sulfonilurea
- Glinid
Jika HbA1C belum
mencapai sasaran
dalam 3 bulan,
tambahkan obat ke-2
(kombinasi 2 obat)
PERKENI 2015
MODIFIKASI GAYA HIDUP SEHAT
+ Monoterapi dalam 3
bulan HbA1C > 7% Gejala ( + )
Kombinasi 2 obat
Kombinasi 2 obat* dengan
mekanisme yang berbeda Insulin ± obat lain
- Agonis GLP1 Kombinasi 3 obat
Kombinasi 3 obat
- Penghambat
- Agonis GLP1
Metformin atau obat lini pertema yang lain
SGLT2 *
- Penghambat
Metformin atau obat lini pertema yang lain
Penghambat SGLT2 *
DPP - 4
- Penghambat DPP - 4
- Tiazolidindion
- Tiazolidindion
- Insulin basal
2 Obat lini kedua
- Insulin basal
- SU / Glinid Mulai pemberian insulin atau lakukan
- SU / Glinid
- Kolesevelam** intensifikasi insulin
- Bromokriptin
- Kolesevelam**
QR** - Bromokriptin QR** Keterangan:
- Penghambat - Penghambat
* Obat yang terdaftar, pemilihan dan
glukosidase alfa glukosidase alfa penggunaannya disarankan mempertimbangkan
faktor keuntungan, kerugian dan ketersediaan
sesuai tabel 11.
** Kolesevelam belum tersedia di Indonesia dan
Jika HbA1C belum Bromokriptin QR umumnya digunakan pada terapi
mencapai sasaran tumor hipofisis
dalam 3 bulan, Jika HbA1C belum mencapai
tambahkan obat ke-3 sasaran dalam 3 bulan, mulai
(kombinasi 3 obat) terapi insulin atau intensifikasi
terapi insulin
 Summary

FORXIGA…
•Has insulin-independent pathway, by removing excess glucose and calories with
urine4
•Provide a significant reduction in PPG, FPG, HbA1C and sustained when used as
add-on to metformin, sulfonylureas and TZDs1,5
•significant and sustained weight loss and blood pressure1
•FORXIGA Provide added benefit of significantly reduce total body weight, blood
pressure1, waist circumference and body fat mass compared to placebo when used as
add-on therapy1,2
•FORXIGA well tolerated1,3

FORXIGA is not indicated for the management of obesity or high blood pressure. 1 Weight change was a secondary endpoint in clinical trials. 1,5
*This information is an estimate derived from the use of information under licence from the following IMS Health information service: NPA Market Dynamics for period February – April 2014. IMS expressly reserves
the rights of copying, distribution and republication.
1. FORXIGA®. Summary of product characteristics, 2014; 2. Del Prato S, et al. Presented at the 73rd American Diabetes Association Scientific Sessions, Chicago, USA. 21–25 June 2013.
Abstract 62-LB; 3. Data on file (Cegedim Strategic Data, Longitudinal Patient Databases, October 2014); 4. Marsenic O. Am J Kidney Dis 2009;53:875–83; 5. Bailey CJ, et al. Lancet 2010;375:2223–33.