Standarized management

with OADs

Sugiarto
Divisi Endocrinology, Metabolic and Diabetes of Internal
Medicine FK / Moewardi Hospital Sebelas Maret University
Surakarta

Best Werstern Hotel, Solo Baru, 29-10-2029

Slide 1
 Slide 2

Standarized mangement with OADs

Main Learning Points

• Understand the different classes of OADs and when to use which

OADs – either as mono therapy or in combination with other OAD’s
/ Insulin
 1Diabetes mellitus
 Penyakit kronik progresif disertai gangguan metabolik dengan
berbagai penyebab (multi faktorial)
 Tanda:
 Hiperglikemia kronik dengan gangguan metabolisme
karbohidrat, protein dan lemak

 akibat :
 Defek sekresi insulin dan glukogon
 Defek aktifitas insulin atau resistensi insulin
 atau lainnya.
 Management diabetes

 Klas Diabetes.
 Komplikasi Diabetes
 Mereview terapi diabetes sebelumnya
 Rencana perawatan dan penatalaksanaan
 Pemeriksaan Laboratorium
 Slide 5

Main pathophysiological defects in type 2 DM

Brain
Intestines Pancreas
pancreatic
incretin insulin
effect secretion

pancreatic
glucagon
secretion ? Kidney
gut
carbohydrate Glucose
delivery and reabsorpsion
absorption
Hyperglycemia
Muscle
Liver

peripheral
glucose
uptake

hepatic
glucose Adipose
production

Adapted from:Inzucchi SE, Sherwin RS. Diabetes Mellitus. In: Goldman L, Ausiello D, eds. Cecil Textbook of Medicine. 23rd Edn. Philadelphia, Pa:
Saunders Elsevier; 2007.
 STUDI UKPDS.

EVERY 1% reduction in HbA1C REDUCED RISK*

Heart attacks - 14%

Deaths from diabetes - 21%

Microvascular complications - 37%

1%
Peripheral vascular disorders - 43%

*p<0.0001
UKPDS 35, BMJ 2000; 321: 405-12
 The benefits of good blood glucose control are
clear

Myocardial
Good control is infarction
≤ 7.0% HbA1c
-14%
HbA1c measures
the average
blood glucose Microvascular
level over the HbA1c complications
last three -1% -37%
months

Deaths related
to diabetes

-21%
Slide 7
Source: UKPDS = United Kingdom Prospective Diabetes Study. Stratton IM
et al. BMJ. 2000;321(7258):405-412.
 Relationship of HbA1C to Risk of Microvascular
Complications
Diabetes Control and Complications Trial
(DCCT)

15
13 Retinopathy
Relative Risk (%)

Nephropathy
11
Neuropathy
9 Microalbuminuria
7
5
3
1
6 7 8 9 10 11 12
HbA1C (%)

Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254. 8

 Updated PERKENI Type 2 Diabetes Treatment
Algorithm
Diabetes
Healthy life style
Note:
1. Therapy failed if
target of HbA1c <
7% is not achieved
within 2-3 months
for each step
2. In case of no HbA1c
test, the use of blood
glucose level is also
permitted. Average
blood glucose level
for a few BG test in
one day can be
converted to HbA1c
(ref: ADA 2010)
*Intensive Insulin: use of basal insulin together with insulin prandial
STEP 1 STEP 2 STEP 3
Healthy life style
+
Mono therapy
Healthy life style
+ Healthy life style
2 OAD Combination +
Combination 2 OAD
Alternative option, if :
+
• No insulin is available
• The patient is objecting insulin Basal insulin
• Blood glucose is still not optimally
controlled
Healthy life style
+ Insulin Intensification*
3 OAD Combination
Slide 9
 Algoritme Pengelolaan DM Tipe 2 di Indonesia KONSENSUS PERKENI 2015

Modifikasi pola hidup sehat

HbA1c < 7.5% HbA1c ≥ 7.5% HbA1c ≥ 9.0%

Gejala (-) Gejala (+)

Monoterapi* dengan salah Kombinasi 2 obat* dengan
Kombinasi 2 obat
satu obat di bawah ini mekanisme kerja yang berbeda

Kombinasi 3 obat Insulin ± obat jenis lain

• Metformin • Agonis GLP-1

• Agonis GLP-1 Kombinasi 3 obat
• Agonis GLP-1 • Penghambat DPP-IV
• Penghambat DPP-IV

Metformin atau obat lini pertama yang lain +

• Penghambat DPP-IV • Tiazolidindion
Metformin atau obat lini pertama yang lain +

• Tiazolidindion
• Penghambat • Penghambat SGLT-2
• Penghambat SGLT-2
Glukosidase Alfa • Insulin Basal

Obat lini kedua +

• Insulin Basal
• Penghambat SGLT- • SU/Glinid
•
• Kolsevelam** Mulai atau intensifikasi
2** Kolsevelam**
• Bromokriptin-QR Insulin
• Tiazolidindion • Bromokriptin-QR
• Penghambat
• Sulfonilurea • Penghambat
Glukosidase Alfa
• Glinid Glukosidase Alfa Keterangan
*Obat yang terdaftar, pemilihan dan penggunaannya
disarankan mempertimbangkan faktor keuntungan,
Jika HbAc1 > 6.4%
kerugian biaya, dan ketersediaan sesuai tabel 11
Jika belum memenuhi sasaran
dalam 3 bulan tambahan Jika belum memenuhi ** Kolsevelam belum tersedia di Indonesia
dalam 3 bulan, mulai terapi insulin
obat ke 2 (kombinasi 2 sasaran dalam 3 bulan, masuk Bromokriptin QR umumnya digunakan pada terapi
atau intensifikasi terapi insulin
obat) ke kombinasi 3 obat tumor hipofisis

Konsensus Pengelolaan dan Pencegahan Diabetes Melitus Tipe 2 di Indonesia. 2015.

ADA Recommendation 2016
 Slide 12

Current available OADs and non-Insulin injectables in

Indonesia

• Metformin
• Sulfonylureas (SUs) and glinides
• α-glucosidase inhibitors (AGIs)
• Glucagon-like peptide-1 (GLP-1) agonists
• Thiazolidinediones (TZDs)
• Dipeptidyl peptidase-4 inhibitors (DPP-4
inhibitors)
 Slide 13

Metformin
Mode of Action

The primary effects of metformin are to decrease hepatic glucose production and
increase insulin-mediated peripheral glucose uptake

FA: Fatty Acids

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

 Slide 14

Metformin
Clinical Overview and Contraindications

Metformin

Safety, Tolerability
Efficacy* Contraindications Advantages
and Adherence

• HbA1c reduction of • Associated with • Renal insufficiency • Do not cause

1-2% diarrhea and • Liver failure hypoglycaemia when
• FPG reduction of 40- abdominal discomfort • Heart failure used as mono-therapy
70 mg/dl • Lactic acidosis if • Severe • Do not cause weight
improperly gastrointestinal gain; may contribute
prescribed disease to weight loss

* Efficacy depends on existing blood glucose levels

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

 Slide 16

Metformin
Little benefit – if any - to go above 2.000 mg

Fasting Plasma Glucose HbA1c

Metformin Dose Metformin Dose

500mg 1000mg 1500mg 2000mg 2500mg 500mg 1000mg 1500mg 2000mg 2500mg
0 0 .0

10
Change vs. Placebo (mg/dl)

Change vs. Placebo (%)

20 1 8 .9 0 .5

30
3 1 .0
40 1 .0 0 .9
4 0 .9
50 1 .2

60 1 .5
6 1 .9 1 .6
70 1 .7

80 7 7 .9 2 .0
2 .0

Garber AJ, Am J Med 1997;102:491-7.

 Slide 17

SUs and Glinides

Mode of Action

Pancreatic β-cell
• Sulfonylureas (SUs) and
glinides increase endogenous ATP-sensitive
insulin secretion by binding to Glucose potassium channel
Glycolysis ATP
pancreatic β-cells and triggering uptake
respiration SUs /
a cascade of intracellular
glinides
events1–3
Glucokinase
• The mode of action of SUs and
glinides is similar, but
stimulation of insulin secretion

n o
Depolarizati
is more rapid and short-acting
with glinides
• SU receptors are also found on
other cells, including the
cardiac myocytes

Insulin release Ca2+

Voltage-gated
ATP = orange calcium channel
Ca2+ = light green
SU: sulfonylurea; GLUT: glucose transporter.

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.
 Pancreatic Mechanism Sulfonylurea

Sulfonilurea
Kalsium

Glukosa
K+ Channel
Calcium
GLUT2 SUR Channel
1 Depolarisasi Sekresi insulin

K+
Kalsium influx
ATP
Eksositosis
granule insulin
Sitoplasma
Glucose- Metabolisme Sel β
6-phasphate
PLEASE INSERT Presentation title 9 December 2021 18
 Slide 19

SUs and Glinides

Clinical Overview

Sulphonylurea Glinides

Safety, Tolerability Safety, Tolerability

Efficacy* Efficacy*
and Adherence and Adherence

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

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

* 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 20

Alpha glucosidase inhibitors

Mode of Action

• Slow digestion of sucrose and

starch and therefore delay
absorption
• Slow post-meal rise in blood
glucose
• Side effects
• Flatulence, abdominal
discomfort , diarrhoea
• As mono-therapy will not
cause hypoglycaemia
• Hypoglycaemia when used
with other medicine (e.g. a
sulphonylurea)

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.
 Slide 21

Alpha glucosidase inhibitors

Clinical Overview

Alpha glucosidase inhibitors

Efficacy*
• HbA1c reduction of 0.5-1%
• FPG reduction of 10-20 mg/dl
• PPG reduction of 40-50 mg/dl
Safety, Tolerability and
Adherence
• Associated with flatulence,
diarrhea and abdominal
discomfort
• As mono-therapy will not
cause hypoglycaemia
• Frequent administration (with
every meal) is required.

* 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 22

Thiazolidinediones (TZDs)
Mode of Action

Thiazolidinediones (TZDs) increase the sensitivity of muscle and adipose cells to

insulin and suppressing hepatic glucose production

TZD: Thiazolidinediones

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

 Slide 23

Thiazolidinediones
Clinical Overview

Thiazolidinediones

Safety, Tolerability
Efficacy* Contraindications Advantages
and Adherence

• HbA1c reduction of • Associated with • Liver disease, heart • Reduced levels of

0.5-1.5% weight gain and failure or history of LDL-cholesterol and
• FPG reduction of 20- edema heart disease increased level of
55 mg/dl • Contraindicated in • Pregnancy and breast HDL-cholesterol
patients with feeding
abnormal liver
function
• Warnings regarding
risk of fractures
• May exacerbate or
precipitate
congestive heart
failure

* 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 24

DPP-4 inhibitors
Mode of Action

Increases and prolongs GLP-1

β-cells
and GIP effects on β-cells
DPP-4
Food intake inhibitor
Glucose-dependent insulin secretion

Pancreas Net effect:

Stomach DPP-4 blood glucose

GI tract Incretins
(GLP-1, GIP) Increases and prolongs
α-cells
GLP-1 effect on α-cells

Glucose-dependent glucagon secretion

Intestine
* 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 25

DPP-4 inhibitors
Clinical Overview

DPP-4 inhibitors
Efficacy*
• HbA1c reduction of 0.5-1%
• FPG reduction of 20 mg/dl
• PPG reduction of 45-55 mg/dl
Safety, Tolerability and
Adherence
• Generally well tolerated
• Low risk of hypoglycemia
• Not associated with weight
gain
• Upper respiratory tract
infection5 has been reported in
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.
Effect of GIP and GLP-1 in human body

Seino et al., 2010)

 Slide 27

GLP 1 Agonist
Mode of Action

Glucagon-like peptide-1 (GLP-1) agonist activates the GLP

receptor in the pancreas. This increases insulin release from
the pancreatic β-cells, while inhibiting glucagon release by
the pancreatic α-cells

• Glucose-dependent insulin biosynthesis

β-cells and secretion
• β-cell proliferation

Pancreas
Net effect:
GLP-1 agonist blood glucose

• Glucagon secretion
α-cell
• β-cell apoptosis

GLP-1: glucagon-like peptide

1. Doyle ME, Egan JM. Pharmacol Ther 2007;113(3):546–93.

 Slide 28

GLP 1 Agonist
Clinical Overview

GLP-1 Agonist
Efficacy*
• HbA1c reduction of 1-2%
• FPG reduction of 6-12 mg/dl
• PPG reduction of 6-18 mg/dl
Safety, Tolerability and
Adherence
• Associated with moderate and
transient nausea, vomiting and
diarrhoea
• Low risk of hypoglycemia and
no evidence of increased CV
risk
• Associated with weight
reduction
• Associated with reduction in
BP

* 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.
 Slide 29

The Principles of OAD Combination Theory

• Two (or more) oral blood glucose-lowering

medicines that have different mechanisms of
action
• Two medications is better rather than increase
in initial medicine to maximum dosage
• Fewer side effects than mono-therapy at higher
doses

Diabetes in elderly people

• Always start with the lowest dose
of any blood glucose-lowering
medicine and increase gradually
• Using shorter-acting medicines
that reduces the risk of
hypoglycaemia
• Hypoglycaemia may increase the
risk of falls and heart attack in
older people
Slide 30
Remember the possibility of
• Forgetfulness
• Poor motivation
• Depression
• Cognitive deficits
• Poly-pharmacy
• Reduced manual dexterity
•These factors impact on the ability to
maintain self-care and achieve
maximum benefits from blood glucose-
lowering medicines.
 Slide 31

OAD’s – a quick summary of the different mechanism of

actions
Incretins :GLP-1 analogue(exen-
atide)/DPP-4 inhibitors Improves Thiazolidinediones
glucose-dependent insulin Increase glucose uptake in
secretion from pancreatic β-cells, skeletal muscle and
suppresses glucagon secretion decrease lipolysis in
from -cells, slows gastric emptying adipose tissue

Meglitinides
Increase insulin secretion from Biguanide (metformin)
pancreatic -cells Decreases hepatic glucose
production and increases
uptake

Sulfonylureas
Increase insulin secretion
from pancreatic -cells
-Glucosidase inhibitors
Delay intestinal carbohydrate
absorption
GLP = glucagon-like peptide.
Adapted from Cheng and Fantus. CMAJ. 2005;172:213–226.
 Slide 32

Properties of available glucose-lowering agents that

may guide treatment choice in Type 2 Diabetes

Class Compounds(s) Cellular Primary Advantages Disadvantages

mechanism Physiological
action(s)
Biguanides Metformin Activates Hepatic Glucose Extensive Gastrointestinal side
AMP-kinase Production  Experience effects
No weight gain Lactic acidosis risk
No hypoglycaemia (rare)
Likely CVD Events  Vitamin B12
deficiency
Multiple
contraindications:
CKD, acidosis,
hypoxia,
dehydration etc.
Sulfonylureas Glibenclamide / Closes KATP Insulin secretion  Extensive Hypoglycemia
glyburide channels on experience Weight gain
Glipizide beta cell Microvascular Risk  Blunts myocardial
Gliclazide plasme (UKPDS) ischaemic
Glimepiride membranes preconditioning ?
Low durability
Meglitinides Repaglinide Closes KATP Insulin secretion  Postprandial Hypoglycemia
Nateglinide channels on glucose excursions  Weight gain
beta cell Dosing flexibility Blunts myocardial
plasme ischaemic
membranes preconditioning ?
Frequent dosing
schedule
in the
cl uded
In
d er
Bin
Inzucci SE, et al. Diabetologia. 2012
 Slide 33

Properties of available glucose-lowering agents that

may guide treatment choice in Type 2 Diabetes cont.
Class Compounds(s) Cellular Primary Advantages Disadvantages
mechanism Physiological
action(s)
Thiazolidinedi Pioglitazone Activates the Insulin Sensitivity  No Weight Gain
ones Rosiglitazone nuclear hypoglycaemia Oedema / Heart
transcription Durability Failure
factor PPAR-y HDL-C  Bone Fractures
Triacylglycerol  LDL-C 
(pioglitazone) (rosiglitazone)
CVD Events ? Mn  (meta-
analyses,
rosiglitazone)
Bladder Cancer ?
(pioglitazone)
a-Glucosidase Acarbose Inhibits Slows intestinal No Modest HbA1c
Inhibitors Migitol intestinal a- carbohydrate hypoglycaemia efficacy
Voglibose glucosidase digestions / Postprandial Gastrointestinal side
absorption glucose effects (flatulence,
excursions  diarrhoea)
CVD Events  Frequent dosing
Non-systemic schedule

DPP-4 Sitagliptin Inhibits DPP-4 Insulin secretion  No Modest HbA1c

Inhibitors Vildagliptin activity, (glucose-dependent) hypoglycaemia efficacy
Saxagliptin increasing Glucagon secretion  Well tolerated Urticardia/Angio-
Linagliptin postprandial (glucose-dependent) oedema
Alogliptin active incretin Pancreatitis ?
(GLP-1, GIP)
in the
ded
concentrations
cl u
In
d er
Bin
Inzucci SE, et al. Diabetologia. 2012
 Slide 34

Properties of available glucose-lowering agents that

may guide treatment choice in Type 2 Diabetes cont.

Class Compounds(s) Cellular Primary Advantages Disadvantages

mechanism Physiological
action(s)
GLP-1 Exenatide Activates GLP- Insulin secretion  No Gastrointestinal side
Receptor Liraglutide 1 receptors (glucose-dependent) hypoglycaemia effects (nausea /
Agents Glucagon secretion  Weight reduction vomiting)
(glucose-dependent) Improved beta Acute pancreatitis ?
Slows gastric cell mass / C cell hyperplasia /
emptying function ? medullary thyroid
Satiety  Cardiovascular tumours
protective Injectable
actions ? Training
Requirements

Insulin Human NPH Activates Glucose disposal  Universally Hypoglycemia

Human Regular insulin Hepatic glucose effective Weight gain
Lispro receptors production  Theoretically Mitogenic effects ?
Aspart unlimited Injectable
Gluisine efficacy Training
Glargine Microvascular Requirements
Determir Risk  (UKPDS) ‘Stigma’ for patients
Pre-mixed
(several types)

in the
cl uded
In
d er
Bin
Inzucci SE, et al. Diabetologia. 2012
 Slide 35

Standarized mangement with OADs

Lecture

Summary Main Learning Points

• Multifactorial of cause diabetes • Understand the different classes of

mellitus OADs and when to use which OADs –
either as mono therapy or in
•Different start and intensification combination with other OAD’s / Insulin
options for OADs exist depending on the
need for the individual patient
• Metformin will generally be the first
drug of choice