RIWAYAT PENDIDIKAN
• Sekolah Rakyat (SR Latihan) :
1958
• SMP Negeri Watan Soppeng :
1961
• SMA negeri 2 Makassar :1964
• Dokter Umum Unhas : 1973
• SPPD UNAIR Surabaya : 1979
• Clinical Endocrinologist
Rotterdam Belanda : 1983
• Konsultan Endokrin (KEMD)
Jakarta : 1986
• Guru besar : 2012
RIWAYAT PEKERJAAN
• Dosen Fakultas Kedokteran
Universitas Hasanuddin
• Staf Bagian Ilmu Penyakit
Dalam FK UNHAS
• Ketua Divisi Endokrinologi
Departemen Ilmu Penyakit
Dalam FK UNHAS
• Guru Besar Fakultas
Kedokteran UNHAS
Prof. Dr. dr. Harsinen Sanusi, Sp.PD, K-EMD
Watansoppeng, 1 Juni 1946
Management therapy in Diabetes
patients with Insulin Resistance:
The Role of Pioglitazone and Metformin
HARSINEN SANUSI
Division of Endocrinology and Metabolic Departement of Internal Medicine
Faculty of Medicine Hasanuddin University Dr Wahidin Sudirohusodo
Makassar

18th MADAM 2021 - 5 November 13.15 – 14.15

 INSULIN RESISTANCE
• Insulin resistance (IR) is a condition in which the cells
of the body resistant to the effects of insulin, that is,
the normal response (abnormal action insulin).
• Insulin resistance has also been defined as the requirement
of 200 or more units of insulin per day to attain glycemic
control and to prevent ketosis.
 INSULIN RESISTANCE (IR)– THE LINK
BETWEEN CVD AND TYPE 2 DIABETES
• Up to 75% of mortality in T2DM is due to CVD1
• ~50% of newly diagnosed patients show signs of CVD5
• IR is an independent predictor of CVD2
• IR closely linked to a number of CVD risk factors3
• IR may develop 20+ years before onset of T2DM
• IGT is a better predictor of T2DM and CVD (DECODE2003)
• T2DM equivalent as a CHD (NCEP)6
1Gray RP & Yudkin JS. In Textbook of Diabetes (2nd Edition), Blackwell Science 1997. Editors: Pickup JC & Williams G. 2Bonora E, et al. Diabetes Care
2002; 25:1135–1141. 3Bonora E, et al. Diabetes 1998; 47:1643–1649.
4Beck-Nielsen H & The EGIR. Drugs 1999; 58 (Suppl. 1):7–10. 5Laakso M. Int J Clin Pract Suppl 2001; 121:8–12.
6NCEP ATP III. JAMA 2001; 285:2486–2497.
 INSULIN RESISTANCE: C

INHERITED AND ACQUIRED INFLUENCES

Inherited Acquired
Rare Mutations l Inactivity
l Insulin receptor l Obesity
l Glucose transporter
l Stress
l Signalling proteins
l Medications
Common Forms
l Glucose toxicity
l Largely unidentified
l Lipotoxicity
INSULIN RESISTANCE
INSULIN RESISTANCE : ASSOCIATED
CONDITIONS
Type 2 Diabetes

Atherosclerosis Hypertension

Dyslipidemia
Impaired Glucose
Insulin Tolerance
Resistance
Decresed Obesity
(Central)
Fibronylitic Activity

Acanthosis Nigricans Polycystic Ovary Disease

Hyperuricemia
Adapted /concensus Development conference of ADA .Diabetes Care .1997
 GENES
High blood pressure
Microalbuminuria
Hyper TG, Low HDL-C
Small dense LDL
Impaired glucose
HYPERINSULINISM tolerance; type 2 DM
INSULIN RESISTANCE

Elevated fibrinogen,
tissue factor & PAI 1
Polycystic ovaries
Non alcoholic fatty
CORONARY HEART DISEASE

liver disease
Syndrome X=Polymetabolic syndrome=Deadly quartet=Dyslipidemic hypertension
ENVIRONMENT
 NGT IGT TYPE 2DM

NATURAL HISTORY OF T2DM

Serum insulin (mU/l)

300

200
Mean insulin during OGTT
(mg/kgffm/min)
Glucose uptake

12

10

8
Mean glucose during OGTT (mmol/l)
 TREATMENT OF IR

•Lifestyle modification
•Metformin (METPHAR IR & XR )
•Pioglitazone (TAZOVEL)
•ACE-inhibitors (?)
 METFORMIN
Metformin was approved in the USA in 1995 as a
treatment for T2DM, single or combination
therapy.
Metformin does not stimulate  cells, does not
increase body weight
Effectively reduce level fasting blood glucose 50-
70 mg/dL, HbA1c (1,5-2.0%)
Effect Pleiotrophic
Hdpatic glucose Sensitivitas to
outout insulin
FA oxidation
EFEK KLINIS METFORMIN XR VS METFORMIN IR
Pleiotropic-effects Metformin
1.Efect metabolic
2.Cardioprotective
3.Renoprotective properties
4.Cancer protective and treatment
5.Polycistic ovary syndrome (PCOS)
 LONG TERM EFFECT METFORMIN
• VLDL-Cholesterol
• Plasma triglyceride
• Total cholesterol
• HDL cholesterol
• Thrombosit Aggregation
• PAI-1
Effect of metformin on weight loss
during 2 years of treatment

The Diabetes Prevention Program Research Group Dia

Care 2012;35:731-737
 HASIL UKPDS : TERAPI INTENSIVE
METFORMIN
Risk Increase/Decrease
Sulfonylurea +
metformin†
Diet + metformin*

Increase
96%

P=0.0023 P=0.017 P=0.011 P=0.01

Decrease 32% P=0.039

42% 36% 39%
Diabetes-
Any diabetes- Diabetes- All-cause MI related
related related mortality mortality
endpoint mortality
*Risk reduction compared with conventional therapy.
†Risk increase compared with sulfonylurea alone.

American Diabetes Association. Diabetes Care. 1999;22(suppl 1):S27-S31.

UKPDS Group. Lancet. 1998;352:854-865.
All Major Guidelines Recognise Metformin
As First Line Therapy in T2 Diabetes
AACE
2015

2015, 2012,
Metformin

IDF
Metformin is the 20123

st
Optimal 1 Therapy in
all Guideline
 METFORMIN
• Metformin (Metfar 500 and Metfar XR) may be safely used in
patients with reduced eGFR; the FDA has revised the label for
metformin to reflect its safety in patients with eGFR ≥30
mL/min/1.73 m2
• A recent randomized trial confirmed previous observations
that metformin use is associated with vitamin B12
deficiency and worsening of symptoms of neuropaty
 PIOGLITAZONE
• Insulin sensitizer : specifically reduces IR in T2DM
• Once-daily therapy to metformin and sulphonylurea therapy
• Improves and maintains glycemic control in pts with T2DM and
is also atheroprotective over the long-term
• Additional lipid effects in dyslipidemic pts ( TG, HDL-C, LDL-C)
THE ROLE OF THIAZOLIDINEDIONES
 EFFECTS OF CARDIOVASCULAR RISK
• Triglicerides
• Increased HDL-C
LIPID • Small dense LDL
• LDL oxidation

• Plasminogenactivator inhibitor (PAI-1)

CLOTTING
FACTORS • Fibrinogen levels

E
VASCULAR
• Carotid intima-media thickness
FACTORS

INFLAMM • C-rective protein levels

ATIONS
 PIOGLITAZONE MONOTHERAPY
IMPROVES GLYCEMIC CONTROL
A 6-month randomized placebo-controlled dose-
response study
Conclusion:
Pioglitazone monotherapy significantly improved
HbA1c, FPG while producing beneficial effects on
serum lipids in patients with T2DM with no evidence
of drug-induced hepatotoxicity

Stephen Aronoff et al. Diabetes care 2000;23:1605-11

 Change in FBG from Baseline
in All Treated Patients
(Fixed-Dose Monotherapy Study)
Placebo (n = 79)
20.0
7.5 mg (n = 80)
10.0
15 mg (n = 79)
0.0 30 mg (n = 84)
-10.0
** 45 mg (n = 77)
D FBG * * * *
(mg/dL) -20.0 * * *
* * * *
-30.0 * *
* *
-40.0 * * * *
* *
-50.0 * - 65.3 mg/dL

* *
-60.0 * p< 0.05 vs. placebo
* * *
0 2 4 6 10 14 18 22 26
Weeks
LOCF

* p< 0.05 vs. baseline

Diabetes 1999; 48(Suppl 1):A109
 CHANGE IN HBA1C FROM BASELINE
(COMBINATION STUDY WITH METFORMIN)
Mean HbA1c Change from baseline
(%) at endpoint (%)
11 0.6

10.5 0.2

10
-0.2

9.5
-0.6

9 *
0 4 8 12 16 -1
-0.8% pt
*p<0.05 vs placebo
Weeks

Placebo + metformin Pioglitazone 30 mg + metformin

Diabetes 1999; 48 (Suppl. 1): A117
 CHICAGO
Carotid intima-media tHICkness in
Atherosclerosis using pioGlitazOne trial

Conclusion
Over 18-month treatment period in
T2DM patients, Pioglitazone slowed
progression of CIMT compared with
glimepiride
 COMBINATION METFORMIN DAN
PIOGLITAZONE

• Improves target cell response to insulin without

increasing insulin secretion from pancreas
• Decreases hepatic glucose output
• Increases insulin-dependent glucose use in
skeletal muscle and, possibly, in liver and adipose
tissue.
 Pioglitazone for Diabetes Prevention in IGT
ACT NOW Study 2011
1. As compared with placebo, pioglitazone reduced the risk of conversion
of IGT) to T2DM by 72% (p<0.001)
2. Pio therapy was also associated with a decrease in diastolic
blood pressure (by 2.0 mm Hg (p=0.03)
3. Pio reduced rate of carotid intima–media thickening (CIMT) (31.5%,
p=0.047
4. Greater increase in the level of HDL p=0.008
5. Weight gain was greater with pio than with placebo (3.9 kg vs.
0.77 kg, P<0.001)
6. edema was more frequent (12.9% vs. 6.4%, P=0.

N Engl J Med 2011;364:1104-15

 MORTALITY BENEFIT WITH COMBINED
INSULIN-SENSITIZING THERAPY
8872 acute MI patients, mean age 76.4 years, discharged
on glucose-lowering medication
No insulin sensitizer (n = 6641)
1.00
Thiazolidinediones (n = 1273)
Metformin (n = 819)
TZD + MET (n = 139)
0.95

Proportion
of patients 0.90
surviving
48% Relative
0.85 risk reduction

0.80
0 50 100 150 200 250 300 350
Days from discharge
Inzucchi SE et al. Diabetes Care. 2005;28:1680-9.
 ADA 2020
FIRST–LINE THERAPY IS METFORMIN AND LIFESTYLE INCLUDING WEIGHT MANAGEMENT AND PHYSICAL ACTIVITY
NO ESTABLISHED ASCVD OR CKD

COST IS A MAJOR ISSUE

METFORMIN + PIOGLITAZONE

METFORMIN +PIOGLITAZONE + SU

BASAL INSULIN THERAPY

 SUMMARY
• Insulin resistance → IGT, T2DM & atherogenic → → predictive of
development of diabetes and o CAD
• The treatment of T2DM and IGT—conditions that are strongly associated
with IR and significant cardiovascular morbidity and mortality
• Medications that reduce insulin resistance (insulin-sensitizing and
antihyperglycemic effects) → metformin (metfar) and the pioglitazone
(tazovel)
• Metformin reduces hepatic glucose output and increases the uptake in the
peripheral tissues (muscle and adipocytes) and decreases glucose
absorbtion
• Metformin is a major drug in the treatment of patients who are obese and
T2DM. The drug enhances weight reduction and improves lipid profile and
vascular integrity
 SUMMARY
• Pioglitazone (Tazovel) lower plasma insulin levels and T2DM
associated with IR
• Pioglitazone (30-45 mg daily) had a reduced the risk of stroke,
myocardial infarction, and diabetes compared to those receiving
placebo. However
• Pioglitazone increased the risk for weight gain, edema, and fracture