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PIOGLIT-MET
The advantages from combining two
insulin sensitizers
Dr. Nizar ALBACHE
Aleppo University- Diabetes Research Unit
President of Syrian Endocrine Society
Vice President of Mediterranean Group for Study of Diabetes
Diabetes Mellitus in Syria 2006
(>25 year)
Epidemiology of Type 2 diabetes mellitus in Aleppo, Syria
N. ALBACHE, R. ALI, S. RASTAM, F. M. FOUAD, F. MZAYEK,. W. MAZIAK; Journal of Diabetes 2 (2009) 1–7
Major progress in the oral treatment of diabetes
1920
1940
1960
1980
2000
?
NPH
Insulin
Insulin
discovered
Glinides
Metformin
Gliptins
Insulin pump
First
sulphonylureas
GLP-1
Lente
Insulins
Glitazones
Human
Insulin
Insulin
analogues
Acarbose
.....But the good glycemic control of the type 2 diabetic
patient remains a challenge
Metformin
-In Europe since 1957
-In USA since 1992
Derived from the plant known as Goat's Rue, French Lilac, Italian Fitch or Professor-weed (Galega officinalis)
Remarkable story of metformin
Undisputed
first choice!
First
disappointments
New success
Discussion
of a possible
withdrawal
Commercialization
craze
1957
UKPDS
FDA
metformin
Fatal lactic
acidosis!
1980
New
“steady – state”
Phenformin
Buformin
Final
withdrawal 1992
1998
progressive
disaffection
2011
Oral Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
Nateglinide
Acarbose
Repaglinide
Rosiglitazone
Pioglitazone
Glimepiride
Glipizide GITS
Metformin
0
-0.5
-1.0
Reduction in A1C (%)
Diabetes Care. 2000;23:202-207; Precose (acarbose) package insert; Drugs. 1995;50:263-288;
J Clin Endocrinol Metab. 2001;86:280-288; Diabetes Care. 2000;23:1605-1611; Diabetes Care. 1996;
19:849-856; Diabetes Care. 1997;20:597-606; Am J Med. 1997;102:491-497
-1.5
-2.0
UKPDS: Global Clinical Outcomes
Overweight patients
Proportion of patients with events
60
Conventional Diet
Insulin or
Sulphonylureas
Any diabetes-related endpoint
40
Metformin
Met v Diet
p=0.0023
 32%
Reduction
Met v Sus or Insulin
p=0.0034
20
0
0
3
6
9
12
Time from randomisation (years)
16
Lancet 1998;352:854-65
UKPDS: Risk reduction with metformin
in overweight patients
N = 4075 with type 2 diabetes
Aggregate endpoints
All-cause mortality
P*
Favors metformin
or intensive
Favors
conventional
0.021
Metformin
Intensive
Myocardial infarction
0.021
Metformin
Intensive
Stroke
0.021
Metformin
Intensive
0.1
1
10
Relative risk reduction
(95% CI)
*metformin vs intensive therapy
UKPDS Group. Lancet. 1998;352:854-65.
Metformin associated with lower mortality
N = 16,417 with diabetes and HF
1.0
0.9
Proportion
of patients
surviving
0.8
Metformin (n = 1861)
0.7
13% Relative
risk reduction
No insulin sensitizer (n = 12,069)
0.6
0.5
0
50
100
Masoudi FA et al. Circulation. 2005;111:583-90.
150
200
Time (days)
250
300
350
Mean change from baseline (%)
Metformin and lipid profiles
5
Metformin (n=143)
Placebo (n=146)
0
-5
p=0.001
p=0.019
-10
Total-C
LDL-C
Triglycerides
HDL-C
DeFronzo RA & Goodman AM. NEJM 1995;333:541-9
Metformin and body fat composition
Selective loss of visceral fat
Change from
% Decrease
p
baseline
from baseline
value
Weight (kg)
- 3.3
4%
0.006
Body Mass Index (Kg/m2)
- 1.2
4%
0.006
Total Body Fat (L)
- 2.8
9%
0.014
Total Subcutaneous Fat (L)
- 2.1
7%
0.025
Abdominal Subcutaneous Fat (L)
- 1.2
11%
0.013
Viscera Fat (L)
- 0.6
15%
0.01
0
No change
NS
Lean Body Mass
Data are Means. Duration of Treatment: 6 Months.
Kurukulasuriya R et al. Diabetes 1999;48:A315
Metformin improves endothelial function
Metformin
1000 mg
(3 months)
400
350
*
300
Increase in
forearm
blood
flow (%)
Placebo
250
200
*
150
100
*
50
0
3
10
30
3
10
30
Acetylcholine (g/min)
Before treatment
* P = 0.0027 vs placebo
After treatment
Mather KJ et al. J Am Coll Cardiol. 2001;37:1344-50.
Myocardial Infarction
Heart Attacks
20
Coronary Deaths
10
p=0.01
p=0.02
NS
Incidence per 1000 patient years
8
39%
15
Reduction
50%
Reduction
6
10
4
5
2
0
0
Insulin
Conventional
Metformin
or
Diet
Sulphonylureas
Conventional
Diet
Metformin
Stroke
P=0.13(NS)
P=0.032
60
40
6
% Risk Reduction
Events per 1000 patient years
8
4
2
14%
20
0
-20
-40
41%
0
Conventional
Metformin
Diet
Insulin or Sulphonyl
-60
Metformin
Insulin or
Sulphonylureas
Survival in Overweight Group
Diabetes Related Deaths
25
p=0.017
NS
12
42%
Reduction
9
6
3
0
Incidence (Deaths per 1000 Patient Years)
Incidence (Deaths per 1000 Patient Years)
15
All Cause Mortality
p=0.011
NS
p=0.021
20
36%
Reduction
15
10
5
Conventional Insulin
Metformin
or
Diet
Sulphonylureas
Insulin
Conventional
Metformin
or
Diet
Sulphonylureas
Mechanisms of vascular protection
1.
2.
3.
4.
5.
6.
Reduce insulin resistance
Improved lipid profiles
Adiposity
Improved hemostasis
Inhibition of glycoxidation
Inhibition of inflammation
Metformin ;effect on cancer risk and
mortality
% decrease
IGT  T2DM
Diabetes Prevention Program (DPP)
60
58%
40
31%
23%
20
0
DIET +
EXERCISE
METFORMIN
DPP, NEJM 2002; 346:393-403
TROGLITAZONE
•
Early metformin therapy to delay menarche and
augment height in girls with precocious pubarche
)Conclusion
Early metformin therapy (age 12 –8years) suffices
Delay menarche
Augment postmenarcheal height
Reduce total, visceral, and hepatic adiposity
Curb the endocrine-metabolic course of LBW-PP girls away from
adolescent PCOS.
Early metformin therapy to delay menarche and augment height in girls with precocious pubarche
Lourdes Ibáñez M.D., Ph.D.a, , , Abel Lopez-Bermejo M.D, Abstract – selected,Fertility and Sterility,Article in Press
Contraindications for metformin
treatment
•
•
•
•
•
•
•
Decrease renal function
Congestive heart failure
Patients > 80 years of age
Liver disease
Chronic alcohol disease
Sepsis or other acute illnesses with decreased
tissue perfusion
During intavenous radiographic contrast
administration(+-)
• Oral Antihyperglycemic Monotherapy
Maximum Therapeutic Effect on A1C
•
•
•
•
•
•
•
•
Metformin associated with lower mortality
Metformin and lipid profiles
Decrease Visceral Fat
Metformin improves endothelial function
Decrease Myocardial Infarction
Decrease Stroke
Decrease risk of Cancers
Decrease the risk of Developing Diabetes(DPP)
63% of Patients With Diabetes
are Not At ADA A1C Goal <7%
National Health and Nutrition Examination Survey (NHANES), 1999-2000.
100
% of Subjects
n = 404
80
60
A1C
12.4%
7.8%
63%
7%
37.2%
>8%
17.0%
>9%
25.8%
>8%
7-8%
40
20
>10%
37.0%
0
Only 7% of adults attained:
A1c <7%, BP 130/80, and
Total Cholesterol <200mg/dL
<7%
1 in 5
Have A1c
> 9%
Need for an early and intensive approach
to type 2 diabetes management
30% of MD2 undiagnosed
At Diagnosis of type 2 diabetes:
50% of patients already have complications1
up to 50% of -cell function has
already been lost2
Current management:
two-thirds of patients do not
achieve target HbA1c3,4
majority require polypharmacy
to meet glycaemic goals over time5
1UKPDS
4Liebl
Group. Diabetologia 1991; 34:877–890. 2Holman RR. Diabetes Res Clin Prac 1998; 40 (Suppl.):S21–S25. 3Saydah SH et al. JAMA 2004; 291:335–342.
A et al. Diabetologia 2002; 45:S23–S28. 5Turner RC et al. JAMA 1999; 281:2005–2012.
Stepwise approach: delays control and
leaves patients at risk of complications
Diet and
exercise
OAD
monotherapy
OAD
monotherapy
uptitration
OAD
combination
OAD +
basal insulin
OAD +
multiple daily
insulin injections
10
HbA1c (%)1
9
Mean
8
7
6
Duration of diabetes
1Adapted
2Stratton
from Del Prato S et al. Int J Clin Pract 2005; 59:1345–1355.
IM et al. BMJ 2000; 321:405–412.
Early, intensive intervention: reach glycaemic
goals and reduce the risk of complications
10
OAD
monotherapy
OAD
combination
OAD
uptitration
HbA1c (%)1
9
8
OAD
uptitration
OAD +
basal insulin
Mean
7
6
Duration of diabetes
1Adapted
2Stratton
from Del Prato S et al. Int J Clin Pract 2005; 59:1345–1355.
IM et al. BMJ 2000; 321:405–412.
OAD + multiple
daily insulin
injections
Metformin Lowers Plasma Glucose by Lowering Hepatic
Glucose Production and by Improving Insulin Sensitivity
Liver
Metformin
↓ Gluconeogenesis
↓ Glycogenolysis
↑ Glycogen synthesis
Blood glucose
Muscle
Adipose
tissue
Liver
1. Kirpichnikov D et al. Ann Intern Med. 2002;137:25–33. 2. Setter SM et al. Clin Ther. 2003;25:2991–3026.
3. Hundal RS et al. Diabetes. 2000;49:2063–2069. 4. Chu CA et al. Metabolism. 2000;49:1619–1626.
5. Bailey CJ et al. N Engl J Med. 1996;334:574–579.
↑Glucose
uptake in
muscle and
fat by
increasing
insulin
sensitivity5
Major Pathophysiologic Defects in Type 2 DM
Islet-cell dysfunction
Glucagon
(alpha cell)
Pancreas
Hepatic
glucose
output
Insulin
(beta cell)
Insulin
resistance
Glucose uptake in
muscle and fat
Hyperglycemia
Liver
Muscle
Liver
Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed.
Lippincott Williams & Wilkins; 2005:145–168.
Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781.
Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.
Adipose
tissue
Complementary
Mechanisms of Action
Combining Pioglitazone and
Metformin
Major Targeted Sites of Oral Drug Classes
Beta-cell
dysfunction
Pancreas
Sulfonylureas
Liver
Muscle
and fat
Meglitinides
Hepatic glucose
overproduction
Insulin
resistance
DPP-4 inhibitors
GLP-1
↓Glucose level
Biguanides
TZDs
DPP-4 inhibitors
Glucose
absorption
Gut
TZDs
Biguanides
Alphaglucosidase
inhibitors
Biguanides
DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones.
DeFronzo RA. Ann Intern Med. 1999;131:281–303.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483.
No Single Class of Oral Antihyperglycemic
Monotherapy Targets All Key Pathophysiologies
Major Pathophysiologies
AlphaGlucosidase
Inhibitors1,2
Insulin
deficiency
Meglitinides3
SUs4,5


TZDs6,7
Metformin8

Insulin
resistance


Excess hepatic
glucose output


Intestinal
glucose
absorption

DPP-4
Inhibitors


1. Glyset [package insert]. New York, NY: Pfizer Inc; 2004. 2. Precose [package insert]. West Haven, Conn: Bayer; 2004.
3. Prandin [package insert]. Princeton, NJ: Novo Nordisk; 2006. 4. Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2007.
5. Glucotrol [package insert]. New York, NY: Pfizer Inc; 2006. 6. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; 2004.
7. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005.
8. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.
Trends in Antidiabetic Therapy
1995
2000
19%
40%
40%
52%
4%
4%
12%
29%
Oral Monotherapy
Oral Combination Therapy
Insulin/Oral Combination Therapy
Insulin Only Therapy
Effects of Pioglitazone and
Metformin on FBG and HbA1c
0.2
5
-5
0.2
0.0
-5
FBG-15
(mg/dL)
change-25
from
baseline-35
-45
C
HbA1c
(%) -0.2
change
from -0.4
baseline
-38 *
-0.6
-0.8
-55
-0.8 *
Placebo + metformin
*P0.05 for comparison with placebo
Egan J et al. Diabetes. 1999;47(suppl 1):A117. Abstract.
Pioglitazone 30 mg + metformin
Early Addition of Rosiglitazone 8 mg/day to 1 g Metformin:
More Patients Reach A1c Goal* vs. MET Monotherapy (2 g)
†
% of Patients Responded
60
50
55%
45%
40
Goal‡
<7%
30
20
10
35%
23%
Goal‡
<6.5%
0
MET 2 g/day
RSG 8 mg/day + MET 1 g/day
*ADA A1c goal <7%, AACE A1C goal 6.5%. †P<0.05.
‡Patients received Avandia® 8 mg/day plus metformin 1 g/day (n=322; baseline A 8.05%) versus maximum dose metformin (n=313;
1c
baseline A1c 7.95%) in a 24-week, randomized, double-blind, parallel-group, multicenter study.
Insulin sensitizers vs other glucoselowering agents following AMI
8872 acute MI patients, mean age 76.4 years, discharged
on glucose-lowering medication
Metformin
TZD
Both
Mortality
0.92
(0.81–1.06)
0.92
(0.80–1.05)
0.52
(0.34–0.82)
Myocardial
infarction
readmission
1.02
(0.86–1.20)
0.92
(0.77–1.10)
0.88
(0.56–1.37)
Heart failure
readmission
1.06
(0.95–1.18)
1.17
(1.05–1.30)
1.24
(0.94–1.63)
All-cause
readmission
1.04
(0.96–1.13)
1.09
(1.00–1.20)
1.06
(0.87–1.30)
Neutral effect of PPAR activation
and metformin on hospital readmission
N = 16,417 with diabetes and HF
Hospital readmission
All-cause
HF
TZD
1.04 (0.99–1.10)
1.06 (1.00–1.12)
Metformin
0.94 (0.89–1.01)
0.92 (0.86–0.99)
TZD = thiazolidinedione
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)
Thiazolidinediones (n = 1273)
Metformin (n = 819)
TZD + MET (n = 139)
1.00
0.95
Proportion
of patients
surviving
0.90
48% Relative
risk reduction
0.85
0.80
0
50
100 150
200
250
Days from discharge
300
350
Fixed-dose combination tablets
may help to increase patient
compliance and improve efficacy
Patient compliance can be a difficult
obstacle to overcome
Among newly DM2=53.8% adhered to their treatment regimen
Compliance problems result in higher A1C levels
10% increase in drug adherence decreased A1C 0.16%
optimal compliance vs the group with the worst compliance =
1.4% difference in A1C
Patient compliance is influenced by
the frequency of doses taken
Patient compliance is dependent on two behavioral aspects:
Dose taking :
QD dosing is 98.7%
BID dosing is 83.1%
TID dosing is 65.8%
Dose timing:
QD dosing is 79.1%
BID dosing is 65.6%
TID dosing is 38.1%
QD dosing regimens are associated with higher rates of adherence than BID or TID
regimens.
Advantages of combination therapy
The side effects and toxicities ;
not altered by combination
dose related in individual patients
lower doses in combination better tolerated
Dosing flexibility may be key to tight control
Patient compliance increases as complexity decreases
ADA/EASD Revised Consensus Statement(2009) David Nathan
Tier 1 : Well-validated core therapies
At diagnosis:
Lifestyle
+
Metformin
Lifestyle + Metformin
+
Basal Insulin
Lifestyle + Metformin
+
Sulphonlyureasa
Step 2
Step 1
Lifestyle + Metformin
+
Intensive Insulin
Step 3
Tier 2 : Less well-validated core therapies
Lifestyle + Metformin
+
Pioglitazone
No hypglycemia
Oedema/CHF
Bone loss
Lifestyle + Metformin
+
GLP-1 agonistb
No hypglycemia
Weight loss
Nausea/Vomitting
Diabetes Care 2009; 32:193-203
Lifestyle + Metformin
+
Pioglitazone
+
Sulphonylureas
Lifestyle + Metformin
+
Basal insulin
Evidence vs. opinion based guidelines for the
management of type 2 diabetic patients
Diabetologia. 2010 July; 53(7): 1258–1269
Debate on The ADA and EASD algorithm(Nathan)
Deficiencies in the algorithm
• Not evidence based approach
• Not offer the best quality of treatment
– on the basis of our understanding of the multifactorial pathophysiology of
type 2 diabetes or the need for individualised therapy
• Based more on an outdated expert opinion
• Priorities for treatment
– on the benefits of all available classes of glucose-lowering agents
– In favouring initial use of metformin monotherapy followed by sulfonylurea, an
approach known to fail
• Does not offer appropriate selection
– of options to individualise and optimise care
Diabetologia. 2010 July; 53(7): 1258–1269
A1C 6.5 – 7.5%**
A1C 7.6 – 9.0%
A1C > 9.0%
Under Treatment
Drug Naive
Symptoms
Monotherapy
MET † DPP4 1
Dual Therapy 8
TZD 2
GLP-1
AGI 3
2 - 3 Mos.***
MET
+
Dual Therapy
GLP-1 or DPP4 1
or TZD 2
INSULIN
SU or Glinide 4,5
± Other
Agent(s) 6
GLP-1 or DPP4 1
MET
GLP-1
or DPP4 1
MET
Triple Therapy 9
TZD
+
MET
+
GLP-1 or DPP4 1
INSULIN
± Other
Agent(s) 6
± TZD 2
May not be appropriate for all patients*
Glinide or SU 5
GLP-1
or DPP4 1
+
± SU 7
TZD 2
GLP-1
or DPP4 1
2 - 3 Mos.***
TZD 2
+
No Symptoms
For patients with diabetes and A1C < 6.5%,
pharmacologic Rx may be considered
+ TZD 2
**
If A1C goal not achieved safely***
Preferred initial agent†
Colesevelam
AGI
MET
3
2 - 3 Mos.
***
Triple Therapy
TZD 2
MET +
GLP-1 or
DPP4 1
+
GLP-1
or DPP4 1
TZD 2
2 - 3 Mos.***
+
Glinide or SU 4,7
2 - 3 Mos.
INSULIN
± Other
Agent(s) 6
***
+ SU 7
INSULIN
± Other
Agent(s) 6
AACE/ACE Algorithm for Glycemic
Control Committee
DPP4 if  PPG and  FPG or GLP-1 if  PPG1
TZD if metabolic syndrome and/or2
Cochairpersons:
Helena W. Rodbard, MD, FACP, MACE
Paul S. Jellinger, MD, MACE
nonalcoholic fatty liver disease (NAFLD)
Zachary T. Bloomgarden, MD, FACE
Jaime A. Davidson, MD, FACP, MACE
Daniel Einhorn, MD, FACP, FACE
Alan J. Garber, MD, PhD, FACE
James R. Gavin III, MD, PhD
George Grunberger, MD, FACP, FACE
Yehuda Handelsman, MD, FACP, FACE
Edward S. Horton, MD, FACE
Harold Lebovitz, MD, FACE
Philip Levy, MD, MACE
Etie S. Moghissi, MD, FACP, FACE
Stanley S. Schwartz, MD, FACE
Low-dose secretagogue recommended5
AGI if  PPG3
Glinide if  PPG or SU if  FPG4
Discontinue insulin secretagoguea)6
with multidose insulin
Can use pramlintide with prandial insulinb)
Decrease secretagogue by 50% when added 7
to GLP-1 or DPP-4
If A1C < 8.5%, combination Rx with agents 8
that cause hypoglycemia should be used
with caution
If A1C > 8.5%, in patients on Dual Therapy,9
insulin should be considered
Available at www.aace.com/pub
© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE
Take home messages
• Guidelines changing now, we expect the new one to
be release soon
• We have many choices to initiate oral TT
• Combination of 2 Sensitizers looks a good one
• With adding Piogl. To Metf. You add the benefits:
Increase patients adherence
More redaction on A1c
Improve Lipid profile
Increase cardiac protection
Decrease the cancer risk
nizar-albache.com