Dr. Nizar ALBACHE Aleppo University- Diabetes Research Unit President of Syrian Endocrine Society Vice President of Mediterranean Group for Study of Diabetes PIOGLIT-MET The advantages from combining two insulin sensitizers
Dec 16, 2015
Dr. Nizar ALBACHE
Aleppo University- Diabetes Research Unit
President of Syrian Endocrine Society
Vice President of Mediterranean Group for Study of Diabetes
PIOGLIT-METThe advantages from combining two
insulin sensitizers
Diabetes Mellitus in Syria 2006 (>25 year)
Epidemiology of Type 2 diabetes mellitus in Aleppo, SyriaN. ALBACHE, R. ALI, S. RASTAM, F. M. FOUAD, F. MZAYEK,. W. MAZIAK; Journal of Diabetes 2 (2009) 1–7
Firstsulphonylureas
Metformin
Glitazones
Acarbose
Gliptins
?
1920 1940 1960 1980 2000
Major progress in the oral treatment of diabetes
LenteInsulins
NPHInsulin
Insulindiscovered Insulin pump
HumanInsulin
GLP-1
Insulinanalogues
Glinides
.....But the good glycemic control of the type 2 diabetic patient remains a challenge
Metformin
Derived from the plant known as Goat's Rue, French Lilac, Italian Fitch or Professor-weed (Galega officinalis)
-In USA since 1992
-In Europe since 1957
craze
First disappointments
Discussion of a possible
withdrawal
Final withdrawal
progressive disaffection
New success
New“steady – state”
Remarkable story of metformin
Undisputed first choice!
Commer-cialization
Fatal lactic acidosis!
1957 1998 2011
metformin
UKPDS
FDA
Phenformin Buformin
1980 1992
Oral Antihyperglycemic MonotherapyMaximum Therapeutic Effect on A1C
-0.50 -1.0 -1.5 -2.0
Nateglinide
Reduction in A1C (%)
Glipizide GITS
Glimepiride
Repaglinide
Pioglitazone
Acarbose
Metformin
Rosiglitazone
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
UKPDS: Global Clinical OutcomesOverweight patients
Met v Sus or Insulinp=0.0034
Met v Diet p=0.0023
0
20
40
60
0 3 6 9 12 16
Pro
port
ion
of p
atie
nts
with
eve
nts
Time from randomisation (years)
Insulin orSulphonylureas
Metformin
Conventional DietAny diabetes-related endpoint
32%Reduction
Lancet 1998;352:854-65
UKPDS: Risk reduction with metformin in overweight patientsN = 4075 with type 2 diabetes
UKPDS Group. Lancet. 1998;352:854-65.
Favors metforminor intensive
Favors conventionalAll-cause mortality
MetforminIntensive
Myocardial infarctionMetforminIntensive
StrokeMetforminIntensive
0.021
0.021
0.021
Aggregate endpoints P*
0.1 1 10
*metformin vs intensive therapy
Relative risk reduction(95% CI)
Metformin associated with lower mortality
Masoudi FA et al. Circulation. 2005;111:583-90.
N = 16,417 with diabetes and HF
Metformin (n = 1861)
No insulin sensitizer (n = 12,069)
Time (days)
1.0
0.9
0.8
0.7
0.6
0.50 50 150 200 250 300 350100
13% Relativerisk reduction
Proportionof patientssurviving
-10
-5
0
5
Total-C LDL-C Triglycerides HDL-C
Mea
n c
han
ge
fro
m b
asel
ine
(%)
Metformin (n=143)
Placebo (n=146)
Metformin and lipid profiles
DeFronzo RA & Goodman AM. NEJM 1995;333:541-9
p=0.001
p=0.019
Kurukulasuriya R et al. Diabetes 1999;48:A315
Data are Means. Duration of Treatment: 6 Months.
Weight (kg)
Body Mass Index (Kg/m2)
Total Body Fat (L)
Total Subcutaneous Fat (L)
Abdominal Subcutaneous Fat (L)
Viscera Fat (L)
Lean Body Mass
Change from
baseline
-3.3 -1.2 -2.8 -2.1 -1.2 -0.6 0
%Decrease
from baseline
4% 4% 9% 7%
11%15%
No change
p
value
0.006 0.006 0.014 0.025 0.013
0.01NS
Selective loss of visceral fat
Metformin and body fat composition
Mather KJ et al. J Am Coll Cardiol. 2001;37:1344-50 . *P = 0.0027 vs placebo
Before treatment After treatment
400
300
250
200
150
50
0
350
Metformin 1000 mg (3 months)
3
Increase in forearm blood
flow)%(
Acetylcholine (g/min)
100
*
Placebo
10 30 3 10 30
*
*
Metformin improves endothelial function
Myocardial Infarction
Heart Attacks
0
5
10
15
20
Inci
de
nce
pe
r 1
00
0 p
atie
nt
yea
rs
Coronary Deaths
0
2
4
6
8
10
Conventional Diet
Insulin or
Sulphonylureas
Metformin
p=0.02
50%Reduction
Conventional Diet
Metformin
p=0.01
39%Reduction
NS
Inci
de
nce
pe
r 1
00
0 p
atie
nt
y ea
r s
Stroke
0
2
4
6
8
Eve
nts
per
100
0 p
atie
nt
year
s
-60
-40
-20
0
20
40
60
% R
isk
Red
uct
ion
41%
14%
P=0.13(NS) P=0.032
MetforminConventional Diet
Insulin or Sulphonyl
Metformin Insulin or Sulphonylureas
Survival in Overweight Group
Diabetes Related Deaths
0
3
6
9
12
15
Inci
denc
e (D
eath
s pe
r 10
00 P
atie
nt Y
ears
)
All Cause Mortality
5
10
15
20
25
Inci
denc
e (D
eath
s pe
r 10
00 P
atie
nt Y
ears
)
Conventional Diet
Insulin or
Sulphonylureas
Metformin
p=0.017
42%Reduction
p=0.011
36%Reduction
Conventional Diet
Insulin or
Sulphonylureas
Metformin
p=0.021
NS
NS
Mechanisms of vascular protection
1. Reduce insulin resistance
2. Improved lipid profiles
3. Adiposity
4. Improved hemostasis
5. Inhibition of glycoxidation
6. Inhibition of inflammation
Metformin ;effect on cancer risk and mortality
Diabetes Prevention Program (DPP)
0
20
40
60
DIET +EXERCISE
METFORMIN TROGLITAZONE
%de
crea
seIG
T
T2D
M
58%
31%23%
DPP, NEJM 2002; 346:393-403
Early metformin therapy to delay menarche and augment height in girls with precocious pubarche
• 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
Conclusion(Early metformin therapy (age 8–12 years) 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.
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 MonotherapyMaximum 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%
0
20
40
60
80
100
>10%
>9%
>8%
7-8%
<7%
37.2%>8%
63%7%
7.8%
25.8%
37.0%
17.0%
12.4%
%of
Sub
ject
sn
= 40
4A1C
National Health and Nutrition Examination Survey (NHANES), 1999-2000.
Only 7% of adults attained :A1c <7%, BP 130/80, and
Total Cholesterol <200mg/dL
1 in 5Have 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 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 .4Liebl 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
1Adapted from Del Prato S et al. Int J Clin Pract 2005; 59:1345–1355. 2Stratton IM et al. BMJ 2000; 321:405–412.
Duration of diabetes
Hb
A1c
(%
)1
7
6
9
8
10
Diet andexercise
OADmonotherapy
OAD combination
OAD +basal insulin
OAD monotherapy
uptitration
OAD + multiple daily
insulin injections
Mean
Complications2
Early, intensive intervention: reach glycaemic goals and reduce the risk of complications
1Adapted from Del Prato S et al. Int J Clin Pract 2005; 59:1345–1355. 2Stratton IM et al. BMJ 2000; 321:405–412.
Duration of diabetes
Hb
A1c
(%
)1
7
6
9
8
10
Complications2
OAD monotherapy
OAD combination
OAD uptitration
OAD + basal insulin
OAD + multipledaily insulin
injections
Mean
OAD uptitration
Metformin Lowers Plasma Glucose by Lowering Hepatic Glucose Production and by Improving Insulin Sensitivity
Metformin
Blood glucose
↑Glucose uptake in muscle and fat by increasing insulin sensitivity5
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.
MuscleAdipose
tissue
Liver
↓Gluconeogenesis ↓Glycogenolysis
↑Glycogen synthesis
↓Glucose production reduced by1–4:
Liver
Hepatic glucose
output
Insulin resistance
Glucose uptake in muscle and fat
Glucagon)alpha cell(
Insulin)beta cell(
Hyperglycemia
Islet-cell dysfunction
Major Pathophysiologic Defects in Type 2 DM
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.
Pancreas
Liver Adipose tissue
Liver
Muscle
Complementary Mechanisms of Action
Combining Pioglitazone and Metformin
Glucose absorption
Hepatic glucoseoverproduction
Beta-celldysfunction
Insulinresistance
Major Targeted Sites of Oral Drug Classes
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.
Pancreas
↓Glucose level
Muscle and fatLiver
Biguanides
TZDs Biguanides
Sulfonylureas
Meglitinides
TZDs
Alpha-glucosidase inhibitors
Gut
DPP-4 inhibitorsGLP-1
DPP-4 inhibitors
Biguanides
No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies
Alpha-Glucosidase Inhibitors1,2
Meglitinides3 SUs4,5 TZDs6,7 Metformin8
DPP-4 Inhibitors
Insulin deficiency
Insulin resistance
Excess hepatic glucose output
Maj
or P
atho
phys
iolo
gies
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 .
Intestinal glucose absorption
52%
4%
4%
40%
Oral MonotherapyOral Combination TherapyInsulin/Oral Combination TherapyInsulin Only Therapy
40%
29%
12%
19%
1995 2000
Trends in Antidiabetic Therapy
Effects of Pioglitazone and Metformin on FBG and HbA1c
Egan J et al. Diabetes. 1999;47(suppl 1):A117. Abstract.
-0.8
0.2
-0.8
-0.6
-0.4
-0.2
0.0
0.2
Placebo + metformin Pioglitazone 30 mg + metformin
-5
-38
-55
-45
-35
-25
-15
-5
5
*P0.05 for comparison with placebo
*
*
C
FBG(mg/dL)
changefrom
baseline
HbA1c
(%)change
frombaseline
35%
23%
0
10
20
30
40
50
60
MET 2 g/day RSG 8 mg/day + MET 1 g/day
% o
f P
ati
en
ts R
es
po
nd
ed
*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 A1c 8.05%) versus maximum dose metformin (n=313; baseline
A1c 7.95%) in a 24-week, randomized, double-blind, parallel-group, multicenter study.
Early Addition of Rosiglitazone 8 mg/day to 1 g Metformin: More Patients Reach A1c Goal* vs. MET Monotherapy (2 g)
45%
55%
Goal‡
<6.5%
Goal‡ <7%
†
Insulin sensitizers vs other glucose-lowering agents following AMI8872 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 failurereadmission
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 activationand metformin on 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)
N = 16,417 with diabetes and HF
Hospital readmission
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)
48% Relativerisk reduction
Days from discharge
1.00
0.95
0.90
0.85
0.800 50 200 250 300 350100
Proportionof patientssurviving
150
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 combinationdose related in individual patientslower doses in combination better tolerated
Patient compliance increases as complexity decreases
Dosing flexibility may be key to tight control
ADA/EASD Revised Consensus Statement(2009)
David Nathan
Diabetes Care 2009; 32:193-203
Tier 1 : Well-validated core therapies
At diagnosis:
Lifestyle+
Metformin
Step 1
Lifestyle + Metformin+
Intensive Insulin
Step 3
Lifestyle + Metformin+
PioglitazoneNo hypglycemia
Oedema/CHFBone loss
Lifestyle + Metformin+
GLP-1 agonistb
No hypglycemiaWeight loss
Nausea/Vomitting
Lifestyle + Metformin+
Pioglitazone+
Sulphonylureas
Lifestyle + Metformin+
Basal insulin
Tier 2 : Less well-validated core therapies
Lifestyle + Metformin+
Basal Insulin
Lifestyle + Metformin+
Sulphonlyureasa
Step 2
Evidence vs. opinion based guidelines for the management of type 2 diabetic patients
. 2010 ; 53)7(: 1258–1269Diabetologia July
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
. 2010 ; 53)7(: 1258–1269Diabetologia July
A1C 6.5 – 7.5%**
Monotherapy
MET +
GLP-1 or DPP4 1
TZD 2
Glinide or SU 5
TZD + GLP-1 or DPP4 1
MET + Colesevelam
AGI 3
2 - 3 Mos.***
2 - 3 Mos.***
2 - 3 Mos.***
Dual Therapy
MET +GLP-1 or DPP4 1
+
TZD 2
Glinide or SU 4,7
A1C < 9.0%
No Symptoms
Drug Naive Under Treatment
INSULIN
± Other
Agent(s) 6
Symptoms
INSULIN
± Other
Agent(s) 6
INSULIN
± Other
Agent(s) 6
Triple Therapy
AACE/ACE Algorithm for Glycemic Control Committee
Cochairpersons:Helena W. Rodbard, MD, FACP, MACEPaul S. Jellinger, MD, MACE
Zachary T. Bloomgarden, MD, FACEJaime A. Davidson, MD, FACP, MACEDaniel Einhorn, MD, FACP, FACEAlan J. Garber, MD, PhD, FACEJames R. Gavin III, MD, PhDGeorge Grunberger, MD, FACP, FACEYehuda Handelsman, MD, FACP, FACEEdward S. Horton, MD, FACEHarold Lebovitz, MD, FACEPhilip Levy, MD, MACEEtie S. Moghissi, MD, FACP, FACEStanley S. Schwartz, MD, FACE
*May not be appropriate for all patients **For patients with diabetes and A1C < 6.5%,
pharmacologic Rx may be considered ***If A1C goal not achieved safely
†Preferred initial agent
1DPP4 if PPG and FPG or GLP-1 if PPG
2TZD if metabolic syndrome and/or
nonalcoholic fatty liver disease (NAFLD)
3AGI if PPG
4Glinide if PPG or SU if FPG
5Low-dose secretagogue recommended
6a)Discontinue insulin secretagoguewith multidose insulin
b)Can use pramlintide with prandial insulin
7Decrease secretagogue by 50% when added to GLP-1 or DPP-4
8If A1C < 8.5%, combination Rx with agents that cause hypoglycemia should be used with caution
9If A1C < 8.5%, in patients on Dual Therapy,insulin should be considered
MET +
GLP-1
or DPP4 1 ± SU 7
TZD 2
GLP-1
or DPP4 1 ± TZD 2
A1C 7.6 – 9.0%
Dual Therapy 8
2 - 3 Mos.***
2 - 3 Mos.***
Triple Therapy 9
INSULIN
± Other
Agent(s) 6
MET +
GLP-1 or DPP4 1
or TZD 2
SU or Glinide 4,5
MET +
GLP-1
or DPP4 1+ TZD 2
GLP-1
or DPP4 1 + SU 7
TZD 2
MET † DPP4 1 GLP-1 TZD 2 AGI 3
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