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Metformin : Prevention of CV complications

in patients with existing disease

Dr Francois-Xavier Lion
Wednesday 17th May 9:30-10:30
Subjects to be discussed

• UKPDS , metformin and secondary prevention

• Benefits of metformin in providing long-term health


benefits in patients with heart disease – ischaemic heart
disease and heart failure

• Explaining the anti-atherogenic and anti-thombotic


actions

• Safety of metformin in contraindicated states

• Revisions to prescribing indications according to


guidance from the literature
What do we learn from UKPDS
Fatal Patients with Absolute risk (events Relative Risk (RR)
MI clinical endpoint per 1000 patient-years) versus Lifestyle
Metformin Lifestyle Metformin Lifestyle

16 36 4.3 8.3 0.50 (0.23-1.09)

50% reduction in fatal myocardial infarction


but was this due to :-

1. Protection from the first heart attack Primary


that proved fatal (case fatality) Prevention

2.Protection from recurrent heart attacks


Secondary
that cumulatively proved fatal Prevention
What do we learn from UKPDS

The answer is that we don’t


know the break down of the
patients who died from a
myocardial infarction as it
was not recorded !!!!!!!!!!!!!!
Benefits of metformin in ischaemic heart disease

• Diabetics have twice


the risk of heart attacks
as non-diabetics.

• 20-30% of diabetics
are admitted with acute
myocardial infarction to
ITU.

• Risk of death
post MI, is almost doubled
compared to non-
diabetics
Where does the evidence come from that
metformin improves morbidity and mortality?

Two prospective studies from Italy in patients


with ischaemic heart disease

One large prospective study from Sweden in patients


admitted to ITU with acute myocardial infarction - DIGAMI

One large prospective study from the USA with a


subgroup of diabetic patients - PRESTO

One cohort of patients from the Saskatchewan database


with heart failure analysed retrospectively
Effects of Metformin at 3 years
follow-up post-myocardial infarction

12
Controls (n=123)
Metformin (n=187)
*
10

8
% Patients

0
Reinfarction Symptoms of Acute CV events Deaths
angina

*p=0.003
T2DM 34%, IGT 52%, NGT 14% Sgambato S et al. Clin Ter 1980;94:77-85.
Effects of Metformin Treatment on the
Symptoms of Cardiovascular Disease

Angina + GTN tablets Myocardial ischaemia


(n=42) (n=102)

100
% Patients

83%  70% 
50

0
Baseline 6 months of
metformin
Montaguti U et al. Res Clin Forums 1979;1:95-103
DIGAMI and Metformin

• DIGAMI = Diabetes Mellitus, Insulin ,Glucose infusion in acute


myocardial infarction
• Controlled trial to determine the benefits of insulin-glucose infusions
at hospitalisation followed by multidose insulin therapy over 3-4
years of follow-up
• Assessments are focussed on improved mortality and morbidity
outcomes. This is because the risk of death post MI is almost
doubled in diabetics versus non-diabetics irrespective of age
• DIGAMI 2 is a second trial to examine three different management
strategies during hospitalisation.
• DIGAMI 2 is of interest to metformin as outcomes were measured
post MI over several years for different glucose lowering therapies

Malmberg K. BMJ;314: 1512-5


Malmberg K. Eur Heart J 2005; 26: 650-661
Benefits of Metformin after acute MI

Melbin LG. Eur Heart J 2008; 29: 166-176


Impact of Glucose Lowering treatment on long-term
prognosis in T2DM with MI – DIGAMI 2

24hr insulin/glucose , insulin 5-7mmol/l

Type 2 Diabetics
Established/newly 24hr insulin/glucose , standard glucose
Diagnosed Lowering therapy 5-7mmol/l
( 75%/25%)
Hospitalised with
Acute MI Standard glucose lowering therapy

N = 1181 hospital survivors


Median follow up 2.2 years

Melbin G et al. Eur Heart J 2008; 29: 166 -176


Digami 2 –Therapies & CV Outcomes

Metformin(200/981)* Hazard ratio ( 95%CI)


Death(33/173)** 0.91(0.61-1.34)
CV Death(24/139)** 0.93(0.60-1.43) Non-fatal MI
or stroke
Death /reinfarction/stroke(56/304)** 0.78(0.58-1.04) ( p=0.03)
Reinfarction/stroke(28/176)** 0.63(0.42-0.95)

Sulfonylureas(268/913)*
Death(51/155)** 1.08(0.78-1.50)
CV Death(41/122)** 1.15(0.80-1.64)
Death/reinfarction/stroke(80/280)** 0.93(0.73-1.20)
Reinfarction/stroke(40/164)** 0.81(0.57-1.14)
Insulin(690/491)*
Death(134/72)** 1.12(0.83-1.51) Non-fatal MI
or stroke
CV Death(105/58)** 1.05(0.75-1.46) ( p=0.0007)
Death/reinfarction/stroke(243/117)** 1.42(1.13-1.78)
Reinfarction/stroke(145/59)** 1.73(1.26-2.37)

*No of patients**No of endpoints 0.50 0.70 1.00 1.45 2.00 4.00


Drug better Drug worse
Mellbin et al. European Heart Journal 2008; 29: 166-176
UKPDS : Improved Survival outcomes with
metformin versus DIGAMI 2

Diabetes Related Deaths All Cause Mortality


15 25
p=0.017 p=0.011

NS

Incidence (Deaths per 1000 Patient Years)


Incidence (Deaths per 1000 Patient Years)

12 NS p=0.021
20

42%
9 Reduction 36%
Reduction
15

Follow
3
–up in UKPDS = 10 years whereas 10
follow-up in DIGAMI 2 was around
3 years CV benefits of metformin are expressed with greater time of exposure

0 5
Lifestyle Insulin Metformin Lifestyle Insulin Metformin
or Su or Su

UKPDS Group. Lancet 1998; 352: 854-865


Morbidity and Mortality outcomes for
metformin treated patients undergoing
revascularisation for CHD : PRESTO

• PRESTO = Prevention of REStenosis with Tranilast and its


Outcomes

• Double-blind, randomised, placebo-controlled trial of tranilast


after percutaneous intervention for myocardial ischaemia
(N=11,484)

• Primary endpoints: combined incidence of MI, death and need for


revascularisation for ischaemia

• 25% of the PRESTO population had type 2 diabetes at baseline

• Diabetes subgroup were analysed retrospectively -metformin vs.


non-insulin sensitiser therapy
Kao J et al. Am J Cardiol 2004;93:1347-50
PRESTO: CV risk factors and
complications at entry to study

Metformin Non-insulin sensitiser


group (n=887) group (n=1110)

Mean age (years) 63 61


Women/men (%) 30/70 30/70
Dyslipidaemia (%) 62 65
Hypertension (%) 74 77
Coronary artery
51 60
disease
History of MI (%) 40 40

Kao J et al. Am J Cardiol 2004; 93: 1347-50


Presto study : Outcomes for the diabetic
sub-group undergoing Coronary Intervention

PRESTO Study a
Retrospective analysis

Multiple Therapies
(-) Metformin
Diabetics with
cardiac disease b N=1110
requiring
revascularisation
Multiple Therapies
(+) Metformin
a Prevention of re-stenosis with tranilast N=887
and its outcomes trial
b Previous MI (40%), previous PCI (55%),

unstable angina (64%), CHF (11%) 9 Month Follow-Up

Coronary Intervention Final Visit


CABG, Angioplasty Re-stenosis
MI, Death
Kao et al. Am J Cardiol 2004; 93: 1347-50
Metformin Effect on clinical
outcomes after Coronary Intervention
1.0
Metformin therapy
Proportion event-free a

0.9
n = 887

0.8 Other therapy


n =1110

0.7 Single Endpoints


Metformin Other
Death 1% 3%*
0.6 All MI 1% 3%*
Kaplan - Meier Revasc 20% 22%
analysis, p = 0.005
0.5
0 50 100 150 200 250

a From either MI, death Days of Follow-up


or revascularisation,
Kao et al. Am J Cardiol 2004; 93: 1347-50
Metformin Effect on clinical
outcomes after Coronary Intervention

Metformin versus non-insulin sensitisers – odds ratios

Any clinical event (p=0.005)

Myocardial infarction (p=0.002)

Death (p=0.007)
Need for revascularisation ( NS )

Favours metformin

0.0 0.2 0.4 0.6 0.8 1.0 1.2


Adjusted odds ratio (95%CI)

Kao et al. Am J Cardiol 2004; 93: 1347-50


Improved Angina Symptoms with Metformin in
Patients with “Cardiac Syndrome X”

Maximum ST depression Episodes/day


during exercise tolerance test of chest pain
0
% Change from baselinea

-10
p=0.67 p=0.45
-20
-30
-40
p=0.007
-50
-60 Metformin (n=16) p=0.039
Placebo (n=17)

aCalculated from mean values at 0 and 8 weeks.

Jadhav S et al. J Am Coll Cardiol 2006;48:956-63


Improved Coronary Circulation with Metformin in
Patients with “Cardiac Syndrome X”

Endothelium-dependent Endothelium-independent
vasodilatation vasodilatation

Increased blood flow (arbitrary units)


Increased blood flow (arbitrary units)

p=0.0003
160 160

120 p=0.50 120

80 80 p=0.46 p=0.95

40 40

0 0
Metformin Placebo Metformin Placebo
(n=16) (n=17) (n=16) (n=17)
Baseline 8 weeks placebo 8 weeks metformin

Jadhav S et al. J Am Coll Cardiol 2006;48:956-63


Metformin and Heart Failure

Fact:- Heart Failure affects about


23% of patients with type 2 diabetes

Eurich et al, Diabetes Care 2005; 28: 2345-51


Saskatchewan Health
Database: key study statistics

• Users of oral antidiabetic therapies from 1991-96


( n =12272)
• No history of Heart Failure prior to 1991
• Incidient heart failure developed in 1833 patients
including 208(metformin) 773 (sulfonylurea ) and 852
in the combined group
• Follow-up = 2.5 years
• Assessments – hospitalisation and mortality

Eurich et al, Diabetes Care 2005; 28: 2345-51


Saskatchewan: improved survival with
metformin alone or combined in heart failure

All cause hospitalisation All cause mortality


N=1,313 N=763
90 74%
70% 69% (632)
(538) (143)
52%
(404)
60

% 33%
(69)
31%
(263)
30

0
SU mono, n=773 SU+Met Combo, n=852
Met mono, n=208
Eurich et al, Diabetes Care 2005; 28: 2345-51
Chronic Heart Failure and Insulin Resistance
are strongly associated

Insulin resistance (IR) predicts


the outcome of patients with CHF.
Trials ongoing ( TAYSIDE) to determine
if metformin reduces IR and CHF.
INSULIN RESISTANCE

UKPDS showed that a 1% reduction


in HbA1c reduced the risk of developing
CHF thereby implicating AGE process

Presence of type 2 diabetes is


associated with worse outcomes in CHF

HEART FAILURE
DEVELOPING INTEREST IN
METFORMIN IN HEART FAILURE

Wong AKF. Cardiovascular Therapeutics 2008;26:203-213


Doehner W. J Am Coll Cardiol 2005; 46: 1019-1026
Thiazolidinediones and heart Failure:
Meta-analysis of risk

Meta-analysis

TREATMENT PROTECTIVE TREATMENT HARMFUL

Time to trigger heart failure

TREATMENT PROTECTIVE TREATMENT HARMFUL


Singh S. Diabetes Care 2007; 30: 2148-2153
Incidence of Heart Failure

10
9
TZD Present = 8.8% TZD
8
TZD Absent = 5.3%
7
Subjects (%)

6
5
4
3 No TZD
2
1
0
0 6 12 18 24 30 36
Months

Delea TE. Diabetes Care 2003; 26: 2983-2989


Vascular Effects of Metformin

Anti-atherogenic actions
 cholesterol deposition
 lipid peroxidation
 endothelial function
 oxidative stress

Antithrombotic actions
 platelet activation
 blood flow
 PAI-1 and fibrin breakdown

Metformin: Intrinsic Vascular Protective Properties


Diabetes Technology and Therapeutics 2000; 2: 259-272
Metformin Effect on
Monocyte Differentiation to Macrophages
Control Metformin 0.1µg/mL

a b

Metformin 0.5µg/mL Metformin 1µg/mL

c d

Human monocytes cultured for 9 days ± metformin.


Formation of macrophages (control) reduced by metformin
Mamputu et al. Br J Diabetes Vasc Dis 2003; 3: 302-310
Inflammatory Process

LDL Oxidised
Plasma
C Reactive Protein
(marker of inflammation)
Foam Cells and Macrophages

Free Radicles
(marker of oxidative stress) Pro-Inflammatory Cytokines
e.g. TNF, IL1
Stimulate

Increased Macrophages and T-cells


Adhesive Molecules
To enter

Leukocyte
Lesion
Infiltration
into Endothelium
Metformin and C-Reactive Protein

Metformin
Patient Group n Dose (mg) Duration CRP P-value

Type 2 1 12 2500 4m  33% <0.01

Type 2 + MS 2 65 2500 3.5 y  33% 0.01

PCOS 3 32 2000 6m  50% <0.01

1 Chu. Diabetes Care 2002; 25: 542-549


2 Akbar. Endocrine 2003; 20: 215-218
3 Morin-Papunen. JCEM 2003
Metformin and Endothelial Function

CH3
Structural
N C NH C NH2
Similarities CH3
NH NH Metformin

COOH
NH2 NH C NH2
CH (CH)3 NH C NH2
NH NH2
NH
Aminoquanidine
Arginine
Potent inhibitor of Advanced Potent precursor of
Glycation End products (AGE) Nitric oxide
Metformin Counters Oxidative Stress

Hyperglycaemia Metformin  Type 2 Patients

8 Weeks
AGE formation
Arginine Infusion Test
Oxidative stress
Arterial compliance  p<0.05
Blood filterability  p<0.05
Nitric Oxide  Platelet aggregation  p<0.05
Blood viscosity  p<0.05

Angiopathy Marfella R. Diabetes Care 1996; 19: 934-939


Postulated Mechanisms of Altered
Fibrinolysis in Diabetes

Cytokines
Insulin  Fibrin
Activated deposits
Proinsulin
platelets
High glucose  Plasmin
Modified LDL Glycation
Modified VLDL
 PAI-1
Plasminogen
(-)  tPA tPA

(-)
 PAI-1 Collagenase
Colwell JA. Diabetes Rev. 1994;2:277-291
Effects of Metformin on PAI-1 Levels in Patients
With Type 2 Diabetes

35
30
PAI-1 activity (U/mL)

25 *
20
15
10
5
0
Basal Placebo Metformin

* P<0.001 compared with placebo. Results at 12 weeks

Nagi DK, Yudkin JS. Diabetes Care. 1993;16:621-629.


Effect of Metformin on Fibrin Clots
Control Metformin

Results: Polymerisation with thinner fibres and smaller pores easier to


lyse and therefore associated with reduced antithrombotic risk.

Standeven. Diabetes 2002; 51: 189-97


UKPDS 10 years FU of intensive glucose control: Did
SU demonstrate a legacy effect ?
UKPDS 10 y. patient flow
4209 newly diagnosed patients

2729 1138 342

UKPDS Intensive conventional Intensive


therapy therapy therapy
1977-1991 SU / Insulin Diet primarily metformin

2118 880 279


Available for Available for Available for
post-trial post-trial post-trial

1010 379 136

1997- 2007 completed post- Completed Completed


trial post trial post-trial

Median F-U: 16.8 years Median F-U: 17.7 years


Intensive glucose control lower micro-v.
disease risk

UKPDS, major findings (1998)


• Intensive glucose therapy
– reduces micro-v. disease risk
– MI risk was non significantly reduced by 16 %
(p=0.52)
• In overweighted patient, metformin reduce
– MI risk by 39% (p=0.01)
– and death from any cause by 36 % (p=0.01)
Metformin initial benefit vs SU+ins. Is
maintained after 10 years

For all diabetes related endpoint, the For all diabetes related endpoint, the
initial benefit in SU+Insulin group initial benefit in metformin group
remains for 10 years remains for 10 years
But at the same level !!! Far below
metformine group benefit.
After 10 years both groups achieved similar
HBA1c levels

Baseline differences in mean HBA1c between intensive vs conventional


were lost after 1 year in both groups,
Metformine reduces MI risk

In SU+Ins. group a limited MI risk MI risk reduction induced by metformine


reduction emerged over time after 10 stays all along the 10 years FU.
years
SU major benefit beyond glucose control
remains in micro-V complications

SU+Insulin reduces microvascular


complications risk all along the 10 In metformine group the microvascular
years FU. complication risk reduction fails to be
significant.
Metformine protection remains all along
the 10 years F-U.

After 10 years SU+Ins. group finally All cause mortality reduction induced by
shows a limited all cause mortality metformine stays all along the 10 years FU.
reduction
Legacy effect of therapy in UKPDS
diabetes diabetes
• In both group (SU+Ins. group and related micro-v. related All cause
endpoint disease death MI death
metformin group) compared to
conventional therapy, significants
reduction in RR observed initially
were maintained after 10 years
• Benefit persisted despite early loss of -9%

within-trial differences in HB A1c -13%


-15%
levels between intensive and
-18% -17%
conventional therapy group = NS
-21%
the so-called legacy effect -24%
-27%
• AND, most of the differences -30%
SU+Ins. -33%
observed between metformin and Metformin
SU+Ins. group were maintained as
well.
Subjects to be discussed

• UKPDS , metformin and secondary prevention

• Benefits of metformin in providing long-term


health benefits in patients with heart disease –
ischaemic heart disease and heart failure

• Safety of metformin in contraindicated states

• Revisions to prescribing indications according


to guidance from the literature
Use of metformin in co-existing disease

Major drawback :-

Limited by safety concerns around lactic acidosis


dating back to the 1960s-1970s when phenformin
was available. At that time UKPDS had not started
and the evidence did not exist that metformin from
diagnosis could reduce the risk of life threatening
complications such as MIs and strokes and reduce
the risk of premature mortality.
Cochrane Database of Systematic Reviews
Efficacy Safety

2006 2006

Unsurpassed benefit for glycaemic control, Risk of lactic acidosis is zero if


body weight and favourable lipid changes prescribed as recommended
Metformin Contraindications

•Renal dysfunction
•Severe liver disease
•Use of iv contrast media
•Major surgical procedures
•Congestive heart failure
•Acute myocardial infarction
•History of lactic acidosis
•History of alcohol abuse
Adherence to contraindications

Holstein A. Diabetologia 2005; 48: 2454-2459


Metformin’s contraindications should be contraindicated
Contraindications Can Damage Your Health
Is Metformin a Case in Point?

Benefits

Contraindications

• Patients needlessly denied metformin


• Withdrawal means replacement
and possibly drug induced
hypos, wt gain, heart failure Diabetologia 2005; 48: 2454-9
Revisions to Metformin Prescribing

Specific Recommendations
Age per se should not be a contraindication.
Renal impairment okay if GFR > 40 ml/min.
Stable heart failure (NHYA I & II)

General Recommendations
Prescribing information should be
harmonised worldwide

Diabetologia 2005; 48: 2454-9


ADA :EASD Consensus Algorithm
Jan 2009

“Metformin –recent studies have suggested


that metformin is safe unless the estimated
glomerular filtration rate falls to < 30ml/min”
Nathan DM et al Diabetes Care 2009 ; 32: 1-11
Metformin Contraindications

•Renal dysfunction CKD stages 4&5

•Severe liver disease Benefits in NALFD / NASH

•Use of iv contrast media Renal toxicity from IV media


•Major surgical procedures Agreed

•Congestive heart failure Classes 3 &4 only

•Acute myocardial infarction Acute phase only


•History of lactic acidosis Agreed
•History of alcohol abuse Alcohol dependence
Conclusions

• There are limited but meaningful data supporting the use


of metformin in patients with co-existing cardiovascular
disease of the heart
• Experimental studies support both anti-atherogenic and
anti-thrombotic actions of the drug
• A long list of contraindications is a major reason for the
lack of studies in secondary prevention
• There is growing recognition that prescribing information
could be revised given the realisation from UKPDS that
metformin is the only antidiabetic agent shown to
improve survival. Denying patients metformin as the
disease and complications advance maybe the wrong
strategy in 2010