METFORMIN RENAISSANCEA NEW ANTI ATHEROSCLEROTIC DRUG

Dr. Rajeev AgarwalaDirector of Cardiology Services

Jaswant Rai Speciality Hospital, Meerut.E-mail: rajeev_jrsh@yahoo.co.in

WHY CARDIOLOGIST WHY CARDIOLOGIST SHOULD TALK DIABETES?SHOULD TALK DIABETES?

WHY CLINICIANS SHOULD WHY CLINICIANS SHOULD USE METFORMIN?USE METFORMIN?

WHY METFORMIN WORKS?WHY METFORMIN WORKS?

QUESTIONQUESTIONNO. 1NO. 1

IN DIABETES, VASCULAR DISEASE IN DIABETES, VASCULAR DISEASE BEGINS EARLYBEGINS EARLY

Insulin Resistance precedes overt Hyperlycemia or Diabetes

Newly diagnosed Diabetics have Vascular Disease at Presentation

DIABETIC ATHEROMADIABETIC ATHEROMAA DIFFERENT DISEASEA DIFFERENT DISEASE

Aim & objective:Aim & objective: Several studies have shown that T2DM is Several studies have shown that T2DM is

associated with progressive atherosclerosis, associated with progressive atherosclerosis, resulting in increased risk of CV events.resulting in increased risk of CV events.

The typical characteristic progression of coronary The typical characteristic progression of coronary plaques in patients with T2DM was evaluated plaques in patients with T2DM was evaluated using integrated backscatter intravascular using integrated backscatter intravascular ultrasound (IB-IVUS) examinationultrasound (IB-IVUS) examination

Eur Heart Jn Cardvs Imag Feb 2012

PERCENT CHANGE IN CONVENTIONAL PERCENT CHANGE IN CONVENTIONAL AND IB-IVUS PROFILES DURING 6 AND IB-IVUS PROFILES DURING 6

MONTH FOLLOW-UPMONTH FOLLOW-UP

Eur Heart Jn Cardvs Imag Feb 2012

Eur Heart Jn Cardvs Imag Feb 2012

THE ENDOTHELIUM:A BIOLOGICALLY ACTIVE, DYNAMIC ORGAN

QUESTIONQUESTIONNO. 2NO. 2

DRUG THERAPYDRUG THERAPY

So….So….

Br J Diabetes Vasc Dis. 2007;7:204-210

UK Prospective Diabetes StudyUK Prospective Diabetes Study

20-year Interventional Trial from 1977 to 1997 5,102 patients with newly-diagnosed DM2

Median follow-up 10.0 years, range 6 to 20 years

Results presented in 1998

10-year Post-Trial Monitoring from 1997 to 2007 Annual follow-up of the survivor cohort

Clinic-based for first five years

Questionnaire-based for last five years

Median overall follow-up 17.0 years, range 16 to 30 years

UKPDS 80. NEJM 2008; 359: 1577-89

UKPDS 34. Lancet 1998; 352: 854-65

Diabetes-related deaths

All –Cause Mortality

Myocardial Infarction

CV Complicationsreduced and Survival increased versus

other therapies

POST-Trial Monitoring

1997 - 2007

-30%

-27%

-33%

-42%

-36%

-39%

UKPDS Trial Intervention

1977 - 1997

CV Complicationsreduced and Survival increase

maintained

Lessons from UKPDS 10-year Follow-up:Lessons from UKPDS 10-year Follow-up:“Legacy Effect ” or “Metabolic Memory” of Earlier “Legacy Effect ” or “Metabolic Memory” of Earlier

Metformin TherapyMetformin Therapy

HbA1c

Microvascular complications e.g. kidney disease and blindness *

Heart attack *

HbA1cHbA1cHbA1cHbA1c

Deaths related to diabetes *

21%

Stratton IM et al. UKPDS 35. BMJ 2000; 321: 405–412

Amputation or fatal peripheral blood vessel disease *

37%

14%

12%

43%

Stroke **

1%

Epidemiological extrapolation showing benefit of a 1% reduction in mean HbA1c

* p<0.0001

** p=0.035

UKPDS 34: CV Risk Reduction with Metformin

N = 4075 with type 2 diabetes

UKPDS 34 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

Intensive = HbA1c < 7%Conventional = HbA1c < 7.9%

Relative risk reduction(95% CI)

36

Arch Intern Med. 2010;170(21):1892-1899

STUDY BACKGROUND

Metformin is recommended in T2DM because it Metformin is recommended in T2DM because it reduced mortality among overweight reduced mortality among overweight participants in the UKPDS (beyond its glycemic participants in the UKPDS (beyond its glycemic benefits) when used mainly as a means of benefits) when used mainly as a means of primary prevention. primary prevention.

However, Metformin is often not considered in However, Metformin is often not considered in patients with CV conditions because of concerns patients with CV conditions because of concerns about its safety.about its safety.

Arch Intern Med. 2010;170(21):1892-1899

REACH Registry Metformin Study Methods

Assessed whether Metformin use was associated with a difference in mortality among patients with atherothrombosis.

The study sample comprised 19 691 (out of 68375 patients) patients having diabetes with established atherothrombosis participating in the Reduction of Atherothrombosis for Continued Health (REACH) Registry between December 1, 2003, and December 31, 2004, treated with or without metformin

Out of 19691 patients, total 7457 patients had used metformin

Multivariable adjustment and propensity score were used to account for baseline differences.

The main outcome measure was 2-year mortality.

Arch Intern Med. 2010;170(21):1892-1899

Metformin use as 20 Prevention & Mortality Reduction in Patients with Diabetes

Arch Intern Med. 2010;170(21):1892-1899

The mortality rates were 6.3% with metformin & 9.8% without metformin;

Adjusted Hazard Ratio (HR) was 0.76 (P.001)

Arch Intern Med. 2010;17021):1892-1899

Metformin use & All-cause mortality: CHF Sub-group

Of 4585 patients with a history of CHF,1428 were prescribed metformin.

Metformin use was associated with lower all-cause mortality after adjusting for prognostic factors and propensity score

(HR, 0.69; 95% CI, 0.54-0.90; P=.006)

REACH for metformin to reduce deaths in REACH for metformin to reduce deaths in patients with diabetes and Atherothrombosispatients with diabetes and Atherothrombosis

Metformin showed - 24% reduced mortalityMetformin showed - 24% reduced mortality These are very interesting results from an observational study. I These are very interesting results from an observational study. I

think it's fascinating. think it's fascinating. Certainly, metformin appears to be very favorable with an impact Certainly, metformin appears to be very favorable with an impact

on mortality.on mortality.

In patients with diabetes and documented Atherothrombosis, the use of metformin was associated with a significant 24% reduction in all-cause mortality after two years of follow-up, according to a subgroup analysis from a large registry study presented at the American Diabetes Association (ADA) 2010 Scientific Sessions.

In patients with diabetes and documented Atherothrombosis, the use of metformin was associated with a significant 24% reduction in all-cause mortality after two years of follow-up, according to a subgroup analysis from a large registry study presented at the American Diabetes Association (ADA) 2010 Scientific Sessions.

METFORMIN USE IS ASSOCIATED WITH LOWER

ALL-CAUSE MORTALITY

Arch Intern Med. 2010;170(21):1892-1899

Metformin use was associated with lower all-cause mortality

(HR, 0.76; 95% CI, 0.65-0.89; P.001)

Hazard Ratio for Mortality with Hazard Ratio for Mortality with Metformin in selected sub-groups Metformin in selected sub-groups

Results: Survival Benefit with Metformin

• At 2-yr follow-up, 15.8% of patients receiving metformin & 25.5% patients not receiving metformin had died.

• Patients hospitalized with HF (11.5% vs 16.4%) & hospitalized for any cause (40.9% vs 47.9%) were lower in patients receiving metformin compared to those not on met therapy over 2 yr of follow-up.

Circ Heart Fail. 2011;4:53-58

TRIAL DISCUSSION

• Several potential mechanisms beyond glycemic control through which metformin may improve outcomes in HF patients.

• Metformin is associated with reduction in weight gain & improvement in measures of insulin resistance.

• In addition, it has been associated with improvements in endothelial function, lipoprotein metabolism, oxidative stress & abnormalities in coagulation.

• These mechanisms contribute to the reduction in macrovascular events in patients on metformin therapy.

Thus…….In a cohort of patients with Diabetes & HF, Metformin was associated with a survival

benefit over 2 yr of follow-up

Circ Heart Fail. 2011;4:53-58

BARI 2 D Summarizes - BARI 2 D Summarizes - A strategy of prompt coronary revascularization in patients who had been treated A strategy of prompt coronary revascularization in patients who had been treated

with intensive medical therapy for diabetes and stable ischemic disease did not with intensive medical therapy for diabetes and stable ischemic disease did not significantly reduce the rate of death from any cause or of major cardiovascular significantly reduce the rate of death from any cause or of major cardiovascular events. events.

Insulin sensitization and insulin provision also had similar Insulin sensitization and insulin provision also had similar cardiovascular outcomes during a 5-year period. cardiovascular outcomes during a 5-year period.

Among patients for whom CABG was deemed to be the appropriate treatment, Among patients for whom CABG was deemed to be the appropriate treatment, prompt revascularization reduced the rate of major cardiovascular events, as prompt revascularization reduced the rate of major cardiovascular events, as compared with medical therapy, particularly among patients who were assigned to compared with medical therapy, particularly among patients who were assigned to receive insulin sensitization. receive insulin sensitization.

In the PCI stratum, however, revascularization did not reduce the rate of death or In the PCI stratum, however, revascularization did not reduce the rate of death or major cardiovascular events when added to medical therapy.major cardiovascular events when added to medical therapy.

N Engl J Med 2009;360:2503-15.

Rates of Survival and Freedom from Major

Cardiovascular Events.

There was no significant difference in rates of survival between the revascularization group and the medical-therapy group (Panel A) and between the insulin-sensitization group and the insulin-provision group (Panel B). The rates of major cardiovascular events (death, myocardial infarction, or stroke) also did not differ significantly between the revascularization group and the medical-therapy group (Panel C) or between the insulin-sensitization group and the insulin-provision group (Panel D)

N Engl J Med 2009;360:2503-15.

200 type 2 diabetic patients post CABG 200 type 2 diabetic patients post CABG received insulin infusion+metformin 1 gm received insulin infusion+metformin 1 gm twice daily vs control group with only insulin.twice daily vs control group with only insulin.

Lactate level, pH, base excess, blood glucose Lactate level, pH, base excess, blood glucose and serum creatinine were measured over five and serum creatinine were measured over five 12 h periods.12 h periods.

METFORMIN USE IN SURGICAL METFORMIN USE IN SURGICAL PROCEDURESPROCEDURES

A recent evaluation of metformin A recent evaluation of metformin indicated that the inadvertent failure to indicated that the inadvertent failure to stop metformin before cardiac surgery stop metformin before cardiac surgery did not increase mortality and morbidity.did not increase mortality and morbidity.

Anesth Analg 2007;104:42-50

0 100 200150 25050

Days of Follow-up

Pro

port

ion

even

t-fr

ee a

0.5

0.6

0.7

0.8

0.9

1.0

Metformin therapyn = 887

Other therapyn =1110

METFORMIN EFFECT ON CLINICAL OUTCOMES AFTER CORONARY INTERVENTION

Kao et al. Am J Cardiol 2004; 93: 1347-50a From either revascularisation, MI or death

Kaplan - Meier analysis, p = 0.005

Death 1% 3%*All MI 1% 3%*Revasc 20% 22%

Single Endpoints Metformin Other

Metformin attenuates progression of carotid arterial wall thickness in patients

with type 2 diabetes

Diabetes Res Clin Pract. 2004;64(3):225-8.

Metformin Control0

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.02

0.07

Cha

nge

in C

CA

-IMT

(mm

)

N = 36 Study Duration: 2 yrs

CCA-IMT: Common Carotid Artery Intima Media Thickness

Improved Cardiovascular outcomes with Improved Cardiovascular outcomes with Metformin in T2DMMetformin in T2DM

61

STUDY MAIN FINDINGS

Randomized Trials

UKPDS 34 Reduced risk of macrovascular diabetic complications

Kooy et al Reduced risk of composite of macrovascular events

Observational Studies

PRESTO Reduced risk of any clinical outcome, MI, Death

Johnson et al 40% reduction in risk of deathReduced risk of mortality, hospitalization, cardiovascular death

Eurich et al 30% reduction in risk of death, 17% reduction in risk of death or hospitalization

Evans et al 3.7 fold lower risk of cardiovascular mortality

Clifford J Bailey, Ian W Campbell, Metformin: The gold standard

The Final Endorsement for Metformin in Vascular Protection…

Metformin Benefits Enlisted in the Metformin Benefits Enlisted in the Cochrane ReviewCochrane Review

Intensive metformin seems to reduce the risk for any clinical Intensive metformin seems to reduce the risk for any clinical endpoint related to diabetes, death related to diabetes, all endpoint related to diabetes, death related to diabetes, all cause mortality & myocardial infarction.cause mortality & myocardial infarction.

Patients assigned to receiving metformin monotherapy Patients assigned to receiving metformin monotherapy showed a significant reduction from baseline for HbA1c, showed a significant reduction from baseline for HbA1c, BMI/weight, cholesterol, LDL-c, TGs, insulin, DBP & BMI/weight, cholesterol, LDL-c, TGs, insulin, DBP & increasing HDL-c.increasing HDL-c.

Thus, tight glycaemia control with metformin monotherapy is Thus, tight glycaemia control with metformin monotherapy is one of the main therapeutic options in the type 2 diabetes one of the main therapeutic options in the type 2 diabetes mellitus in patients with overweight or obesitymellitus in patients with overweight or obesity

Metformin Superior to Glipizide for reducing Metformin Superior to Glipizide for reducing CVD events in Diabeticd with CADCVD events in Diabeticd with CAD

Significant 52% relative risk reduction.(70% statin usage)Significant 52% relative risk reduction.(70% statin usage)

Reduces markers of inflammation, reduces vascular Reduces markers of inflammation, reduces vascular adhesion molecules,reduces coagulation adhesion molecules,reduces coagulation parameters,reduces endothelial dysfunction.parameters,reduces endothelial dysfunction.

-Hong J et. al. -Hong J et. al. Diabetes Care 2012 ;Diabetes Care 2012 ;1010thth DecemberDecember..

Improved Lipoprotein Lipase mass & LDL Particle Size

Diabetes Res Clin Pract. 2007;78(1):34-41.

Thus, metformin may diminish insulin resistance and increase LPL production, increasing LDL particle size as a result.

Metformin, increased preheparin Lipoprotein Lipase (LPL) mass levels accompanied by enlargement of LDL particle.

PROPOSED RECOMMENDATIONS PROPOSED RECOMMENDATIONS FOR METFORMIN USE BASED ON FOR METFORMIN USE BASED ON

eGFReGFR

QUESTIONQUESTIONNO. 3NO. 3

MECHANISMMECHANISM

Improvement in Endothelium dependant Improvement in Endothelium dependant vasodilatationvasodilatation

Wuffele MG., et al. Journal of Internal Medicine , 256, 1 - 1477

Improved Fibrinolysis

Gregorioet al., Diabetic medicine, 16, 1016 - 1024

Decreased PAI-1 activity & increased tPA activity

Effect of Metformin Therapy on Various CV Risk Factors

Administration of metformin improved glycemic control and led to a decrease in several CVD risk factors in patients with type 2

diabetes.

FFA: Free Fatty AcidRLP-c: remnant lipoprotein cholesterol Metabolism. 2004;53(2):159-64.

Effects of Metformin on Lipids: Data from Experimental Studies

• Metformin reduces lipid accumulation in macrophages.1

• Metformin has demonstrated efficacy in protecting HDL from glycation-induced impairment.2

• Metformin has anti-inflammatory effects on endothelial cells through TNF-α-induced inhibitory action.3

• Additional mechanisms for the atheroprotective effect of metformin include inhibition of cellular events involved in atherogenesis such as

• Leukocyte-endothelial interaction,

• Foam cell formation, smooth muscle cell proliferation &

• Platelet aggregation.4

1. Biochem Biophys Res Commun. 2010;393(1):89-94. 2. Atherosclerosis.2009;206(2):434-8.3. Int J Cardiol. 2009;134(2):169-75.  4. Diabetes Metab. 2003;29:6S71-6S76

Effect on Lipid ProfileEffect on Lipid Profile

Wuffele MG., et al. Journal of Internal Medicine , 256, 1 - 1483

Genetic targets in lipid modulationGenetic targets in lipid modulation

Possible gentic targets of metformin in Possible gentic targets of metformin in modulation of lipids includemodulation of lipids include Hepatic orphan nuclear receptor small heterodimer Hepatic orphan nuclear receptor small heterodimer

partner (SHP)partner (SHP) Hepatic nuclear factor (hnf)-4aHepatic nuclear factor (hnf)-4a Forkhead transcription factor (fox) 01 and foxa2Forkhead transcription factor (fox) 01 and foxa2 Ampactivated protein kinase (AMPK)Ampactivated protein kinase (AMPK)

Gerald H. Tomkin; The effect of antidiabetic drugs on genes regulatinglipid metabolism; Current Opinion in Lipidology 2009, 20:10–16

““Metformin – a Vascular drug” Metformin – a Vascular drug”

• Antihypertensive effect demonstrated in animals and humansAntihypertensive effect demonstrated in animals and humans

• Mechanisms involved complex:Mechanisms involved complex:– Calcium flux modulation, nitric oxide and central regulationCalcium flux modulation, nitric oxide and central regulation

– Anti-glycating properties and in turn reducing oxidative Anti-glycating properties and in turn reducing oxidative stress stress

– Impressive anti-apoptotic actions Impressive anti-apoptotic actions

Br J Diabetes Vasc Dis. 2007;7:204-210

Latest ADA-EASD Position Statement: Latest ADA-EASD Position Statement: Importance of Cardiovascular risk reductionImportance of Cardiovascular risk reduction

Comprehensive cardiovascular risk reduction must be a major focus of therapy.

Diabetes Care. Published ahead of print. April 19; 2012

RECOMMENDATIONS ON RECOMMENDATIONS ON DIABETES MELLITUSDIABETES MELLITUS

Joint ESC Guidelines-2012 European Heart Journal doi:10.1093/eurheartj/ehs092

Steno 2 :what reduced the risk ?Steno 2 :what reduced the risk ?

Steno 2 “ A watershed study ”Steno 2 “ A watershed study ”

THE ACHILES HEELTHE ACHILES HEEL

SUMMARY

Diabetes is a hydra headed Diabetes is a hydra headed problemproblem

Metformin is a poly pill for Metformin is a poly pill for diabetesdiabetes

Thank YouThank You

““I have approximate answers and possible beliefs I have approximate answers and possible beliefs in different degrees of certainty about different in different degrees of certainty about different

things, but I am not sure of anything.”things, but I am not sure of anything.”

Richard Feyman American Richard Feyman American Physicist Physicist