1. METFORMIN RENAISSANCE
A NEW ANTI ATHEROSCLEROTIC DRUG
Dr. Rajeev Agarwala
Director of Cardiology Services
Jaswant Rai Speciality Hospital, Meerut.
E-mail: rajeev_jrsh@yahoo.co.in

2. WHY CARDIOLOGISTWHY CARDIOLOGIST
SHOULD TALK DIABETES?SHOULD TALK DIABETES?
WHY CLINICIANS SHOULDWHY CLINICIANS SHOULD
USE METFORMIN?USE METFORMIN?
WHY METFORMIN WORKS?WHY METFORMIN WORKS?

3. QUESTIONQUESTION
NO. 1NO. 1

4. IN DIABETES, VASCULAR DISEASEIN DIABETES, VASCULAR DISEASE
BEGINS EARLYBEGINS EARLY
Insulin Resistance precedes overt Hyperlycemia or Diabetes
Newly diagnosed Diabetics have Vascular Disease at Presentation

8. DIABETIC ATHEROMADIABETIC ATHEROMA
A DIFFERENT DISEASEA DIFFERENT DISEASE

14.  Aim & objective:Aim & objective:
 Several studies have shown that T2DM isSeveral 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 coronaryThe typical characteristic progression of coronary
plaques in patients with T2DM was evaluatedplaques in patients with T2DM was evaluated
using integrated backscatter intravascularusing integrated backscatter intravascular
ultrasound (IB-IVUS) examinationultrasound (IB-IVUS) examination
Eur Heart Jn Cardvs Imag Feb 2012

15. PERCENT CHANGE IN CONVENTIONALPERCENT CHANGE IN CONVENTIONAL
AND IB-IVUS PROFILES DURING 6AND IB-IVUS PROFILES DURING 6
MONTH FOLLOW-UPMONTH FOLLOW-UP
Eur Heart Jn Cardvs Imag Feb 2012

16. Eur Heart Jn Cardvs Imag Feb 2012

17. THE ENDOTHELIUM:
A BIOLOGICALLY ACTIVE, DYNAMIC ORGAN

24. QUESTIONQUESTION
NO. 2NO. 2

25. DRUG THERAPYDRUG THERAPY

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

28. 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

29. UKPDS 80. NEJM 2008; 359: 1577-89
UKPDS 34. Lancet 1998; 352: 854-65
Diabetes-related deaths
All –Cause Mortality
Myocardial Infarction
CV Complications
reduced and Survival increased versus
other therapies
POST-Trial
Monitoring
1997 - 2007
-30%
-27%
-33%
-42%
-36%
-39%
UKPDS Trial
Intervention
1977 - 1997
CV Complications
reduced 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

30. 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

32. UKPDS 34: CV Risk Reduction with Metformin
N = 4075 with type 2 diabetes
UKPDS 34 Group. Lancet. 1998;352:854-65.
Favors metformin
or intensive
Favors
conventional
All-cause mortality
Metformin
Intensive
Myocardial infarction
Metformin
Intensive
Stroke
Metformin
Intensive
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

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

35. STUDY BACKGROUND
 Metformin is recommended in T2DM because itMetformin is recommended in T2DM because it
reduced mortality among overweightreduced mortality among overweight
participants in the UKPDS (beyond its glycemicparticipants in the UKPDS (beyond its glycemic
benefits) when used mainly as a means ofbenefits) when used mainly as a means of
primary prevention.primary prevention.
 However, Metformin is often not considered inHowever, Metformin is often not considered in
patients with CV conditions because of concernspatients with CV conditions because of concerns
about its safety.about its safety.
Arch Intern Med. 2010;170(21):1892-1899

36. 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

37. 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)

38. 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)

39. REACH for metformin to reduce deaths inREACH 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. IThese 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 impactCertainly, 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.

40. 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)

41. Hazard Ratio for Mortality withHazard Ratio for Mortality with
Metformin in selected sub-groupsMetformin in selected sub-groups

43. 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

44. 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

45. BARI 2 D Summarizes -BARI 2 D Summarizes -
 A strategy of prompt coronary revascularization in patients who had been treatedA strategy of prompt coronary revascularization in patients who had been treated
with intensive medical therapy for diabetes and stable ischemic disease did notwith intensive medical therapy for diabetes and stable ischemic disease did not
significantly reduce the rate of death from any cause or of major cardiovascularsignificantly reduce the rate of death from any cause or of major cardiovascular
events.events.
 Insulin sensitization and insulin provision also had similarInsulin 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, asprompt revascularization reduced the rate of major cardiovascular events, as
compared with medical therapy, particularly among patients who were assigned tocompared 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 orIn 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.

46. 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.

47.  200 type 2 diabetic patients post CABG200 type 2 diabetic patients post CABG
received insulin infusion+metformin 1 gmreceived 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 glucoseLactate level, pH, base excess, blood glucose
and serum creatinine were measured over fiveand serum creatinine were measured over five
12 h periods.12 h periods.

48. METFORMIN USE IN SURGICALMETFORMIN USE IN SURGICAL
PROCEDURESPROCEDURES
 A recent evaluation of metforminA recent evaluation of metformin
indicated that the inadvertent failure toindicated that the inadvertent failure to
stop metformin before cardiac surgerystop metformin before cardiac surgery
did not increase mortality and morbidity.did not increase mortality and morbidity.
Anesth Analg 2007;104:42-50

49. 0 100 200150 25050
Days of Follow-up
Proportionevent-freea
0.5
0.6
0.7
0.8
0.9
1.0
Metformin therapy
n = 887
Other therapy
n =1110
METFORMIN EFFECT ON CLINICAL OUTCOMES
AFTER CORONARY INTERVENTION
Kao et al. Am J Cardiol 2004; 93: 1347-50
a
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

51. Metformin attenuates progression of
carotid arterial wall thickness in patients
with type 2 diabetes
Diabetes Res Clin Pract. 2004;64(3):225-8.
Metformin Control
0
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.02
0.07
ChangeinCCA-IMT(mm)
N = 36
Study Duration: 2 yrs
CCA-IMT: Common Carotid Artery Intima Media Thickness

52. Improved Cardiovascular outcomes withImproved 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 death
Reduced 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

53. The Final Endorsement for Metformin in
Vascular Protection…

54. Metformin Benefits Enlisted in theMetformin Benefits Enlisted in the
Cochrane ReviewCochrane Review
 Intensive metformin seems to reduce the risk for any clinicalIntensive metformin seems to reduce the risk for any clinical
endpoint related to diabetes, death related to diabetes, allendpoint related to diabetes, death related to diabetes, all
cause mortality & myocardial infarction.cause mortality & myocardial infarction.
 Patients assigned to receiving metformin monotherapyPatients 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 isThus, tight glycaemia control with metformin monotherapy is
one of the main therapeutic options in the type 2 diabetesone of the main therapeutic options in the type 2 diabetes
mellitus in patients with overweight or obesitymellitus in patients with overweight or obesity

57. Metformin Superior to Glipizide for reducingMetformin 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 vascularReduces markers of inflammation, reduces vascular
adhesion molecules,reduces coagulationadhesion 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..

58. 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.

59. PROPOSED RECOMMENDATIONSPROPOSED RECOMMENDATIONS
FOR METFORMIN USE BASED ONFOR METFORMIN USE BASED ON
eGFReGFR

60. QUESTIONQUESTION
NO. 3NO. 3

61. MECHANISMMECHANISM

62. Improvement in Endothelium dependantImprovement in Endothelium dependant
vasodilatationvasodilatation
Wuffele MG., et al. Journal of Internal Medicine , 256, 1 - 14
77

63. Improved Fibrinolysis
Gregorioet al., Diabetic medicine, 16, 1016 - 1024
Decreased PAI-1 activity & increased tPA
activity

64. 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 Acid
RLP-c: remnant lipoprotein cholesterol Metabolism. 2004;53(2):159-64.

65. 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

66. Effect on Lipid ProfileEffect on Lipid Profile
Wuffele MG., et al. Journal of Internal Medicine , 256, 1 - 14
83

67. Genetic targets in lipid modulationGenetic targets in lipid modulation
 Possible gentic targets of metformin inPossible gentic targets of metformin in
modulation of lipids includemodulation of lipids include
 Hepatic orphan nuclear receptor small heterodimerHepatic 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 regulating
lipid metabolism; Current Opinion in Lipidology 2009, 20:10–16

68. ““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 oxidativeAnti-glycating properties and in turn reducing oxidative
stressstress
– Impressive anti-apoptotic actionsImpressive anti-apoptotic actions
Br J Diabetes Vasc Dis. 2007;7:204-210

69. 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

70. RECOMMENDATIONS ONRECOMMENDATIONS ON
DIABETES MELLITUSDIABETES MELLITUS
Joint ESC Guidelines-2012 European Heart Journal doi:10.1093/eurheartj/ehs092

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

73. Steno 2 “ A watershed study ”Steno 2 “ A watershed study ”

74. THE ACHILES HEELTHE ACHILES HEEL

75. SUMMARY
Diabetes is a hydra headedDiabetes is a hydra headed
problemproblem
Metformin is a poly pill forMetformin is a poly pill for
diabetesdiabetes

76. Thank YouThank You

78. ““I have approximate answers and possible beliefsI have approximate answers and possible beliefs
in different degrees of certainty about differentin different degrees of certainty about different
things, but I am not sure of anything.”things, but I am not sure of anything.”
Richard Feyman AmericanRichard Feyman American
PhysicistPhysicist