This document discusses the history and uses of the diabetes medication metformin. It traces metformin back to galega officinalis which was used in the Middle Ages to reduce diabetes symptoms. Metformin was first identified and studied in the 1950s and approved for use in the US in 1994. The document highlights that metformin is now recommended as a first-line treatment for type 2 diabetes and has been shown to reduce cardiovascular events and mortality in diabetes patients. Metformin is also effective in preventing or delaying the onset of diabetes in patients with prediabetes.

1. Metformin
Old Molecule….
New Benefits
Dr.T.V.Narayan Rao, M. D.
E.S.I.Hospital,
Andhra Hospitals

2. Galega Officinalis, Goat’s rue, French
Lilac, Italian Fitch, professor -weed

3. History of metformin

Galega officinalis – known to reduce symptoms of DM in
middle ages

Found to contain Guanidine in late 1800’s

Georges Tanret identified Galegine in 1920

Synthalin A & B – less Toxic – 1920’s

Advent of Insulin in 1930’s

Flumamine ( Dimethyl Biguanide ) – used for Influenza in
Philippines

5. History of Metformin
 Jean
Sterne – Aron Labs & Hopital Laennec
in Paris – studied several Biguanides in 1956
 Selected
Metformin (DI methyl Biguanide)
 Published
 Ungar
in 1957, named “Glucophage”
– Phenformin in 1957
 Mehnert
- Buformin

6. Jean Sterne (1909–1997)- the Hôpital Laennec
in Paris

7. Metformin History
 Aron
Labs acquired by Lipha
Pharmaceuticals, now Merck
 Metformin
brought to US in 1995 under franchise
to BMS
 Introduced
 US
in UK in 1958, Canada in 1972
FDA approval in 1994!

8. TYPE 2 DIABETES

On the verge of becoming a pandemic in India.

According to WHO reports



presently India has 32 million diabetic subjects
projected to increase to 100 million i.e. a rise by 250 % by the
year 2035.
Life expectancy of people with diabetes is reduced by
nearly eight years due to increased mortality.
J Diabetes Sci Technol 2010;4(1):158–170, Medicine Update 2005,

9. MANAGEMENT OF T2DM

The drug armamentarium has grown in recent years and
now provides the physician with treatment regimens that
can be tailored to the individual patient's needs
AGENTS AVAILABLE CURRENTLY FOR MANAGEMENT OF T2DM
Biguanides
Sulfonylureas
Meglitinide derivatives
Alpha-glucosidase
inhibitors
Thiazolidinediones
(TZDs)
Glucagonlike peptide–1
(GLP-1) agonists
Dipeptidyl peptidase
IV (DPP-4) inhibitors
Selective sodiumglucose transporter-2
(SGLT-2) inhibitors
Amylinomimetics
Insulins
Bile acid sequestrants
Dopamine agonists
Lilian Rojas and Gomes Diabetology & Metabolic Syndrome 2013, 5:6,
http://emedicine.medscape.com/article/117853-treatment#aw2aab6b6b2

10. METFORMIN- FIRST LINE AGENT

50 year old molecule

Current guidelines from the ADA/EASD and the AACE/ACE
recommend early initiation of metformin as a first-line drug for
monotherapy and combination therapy for patients with
T2DM

Lowers FPG
70 mg/dl

Decreases HbA1c level by
27.5% after 16 Weeks*
by
upto
* Metformin & lifestyle interventions, ADA- EASDAmerican Diabetes Association/ European Association for the Study of Diabetes , AACE/ACE American Association of Clinical Endocrinologists/American College of Endocrinology, Arrigo F.G. Cicero et al. Arch Med Sci 2012 Oct; 907917, Clinical Diabetes April 2012 vol. 30 no. 2 72-75, J. Med. Invest. 59 : 166-173, February, 2012

11. Mechanism of Action of Metformin
Bailey CJ, Turner RC. N Engl J Med 1996;334:574-579.

12. Contraindications for Metformin
Bailey CJ, Turner RC. N Engl J Med 1996;334:574-579.

13. CMAJ • AUG. 30, 2005; 173 (5)

14. CMAJ • AUG. 30, 2005; 173 (5)

16. Metformin – clinical usage
•
•
•
•
•
•
Monotherapy or in combination with others
Maximum daily dose is 2550 mgs
Side effects are predominantly GI related
Start with small dose and uptitrate
Use sustained release preparations
Size of the tablet ?

17. Metformin in Diabetes/IGT
1.Metformin is documented to reduce CV
events and mortality in Diabetes.

18. REACH for metformin to reduce deaths in patients
with diabetes and Atherothrombosis
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 showed - 24% reduced mortality
These are very interesting results from an observational
study. I think it's fascinating.
Certainly, metformin appears to be very favorable with an
impact on mortality.

19. The Final Endorsement for Metformin in
Vascular Protection…

Intensive metformin seems to reduce the risk for any clinical
endpoint related to diabetes, death related to diabetes, all
cause mortality & myocardial infarction.

Patients assigned to receiving metformin monotherapy
showed a significant reduction from baseline for
HbA1c, BMI/weight, cholesterol, LDL-c, TGs, insulin, DBP &
increasing HDL-c.

20. Improved CV outcomes with Metformin in
T2DM: Plethora of Evidence
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
REACH
Registry
24% risk reduction in mortality in patients with atherothrombosis
Clifford J Bailey, Ian W Campbell, Metformin: The gold standard

21. METFORMIN - CARDIOPROTECTIVE
EFFECTS
Improves
Decreases
diastolic function
 hyperglycemia
 HDL-C
 TC, VLDL, LDL-C
 vascular relaxation
 oxidative stress
 tPA activity
 PAI-1 levels
 von Willebrand factor levels
 platelet aggregation and
adhesion
Ann Intern Med 2002;137:25-33.

22. METFORMIN – PROVIDES
CARDIOVASCULAR PROTECTION

Reduces incidence of macro vascular events
Rojas and Gomes Diabetology & Metabolic Syndrome 2013, 5:6

23. Metformin in Diabetes/IGT
1.Metformin is documented to reduce CV
events and mortality in Diabetes.
2.Metformin is known to prevent CV events
in diabetic patients with cardiac disease
undergoing intervention

24. Survival Benefits of Metformin in ACS Patients
Undergoing Coronary Intervention
PRESTO Study a
Retrospective analysis
Diabetics with
cardiac disease b
requiring
revascularisation
Multiple Therapies
(-) Metformin
N=1110
Multiple Therapies
(+) Metformin
N=887
9 Month Follow-Up
a
Prevention of re-stenosis with tranilast
and its outcomes trial
b Previous MI (40%), previous PCI (55%),
unstable angina (64%), CHF (11%)
Coronary Intervention
CABG, Angioplasty
Final Visit
Re-stenosis
MI, Death
Kao et al. Am J Cardiol 2004; 93: 1347-50

25. Metformin Effect on Clinical Outcomes After
Coronary Intervention
1.0
Proportion event-free
a
Metformin therapy
n = 887
0.9
Other therapy
n =1110
0.8
0.7
0.6
Kaplan - Meier
analysis, p = 0.005
0.5
0
50
100
150
200
250
Days of Follow-up
a
From either revascularisation, MI or death
Kao et al. Am J Cardiol 2004; 93: 1347-50

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

27. Metformin in Diabetes/IGT
1. Metformin is documented to reduce CV
events and mortality in Diabetes.
1. Metformin is known to prevent CV events
in diabetic patients with cardiac disease
undergoing intervention
2. Metformin is known to prevent onset of
diabetes in patients with IGT

28. Diabetes Prevention Program: Benefit of
Metformin in reducing progression to Type 2
Diabetes
Cases/100 person-years
Average follow-up of 2.8 years
12
Metformin reduced the incidence of developing diabetes by 31%
as compared with placebo.
10
 31%*
8
DPP Study showed that treatment with metformin was one
6
 58%*
of the highly effective means of delaying or preventing type
4
2 diabetes.
2
0
Placebo
Metformin
Intensive
lifestyle
*All pairwise comparisons significantly different by group; sequential log-rank test.
The Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393.

29. The cumulative incidence of
Diabetes in Metformin group was
40.5% as compared to 55% in
control group.
The absolute & relative risk
reduction with Metformin was
26.4%
Control
LSM
Metformin
LSM + Metformin
Diabetologica. 2006;49:289-297

30. Metformin in the IDPP Study

Metformin was effective to reduce the progression rate of IGT to
diabetes in the Asian Indian population at a much smaller dose
(500 mg/day) as compared to DPP (1700 mg/day).

Lower number of people needed to be treated with metformin to
prevent 1 case of diabetes (6.9) as compared to the DPP (13.9).
There was no additional benefit of combining metformin with
LSM as compared to Metformin alone.
The IDPP showed that Metformin used at lower doses was
equally effective as LSM to prevent diabetes in Asian
Indians at high risk.
Diabetologia. 2006;49:289-297

31. 

3 RCTs varied in ethnicity of the population studied, in the rates of
conversion to diabetes from prediabetes, and in the dose of metformin used
Metformin significantly reduced the conversion from prediabetes to diabetes


NNT was between 7 and 14 for treatment over a 3-year period
This was true at higher dosage (850 mg twice daily) and even lower dosage (250
mg 3 times daily).
Can Fam Physician 2009;55:363-9

32. Metformin in Prediabetes: ADA 2013
Endorsement

Role of Metformin in
prevention or delay in
progression of IGT to
diabetes is well known &
evidence based.
Diabetes Care. 2013;36(Suppl 1):S11-S66

33. Metformin in Prediabetes: AACE 2013
Endorsement
AGI
Endocrine Practice April, 2013; Vol 19(2)

35. BMJ VOLUME 327 25 OCTOBER 2003 bmj.com

36. Conclusions
Metformin is an effective treatment for anovulation in women with
polycystic ovary syndrome. Its choice as a first line agent seems
justified, and there is some evidence of benefit on variables of the
metabolic syndrome.
No data are available regarding the safety of metformin in long
term use in young women and only limited data on its safety in early
pregnancy. It should be used as an adjuvant to general lifestyle
improvements and not as a replacement for increased exercise and
improved diet.
BMJ VOLUME 327 25 OCTOBER 2003 bmj.com

37. TAKE HOME MESSAGE
Metformin

An old and widely accepted first line agent

Stands out not only for its antihyperglycemic properties but
also for its effects beyond glycemic control such as
improvements in endothelial dysfunction, hemostasis and
oxidative stress, insulin resistance, lipid profiles, and fat
redistribution.

High safety profile due to

Negligible risk of hypoglycemia in monotherapy

Few drug interactions of clinical relevance
Lilian Beatriz Aguayo Rojas and Marilia Brito Gomes, Diabetology & Metabolic Syndrome 2013, 5:6

38. TAKE HOME MESSAGE
Metformin

The only oral antidiabetic agent to show a significant effect
on CV risk

Has benefits beyond glucose lowering – reduces weight and
improves lipid profile

Thus, Metformin is OLD but GOLD

Small tablet size is preferred by both patients and doctors &
helps improve adherence to therapy

Technologically advanced Metformin XR may the ideal
choice, when you need to prescribe Metformin

39. “The right dose
differentiates a poison
from a useful
medicine”
Theopharastus Bombastus
von Hohenhein
Better Known as Paracelsus
(1493 – 1541)
Swiss Physician

40. “I wish to say what I think and feel today
with the proviso that tomorrow
probably I shall contradict it all”
– Ralph Waldo Emerson
Thank you