METFORMIN – MORE THAN ‘GOLD STANDARD’ IN THE TREATMENT OF TYPE 2 DIABETES MELLITUS

Key words: diabetes mellitus, metformin, polycystic
ovary, nonalcoholic steatohepatitis,
HIV lipodystrophy, neoplasms
SUMMARY
The primary aim of type 2 diabetes mellitus treatment
is to achieve and maintain good glycemic control, and
to minimize the mortality and risk of microvascular
and macrovascular complications. Current algorithms
for medical management of type 2 diabetes mellitus
recommend a combination of lifestyle intervention and
metformin as initial therapy and ‘gold standard’
treatment. Numerous studies suggest positive
antihyperglycemic and metabolic effects of metformin,
with a wide safety profile. There is an increasing
evidence for the potential efficacy of this drug in other
diseases such as polycystic ovary syndrome,
nonalcoholic steatohepatitis, HIV lipodystrophy, and
neoplasms.
INTRODUCTION
The prevalence of type 2 diabetes mellitus (DM) is
increasing rapidly worldwide, with a prediction of
more than 380 million people to be affected by 2025
(1). Insulin resistance in peripheral tissues in
combination with relatively impaired insulin secretion
is essential in the pathogenesis of the disease, leading
to hyperglycemia and compensatory hyperinsulinemia
(2). The primary goal of type 2 DM treatment is to
achieve and maintain good glycemic control, and to
reduce the mortality and risk of microvascular and
macrovascular complications (3). The current
consensus algorithms for medical management of type

2 DM recommend a combination of lifestyle
intervention and metformin as initial therapy for type
2 DM (4), followed by other oral hypoglycemic agents
and insulin. Besides biguanides (metformin), other
antidiabetic agents include several groups of drugs, i.e.
sulfonylureas, glitinides, thiazolidinediones or
glitazones, α-glucosidase inhibitors (acarbose), GLP-1
analogues, dipeptidyl peptidase 4 inhibitors, and
amylin agonists (pramlintide). Therapeutic profile of
metformin has been evaluated for more than five
decades. Experimental and clinical studies have shed
new light on the multiple beneficial effects of this
drug, not only in the treatment of diabetes.
95
Diabetologia Croatica 39-3, 2010
Department of Internal Medicine, Čakovec County Hospital,
Čakovec, Croatia
Review
Received: July 22, 2010
Accepted: August 9, 2010
METFORMIN – MORE THAN ‘GOLD STANDARD’ IN THE
TREATMENT OF TYPE 2 DIABETES MELLITUS
Andreja Marić
Corresponding author: Andreja Marić, MD, Department of Internal
Medicine, Čakovec County Hospital, Ivana Gorana Kovačića 1E, HR-
40000 Čakovec, Croatia
E-mail:
DISCOVERY OF METFORMIN
The work of Dr Jean Sterne, a French clinician and
his colleagues led to the discovery of metformin as an

oral antidiabetic agent in the 1950s in Paris (5). The
first synthesis of metformin (dimethyl biguanide) is
attributed to Werner and Bell from Trinity College,
Dublin, Ireland, in 1922 (6), and was a basis for further
experimental and clinical studies on the potential
therapeutic application of biguanides, particularly
metformin. The other two biguanide agents,
phenformin and buformin, were soon withdrawn from
widespread clinical use due to their toxicity, especially
lactic acidosis. However, five decades were needed to
promote metformin from a minor product to the ‘gold
standard’ in the treatment of type 2 DM, with a wide
safety profile.
METFORMIN AND
ANTIHYPERGLYCEMIC ACTION
Metformin reduces blood glucose levels by
inhibiting hepatic glucose production and reducing
insulin resistance, particularly in liver and skeletal
muscle (7). The plasma insulin levels are unchanged or
reduced (8). Metformin decreases intestinal absorption
of glucose, and increases insulin sensitivity by
enhanced glucose uptake and utilization in peripheral
tissues. In vitro and in vivo studies have demonstrated
the effects of metformin on membrane-related events,
including plasma membrane fluidity, plasticity of
receptors and transporters (9); suppression of the
mitochondrial respiratory chain (10); increased
insulin-stimulated receptor phosphorylation and
tyrosine kinase activity (7); stimulation of
translocation of GLUT4 transporters to the plasma

membrane (11); and enzymatic effects on metabolic
pathways, e.g., LKB1 activation of AMP-activated
protein kinase – AMPK (12), which inhibits
gluconeogenesis and lipogenesis.
Metformin monotherapy will lower HbA
1c
levels by
approximately 1.5% (13), without causing
hypoglycemia. In combination with sulfonylureas,
HbA
1c
was decreased by 1.25% with glibenclamide,
0.75% with glipizide and 0.7% with glimepiride in
several studies. Glitazones added to metformin
decreased HbA
1c
from 8.1% to 6.8% (13-15). When
acarbose was added to metformin, HbA
1c
was reduced
by 0.8%-1.0% (16). A combination of bedtime insulin
and metformin was more effective in controlling
glycemia, with a significantly less weight gain
compared with bedtime insulin plus glibenclamide,
bedtime insulin plus metformin plus glibenclamide, or
morning and bedtime insulin (17). Metformin and the
GLP-agonists exenatide or liraglutide significantly
reduced HbA
1c
compared to placebo (18,19).

METFORMIN AND SAFETY PROFILE
Gastrointestinal side effects, i.e. diarrhea, nausea,
bloating and metallic taste in the palate are not
uncommon when treatment with metformin is started,
affecting 1%-30% of patients. Increasing the dose
gradually, most side affects may be diminished. There
is clear relationship between the dosage and effect of
metformin, so the most effective dosage of metformin
observed in studies (20) was 2000 mg/day. Increasing
the metformin dosage from 2000 to 3000 mg/day only
reduced fasting blood glucose levels by further 5%,
raising the incidence of gastrointestinal side effects.
The risk of hypoglycemia was low, almost the same as
in the placebo group (8). Lactic acidosis is the most
dangerous side effect, fortunately rare, with an
incidence of 0-0.084 cases/1000 patient years (21). To
minimize the risk of lactic acidosis, contraindications
should be observed, i.e. impaired renal function (limit
value of creatinine clearance 60 mL/min), severe liver
disease, pancreatitis, alcoholism, hypoxic states,
respiratory insufficiency, severe cardiac insufficiency
(NYHA III/IV), cardiovascular shock, metabolic
acidosis, diabetic ketoacidosis, consumptive diseases,
low serum level of vitamin B
12
, preoperative,
perioperative and postoperative states, radiological
procedures using contrast, advanced age, and calorie
restrictions (<1000 cal per day) (22).
96

A. Marić / METFORMIN – MORE THAN ‘GOLD STANDARD’ IN THE TREATMENT OF TYPE 2 DIABETES MELLITUS
METFORMIN AND BODY WEIGHT
While insulin secretagogues, thiazolidinediones and
insulin itself promote increased body weight in many
patients, treatment with metformin usually results in
no change in body weight or in modest weight loss,
and in combination with other agents it may mitigate
weight gain (8). A meta-analysis of nine trials of at
least 6-week duration found an average difference in
body weight of -4 kg for metformin versus a
sulfonylurea, unaffected by patient age (23). The
ADOPT (A Diabetes Progression Outcomes Trial)
study showed the mean increase in body weight at
study end in the rosiglitazone group relative to
metformin of 6.9 kg (95% CI 6.3 to 7.4%; P<0.001)
(24). A 26-week study in a comparable patient
population showed a reduction in body weight of 2.0
kg with metformin (P<0.05 versus baseline) compared
with an increase of 0.6 kg with rosiglitazone (not
significant versus baseline) (25). A 12-month study
reported a decrease in body weight of 2.5 kg with
metformin compared with an increase of 1.9 kg with
pioglitazone (26). The anorectic effect of metformin
may be at least partly attributable to the inhibiting
effect of DPP-4 (27). Adding metformin in patients
suboptimally controlled on insulin therapy compared
with intensification of the insulin dose by 20%
resulted in lower body weight, lower body mass index,
insulin dose and HbA
1c

at the end of the study in the
metformin arm (28). Modest weight loss with
metformin has also been observed in subjects with
impaired glucose tolerance enrolled in the Diabetes
Prevention Program (29) and in the Indian Diabetes
Prevention Program (30). Although a meta-analysis of
studies in patients with polycystic ovary syndrome
(PCOS) treated with metformin suggests no
significant effect of metformin on body weight
compared to placebo, some studies have reported a
mean weight loss (1.5-3.6 kg) during 8 months of
treatment with metformin in obese women with PCOS
(31).
METFORMIN AND LIPID PROFILE
A meta-analysis of 41 randomized, controlled
evaluations of metformin of at least 6-week duration
showed significant reductions in total cholesterol,
LDL cholesterol and triglycerides in patients
randomized to metformin relative to comparator
treatments (32); HDL-cholesterol was rarely improved
by metformin treatment. Some non-randomized
studies have demonstrated significant reductions in
free fatty acids following treatment with metformin
(33), while others did not (34). In nondiabetic persons
and those with impaired glucose tolerance randomized
in the Diabetes Prevention Program (35), the
metformin effect on lipid profile was modest and
generally smaller than the effect of the intensive
lifestyle intervention included in this trial. It suggests
that reductions in the risk of macrovascular endpoints

with metformin, showed in the UK Prospective
Diabetes Study (UKPDS) (8), is associated with other
mechanisms, not only the effects on lipids.
METFORMIN AND CARDIOVASCULAR
EFFECTS
Patients with type 2 DM have a two- to fourfold risk
of heart disease and stroke found in the general
population, with a reduction in life expectancy of five
to ten years (36). UKPDS (8) was the first randomized
trial demonstrating that metformin treatment was
associated with significant reductions compared with
diet in the risk of any endpoint related to diabetes (risk
reduction 32%; P=0.0023), myocardial infarction (risk
reduction 39%; P=0.01), all-cause mortality (risk
reduction 35%; P=0.011), and diabetes-related death
(risk reduction 42%; P=0.017). Reductions in the risk
of stroke, peripheral vascular disease and
microvascular endpoints did not achieve statistical
significance for metformin compared with diet.
Randomization to sulfonylurea/insulin was not
associated with significant reductions in any of the
clinical outcomes mentioned above (although
significant microvascular benefits were observed with
this treatment in a larger analysis of UKPDS 33) (8).
97
Diabetologia Croatica 39-3, 2010
A. Marić / METFORMIN – MORE THAN ‘GOLD STANDARD’ IN THE TREATMENT OF TYPE 2 DIABETES MELLITUS
Retrospective and prospective observational studies
showed a strong cardioprotective effect of metformin
in patients with a high prevalence of cardiovascular

disease, including patients with prior coronary heart
disease events, heart failure, or symptomatic angina
pectoris (37,38).
Besides the effects on the classic cardiometabolic
risk factors (dysglycemia, insulin resistance, obesity,
dyslipidemia and high blood pressure) observed in
type 2 DM patients and demonstrated in several
studies, metformin has other potential anti-
atherothrombotic actions. Treatment with metformin
improves endothelial function by decreasing
circulating levels of sVCAM-1 and E-selectin, which
are markers of endothelial activation (39); reduces
circulating levels of plasminogen activator inhibitor-1
(40); improves other hemostatic parameters,
decreasing Factor XIII activity and reducing the levels
of Factor VII, a powerful endogenous promoter of
coagulation (41). Metformin reduces circulating C-
reactive protein level (42); inhibits activation of the
pro-inflammatory nuclear transcription factor, NF-
kappaB, secondary to an increase in the activity of the
enzyme AMP-kinase (AMPK), which has been
proposed as a cellular mechanism for the anti-
inflammatory effects of metformin (43). Metformin
also decreases oxidative stress, inhibits lipid
peroxidation of LDL and HDL, and the production of
the superoxide free radical (O
2
-) in platelets (44).
Metformin may reduce the production of advanced
glycation endproducts (AGE) indirectly, by reduction

of hyperglycemia, and directly by an insulin-
independent mechanism (45). Experimental studies
suggest that metformin may inhibit the binding of
monocytes to cultured vascular cells, and
differentiation of monocytes into macrophages and
their transformation into foam cells (46).
METFORMIN AND POLYCYSTIC OVARY
SYNDROME
Polycystic ovary syndrome (PCOS) is the most
common endocrine disease in women, affecting 5%-
10% of those in reproductive age (47). PCOS includes
several cardiometabolic risk factors associated with
insulin resistance, such as abdominal obesity,
hypertension, hyperinsulinemia, low HDL cholesterol,
hypertriglyceridemia and impaired fibrinolysis,
resembling the metabolic syndrome (48-50). A meta-
analysis of studies comparing metformin with placebo
or no treatment in women with PCOS showed that
metformin significantly reduced fasting plasma
glucose, systolic and diastolic blood pressure, LDL
cholesterol and fasting insulin, although total
cholesterol, HDL cholesterol or triglycerides did not
change significantly (51). A Cochrane meta-analysis
of trials that compared metformin with the oral
contraceptive pill showed significant improvement in
fasting insulin and triglycerides with metformin, but
no overall improvement in fasting glucose (52).
Besides, both meta-analyses revealed that metformin
significantly reduced serum testosterone,
androstenedione and dehydroepiandrostenedione

sulfate. Many guidelines suggest the use of metformin
as initial pharmacological therapy for most women
with PCOS, particularly when overweight or obese
(53), or in addition to clomifene in clomifene-resistant
anovulatory women (54). Although metformin crosses
the placenta, observational studies to date suggest that
metformin does not adversely affect fetal or neonatal
development (55-57). Metformin used during
pregnancy decreased the risk of gestational diabetes in
women with PCOS (58,59).
The mechanisms of metformin effects in PCOS
pertain to its central and peripheral action. At the
central level, the possible effect is reduction in serum
LH level. At the peripheral level, metformin decreases
hepatic gluconeogenesis, increases the synthesis of sex
hormone-binding globulin (SHBG), consecutively
decreasing free androgen levels. Metformin also
increases insulin sensitivity in peripheral tissues,
reduces free fatty acid oxidation, and reduces ovarian
and adrenal secretion of androgens. Pleiotropic actions
of metformin are mediated by the AMPK pathway.
Experimental data show the effect of metformin on the
expression of some genes involved in glucose
metabolism (60).
98
A. Marić / METFORMIN – MORE THAN ‘GOLD STANDARD’ IN THE TREATMENT OF TYPE 2 DIABETES MELLITUS
METFORMIN AND OTHER POTENTIAL
FUTURE USES
Nonalcoholic fatty liver disease (NAFLD),
nonalcoholic steatohepatitis (NASH) and

lipodystrophy syndrome associated with highly-active
antiretroviral therapy (HAART) for human
immunodeficiency virus (HIV) are associated with
insulin resistance and cardiovascular and metabolic
risk factors.
The management of NASH includes lifestyle
intervention with gradual weight loss, fibrates to
control hypertriglyceridemia, gastrointestinal lipase
inhibitor, orlistat, and agents that improve insulin
sensitivity (metformin and thiazolidinedione) (61). In
randomized studies comparing metformin plus diet
versus diet, plasma glucose, body mass index, plasma
insulin and plasma cholesterol improved significantly
in both groups, while plasma C-peptide and insulin
resistance index improved significantly only on
metformin plus diet treatment (62). Another study
compared metformin with vitamin E in patients with
NAFLD and found significant improvement in
metabolic parameters in the metformin group (63).
In patients with HIV-associated lipodystrophy,
metformin significantly reduces hyperinsulinemia,
body weight and diastolic blood pressure (64), and has
superior effects on lipids and endothelial function
compared to diet, placebo and rosiglitazone, although
a combination of treatments is more effective than
metformin alone (65).
METFORMIN AND ITS POTENTIAL FOR
THE TREATMENT OF NEOPLASTIC
DISEASE
Experimental studies suggest a role for the enzyme

AMPK among the important molecular mechanisms
responsible for the beneficial metabolic actions of
metformin. Metformin induces tumor suppressor
LKB1, which is an upstream regulator of AMPK,
supporting the hypothesis on the potential anti-
neoplastic effect of metformin. Activating AMPK,
metformin negatively regulates mTORC1
(mammalian target of rapamycin), which is associated
with a number of human pathologies (66). In vitro
studies in human breast cancer cells showed that
metformin inhibited cell proliferation, reduced colony
formation, and caused partial cell cycle arrest (67).
Metformin was also a potent inhibitor of cell
proliferation in endometrial cancer lines (68). A
combination of metformin and 2-deoxyglucose
induced p53-dependent apoptosis in prostate cancer
cells (69). Two large observational studies report on a
decreased incidence of neoplastic disease in type 2
DM patients treated with metformin, compared with
sulfonylurea and insulin (70,71). UKPDS revealed that
metformin treatment reduced the risk of death from
cancer by 29% relative to diet. Other studies also
observed significantly lower cancer mortality rate in
patients treated with metformin versus patients not
receiving metformin (72).
CONCLUSION
Distinctive positive antihyperglycemic and
metabolic effects of metformin have been observed
and demonstrated in numerous trials and meta-
analyses. The potential metformin action in other

diseases such as PCOS, NASH, HIV lipodystrophy
and neoplasms has been suggested in several studies.
Metformin is not currently indicated for the
management of these conditions. Thus, additional
prospective randomized studies are needed for
approval of indications for the treatment and
prevention of the mentioned diseases.
99
Diabetologia Croatica 39-3, 2010
A. Marić / METFORMIN – MORE THAN ‘GOLD STANDARD’ IN THE TREATMENT OF TYPE 2 DIABETES MELLITUS
REFERENCES
1. Metformin. The gold standard. A scientific
handbook. Bailey CJ, Campbell IW, Chan JCN,
Davidson JA, Howlett HCS, Ritz P, editors.
England: John Wiley & Sons, Ltd., 2007; pp 1-2.
2. LeRoith D. Beta-cell dysfunction and insulin
resistance in type 2 diabetes: role of metabolic and
genetic abnormalities. Am J Med 2002;113:3S-
11S.
3. Hemmingsen B, Lund SS, Wetterslev J, Vaag A.
Oral hypoglycaemic agents, insulin resistance and
cardiovascular disease in patients with type 2
diabetes. Eur J Endocrinol 2009;161:1-9.
4. Nathan DM, Buse JB, Davidson MB, Ferrannini E,
Holman RR, Sherwin R, et al. Medical
management of hyperglycemia in type 2 diabetes:
a consensus algorithm for the initiation and
adjustment of therapy: a consensus statement of
the American Diabetes Association and the
European Association for the Study of Diabetes.

Diabetes Care 2009;32:193-203.
5. Sterne J. Treatment of diabetes mellitus with N,N-
dimethylguanylguanidine (LA. 6023, glucophage).
Therapie 1959;14:625-630.
6. Werner A, Bell J. CCX1V. The preparation of
methylguanidine and of ââ-dimethylguanidine by
the interaction of dicyanodiamide and
methylammonium and dimethylammonium
chlorides respectively. J Chem Soc Transact
1922;121:1790-1794.
7. Giannarelli R, Aragona M, Coppelli A, Del Prato
S. Reducing insulin resistance with metformin: the
evidence today. Diabetes Metab 2003;29:6S28-
6S35.
8. UK Prospective Diabetes study Group. Effect of
intensive blood glucose control with metformin on
complications in overweight patients with type 2
diabetes (UKPDS 34). Lancet 1998;352:854-865.
9. Muller S, Denet S, Candiloros H, Barrois R,
Wiernsperger N, Donner M, et al. Action of
metformin on erythrocyte membrane fluidity in
vitro and in vivo. Eur J Pharmacol 1997;337:103-
110.
10. Detaille D, Guigas B, Leverve X, Wiernsperger N,
Devos P. Obligatory role of membrane events in
the regulatory effect of metformin on the
respiratory chain function. Biochem Pharmacol
2002;63:1259-1272.
11. Matthaei S, Reibold JP, Hamann A, Benecke H,
Haring HU, Greten H, et al. In vivo metformin

treatment ameliorates insulin resistance: evidence
for potentiation of insulin-induced translocation
and increased functional activity of glucose
transporters in obese (fa/fa) Zucker rat adipocytes.
Endocrinology 1993;133:304-311.
12. Musi N, Hirsman MF, Nygren J, Svanfeldt M,
Bavenholm P, Rooyackers O, et al. Metformin
increases AMP-activated protein kinase activity in
skeletal muscle of subjects with type 2 diabetes.
Diabetes 2002;51:2074-2081.
13. DeFronzo R, Goodman A. Efficacy of metformin
in patients with non-insulin-dependent diabetes
mellitus. The Multicenter Metformin Study Group.
N Engl J Med 1995;333:541-549.
14. Blonde L, Rosenstock J, Mooradian AD, Piper BA,
Henry D. Glyburide/metformin combination
product is safe and efficacious in patients with type
2 diabetes failing sulphonylurea therapy. Diabetes
Obes Metab 2002;4:368-375.
15. Goldstein BJ, Pans M, Rubin CJ. Muticenter,
randomized, double-masked, parallel-group
assessment of simultaneous glipizide/metformin as
second-line pharmacologic treatment for patients
with type 2 diabetes mellitus that is inadequately
controlled by a sulfonylurea. Clin Ther
2003;25:890-903.
100
A. Marić / METFORMIN – MORE THAN ‘GOLD STANDARD’ IN THE TREATMENT OF TYPE 2 DIABETES MELLITUS
16. Halimi S, Le Berre MA, Grange V. Efficacy and
safety of acarbose add-on therapy in the treatment

of overweight patients with type 2 diabetes
inadequately controlled with metformin: a double-
blind, placebo controlled study. Diab Res Clin
Pract 2000;50:49-56.
17. Yki-Jarvinen H, Ryysy L, Nikkila K, Tulokas T,
Vanamo R, Heikkila M. Comparison of bedtime
insulin regimens in patients with type 2 diabetes
mellitus. Ann Int Med 1999;130:389-396.
18. Fineman MS, Bicsak TA, Shen LZ, Taylor K,
Geines E, Varns A, et al. Effect on glycemic
control of exenatide (synthetic exendin-4) additive
to existing metformin and/or sulfonylurea
treatment in patients with type 2 diabetes. Diabetes
Care 2003;26:2370-2377.
19. Feinglos MN, Saad MF, Pi-Sunyer FX, An B,
Santiago O. Effects of liraglutide (NN2211), a
long-acting GLP-2 analogue, on glycaemic control
and body weight in subjects with type 2 diabetes.
Diabet Med 2005;22:1016-1023.
20. Garber A, Duncan T, Goodman A, Mills D, Rohlf
J. Efficacy of metformin in type-II diabetes: results
of a double-blind, placebo controlled, dose-
response trial. Am J Med 1997;102:491-497.
21. Chan NN, Brain HP, Feher MD. Metformin-
associated lactic acidosis: a rare or very rare
clinical entity? Diabetes Care 1998;21:1659-1663.
22. Matthaei S, Bierwirth R, Fritsche A, Gallwitz B,
Haring HU, Joost HG. Medical
antihyperglycaemic treatment of diabetes mellitus
type 2. Update of the evidence-based guideline of

the German Diabetes Association. 2008; pp 1-75.
23. Campbell IW, Howlett HC. Worldwide experience
of metformin as an effective glucose-lowering
agent: a meta-analysis. Diabet Metab Rev
1995;11:S57-S62.
24. Kahn SE, Haffner SM, Heise MA, Herman WH,
Holman RR, Kravitz BG, et al. Glycemic
durability of rosiglitazone, metformin, or
glyburide monotherapy. N Engl J Med
2006;355:2427-2443.
25. Hallsten K, Virtanen KA, Lonnqvist F, Sipila H,
Oksanen A, Viljanen T, et al. Rosiglitazone but not
metformin enhances insulin- and exercise-
stimulated skeletal muscle glucose uptake in
patients with newly diagnosed type 2 diabetes.
Diabetes 2002;51:3479-3485.
26. Schernthaner G, Matthews DR, Charbonnel B,
Hanefeld M, Brunetti P. Efficacy and safety of
pioglitazone versus metformin in patients with
type 2 diabetes mellitus: a double-blind,
randomized trial. J Clin Endocrinol Metab
2004;89:6068-6076.
27. Lindsay JR, Duffy NA, McKillop AM, Ardill J,
O'Harte FP, Flatt PR, et al. Inhibition of dipeptidyl
peptidase IV activity by oral metformin in type 2
diabetes. Diabet Med 2005;22:654-657.
28. Relimpio F, Pumar A, Losada F, Mangas MA,
Acosta D, Astorga R. Adding metformin versus
insulin dose increase in insulin-treated but poorly
controlled type 2 diabetes mellitus: an open-label

randomized trial. Diabet Med 1998;15:997-1002.
29. Knowler WC, Barrett-Connor E, Fowler SE,
Hamman RF, Lachin JM, Walker EA, et al.
Reduction in the incidence of type 2 diabetes with
lifestyle intervention of metformin. N Engl J Med
2002;346:393-403.
30. Ramachandran A, Snehalatha C, Mary S, Mukesh
B, Bhaskar AD, Vijay V, et al. The Indian Diabetes
Prevention Programme shows that lifestyle
modification and metformin prevent type 2
diabetes in Asian Indian subjects with impaired
glucose tolerance (IDDP-1). Diabetologia
2006;49:289-297.
31. Harborne LR, Sattar N, Norman JE, Fleming R.
Metformin and weight loss in obese women with
polycystic ovary syndrome: comparison of doses. J
Clin Endocrinol Metab 2005;90:4593-4598.
32. Wulffele MG, Kooy A, de Zeeuw D, Stehouwer
CD, Gansevoort RT. The effect of metformin on
blood pressure, plasma cholesterol and
triglycerides in type 2 diabetes mellitus: a
systematic review. J Int Med 2004;256:1-14.
101
Diabetologia Croatica 39-3, 2010
A. Marić / METFORMIN – MORE THAN ‘GOLD STANDARD’ IN THE TREATMENT OF TYPE 2 DIABETES MELLITUS
33. Manzella D, Grella R, Esposito K, Giugliano D,
Barbagallo M, Paliosso G. Blood pressure and
cardiac autonomic nervous system in obese type 2
diabetic patients: effect of metformin
administration. Am J Hypert 2004;17:223-227.

34. Jung HS, Youn BS, Cho YM, Yu KY, Park HJ, Shin
CS, et al. The effects of rosiglitazone and
metformin on the plasma concentrations of resistin
in patients with type 2 diabetes mellitus.
Metabolism 2005;6:8-15.
35. Diabetes Prevention Program Research Group.
Reduction in the incidence of type 2 diabetes with
lifestyle intervention of metformin. N Engl J Med
2002;346:393-403.
36. Holman R. Cardiovascular benefits. In:
Metformin. The gold standard. A scientific
handbook. Bailey CJ, Campbell IW, Chan JCN,
Davidson JA, Howlett HCS, Ritz P, editors.
England: John Wiley & Sons, Ltd., 2007; p 115.
37. Eurich DT, Majumdar SR, McAlister FA, Tsuyuki
RT, Johnson JA. Improved clinical outcomes
associated with metformin in patients with
diabetes and heart failure. Diabetes Care
2005;28:2345-2351.
38. Montaguti U, Celin D, Ceredi C, Descovitch GC.
Efficacy of the long-term administration of
metformin in hyperlipidaemic patients. Res Clin
Forums 1979;1:95-103.
39. De Jager J, Kooy A, Lehert P, Bets D, Wulffele
MG, Teerlink T, et al. Effects of short-term
treatment with metformin on markers of
endothelial function and inflammatory activity in
type 2 diabetes mellitus: a randomized, placebo-
controlled trial. J Int Med 2005;257:100-109.
40. Gin H, Roudat MF, Vergnot V, Baillet L, Rigalleau

V. Effect of metformin on fibrinolytic parameters
in insulin-treated, type 2 diabetic patients.
Diabetes Metab 2003;29:505-508.
41. Grant PJ. Beneficial effects of metformin on
haemostasis and vascular function in man.
Diabetes Metab 2003;29:6S44-6S52.
42. Carter AM, Bennett CE, Bostock JA, Grant PJ.
Metformin reduces C-reactive protein but not
complement factor C3 in overweight patients with
type 2 diabetes mellitus. Diabetes Med
2005;22:1282-1284.
43. Hattori Y, Suzuki K, Hattori S, Kasai K.
Metformin inhibits cytokine-induced nuclear
factor kappaB activation via AMP-activated
protein kinase activation in vascular endothelial
cells. Hypertension 2006;47:1813-1822.
44. Gargiulo P, Caccese D, Pignatelli P, Brufani C, De
Vito F, Marino R, et al. Metformin decreases
platelet superoxide anion production in diabetic
patients. Diabetes Metab Res Rev 2002;18:156-
159.
45. Beisswenger P, Ruggiero-Lopez, D. Metformin
inhibition of glycation processes. Diabetes Metab
2003;29:6S95-6S103.
46. Mamputu JC, Wiernsperger NF, Reiner G.
Antiatherogenic properties of metformin: the
experimental evidence. Diabetes Metab
2003;29:6S71-6S76.
47. Azziz R, Woods KS, Reyna R, Key TJ,
Knochenhauer ES, Yildiz BO. The prevalence and

features of the polycystic ovary syndrome in an
unselected population. J Clin Endocrin Metab
2004;89:2745-2749.
48. Dunaif A, Segal KR, Futterweit W, Dobrjansky A.
Profound peripheral insulin resistance,
independent of obesity, in polycystic ovary
syndrome. Diabetes 1989;38:1165-1174.
49. Dokras A, Bochner M, Hollinrake E, Markham S,
Vanvoorhis B, Jagasia DH. Screening women with
polycystic ovary syndrome for metabolic
syndrome. Obstet Gynecol 2005;106:131-137.
50. Rotterdam ESHRE/ASRM Sponsored PCOS
Consensus Workshop Group. Revised 2003
consensus on diagnostic criteria and long-term
health risks related to polycystic ovary syndrome.
Fertil Steril 2004;81:19-25.
102
A. Marić / METFORMIN – MORE THAN ‘GOLD STANDARD’ IN THE TREATMENT OF TYPE 2 DIABETES MELLITUS
51. Lord JM, Flight IH, Norman RJ. Insulin-
sensitising drugs (metformin, troglitazone,
rosiglitazone, pioglitazone, D-chiro-inositol) for
polycystic ovary syndrome. Cochrane Database
Syst Rev 2003;(3):CD003053.
52. Costello MF, Shrestha B, Eden J, Johnson NP,
Sjoblom P. Metformin versus oral contraceptive
pill in polycystic ovary syndrome: a Cochrane
review. Hum Reprod 2007;22:1200-1209.
53. American Association of Clinical Endocrino-
logists. Position statement on metabolic and
cardiovascular consequences of polycystic ovary

syndrome. Available from: />pub/pdf/guidelines/PCOSpositionstatement.pdf.
54. National Institute for Health and Clinical
Excellence. Guideline CG11 Fertility. Available
from: />guidance/pdf/English.
55. Glueck CJ, Wang P, Goldenberg N, Sieve-Smith L.
Pregnancy outcomes among women with
polycystic ovary syndrome treated with
metformin. Hum Reprod 2002;17:2858-2864.
56. Glueck CJ, Goldenberg N, Pranikoff J, Loftspring
M, Sieve L, Wang P. Height, weight, and motor-
social development during the first 18 months of
life in 126 infants born to 109 mothers with
polycystic ovary syndrome who conceived on and
continued metformin through pregnancy. Hum
Reprod 2004;19:1323-1330.
57. Gilbert C, Valois M, Koren G. Pregnancy outcome
after first-trimester exposure to metformin: a meta-
analysis. Fertil Steril 2006;86:658-663.
58. Norman RJ, Wang JX, Hague W. Should we
continue or stop insulin sensitising drugs during
pregnancy? Curr Opin Obstet Gynecol
2004;16:245-250.
59. Glueck CJ, Goldenberg N, Wang P, Loftspring M,
Sherman A. Metformin during pregnancy reduces
insulin, insulin resistance, insulin secretion,
weight, testosterone and development of
gestational diabetes: prospective longitudinal
assessment of women with polycystic ovary
syndrome from preconception throughout
pregnancy. Hum Reprod 2004;19:510-521.

60. Palomba S, Falbo A, Zullo F, Orio F Jr. Evidence-
based and potential benefits of metformin in the
polycystic ovary syndrome: a comprehensive
review. Endocr Rev 2009;30(1):1-50.
61. Medina J, Fernandez-Salazar LI, Garcia-Buey L,
Moreno-Otero R. Approach to the pathogenesis
and treatment of nonalcoholic steatohepatitis.
Diabetes Care 2004;27:2057-2066.
62. Uygun A, Kadayifci A, Isik AT, Ozgurtas T, Deveci
S, Tuzun A, et al. Metformin in the treatment of
patients with non-alcoholic steatohepatitis.
Aliment Pharmacol Ther 2004;19:537-544.
63. Bugianesi E, Gentilcore E, Manini R, Natale S,
Vanni E, Villanova N, et al. A randomized
controlled trial of metformin versus vitamin E or
prescriptive diet in nonalcoholic fatty liver disease.
Am J Gastroenterol 2005;100:1082-1090.
64. Hadigan C, Corcoran C, Basgoz N, Davis B, Sax P,
Grinspoon S. Metformin in the treatment of HIV
lipodystrophy syndrome: a randomized controlled
trial. JAMA 2000;284:472-477.
65. Van Wijk JP, de Koning EJ, Cabezas MC, op't
Roodt J, Joven J, Rabelink TJ, et al. Comparison of
rosiglitazone and metformin for treating HIV
lipodystrophy: a randomized trial. Ann Intern Med
2005;143:337-346.
66. Kalender A, Selvaraj A, Kim SY, Gulati P, Brule S,
Viollet B, et al. Metformin, independent of AMPK,
inhibits mTORC1 in a rag GTPase-dependent
manner. Cell Metab 2010;11(5):390-401.

67. Alimova IN, Liu B, Fan Z, Edgerton SM, Dillon T,
Lind SE, et al. Metformin inhibits breast cancer
cell growth, colony formation and induces cell
cycle arrest in vitro. Cell Cycle 2009;8:909-915.
103
Diabetologia Croatica 39-3, 2010
A. Marić / METFORMIN – MORE THAN ‘GOLD STANDARD’ IN THE TREATMENT OF TYPE 2 DIABETES MELLITUS
68. Cantrell LA, Zhou C, Mendivil A, Malloy KM,
Gehrig PA, Bae-Jump VL. Metformin is a potent
inhibitor of endometrial cancer cell proliferation –
implications for a novel treatment strategy.
Gynecol Oncol 2010;116(1):92-98.
69. Ben Sahra I, Laureni K, Giuliano S, Larbret F,
Ponzio G, Guonon P, et al. Targeting cancer cell
metabolism: the combination of metformin and 2-
deoxyglucose induces p53-dependent apoptosis in
prostate cancer cells. Cancer Res
2010;70(6):2465-2475.
70. Evans JM, Donnelly LA, Emslie-Smith AM,
Alessi DR, Morris AD. Metformin and reduced
risk of cancer in diabetic patients. BMJ
2005;330:1304-1305.
71. Bowker SL, Majumdar SR, Veugelers P, Johnson
JA. Increased cancer-related mortality for patients
with type 2 diabetes who use sulfonylureas or
insulin. Diabetes Care 2006;29:254-258.
72. Landman GW, Kleefstra N, van Hateren KJ,
Groenier KH, Gans RO, Bilo HJ. Metformin
associated with lower cancer mortality in type 2
diabetes. ZODIAC-16.

104
A. Marić / METFORMIN – MORE THAN ‘GOLD STANDARD’ IN THE TREATMENT OF TYPE 2 DIABETES MELLITUS