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Department of Internal Medicine, Čakovec County Hospital, Review Čakovec, Croatia

Received: July 22, 2010


Accepted: August 9, 2010

METFORMIN – MORE THAN ‘GOLD STANDARD’ IN THE


TREATMENT OF TYPE 2 DIABETES MELLITUS
Andreja Marić

Key words: diabetes mellitus, metformin, polycystic INTRODUCTION


ovary, nonalcoholic steatohepatitis,
The prevalence of type 2 diabetes mellitus (DM) is
HIV lipodystrophy, neoplasms
increasing rapidly worldwide, with a prediction of
more than 380 million people to be affected by 2025
SUMMARY (1). Insulin resistance in peripheral tissues in
combination with relatively impaired insulin secretion is
The primary aim of type 2 diabetes mellitus essential in the pathogenesis of the disease, leading to
treatment is to achieve and maintain good glycemic hyperglycemia and compensatory hyperinsulinemia
control, and to minimize the mortality and risk of (2). The primary goal of type 2 DM treatment is to
microvascular and macrovascular complications. achieve and maintain good glycemic control, and to
reduce the mortality and risk of microvascular and
Current algorithms for medical management of type 2
macrovascular complications (3). The current
diabetes mellitus recommend a combination of consensus algorithms for medical management of
lifestyle intervention and metformin as initial therapy type 2 DM recommend a combination of lifestyle
and ‘gold standard’ treatment. Numerous studies intervention and metformin as initial therapy for type
2 DM (4), followed by other oral hypoglycemic
suggest positive antihyperglycemic and metabolic
agents and insulin. Besides biguanides (metformin),
effects of metformin, with a wide safety profile. There other antidiabetic agents include several groups of
is an increasing evidence for the potential efficacy of drugs, i.e. sulfonylureas, glitinides, thiazolidinediones
this drug in other diseases such as polycystic ovary or glitazones, α-glucosidase inhibitors (acarbose),
GLP-1 analogues, dipeptidyl peptidase 4 inhibitors,
syndrome, nonalcoholic steatohepatitis, HIV
and amylin agonists (pramlintide). Therapeutic
lipodystrophy, and neoplasms. profile of metformin has been evaluated for more than
Corresponding author: Andreja Marić, MD, Department of Internal five decades. Experimental and clinical studies have
Medicine, Čakovec County Hospital, Ivana Gorana Kovačića 1E, HR-
40000 Čakovec, Croatia
shed new light on the multiple beneficial effects of
E-mail: andreja.maric@hi.htnet.hr this drug, not only in the treatment of diabetes.

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DISCOVERY OF METFORMIN several studies. Glitazones added to metformin


decreased HbA1c from 8.1% to 6.8% (13-15). When
The work of Dr Jean Sterne, a French clinician and
his colleagues led to the discovery of metformin as an acarbose was added to metformin, HbA1c was reduced
oral antidiabetic agent in the 1950s in Paris (5). The by 0.8%-1.0% (16). A combination of bedtime insulin
first synthesis of metformin (dimethyl biguanide) is and metformin was more effective in controlling
attributed to Werner and Bell from Trinity College, glycemia, with a significantly less weight gain compared
Dublin, Ireland, in 1922 (6), and was a basis for with bedtime insulin plus glibenclamide, bedtime insulin
further experimental and clinical studies on the plus metformin plus glibenclamide, or morning and
potential therapeutic application of biguanides, bedtime insulin (17). Metformin and the GLP-agonists
particularly metformin. The other two biguanide
exenatide or liraglutide significantly reduced HbA1c
agents, phenformin and buformin, were soon
withdrawn from widespread clinical use due to their compared to placebo (18,19).
toxicity, especially lactic acidosis. However, five
decades were needed to promote metformin from a METFORMIN AND SAFETY PROFILE
minor product to the ‘gold standard’ in the treatment
of type 2 DM, with a wide safety profile.
Gastrointestinal side effects, i.e. diarrhea, nausea,
bloating and metallic taste in the palate are not
METFORMIN AND uncommon when treatment with metformin is started,
ANTIHYPERGLYCEMIC ACTION affecting 1%-30% of patients. Increasing the dose
gradually, most side affects may be diminished. There is
Metformin reduces blood glucose levels by
clear relationship between the dosage and effect of
inhibiting hepatic glucose production and reducing
metformin, so the most effective dosage of metformin
insulin resistance, particularly in liver and skeletal
muscle (7). The plasma insulin levels are unchanged observed in studies (20) was 2000 mg/day. Increasing
or reduced (8). Metformin decreases intestinal the metformin dosage from 2000 to 3000 mg/day only
absorption of glucose, and increases insulin reduced fasting blood glucose levels by further 5%,
sensitivity by enhanced glucose uptake and utilization raising the incidence of gastrointestinal side effects. The
in peripheral tissues. In vitro and in vivo studies have risk of hypoglycemia was low, almost the same as in the
demonstrated the effects of metformin on membrane-
placebo group (8). Lactic acidosis is the most dangerous
related events, including plasma membrane fluidity,
side effect, fortunately rare, with an incidence of 0-0.084
plasticity of receptors and transporters (9);
suppression of the mitochondrial respiratory chain cases/1000 patient years (21). To minimize the risk of
(10); increased insulin-stimulated receptor lactic acidosis, contraindications should be observed, i.e.
phosphorylation and tyrosine kinase activity (7); impaired renal function (limit value of creatinine
stimulation of translocation of GLUT4 transporters to clearance 60 mL/min), severe liver disease, pancreatitis,
the plasma membrane (11); and enzymatic effects on alcoholism, hypoxic states, respiratory insufficiency,
metabolic pathways, e.g., LKB1 activation of AMP- severe cardiac insufficiency (NYHA III/IV),
activated protein kinase – AMPK (12), which inhibits
cardiovascular shock, metabolic acidosis, diabetic
gluconeogenesis and lipogenesis.
ketoacidosis, consumptive diseases, low serum level of
Metformin monotherapy will lower HbA1c levels by vitamin B12, preoperative, perioperative and
approximately 1.5% (13), without causing
hypoglycemia. In combination with sulfonylureas, postoperative states, radiological procedures using
HbA1c was decreased by 1.25% with glibenclamide, contrast, advanced age, and calorie restrictions (<1000
0.75% with glipizide and 0.7% with glimepiride in cal per day) (22).

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

METFORMIN AND BODY WEIGHT METFORMIN AND LIPID PROFILE

While insulin secretagogues, thiazolidinediones and A meta-analysis of 41 randomized, controlled


insulin itself promote increased body weight in many evaluations of metformin of at least 6-week duration
patients, treatment with metformin usually results in showed significant reductions in total cholesterol, LDL
no change in body weight or in modest weight loss, cholesterol and triglycerides in patients randomized to
metformin relative to comparator treatments (32); HDL-
and in combination with other agents it may mitigate
cholesterol was rarely improved by metformin treatment.
weight gain (8). A meta-analysis of nine trials of at
Some non-randomized studies have demonstrated
least 6-week duration found an average difference in
significant reductions in free fatty acids following
body weight of -4 kg for metformin versus a treatment with metformin (33), while others did not (34).
sulfonylurea, unaffected by patient age (23). The In nondiabetic persons and those with impaired glucose
ADOPT (A Diabetes Progression Outcomes Trial) tolerance randomized in the Diabetes Prevention
study showed the mean increase in body weight at Program (35), the metformin effect on lipid profile was
study end in the rosiglitazone group relative to modest and generally smaller than the effect of the
metformin of 6.9 kg (95% CI 6.3 to 7.4%; P<0.001) intensive lifestyle intervention included in this trial. It
(24). A 26-week study in a comparable patient suggests that reductions in the risk of macrovascular
population showed a reduction in body weight of 2.0 endpoints with metformin, showed in the UK
kg with metformin (P<0.05 versus baseline) Prospective Diabetes Study (UKPDS) (8), is associated
compared with an increase of 0.6 kg with with other mechanisms, not only the effects on lipids.
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 METFORMIN AND
1.9 kg with pioglitazone (26). The anorectic effect of CARDIOVASCULAR EFFECTS
metformin may be at least partly attributable to the
inhibiting effect of DPP-4 (27). Adding metformin in Patients with type 2 DM have a two- to fourfold risk of
heart disease and stroke found in the general population,
patients suboptimally controlled on insulin therapy
with a reduction in life expectancy of five to ten years
compared with intensification of the insulin dose by
(36). UKPDS (8) was the first randomized trial
20% resulted in lower body weight, lower body mass
demonstrating that metformin treatment was associated
index, insulin dose and HbA1c at the end of the study with significant reductions compared with diet in the
in the metformin arm (28). Modest weight loss with risk of any endpoint related to diabetes (risk reduction
metformin has also been observed in subjects with 32%; P=0.0023), myocardial infarction (risk reduction
impaired glucose tolerance enrolled in the Diabetes 39%; P=0.01), all-cause mortality (risk reduction 35%;
Prevention Program (29) and in the Indian Diabetes P=0.011), and diabetes-related death (risk reduction
42%; P=0.017). Reductions in the risk of stroke,
Prevention Program (30). Although a meta-analysis
peripheral vascular disease and microvascular endpoints
of studies in patients with polycystic ovary syndrome
did not achieve statistical significance for metformin
(PCOS) treated with metformin suggests no
compared with diet. Randomization to
significant effect of metformin on body weight sulfonylurea/insulin was not associated with significant
compared to placebo, some studies have reported a reductions in any of the clinical outcomes mentioned
mean weight loss (1.5-3.6 kg) during 8 months of above (although significant microvascular benefits were
treatment with metformin in obese women with observed with this treatment in a larger analysis of
PCOS (31). UKPDS 33) (8).

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Retrospective and prospective observational studies insulin resistance, such as abdominal obesity,
showed a strong cardioprotective effect of metformin hypertension, hyperinsulinemia, low HDL
in patients with a high prevalence of cardiovascular cholesterol, hypertriglyceridemia and impaired
disease, including patients with prior coronary heart fibrinolysis, resembling the metabolic syndrome (48-
disease events, heart failure, or symptomatic angina
50). A meta-analysis of studies comparing metformin
pectoris (37,38).
with placebo or no treatment in women with PCOS
Besides the effects on the classic cardiometabolic showed that metformin significantly reduced fasting
risk factors (dysglycemia, insulin resistance, obesity, plasma glucose, systolic and diastolic blood pressure,
dyslipidemia and high blood pressure) observed in LDL cholesterol and fasting insulin, although total
type 2 DM patients and demonstrated in several cholesterol, HDL cholesterol or triglycerides did not
studies, metformin has other potential anti-
change significantly (51). A Cochrane meta-analysis
atherothrombotic actions. Treatment with metformin
of trials that compared metformin with the oral
improves endothelial function by decreasing
contraceptive pill showed significant improvement in
circulating levels of sVCAM-1 and E-selectin, which
are markers of endothelial activation (39); reduces fasting insulin and triglycerides with metformin, but
circulating levels of plasminogen activator inhibitor-1 no overall improvement in fasting glucose (52).
(40); improves other hemostatic parameters, Besides, both meta-analyses revealed that metformin
decreasing Factor XIII activity and reducing the significantly reduced serum testosterone,
levels of Factor VII, a powerful endogenous promoter androstenedione and dehydroepiandrostenedione
of coagulation (41). Metformin reduces circulating C- sulfate. Many guidelines suggest the use of
reactive protein level (42); inhibits activation of the metformin as initial pharmacological therapy for most
pro-inflammatory nuclear transcription factor, NF- women with PCOS, particularly when overweight or
kappaB, secondary to an increase in the activity of the
obese (53), or in addition to clomifene in clomifene-
enzyme AMP-kinase (AMPK), which has been
resistant anovulatory women (54). Although
proposed as a cellular mechanism for the anti-
inflammatory effects of metformin (43). Metformin metformin crosses the placenta, observational studies
also decreases oxidative stress, inhibits lipid to date suggest that metformin does not adversely
peroxidation of LDL and HDL, and the production of affect fetal or neonatal development (55-57).
the superoxide free radical (O2-) in platelets (44). Metformin used during pregnancy decreased the risk
of gestational diabetes in women with PCOS (58,59).
Metformin may reduce the production of advanced
glycation endproducts (AGE) indirectly, by reduction The mechanisms of metformin effects in PCOS
of hyperglycemia, and directly by an insulin-
pertain to its central and peripheral action. At the
independent mechanism (45). Experimental studies
central level, the possible effect is reduction in serum
suggest that metformin may inhibit the binding of
LH level. At the peripheral level, metformin
monocytes to cultured vascular cells, and
differentiation of monocytes into macrophages and decreases hepatic gluconeogenesis, increases the
their transformation into foam cells (46). synthesis of sex hormone-binding globulin (SHBG),
consecutively decreasing free androgen levels.
Metformin also increases insulin sensitivity in
METFORMIN AND POLYCYSTIC peripheral tissues, reduces free fatty acid oxidation,
OVARY SYNDROME
and reduces ovarian and adrenal secretion of
Polycystic ovary syndrome (PCOS) is the most
androgens. Pleiotropic actions of metformin are
common endocrine disease in women, affecting 5%- mediated by the AMPK pathway. Experimental data
10% of those in reproductive age (47). PCOS includes show the effect of metformin on the expression of
several cardiometabolic risk factors associated with some genes involved in glucose metabolism (60).

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

METFORMIN AND OTHER metformin. Metformin induces tumor suppressor


POTENTIAL FUTURE USES LKB1, which is an upstream regulator of AMPK,
supporting the hypothesis on the potential anti-
Nonalcoholic fatty liver disease (NAFLD), neoplastic effect of metformin. Activating AMPK,
nonalcoholic steatohepatitis (NASH) and
metformin negatively regulates mTORC1
lipodystrophy syndrome associated with highly-active
(mammalian target of rapamycin), which is associated
antiretroviral therapy (HAART) for human
immunodeficiency virus (HIV) are associated with with a number of human pathologies (66). In vitro
insulin resistance and cardiovascular and metabolic studies in human breast cancer cells showed that
risk factors. metformin inhibited cell proliferation, reduced colony
formation, and caused partial cell cycle arrest (67).
The management of NASH includes lifestyle
Metformin was also a potent inhibitor of cell
intervention with gradual weight loss, fibrates to
proliferation in endometrial cancer lines (68). A
control hypertriglyceridemia, gastrointestinal lipase
combination of metformin and 2-deoxyglucose
inhibitor, orlistat, and agents that improve insulin
sensitivity (metformin and thiazolidinedione) (61). In induced p53-dependent apoptosis in prostate cancer
randomized studies comparing metformin plus diet cells (69). Two large observational studies report on a
versus diet, plasma glucose, body mass index, plasma decreased incidence of neoplastic disease in type 2
insulin and plasma cholesterol improved significantly DM patients treated with metformin, compared with
in both groups, while plasma C-peptide and insulin sulfonylurea and insulin (70,71). UKPDS revealed
resistance index improved significantly only on that metformin treatment reduced the risk of death
metformin plus diet treatment (62). Another study from cancer by 29% relative to diet. Other studies
compared metformin with vitamin E in patients with also observed significantly lower cancer mortality
NAFLD and found significant improvement in rate in patients treated with metformin versus patients
metabolic parameters in the metformin group (63).
not receiving metformin (72).
In patients with HIV-associated lipodystrophy,
metformin significantly reduces hyperinsulinemia,
CONCLUSION
body weight and diastolic blood pressure (64), and
has superior effects on lipids and endothelial function
compared to diet, placebo and rosiglitazone, although Distinctive positive antihyperglycemic and
a combination of treatments is more effective than metabolic effects of metformin have been observed
metformin alone (65). and demonstrated in numerous trials and meta-
analyses. The potential metformin action in other
diseases such as PCOS, NASH, HIV lipodystrophy
METFORMIN AND ITS POTENTIAL and neoplasms has been suggested in several studies.
FOR THE TREATMENT OF
Metformin is not currently indicated for the
NEOPLASTIC DISEASE
management of these conditions. Thus, additional
Experimental studies suggest a role for the enzyme prospective randomized studies are needed for
AMPK among the important molecular mechanisms approval of indications for the treatment and
responsible for the beneficial metabolic actions of prevention of the mentioned diseases.

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REFERENCES

1. Metformin. The gold standard. A scientific 9. Muller S, Denet S, Candiloros H, Barrois R,


handbook. Bailey CJ, Campbell IW, Chan JCN, Wiernsperger N, Donner M, et al. Action of
Davidson JA, Howlett HCS, Ritz P, editors. metformin on erythrocyte membrane fluidity in
England: John Wiley & Sons, Ltd., 2007; pp 1-2. vitro and in vivo. Eur J Pharmacol 1997;337:103-
110.
2. LeRoith D. Beta-cell dysfunction and insulin
resistance in type 2 diabetes: role of metabolic and 10. Detaille D, Guigas B, Leverve X, Wiernsperger
genetic abnormalities. Am J Med 2002;113:3S- N, Devos P. Obligatory role of membrane events
11S. in the regulatory effect of metformin on the
respiratory chain function. Biochem Pharmacol
3. Hemmingsen B, Lund SS, Wetterslev J, Vaag A. 2002;63:1259-1272.
Oral hypoglycaemic agents, insulin resistance and
cardiovascular disease in patients with type 2 11. Matthaei S, Reibold JP, Hamann A, Benecke H,
diabetes. Eur J Endocrinol 2009;161:1-9. Haring HU, Greten H, et al. In vivo metformin
treatment ameliorates insulin resistance: evidence
4. Nathan DM, Buse JB, Davidson MB, Ferrannini for potentiation of insulin-induced translocation
E, Holman RR, Sherwin R, et al. Medical and increased functional activity of glucose
management of hyperglycemia in type 2 diabetes: transporters in obese (fa/fa) Zucker rat adipocytes.
a consensus algorithm for the initiation and Endocrinology 1993;133:304-311.
adjustment of therapy: a consensus statement of
the American Diabetes Association and the 12. Musi N, Hirsman MF, Nygren J, Svanfeldt M,
European Association for the Study of Diabetes. Bavenholm P, Rooyackers O, et al. Metformin
Diabetes Care 2009;32:193-203. increases AMP-activated protein kinase activity in
skeletal muscle of subjects with type 2 diabetes.
5. Sterne J. Treatment of diabetes mellitus with N,N- Diabetes 2002;51:2074-2081.
dimethylguanylguanidine (LA. 6023,
glucophage). Therapie 1959;14:625-630. 13. DeFronzo R, Goodman A. Efficacy of metformin
in patients with non-insulin-dependent diabetes
6. Werner A, Bell J. CCX1V. The preparation of mellitus. The Multicenter Metformin Study
methylguanidine and of ââ-dimethylguanidine by Group. N Engl J Med 1995;333:541-549.
the interaction of dicyanodiamide and
methylammonium and dimethylammonium 14. Blonde L, Rosenstock J, Mooradian AD, Piper
chlorides respectively. J Chem Soc Transact BA, Henry D. Glyburide/metformin combination
product is safe and efficacious in patients with
1922;121:1790-1794.
type 2 diabetes failing sulphonylurea therapy.
7. Giannarelli R, Aragona M, Coppelli A, Del Prato Diabetes Obes Metab 2002;4:368-375.
S. Reducing insulin resistance with metformin:
15. Goldstein BJ, Pans M, Rubin CJ. Muticenter,
the evidence today. Diabetes Metab
randomized, double-masked, parallel-group
2003;29:6S28-6S35.
assessment of simultaneous glipizide/metformin
8. UK Prospective Diabetes study Group. Effect of as second-line pharmacologic treatment for
intensive blood glucose control with metformin on patients with type 2 diabetes mellitus that is
complications in overweight patients with type 2 inadequately controlled by a sulfonylurea. Clin
diabetes (UKPDS 34). Lancet 1998;352:854-865. 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 25. Hallsten K, Virtanen KA, Lonnqvist F, Sipila H,
safety of acarbose add-on therapy in the treatment Oksanen A, Viljanen T, et al. Rosiglitazone but
of overweight patients with type 2 diabetes not metformin enhances insulin- and exercise-
inadequately controlled with metformin: a double- stimulated skeletal muscle glucose uptake in
blind, placebo controlled study. Diab Res Clin patients with newly diagnosed type 2 diabetes.
Pract 2000;50:49-56. Diabetes 2002;51:3479-3485.

17. Yki-Jarvinen H, Ryysy L, Nikkila K, Tulokas T, 26. Schernthaner G, Matthews DR, Charbonnel B,
Vanamo R, Heikkila M. Comparison of bedtime Hanefeld M, Brunetti P. Efficacy and safety of
insulin regimens in patients with type 2 diabetes pioglitazone versus metformin in patients with
mellitus. Ann Int Med 1999;130:389-396. type 2 diabetes mellitus: a double-blind,
randomized trial. J Clin Endocrinol Metab
18. Fineman MS, Bicsak TA, Shen LZ, Taylor K,
2004;89:6068-6076.
Geines E, Varns A, et al. Effect on glycemic
control of exenatide (synthetic exendin-4) additive 27. Lindsay JR, Duffy NA, McKillop AM, Ardill J,
to existing metformin and/or sulfonylurea O'Harte FP, Flatt PR, et al. Inhibition of
treatment in patients with type 2 diabetes. dipeptidyl peptidase IV activity by oral metformin
Diabetes Care 2003;26:2370-2377. in type 2 diabetes. Diabet Med 2005;22:654-657.
19. Feinglos MN, Saad MF, Pi-Sunyer FX, An B, 28. Relimpio F, Pumar A, Losada F, Mangas MA,
Santiago O. Effects of liraglutide (NN2211), a Acosta D, Astorga R. Adding metformin versus
long-acting GLP-2 analogue, on glycaemic insulin dose increase in insulin-treated but poorly
control and body weight in subjects with type 2 controlled type 2 diabetes mellitus: an open-label
diabetes. Diabet Med 2005;22:1016-1023. randomized trial. Diabet Med 1998;15:997-1002.
20. Garber A, Duncan T, Goodman A, Mills D, Rohlf 29. Knowler WC, Barrett-Connor E, Fowler SE,
J. Efficacy of metformin in type-II diabetes: Hamman RF, Lachin JM, Walker EA, et al.
results of a double-blind, placebo controlled, Reduction in the incidence of type 2 diabetes with
dose-response trial. Am J Med 1997;102:491-497. lifestyle intervention of metformin. N Engl J Med
21. Chan NN, Brain HP, Feher MD. Metformin- 2002;346:393-403.
associated lactic acidosis: a rare or very rare
30. Ramachandran A, Snehalatha C, Mary S, Mukesh
clinical entity? Diabetes Care 1998;21:1659-1663.
B, Bhaskar AD, Vijay V, et al. The Indian
22. Matthaei S, Bierwirth R, Fritsche A, Gallwitz B, Diabetes Prevention Programme shows that
Haring HU, Joost HG. Medical lifestyle modification and metformin prevent type
antihyperglycaemic treatment of diabetes mellitus 2 diabetes in Asian Indian subjects with impaired
type 2. Update of the evidence-based guideline of glucose tolerance (IDDP-1). Diabetologia
the German Diabetes Association. 2008; pp 1-75. 2006;49:289-297.

23. Campbell IW, Howlett HC. Worldwide 31. Harborne LR, Sattar N, Norman JE, Fleming R.
experience of metformin as an effective glucose- Metformin and weight loss in obese women with
lowering agent: a meta-analysis. Diabet Metab polycystic ovary syndrome: comparison of doses.
Rev 1995;11:S57-S62. J Clin Endocrinol Metab 2005;90:4593-4598.

24. Kahn SE, Haffner SM, Heise MA, Herman WH, 32. Wulffele MG, Kooy A, de Zeeuw D, Stehouwer
Holman RR, Kravitz BG, et al. Glycemic CD, Gansevoort RT. The effect of metformin on
durability of rosiglitazone, metformin, or blood pressure, plasma cholesterol and
glyburide monotherapy. N Engl J Med triglycerides in type 2 diabetes mellitus: a
2006;355:2427-2443. systematic review. J Int Med 2004;256:1-14.

Diabetologia Croatica 39-3, 2010 101


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

33. Manzella D, Grella R, Esposito K, Giugliano D, 42. Carter AM, Bennett CE, Bostock JA, Grant PJ.
Barbagallo M, Paliosso G. Blood pressure and Metformin reduces C-reactive protein but not
cardiac autonomic nervous system in obese type 2 complement factor C3 in overweight patients with
diabetic patients: effect of metformin type 2 diabetes mellitus. Diabetes Med
administration. Am J Hypert 2004;17:223-227. 2005;22:1282-1284.

34. Jung HS, Youn BS, Cho YM, Yu KY, Park HJ, 43. Hattori Y, Suzuki K, Hattori S, Kasai K.
Shin CS, et al. The effects of rosiglitazone and Metformin inhibits cytokine-induced nuclear
metformin on the plasma concentrations of factor kappaB activation via AMP-activated
resistin in patients with type 2 diabetes mellitus. protein kinase activation in vascular endothelial
Metabolism 2005;6:8-15. cells. Hypertension 2006;47:1813-1822.
35. Diabetes Prevention Program Research Group. 44. Gargiulo P, Caccese D, Pignatelli P, Brufani C,
Reduction in the incidence of type 2 diabetes with De Vito F, Marino R, et al. Metformin decreases
lifestyle intervention of metformin. N Engl J Med platelet superoxide anion production in diabetic
2002;346:393-403.
patients. Diabetes Metab Res Rev 2002;18:156-
36. Holman R. Cardiovascular benefits. In: 159.
Metformin. The gold standard. A scientific
45. Beisswenger P, Ruggiero-Lopez, D. Metformin
handbook. Bailey CJ, Campbell IW, Chan JCN,
inhibition of glycation processes. Diabetes Metab
Davidson JA, Howlett HCS, Ritz P, editors.
2003;29:6S95-6S103.
England: John Wiley & Sons, Ltd., 2007; p 115.
46. Mamputu JC, Wiernsperger NF, Reiner G.
37. Eurich DT, Majumdar SR, McAlister FA, Tsuyuki
Antiatherogenic properties of metformin: the
RT, Johnson JA. Improved clinical outcomes
experimental evidence. Diabetes Metab
associated with metformin in patients with
2003;29:6S71-6S76.
diabetes and heart failure. Diabetes Care
2005;28:2345-2351. 47. Azziz R, Woods KS, Reyna R, Key TJ,
Knochenhauer ES, Yildiz BO. The prevalence and
38. Montaguti U, Celin D, Ceredi C, Descovitch GC.
features of the polycystic ovary syndrome in an
Efficacy of the long-term administration of
unselected population. J Clin Endocrin Metab
metformin in hyperlipidaemic patients. Res Clin
Forums 1979;1:95-103. 2004;89:2745-2749.

39. De Jager J, Kooy A, Lehert P, Bets D, Wulffele 48. Dunaif A, Segal KR, Futterweit W, Dobrjansky
MG, Teerlink T, et al. Effects of short-term A. Profound peripheral insulin resistance,
treatment with metformin on markers of independent of obesity, in polycystic ovary
endothelial function and inflammatory activity in syndrome. Diabetes 1989;38:1165-1174.
type 2 diabetes mellitus: a randomized, placebo-
49. Dokras A, Bochner M, Hollinrake E, Markham S,
controlled trial. J Int Med 2005;257:100-109.
Vanvoorhis B, Jagasia DH. Screening women
40. Gin H, Roudat MF, Vergnot V, Baillet L, with polycystic ovary syndrome for metabolic
Rigalleau V. Effect of metformin on fibrinolytic syndrome. Obstet Gynecol 2005;106:131-137.
parameters in insulin-treated, type 2 diabetic
50. Rotterdam ESHRE/ASRM Sponsored PCOS
patients. Diabetes Metab 2003;29:505-508.
Consensus Workshop Group. Revised 2003
41. Grant PJ. Beneficial effects of metformin on consensus on diagnostic criteria and long-term
haemostasis and vascular function in man. health risks related to polycystic ovary syndrome.
Diabetes Metab 2003;29:6S44-6S52. 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- 59. Glueck CJ, Goldenberg N, Wang P, Loftspring M,
sensitising drugs (metformin, troglitazone, Sherman A. Metformin during pregnancy reduces
rosiglitazone, pioglitazone, D-chiro-inositol) for insulin, insulin resistance, insulin secretion,
weight, testosterone and development of
polycystic ovary syndrome. Cochrane Database
gestational diabetes: prospective longitudinal
Syst Rev 2003;(3):CD003053. assessment of women with polycystic ovary
syndrome from preconception throughout
52. Costello MF, Shrestha B, Eden J, Johnson NP,
pregnancy. Hum Reprod 2004;19:510-521.
Sjoblom P. Metformin versus oral contraceptive
pill in polycystic ovary syndrome: a Cochrane 60. Palomba S, Falbo A, Zullo F, Orio F Jr. Evidence-
review. Hum Reprod 2007;22:1200-1209. based and potential benefits of metformin in the
polycystic ovary syndrome: a comprehensive
53. American Association of Clinical Endocrino- review. Endocr Rev 2009;30(1):1-50.
logists. Position statement on metabolic and 61. Medina J, Fernandez-Salazar LI, Garcia-Buey L,
cardiovascular consequences of polycystic ovary Moreno-Otero R. Approach to the pathogenesis
syndrome. Available from: http://www.aace.com/ and treatment of nonalcoholic steatohepatitis.
pub/pdf/guidelines/PCOSpositionstatement.pdf. Diabetes Care 2004;27:2057-2066.

62. Uygun A, Kadayifci A, Isik AT, Ozgurtas T, Deveci


54. National Institute for Health and Clinical S, Tuzun A, et al. Metformin in the treatment of
Excellence. Guideline CG11 Fertility. Available patients with non-alcoholic steatohepatitis. Aliment
from: http://www.nice.org.uk/guidance/CG11/ Pharmacol Ther 2004;19:537-544.
guidance/pdf/English.
63. Bugianesi E, Gentilcore E, Manini R, Natale S,
55. Glueck CJ, Wang P, Goldenberg N, Sieve-Smith Vanni E, Villanova N, et al. A randomized
controlled trial of metformin versus vitamin E or
L. Pregnancy outcomes among women with
prescriptive diet in nonalcoholic fatty liver
polycystic ovary syndrome treated with disease. Am J Gastroenterol 2005;100:1082-1090.
metformin. Hum Reprod 2002;17:2858-2864.
64. Hadigan C, Corcoran C, Basgoz N, Davis B, Sax
56. Glueck CJ, Goldenberg N, Pranikoff J, Loftspring P, Grinspoon S. Metformin in the treatment of
M, Sieve L, Wang P. Height, weight, and motor- HIV lipodystrophy syndrome: a randomized
controlled trial. JAMA 2000;284:472-477.
social development during the first 18 months of
life in 126 infants born to 109 mothers with 65. Van Wijk JP, de Koning EJ, Cabezas MC, op't
polycystic ovary syndrome who conceived on and Roodt J, Joven J, Rabelink TJ, et al. Comparison
of rosiglitazone and metformin for treating HIV
continued metformin through pregnancy. Hum
lipodystrophy: a randomized trial. Ann Intern
Reprod 2004;19:1323-1330. Med 2005;143:337-346.
57. Gilbert C, Valois M, Koren G. Pregnancy outcome 66. Kalender A, Selvaraj A, Kim SY, Gulati P, Brule S,
after first-trimester exposure to metformin: a meta- Viollet B, et al. Metformin, independent of AMPK,
analysis. Fertil Steril 2006;86:658-663. inhibits mTORC1 in a rag GTPase-dependent
manner. Cell Metab 2010;11(5):390-401.
58. Norman RJ, Wang JX, Hague W. Should we
67. Alimova IN, Liu B, Fan Z, Edgerton SM, Dillon
continue or stop insulin sensitising drugs during T, Lind SE, et al. Metformin inhibits breast cancer
pregnancy? Curr Opin Obstet Gynecol cell growth, colony formation and induces cell
2004;16:245-250. cycle arrest in vitro. Cell Cycle 2009;8:909-915.

Diabetologia Croatica 39-3, 2010 103


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

68. Cantrell LA, Zhou C, Mendivil A, Malloy KM, 70. Evans JM, Donnelly LA, Emslie-Smith AM,
Gehrig PA, Bae-Jump VL. Metformin is a potent Alessi DR, Morris AD. Metformin and reduced
inhibitor of endometrial cancer cell proliferation – risk of cancer in diabetic patients. BMJ
implications for a novel treatment strategy. 2005;330:1304-1305.
Gynecol Oncol 2010;116(1):92-98.
71. Bowker SL, Majumdar SR, Veugelers P, Johnson
69. Ben Sahra I, Laureni K, Giuliano S, Larbret F, JA. Increased cancer-related mortality for patients
Ponzio G, Guonon P, et al. Targeting cancer cell with type 2 diabetes who use sulfonylureas or
metabolism: the combination of metformin and 2- insulin. Diabetes Care 2006;29:254-258.
deoxyglucose induces p53-dependent apoptosis in
prostate cancer cells. Cancer Res 72. Landman GW, Kleefstra N, van Hateren KJ,
Groenier KH, Gans RO, Bilo HJ. Metformin
2010;70(6):2465-2475.
associated with lower cancer mortality in type 2
diabetes. ZODIAC-16.

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