Beruflich Dokumente
Kultur Dokumente
96
A. Marić / METFORMIN – MORE THAN ‘GOLD STANDARD’ IN THE TREATMENT OF TYPE 2 DIABETES MELLITUS
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).
98
A. Marić / METFORMIN – MORE THAN ‘GOLD STANDARD’ IN THE TREATMENT OF TYPE 2 DIABETES MELLITUS
REFERENCES
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.
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.
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.
104