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Braz J Med Biol Res. 2007 Feb;40(2):229-35.

Are the beneficial cardiovascular effects of simvastatin and metformin also


associated with a hormone-dependent mechanism improving insulin
sensitivity?
Bulco C1, Giuffrida FM, Ribeiro-Filho FF, Ferreira SR.

Author information
Abstract
In addition to lipid-lowering and cardiovascular protective actions, statins may have beneficial effects on
insulin sensitivity. The objective of the present study was to evaluate the effect of simvastatin therapy on
insulin resistance and on leptin, adiponectin, and C-reactive protein (CRP) levels, as compared
to metformin, in overweight pre-diabetic subjects. Forty-one subjects with BMI >25 kg/m(2) and impaired
fasting glucose or impaired glucose tolerance were randomized to take simvastatin, 20 mg/day (N = 20)
or metformin, 1.7 g/day (N = 21) for 16 weeks. Blood samples for the determination of metabolic,
hormonal, and inflammatory parameters were obtained at baseline and after each treatment.
After metformin therapy, significant reductions in mean BMI and waist circumference were observed, and
after simvastatin treatment LDL and triglyceride levels were significantly reduced. Insulin resistance
determined by the homeostasis model assessment decreased only with metformin. Independently of the
type of medication, a significant decrease in CRP levels was detected from baseline to the end of the
study. CRP showed a mean reduction of 0.12 +/- 0.04 mg/dL (P = 0.002) over time. No change in leptin or
adiponectin levels was induced by any therapy. The data suggest that a low dose ofsimvastatin does not
affect insulin resistance in overweight pre-diabetic subjects and has no effect on leptin or adiponectin
levels. Further studies including a larger sample size, higher doses of statins, and a placebo control group
are necessary to confirm the present data.
PMID:

17273659

[PubMed - indexed for MEDLINE]

2010 Nov;94(6):2208-13. doi: 10.1016/j.fertnstert.2009.11.045. Epub 2010 Jan 15.

Effects of metformin plus simvastatin on polycystic ovary syndrome: a prospective,


randomized, double-blind, placebo-controlled study.
Kazerooni T1, Shojaei-Baghini A, Dehbashi S, Asadi N, Ghaffarpasand F, Kazerooni Y.

Author information

Abstract

OBJECTIVE:
To evaluate the effect of a combination of simvastatin and metformin on biochemical parameters in
women with polycystic ovary syndrome (PCOS).
DESIGN:
A prospective, randomized, double-blind, placebo-controlled study.
SETTING:
University hospital.
PATIENT(S):
Eighty-four women with PCOS randomly divided to two study groups.
INTERVENTION(S):
Patients were randomly assigned to receive metformin (500 mg three times a day) plus simvastatin (20
mg/day, n=42; group 1) or metformin (500 mg three times a day) plus placebo (once a day, n=42; group
2) for 12 weeks. Blood samples were obtained before and after treatment.
MAIN OUTCOME MEASURE(S):
Testosterone.
RESULT(S):
After 12 weeks of treatment, serum T levels decreased by 25.5% in group 1 and by 16.8% in group 2.
There was a greater decrease of LH (45.5% vs. 6.7%) and a greater decline of the LH/FSH ratio (38.3%
decreased vs. 4.4% increased) in the first group. In group 1 there was a greater decrease of total
cholesterol (29.5% vs. 4.2%), low-density lipoprotein (LDL; 18.5% vs. 1.5%), and triglycerides (32% vs.
5.3%). High-density lipoprotein (HDL) increased in the first group by 14%, whereas it decreased by 1% in
the second group.
CONCLUSION(S):
This report has demonstrated that the combination of metformin and simvastatin could lead to a better
reduction of T and LH levels and thus reversing the LH:FSH ratio, lipid profile, and insulin resistance in
patients with PCOS and may be an appropriate management option for patients with PCOS.
Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights
reserved.
PMID:

20079899

[PubMed - indexed for MEDLINE]


2012 Dec;225(2):403-7. doi: 10.1016/j.atherosclerosis.2012.09.034. Epub 2012 Oct 12.

Lymphocyte-suppressing and systemic anti-inflammatory effects of highdose metformin in simvastatin-treated patients with impaired fasting glucose.
Krysiak R1, Okopien B.

Author information

Abstract
OBJECTIVE:
No previous study has investigated whether metformin produces any effect on lymphocyte secretory
function in patients with glucose metabolism abnormalities.
METHODS:
Sixty-two subjects with impaired fasting glucose (IFG) treated for at least 3 months with simvastatin were
allocated into one of two groups receiving, respectively, metformin (3 g daily) or placebo for the following
90 days. Plasma lipids, glucose homeostasis markers, plasma C-reactive protein and intercellular
adhesion molecule-1 levels, as well as lymphocyte release of proinflammatory cytokines were determined
before randomization and at the end of the treatment.
RESULTS:
Fifty-eight patients completed the study. Metformin, but not placebo, administered to simvastatin-treated
IFG subjects reduced plasma levels of C-reactive protein, soluble intercellular adhesion molecule-1, as
well as lymphocyte release of interleukin-2, interferon- and tumor necrosis factor-, which was
accompanied by the improvement in insulin sensitivity and a reduction in free fatty acid levels.
CONCLUSIONS:
The obtained results indicate that metformin potentiates lymphocyte-suppressing and systemic antiinflammatory effects ofsimvastatin in subjects with IFG. These effects of statin-metformin combination
therapy may play a role in the prevention and treatment of atherosclerosis and its complications in
patients with early glucose metabolism abnormalities.
Copyright 2012 Elsevier Ireland Ltd. All rights reserved.

PMID:

23107042

[PubMed - indexed for MEDLINE]


2012 Dec;111(6):380-4. doi: 10.1111/j.1742-7843.2012.00913.x. Epub 2012 Jul 7.

Haemostatic effects of metformin in simvastatin-treated volunteers with


impaired fasting glucose.
Krysiak R1, Okopien B.

Author information
Abstract
Our study investigated whether metformin has an impact on haemostasis in patients with pre-diabetes
receiving statin therapy. The study included 41simvastatin-treated patients with impaired fasting glucose
who were randomized to either metformin (3 g daily) or placebo. The international normalized ratio, the
partial thromboplastin time, fibrinogen, factor VII coagulant activity, plasminogen activator inhibitor-1 and
von Willebrand factor were assessed on the day of randomization and after 90 days of
treatment. Metformin treatment reduced plasma levels/activity of the assessed haemostatic risk factors,
and this effect correlated with the improvement in insulin sensitivity. The obtained results indicate that
high-dose metforminproduces a multi-directional beneficial effect on coagulation and fibrinolysis in
patients with impaired fasting glucose already receiving statin therapy. The effect of metformin on
haemostasis may play a role in the prevention of atherosclerosis-related disorders and acute vascular
events in this pre-diabetic state.
2012 The Authors Basic & Clinical Pharmacology & Toxicology 2012 Nordic Pharmacological Society.
PMID:

22716204

[PubMed - indexed for MEDLINE]

OBJECTIVE:
This study was designed to investigate whether metformin affects monocyte secretory function in patients
with impaired fasting glucose receiving chronic statin therapy.
MATERIALS/METHODS:
The study included 48 patients with impaired fasting glucose treated for at least three months
with simvastatin (40 mg daily). These patients were randomized to either metformin (3 g daily) or placebo,
which was administered together with simvastatin for 90 days. Plasma lipids, glucose homeostasis

markers, monocyte cytokine release and plasma C-reactive protein levels were determined before
randomization and at the end of the treatment.
RESULTS:
Compared to placebo, metformin reduced monocyte release of tumor necrosis factor-, interleukin-1,
interleukin-6, monocyte chemoattractant protein-1 and interleukin-8, as well as decreased plasma Creactive protein levels, which were accompanied by an improvement in insulin sensitivity.
CONCLUSIONS:
The obtained results suggest that metformin may inhibit monocyte secretory function and reduce systemic
inflammation in statin-treated patients with prediabetes. Impaired fasting glucose patients with high
cardiovascular risk may receive the greatest benefits from concomitant treatment with a statin
and metformin.
Copyright 2013 Elsevier Inc. All rights reserved.
PMID:

22841520

[PubMed - indexed for MEDLINE]


Gynecol Endocrinol. 2013 May;29(5):483-7. doi: 10.3109/09513590.2013.774360. Epub 2013 Mar 12.

Free fatty acid binding protein-4 and retinol binding protein-4 in polycystic
ovary syndrome: response tosimvastatin and metformin therapies.
Karakas SE1, Banaszewska B, Spaczynski RZ, Pawelczyk L, Duleba A.

Author information
Abstract
Free fatty acid binding protein-4 (FABP4) and retinol binding protein-4 (RBP4) contribute to metabolic
syndrome. We investigated serum FABP4 and RBP4 responses to insulin sensitizing and lipid lowering
therapies in polycystic ovary syndrome (PCOS). Sixty-two healthy, untreated women with PCOS (age
25.1 3.6 years, BMI: 24.0 4.7 kg/m(2)) were randomized to metformin (n = 24), simvastatin (n = 20)
or metformin plus simvastatin (n = 18) for 3 months. Anthropometric measures, fasting blood tests and
oral glucose tolerance tests (OGTT) were obtained at the baseline and the end. At the baseline serum
FABP4 correlated with obesity (BMI: r = 0.63, p < 0.001), insulin resistance (fasting insulin: r = 0.44, p =
0.0002; QUICKI: r = -0.30, p = 0.02; OGTT-insulin sensitivity index: r = -0.27, p = 0.04), dyslipidemia
(HDL: r = -0.26, p = 0.03) and hyperandrogenemia (free-testosterone: r = 0.23, p = 0.03; SHBG: r = -0.28,
p = 0.03); while RBP4 correlated with total-cholesterol (r = 0.33, p = 0.009). Multiple regression analysis
indicated that t best predictors of serum FABP4 and RBP4 were BMI ( = 1.02, p = 0.0003) and total
cholesterol ( = 2326, p = 0.01), respectively.Simvastatin, alone or with metformin did not affect serum

FABP4 or RBP4. Serum FABP4 related to the obesity, insulin resistance and inflammation while RBP4
related to lipids. Insulin sensitizing and lipid lowering therapies did not affect FABP4 or RBP4 levels in
PCOS

Am J Cardiovasc Drugs. 2007;7(3):219-24.

Effects of simvastatin and metformin on inflammation and insulin resistance in


individuals with mild metabolic syndrome.
Bulco C1, Ribeiro-Filho FF, Saudo A, Roberta Ferreira SG.

Author information

Abstract
BACKGROUND:
In addition to lipid-lowering and insulin-sensitizing actions, statins (HMG-CoA reductase inhibitors)
and metformin may have pleiotropic effects.
OBJECTIVE:
To study the effect of simvastatin and metformin on insulin sensitivity and inflammatory markers.
METHODS:
Forty-one subjects with body mass index (BMI) 25-39.9 kg/m(2) and impaired glucose tolerance were
randomized to receive simvastatinor metformin for 16 weeks. Blood samples were obtained for
measurement of metabolic and inflammatory parameters before and after each treatment.
RESULTS:
As expected, when compared with simvastatin, metformin therapy resulted in significant reductions in
mean BMI, fasting plasma glucose, and homeostasis model assessment-insulin resistance (HOMA-IR),
whereas simvastatin treatment resulted in significantly reduced total cholesterol, low-density lipoproteincholesterol (LDL-C), and apolipoprotein B levels. Independently of the medication used, significant
decreases in C-reactive protein (CRP) and interleukin (IL)-6 were detected from baseline to treatment
end. CRP showed a mean reduction of 0.12 +/- 0.04 mg/dL (p = 0.002) over the 16-week intervention
period and IL-6 a mean reduction was 0.35 +/- 0.17 pg/mL (p = 0.046). No change was observed in the
tumor necrosis factor-alpha levels. Baseline values of CRP and IL-6 and their percentage declines were
correlated (r = 0.71 and r = 0.67, respectively; p < 0.001). Insimvastatin recipients, no correlation was
detected between reductions in CRP or IL-6 and lipids, whereas in metformin recipients, reductions in
inflammatory markers were not correlated to BMI and HOMA-IR.

CONCLUSION:
Our findings suggest that both metformin and simvastatin have similar beneficial effects on low-grade
inflammation, in addition to their classical effects on glucose and lipid metabolism. Moreover, they confirm
the importance of treating at-risk individuals even before the precipitation of overt diabetes mellitus or fullblown metabolic syndrome