Nutrition, Metabolism & Cardiovascular Diseases (2017) 27, 657e669

Available online at www.sciencedirect.com

Nutrition, Metabolism & Cardiovascular Diseases

journal homepage: www.elsevier.com/locate/nmcd

REVIEW

Metformin effects on the heart and the cardiovascular system:

A review of experimental and clinical data
L. Nesti, A. Natali*
Department of Clinical and Experimental Medicine, University of Pisa, Italy

Received 9 February 2017; received in revised form 12 April 2017; accepted 21 April 2017
Available online 10 May 2017

KEYWORDS Abstract Background: Metformin, the eldest and most widely used glucose lowering drug, is
Metformin; likely to be effective also on cardiac and vascular disease prevention. Nonetheless, uncertainty
Heart; still exists with regard to its effects on the cardiovascular system as a whole and specifically
Cardiovascular on the myocardium, both at the organ and cellular levels.
Methods: We reviewed the available data on the cardiac and vascular effects of metformin, en-
compassing both in vitro, either tissue or isolated organ, and in vivo studies in experimental an-
imals and humans, as well as the evidence generated by major clinical trials.
Results: At the cellular level metformin’s produces both AMP-activated kinase (AMPK) dependent
and independent effects. At the systemic level, possibly also through other pathways, this drug
improves endothelial function, protects from oxidative stress and inflammation, and from the
negative effects of angiotensin II. On the myocardium it attenuates ischemia-reperfusion injury
and prevents adverse remodeling induced by humoral and hemodynamic factors. The effects on
myocardial cell metabolism and contractile function being not evident at rest or in more
advanced stages of cardiac dysfunction, could be relevant during transient ischemia, during an
acute increase in workload and in the early stages of diabetic/hypertensive cardiomyopathy as
confirmed by few small clinical trials and some observational studies. The overall evidence
emerging from both clinical trials and real world registry is in favor of a protective effect of met-
formin with respect to both coronary events and progression to heart failure.
Conclusions: Given this potential, its efficacy and its safety (and also its low cost) metformin re-
mains the central pillar of the therapy of diabetes.
ª 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the
Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Feder-
ico II University. Published by Elsevier B.V. All rights reserved.

Introduction with any other blood glucose-lowering drugs. Originally

Metformin, a biguanide derivative (dimethylbiguanide), is
worldwide the most used drug for the treatment of diabetes
mellitus type 2 (DM2), being recommended by major
guidelines both as first-line therapy and in combination
* Corresponding author. Department of Clinical and Experimental
Medicine, University of Pisa, Via Savi 8, 56100 Pisa, Italy.
E-mail address: andrea.natali@med.unipi.it (A. Natali).
derived from galegine (isoamylene guanidine), a guanidine
derivative found in the French lilac Galega officinalis, more
than 50 years ago, this drug has an incredible enduring re-
cord. The hypoglycemic effect of metformin derives from an
insulin-sensitizing action both on the liver, resulting in a
reduced hepatic glucose release, and, to a minor extent, at
the level of peripheral tissues, where it promotes glucose
uptake [1]. Together with intestinal disturbances, the major
metformin-related adverse effect is the rise in blood lactate

http://dx.doi.org/10.1016/j.numecd.2017.04.009
0939-4753/ª 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical
Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.
658 L. Nesti, A. Natali

levels, for which its use has been discouraged in patients
with chronic kidney disease, hepatic or respiratory insuffi-
ciency, and heart failure (HF). More recently, however, the
evidence that metformin-related lactic acidosis has a very
low incidence even in the presence of predisposing
comorbidities [2e5], has led to a revision by the FDA and
EMEA of the drug labeling [6], allowing its use in subjects
with estimated glomerular filtration rate values above
30 ml/min/1.73 m2 and, with some cautions, in chronic HF.
Besides having few adverse effects, metformin pos-
sesses several additional properties beyond glycemic
control. There is research and clinical interest in using this
drug for polycystic ovary disease [7] as well as in cancer
prevention and treatment [8,9]. A potential beneficial role
for metformin has been also suggested in preeclampsia
prevention and treatment [10] and in multiple sclerosis
[11]. Interestingly, by mimicking some of the benefits of
caloric restriction, both in drosophila and in mice, met-
formin has been observed to improve healthspan and
lifespan [12]. Despite the evidence from the United
Kingdom Prospective Diabetes Study (UKPDS) clinical trial
that metformin therapy in overweight newly diagnosed
DM2 patients is associated with a relevant reduction in
cardiovascular endpoints [13], information on the cardio-
vascular effects of metformin is controversial, sparse, and
limited. With this review, we aim at synthetizing and
critically evaluating the available evidence on metformin’s
effects on the cardiovascular system, heart functions,
structure, and metabolism, and, when possible, discuss the
involved mechanisms and the relevance. For each topic,
we will focus first on experimental and then on clinical
studies.
Effects of metformin on glucose and lipid cell
metabolism (Fig. 1)
Despite its long-term use, the pharmacodynamics of
metformin has been only recently fully clarified. Its effects
were initially supposed to be mediated mainly by the
activation of AMP-activated protein kinase (AMPK), which
is highly expressed not only in the liver but also in other
tissues, including the intestine, adipose, and skeletal
muscle and in the myocardium. More recently, however,
other AMPK-independent actions have also been
demonstrated.
AMPK-dependent mechanisms of action
Both in vitro and in vivo, metformin can activate AMPK, with
either direct or indirect pathways [14]. Noteworthy, the
metabolic effect of metformin, both after acute [15] and
chronic treatment [16], occurs without an evident increase
in intracellular total AMPK levels, being therefore depen-
dent upon the increase in the phosphorylated-to-
unphosphorylated AMPK ratio. It directly binds to AMPK
subunits, resulting in an increased assembly of the enzy-
matically active, heterotrimeric complex, which is more

Figure 1 Effects of metformin on cell metabolism. Intracellular signaling molecules activated by metformin are shown with red continuous lines;
those being inhibited are shown with blue dotted lines. The black lines describe the consequences on other substrates or on metabolic pathways (in
italics). Blue and red boxes indicate inhibited and activated proteins, respectively. ACC1/2: Acetyl-CoA Carboxylase-1/2. AMPK: AMP-activated
protein kinase. FFA: free fatty acids. AKT: also known as protein kinase B. FOxO1: Forkhead box protein 1. GLUT4: glucose transporter 4. PCK-e:
protein kinase C-epsilon. PFKFB3: 6-phosphofrutto-2-kinase/fructose-2, 6-biphosphatase 3 kinase.
Metformin effects on the heart and the cardiovascular system
accessible for upstream kinases [17,18]. In addition, metfor-
min is also capable of indirectly activating AMPK, that is by
altering AMP/ADP-to-ATP ratio in at least two ways: first, by
blocking AMP-deaminase [19], and second, by inhibiting
mitochondrial complex 1, a transmembrane protein
involved in the respiratory chain [20]. The consequence is an
increase in AMP/ADP-to-ATP ratio, which is in turn
responsible for AMPK activation. In this regard, metformin
mimics a condition of imbalance between energy supply and
use similar to the conditions of fasting and exercise.
This increase in AMPK catalytic activity affects
numerous metabolic pathways modulating some key en-
zymes in energy-consuming biosynthetic pathways, such
as hydroxymethylglutaryl-CoA reductase, acetyl-CoA
carboxylase 1 and 2 (ACC1 and ACC2), and glycogen syn-
thase [21]. Interestingly, in muscle and fat tissues, AMPK
regulates glucose uptake through effects on the RabGAP
TBC1D1 protein, thus influencing GLUT4-mediated glucose
uptake [22]. In addition to acutely regulate these enzymes,
AMPK is also involved in an adaptive reprogramming of
metabolism through transcriptional changes. One example
is the recently discovered inhibition of the lipogenic
transcriptional factor Srebp1 [23] that induces ACC1
stimulated fatty acid synthesis. As a consequence, AMPK
activation prompts a switch from ATP-consuming anabolic
pathways to ATP-generating catabolic pathways, particu-
larly inhibiting the synthesis of triglycerides and proteins,
and stimulating fatty acid oxidation, promoting glucose
transport, and accelerating glycolysis [24], thereby
reducing intracellular lipid stores. Pathological accumula-
tion of lipids in the liver impairs insulin signaling through
the diacylglycerols mediated activation of protein kinase C
ε (PKC-ε) [25]. The central role of intracellular lipids has
been proven by Fullerton et al. [26] who observed that
metformin’s hypoglycemic effect depends on its ability to
lower cellular fatty acid levels through the AMPK-
dependent phosphorylation of ACC1 and ACC2. Further-
more, metformin also seems to improve glucose homeo-
stasis indirectly through the so-called “gut-brain-liver axis”
[27]. In rats, the intraduodenal metformin infusion is
capable of reducing liver fasting glucose production by
activating duodenal enterocyte AMPK and PKA-dependent
GLP-1 secretion [28].
AMPK-independent mechanisms of action
Recently, it was demonstrated that metformin action on
glucose control is maintained in AMPK/LKB1 knockout
rodents [29], in which it inhibits hepatic gluconeogenesis
by decreasing the hepatocyte global energy state [30]. The
mechanism is through the inhibition of mitochondrial
glycerol-3-phosphate dehydrogenase, which alters the
cytosolic redox state (as reflected by a higher lactate-to-
pyruvate ratio) and increases the mitochondrial redox
state (as reflected by beta-hydroxybutyrrate-to-
acetoacetate ratio) [16]. By blocking this enzyme, metfor-
min reduces the NADþ available for converting lactate into
pyruvate, thereby reducing gluconeogenesis and sup-
pressing fasting hepatic glucose production.
659
Moreover, insulin-sensitizing effects of metformin have
also been linked to a modification in microbiota compo-
sition [31e33]. In high-fat diet-fed and diabetic rodents, it
leads to a decrease in postprandial serum gut microbiota-
derived lipopolysaccharide (LPS) [34], which has been
recently recognized to have an important role in the
development of insulin resistance and endothelial
dysfunction [35]. Interestingly, metformin reduction of
postprandial hyperglycemia has been linked to an increase
in gut Akkermansia spp. population and attenuation in
adipose tissue inflammation by inducing Foxp3 regulatory
T cells [36].
Effects of metformin on the vascular system (Fig. 2)
Oxidative stress, inflammation and endothelial function
Metformin seemingly participates in protecting against
oxidative stress [37,38]. It attenuates LPS-induced [39] and
oxidized LDL-induced proinflammatory responses [40,41],
suppresses macrophage proinflammatory responses
[39,42,43], and promotes macrophage differentiation to an
anti-inflammatory functional phenotype [44]. In a model
of fatty liver disease, metformin therapy normalizes he-
patic anaplerosis/cataplerosis and reduces the markers of
inflammation by preventing the concomitant elevation of
oxidative metabolism [45]. The decreased production of
ROS is linked to the inhibition of PKC [46] and complex 1 of
the respiratory chain [47,48], while the anti-inflammatory
effect to the inhibition of IKKa/b [49]. Moreover, the
transcription factor SKN-1/Nrf2 is activated upon metfor-
min treatment, resulting in an increased expression of
antioxidant genes in cells and animal models [50]. Inter-
estingly, metformin yields its anti-inflammatory effect
irrespective of diabetic status [49].
In a chronic heart transplantation model, Chin et al. [51]
demonstrated that metformin significantly reduced the
extent of microvascular damage, and this was associated
with improved cardiac grafts function. It has been reported
that in aortic endothelial cells, the activation of AMPK by
metformin limits endothelial cell damage caused by
oxidative stress under hyperglycaemic conditions through
the inhibition of the protein kinase C-NAD(P)H oxidase
pathway [52]. The resulting reduction in ROS generation
halts the activation of endothelial apoptosis triggered by
the loss of mitochondrial membrane potential [53]. Met-
formin has shown a beneficial effect on nonendothelial
function as well, potentiating phenylephrine-induced
AMPK phosphorylation and promoting vasorelaxation in
endothelium-denuded rat aortic rings [54]. Furthermore,
both in isolated cardiomyocytes and in the beating heart, it
can mitigate endothelial dysfunction by inhibiting oxida-
tive stress-activated poly (ADP-ribose) polymerase 1
(PARP1) [55]. Davis et al. [56] reported that metformin
increased the phosphorylation of eNOS in an AMPK-
dependent manner, which in turn increased eNOS activ-
ity and NO bioavailability. Interestingly, in the heart, eNOS
is expressed not only by vascular endothelial cells but also
by cardiomyocytes [57]. Moreover, early treatment with
660
Figure 2 Effects of metformin on the vasculature. Metformin can indirectly exert a protective effect on the vasculature mainly by reducing
inflammation and oxidative stress and protecting from fibrosis and remodeling. Blue and red indicate inhibition and activation, respectively. AT1R:
Angiotensin II receptor 1. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
metformin was observed to reduce pulmonary pressures
and vascular remodeling in a rat model of pulmonary hy-
pertension associated with HF with preserved ejection
fraction (EF), an effect that was associated with a signifi-
cant activation of SIRT3 and AMPK [58]. Interestingly, in
rodents, metformin seems to also reverse pulmonary hy-
pertension by inhibiting aromatase and estrogen [59],
which in the smooth muscle cell of the pulmonary artery
are a promitogen factor. Moreover, it can modulate pul-
monary vascular remodeling by reducing smooth muscle
cells proliferation through the inhibition of mTOR [60].
In humans, there is consistent evidence supporting an
anti-inflammatory effect of metformin particularly in
obese women with impaired glucose tolerance (IGT) [61]
and polycystic ovary disease [62]. In the BARI trial, the
insulin-sensitizing strategy (mainly metformin, but also
thiazolidinediones) led to lower C-reactive protein and
fibrinogen serum concentrations at all follow-up evalua-
tions after baseline in subjects with DM2 and coronary
artery disease [63]. In a large and accurate trial versus
placebo with similar glucose control [64], the positive ef-
fect of metformin extended to several plasma markers of
endothelial dysfunctions (s-ICAM, sVCAM-1, t-PA, and PAI-
1) and persisted for the whole 52 weeks of the observation
period. With regard to vascular endothelial function, 8
weeks of treatment with metformin 500 mg bid resulted
in an improvement in skin microcirculation, endothelial
function, and decreased myocardial ischemia in nondia-
betic women with microvascular angina (positive exercise
test and normal coronaries) [65]. Two studies in DM2
patients focused on resistance arteries, yielding either
L. Nesti, A. Natali
positive [66] or negative [67] results. However, while the
former study did not control for the improvement in
plasma glucose being versus placebo, the latter had an
active treatment arm.
We can conclude that metformin produces a selective
inhibition of oxidative stress and inflammation both
directly and indirectly. Moreover, it can reduce cellular
metabolic overload and the insulin resistance-induced
inflammation in several tissues and act directly on
monocytes by inhibiting their differentiation to macro-
phages. The beneficial effects of metformin on endothelial
function, evident in animals, still have to be convincingly
confirmed in humans. The effects observed in animal
models on pulmonary hypertension are of particular in-
terest and deserve further research.
Renin-angiotensin-aldosterone system
There is some evidence suggesting that metformin might
interfere with the renin-angiotensin-aldosterone system
(RAAS). The study by Lee et al. [68], performed in cultured
proximal renal tubule cells, observed metformin-induced
activation of AMPK to reduce angiotensin II (AngII) and
aldosterone-induced epithelialemesenchymal transition.
In the same study, metformin reduced fibrogenesis
through the reduction of cytosolic reactive oxygen species
(ROS) production. In addition, in fibroblasts, pretreatment
with metformin could decrease the production of extra-
cellular matrix and the activation of ERK signaling induced
by AngII. More interestingly, in AngII-induced hypertrophy
Metformin effects on the heart and the cardiovascular system
in cultured cardiomyocytes, metformin exerted anti-
hypertrophic effects and prevented AngII-induced cell
death [69]. This effect was related to blunting of AngII-
induced upregulation of AngII type 1 receptor (AT1R).
Moreover, metformin attenuated mitochondrial dysfunc-
tion and hypertrophy through the eNOS/SIRT1/p53
pathway. However, the exact mechanisms through which
metformin-induced AMPK activation leads to AT1R inhi-
bition in cardiomyocyte mitochondria are still to be
elucidated. It is noteworthy that metformin has been
shown [70] to attenuate atherosclerosis and vascular
senescence in a high-fat diet-fed mice and to prevent the
upregulation of AT1R by a high-fat diet in the aortas of
mice. We are not aware of data concerning the influence of
metformin on the RAAS in humans.
In synthesis, it seems unlikely that metformin directly
modulates the RAAS. However, it might prevent the adverse
effect of AngII both at the level of the myocardium (fibrosis)
and the vasculature (atherosclerosis).
Blood pressure and sympathetic activity
In mouse models, intravenous administration of metfor-
min produced a dose-dependent reversible decrease in
mean arterial pressure, heart rate, and efferent renal
sympathetic activity [71]. Other studies confirmed an
antihypertensive effect of metformin in animals. In
particular, metformin has been proven to attenuate salt-
induced hypertension in spontaneously hypertensive rats
[72], although it did not affect blood pressure in animals
on normal salt diet [73].
Two preliminary small studies in humans showed a
slight blood pressure lowering effect of metformin in DM2
patients with hypertension [74,75]. These observations
were not confirmed in more recent studies in subjects
with DM2 [76e79] and in nondiabetic, hypertensive pa-
tients [80e83], in whom the measurement of blood pres-
sure was generally more accurate. Interestingly, the effect
of metformin was not additive to the effect of exercise in
normotensive subjects with IGT [84] and was unable to
prevent the development of hypertension in IGT subjects
[61,85,86]. A recent meta-analysis, however, suggested
that metformin could effectively lower systolic blood
pressure in nondiabetic patients, especially in those with
IGT or obesity [87], a result possibly related to the small
size of the effect and of the sample of each single study.
With regard to autonomic function, despite one work on
heart rate variability suggested a positive effect for met-
formin in affecting cardiac autonomic tone [76], more ac-
curate studies using micro neuronography and
norepinephrine kinetics showed no effect of metformin on
the sympathetic nervous system [82].
The overall balance of evidence indicates that metfor-
min does not have a significant direct effect on sympa-
thetic activity, while it might have some positive, though
small, effects in reducing systolic blood pressure. The ef-
fect seems to be more relevant in patients with obesity
and/or IGT, possibly secondary to the metformin-related
body weight reduction.
661
Effects of metformin on the heart (Fig. 3)
Several in vitro and in vivo animal studies documented
some direct effects of metformin both on isolated car-
diomyocytes and on the beating heart. On the contrary,
studies in humans are far less abundant. Compelling evi-
dence suggests that metformin plays several roles in
different cardiomyocyte activities, such as electric activity,
energy metabolism, ischemia-reperfusion injury, cardiac
remodeling, as well as systolic and diastolic functions.
Electric potential and conduction
Few data are available regarding metformin influence on
cardiomyocytes electric activity. In a type 1 diabetes
mouse model (diabetes induced by alloxan infusion),
chronic treatment with metformin doses effective in
achieving plasma glucose control prevented the increase
in QT interval and dispersion induced by the induction of
diabetes [88]. In a rat model of acute myocardial infarction
(MI), short-term oral administration of metformin
strongly prevented pathologic alterations in the ECG,
indicating its protective effects on cell membrane function
[89]. As far as humans are concerned, only one study has
been conducted, wherein DM2 patients reported a 12
msec reduction in corrected QT interval (QTc) and a
neutral effect in QTc dispersion after 2 months of met-
formin treatment [90].
In conclusion, there is no clear evidence of a direct,
significant influence of metformin treatment on car-
diomyocyte electric activity.
Energy metabolism of the normal heart
In isolated cardiomyocytes, metformin activates glucose
uptake and glycolysis by both AMPK-dependent [91,92]
and AMPK-independent (p38-MAPK and PKC) [93] mech-
anisms, depending on the concentration and duration of
exposure to the drug, while the increase in fatty acid
oxidation is evident only if AMPK is activated [94]. In intact
myocardium, metformin promotes glucose transport, ac-
celerates glycolysis, and stimulates fatty acid oxidation,
inhibiting the synthesis of triglycerides. In particular, in
the normal intact heart, the effect of metformin on fatty
acid utilization appears to predominate and to occur
independently of AMPK activation [93]. In an in vivo DM2
experimental animal model (fa/fa), however, chronic
treatment with metformin (16 mg/k/die) was not associ-
ated with a different pattern of myocardial substrates
utilization [95].
Studies in humans with positron emission tomography
are somewhat conflicting: while no effect on glucose up-
take was observed by Hällsten [96], van der Meer [97]
demonstrated a small reduction in both glucose and FFA
utilization, and Lyons [98] reported no direct effect on
substrate utilization.
Considering the data summarized above, despite the
effect observed in vitro, metformin at “normal” pharma-
cologic concentrations is unlikely to produce major
662
Figure 3 Effects of metformin on the heart. Metformin has been suggested to exert effects on electric activity, cardiomyocyte metabolism, ischemia,
remodeling, as well as on myocardial systolic and diastolic functions. For each function, we have summarized the evidence according to the type of
experiments. IGT: impaired glucose tolerance. DM: diabetes mellitus. LV: left ventricle.
changes in myocardial substrate utilization in the intact
beating heart, under normal resting conditions. Nonethe-
less, it should be noted that in resting and fasting condi-
tions, the energy metabolism of the heart relies mainly on
the availability of circulating FFA, whose serum concen-
tration is extremely sensitive to factors such as the dura-
tion of fasting, stress, fat mass, insulin, and glucagon
relative serum concentrations. As such, it cannot be
excluded that some of these confounding factors might be
responsible for the variability observed in the results
in vivo.
Ischemia-reperfusion injury
In a study performed in the nondiabetic isolated rat heart
model, it has been found that adding metformin to the
perfusate resulted in the attenuation of LV postischemic
dysfunction (stunning) [99]. The beneficial effects of short-
term metformin administration have been further sus-
tained by some studies in vivo, wherein acute metformin
therapy significantly reduced postischemic myocardial
damage [100]. Several studies, performed in both isolated
hearts and intact animals [101e105], provided support to
the notion that metformin administration can reduce
infarct size: compared to the control group, metformin
administration before or during ischemia-reperfusion
injury was associated with an infarct size reduction be-
tween 22% [101] and 65% [105]. The infarct size-limiting
effect of metformin was demonstrated in mice after
either a single intraperitoneal injection or a single intra-
ventricular administration during reperfusion.
L. Nesti, A. Natali
Noteworthy, the cardioprotective effect of metformin in
ischemia-reperfusion injury has been demonstrated both
in diabetic [105] and in nondiabetic rodent models
[100e104]. The beneficial effects of metformin on
ischemia-reperfusion injury have been proposed to be
secondary to either a more efficient shift from fatty acid
aerobic oxidation to glucose anaerobic utilization or to an
improvement in cardiomyocyte insulin signaling [106].
Finally, the cytoprotective effects of metformin were
associated with AKT phosphorylation and successive in-
hibition of mitochondrial permeability transition pore
opening [107].
Observational studies in humans are consistent with a
protective role for metformin in acute ischemic heart
disease, although a potential harm of other blood glucose
lowering therapy has been proposed as a confounding
factor. In particular, metformin treatment, when compared
to other hypoglycemic agents, was associated with
improved survival after ST-elevation MI (STEMI) in pa-
tients with DM2 [108]. More recent studies confirmed that
in patients with DM2 and a history of MI, treatment with
metformin was associated with a lower mortality rate in
comparison with sulfonylureas (SUDs) [13,109]. A retro-
spective study suggested a role for metformin in reducing
the incidence of the so-called no-reflow phenomenon in
patients with DM2 after primary angioplasty for acute MI
[110]. In DM2 patients with acute MI treated with met-
formin, with regard to nonmetformin-treated diabetic
patients, lower peak values of cardiac cell death markers,
such as creatine kinase (CK), mbCK, and troponins, were
observed [111]. Moreover, the same study demonstrated a
smaller infarct size in metformin-treated DM2 patients
Metformin effects on the heart and the cardiovascular system
than in the nondiabetic patients, not taking the drug [111].
A similar study, however, did not confirm this finding
[112]. However, despite the substantial effect in diabetic
patients, metformin treatment (500 mg bid) initiated
immediately after percutaneous transluminal coronary
angioplasty (PTCA) in nondiabetic patients suffering from
coronary heart disease was associated with no clear
beneficial effect on NT-proBNP levels or LVEF at 4 months,
as demonstrated by the Glycometabolic Intervention as
Adjunct to Primary Percutaneous Coronary Intervention in
ST-Segment Elevation Myocardial Infarction (GIPS-III) trial
[113]. No other beneficial effect has been observed in
nondiabetic subjects suffering from coronary artery dis-
ease [114]. Similarly, short-term metformin pretreatment
was not effective in reducing peri-procedural myocardial
injury in nondiabetic patients undergoing coronary artery
bypass graft surgery [115]. However, in patients with
metabolic syndrome, metformin treatment (250 mg, 3
times daily) started 7 days prior to elective percutaneous
coronary intervention resulted in both a smaller (50%)
cardiac biomarker release after intervention and an
extremely favorable 1-year clinical outcome (8% vs. 29%
major clinical events) [116].
In conclusion, in nondiabetic subjects, acute adminis-
tration of the drug during or soon after an ischemic event
yields no cardioprotection. Conversely, data strongly sug-
gest that in subjects with diabetes or with metabolic
syndrome, as well as in diabetic animal models, chronic
pretreatment with metformin exerts beneficial anti-
ischemic effects, reducing ischemia-reperfusion injury,
infarct size, and cardiac cell death markers serum levels,
possibly justifying the improved survival after an ischemic
event reported in the observational studies.
Remodeling
Metformin reduces cardiac hypertrophy in mice subjected
to chronic pressure overload, partially through AMPK-
independent molecular pathways [117]. Metformin was
also shown to attenuate cardiac fibrosis and inhibit
collagen synthesis in both a mouse model of pressure
overload-induced HF [118] and a mouse model of oxidative
stress-induced ventricular hypertrophy, in which it can
significantly inhibit the overexpression of TGF-b1 and
bFGF [119]. In a rat model, while 2 days-long isoproterenol
administration resulted in cardiac hypertrophy and
increased edematous intramuscular space with decreased
myocardial compliance, the concomitant oral administra-
tion of metformin clearly and dose-dependently prevented
myocardial injury, edema, and massive fibrosis. Interest-
ingly, in a canine model of tachycardia-induced HF, met-
formin reduced myocardial fibrosis through reduced
TGFb1 mRNA and could prevent the progression of HF as
well [120]. Nevertheless, in mice exposed to transverse
aortic constriction-induced hypertrophy, metformin
significantly improved LV fractional shortening, attenuated
LV dilation, and was associated with a smaller increase in
serum ANP [121]. This effect was observed in both wild-
type and AMPK-knockout animals, indicating that
663
metformin can exert cardiac protective effects through an
AMPK-independent molecular pathway.
Similar beneficial effects have also been proved for long-
term metformin administration in rodent models of
ischemic HF, wherein both short- (4 weeks) [122] and long-
term (12 weeks) [101] metformin treatment after MI
significantly attenuated cardiac remodeling and retarded
the progression of ischemic cardiomyopathy and HF.
Particularly, rats treated with metformin showed reduced
MI size, improved echocardiographically assessed LV ge-
ometry, and a smaller increase in molecular correlates of LV
remodeling, such as ANP and collagen production. In
addition, in models of postischemic HF after permanent left
coronary artery occlusion, metformin administration
significantly improved LV remodeling, as evidenced by in-
creases in LV systolic pressure and LVEF, as well as by de-
creases in LV end-diastolic diameter and LV end-systolic
diameter [102,122]. These beneficial effects of metformin
were associated with increased AMPK and eNOS phos-
phorylation. Of note, a genetic link between AMPK and
cardiac fibrosis has been recently demonstrated in a MI
mouse model [123]. In addition, a model of spontaneously
hypertensive, insulin-resistant rats [124] demonstrated
that 12 months-long metformin treatment was associated
with reduced echographically assessed LV volumes and
wall stress, as well as histologically proven perivascular
fibrosis and cardiac lipid accumulation in an AMPK-
dependent mechanism. In the same study, metformin
induced a marked activation of eNOS and vascular endo-
thelial growth factor, and reduced TNF-a expression and
myocyte apoptosis. Myocyte apoptosis has been also stud-
ied after metformin administration in a swine model of
chronic myocardial ischemia, wherein metformin treat-
ment reduced the percentage of apoptotic cells in both
ischemic and nonischemic myocardium [106]. This car-
dioprotective effect was due to both upregulation of pro-
survival proteins, such as extracellular signal-regulated ki-
nases, nuclear factor kB, phosphorylated eNOS, and P38,
and downregulation of pro-apoptotic proteins, such as
FOXO3 and caspase 3. In diabetic mice, cardiac autophagic
activities were also enhanced by metformin [125]. How-
ever, a conclusive link between increased autophagy and
cardiac remodeling in metformin-treated diabetic hearts
has not been demonstrated.
To date, no clinical study has been conducted to
investigate the effect of metformin on LV remodeling. The
results of the ongoing MET-REMODEL trial [126], a phase
IV, randomized, placebo-controlled trial, aimed at inves-
tigating the efficacy of metformin in regression of LV hy-
pertrophy in patients with coronary artery disease and
insulin resistance are eagerly awaited. The primary
endpoint of this trial is to investigate any change in LV
mass index. Secondary endpoints include changes in in-
sulin resistance measured using fasting insulin resistance
index (FIRI), obesity, and LV size and function, thus
possibly clarifying metformin’s effect on remodeling in
humans.
In conclusion, while studies in humans are currently
lacking, in animal models, metformin shows potent anti-
664
remodeling properties, seemingly through reduced inter-
stitial fibrosis, reduced inflammation-related myocardial
damage, and seemingly limiting myocardial hypertrophy.
Interestingly, these beneficial effects are present irre-
spective of either the nature of myocardial insults or the
glycemic status.
Systolic and diastolic functions
In models of postischemic HF after permanent left coro-
nary artery occlusion, metformin administration signifi-
cantly improved LVEF [102,122] and daily survival by 47%
(vs. vehicle) at 4 weeks following permanent left coronary
artery occlusion [102]. Furthermore, 1-month-long met-
formin treatment was associated with preserved cardiac
function in an in vivo rat model of posteMI cardiac
remodeling [101]. In the setting of nonischemic HF, while
in the rodent model of volume-overload HF, metformin did
not show any effect on systolic or diastolic function [127],
but in streptozotocin-treated animals, long-term oral
administration of metformin increased the myocardial
performance to an increase in preload [128]. The protec-
tive effect of metformin in workload-dependent HF has
been shown to be dependent on the AMPK pathway [129].
In their impressive series of experiments in the working
rat ex vivo, Taegtmeyer and colleagues [129] showed that
the accumulation of G6P, due to the glucose uptake/
oxidation mismatch induced by an increased workload, is
responsible for downstream mTOR activation with the
consequent endoplasmatic reticulum stress and contractile
dysfunction. Metformin treatment in vivo, and added to
the perfusate, by preventing the AMPK downregulation
preserved the coupling between glucose uptake and
oxidation, avoided the intracellular accumulation of G6P,
and improved myocardial energetics at high workload.
Similarly, as mentioned earlier, in an elegant rodent model
of HF with preserved EF, the chronic treatment with
metformin could reduce the elevation in right ventricular
pressure and the extent of pulmonary small arteries hy-
pertrophy [58]. Finally, also in a canine model of DM2,
short-term metformin treatment has been shown to
attenuate the increment of LV diastolic chamber stiffness
and diastolic dysfunction [130].
An observational study on diabetic subjects [131]
found that myocardial diastolic dysfunction (Em) was
independently predicted by age (p Z 0.013), hypertension
(p Z 0.001), insulin (p Z 0.008), and, unexpectedly,
metformin (p Z 0.01) treatment. However, it has to be
pointed out that the subjects treated with metformin had
a higher BMI value; as a consequence, the weak, adverse
effect of metformin on diastolic function might be due to
this confounding factor. In a more recent study [132],
metformin therapy was an independent predictor of left
ventricular dysfunction. Nonetheless, in the same study,
waist circumference and metformin were adversely
associated with systolic dysfunction (OR 1.02, 95% CI
[1.01e1.04] and 1.57, 95% CI [1.01e2.43], respectively),
confirming that in this setting metformin therapy might
rather represent a marker of visceral adiposity. Other
L. Nesti, A. Natali
observation found no clear effect of metformin on systolic
and diastolic function. In a small randomized clinical trial,
24 weeks of treatment with metformin (2000 mg) had no
effect on diastolic function as assessed by echocardiog-
raphy [97] in patients with normal left ventricular func-
tion and negative dobutamine stress test. Finally, the
already cited GIPSS trial [13,114] observed no change in
LVEF in diabetic patients treated with metformin. How-
ever, it should be noted that in the GIPS III study, the low
dose of metformin used (1 g daily) and the short treat-
ment period of treatment (4 months) may not be enough
to have an impact on the endpoint of LVEF modification.
Very recently, a clinical trial in 105 patients with DM2
without history of cardiac disease, aiming at evaluating
the effect of improving metabolic control on left ventric-
ular systolic function (as measured by global longitudinal
strain), reported that the use of metformin was the only
other independent predictor of the improvement in left
ventricular contractility in addition to the change in
HbA1c and weight [133].
In conclusion, only in the presence of acute stress
(ischemia, acute preload and post preload increase) and in
early diabetic cardiomyopathy, metformin might positively
affect cardiac performance.
Metformin and major cardiac clinical outcomes
Ischemic cardiovascular events prevention
Three relatively small, randomized clinical trials have
reached similar conclusions with regard to the potential
positive effects of metformin on macrovascular outcomes.
In 1998, the UKPDS study [134] demonstrated that in obese
subjects with DM2, metformin compared to insulin or SUDs
therapy, despite similar glycemic control, was associated
with a reduction in 10-year overall mortality and diabetes-
related death by 36% and 42%, respectively, and lowered the
risk of MI by 39%. Importantly, the beneficial effects of
metformin persisted for 10-year of post-trial follow-up [13].
A similar (40%) reduction of macrovascular events (as a
heterogeneous composite secondary endpoint) was
observed over 4.3 years in the HOME trial [135], in which
metformin was compared to placebo as add-on on basal
insulin; also in this trial, the degree of metabolic control
was superimposable in the two arms. In the SPREAD-
DIMCAD trial, the patients with DM2 and cardiovascular
disease treated with metformin showed a 46% reduction in
recurrent cardiovascular events (as composite endpoint)
when compared to the active comparator (glipizide) [136].
These results stand in contrast with the neutral results of
the BARI2D trial performed in type 2 diabetic patients who
were eligible for coronary artery revascularization [137].
This study, however, compared two therapeutic strategies,
insulin sensitizing (metformin and/or thiazolidinediones)
versus insulin providing (SUDs and/or insulin) drugs,
therefore it does not provide direct information on the ef-
fect of metformin per se.
In 2010, Roussel et al. [138] demonstrated that data
from the observational Reduction of Atherothrombosis for
Metformin effects on the heart and the cardiovascular system
Continued Health Registry indicated that the use of met-
formin was associated with a significant 24% reduction in
all-cause mortality after a 2-year follow-up. Meta-analyses
of observational studies confirm that, compared to sulfo-
nylureas, metformin is related to a reduced risk of MI
[139], and that metformin monotherapy can improve
survival versus placebo or no treatment or SUDs [109].
Nevertheless, when randomized clinical trials have been
meta-analyzed, the effectiveness of metformin to reduce
cardiovascular events was not so evident, particularly in
the smaller and shorter studies [109,140].
Concluding the evidence that metformin reduces the
risk of cardiovascular events though limited is rather
consistent, particularly with regard to sulfonylureas. This is
somewhat in keeping with the positive effects of the car-
diovascular systems observed in experimental studies,
which also suggest that the effects are proportional to the
load of metabolic and/or hemodynamic stress. Accord-
ingly, metformin could be particularly effective in specific
subgroups of patients; for example in sedentary or obese
patients with less-controlled blood pressure as suggested
by the impressive results of the UKPDS.
Heart failure
Evans et al. [141] demonstrated that patients with DM2
and HF who were treated with metformin alone or in
combination with SUDs were at significantly lower risk of
all-cause mortality during a 1-year follow-up than those
who were treated with SUDs alone. In addition, Aguilar
et al. [142] confirmed that metformin therapy was asso-
ciated with a survival benefit over a 2-year follow-up.
Importantly, this benefit was consistent across sub-
groups of diabetic patients with HF, and several comor-
bidities usually excluded from clinical trials, such as renal
insufficiency, prior MI, and obesity. The study of Romero
et al. [143] demonstrated in more than 1500 patients with
new-onset DM and HF that initiation of metformin ther-
apy was associated not only with a decrease in all-cause
and cardiovascular mortality but also with a lower hos-
pitalization rate for HF in a 2-year follow-up. In this
setting, a recent interesting study evaluating the effect of
metformin in insulin-resistant adults with HF on exercise
showed that metformin increased the VE/VCO2 slope (the
ratio of minute ventilation to carbon dioxide production,
which in this population is a more sensitive index of the
cardio respiratory performance with regard to VO2max)
[144]. In another small study in subjects with normal
cardiac function, metformin did not reduce VO2max but
increased the max workload [145]. This suggests a
possible mechanism of action for metformin in reducing
HF-related outcomes. Importantly, in diabetic patients
with HF, a recent meta-analysis of cohort studies
confirmed that metformin, with regard to other glucose-
lowering agents, is associated with a reduced mortality
and all-cause hospitalization across the different classes
of kidney dysfunction and EF [5].
In summary, the effects that metformin therapy appears
to have on the survival of patients with HF and DM2 are
665
mainly due to a decreased cardiovascular mortality, irre-
spective of gender, age, and etiology of HF. Such hypothesis
requires to be challenged in an ad-hoc designed random-
ized clinical trial, the power of which could be increased
using mechanism-based biomarkers of metformin action
rather than parameters of diabetes control.
Concluding remarks
Metformin in experimental studies exerts positive effects
on cardiac energetic metabolism, structure, and function
through reduced oxidative stress and inflammation, and
improved endothelial function. It reduces ROS production
by inhibiting the activity of protein kinase C-NAD(P)H
oxidase pathway, promotes macrophage differentiation to
the anti-inflammatory functional phenotype, increases the
expression of antioxidant genes, and increases eNOS ac-
tivity. In intact animals, metformin appears to attenuate
cardiac remodeling by reducing fibrosis, hypertrophy, and
inflammation-induced damage, thereby preserving LV
morphology and systo-diastolic performance from meta-
bolic, hemodynamic, and ischemic-induced damages. The
overall evidence emerging from both clinical trials and real
world registry is in favor of a protective effect of metfor-
min with regard to both coronary events and progression
to HF. Given this potential, its efficacy, and its safety (also
its low cost), metformin remains the central pillar of the
therapy of diabetes. Therefore, a large clinical trial
designed ad hoc to estimate with more precision the size
of its effects on these cardiovascular outcomes would be
very difficult, if not unethical; however, hypothesis-driven
small trials on specific subgroups of patients focusing on
robust surrogate endpoints might help in refining our
knowledge and would allow the full exploitation of the
potential of this drug.
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