CARDIOVASCULAR PROTECTION ASSOCIATED WITH METFORMIN
Sars-Cov-2 can cause or aggravate cardiovascular events in patients with
or without comorbidities. A meta-analysis of six Chinese studies, with
1527 patients with COVID-19, reported prevalence of diabetes (9.7%),
cardio-cerebrovascular disease (16.4%) and hypertension (17.1%) among
the participants. Recent data showed that systemic inflammation and
increase of catecholamine caused by COVID-19 can lead to acute
atherosclerotic plaque rupture, resulting in acute coronary syndrome. In
addition, coagulation cascade deregulation may occur with micro-thrombus
formation in terminal organs [73]. In view of this, the important
role that MET can play in the treatment and functional recovery of
cardio-cerebrovascular diseases, such as stroke and myocardial
infarction (MI), conditions present in the severe form of COVID-19 is
verified.
Most studies that evaluate the mechanisms of action of MET, when used in
stroke, use as a resource the middle cerebral artery occlusion (MCAO) in
rats, transitory or permanently. When transient, they usually cause
ischemia between 60 and 90 minutes, followed by reperfusion. The daily
doses of MET used vary between 10 and 300 mg/kg. It was reported that
the moment of administration (pre- or post-stroke), the duration of
treatment (acute or chronic) and the degree of activation of AMPK are
important factors in physiological responses to the ischemia generated
in the brain [74]. MET-induced AMPK activation provides protection
against brain ischemia (Chart 2) [62]. There is a lot of discussion
about pre-stroke treatment with MET. While the acute treatment three
days before the experimental stroke caused more damage from the
infarction after 24h of the MCAO because it caused deleterious
activation of the AMPK, the treatment for three weeks provided reduction
of the acute infarction 24h after the occlusion by reducing this
activation [62]. It was observed that these post-ischemic
alterations can be mediated by neuronal nitric oxidase (nNOS), since its
exclusion abolished the deleterious and beneficial effects presented in
each case [62, 74]. It has also been demonstrated that pre-treatment
for two weeks with MET provides neuroprotection by activating AMPK. On
the other hand, it was observed that the acute pre-treatment 24h before
pre-conditioning induced by permanent occlusion of the middle cerebral
artery conferred the same effect 24h after ischemia [62]. The
divergence in the results may be related to the different MET doses and
the ischemia models used. The effects of the treatment in post-stroke
are better established, suggesting that there is not only reduction of
acute infarction, but also long-term functional recovery. The mechanisms
that explain the effect of the drug in post-stroke are described in
Chart 2 [62, 63]
The vast majority of studies that evaluated the cardiovascular effects
of MET induced MI in rats by occlusion of the left anterior descending
artery, causing ischemia (30 to 35 minutes) followed by reperfusion, or
through administration of isoproterenol (doses between 25 and 250
mg/kg). One study reported that the drug uses several biochemical
pathways to realize its effects. Attenuation of mitochondrial
respiratory decoupling in mice treated with MET compared to those
treated with saline solution was found. In addition, AMPK has been
proven to be an important regulator of myocardial energy balance,
activated also in I/R lesions. Activation during reperfusion maintains
cardiac viability by limiting apoptosis. Other mechanisms act to
minimize cardiovascular damage through nitric oxide (NO) production
[64], of adenosine receptor stimulus [64, 65], the suppression
of TLR4 signaling [66] and the reduction of cardiac remodeling and
neutrophilic activity [67] (Chart 2).
The clinical use of MET to reduce cardiovascular diseases, such as MI
and stroke, needs further investigation. A case-control study with
patients of MI (n=413), stroke (n=247) and case-control (n=443), in
which all used insulin, followed the effect of MET and oral hypoglycemic
agents. It was observed that the use of MET compared to non-use provided
a lower risk of stroke (OR 0.54; 95%IC, 0.31-0.95), however, the same
result was not obtained for MI (OR 0.85; 95%IC, 0.55-1.30) [75].
The clinical benefit of this biguanide was also evaluated at MI, where
380 non-diabetic patients (n=191, MET 500mg twice a day and n=189,
placebo), who presented MI with ST segment superstructure submitted to
primary percutaneous coronary intervention (PCI), did not obtain
improvement in the left ventricle ejection fraction after 4 months of
treatment [76]. This same group was analyzed after two years, where
it was also found absence of clinical benefits [77]. More promising
results are seen in patients who have some pre-established metabolic
disorder and who needed an elective PCI without having done previous
treatment with the drug. In these, the levels of CK-MB and cardiac
troponin I were reduced and, after one year of follow-up, the cardiac
events were less frequent [78].