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].