Metformin’s Effects

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Alina Yu Babenko	--	4044	2022-04-21 15:15:55	\|
2	layout	Camila Xu	-3 word(s)	4041	2022-04-22 05:21:23	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms23042363

Today the area of application of metformin is expanding, the recent important change is a removal of a number of restrictions on its use in patients with heart failure, acute coronary syndrome and chronic kidney disease.

metformin molecular mechanisms atherosclerosis heart failure chronic kidney disease lactate diabetes mellitus obesity

1. Metformin’s Effects on the Inhibition of the Mechanisms of Cardiorenal Continuum Formation—HFpEF and CKD

As discussed in the recent research, metformin blocks the development and the progression of both heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) through a variety of complex pleiotropic effects, in particular, by its direct effects on myocardial structure and function, allowing the maintenance of normal LV morphology and functional activity ^[1]. These mechanisms are described in detail in this research, so researchers will not dwell on them here.

Hyperuricemia has been identified as an important factor in oxidative stress and activation of fibrogenesis in the myocardium and kidneys. Metformin in experimental rat models decreased serum uric acid levels and, through cyclic adenosine monophosphate (AMP)-dependent protein kinase, reduced the negative effects of hyperuricemia ^[2]^[3]. Metformin can reduce the severity of hyperuricemia by activating AMPK and its phosphorylation and protecting against IR caused by hyperuricemia in cardiomyocytes, skeletal muscles ^[4], and associated pathological processes, including increased fibrogenesis (elevated level of galectin-3 (Gal-3), procollagen types 1 and 3).

Metformin, as a powerful AMP-activated protein kinase (AMPK) activator, is a promising drug for reducing or reversing the fibrosis. Numerous studies examining the mechanisms of metformin on fibrosis have shown that it mainly exerts an anti-fibrotic effect, affecting the signaling pathway of transforming growth factor β (TGF-β), cellular metabolism, and oxidative stress, including that induced by hyperuricemia. Metformin has a direct anti-fibrotic effect, inhibiting the production of TGF-β1 ^[5]^[6]^[7]^[8]^[9]^[10]^[11]^[12].

In a hybrid study involving in vitro experiments, animal models, and clinical evaluation of patients, its production was shown to be higher in the VAT than in the SAT and in circulation. Gal-3 showed a positive body mass index (BMI)-dependent correlation with leptin, resistin, interleukin-6, and age ^[13]. In patients with type 2 diabetes mellitus (DM), Gal-3 was elevated in serum. It positively correlated with the level of C-reactive protein. Metformin treatment was associated with lower levels of Gal-3 in the systemic circulation in patients with type 2 DM. The ability of this drug to reduce the severity of oxidative stress and the formation of advanced glycation end products (AGEs) ^[14], which, in turn, induce the expression of Gal-3, is considered as a possible mechanism for reducing the level of Gal-3 during metformin therapy. The contribution of AMPK activity modulation is also being considered. Oxidative stress is a central mechanism involved in fibrotic progression. AMPK is the oxidative stress suppressor and is critical for regulating reactive oxygen species (ROS) production. Metformin, as an AMPK activator, reduces ROS production and suppresses oxidative stress ^[9]^[12]^[15]^[16]^[17]^[18].

The cardioprotective effects of metformin have been largely determined by its ability to decrease the severity of cardiac fibrosis caused by pressure overload, MI, and many other causes ^[6]^[15]^[19]^[20]^[21]. Similarly, experimental renal fibrosis associated with high-fat diets ^[22], unilateral ureteral obstruction ^[23], high-dose folate intake ^[7], adenine ^[24], and cyclosporin A ^[25] was significantly reduced with metformin. Accumulated data have shown that metformin has great potential in reducing the progression of fibrosis in various organs, including the visceral adipose tissue (VAT) ^[25]^[26], subcutaneous adipose tissue (SAT) ^[27], uterus and ovaries ^[28], lungs ^[5]^[21], and liver ^[29]. At the same time, metformin decreased not only the severity of fibrosis induced by hyperinsulinemia, oxidative stress, and hyperglycemia in metabolic syndrome and type 2 DM, but also fibrosis of a different genesis—ischemic, toxic, and drug induced.

Interestingly, metformin administration did not alter AMPK and p38 mitogen-activated protein kinase (MAPK) activity or collagen levels in TGF-β1 or cardiac fibroblasts with high glucose content ^[30]. This may support the idea that the anti-fibrotic effects of metformin are also most pronounced at the stages of high-fat nutrition, hyperinsulinemia, and IR prior to the formation of severe hyperglycemia. At the same time, metformin can reduce the hyperglycemia-induced inhibition of the B1/AMPK/Akt pathway, activate GSK3-β, and prevent diabetes-induced cardiomyopathy ^[31], suggesting that, while some mechanisms of the protective effects of metformin are weakened under hyperglycemic conditions, others are characterized by high functionality.

Nearly all the mechanisms underlying the development of HFpEF and diabetic kidney injury are blocked by metformin. In general, they reflect the universal processes of diabetic damage under the conditions of hyperinsulinemia and hyperglycemia: changes in the signaling of the Akt–AMPK–mTOR axis, induction of endoplasmic reticulum (ER) stress and epithelial-to-mesenchymal transition (EMT), inhibition of autophagy processes, generation and accumulation of ROS and AGE; under the influence of chronic hypoxia, an increase in hypoxia-inducible factor (HIF) activity, lipotoxicity, including inhibition of CREBP1 and FAS occurs. ER stress under hyperglycemic conditions is caused by protein accumulation, ROS generation, and mTOR activation in both cardiomyocytes and renal epithelial cells. AMPK activation by metformin protects the myocardium, renal epithelial cells, and other tissues from ER stress by inhibiting the long-term UPR, ROS generation, and mTOR activation. In obesity and type 2 DM, ER stress, which develops under the influence of hypoxia and/or glucose deficiency in the cell, plays an essential role in the activation of the expression of glucose-regulated protein 78 (GRP78). Recently, data on the ability of metformin to influence its activity have been obtained ^[32].

Moreover, the modulation of GRP78 activity by metformin turned out to play a significant role in its antitumor activity ^[33] and in improving the prognosis in COVID-19. Modulation of GRP78 activity may contribute to the implementation of many metformin action mechanisms. Normally, GRP78 is localized in the ER, where it plays an important role in the folding and assembly of proteins and, conversely, in the “re-folding” of misfolded/unfolded proteins or their degradation ^[33].

Under pathological conditions, such as during hypoxia, glucose starvation, in cells infected with fungi and viruses, and in tumor cells, this protein is overexpressed on the cell membrane and can be detected in the circulation in a soluble form. Overexpression of GRP78 on the cell surface facilitates the entry of pathogens (bacterial, fungal, and viral) into the cells and increases the aggressiveness of cancers. The pronounced overexpression of GRP78 in adipose tissue and pancreatic cells in visceral obesity, which is a consequence of hypoxia and intracellular glucose deficiency as a result of IR, is most likely the primary target of metformin in realizing its effects on adipose tissue health, improving the prognosis in COVID-19, and improving the response to treatment of many tumors. In fact, improving cell viability under hypoxic conditions can be identified as the key effect of metformin. Hypoxia and an increase in the level of angiotensin II under its influence in diabetic nephropathy cause the elevation in intrarenal and systemic pressure and the accumulation of collagen. These processes are accompanied by hypoxia-induced rise in HIF1a. The ability of metformin to reduce the severity of these processes has been confirmed by the effect of metformin on the HIF1a level in diabetic nephropathy, which is realized through the inhibition of the mitochondrial respiratory complex I and the oxygen redistribution in the cells. Metformin reduces oxygen demand and consumption and lowers adenosine triphosphate (ATP) levels, which in turn promotes proteasome degradation of HIF1a and prevents hypoxia-induced damage to renal epithelial cells. Metformin may also protect podocytes in diabetic nephropathy ^[34]. Metformin, blocking the AGEs–AGER–ROS axis, exhibits its antioxidant effect and reduces the risk of cellular damage, which has been found to contribute to non-diabetic kidney disease, thus reducing the risk of kidney stones formation. Metformin decreases the severity of inflammation, the penetration of immunocytes into the renal epithelium, and modulates their functions (including in acute renal injury), activates the autophagy process in renal diseases, and reduces apoptosis in an AMPK-dependent way, through mechanisms similar to those described above for HFpEF. Finally, metformin reduces lipotoxicity by inhibiting the cellular damage processes even at the stage of obesity, improving lipid metabolism and protecting cardiomyocytes and mesangial kidney cells from apoptosis caused by lipotoxicity. As already noted, metformin resolves or inhibits pathological processes in non-diabetic renal damage as well. In addition to the abovementioned effect on urolithiasis development, metformin inhibits the progression of autosomal dominant polycystic kidney disease, interfering with cell proliferation and inhibiting cystic fibrosis transmembrane conductance regulator (CFTR) and mTOR signals through AMPK. The ability of metformin to protect the kidney from the toxic effects of nephrotoxic drugs deserves special attention. It protects the renal tubules from damage by regulating oxidative stress and repairing biochemical changes.

An important metformin effect on inhibiting the progression of virtually any renal pathology is its ability to protect against the development of renal fibrosis. Metformin slows down the renal hypoxia-induced fibrosis by inhibiting the stabilization of HIF1α, decreasing renal oxygen consumption, reducing the TGF-β1 level, and blocking its binding to the receptor.

2. Clinical Findings for the Cardioprotective Effects of Metformin on the Cardiorenal Continuum (HFpEF and CKD)

Currently, the effects of metformin therapy have been evaluated in different heart failure (HF) phenotypes. If in HF with reduced ejection fraction metformin had a neutral effect on the risk of death and reduced the risk of hospitalizations, then in HFpEF, metformin therapy was associated with a decrease in the risk of death, as in acute HF. In the abovementioned meta-analysis by Halabi et al., a significantly greater protective effect was observed in patients with EF > 50% (p = 0.003).

In patients with diabetes mellitus, metformin improved both the Doppler measurement of the long-axis lengthening rate (e0) and the isovolumic relaxation time, which indicates an improvement in the echocardiography changes that are characteristic of HFpEF ^[35].

The results of Facila et al. (2016) look impressive: according to this research the use of metformin in the treatment of patients with type 2 DM and acute HF has beneficial effects, reducing the risk of death by 67% (p < 0.001), regardless of age, gender, EF, GFR, and prescribed antidiabetic drugs ^[36]. However, despite growing evidence of the reduced death risk, the current guidelines require discontinuation of metformin therapy in patients with acute conditions associated with the risk of lactic acidosis (LA), such as cardiogenic shock or acute HF ^[37].

3. Metformin in Atherogenesis Inhibition

3.1. Experimental Findings Concerning Metformin Effects on Atherogenesis

Currently, a large pool of data has accumulated demonstrating the important effects of metformin on (a) the elastic properties and biological age of the blood vessels, (b) the processes of lipid accumulation in the vascular wall, and (c) the activation processes of macrophages, formation of their various phenotypes, formation of foam cells, and in a clinical aspect, the formation and stability of atherosclerotic plaque. Virtually all signs of early vascular aging (genomic instability, epigenetic changes, telomere attrition, proteostasis, loss of proteostasis, mitochondrial dysfunction, deregulated nutrient sensing, cellular senescence, stem cell exhaustion, altered intercellular communication) can be modulated by metformin ^[38]^[39]. These data include the ability of metformin to slow the increase in arterial stiffness and pulse wave velocity and the formation of impaired endothelial function and vasodilation; to inhibit chronic vascular inflammation and intima-media complex thickening; to prevent or to reduce the impairment of the blood rheological properties; to prevent the depletion of the capillary network and its dysfunction; to decrease telomere length and telomerase activity; to prevent impaired glucose and lipid metabolism and oxidative stress; to inhibit arterial calcification, an increase the matrix substances deposition, and disorganization of the small vessels in the kidneys and brain; and to level the increase in load on the LV, reducing its hypertrophy. It is important to note that, even at the insulin resistance (IR) stage, the ability of adipocytes to accumulate free fatty acids is impaired, and their level in circulation, especially in the postprandial status, increases, which leads to an increase in the de novo synthesis of diacylglycerol (DAG). This activates α protein kinase C (PKC), which in turn is responsible for the hyperproduction of endothelial O₂ radicals and eNOS inhibition. Metformin prevents the adverse effects of excess dietary fat and carbohydrates, including the effects on vascular function ^[40]. At the DM stage, metformin can reduce hyperglycemia-induced endothelial senescence and apoptosis through a SIRT1-dependent pathway and inhibit OS both under hyperglycemic conditions (in rats and humans) and under fructose or palmitic acid-rich diets. Metformin increases endogenous antioxidant defenses by preventing hyperglycemia-related inhibition of glucose-6-phosphate dehydrogenase, which prevents a decrease in superoxide dismutase-1 production and counteracts the proatherogenic effects of oxidized low-density lipoproteins (oxLDLs) and lectin-like oxLDL receptor LOX-1 ^[40].

Inhibition of the respiratory complex I in mitochondria by metformin is accompanied by a decrease in ATP production and a concomitant increase in adenosine diphosphate and AMP. This altered cellular energy charge is detected by the main cellular energy sensor, AMPK ^[41]^[42]. Experimental studies in ApoE -/- mice have demonstrated the ability of metformin to inhibit atherosclerotic plaque formation, compared to untreated animals.

Metformin protects against atherosclerosis by maintaining endothelial integrity and preventing plaque formation by inhibiting lipid entry into the vascular wall. DM is well-known to be characterized by severe plaque instability ^[43].

In addition, metformin exhibits antithrombotic properties, counteracting the stimulating effect of hyperinsulinemia on the production of an inhibitor of plasminogen activator inhibitor 1 (PAI-1), a negative regulator of fibrinolysis. Metformin directly inhibits the expression of the PAI-1 gene. Studies that examined the effect of metformin on the course of acute myocardial ischemia have yielded fewer striking results. In the center, a clinical and experimental study on the effect of metformin on myocardial resistance to ischemia both in diabetes and in its absence was carried out. The effect of metformin on myocardial resistance to ischemic and reperfusion injury was shown only after its intracoronary administration in animals without DM. These results were explained by the highest concentration of the drug achieved in the myocardium. In addition, given that diabetes itself affected ischemic preconditioning of the myocardium, it is possible that the activation of the defense mechanisms in the myocardium associated with the presence of diabetes cannot be enhanced by an additional stimulus ^[44]. In experimental studies, treatment with metformin was accompanied by the improvement in the functional state of the heart and the inhibition of the HF progression of ischemic and non-ischemic etiology, improving the energy status of the myocardium ^[45].

3.2. Clinical Evidence of the Cardioprotective Effects of Metformin on Atherosclerotic Cardiovascilar Diseases

According to a recent review ^[40], metformin reduces the risk of the development and the progression of atherosclerosis by reducing the severity of IR and inflammation, most importantly, and a number of cardiovascular (CV) risk factors (dyslipidemia, hypertension, glycemia, obesity) and by counteracting the proatherogenic role of oxLDL and LOX-1. These effects have been confirmed in studies on patients with and without type 2 DM. The researchers fully support the opinion that the main atheroprotection effect of metformin is provided by an improvement in insulin sensitivity and, as a result, a decrease in the severity of inflammation and oxidative stress (OS).

One of the earliest and longest-running studies demonstrating the positive effects of metformin on the cardiovascular diseases (CVD) prognosis was the UKPDS study, which demonstrated the ability of metformin to reduce the risk of atherosclerotic cardiovascular events (myocardial infarction (MI)), overall mortality, and diabetes-associated death after the end of the study (UKPDS34) and after 10 years of follow-up (UKPDS80).

The efficacy of metformin in the primary prevention of CV events has been confirmed in a retrospective study ^[46] that compared 3400 patients with type 2 DM who received metformin and lifestyle modification with patients (n = 3400) treated only with lifestyle modification (control group). All patients had no CVD. The average follow-up period was 62.5 months (about 5 years). In the metformin group, there was a decrease in the risk of mortality from all causes by 29.5% (p = 0.007), coronary heart disease by 35.5% (p = 0.004), chronic HF by 31.2% (p = 0.109), and stroke by 30.2% (p = 0.024) in comparison with the control group.

Regarding the ability of metformin to provide a secondary prevention of atherothrombotic events, the Reduction of Atherothrombosis for Continued Health (REACH) Registry provided a strong evidence base in the analysis of almost 20,000 patients. A decrease in overall mortality was demonstrated when taking metformin for 2 years (hazard ratio 0.67; 95% confidence interval (CI) 0.59–0.75; adjusted hazard ratio 0.76; 95% confidence interval 0.65–0.89 (p-value 0.001 for both, log-rank test)). Hazard ratios were adjusted for age, gender, and significant risk factors ^[47]^[48].

Mortality was 6.3% (95% CI 5.2–7.4%) with metformin and 9.8% (95% CI 8.4–11.2%) without metformin (relative risk 0.76 (95% CI 0.65–0.89; p < 0.001)). Association with lower mortality was consistent among the subgroups, including those with a history of congestive HF (relative risk 0.69; 95% CI 0.54–0.90; p = 0.006), elderly patients (>65 years old (0.77; 0.62–0.95; p = 0.02), and patients with glomerular filtration rate (GFR) 30–60 mL/min/1.73 m² (0.64; 95% CI, 0.48–0.86; p = 0.003). Metformin use has been shown to reduce mortality among diabetic patients as a secondary prophylaxis, including those subgroups of patients in which the use of metformin had not been recommended.

Until recently, metformin was not recommended for patients with acute MI ^[49]; however, publications in recent years have indicated the need to change the current paradigm. They have evidenced a reduced risk of death in patients with MI when receiving metformin, while insulin therapy, on the contrary, worsened the prognosis ^[50]. Another analysis compared the effect of metformin with sulfonylurea drugs and thiazolidinediones on the outcome of the first MI. Type 2 DM patients receiving metformin during the acute phase of the first MI showed a significantly lower incidence of CV complications (p = 0.005) compared with those who did not receive it, including the risk of recurrent MI based on multivariate analysis (hazard ratio 0.33; 95% CI 0.12–0.91; p = 0.032). The effect persisted after the adjustment for other risk factors ^[51].

As noted above, HFrEF is predominantly an outcome of atherosclerotic CVD, especially with acute events (MI), so the effects of metformin on its course should be considered in this section. In the study by Eurich et al., in individuals with chronic HF and low left ventricular ejection fraction, metformin did not increase or decrease the risk of death (relative risk 0.91, 95% CI 0.72–1.14; p = 0.34) ^[52]. At the same time, the use of metformin was associated with a significant reduction in the risk of all hospitalizations by 7% (95% CI 0.89–0.98; p = 0.01) without a rise in the risk of lactic acidosis. For many years, metformin has not been recommended for HF because of the risk of increased lactate levels and the development of lactic acidosis. However, the results of clinical observations have shown that this risk is ephemeral, and in reality, metformin therapy improves the survival rate of patients with HF. The mechanism of this effect includes the activation of AMP, which ensures the regression of cardiomyocyte hypertrophy, the suppression of cell apoptosis, the prevention of myocardial fibrosis, and the stimulation of NO synthesis. Researchers will discuss the role of lactate in these processes below. In the later meta-analysis, metformin reduced mortality in HF with both preserved and reduced EF after adjusting for HF treatments such as ACE inhibitors and beta-blockers (β = −0.2 (95% CI −0.3 to −0.1), p = 0.02) ^[53].

4. Role of Lactate Elevation in Realization of Metformin Effects

Meanwhile, studies in recent years have changed the view concerning the role of lactate in the organism. An increase in lactate production occurs with a reduction in aerobic glycolysis under hypoxic conditions, which is accompanied by a compensatory increase in the activity of anaerobic glycolysis and the level of lactate in the circulation. In this variant, lactate acts as a marker of metabolic health ^[54]. Lactate level in the blood in obese patients is significantly higher than in people with normal body weight, reflecting an increase in tissue hypoxia, in particular, hypoxia of adipose tissue, as adipocyte hypertrophy develops. These changes predict the development of oxidative stress and chronic inflammation, which characterize the deterioration of metabolic health. The opposite results were also noted: after bariatric treatment with normalization of the body weight, there was also a decrease in lactate level in the circulation ^[54]. Moderately elevated lactate levels are often observed in patients with an advanced functional class of HF and in other critical conditions (patients with severe renal failure, brain injury). This, to a certain extent, reflects the characteristics of energy metabolism in hypoxic conditions. New data regarding the role of increased muscle lactate in exercise tolerance have also been obtained. A moderate increase in lactate seems to improve the muscle tolerance to stress, and at high concentrations it worsens. With physical exertion, the need for ATP in the muscles increases with insufficient oxygen supply, and the production of lactate grows. Lactate is involved in muscle fiber interactions (lactate intercellular shuttle) during physical activity. Lactate is actively used by the myocardial fibers and the brain. Thus, in recent years, the place of lactate in energy metabolism has dramatically changed, especially in neural energy metabolism ^[55]. There is accumulated evidence that lactate may act as a “critical rescue fuel” for the (central nervous system) CNS when glucose concentrations fluctuate over a wide range. In the CNS, the lactic acid shuttle of astrocyte neurons provides a mechanism through which astrocytes provide energy metabolism, converting glucose to lactate via glycolysis. This astrocytic lactate spreads from astrocytes to the adjacent neurons, where it is oxidized in the mitochondria (to CO₂ + H₂O) to resynthesize ATP and/or be used to produce amino acid neurotransmitters (e.g., glutamate, aspartate, and γ-aminobutyric acid (GABA)). An increased level of lactate in the CNS plays an important role in tumors. Lactate is the “rescue fuel” for the normal CNS cells in cancer, since tumor cells actively exporting lactate have a very low ability to import and use lactate for metabolism. At the same time, tumor cells are more active glucose consumers, which can lead to “consumption hypoglycemia.” Thus, tumor cells actively consume glucose, but they are unable to utilize lactate ^[56]. Hyperlactatemia is a compensatory mechanism that provides energy to normal cells in cancer, including in conditions of hypoglycemia, and this may be one of the mechanisms for improving the prognosis in cancer patients given metformin.

Today lactate is discussed as an extremely useful energy substrate and anti-inflammatory agent, since in inflammatory processes it can inhibit inflammasomes in traumatic brain injury; in acute damage of the pancreas and the liver; in MI, heart surgery and acute HF; and in several other urgent situations ^[57]. At the same time, the regulation of redox/ROS, calcium/calmodulin-activated protein kinase II (CaMK II)/PKC and PGC1a has been discussed as the key mechanisms of its action, which indicates the role of lactate in the realization of metformin’s effects. Therefore, the view of metformin therapy as an option that must be interrupted in urgent situations because of the risk of LA may be outdated. The research discussing the risk of LA from metformin therapy claimed that metformin-induced LA arises only in cases where three conditions are met: lactate level >5mmol/L, pH < 7.35, and metformin concentration in the circulation >5mg/L. Only 10% of cases of LA described as metformin-associated met these criteria ^[58]. In most cases that are recorded as metformin-induced LA, the latter only limited the ability of patients to cope with an increase in lactate levels caused by another event (not metformin) that triggered LA. Moreover, LA patients treated with metformin have a significantly better prognosis than LA patients not receiving metformin ^[59]. Thus, the risk of LA developing from metformin is seriously exaggerated, and in most cases, this therapy gives only moderate hyperlactatemia, which does not worsen the prognosis in urgent situations, but, on the contrary, can improve the energy metabolism and survival. In addition, the latest theories of diabetes development have put redox stress on the list of the earliest changes, appearing long before the development of carbohydrate metabolism disorders inducing a cascade of subsequent pathological events. This once again leads to the usefulness of the earliest administration of metformin in situations with a high risk of prediabetes and diabetes development.

It is possible to draw an analogy to the effects of sodium glucose cotransporter 2 (SGLT2) inhibitors. The increase in the production of ketones allows these drugs to provide a convenient and economical treatment in terms of an oxygen consumption variant of the energy substrate, which is much more suitable for organs in the state of hypoxia. Energy metabolism changes from lipolysis to ketolysis in damaged kidneys ^[60] and heart ^[61]. Hyperactivation of mTORC1 leads to a decrease in renal lipolysis with subsequent renal damage. Elevated ketone bodies increase the severity of renal damage by blocking mTORC1 signals. Thus, the mechanisms of reno- and cardioprotection of SGLT2 inhibitors include the inhibition of mTORC1 by ketone bodies ^[60], and this largely resembles the effects of metformin, also including the inhibition of mTOR and providing an energy substrate suitable for use under hypoxic conditions (lactate).

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