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Received: February 10, 2022 / Revised: February 28, 2022 / Accepted: March 1, 2022 / Published: March 4, 2022
The biguanide metformin has been used as first-line therapy in the treatment of type 2 diabetes mellitus (T2DM) for decades. In addition to its glucose-lowering and weight gain prevention properties, the major UK Prospective Diabetes Study (UKPDS) showed cardiovascular protective properties in obese patients with T2DM. Metformin, together with its favorable side effect profile and low cost, has become a cornerstone in the treatment of T2DM worldwide. Additionally, metformin is increasingly being investigated for its potential anticancer and neuroprotective properties in both T2DM patients and non-diabetic patients. Meanwhile, new drugs with strong cardioprotective properties have been introduced to compete with metformin in the treatment of T2DM. In this review, we will discuss real insights into metformin’s various mechanisms of action and evidence of its beneficial effects in cardiovascular disease, cancer and dementia (prevention). In addition to observational evidence, emphasis is placed on randomized trials and recent meta-analyses to provide an up-to-date overview of the use of metformin in clinical practice.
Metformin, a synthetic biguanide, was first synthesized over 100 years ago, in 1922 . It has been on the European market as an antidiabetic drug since 1958. However, competing glucose-lowering biguanides were considered superior and sidelined metformin’s place. In the late 1970s, when competing biguanides, especially phenformin, were withdrawn due to lactic acidosis, metformin was the only biguanide available on the market.
It would be another 25 years before metformin was approved on the US market in 1995. This was due to concerns about the safety profile, particularly the incidence of lactic acidosis. The FDA required a post-marketing safety surveillance study published in 2005 to further strengthen metformin’s safety profile. The Comparative Outcomes Study of Metformin and Conventional Intervention (COSMIC) showed no difference in serious side effects between metformin and metformin alone. Traditional treatment and, in particular, no incidence of lactic acidosis .
Meanwhile, the United Kingdom Prospective Diabetes Study (UKPDS) published in 1998 found that metformin reduced blood glucose and cardiovascular mortality in obese patients with T2DM. This finding was further strengthened by the publication of the UKPDS 10-year follow-up in 2008, which showed a sustained significant reduction in the diabetes-related endpoint (risk reduction (RR) 0.79, 95% confidence interval (CI) 0.66–0.95) in the metformin group. myocardial infarction (RR 0.67 95% CI 0.51-0.89) and death from any cause (RR 0.73 95% CI 0.59 -0.89) .
Based on an ever-growing body of evidence for the positive effects of metformin, a good safety profile, weight gain prevention, and low cost, metformin has become a commonly prescribed drug in type 2 diabetes mellitus (T2DM) and treatment. It is recommended in European and American guidelines as first-line treatment in T2DM .
However, its leading position is now being debated as two new classes of drugs with strong cardioprotective properties have entered the market. These include sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists. With strong evidence for these new drug classes in large cardiovascular outcome studies, metformin’s place is being reevaluated.
In addition to cardiovascular benefits, there is growing evidence that metformin is beneficial for other age-related diseases such as cancer, cognitive impairment, and dementia. Additionally, metformin has been studied in various diseases such as polycystic ovary syndrome (PCOS), osteoporosis, periodontitis, inflammatory bowel disease, non-alcoholic fatty liver disease, covid-19 and anti-aging in general. ].
Thus, metformin’s field of application has been expanding in recent decades, and metformin is re-emerging as a geoprotective agent that can promote healthy aging and extend lifespan. This review will provide an update of the available evidence on the beneficial health effects of metformin on cardiovascular disease, cancer, cognitive impairment and dementia in diabetic and non-diabetic populations.
Biguanides are known to have a wide range of therapeutic indications. Among others, they are used as antidiabetic, antimalarial, anticancer, antimicrobial and antiviral agents . Of all the biguanides, the most research has been done with metformin.
The first clinical use of metformin was as an anti-febrile drug in malaria patients by Garcia in 1950 . Garcia noted the glucose-lowering effect and considered a possible mechanism by which metformin could destroy malaria parasites. Stern changed the paradigm and proposed metformin as the primary antidiabetic agent in 1957 .
A more relevant side effect of biguanides is mitochondrial toxicity leading to lactic acidosis. Although biguanides inhibit isolated mitochondrial complex 1, only biguanides that enter mitochondria do so in vivo. Biguanide-associated activation of AMP-activated protein kinase (AMPK), resulting in glucose depletion, is associated with access to the mitochondrial compartment . This is the reason why some biguanides have glucose-lowering properties but are also highly toxic. Metformin hits the sweet spot with low toxicity and efficient AMPK activation.
Metformin is a hydrophilic cation with metal binding properties, especially copper. Because of its hydrophilic nature, it cannot diffuse across lipid-rich membranes and requires a transporter. Organic cation transporter 1 (OCT1) is an important transporter of metformin and expression of OCT1 cells affects metformin uptake. However, polymorphisms of this transporter do not affect the glycemic response to metformin .
The oral bioavailability of metformin is 50 to 60%. Besides the kidneys and bladder, where unmetabolized metformin is eliminated, increased concentrations of metformin are observed primarily in the intestine, colon, and liver at a tissue-to-plasma ratio of 300 and 3, respectively .
The main glucose-lowering property of metformin is the lowering of fasting blood glucose. Historically, this has been attributed to decreased hepatic gluconeogenesis and thus decreased endogenous hepatic glucose production. Especially in long-term T2DM, this is an important mechanism because increased hepatic glucose production is a well-known pathophysiological mechanism .
However, a systematic review found that reduced endogenous glucose production explains only part of the fasting glucose reduction and that increased glucose disposal is the other major component . This is further supported by recent studies that, in recent-onset T2DM, metformin may increase endogenous glucose production .
The intestinal tract may be the main activity involved in glucose disposal. Metformin restores glucose absorption in the small and large intestine. A 26-week, randomized, placebo-controlled trial assessing intestinal glucose uptake by fluorodeoxyglucose positron emission tomography (FDG-PET) showed a 2-fold increase in the small intestine and a 3-fold increase in the colon in metformin users. . In addition, metformin alters the composition of the gut microbiome and stimulates the secretion of GLP-1 by enterocytes, as well as sensitization to GLP-1 . These are additional mechanisms as the effects of metformin on intestinal glucose transport are independent of GLP-1 secretion .
A significant intestinal action is also consistent with studies showing that delayed absorption targeting the ileum was equally effective compared to immediate absorption of metformin. The glycemic effects of metformin were sustained despite lower metformin plasma levels in the delayed absorption group . In addition, intravenous administration of metformin did not show severe changes in glucose metabolism, unlike oral administration .
In addition, side effects of metformin are related to the gastrointestinal tract. Up to 30% of metformin users experience nausea, vomiting, diarrhea, bloating, or abdominal pain . Impaired absorption of bile salts from the ileum contributes to osmotic bile salt diarrhea. Nausea, taste aversion and decreased
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