Metformin is an oral medication commonly used to treat type 2 diabetes. [R] Metformin works by reducing the amount of glucose produced by the liver and increasing the sensitivity of muscle and fat cells to insulin, allowing them to take up more glucose from the bloodstream. This leads to a decrease in blood glucose levels. [R]
Diabetes, a chronic metabolic illness is defined by either insufficient insulin production or an inability of the body to react to it. Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia are the disease’s hallmarks and are brought on by problems with insulin secretion, decreased sensitivity of the tissue to insulin (insulin resistance), or a combination of the two. It is a dangerous endocrine syndrome that is marked by poor metabolic management and increases the risk of cardiovascular illnesses, such as atherosclerosis, renal failure, blindness, or diabetic cataract [R].
Type-1 diabetes (insulin-dependent diabetes mellitus, or IDDM) and Type-2 diabetes (non-insulin-dependent diabetes mellitus, or NIDDM) are two different types of the disease. About 10% of people worldwide have diabetes, and 90% of those cases are Type-2. [R]
Also known by synonyms as Metformin hydrochloride, N,N-dimethylbiguanide
What is Metformin?
Metformin medication is the most often prescribed antidiabetic medication in the world and has been the first-line treatment for the population with type 2 diabetes (T2DM) over the past 20 years. [R]
The original source of the biguanide drug metformin was a guanidine derivative identified in the plant Galega officinalis. It has an insulin-sensitizing effect and mostly affects the liver’s metabolism. [R]
The main purpose of metformin tablets is to treat type 2 diabetes, especially in the obese affected population. Comparing metformin to insulin, glibenclamide, and chlorpropamide, it has been demonstrated that metformin reduces diabetes mortality and complications by 30%. [R]
How does Metformin work in lowering sugar levels?
Metformin lowers serum glucose levels through a number of various mechanisms, most notably non-pancreatic ones that don’t result in an increase in insulin secretion. It is known as an “insulin sensitizer” because it makes insulin work more effectively. The liver’s endogenous glucose synthesis is similarly suppressed by metformin, primarily as a result of a decrease in the rate of gluconeogenesis and a minor impact on glycogenolysis. Furthermore, metformin stimulates insulin signaling and glucose transport in muscles while inhibiting key enzymes involved in gluconeogenesis and glycogen production in the liver when the enzyme adenosine monophosphate kinase (AMPK) is activated. Any drop in hepatic energy causes AMPK to become active since it controls cellular and organ metabolism. [R] [R]
The peripheral glucose disposal is also boosted by metformin, primarily as a result of increased non-oxidative glucose disposal into skeletal muscle. It typically does not result in hypoglycemia, which makes it a special anti-diabetic medication. [R]
Here’s a more detailed explanation of the mechanism of metformin: [R]
Liver’s inhibition of glucose production: The liver’s normal function is to create glucose through a process known as gluconeogenesis, which is crucial for maintaining blood glucose levels while fasting. However, type 2 diabetics may have excessive liver glucose production, which raises blood sugar levels. Hepatic gluconeogenesis is an enzyme that metformin blocks, which lowers the amount of glucose the liver produces.
Enhanced insulin sensitivity: The hormone insulin aids in the uptake of glucose from the bloodstream by muscle and fat cells. When a person has type 2 diabetes, their cells may develop insulin resistance, which prevents them from correctly responding to insulin signals and absorbing enough glucose from the bloodstream. Metformin works by enhancing insulin sensitivity, which makes cells more receptive to insulin and capable of absorbing more blood glucose.
Slower absorption of glucose from the gut: Metformin may also operate by reducing the rate at which glucose enters the bloodstream after a meal by slowing down the absorption of glucose from the gut.
Overall, metformin’s ability to lower glucose synthesis by the liver, enhance insulin sensitivity, and postpone intestinal glucose absorption are all factors in this medication’s ability to lower blood sugar.
Research has been carried out to evaluate the efficacy and safety of metformin. Metformin has been extensively studied for its potential advantages in a number of additional disorders in addition to its well-established role in glycemic control. Here are a few current areas of metformin research:
Metformin and Glycemic Control
To test the hypothesis that hyperglycemia induces the generation of reactive oxygen species (ROS) by mitochondria, and that treatment with metformin can reduce the oxidative stress exerted. The activity of mitochondrial aconitase was assessed in Goto-Kakizaki (GK) rats, a type 2 diabetes model, to gauge the production of ROS in the mitochondria. The researchers measured the generation of oxidative stress in the aortic tissue, heart, and kidney of GK rats as they developed diabetes, by measuring lipid peroxides, oxidized proteins (carbonyl activity), and mitochondrial aconitase activity. They also measured vascular activity in the aortae by testing the response to acetylcholine and phenylephrine. The results showed that at the age of 12-14 weeks, the blood glucose levels rose dramatically, indicating overt diabetes. The glucose tolerance was impaired, but the increase in blood glucose was not accompanied by changes in plasma insulin.
The amount of oxidized proteins and tissue lipid peroxides increased, while the activity of mitochondrial aconitase was reduced in the aorta and kidney, but not in the heart of diabetic animals. Treatment with metformin almost brought hyperglycemia under control stopped the growth of tissue lipid peroxides and carbonyl peroxides and reversed the decline in aconitase activity. The reaction of aortae in response to phenylephrine was strongly enhanced in diabetic animals, but treatment with metformin prevented these changes. The endothelium-dependent vasodilatation was not affected by diabetes. The study provides evidence that the generation of ROS plays an important role in the onset of diabetes and the development of vascular dysfunction in GK rats with type 2 diabetes and that treatment with metformin can reduce the oxidative stress exerted. [R]
Intensive lifestyle intervention and metformin therapy were shown to slow the progression to diabetes by 58 and 31%, respectively, compared to placebo, in the Diabetes Prevention Program randomized clinical trial. All groups benefited from lifestyle changes, but metformin specifically had a bigger impact on test subjects who were more obese, had higher fasting blood sugar levels, had a history of gestational diabetes, or were younger. In the long run, metformin reduced diabetes by 18% over 15 years compared to placebo, reduced microvascular complications in test subjects who did not develop diabetes (without affecting treatment groups), and suggested a potential effect on atherosclerosis in men through coronary calcium assessment. [R]
In another race of test subjects, in order to determine whether metformin, lifestyle changes, or a combination of both could slow the progression of impaired glucose tolerance (IGT) to diabetes, researchers developed the Indian Diabetes Prevention Programme (IDPP). 531 test subjects were divided into lifestyle modification, metformin, metformin plus lifestyle modification, or control groups in the study. This investigation was not blinded. 250 mg of metformin was administered twice daily. After attempts to increase the dose to 500 mg twice daily in the first 50 subjects resulted in significant intolerability, with reporting symptoms of hypoglycemia, including excessive hunger, sweating, and giddiness, the dose of metformin was decreased to 250 mg twice daily for the remaining participants and the duration of the study. All intervention groups in the IDDP demonstrated a significant reduction in the progression to diabetes, with a lifestyle group showing a reduction of 28.5% (95% CI 20.5-37.3%), a metformin group showing a reduction of 26.4% (95% CI 19.1-35.1%), and a lifestyle modification group showing a reduction of 28.2% (95% CI 20.3-37.0%) compared to control, with no difference between the lifestyle group and the combination of lifestyle with metformin. The number needed to treat with metformin in this high-risk population, which had a cumulative incidence of 55% in the control group at 3 years, was 6.9, comparable to the 6.4 with lifestyle change despite the modest dose of metformin employed in this trial. [R]
Metformin and High Blood Pressure
One study aimed to investigate how metformin, through the activation of the LKB1-AMPK signaling pathway, affects vascular smooth muscle contraction, which is essential for regulating blood flow. The researchers used cultured rat vascular smooth muscle cells and measured myosin light chain kinase (MLCK) and myosin light chain phosphorylation (p-MLC) in response to phenylephrine. They found that metformin inhibited the phenylephrine-mediated increase in MLCK and p-MLC phosphorylation, which was reversed upon inhibition of AMPK and LKB1. The researchers also measured the tension trace in rat aortic rings and found that AMPK activation by metformin decreased phenylephrine-induced contraction. Moreover, metformin inhibited the co-localization of p-MLC and α-smooth muscle actin in response to phenylephrine. The results suggest that activation of AMPK by LKB1 reduces vascular smooth muscle contraction by inhibiting MLCK and p-MLC, which may represent a new therapeutic target for treating high blood pressure. [R]
Metformin and Cancer
Metformin has been shown to have anticancer properties and may help prevent or treat a variety of cancers. [R]
The study investigated the potential mechanisms underlying the cancer-protective effect of metformin in female test subjects with operable endometrial cancer (EC). The study used a “window of opportunity” design, where 11 newly diagnosed, untreated, non-diabetic test subjects with EC received metformin 500 mg from diagnostic biopsy to surgery. Plasma insulin, IGF-1, IGFBP-1, and IGFBP-7 measurements were taken before and after metformin treatment and immunohistochemistry staining was performed on the endometrial cancer before and after metformin treatment. The study found that metformin significantly reduced plasma insulin, IGF-1, and IGFBP-7 levels, and resulted in a clear reduction in ki-67 and pS6 expression, which are markers of cell proliferation. The study suggests that metformin may have anti-proliferative effects in female test subjects with EC in the clinical setting. [R]
According to significant case-control research, metformin may shield the population from pancreatic cancer. In this trial, the risk of pancreatic cancer was 62% lower in the metformin group than in the placebo group, which did not take the drug. In comparison to the placebo group, it was discovered that test subjects taking sulfonylureas or insulin had a 2.5-fold and 5-fold greater incidence of pancreatic cancer, respectively. [R]
Metformin and Cardiovascular disease
Metformin has been found to have cardio-protective effects, including reducing the risk of cardiovascular disease and improving outcomes in test subjects with heart failure. It may also have benefits for peripheral artery disease and other vascular disorders.
The aim of one study was to evaluate the safety and effectiveness of metformin in test subjects with diabetes mellitus and heart failure (HF). The researchers conducted a systematic review of controlled studies and pooled risk estimates where appropriate. Based on these findings, the researchers concluded that metformin is at least as safe as other glucose-lowering treatments in test subjects with diabetes mellitus and HF, even in those with reduced left ventricular ejection fraction or concomitant chronic kidney disease. Thus, metformin may be considered the treatment of choice for test subjects with diabetes mellitus and HF. [R]
In another study, the objective was to compare the effects of glipizide and metformin on major cardiovascular events in type 2 diabetic test subjects with a history of coronary artery disease. The study was a multicenter, randomized, double-blind, placebo-controlled clinical trial, with 304 subjects enrolled. Subject participants were randomly assigned to receive either glipizide (30 mg daily) or metformin (1.5 g daily) for 3 years. The primary endpoints were times to the composite of recurrent cardiovascular events, including death from a cardiovascular cause, death from any cause, nonfatal myocardial infarction, nonfatal stroke, or arterial revascularization. The results of the investigation showed that at the conclusion of the study drug administration, the level of glycated hemoglobin was significantly lower in both groups. At a median follow-up of 5.0 years, 91 subject participants had developed 103 primary endpoints. The results showed that metformin substantially reduced major cardiovascular events compared to glipizide, with an adjusted hazard ratio of 0.54. The secondary endpoints and adverse events were not significantly different between the two groups. The study suggested a potential benefit of metformin therapy on cardiovascular outcomes in high-risk test subjects. [R]
Metformin and Obesity and metabolic syndrome
Large cohort studies have demonstrated the advantages of metformin treatment for weight loss. Traditional theories associated this impact with metabolic repercussions, such as decreased insulin synthesis and hepatic gluconeogenesis. Increasingly convincing evidence points to the manipulation of hypothalamic appetite-regulating centers, modification of the gut microbiome, and reversal of aging-related effects as the causes of metformin-associated weight loss. The therapy of obesity’s side effects, such as hepatic steatosis, obstructive sleep apnea, and osteoarthritis, is another area where metformin is being investigated. [R]
Despite several findings of research regarding weight loss management of this drug, the FDA has not authorized metformin as a weight reduction aid due to the meager and erratic effects of weight loss. Metformin is not recommended as a monotherapy for obese test subjects without metabolic problems like diabetes in the 2015 Endocrine Society Practice Guideline on Pharmacology for Obesity. Metformin is advised for obese test subjects with prediabetes or insulin resistance who do not react to lifestyle changes or other anti-obesity drugs (Grade A; BEL 1), according to the 2016 AACE/ACE guidelines for obesity management. Even though it is currently off-label, metformin is commonly used in individuals who are at high risk for metabolic problems and who cannot tolerate alternative therapies. [R] [R] [R]
Metformin on Aging and Longevity
Some studies have suggested that metformin may have anti-aging and longevity-promoting effects, possibly through its ability to reduce inflammation and oxidative stress. Clinical trials are currently underway to investigate the effects of metformin on age-related conditions such as frailty and cognitive decline.
For example, an article summarizes the current literature on the potential anti-aging effects of metformin. While pre-clinical studies have shown promise, clinical trials investigating metformin’s effects on aging and lifespan have yielded mixed results, with some studies suggesting potential benefits and others finding no significant effect. However, there is a consensus that metformin can improve health span, or the period of life spent in good health, by reducing early mortality associated with various diseases, including diabetes, cardiovascular disease, cognitive decline, and cancer. The review also highlights the need for further research on the pharmacokinetic and pharmacodynamic properties of metformin to better understand its mechanisms of action. Overall, while the evidence for metformin’s ability to increase lifespan is still inconclusive, its ability to improve health span and reduce early mortality associated with various diseases makes it a promising candidate for anti-aging interventions. [R]
Metformin and HIV-associated diabetes
Some antiviral medications have been linked to impaired glucose tolerance, insulin resistance, hyperinsulinemia, and type 2 diabetes mellitus in HIV-infected individuals. These test subjects have been reported to have low HDL, hypertriglyceridemia, and a high risk of cardiovascular illnesses. These metabolic changes are typically accompanied by increased visceral fat and decreased subcutaneous fat. [R]
Protease inhibitor-based antiretroviral treatments block glucose transporter (GLUT)-4-mediated glucose transfer. They are probably partially to blame for the body composition abnormalities and insulin resistance seen in HIV-positive test subjects. After 8 weeks of medication therapy at a dose of 850 mg, three times per day, metformin has been demonstrated to reduce visceral adiposity and insulin resistance. [R] [R]
Overall, metformin is a promising drug with a wide range of potential benefits. However, more research is needed to fully understand its mechanisms of action and its effects on various conditions.
Metformin Side Effects
Common side effects may experience nausea, vomiting, diarrhea, upset stomach, abdominal pain, loss of appetite, headache, metallic aftertaste in the mouth, and rash are typical adverse effects. The majority of the time, these side effects are minor and go away on their own within a few days or weeks. [R]
Lactic acidosis, a rare but potentially fatal condition that can happen when there is a buildup of lactic acid in the body, is one of metformin’s less frequent but more severe side effects. Lactic acidosis symptoms include confusion, weakness, discomfort in the muscles, difficulty breathing, and stomach pain. persons with renal or liver issues, heavy drinkers, persons with heart failure, and with other major medical disorders are more likely to develop lactic acidosis. [R]
It is essential to do blood sugar measurements regularly if the subject is administered generic metformin ER tablets (extended-release). When combined with other diabetes drugs that also lower blood sugar, metformin can result in hypoglycemia (developing low blood sugar). Sweating, shivering, bewilderment, a quick heartbeat, and feeling dizzy are all signs of hypoglycemia. [R] Blood sugar testing is necessary to ensure that the experiment is working correctly, and if the blood sugar falls too low, it is crucial to treat low blood sugar immediately.
A very serious allergic reaction to metformin is rare, including swelling of the face, lips, tongue, or throat, and Stevens-Johnson syndrome, a severe skin rash. A vitamin B12 deficiency, which can cause anemia and nerve damage, may also be linked to long-term metformin use. [R]
Frequently Asked Questions (FAQs)
What is the half-life of Metformin?
After being taken orally, metformin is excreted by the kidneys and has a mean plasma elimination half-life of between 4.0 and 8.7 hours. [R]
Is Metformin legal?
Metformin is USFDA approved medication for diabetes. [R]
It is a prescription medication, thus metformin otc is not available. It can only be obtained from a healthcare provider or with a metformin prescription online. It’s essential to follow your healthcare provider’s instructions regarding the use of metformin, including dosage, frequency, and monitoring blood sugar regularly.
Metformin is an oral medication commonly used to treat type 2 diabetes by reducing the amount of glucose produced by the liver and increasing the sensitivity of muscle and fat cells to insulin. This leads to a decrease in blood glucose levels. Metformin works by inhibiting hepatic gluconeogenesis, enhancing insulin sensitivity, and slowing down the absorption of glucose from the gut. Metformin is an insulin sensitizer, which means it makes insulin work more effectively. It is the most often prescribed antidiabetic medication in the world and has been the first-line treatment for the population with type 2 diabetes over the past 20 years. It is known to reduce diabetes mortality and complications by 30%.
Metformin has been researched in several areas, including cancer prevention and treatment, cardiovascular disease, obesity and metabolic syndrome, aging and longevity, and even HIV. Studies have shown that metformin may have anticancer properties and can reduce the risk of cardiovascular disease while improving outcomes in test subjects with heart failure. Metformin can also aid in weight loss, improve metabolic health, and reduce inflammation. In addition, some research suggests that metformin may have anti-aging and longevity-promoting effects. Clinical trials are ongoing to investigate the potential benefits of metformin on age-related conditions such as frailty and cognitive decline.
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