Metformin or Glucophage is an oral hypoglycemic drug from the group of biguanides (dimethyl biguanide). Metformin’s capacity to inhibit gluconeogenesis, the production of free fatty acids and fat oxidation is linked to its mode of action. The medication improves the sensitivity of peripheral insulin receptors and cellular glucose uptake. There is no impact of Metformin on blood insulin levels (Zhou et al., 2018). The ratio of bound to free insulin is still decreased, and the proportion of insulin to proinsulin is increased, altering the pharmacodynamics.
To start with, Metformin is not a newly introduced drug and has been used for decades. It was discovered in 1950 that Metformin, unlike other similar substances, did not lower animal blood pressure and heart rate (LaMoia & Shulman, 2020). By interfering with glycogen synthase, Metformin promotes glycogen synthesis and boosts the transport capabilities of all kinds of membrane glucose carriers (LaMoia & Shulman, 2020). The medication postpones glucose absorption in the gut. Additionally, it lowers triglyceride, LDL, and VLDL levels (LaMoia & Shulman, 2020). Metformin reduces the tissue-type plasminogen activator inhibitor, which enhances the blood’s fibrinolytic capabilities. The patient’s body weight stays steady or slightly drops while taking Metformin.
By interfering with glycogen synthase, Metformin promotes glycogen production and boosts the ability of all kinds of membrane glucose carriers to transport glucose. The medication slows down the intestinal absorption of glucose. Additionally, it lowers LDL, VLDL, and triglycerides (Zhou et al., 2018). Metformin enhances the blood’s fibrinolytic capabilities by inhibiting the tissue-type plasminogen activator inhibitor. The patient’s body weight either stays steady throughout treatment with Metformin or slightly drops.
When appropriately used, Metformin has few adverse effects, such as gastrointestinal issues, and it has a low risk of hypoglycemia. In those with contraindications, lactic acidosis, the buildup of lactic acid in the blood, can be a severe issue of an overdose, although there is generally very little danger (Lv & Guo, 2020). Metformin does not result in weight gain while lowering triglycerides and LDL cholesterol (Lv & Guo, 2020). Metformin has several important benefits, including a decreasing death rate among patients with diabetes mellitus (Lv & Guo, 2020). Along with the oral anti-diabetic medication glibenclamide, it is included on the World Health Organization’s list of essential medications.
Moreover, Metformin is slowly and insufficiently absorbed from the digestive system after oral treatment. Cmax is obtained in plasma after 2.5 hours, about (Price and Patel, 2022). The absolute bioavailability is between 50 and 60 percent with a single 500 mg dosage (Price and Patel, 2022). The absorption of Metformin is slowed and lowered when food is consumed simultaneously (Zhou et al., 2018). The body quickly absorbs Metformin into the tissues and hardly never binds to plasma proteins. It builds up in the kidneys, liver, and salivary glands. The kidneys unchanged eliminate them. Plasma T1/T2 is 2–6 hours (Zhou et al., 2018). Metformin may build up when renal function is compromised.
What is more, Metformin’s key advantage is its ability to treat type 2 diabetes, especially in obese people. Metformin reduced mortality and the risk of diabetes complications in this group after a ten-year therapy term by around 30% compared to insulin plus sulfonylurea drugs (glibenclamide and chlorpropamide) and by about 40% compared to the group that just got dietary advice (Lv & Guo, 2020). These discrepancies are still present in patients who were followed up for 5–10 years following the investigation (Zhou et al., 2018). Metformin may be the best option for these individuals as intense blood glucose management is linked to less weight gain and fewer hypoglycemia episodes than those treated with insulin and sulfonylurea drugs (Zhou et al., 2018). This is because, among diabetic patients who are overweight, Metformin reduces the risk of diabetes-related outcomes.
Furthermore, compared to sulfonylurea medications, Metformin has a decreased risk of hypoglycemia, while it can still happen sometimes with vigorous activity, a calorie deficit, or when combined with other hypoglycemic medications. Metformin does not cause weight gain and slightly lowers triglyceride and LDL levels (LaMoia & Shulman, 2020). Additionally, it can be used in combination therapy with other medications to manage obesity (Lv & Guo, 2020). Other disorders that exhibit insulin resistance, such as polycystic ovary syndrome (PCOS), non-alcoholic fatty liver disease, and precocious puberty, are being treated with Metformin more and more often. These results are currently regarded as preliminary. Metformin’s advantage in non-alcoholic fatty liver disease has not received much research (Lv & Guo, 2020). The data is currently weak, even though several randomized controlled trials have indicated a considerable benefit with its use.
With the help of Metformin, people at risk of acquiring type 2 diabetes may see a reduction in the condition by taking Metformin. However, vigorous exercise and dietary changes are more appropriate for this goal (Zhou et al., 2018). Participants were split into groups in a significant US trial known as the Diabetes Prevention Program (Zhou et al., 2018). All three groups—one receiving a placebo, one taking Metformin, and the other getting lifestyle recommendations—were observed for an average of three years (Lv & Guo, 2020). Patients were instructed to lose 7% of their body weight and engage in at least 150 minutes of physical activity each week throughout the 16 courses on nutrition and exercise (Lv & Guo, 2020). As a result, this Intensive Lifestyle Program allowed to monitor the progress of the sample.
Consequently, the drug showed improvements among the participants and their quality of life. The diabetes mellitus was 31% and 58% lower in the metformin and lifestyle change groups (LaMoia & Shulman, 2020). Lifestyle changes had no more significant impact on weight loss among younger patients with higher body mass indices than Metformin. For elderly individuals with a low BMI, Metformin was no more effective at preventing diabetes than a placebo (LaMoia & Shulman, 2020). After ten years, diabetes mellitus was 34% lower in those who changed their lifestyles and 18% lower in the group that used Metformin (LaMoia & Shulman, 2020). It is uncertain if Metformin prevented the development of diabetes or only had a hypoglycemic impact on the risk of getting the disease by slowing the evolution of prediabetes into diabetes mellitus (treatment effect).
Lifestyle changes had no more significant impact on weight loss among younger patients with higher body mass indices than Metformin. For elderly individuals with a low BMI, Metformin was no more effective at preventing diabetes than a placebo (Zhou et al., 2018). After ten years, diabetes mellitus was 34% lower in those who changed their lifestyles and 18% lower in the Metformin group (Lv & Guo, 2020). It is uncertain if Metformin prevented the development of diabetes or only had a hypoglycemic impact on the risk of getting the disease by slowing the evolution of prediabetes into diabetes mellitus (treatment effect).
Two days before any radiographic procedure involving the use of iodinated contrast (such as a CT scan or contrast-enhanced angiography), it is advised to stop taking Metformin temporarily. This is done because the contrast agent may temporarily impair kidney function, which could result in lactic acidosis and the retention of Metformin in the body. It is advised to retake Metformin just two days after renal function has returned (LaMoia & Shulman, 2020). Additionally, contraindications include lactic acidosis (with a history of it), hypersensitivity, hyperglycemic coma, ketoacidosis, acute myocardial infarction, dehydration, hypocaloric diet (less than 1,000 kcal/day), pregnancy, and breastfeeding.
Since both cimetidine and Metformin are excreted from the body through tubular secretion, the H2-histamine receptor blocker cimetidine causes an increase in the plasma concentration of Metformin by decreasing its excretion by the kidneys. In particular, cimetidine’s cationic (positively charged) form can compete with Metformin for the exact transport mechanism (Lv & Guo, 2020). A short, double-blind, randomized experiment demonstrated the exact mechanism by which cephalexin boosted metformin levels. Amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, and vancomycin are additional cationic medications that may have a similar impact.
Metformin is incompatible with ethanol, also known as lactate acidosis. Appointments combined with indirect anticoagulants should be avoided. The effect is intensified by the incorporation of salicylates, sulfonylureas, insulin, acarbose, MAO inhibitors, oxytetracycline, ACE inhibitors, clofibrate, and cyclophosphamide (LaMoia & Shulman, 2020). It is possible to lessen the hypoglycemic impact of Metformin when used together with GCS, oral hormonal contraceptives, epinephrine, glucagon, thyroid hormones, phenothiazine derivatives, thiazide diuretics, and derivatives of nicotinic acid (LaMoia & Shulman, 2020). Nifedipine speeds up Cmax while slowing down excretion.
However, alternatives to Metformin should be considered in order to diversify treatment and lower risks. Insulin remains the most effective therapy for lowering glucose levels, especially compared to most oral type 2 drugs (including Metformin). Although these treatments are among the best known, many other medications are available for people with type 2 (Lv & Guo, 2020). These additional drugs have dramatic effects; many of them can reduce the risk of various complications associated with diabetes while maintaining similar glucose-lowering properties.
The most typical overdose symptoms include tachycardia, sleepiness, nausea, vomiting, diarrhea, stomach discomfort, and, less frequently, hypoglycemia or hyperglycemia. Lactic acidosis, which results in the buildup of lactate in the body, is the primary potentially fatal side effect of metformin overdose. Patients with lactic acidosis symptoms must be admitted to the hospital (LaMoia & Shulman, 2020). The overuse of Metformin has no particular remedy. Lactic acidosis may initially be treated with sodium bicarbonate solution; however, excessive dosages are not advised since they could worsen intracellular acidosis (Lv & Guo, 2020). Standard hemodialysis or continuous venovenous hemofiltration are required for acidosis that does not respond to sodium bicarbonate. These techniques successfully remove Metformin from blood plasma, preventing additional lactate buildup due to its low molecular weight and lack of affinity for plasma proteins.
It is feasible to monitor therapy, confirm the overdose diagnosis in hospitalized patients, or determine the cause of death during a forensic examination by determining the quantity of Metformin in plasma or serum. In general, the concentration of Metformin in the blood or plasma is 1-4 mg/l in patients getting the medication for therapeutic purposes, 40–120 mg/l in patients experiencing an overdose, and 80–200 mg/l in patients who pass away (LaMoia & Shulman, 2020). In this situation, chromatographic techniques are typically employed for best effect.
Hence, Metformin, also known as Glucophage, is a biguanide-class oral hypoglycemic medication. Metformin stimulates glycogen formation and improves the transmission capacities of all varieties of membrane glucose carriers by interacting with glycogen synthase. In other case, the drug delays the gut’s absorption of glucose. The primary benefit of metformin is its capacity to treat type 2 diabetes, particularly in obese individuals. The metformin and lifestyle change groups had 31% and 58% lower rates of diabetes mellitus, respectively.
LaMoia, T. E., & Shulman, G. I. (2020). Cellular and molecular mechanisms of Metformin action. Endocrine Reviews, 42(1), 77–96.
Lv, Z., & Guo, Y. (2020). Metformin and its benefits for various diseases. Frontiers in Endocrinology, 11.
Price, G. & Patel D. A. (2022). Drug bioavailability. National Library of Medicine.
Zhou, J., Massey, S., Story, D., & Li, L. (2018). Metformin: An old drug with new applications. International Journal of Molecular Sciences, 19(10), 2863.