Description

Simple

A medication used with diet and exercise to control blood sugar in diabetes and is sometimes used to control high blood sugar in a disease called polycystic ovary syndrome (or PCOS).

Clinical

A biguanide drug used in conjunction with diet and exercise for glycemic control in type 2 diabetes mellitus and used off-label for insulin resistance in polycystic ovary syndrome (PCOS).

Overview

Metformin is an antihyperglycemic agent of the _biguanide_ class, used for the management of type II diabetes) [FDA label]. Currently, metformin is the first drug of choice for the management of type II diabetes and is prescribed to at least 120 million people worldwide [14].

Metformin is considered an antihyperglycemic drug because it lowers blood glucose concentrations in type II diabetes without causing hypoglycemia. Metformin is commonly described as an _insulin sensitizer_ leading to a decrease in insulin resistance and a clinically significant reduction of plasma fasting insulin levels [14]. Another well-known benefit of this drug is modest weight loss. Metformin is the drug of choice for obese type II diabetes patients [Read more

Metformin is an antihyperglycemic agent of the _biguanide_ class, used for the management of type II diabetes) [FDA label]. Currently, metformin is the first drug of choice for the management of type II diabetes and is prescribed to at least 120 million people worldwide [14].

Metformin is considered an antihyperglycemic drug because it lowers blood glucose concentrations in type II diabetes without causing hypoglycemia. Metformin is commonly described as an _insulin sensitizer_ leading to a decrease in insulin resistance and a clinically significant reduction of plasma fasting insulin levels [14]. Another well-known benefit of this drug is modest weight loss. Metformin is the drug of choice for obese type II diabetes patients [12].

Metformin was first approved in Canada in 1972 [8], followed by 1995 in the USA [FDA label]. This drug is available in regular and extended-release forms [FDA label]. Read Less

Pharmacology

Indication

**Metformin tablet**

Metformin is indicated as an adjunct to diet and exercise to increase glycemic control in _adults and pediatric patients_ 10 years of age and older diagnosed with type 2 diabetes mellitus.[FDA label]

**Metformin extended-release tablet (XR)**

The extended-release form... Read more

**Metformin tablet**

Metformin is indicated as an adjunct to diet and exercise to increase glycemic control in _adults and pediatric patients_ 10 years of age and older diagnosed with type 2 diabetes mellitus.[FDA label]

**Metformin extended-release tablet (XR)**

The extended-release form is indicated as an adjunct to diet and exercise to improve glycemic control in only _adults_ with type 2 diabetes mellitus. Safety in children has not been determined to this date.[FDA label]

An extended-release combination product containing empagliflozin, linagliptin, and metformin was approved by the FDA in January 2020 for the improvement of glycemic control in adults with type 2 diabetes mellitus when used adjunctively with diet and exercise.[22] Read Less

Pharmacodynamic

**General effects**

Insulin is an important hormone that regulates blood glucose levels [19]. Type II diabetes is characte... Read more

**General effects**

Insulin is an important hormone that regulates blood glucose levels [19]. Type II diabetes is characterized by a decrease in sensitivity to insulin, resulting in eventual elevations in blood glucose when the pancreas can no longer compensate. In patients diagnosed with type 2 diabetes, insulin no longer exerts adequate effects on tissues and cells (called insulin resistance) [19] and insulin deficiency may also be present [21].

Metformin reduces liver (hepatic) production of glucose, decreases the intestinal absorption of glucose, and enhances insulin sensitivity by increasing both peripheral glucose uptake and utilization. In contrast with drugs of the _sulfonylurea_ class, which lead to hyperinsulinemia, the secretion of insulin is unchanged with metformin use [FDA label].

**Effect on fasting plasma glucose (FPG) and Glycosylated hemoglobin (HbA1c)**

HbA1c is an important periodic measure of glycemic control that is used to monitor diabetic patients. Fasting plasma glucose is also a useful and important measure of glycemic control. In a 29-week clinical trial of subjects diagnosed with type II diabetes, metformin decreased the fasting plasma glucose levels by an average of 59 mg/dL from baseline, compared to an average increase of 6.3 mg/dL from baseline in subjects taking a placebo [FDA label]. Glycosylated hemoglobin (HbA1c) was decreased by about 1.4% in subjects receiving metformin, and increased by 0.4% in subjects receiving placebo only [FDA label]. Read Less

Mechanism of action

Metformin's mechanisms of action are unique from other classes of oral antihyperglycemic drugs. Metformin decreases blood glucose levels by decreasing hepatic glucose production (gluconeogenesis), decreasing the intestinal absorption of glucose, and increasing insulin sensitivity by increasing per... Read more

Metformin's mechanisms of action are unique from other classes of oral antihyperglycemic drugs. Metformin decreases blood glucose levels by decreasing hepatic glucose production (gluconeogenesis), decreasing the intestinal absorption of glucose, and increasing insulin sensitivity by increasing peripheral glucose uptake and utilization [FDA label]. It is well established that metformin inhibits mitochondrial complex I activity, and it has since been generally postulated that its potent antidiabetic effects occur through this mechanism [6, 11]. The above processes lead to a decrease in blood glucose, managing type II diabetes and exerting positive effects on glycemic control.

After ingestion, the organic cation transporter-1 (OCT1) is responsible for the uptake of metformin into hepatocytes (liver cells). As this drug is positively charged, it accumulates in cells and in the mitochondria because of the membrane potentials across the plasma membrane as well as the mitochondrial inner membrane. Metformin inhibits mitochondrial complex I, preventing the production of mitochondrial ATP leading to increased cytoplasmic ADP:ATP and AMP:ATP ratios [6]. These changes activate AMP-activated protein kinase (AMPK), an enzyme that plays an important role in the regulation of glucose metabolism [15]. Aside from this mechanism, AMPK can be activated by a lysosomal mechanism involving other activators. Following this process, increases in AMP:ATP ratio also inhibit _fructose-1,6-bisphosphatase_ enzyme, resulting in the inhibition of gluconeogenesis, while also inhibiting _adenylate cyclase_ and decreasing the production of cyclic adenosine monophosphate (cAMP) [6], a derivative of ATP used for cell signaling [16]. Activated AMPK phosphorylates two isoforms of acetyl-CoA carboxylase enzyme, thereby inhibiting fat synthesis and leading to fat oxidation, reducing hepatic lipid stores and increasing liver sensitivity to insulin [6].

In the intestines, metformin increases anaerobic glucose metabolism in enterocytes (intestinal cells), leading to reduced net glucose uptake and increased delivery of lactate to the liver. Recent studies have also implicated the gut as a primary site of action of metformin and suggest that the liver may not be as important for metformin action in patients with type 2 diabetes. Some of the ways metformin may play a role on the intestines is by promoting the metabolism of glucose by increasing glucagon-like peptide I (GLP-1) as well as increasing gut utilization of glucose [6].

In addition to the above pathway, the mechanism of action of metformin may be explained by other ways, and its exact mechanism of action has been under extensive study in recent years [7, 9, 10, 11]. Read Less

Absorption

**Regular tablet absorption**

The absolute bioavailability of a metformin 500 mg tablet administered in the fasting state is about 50%-60%. Single-dose clinical studies using oral doses of metformin 500 to 1500 mg and 850 to 2550 mg show that there is a lack of dose proportionality with an incr... Read more

**Regular tablet absorption**

The absolute bioavailability of a metformin 500 mg tablet administered in the fasting state is about 50%-60%. Single-dose clinical studies using oral doses of metformin 500 to 1500 mg and 850 to 2550 mg show that there is a lack of dose proportionality with an increase in metformin dose, attributed to decreased absorption rather than changes in elimination [FDA label].

At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are achieved within 24-48 hours and are normally measured at <1 μg/mL [FDA label].

**Extended-release tablet absorption**

After a single oral dose of metformin extended-release, Cmax is reached with a median value of 7 hours and a range of between 4 and 8 hours. Peak plasma levels are measured to be about 20% lower compared to the same dose of regular metformin, however, the extent of absorption of both forms (as measured by area under the curve - AUC), are similar [FDA label].

**Effect of food**

Food reduces the absorption of metformin, as demonstrated by about a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute increase in time to peak plasma concentration (Tmax) after ingestion of an 850 mg tablet of metformin taken with food, compared to the same dose administered during fasting [FDA label].

Though the extent of metformin absorption (measured by the area under the curve - AUC) from the metformin extended-release tablet is increased by about 50% when given with food, no effect of food on Cmax and Tmax of metformin is observed. High and low-fat meals exert similar effects on the pharmacokinetics of extended-release metformin [FDA label]. Read Less

Protein binding

Metformin is negligibly bound to plasma proteins [FDA label], in contrast to sulfonylureas, which are more than 90% protein bound [ Read more

Metformin is negligibly bound to plasma proteins [FDA label], in contrast to sulfonylureas, which are more than 90% protein bound [13]. Read Less

Volume of distribution

The apparent volume of distribution (V/F) of metformin after one oral dose of metformin 850 mg averaged at 654 ± 358 L [FDA label].

The apparent volume of distribution (V/F) of metformin after one oral dose of metformin 850 mg averaged at 654 ± 358 L [FDA label]. Read Less

Clearance

Renal clearance is about 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours [FDA label].

Renal clearance is about 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours [FDA label]. Read Less

Half life

Approximately 6.2 hours in the plasma [FDA label] and in the blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution [FDA label].

Approximately 6.2 hours in the plasma [FDA label] and in the blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution [FDA label]. Read Less

Route of elimination

This drug is substantially excreted by the kidney [FDA label].

Renal clearance of metformin is about 3.5 times higher than creatinine clearance, which shows that renal tubular secretion is the major route of metformin elimination. After oral administration, about 90% of absorbed metformin is eli... Read more

This drug is substantially excreted by the kidney [FDA label].

Renal clearance of metformin is about 3.5 times higher than creatinine clearance, which shows that renal tubular secretion is the major route of metformin elimination. After oral administration, about 90% of absorbed metformin is eliminated by the kidneys within the first 24 hours post-ingestion [FDA label]. Read Less

Toxicity

**Metformin (hydrochloride) toxicity data**:

Oral LD50 (rat): 1 g/kg; Intraperitoneal LD50 (rat): 500 mg/kg; Subcutaneous LD50 (rat): 300 mg/kg; Oral LD50 (mouse): 1450 mg/kg; Intraperitoneal LD50 (mouse): 420 mg/kg; Subcutaneous LD50 (mouse): 225 mg/kg [MSDS].

**A note on lactic acidosis**... Read more

**Metformin (hydrochloride) toxicity data**:

Oral LD50 (rat): 1 g/kg; Intraperitoneal LD50 (rat): 500 mg/kg; Subcutaneous LD50 (rat): 300 mg/kg; Oral LD50 (mouse): 1450 mg/kg; Intraperitoneal LD50 (mouse): 420 mg/kg; Subcutaneous LD50 (mouse): 225 mg/kg [MSDS].

**A note on lactic acidosis**

Metformin decreases liver uptake of lactate, thereby increasing lactate blood levels which may increase the risk of lactic acidosis [FDA label]. There have been reported postmarketing cases of metformin-associated lactic acidosis, including some fatal cases. Such cases had a subtle onset and were accompanied by nonspecific symptoms including malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence. In certain cases, hypotension and resistant bradyarrhythmias have occurred with severe lactic acidosis [FDA label]. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), as well as an increased lactate:pyruvate ratio; metformin plasma levels were generally >5 mcg/mL[FDA label].

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment [FDA label].

**A note on renal function**

In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [FDA label].

Metformin should be avoided in those with severely compromised renal function (creatinine clearance < 30 ml/min), acute/decompensated heart failure, severe liver disease and for 48 hours after the use of iodinated contrast dyes due to the risk of lactic acidosis [FDA label]. Lower doses should be used in the elderly and those with decreased renal function. Metformin decreases fasting plasma glucose, postprandial blood glucose and glycosolated hemoglobin (HbA1c) levels, which are reflective of the last 8-10 weeks of glucose control. Metformin may also have a positive effect on lipid levels.

**A note on hypoglycemia**

When used alone, metformin does not cause hypoglycemia, however, it may potentiate the hypoglycemic effects of sulfonylureas and insulin when they are used together [FDA label].

**Use in pregnancy**

Available data from post-marketing studies have not indicated a clear association of metformin with major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was ingested during pregnancy. Despite this, the abovementioned studies cannot definitively establish the absence of any metformin-associated risk due to methodological limitations, including small sample size and inconsistent study groups [FDA label].

**Use in nursing**

A limited number of published studies indicate that metformin is present in human milk. There is insufficient information to confirm the effects of metformin on the nursing infant and no available data on the effects of metformin on the production of milk. The developmental and health benefits of breastfeeding should be considered as well as the mother’s clinical need for metformin and any possible adverse effects on the nursing child [FDA label]. Read Less

Adverse Effects

Contraindications