Metformin hydrochloride, deep history, Action, best uses, Side effects, Dosage, & Top 12 brands

Introduction

Metformin hydrochloride, commonly known by its brand name Glucophage, is a widely used medication primarily prescribed for the management of type 2 diabetes. It helps control blood sugar levels by decreasing glucose production in the liver and improving the body’s sensitivity to insulin.

History of Metformin HCL

The biguanide class of antidiabetic medications, including metformin, phenformin, and buformin, originates from the plant Galega officinalis, also known as goat’s rue, French lilac, and several other names. However, Galega officinalis itself does not contain biguanide medications. Instead, these are chemically synthesized compounds composed of two guanidine molecules, designed to be less toxic than the plant-derived parent compounds guanidine and glargine.

Initial Research and Synthesis

Metformin was first described in the scientific literature in 1922 by Emil Werner and James Bell as a product of the synthesis of N, N-dimethylguanidine. In 1929, these two scientists Slotta and Tschesche discovered its sugar-lowering action in rabbits, finding it the most potent biguanide analog they studied. Despite this, their findings were largely ignored at the time due to the overshadowing development and success of insulin.

Renewed Interest and Early Clinical Use

Interest in metformin resurfaced in the late 1940s. In 1950, it was found that metformin, unlike some other similar compounds, did not decrease blood pressure and heart rate in animals. In the same year, Filipino physician Eusebio Y. Garcia used metformin, which he called “Fluamine,” to treat influenza.

He noted that it lowered blood sugar to the minimum physiological limit and was not toxic. Garcia believed metformin had multiple therapeutic actions, including bacteriostatic, antiviral, antimalarial, antipyretic, and analgesic effects.

Development and Approval

French diabetologist Jean Sterne was instrumental in bringing metformin to clinical use for diabetes treatment. Studying the antihyperglycemic properties of galegine, an alkaloid related to metformin, Sterne conducted trials on humans and coined the name “Glucophage” (glucose eater) for the medication. His results were published in 1957, marking a significant milestone in metformin’s history.

Global Acceptance and Current Use

Metformin was approved in Canada in 1972, but it took until 1994 for the U.S. Food and Drug Administration (FDA) to approve it for the treatment of type 2 diabetes. Bristol-Myers Squibb produced the first branded formulation of metformin, marketed in the U.S. as Glucophage starting on March 3, 1995. Today, generic formulations of metformin are available in many countries, and it has become one of the world’s most widely prescribed antidiabetic medications.

Metformin HCL mechanism of action

Metformin hydrochloride is a foundation in the treatment of type 2 diabetes mellitus due to its unique mechanism of action that primarily focuses on reducing hepatic glucose production and improving insulin sensitivity. Here’s a detailed look at how metformin works:

1. Inhibition of Hepatic Gluconeogenesis

Metformin primarily acts by reducing the amount of glucose produced by the liver. It achieves this through several biochemical pathways:

Activation of AMPK (AMP-activated protein kinase): Metformin hydrochloride activates AMPK, an enzyme that plays a key role in cellular energy homeostasis. When AMPK is activated, it inhibits gluconeogenesis, the process by which the liver produces glucose from non-carbohydrate sources. This leads to a decrease in hepatic glucose output.

Reduction of mitochondrial respiration: Metformin inhibits complex I of the mitochondrial electron transport chain, which reduces ATP production and increases AMP levels. The increased AMP/ATP ratio further activates AMPK and inhibits the enzymes involved in gluconeogenesis, leading to decreased glucose production.

2. Enhancement of Peripheral Glucose Uptake

Metformin hydrochloride improves insulin sensitivity in peripheral tissues, such as skeletal muscle and adipose tissue, which enhances glucose uptake and utilization:

Increased GLUT4 translocation: By activating AMPK, metformin promotes the translocation of GLUT4 (glucose transporter type 4) to the cell membrane, facilitating glucose uptake into muscle cells.

Improvement in insulin receptor function: It enhances the insulin signaling pathway, thereby increasing the efficiency of insulin receptors and improving glucose uptake.

3. Reduction of Intestinal Glucose Absorption

Metformin also reduces the absorption of glucose from the gastrointestinal tract, contributing to its antihyperglycemic effect:

Delayed carbohydrate absorption: Metformin slows down the absorption of carbohydrates in the intestines, which helps in lowering postprandial (after-meal) glucose levels.

4. Impact on Lipid Metabolism

Metformin has favorable effects on lipid metabolism, which can help reduce cardiovascular risks associated with diabetes:

Decrease in serum triglycerides and LDL cholesterol: Metformin hydrochloride lowers triglycerides and low-density lipoprotein (LDL) cholesterol levels, while it may slightly increase high-density lipoprotein (HDL) cholesterol.

5. Effects on Gut Microbiota

Recent research has suggested that metformin hydrochloride alter the composition of the gut microbiota, contributing to its glucose-lowering effects. Changes in the gut microbiome can influence metabolic processes and improve glucose homeostasis.

Metformin hydrochloride uses

Metformin hydrochloride is a versatile and widely prescribed medication used primarily for the management of type 2 diabetes mellitus. Its efficacy, safety profile, and various additional benefits make it a cornerstone in diabetes treatment. Here are the primary uses of metformin hydrochloride:

1. Management of Type 2 Diabetes Mellitus

First-line therapy: Metformin is the preferred initial pharmacological treatment for type 2 diabetes. It is often prescribed as monotherapy or in combination with other antidiabetic medications, such as sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, and insulin.

Glycemic control: Metformin hydrochloride helps lower blood glucose levels by reducing hepatic glucose production, increasing peripheral glucose uptake, and improving insulin sensitivity. It effectively reduces both fasting and postprandial blood glucose levels.

Prevention of complications: By maintaining glycemic control, metformin helps prevent or delay the onset of diabetes-related complications, such as cardiovascular disease, neuropathy, nephropathy, and retinopathy.

2. Management of Prediabetes

Risk reduction: For individuals with prediabetes (impaired glucose tolerance or impaired fasting glucose), metformin can help reduce the risk of progression to type 2 diabetes. It is particularly beneficial for those who are overweight or obese and have additional risk factors like hypertension or dyslipidemia.

3. Polycystic Ovary Syndrome (PCOS)

Insulin resistance improvement: It is commonly used off-label to manage PCOS, a condition often associated with insulin resistance. By improving insulin sensitivity, metformin can help regulate menstrual cycles, reduce androgen levels, and improve ovulation.

Weight management: Metformin can aid in weight loss or prevent weight gain, which is beneficial for women with PCOS who are often overweight or obese.

4. Gestational Diabetes Mellitus (GDM)

Glycemic control during pregnancy: In some cases, this medicine is used to manage gestational diabetes when lifestyle modifications alone are insufficient. It helps maintain blood glucose levels within the target range, reducing the risk of complications for both the mother and the baby.

5. Treatment of Non-Alcoholic Fatty Liver Disease (NAFLD)

Reduction in liver fat: Metformin hydrochloride has shown promise in reducing liver fat content and improving liver enzyme levels in patients with NAFLD, particularly those who are also insulin resistant.

6. Weight Management and Obesity

Support in weight loss: While not a primary weight-loss drug, metformin can support weight loss in obese or overweight individuals, especially those with insulin resistance or metabolic syndrome.

7. Potential Cardiovascular Benefits

Cardioprotective effects: Metformin is associated with a lower risk of cardiovascular events and mortality in patients with type 2 diabetes. Its beneficial effects on lipid profiles, blood pressure, and endothelial function contribute to its cardioprotective properties.

Metformin Hydrochloride Side effects

Like any medication, metformin hydrochloride can cause side effects in certain people, although it is generally well tolerated. Most side effects are mild and transient, occurring primarily during the initial stages of treatment. Here are the common and less Common side effects associated with metformin hydrochloride:

Common Side Effects

Gastrointestinal Disturbances

• Nausea and vomiting: These symptoms can occur, especially when starting metformin or with higher doses. Taking the medication with meals or starting with a lower dose can help mitigate these effects.
• Diarrhea or stomach discomfort: Some people may experience diarrhea, abdominal pain, or bloating.
• Loss of Appetite Metformin can occasionally reduce appetite, leading to decreased food intake.
• Taste Disturbances: A metallic taste in the mouth or a change in taste perception has been reported by some users of metformin.

Less Common Side Effects

Lactic Acidosis

While rare, lactic acidosis is a serious potential side effect of metformin hydrochloride. It occurs when there is an excessive buildup of lactic acid in the bloodstream. Symptoms include muscle pain or weakness, trouble breathing, stomach pain, nausea, dizziness, and feeling cold. Lactic acidosis requires immediate medical attention and can be fatal if not treated promptly.

Vitamin B12 Deficiency

Prolonged use of metformin may lead to reduced absorption of vitamin B12, potentially causing symptoms such as anemia, neuropathy (nerve damage), or cognitive changes. Regular monitoring of vitamin B12 levels and necessary supplementation are recommended for long-term users.

Hypoglycemia (Low Blood Sugar)

Metformin hydrochloride alone rarely causes hypoglycemia unless used with other diabetes medications that lower blood sugar. However, in some cases, hypoglycemia may occur if food intake is reduced or exercise levels increase significantly.

Liver Function Changes

Transient increases in liver enzymes have been reported in some individuals taking metformin hydrochloride. These changes are usually mild and reversible upon discontinuation of the medication.

Renal Function

Metformin hydrochloride is excreted primarily by the kidneys. In rare cases, it may affect renal function, particularly in individuals with pre-existing kidney disease or conditions predisposing them to renal impairment.

Metformin hydrochloride Dosage

Usual Adult Dose for Type 2 Diabetes

When it comes to the treatment of type 2 diabetes in adults, metformin hydrochloride is commonly prescribed. The dosage may vary depending on individual needs and the guidance of a healthcare provider. Here are the usual adult doses for both immediate-release and extended-release formulations of metformin:

Immediate-Release Metformin

• Initial Dose: The typical starting dose for immediate-release metformin is usually 500 mg orally twice a day or 850 mg once a day.
• Dose Titration: The dosage may be increased gradually based on how well it is tolerated. This can be done by increasing the dosage in 500 mg increments weekly or 850 mg every 2 weeks.
• Maintenance Dose: The usual maintenance dose for immediate-release metformin is 2000 mg per day, divided into two or three doses.
• Maximum Dose: The maximum recommended daily dose of immediate-release metformin is 2550 mg.

Extended-Release Metformin

• Initial Dose: For extended-release metformin, the starting dose is typically 500 to 1000 mg orally once a day.
• Dose Titration: Similar to immediate-release metformin, the dosage can be increased by 500 mg increments weekly, as tolerated.
• Maximum Dose: The maximum recommended daily dose of extended-release metformin is 2000 mg.

Usual Pediatric Dose for Type 2 Diabetes

When it comes to treating type 2 diabetes in pediatric patients aged 10 years or older, metformin hydrochloride may be prescribed. The dosage for pediatric patients may vary based on individual needs and the guidance of a healthcare provider. Here are the typical doses for both immediate-release and extended-release formulations of metformin:

Immediate-Release Metformin

• Initial Dose: For pediatric patients, the usual starting dose of immediate-release metformin is 500 mg orally twice a day.
• Dose Titration: The dosage can be gradually increased by 500 mg increments weekly, as tolerated. The daily dose should be divided into 2 to 3 doses and taken with meals.
• Maximum Dose: The maximum recommended daily dose of immediate-release metformin for pediatric patients is 2000 mg.

Extended-Release Oral Suspension

Initial Dose: For pediatric patients, the starting dose of extended-release metformin is typically 500 mg orally once a day with the evening meal.

Precautions and Warnings

Metformin hydrochloride is generally considered safe and effective for the treatment of type 2 diabetes. However, like any medication, certain precautions and warnings should be considered. It is important to discuss these with your doctor or healthcare provider before starting metformin. Here are some key precautions and warnings associated with metformin hydrochloride:

Kidney Function:Metformin is primarily eliminated by the kidneys. Therefore, it is important to assess kidney function before starting metformin therapy. If you have significant kidney impairment or are undergoing dialysis, metformin may not be suitable for you. Your healthcare provider will determine the appropriate dosage or alternative treatments based on your kidney function.

Lactic Acidosis:Lactic acidosis is a rare but serious side effect associated with metformin use. It occurs when there is a buildup of lactic acid in the body. This condition is more likely to occur in individuals with kidney or liver disease, congestive heart failure, severe infection, or those who consume excessive alcohol. Seek immediate medical attention if you experience symptoms such as rapid breathing, muscle pain, weakness, abdominal discomfort, or dizziness.

Hypoglycemia (Low Blood Sugar):While metformin itself does not usually cause hypoglycemia, it can increase the risk of low blood sugar when used in combination with other antidiabetic medications or insulin. It is important to monitor your blood sugar regularly and be aware of the signs and symptoms of low blood sugar, such as sweating, dizziness, confusion, and shakiness.

Vitamin B12 Deficiency: Long-term use of metformin has been associated with a potential risk of vitamin B12 deficiency. Regular monitoring of vitamin B12 levels and supplementation if necessary may be recommended.

Drug interactions

Metformin hydrochloride can interact with various medications, including prescription drugs, over-the-counter medicines, vitamins, and herbal supplements. These interactions can affect the effectiveness of metformin or increase the risk of certain side effects. It is important to inform your doctor about all the medications you are taking, including any changes in your medication regimen. Here are some common drug interactions associated with metformin hydrochloride:

Insulin and Other Diabetes Medications: Metformin may interact with insulin and other diabetes medications, such as sulfonylureas (e.g., glipizide) or meglitinides (e.g., repaglinide). These combinations can increase the risk of hypoglycemia (low blood sugar) and may require adjustments in medication dosages.

Certain Blood Pressure Medications: Some blood pressure medications, such as beta-blockers (e.g., Concor) and thiazide diuretics (e.g., hydrochlorothiazide), can affect blood sugar control and may require dosage adjustments of metformin or the blood pressure medication.

Corticosteroids: Corticosteroids, such as prednisone, can increase blood sugar levels and may reduce the effectiveness of metformin. Dose adjustments may be necessary if you are taking corticosteroids alongside metformin.

Certain Antibiotics: Some antibiotics, such as trimethoprim/sulfamethoxazole and ciprofloxacin, can increase the risk of high blood sugar levels when taken with metformin. Regular monitoring of blood sugar levels is important in such cases.

Medications that Affect Kidney Function: Metformin is primarily eliminated by the kidneys. Medications that affect kidney function, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and some ACE inhibitors (e.g., lisinopril), can increase the risk of lactic acidosis, a rare but serious side effect of metformin. It is important to discuss the use of these medications with your doctor.

Vitamin B12 Supplements: Long-term use of metformin has been associated with a potential risk of vitamin B12 deficiency. If you are taking vitamin B12 supplements, inform your doctor as they may need to monitor your B12 levels and adjust the dosage if necessary.

Metformin hydrochloride brand name in Pakistan

In Pakistan, Metformin hydrochloride is marketed under various brand names. Some common brand names for Metformin hydrochloride in Pakistan include:

Glucophage Tablet 1g– It is manufactured by Martin dow Pharma

Neodipar Tablet– It is manufactured by Sanofi Pharmaceuticals

Getformin tablets– It is manufactured by Getz Pharma

Glucophage tablets 500mg– It is  manufactured by Martin Dow Pharma

Sitaglu Met tablet– It is manufactured by Hilton Pharma

Xenglu-Met Tablet– It is manufactured by Hilton Pharma

Meteor tablet 500mg– It is manufactured by Asian Continental

Tagipmet xr Tablet– It is manufactured by Highnoon Laboratories Ltd

Xiga-Met tablet– It is Manufactured by CCL Pharma

D-FORMIN MR- It is manufactured by Getz Pharma

NEOPHAGE- It is manufactured by Abbott Laboratories

TABROPHAGE- It is manufactured by Tabros Pharma

Inosita Plus tablet– It is manufactured by Pharmevo Pharma