Metformin – Dosage, Side Effects, and Warnings

What is metformin?

Metformin is an FDA-approved antidiabetic agent that manages high blood sugar levels in type 2 diabetes patients. It reduces glucose absorption from the intestines, lowers liver glucose production, and improves insulin sensitivity. Metformin is recommended with dietary changes and exercise for better results.

Managing blood sugar levels with medications like metformin can prevent complications such as kidney damage, nerve issues, blindness, amputations, and sexual dysfunction. Effective diabetes control can also lower the risk of heart attacks or strokes.

Properties and characteristics of metformin

Drug class	Biguanides
Brand Names	Actoplus Met, Avandamet, Fortamet, Glucophage, Glucovance, Glumetza, Glycon, Invokamet, Janumet, Jentadueto, Kazano, Kombiglyze, Komboglyze, Qternmet, Riomet, Segluromet, Synjardy, Trijardy, Velmetia, Xigduo
Synonyms	Dimethylbiguanid, Metformin, Metformina, Metformine, Metforminum
Molecular Formula	C4H11N5
Molecular Weight	129.16 g/mol
IUPAC Name	3-(diaminomethylidene)-1,1-dimethylguanidine
Structural formula of main components
Pure active ingredient	Metformin
Appearance	Solid
Melting point	223-226 °C
Solubility	Freely soluble
Excretion	This drug is substantially excreted by the kidney
Storage	Recommended storage temperature 2 – 8 °C.
Available Forms	Tablet, Powder
Prescription	Doctor prescription is required

Why Metformin is used for?

Metformin oral tablets are used to treat high blood sugar levels caused by type 2 diabetes. They’re used in combination with diet and exercise.

This drug may be used as part of combination therapy. That means you may need to take it with other drugs.

Side effects of Metformin

Side effects of metformin include:

• Physical weakness (asthenia)
• Diarrhea
• Gas (flatulence)
• Symptoms of weakness, muscle pain (myalgia)
• Upper respiratory tract infection
• Low blood sugar (hypoglycemia)
• Abdominal pain (GI complaints), lactic acidosis (rare)
• Low blood levels of vitamin B-12
• Nausea
• Vomiting
• Chest discomfort
• Chills, dizziness
• Bloating/abdominal distention
• Constipation
• Heartburn

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

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 (also called gluconeogenesis), decreasing the intestinal absorption of glucose, and increasing insulin sensitivity by increasing peripheral glucose uptake and utilization. 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. 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. 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), a derivative of ATP used for cell signaling. 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.

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.

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.

Metformin may interact with other medications

Metformin oral tablet can interact with several other medications. Different interactions can cause different effects. For instance, some can interfere with how well a drug works, while others can cause increased side effects.

Below is a list of medications that can interact with metformin. This list does not contain all drugs that may interact with metformin.

Before taking metformin, be sure to tell your doctor and pharmacist about all prescription, over-the-counter, and other drugs you take. Also tell them about any vitamins, herbs, and supplements you use. Sharing this information can help you avoid potential interactions.

If you have questions about drug interactions that may affect you, ask your doctor or pharmacist.

Diabetes drugs

Using certain diabetes drugs with metformin can cause low blood sugar levels. If you start taking metformin, your doctor may reduce the dosage of your other diabetes medications. Examples of these drugs include:

• Insulin
• Medications that release insulin, such as glyburide

Blood pressure drugs

Diuretics are used to lower blood pressure and may increase your blood sugar levels. Taking these drugs with metformin may interfere with the effectiveness of metformin. Examples of these drugs include:

• Furosemide
• Hydrochlorothiazide

Nifedipine is a calcium channel blocker used to lower blood pressure. It increases the amount of metformin in your body, which may increase your risk of side effects from metformin.

Cholesterol drug

Taking nicotinic acid with metformin may make metformin less effective in lowering your blood sugar.

Glaucoma drugs

Taking metformin with drugs used to treat glaucoma may increase your risk of lactic acidosis. Examples of these drugs include:

• Acetazolamide
• Brinzolamide
• Dorzolamide
• Methazolamide

Topiramate

Taking metformin with topiramate, which is used to treat nerve pain and seizures, may increase your risk of lactic acidosis. You shouldn’t use these medications together.

Phenytoin

Taking metformin with phenytoin, which is used to treat seizures, may make metformin less effective in lowering your blood sugar.

Stomach problem drugs

Taking metformin with cimetidine, which is used to treat heartburn and other stomach issues, may increase your risk of lactic acidosis. If you’re taking metformin, your doctor may choose a different medication for you instead of cimetidine.

Phenothiazines

Taking metformin with phenothiazines, which are antipsychotic medications, may make metformin less effective in lowering your blood sugar. Examples of these drugs include:

• Chlorpromazine
• Fluphenazine
• Prochlorperazine

Hormone drugs

Taking metformin with certain hormone drugs may make metformin less effective in lowering your blood sugar. Examples of these drugs include:

• Corticosteroids (inhaled and oral) such as:
  • Budesonide
  • Fluticasone
  • Prednisone
  • Betamethasone
• Estrogens such as:
  • Hormonal birth control, including birth control pills or patches
  • Conjugated estrogens
  • Estradiol

Tuberculosis drug

Taking isoniazid with metformin may make metformin less effective in lowering your blood sugar.

Thyroid drugs

Taking metformin with certain thyroid drugs may make metformin less effective in lowering your blood sugar. Examples of these drugs include:

• desiccated thyroid
• levothyroxine
• liothyronine
• liotrix

Dosing of Metformin

The dose of this medicine will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For type 2 diabetes:
  • For oral dosage form (extended-release tablets):
    • Adults—
      • Metformin alone (Fortamet®): At first, 1000 milligrams (mg) once a day taken with the evening meal. Your doctor may increase your dose if needed until your blood sugar is controlled. However, the dose is usually not more than 2500 mg per day.
      • Metformin alone (Glucophage® XR): At first, 500 mg once daily with the evening meal. Your doctor may increase your dose if needed until your blood sugar is controlled. However, the dose is usually not more than 2000 mg per day.
      • Metformin alone (Glumetza®): At first, 500 mg once a day taken with the evening meal. Then, your doctor may increase your dose if needed until your blood sugar is controlled. However, the dose is usually not more than 2000 mg per day.
      • Metformin with a sulfonylurea: Your doctor will determine the dose of each medicine.
      • Metformin with insulin: At first, 500 mg once a day. Then, your doctor may increase your dose by 500 mg every week if needed until your blood sugar is controlled. However, the dose is usually not more than 2500 mg per day.
    • Children—Use and dose must be determined by your doctor.
  • For oral dosage form (extended-release suspension):
    • Adults—At first, 5 milliliters (mL) once a day taken with the evening meal. Your doctor may increase your dose by 5 mL weekly if needed until your blood sugar is controlled. However, the dose is usually not more than 20 mL per day.
    • Children 10 to 16 years of age—At first, 5 mL once a day taken with the evening meal. Your doctor may increase your dose by 5 mL weekly if needed until your blood sugar is controlled. However, the dose is usually not more than 20 mL per day.
    • Children younger than 10 years of age—Use and dose must be determined by your doctor.
  • For oral dosage form (solution):
    • Adults—
      • Metformin alone: At first, 5 milliliters (mL) two times a day, or 8.5 mL once a day with meals. Your doctor may increase your dose if needed until your blood sugar is controlled. However, the dose is usually not more than 25.5 mL per day.
      • Metformin with a sulfonylurea: Your doctor will determine the dose of each medicine.
      • Metformin with insulin: At first, 5 mL once a day. Your doctor may increase your dose if needed until your blood sugar is controlled. However, the dose is usually not more than 25 mL per day.
    • Children 10 to 16 years of age—At first, 5 mL two times a day with meals. Your doctor may increase your dose if needed until your blood sugar is controlled. However, the dose is usually not more than 20 mL per day.
    • Children younger than 10 years of age—Use and dose must be determined by your doctor.
  • For oral dosage form (tablets):
    • Adults—
      • Metformin alone: At first, 500 milligrams (mg) two times a day taken with the morning and evening meals, or 850 mg a day taken with the morning meal. Your doctor may increase your dose if needed until your blood sugar is controlled. Later, your doctor may want you to take 500 or 850 mg two to three times a day with meals. However, the dose is usually not more than 2550 mg per day.
      • Metformin with a sulfonylurea: Your doctor will determine the dose of each medicine.
      • Metformin with insulin: At first, 500 mg a day. Your doctor may increase your dose by 500 mg every week if needed until your blood sugar is controlled. However, the dose is usually not more than 2500 mg per day.
    • Children 10 to 16 years of age—At first, 500 mg two times a day taken with the morning and evening meals. Your doctor may increase your dose if needed until your blood sugar is controlled. However, the dose is usually not more than 2000 mg per day.
    • Children younger than 10 years of age—Use and dose must be determined by your doctor.

In case of emergency/overdose

In case of overdose, call the poison control helpline in your locality. If the victim has collapsed, had a seizure, has trouble breathing, or can’t be awakened, immediately call emergency services.

Symptoms of overdose may include hypoglycemia symptoms as well as the following:

• Extreme tiredness
• Weakness
• Discomfort
• Vomiting
• Nausea
• Stomach pain
• Decreased appetite
• Deep, rapid breathing
• Shortness of breath
• Dizziness
• Lightheadedness
• Abnormally fast or slow heartbeat
• Flushing of the skin
• Muscle pain
• Feeling cold

Warnings for Metformin

Metformin has moderate interactions with at least 74 different drugs.

Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center immediately.

Contraindications: Contraindication includes hypersensitivity, chronic heart failure, metabolic acidosis with or without coma, diabetic ketoacidosis (DKA), severe renal disease, abnormal creatinine clearance resulting from shock, septicemia, or myocardial infarction and lactation.

Effects of Drug Abuse: There are no effects of drug abuse from the use of metformin.

Short-Term Effects: There are no short-term effects from the use of metformin.

Long-Term Effects: There are no long-term effects from the use of metformin.

Cautions

• Use with caution in patients with congestive heart failure, fever, trauma, surgery, the elderly, renal impairment, or hepatic impairment.
• Instruct patients to avoid heavy alcohol use.
• Suspend therapy prior to any type of surgery.
• Rare, but serious, lactic acidosis can occur due to accumulation.
• Possible increased risk of cardiovascular (CV) mortality.
• May cause ovulation in anovulatory and premenopausal polycystic ovary syndrome (PCOS) patients.
• It may be necessary to discontinue therapy with metformin and administer insulin if patient is exposed to stress (fever, trauma, or infection).
• Ethanol may potentiate metformin’s effect on lactate metabolism.
• May impair vitamin B12 or calcium intake/absorption; monitor B12 serum concentrations periodically with long-term therapy.
• Not indicated for use in patients with type 1 diabetes mellitus that are insulin dependent due to lack of efficacy.
• Withhold in patients with dehydration and/or prerenal azotemia.
• Iodinated contrast imaging procedures.
• Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinate contrast.
• Reevaluate eGFR 48 hr after the imaging procedure; restart metformin if renal function is stable.

Pregnancy and Lactation

Use in pregnancy may be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

Not recommended when lactating as metformin enters breast milk.