Diabetes and Lipid Clinic of Alaska



About Metformin (Glucophage)

Metformin belongs to a class of medications called biguanides. They are used to lower glucose (blood sugar) levels by preventing the liver from producing too much glucose and reduce the amount of glucose from dietary sources. They also increase the sensitivity of muscle tissue to insulin, a hormone made in the pancreas that carries glucose from the bloodstream into the cells. This allows for better absorption of glucose. Biguanides also slow the absorption of glucose from food digested in the small intestine.

In type 2 diabetes, the body maintains excessively high blood glucose levels (hyperglycemia) because the cells are resistant to absorbing glucose. This condition, known as insulin resistance, triggers many health problems, all of which raise the risk for heart attack and stroke. These include:

  • Obesity
  • Low levels of HDL “good” cholesterol
  • High blood pressure
  • High levels of insulin in the blood (hyperinsulinemia)
  • High triglyceride and LDL “bad” cholesterol levels

Biguanides lower glucose by regulating the amount of it in the bloodstream. They also help insulin to move glucose into the cells.

Glucose is a major source of energy for the cells in the body. People get glucose from the foods they eat and from their liver, which produces glucose as a source of energy between meals, particularly at night. However, the liver often begins to overproduce glucose in patients with type 2 diabetes. This can contribute to hyperglycemia.

Glucose control is the main advantage of using biguanides but not the only benefit. Biguanides have also been shown to decrease levels of blood fats (lipids) such as triglycerides and LDL cholesterol. Unlike many anti-diabetic agents, biguanides do not cause patients to gain weight. In fact, many patients find that biguanides help them lose weight.

These factors may help reduce the risk of developing diseases of the large blood vessels such as atherosclerosis (narrowing and hardening of the arteries).

Another advantage of biguanides is that, unlike other anti-diabetic agents, they do not trigger hypoglycemia. In contrast, many other anti-diabetic agents increase insulin production, which also boosts the risk of hypoglycemia.

In addition, biguanides can be a good alternative for patients whose sulfa allergies prevent treatment with other anti-diabetic agents.

Biguanides were introduced into the United States in 1977, but the Food and Drug Administration (FDA) restricted their use after complications were reported. However, the FDA reinstated biguanides in 1994 after they had earned long–term track records of safety in Europe (30 years) and Canada (20 years). In 2005, researchers reviewing 29 clinical trials involving more than 5,000 patients compared the biguanide metformin to other treatments for type 2 diabetes. This meta–analysis found that metformin especially benefited obese patients in controlling glucose, weight, blood pressure and blood fats such as cholesterol.

Researchers are investigating metformin as a treatment for polycystic ovarian syndrome (PCOS), an endocrine disorder that girls and women with prediabetes and type 2 diabetes have an increased risk of developing. The FDA has not specifically approved metformin to treat PCOS, but some physicians prescribe it “off–label” for this purpose.

Biguanides generally are taken two to three times daily with meals. A physician can advise about the best times to take these drugs. The extended–release formula of these drugs is taken once daily, usually with dinner.

Patients who forget to take their dose of biguanides may be advised by their physician or pharmacist to make up the dose only if it is within two hours of their regularly scheduled time. Patients should ask in advance what to do if more than two hours have elapsed, or contact their physician if they have not asked earlier. It is important not to take two doses in close proximity.

In some cases, the glucose–reducing effects of biguanides can be combined with the insulin–enhancing effects of another antidiabetic agent, such as a sulfonylurea. Biguanide effectiveness appears to be particularly enhanced when therapy is combined with the sulfonylurea glyburide. In 2000, the FDA approved a combination of metformin and glyburide, which is marketed under the brand name Glucovance. Another sulfonylurea (glipizide) in combination with metformin was approved by the FDA in 2002.

Biguanides also are sometimes prescribed in tandem with insulin injections.

Types and differences of Biguanides

To date, metformin is the only FDA–approved biguanide available in the United States. It is sold in the following formulations and brand names:

Generic Name

Brand Name(s)



metformin hydrocholoride
extended release

Glucophage XR


Glucovance (with glyburide)
Metaglip (with glipizide)

Conditions of concern with Biguanides

People with kidney disease (diabetic nephropathy) should not use biguanides. They are at high risk of developing a buildup of lactic acid in the blood (lactic acidosis). This is the most serious side effect associated with biguanides and is potentially life–threatening.

A physician should test the kidney function of candidates for biguanide therapy. This can be done using a blood test called the serum creatinine, or a urine test.

Symptoms of lactic acidosis include:

  • Weakness or fatigue
  • Unusual muscle pain
  • Stomach discomfort

Liver disease, heart failure and alcohol abuse (including sporadic episodes of “binge” drinking) all can trigger lactic acidosis. Patients with a history of those conditions may not be good candidates for biguanide therapy. Dehydration also raises the risk of lactic acidosis, so patients should talk to their physician about ways to keep hydrated in all circumstances.

Patients who are having surgery or medical tests that use dye should inform their physician of their use of biguanides. The dyes can impair kidney function, causing the drug to build up in the blood. Patients may be advised to suspend their use of these medications for a period of time.

Other conditions that may affect use of biguanides include:

  • Severe injury, infection or burns
  • High fever
  • Ketones (produced when the body burns fat for energy instead of glucose) in the urine
  • Vomiting, severe diarrhea, slow stomach emptying (gastroparesis) or any other condition that impedes consumption or absorption of food
  • Conditions that cause low glucose (hypoglycemia) or rapid changes in glucose
  • Female hormone changes during puberty, pregnancy or menstruation
  • Overactive or underactive adrenal gland
  • Overactive or underactive thyroid gland
  • Underactive pituitary gland
  • Major surgery
  • Disorders of the heart or blood vessels
  • Weakened or malnourished physical condition
  • Severe mental stress

Potential side effects of Biguanides

Side effects associated with biguanides often can be greatly reduced by taking the medication with food. Side effects include:

  • Vomiting
  • Diarrhea
  • Breathing difficulties
  • Nausea or other stomach symptoms
  • Abdominal bloating or gas
  • Buildup of lactic acid in the blood (lactic acidosis)
  • Resumption of ovulation in premenopausal women who had stopped ovulating

Biguanides can cause a significant increase in ovulation (up to eight times).

Women taking biguanides should consult with a physican about the medication’s affect on fertility.

Patients taking the combination medication metformin and glyburide may experience the following side effects:

  • Skin reaction
  • Dark urine
  • Increased sensitivity to the sun
  • Potentiation of hypoglycemia

Drug or other interactions with Biguanides

Biguanides usually interact well with other medications. However, patients should consult their physicians before taking any additional prescriptions, over–the–counter medications, nutritional supplements or herbal medications.

Patients who take biguanides must be careful to limit their consumption of alcohol, as they can become sick if they consume more than two to four drinks a week.
Medications that may interact poorly with biguanides include:

  • Calcium channel blockers
  • Quinidine (used to treat irregular heartbeat)
  • Amiloride (used to reduce fluid retention)
  • Quinine (used to treat malaria)
  • Cimetidine (used to treat stomach conditions)
  • Ranitidine (used to treat stomach conditions)
  • Dioxin (heart medication)
  • Triamterene (used to reduce edema and fluid retention)
  • Furosemide (used to reduce edema and fluid retention)
  • Trimethoprim (used to treat urinary tract infections)
  • Morphine (painkiller)
  • Vancomycin (antibiotic)
  • Procainamide (used to treat irregular heartbeat)
  • Warfarin (anticoagulant)

Pregnancy use issues with Biguanides

The safety of using biguanides during pregnancy has not been established. Many physicians recommend for women to continue metformin during pregnancy, particularly if there has been a history of irregular menses, miscarriage, high doses of insulin are needed for controlling glucose.

Nor is it known whether these medications are passed to babies during breastfeeding.

Women who are pregnant or may become pregnant should inform their physician.

Pregnant women must maintain proper glucose (blood sugar) levels, as high glucose can cause birth defects or excessive weight gain in babies.

For more information, please consult with the medical professionals at Diabetes and Lipid Clinic of Alaska.

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