Biguanides are a group of oral antidiabetic agents that can be used along with exercise and diet to treat type 2 diabetes. They lower glucose (blood sugar) in the body by ensuring the liver does not make too much glucose. They also slow the absorption of glucose from food in the small intestine and increase the sensitivity of muscle tissue to insulin, a hormone that allows glucose from the bloodstream into the cells.

Biguanides can also help lower levels of blood fats (lipids) such as triglycerides and cholesterol. They may help patients lose weight by promoting feelings of fullness after meals.

Another potential benefit is that biguanides may help prevent diseases of the large blood vessels such as atherosclerosis. In addition, they are being studied as a treatment for polycystic ovarian syndrome, a female endocrine disorder.

Biguanides are not recommended for people with certain complications, including kidney disease.

The only biguanide approved by the U.S. Food and Drug Administration is metformin. It is one of the few diabetes drugs cleared for use by children. Metformin is also available in several combination drugs.

Biguanides belong to a group of oral medications known as antidiabetic agents, used to treat cases of type 2 diabetes that cannot be controlled solely by exercise and diet. They 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. Biguanides also slow the absorption of glucose from food digested in the small intestine.

In type 2 diabetes, glucose builds up in the bloodstream (hyperglycemia) because the cells are resistant to absorbing it. This insulin resistance triggers many health problems that, among other things, increase the risk for heart attack and stroke. These conditions include:

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

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 antidiabetic 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) and heart conditions.

Another advantage of biguanides is that, unlike many other antidiabetic agents, they do not trigger hypoglycemia. In contrast, many other antidiabetic agents increase insulin production, which boosts the risk of low glucose.

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

Biguanides were introduced into the United States in 1977, but the Food and Drug Administration (FDA) restricted their use after complications from phenformin 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.

Recent research suggests that patients' response to metformin may be gauged early. Those who have significant improvements in glucose control or weight loss within the first year of therapy may not need a different or additional drug for years to come.

The landmark Diabetes Prevention Program (DPP) found that people with prediabetes who took metformin reduced their risk of becoming diabetic, though not as much as the group that relied on exercise and diet. A recent follow-up to the DPP found antidepressants to be a risk factor for developing diabetes, but no increased risk was noted in those who also took metformin. Further study would be needed to explain why use of metformin may reduce risk of diabetes in people who use antidepressants.

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. Other treatments for PCOS include ovulation (fertility) drugs, which are usually the first line of treatment. The FDA has not specifically approved metformin to treat PCOS, prediabetes or insulin resistance, but some physicians prescribe it "off label" for these purposes. Researchers are also studying metformin as a means of preventing weight gain in children taking certain antipsychotic medications.

Biguanides generally are taken two to three times daily with meals. A physician can advise individual patients about the best times for them 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, thiazolidinedione or DPP-4 inhibitor. Biguanides also are sometimes prescribed in tandem with insulin injections.

Metformin is the only biguanide approved by the U.S. Food and Drug Administration (FDA). It is sold in the following formulations and brand names:

A biguanide called buformin may be available in some other countries.

In June 2007 the FDA announced it was seeking stronger “black box” warnings on packaging for thiazolidinediones (TZDs) because of concerns about a potential heightened risk of heart problems. Recent studies have produced mixed findings on whether rosiglitazone increases this risk.

An application for Synordia, a combination of metformin and a cholesterol-reducing drug called fenofibrate, was submitted to European regulators in 2006 but withdrawn late that year by the manufacturer, which said it might resubmit an application in the future. If the application is eventually approved, this would be the first time an antidiabetic agent and a cholesterol drug were available in one pill.

People with kidney disease (diabetic nephropathy) should not use biguanides. They are at increased 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. Other forms of metabolic acidosis, including acute or chronic diabetic ketoacidosis, also rule out use of metformin, according to the FDA.

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. Recent research suggests that metformin may benefit some diabetic patients with heart failure, but the FDA cautions against prescribing it for people with congestive heart failure.

Dehydration also raises the risk of 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, such as barium x-rays, 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
  
  
• Ketosis, a buildup of ketones (waste products produced when the body burns fat for energy instead of glucose
  
  
• 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 glands (e.g., Cushing's syndrome or Addison's disease
  
  
• Overactive or or underactive thyroid gland (hyperthyroidism or hypothyroidism)
  
  
• Underactive pituitary gland (hypopituitarism)
  
  
• Major surgery
  
  
• Disorders of the heart or blood vessels
  
  
• Weakened or malnourished physical condition
  
  
• Severe mental stress

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

Some patients may find that use of biguanides impedes the body’s absorption of vitamin B12. This can increase the risk of B12 deficiency, which causes nerve damage and other problems. It is especially important to avoid this because people with diabetes are already at risk of nerve damage from diabetic neuropathy. A physician may suggest vitamin supplements as a way to restore proper levels of vitamin B12.

Biguanides can cause a significant increase in ovulation (up to eight times). As a result, biguanides are sometimes used to treat polycystic ovarian syndrome. Women taking biguanides should consult with a physician 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

Symptoms of overdose can be similar to the medication’s side effects but are usually more severe.

Biguanides usually interact well with most 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, a group of antihypertensives
  
  
• The antibiotics trimethoprim (Proloprim) or vancomycin (Vancocin)
  
  
• The diuretics amiloride (Midamor), furosemide (Lasix) or triamterene (Dyrenium)
  
  
• The gastrointestinal medications cimetidine (Tagamet) or ranitidine (Tritec, Zantac)
  
  
• The heart medications digoxin (Digitek, Lanoxicaps, Lanoxin), procainamide (Procanbid) or quinidine (Cardioquin, Quinaglute, Quinidex, Quinora)
  
  
• Morphine, an opioid painkiller
  
  
• Quinine (Quinamm, Quiphile), used to treat malaria
  
  
• Warfarin (Coumadin), an anticoagulant

Type 2 diabetes has become more common among children along with obesity. Biguanides (metformin) and a sulfonylurea are the only antidiabetic agents approved for use in this age group by the U.S. Food and Drug Administration (FDA).

Other diabetes drugs being assessed in clinical trials for pediatric use include thiazolidinediones.

Preparing questions in advance can help patients have more meaningful discussions with their physicians regarding their conditions. Patients may wish to ask their doctor the following questions about biguanides:

1. What are the advantages and disadvantages of biguanides for me, compared to other treatments for type 2 diabetes?
   
   
2. Do I have any conditions that rule out or raise concerns about use of biguanides? May I take biguanides if I have heart failure? What if I have kidney or liver disease or have abused alcohol?
   
   
3. Which variety of biguanide or combination drug is best for me?
   
   
4. When and how should I take this drug?
   
   
5. What is my dosage? What should I do if I miss a dosage?
   
   
6. Could any of my other medications interact negatively with biguanides?
   
   
7. How will we know if my dosage or schedule needs to be adjusted?
    
8. Can I expect to lose any weight when taking biguanides?
   
   
9. What side effects might I experience from biguanides? Will lactic acidosis or diabetic ketoacidosis be a concern for me? At what point do I need to notify you of side effects?
   
   
10. Should I take supplements of vitamin B12 when using biguanides?
    
    
11. How should my kidney function be monitored, and how often?
    
    
12. Should I perform regular ketone tests when taking biguanides?
    
    
13. How much alcohol, if any, can I safely drink when using biguanides?
    
    
14. Are biguanides safe for children, elders and pregnant women?
    
    
15. Can improvements in diet and exercise habits reduce or eliminate my need for biguanides?
    
    
16. Can biguanides be prescribed for me if I have prediabetes or insulin resistance? Can they be prescribed to nondiabetic women who have polycystic ovarian syndrome?