Metformin (Glucophage): Drug Whys


Generic name: Metformin (multiple manufacturers)
Common U.S. brand names: Glucophage (Bristol-Myers Squibb, USA)
Popularity: Sixteenth most commonly prescribed drug between 2002-2006 (U.S.)
Class: Antidiabetic

Treatment Uses — For treatment of Type 2 diabetes mellitus (DM) when drug therapy is necessary. Metformin is the first drug of choice for Type 2 diabetics. In obese patients, unlike some other antidiabetic agents, it is not associated with weight gain and actually promotes weight loss. May afford better glycemic control when used as an adjunct to insulin therapy in Type 1 DM. Beneficial for preventing development of gestational diabetes in women with insulin resistance or polycystic ovary syndrome (PCOS). In combination with carbohydrate-modified diet, metformin has been used to help nondiabetic, hyperinsulinemic, obese women and adolescents achieve and sustain long-term weight loss. In combination with other agents, metformin reduces a variety of symptoms in adolescents with hyperinsulinemic hypersecretion of ovarian androgens. In PCOS, metformin has increased return of normal menses and ovulation in obese women and is being studied for treatment of infertility. Metformin is not effective for prevention of DM in high-risk patients, in prevention of fibrosis (progressive damage) in non-alcoholic fatty liver, or in reducing fat deposits in HIV patients taking protease inhibitors. In maturity onset diabetes of the young (MODY) — an inherited genetic mutation — metformin performs significantly worse at controlling disease than gliclazide (a different type of antidiabetic agent).   

Diabetes is relatively common: 20.8 million Americans — 7 percent of the total population — have it. Treatment for diabetes is evolving rapidly and will continue to progress with the introduction of newer and different insulins. There are four types of diabetes in the current classification scheme: Type 1, Type 2, other, and gestational diabetes mellitus (GDM). Type 1 results from destruction of the insulin-producing beta-cells, whether immune mediated or from other causes, resulting in an absolute insulin deficiency. Type 2 ranges from insulin resistance in the body to decreased production of insulin, sometimes accompanied by insulin resistance. Other includes genetic defects, diseases of the pancreas or endocrine glands, drug or chemically-induced insulin problems, infections and uncommon forms of immune-mediated diabetes. GDM occurs only during pregnancy. Diet and exercise are the first treatments for DM. When ineffective, drugs are added. Type 1 DM requires insulin. Type 2 is initially treated with oral agents such as metformin, although combined use of oral agents and insulin is becoming an increasingly popular means of achieving better glycemic control.  The terms Insulin Dependent DM (IDDM) and Non-Insulin Dependent DM (NIDDM) are no longer used.

The consequences of untreated or poorly managed diabetes are catastrophic.  As a chronic and progressive disease, tight control of glucose levels (glycemic control) is essential in preventing complications. Diabetes results in a cascade of vascular complications including:

  • Decreased blood supply to the eyes (retinopathy) resulting in loss of sight
  • Poor circulation to the kidneys, eventually requiring dialysis
  • Diminished blood flow to the extremities causing pain syndromes, loss of sensation, greater susceptibility to infections and need for limb amputations
  • Significantly accelerated cardiovascular disease leading to heart attacks and strokes

The overall risk of death for diabetics is twice that of non-diabetics. 

Dosing and Administration — In adults with Type 2 DM, the recommended oral starting dose of metformin is either 500 milligrams twice daily or 850 milligrams once daily. Doses should be taken with meals and are adjusted upward at intervals of one to two weeks based on blood glucose. The maximum daily dose is 2,550 milligrams, which should be taken in two or three divided doses. Usual adult maintenance doses range from 1,000 to 2,550 milligrams daily. There are several extended release versions of metformin on the market with the advantage of once-daily dosing. The recommended oral starting dose in adults for extended release metformin is 500 milligrams once daily with the evening meal, titrated upward in the same fashion as the regular release formulation.  Dose limits for extended release metformin vary by manufacturer. Metformin is not recommended for children under 10 years old. For children aged 10 to 16 years, the recommended oral starting dose is 500 milligrams twice daily with meals. Dosing can be adjusted upward by 500 milligrams weekly (based on blood glucose) to a maximum 2,000 milligrams total daily dose. Safety and effectiveness of extended release metformin in pediatric patients have not been established. Liquid oral formulations of metformin are available.

While absorption is significantly affected by food, it is necessary to take metformin with meals in order to reduce or eliminate considerable gastrointestinal side effects. The effect curiously depends on the dosage form.  Food increases the absorption of extended release metformin by approximately 50 percent, decreases absorption of regular release drug by 40 percent and increases absorption of liquid drug by 17-21 percent depending on the fat content of the meal. Metformin is contraindicated in patients with renal (kidney) dysfunction owing to increased drug accumulation and risk for developing lactic acidosis, a serious and potentially lethal side effect. It should also not be given to patients with hepatic (liver) insufficiency because of the lactic acidosis risk. Metformin can be used in the geriatric population if renal function is normal. 

Overdoses of metformin can result in lactic acidosis, renal failure, hypotension and hypoglycemia. These effects have been observed in adults following overdoses ranging from 45 to 63 grams (45,000 to 63,000 milligrams). Doses of up to 1,700 milligrams produced no significant side effects in health children and adolescents. Usual supportive care and treatments are effective in symptomatic patients. Metformin is dialyzable and hemodialysis offers the added benefit of restoring acid-base balance in overdoses exhibiting significant lactic acidosis.  Hemodialysis should be seriously considered in significantly symptomatic metformin overdoses.

Pharmacology/Pharmacokinetics/Stability — Oral metformin is rapidly absorbed.  Peak blood levels are reached within one to three hours after ingestion of regular release metformin and four to eight hours following extended release ingestion.  The average half-life — time needed for half the active drug to be eliminated from the body — of metformin in the blood is 17.6 hours. Nearly all metformin (90 percent) is excreted by the kidneys; any degree of renal insufficiency prolongs clearance from the body. It is not uncommon for patients taking extended release metformin to observe parts of the pill pass in their stool. There are no studies of metformin use during human pregnancy. While hyperglycemia during pregnancy correlates with significantly higher incidence of congenital abnormalities in the fetus, insulin is the recommended treatment for GDM. Studies of metformin in pregnant rats and rabbits at doses comparable to six times the maximum human daily dose did not result in any birth defects. Nonetheless, until human studies demonstrate safety, metformin should only be taken during pregnancy if clearly needed. Metformin is compatible with breastfeeding. While trace levels of the drug have been found in breast milk, it was undetectable in infants' plasma.

Metformin’s exact mechanism of action is not completely clear. It is believed to work by decreasing hepatic (liver) production of glucose, reducing intestinal absorption of glucose and increasing insulin sensitivity (improving glucose uptake and use at the cellular level).

Metformin tablets come in 500, 850 and 1,000 milligram strengths. Metformin extended release tablets come in 500, 750 and 1,000 milligram strengths, depending on manufacturer. Color, shape and size of tablets vary by manufacturer. Tablets should be stored at room temperature between 68-77 F and protected from light. Occasional temperature variations to 59-86 F are permitted.

Cautions and Warnings — Abnormal renal function decreases clearance of metformin and substantially increases risks of side effects. Kidney function should be monitored before starting metformin and at least annually thereafter.  Any injury, new medication prescription or procedure likely to interfere with renal function should send up a warning flag that metformin may need to be discontinued. These include major surgeries, radiology or catheterization procedures using intravascular contrast dyes, major illnesses and shock states from any cause, or profound dehydration. Patients should be switched to insulin for control of glucose until renal function returns to normal. Patients should also be counseled to monitor their hydration status as renal function depends on adequate fluid volume. They should also be reminded that if they are scheduled for a scan or imaging test requiring injection of intravenous contrast or dye, they should be certain to make everyone involved aware that they are taking metformin.

Metformin contains a “Black Box Warning” from the U.S. Food and Drug Administration (FDA) about a rare but potentially fatal side effect of lactic acidosis. Black Box Warnings are the strongest warning the FDA can require and appear in a black bordered box on drug package inserts warning that studies have shown the medication can cause serious or life-threatening adverse effects. Lactic acidosis from metformin occurs from accumulation of the drug during treatment. It is extremely rare and nearly all cases have occurred in patients with renal insufficiency, either new, onset or preexisting. Half of all cases have been fatal. Symptoms are very vague and might include weakness, excessive sleepiness, vague abdominal discomfort, aches and perhaps respiratory distress.  Patients should be cautioned to report these signs and symptoms immediately. Since alcohol increases the effects of metformin on lactate metabolism, patients taking metformin should be cautioned against excessive alcohol consumption, both acutely and chronically.

Important Side Effects and Interactions — Gastrointestinal side effects are the most commonly reported metformin side effect, occurring in up to 30 percent of all patients at the start of therapy. These include indigestion, nausea, flatulence, bloating, diarrhea and vomiting. The symptoms are nearly always transient and resolve with continued use of metformin. Starting metformin at low doses with gradual dose increases and taking the drug with meals limit GI side effects. In one study, 7 percent of patients on long-term metformin therapy developed asymptomatic vitamin B12 deficiency. The implications of this are unclear but do not appear to be a cause for concern presently.

Hypoglycemia is an obvious potential side effect of any antidiabetic agent. Signs and symptoms of hypoglycemia vary with individuals. The patient and their families should be familiar with their hypoglycemic signs and symptoms, and carry carbohydrate with them should they require it.

There are 65 drugs specifically reported to interact with metformin. Most are either poorly documented or extremely uncommon. Cimetidine, available both over the counter and by prescription to inhibit stomach acid production significantly increases metformin concentrations in the body and also inhibits renal clearance. Dose adjustments of metformin may be necessary. Drugs known to induce hypoglycemia such as steroids and hormones also require attention to metformin dosing.
 
Average Costs — U.S.
• 500 mg, 850 mg and 1,000 mg tablet (generic)
Patient cost: $0.37 each*
Large hospital cost: $0.06 each
*($4.00 at Wal Mart® and Target for one month supply)


References:
1. MICROMEDEX® Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed November, 2007).
2. Albany Medical Center Pharmacy, Albany, New York.
3. ADA Clinical Practice Recommendations.  Diabetes Care. 2007;30(suppl 1):S4-41.

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