Many pharmacists probably already have seen prescriptions for Glucophage (metformin hydrochloride), a new drug developed for patients with noninsulin-dependent diabetes mellitus, or NIDDM.
The oral antihyperglycemic, from Bristol-Myers Squibb Co., Princeton, N.J., won Food and Drug Administration approval in the spring and is indicated for some people with NIDDM, either as an adjunct to diet therapy or in conjunction with a sulfonylurea, such as chlorpropamide or glyburide. While Glucophage is new, metformin actually is not. Its lively history and the findings of studies on its safety and efficacy are important to note in making future recommendations to patients, many of whom develop the milder form of diabetes as adults because of poor diets or excessive alcohol consumption. Metformin is categorized as a biguanide, and its ancestry can be traced to medieval times when French lilac, or goat's rue -- a plant rich in guanidine -- was used as a diabetes treatment in Southern and Eastern Europe. But when guanidine was mass-extracted from the plant and offered widely for its glucose-lowering effect around World War I, the substance was found to be too toxic for general use. The development of insulin gained speed in the 1920s, leaving most biguanide research in its dust. In the 1940s, chlorguanidine was introduced as an antimalarial with a mild glucose-lowering effect. But it was not until the 1950s, prompted by the introduction of the oral sulfonylureas, that the biguanides became the focus of diabetes studies once again. In 1957, metformin and phenformin were introduced as oral glucose-lowering agents to treat NIDDM. Phenformin was withdrawn in many countries in the 1970s because of its association with lactic acidosis. Metformin, although it did not have the same risk if properly prescribed, also fell out of favor in America about the same time because of possible toxic effects.
But use of metformin has continued abroad because of its novel approach to lowering blood glucose. It is readily distinguished from the sulfonylureas in three ways:
It ameliorates hyperglycemia without stimulating insulin.
It does so without promoting weight gain.
Its use is without the risk of clinical hypoglycemia.
Metformin may also benefit lipid homeostasis. As a result, the drug is often preferred for the treatment of overweight NIDDM patients.
The launch of Glucophage follows the publication of several studies on metformin in recent years. Two studies in particular, published in the journal Diabetes in 1993, looked at the safety and efficacy of metformin as well as the drug's efficacy when combined with glyburide in patients not responding to maximal dose sulfonylureas. One of the studies took diabetes subjects who were not controlled by diet alone and gave them metformin for six months. At the end .of the study, the mean fasting plasma glucose was 183 for the metformin group, compared with 240 for the placebo group. Metformin was found to improve the lipid profile as well, lowering cholesterol by an average of 22 points and triglycerides by 82. While the metformin group had more gastrointestinal complaints, most were self-limiting diarrhea and nausea. No documented hypoglycemia occurred in the metformin group. The investigators found that metformin treatment in NIDDM patients who were less than optimally controlled with diet alone produced statistically significant improvement in glycemic control and lipid profile without causing either hyperinsulinemia -- and subsequent hypoglycemia -- or body weight gain.
The study concluded that in the majority of NIDDM patients who fail on sulfonylureas, combined metformin-glyburide therapy can achieve good glycemic control without causing hypoglycemia and can positively affect the lipid profile -- better than either metformin or glyburide alone. Pharmacists will find that when they receive prescriptions for metformin, the physician may or may not decrease the dosage of the sulfonylurea. If the physician does not, then the pharmacist should remind the patient what to monitor in terms of drug-induced hypoglycemia.
The Lowdown on Hypoglycemia
Low blood sugar, hypoglycemia, can be as knotty a problem as hyperglycemia. Hypoglycemia occurs when insulin activity is inappropriately high in relation to the amount of sugar in the blood.
Studies have shown that in terms of drug-induced hypoglycemia, 90% of cases are caused by the sulfonylureas and the other 10% are associated with combinations of agents known to cause or predispose patients to hypoglycemia. In this time when people are quick to suspect Alzheimer's disease when elderly people exhibit symptoms of dementia, hypoglycemia often goes unconsidered. In fact, hypoglycemia, if sufficiently severe and frequent, can lead to a progressive dementia, especially if the person with diabetes has the disease in its most brittle form and has a history of poorly controlled blood glucose.
Elderly patients, whose drug profile shows irregular antihyperglycemia medication refills and who show up at the pharmacy with new psychotropic prescriptions, may benefit from some interaction with the pharmacist -- for example, blood glucose monitoring or a discussion with the patient's caregiver or a family member.
The elderly have a higher prevalence of hypoglycemia precipitated by the sulfonylureas than younger folks. Long-acting agents include chlorpropamide, which in the average adult has a half-life of 30 to 42 hours and can stay at therapeutic blood levels much longer in the elderly, often up to 100 hours. Glyburide can also cause hypoglycemia in the elderly. Typically, its half-life is five to 16 hours, but this can be prolonged in the elderly with renal insufficiency. Just how tightly an elderly patient's blood glucose should be monitored is a controversial topic. Such people, who are prone to a variety of nutritional and vitamin deficiencies, particularly if they have increasingly limited food preparation skills, have little to gain from hammering their blood sugar down to the 80 to 140 mg/dL range of younger adults. A fasting blood sugar range of 100 to 180 is now considered acceptable.
This is not to minimize the dire effects of diabetes. Indeed, the consequences seem to compound over time. According to a Journal of the American Medical Association meta-analysis published in May 1995, pancreatic cancer occurs with increased frequency among persons with long-standing diabetes. The study concluded that people who had diabetes for at least five years had exactly twice the risk of pancreatic cancer than people without diabetes.
Another report, published by the American Heart Association in its journal Circulation in May 1995, said that while diabetes has been shown to increase the risk of dying from heart and blood vessel disease, most studies have not been large enough or have not lasted long enough to show a connection between the disease and sudden cardiac death.
The 23-year study, led by the Honolulu Heart Program, which looked at 8,002 Japanese-American men living on Oahu, indicates that relative risk of sudden death within 24 hours after symptoms first occurred among men with diagnosed diabetes was almost three times higher than for men with glucose levels in the normal range.
The researchers concluded that the data suggest prevention of diabetes and impaired glucose tolerance may have important implications for the prevention of sudden death. In other words, people with diabetes should continue to tightly monitor their blood glucose, scrupulously follow an approved diet and take their medication as directed.
Ron Gasbarro is a registered pharmacist, a medical journalist and a Doctor of Pharmacy candidate at the University of Maryland.
