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![[U.S. Food and Drug Administration]](http://www.pueblo.gsa.gov/cic_text/health/diabetes-triad/header.gif){kind=small}
by Audrey Hingley
Actress Mary Tyler Moore battles it. Country singer Mark Collie has it. Rhythm and blues singer Pattie LaBelle was diagnosed with it recently.
Celebrities like Moore, Collie and LaBelle are just three well-known faces amid the 16 million Americans suffering from diabetes mellitus, a chronic disease in which the pancreas produces too little or no insulin, impairing the body's ability to turn sugar into usable energy.
In recent years, the Food and Drug Administration has approved a fast-acting form of human insulin and several new oral diabetes drugs, including the most recent, Rezulin (troglitazone), the first of a new class of drugs called insulin sensitizers. This drug is designed to help Type II diabetics make better use of the insulin produced by their bodies and could help as many as 1 million Type II diabetics reduce or eliminate their need for insulin injections.
While it is treatable, diabetes is still a killer. The fourth leading cause of death in America, diabetes claims an estimated 178,000 lives each year. So the treatment is aimed at holding the disease in check, reversing it where possible, and preventing complications.
Philip Cryer, M.D., a professor at Washington University School of Medicine in St. Louis and president of the American Diabetes Association, believes that most people simply don't understand the magnitude of the diabetes problem. "Diabetes is an increasingly common, potentially devastating, treatable yet incurable, lifelong disease. It's the leading cause of blindness in working-age adults, the most common cause of kidney failure leading to dialysis or transplants, and is a leading cause of amputation," he says. "The most recent estimate we have of diabetes' cost [in terms of] direct medical care is $90 billion dollars annually--more than heart disease, cancer, or AIDS."
At the heart of diabetes control are dietary management and drug treatment. The increasing emphasis on the importance of a healthy diet, the availability of glucose monitoring devices that can help diabetics keep a close watch over blood sugar levels, and the wide range of drug treatments enable most diabetics to live a near-normal life.
Managing the diet is easier now because of food labeling regulations that went into effect in 1994 (see "The New Food Label: Coping with Diabetes" in the November 1994 FDA Consumer).
Two Types of Diabetes
There are two main types of diabetes, Type I and Type II. Insulin-dependent, or Type I, diabetes affects about 5 percent of all diabetics. It's also known as juvenile diabetes because it often occurs in people under 35 and commonly appears in children or adolescents. For example, Mary Tyler Moore, a Type I diabetic who is international chairman of the Juvenile Diabetes Foundation, was diagnosed in her late 20s, following a miscarriage. A routine test found her blood sugar level was 750 milligrams per deciliter (mg/dl), as compared with the normal level, 70 mg/dl to 105 mg/dl. And Collie has been diabetic since age 17.
In Type I diabetes, the insulin-secreting cells of the pancreas are destroyed, with insulin production almost ceasing. Experts believe that this may be the result of an immune response after a viral infection.
Type I diabetics must inject insulin regularly under the skin. Insulin cannot be taken by mouth because it cannot be absorbed from the gastrointestinal tract into the bloodstream. Doses range from one or two up to five injections a day, adjusted in response to regular blood sugar monitoring.
Insulin regulates both blood sugar and the speed at which sugar moves into cells. Because food intake affects the cells' need for insulin and insulin's ability to lower blood sugar, the diet is the cornerstone of diabetes management: Insulin is not a replacement for proper diet.
Symptoms of untreated insulin-dependent diabetes include:
If Type I diabetes goes untreated, a life-threatening condition called ketoacidosis can quickly develop. If this condition is not treated, coma and death will follow.
Type II, or non-insulin-dependent, diabetes is the most common type. It results when the body produces insufficient insulin to meet the body's needs, or when the cells of the body have become resistant to insulin's effect. While all Type I diabetics develop symptoms, only a third of those who have Type II diabetes develop symptoms. Many people suffer from a mild form of the disease and are unaware of it. Often it's diagnosed only after complications are detected.
When they occur, Type II symptoms usually include frequent urination, excessive thirst, fatigue, an increase in infections, blurred vision, tingling in hands or feet, impotence in men, and absence of menstrual periods in women.
Type II diabetes usually develops in people over 40, and it often runs in families. For instance, Pattie LaBelle was diagnosed with Type II diabetes at age 50, and her mother died of the disease.
Type II diabetes is often linked to obesity and inactivity and can often be controlled with diet and exercise alone. Type II diabetics sometimes use insulin, but usually oral medications are prescribed if diet and exercise alone do not control the disease.
Malfunction in Glucose Metabolism
In a normal body, carbohydrates (sugars and starches) are broken down in the intestines to simple sugars (mostly glucose), which then circulate in the blood, entering cells, where they are used to produce energy. Diabetics respond inappropriately to carbohydrate metabolism, and glucose can't enter the cells normally.
Insulin--a hormone that is made in the pancreas and released into the bloodstream and carried throughout the body--enables the organs to take sugar from the blood and use it for energy. If body cells become resistant to insulin's effect or if there isn't enough insulin, sugar stays in the blood and accumulates, causing high blood sugar. At the same time, cells starve because there's no insulin to help move sugar into the cells.
Diabetes is diagnosed by measuring blood sugar levels. This can begin with a urine test sampled for glucose because excess sugar in the blood spills over into the urine. Further testing involves taking blood samples after an overnight fast. Normal fasting blood glucose levels are between 70 mg/dl and 105 mg/dl; a fasting blood glucose measurement greater than 140 mg/dl on two separate occasions indicates diabetes.
Diabetes can result in many complications, including nerve damage, foot and leg ulcers, and eye problems that can lead to blindness. Diabetics also are at greater risk for heart disease, stroke, narrowing of the arteries, and kidney failure. But evidence shows that the better the patient controls his or her blood sugar levels, the greater the chances that the disease's serious complications can be reduced.
Shot of Insulin
The first insulin for diabetes was derived from the pancreas of cows and pigs. Today, chemically synthesized human insulin is the most often used. It is prepared from bacteria with DNA technology. Human insulin is not necessarily an advantage over animal insulin, and most doctors don't recommend that patients on animal insulin automatically switch to human insulin. But if they do switch, dosages may change. Human insulin is preferred for those patients who take insulin intermittently.
According to Robert Misbin, M.D., medical officer for metabolic and endocrine drug products in FDA's Center for Drug Evaluation and Research and a practicing physician, some diabetics take beef insulin for religious reasons because of dietary restrictions against pork. "But the vast majority of insulin-dependent diabetics take synthesized human insulin," he says. "Those who are taking a beef or pork insulin and doing well--you don't necessarily change the type of insulin they take. But for new patients I see, I would start them on human insulin."
Diabetics on intensified insulin therapy--that is, those needing multiple daily injections or an insulin pump, which is worn 24 hours a day--can have flexibility in when and what they eat. Other diabetics on insulin therapy must eat at consistent times, synchronized with the time-action of the insulin they use.
In 1996, FDA approved Humalog, which Misbin describes as "a modified human insulin." Humalog is absorbed and dissipated more rapidly than regular human insulin. Misbin says that Humalog is of particular benefit to Type I diabetics who are on very strict regimens.
Julio V. Santiago, M.D., director of the Diabetes Research and Training Center at Washington University's School of Medicine in St. Louis, notes that Humalog is most helpful for diabetics monitoring their blood sugar levels and taking three or more injections of insulin a day. He reports switching most of his Type I patients who fit that profile to the new insulin.
Oral Drugs
Four classes of oral diabetes drugs are now available. The oldest class, sulfonylureas (SFUs), act on the pancreatic tissue to produce insulin. The newest one is Glimepiride, approved by FDA in 1996.
Because SFUs can become less effective after 10 or more years of use, other drugs often are needed. Also, there is some controversy regarding SFUs; some of these agents have been shown in studies to contribute to increased risk of death from cardiovascular disease.
A newer class is the biguanides, including Metformin, which was approved by FDA in 1995. This drug acts by lowering cells' resistance to insulin, a common problem in Type II diabetes.
A third class is the alpha-glucosidase inhibitors, which include Precose, approved by FDA in 1995, and Miglitol, approved in 1996. These drugs slow the body's digestion of carbohydrates, delaying absorption of glucose from the intestines.
In January 1997, FDA approved the first in a new class of diabetes drugs, Rezulin. The new medicine helps Type II diabetics make better use of their own insulin by resensitizing body tissues to the insulin. Parke-Davis, a division of Warner-Lambert of Morris Plains, N.J., plans to begin marketing the drug by summer 1997.
"It will be useful in patients who, despite taking large doses of insulin, still are not achieving adequate glucose control," Misbin says.
Some oral drugs may be used in combination to improve blood sugar control. For example, FDA's Misbin says, Metformin, with an SFU, is particularly useful for Type II diabetics who are obese. "Type II patients who would ordinarily use [only] SFUs do not gain weight with Metformin," he explains. "[The combination] also is used for people taking SFUs but are no longer getting the SFUs' full effect. Studies show that when you add Metformin to a regimen of an SFU, you get a treatment that is better than either drug used alone."
Metformin makes users more sensitive to the body's naturally produced insulin and decreases excessive production of sugar by the liver, another characteristic of Type II diabetes.
The drugs are not without side effects. Metformin, for example, can cause serious cramps and diarrhea, and it can't be used in people with kidney problems. "So if you have to go on this drug, you need to have kidney function tests," Santiago says.
Metformin is also contraindicated in patients with liver dysfunction. "It should be used only in healthy patients, and it's not for the elderly," Misbin says.
Precose is less effective but usually safer to use than Metformin, he points out. Precose's one major side effect is flatulence. Precose stops, or delays, absorption of carbohydrates and in doing so delivers glucose and other carbohydrates, which cause gas, Santiago explains. "Flatulence can occur when the drug is used at high doses, but this can be reduced by beginning the drug at a low dose and going up ... a 'start-low, go-slow' approach."
Product labeling recommends that doctors start patients on lower doses to combat the flatulence problem.
"Although the lowest effective dose is 25 milligrams three times a day with meals, some physicians are starting patients on just 25 mg daily to minimize this side effect," Misbin says.
The newest drug, Rezulin, was well-tolerated in clinical studies. The most commonly reported side effects were infection, pain and headache, but these occurred at rates comparable to those in the placebo-treated patients. The drug should be prescribed with caution in patients with advanced heart failure or liver disease.
Some diabetes experts report that when it comes to prescribing initial therapy for Type II diabetics, some doctors tend to follow a "treatment of laziness"--for example, prescribing SFUs if they perceive difficulties in the patient's ability to change dietary habits or lifestyle.
"Sometimes, patients with diabetes are treated with drugs when it's not really necessary," Misbin says. "Oral pills should be used in Type II diabetes only when diet and exercise are not effective. It's very common for overweight patients who lose weight to lower their own blood sugar levels and come off the medicines. The problem is that it's very difficult to get patients to lose weight."
So, the bottom line in diabetes control still hinges on patients' ability to manage the disease themselves. "I don't know of a chronic disease in which the person who suffers from it is so responsible for its management," says ADA president Cryer. "The patient has to become an expert regarding their own diabetes."
Although drug treatment makes a difference to many diabetics and their quality of life, Cryer adds that current diabetes treatments are still "not ideal." He hopes that continuing research will someday find the answer to the diabetes dilemma.
Audrey Hingley is a writer in Mechanicsville, Va.
For millions of Americans with diabetes, regular home testing of blood glucose levels is critical in controlling their disease.
"The most near-normal glucose patterns you can get will have a terrific long-term impact on how well people with diabetes do," says Steven Gutman, M.D., director of the division of clinical laboratory devices in FDA's Office of Device Evaluation. But he adds, "Tight control isn't easy because it requires multiple glucose measurements."
For many years, diabetics relied on home urine glucose testing to monitor blood sugar levels. But the method was not without drawbacks. Monitoring glucose levels via the urine is problematic for several reasons: First, blood glucose concentrations above which glucose appears in the urine vary widely among individuals, so the tests are not very reliable. Second, factors such as fluid or vitamin C intakes can influence test results. And third, negative tests can't distinguish between normal, low, and moderately high blood sugar levels.
By the late 1960s, manufacturers began introducing home blood glucose monitoring kits. These kits allowed diabetics to detect blood sugar levels by looking at color changes on a chemical test strip using a single drop of blood from a pricked finger. Portable meters that could electronically read the strip and provide immediate results came along in the late 1970s.
Although today's monitors are small, easier to use than early ones, and reasonably priced at between $50 and $100, they all require users to prick their fingers to provide a blood sample for testing. So diabetics were understandably enthusiastic when a noninvasive glucose sensor monitoring device was developed. It doesn't require a finger prick but instead uses infrared technology to measure blood glucose. But after reviewing data from the device's manufacturer, the Clinical Chemistry and Clinical Toxicology Devices Advisory Panel of FDA's Medical Devices Advisory Committee decided more data were needed to ensure the device's safety and effectiveness.
"The idea of being able to test yourself without a painful prick is very attractive. It would probably increase compliance because some patients simply don't want to prick their fingers," Gutman says. "It's a very promising technology. But you have to balance technology against performance."
Gutman said the criteria the company chose to deem the device successful--that 50 percent of readings agree with 20 percent of readings from the patient's finger-prick device--was not an appropriate target. The panel agreed that success should be defined as having 80 to 90 percent of values correlating to values obtained with finger-prick tests. So, the FDA advisory committee also recommended that the sponsor conduct more studies, doing them at multiple sites and involving more women who develop diabetes while pregnant and more children. Also, the committee suggested that the sponsor base the studies on specific study objectives related to performance claims, with the data sufficient to ensure safety and effectiveness.
Julio V. Santiago, M.D., an internist specializing in diabetes and a former member of FDA's Endocrine Advisory Committee, says, "It's an exciting new technology that diabetics could benefit from, so we were rooting for the company. But they failed to demonstrate that the device worked long term for home use."
Santiago says that current invasive finger-prick devices are very reliable, with accuracy within 15 percent of real measurements 80 to 90 percent of the time. Their biggest disadvantage is cost, since each test strip costs 50 cents, and several are often used in one day. A spokesman for Boehringer Mannheim Corp., Rick Naples, says the cost of test strips and lancets needed to perform self blood-glucose monitoring can average between $600 and $1,000 a year.
Gutman says FDA appreciates the need for noninvasive glucose monitors and is anxious to work with companies early in the development of these devices. The Center for Devices and Radiological Health has implemented an expedited review program for devices like noninvasive glucose monitors so items that may be in the interest of public health can be made available in an expedited way without compromising the devices' safety and effectiveness, he says. "Such expedited reviews are given precedence over routine reviews."
Gutman is optimistic about future approval of a noninvasive blood glucose monitoring kit for diabetics. "I'd be very disappointed if we don't eventually see a noninvasive model in the future," he says.
--A.H.
Juvenile Diabetes Foundation
120 Wall St., 19th Floor
New
York, NY 10005
(1-800) 533-2873)
American Diabetes Association
1660 Duke St.
Alexandria, VA
22314
(Or write to your local affiliate)
(1-800) 342-2383)
For catalog of available materials:
(1-800) 232-6733
World Wide
Web: http://www.diabetes.org/
National Diabetes Information Clearinghouse
1 Information Way
Bethesda, MD 20892-3560
(301) 654-3327
E-mail: ndic@aerie.com
FDA Consumer magazine (May-June1997)
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