Cholesterol Reducing Drugs

Cholesterol-reducing drugs are medicines that lower the amount of cholesterol (a fat-like substance) in the blood.

Purpose

Cholesterol is a chemical that can both benefit and harm the body. On the good side, cholesterol plays important roles in the structure of cells and in the production of hormones. But too much cholesterol in the blood can lead to heart and blood vessel disease. To complicate matters, not all cholesterol contributes to heart and blood vessel problems. One type, called high-density lipoprotein (HDL) cholesterol, or "good cholesterol," actually lowers the risk of these problems. The other type, low-density lipoprotein (LDL) cholesterol, or "bad cholesterol," is the type that threatens people's health. The names reflect the way cholesterol moves through the body. To travel through the bloodstream, cholesterol must attach itself to a protein. The combination of a protein and a fatty substance like cholesterol is called a lipoprotein.

Many factors may contribute to the fact that some people have higher cholesterol levels than others. A diet high in certain types of fats is one factor. Medical problems such as poorly controlled diabetes, an underactive thyroid gland, an overactive pituitary gland, liver disease or kidney failure also may cause high cholesterol levels. And some people have inherited disorders that prevent their bodies from properly using and eliminating fats. This allows cholesterol to build up in the blood.

Treatment for high cholesterol levels usually begins with changes in daily habits. By losing weight, stopping smoking, exercising more and reducing the amount of fat and cholesterol in the diet, many people can bring their cholesterol levels down to acceptable levels. However, some may need to use cholesterol-reducing drugs to reduce their risk of health problems.

Description

There are four different classes of cholesterol lowering drugs:

Bile acid sequesterants are drugs that act by binding with the bile produced by the liver. Bile helps the digestion and absorption of fats in the intestine. By blocking the digestion of fats, bile acid sequesterants prevent the formation of cholesterol. Drugs in this class include: cholestyramine (Questran); colestipol (Colestid); and colesevalam (Welchol).

HMG-CoA inhibitors, often called "statins," are drugs that block an enzyme called "3-hydroxy-3-methyl-glutaryl-coenzyme A reductase." This blocks one of the steps in converting fat to cholesterol. These are the most effective cholesterol lowering agents available and in recent years have received increased attention for their benefits beyond helping patients with high cholesterol. In 2003, researchers reported that people with heart failure but no coronary artery disease received benefits after only 14 weeks of statin therapy. In addition, some research has connected the drugs to reduced risk for depression and dementia. Drugs in this group include: atorvastatin (Lipitor); cerivastatin (Baycol); fluvastatin (Lescol); lovastatin (Mevacor); pravastatin (Pravachol); simvastatin (Zocor); and the newest approved drug rosuvastatin (Crestor).

Fibric acid derivatives include clofibrate (Atromid-S); gemfibrozil (Lopid); and fenofibrate (Tricor). Although these drugs are less effective than the statins at lowering total cholesterol, they may be able to lower the low density lipoprotein (LDL) cholesterol while raising the high density lipoprotein (HDL) cholesterol. They probably act by inhibiting lipoprotein lipase activity.

Niacin, or vitamin B-3, also is effective in lowering cholesterol levels. Although the normal vitamin dose of niacin is only 20 mg, the dose required to reduce cholesterol levels is at least 500 mg each day. Niacin probably helps reduce cholesterol by inhibiting very low density lipoprotein (VLDL) secretion in the bloodstream.

Recommended dosage

The recommended dosage depends on the type of cholesterol-reducing drug used. The prescribing physician or the pharmacist who filled the prescription can advise about the correct dosage.

Cholesterol-reducing drugs should be taken exactly as directed and doses should not be missed. Double doses should not be taken to make up for a missed dose.

Physicians may prescribe a combination of cholesterol-reducing drugs, such as pravastatin and colestipol. Following the directions for how and when to take the drugs is very important. The medicine may not work properly if both drugs are taken at the same time of day.

Niacin should not be taken at the same time as an HMG-CoA inhibitor, as this combination may cause severe muscle problems. If niacin is taken in an over-the-counter form, both the prescribing physician and pharmacist should be informed. There are no problems when the niacin is taken in normal doses as a vitamin.

The prescription should not be stopped without first checking with the physician who prescribed it. Cholesterol levels may increase when the medicine is stopped, and the physician may prescribe a special diet to make this less likely.

Precautions

Seeing a physician regularly while taking cholesterol-reducing drugs is important. The physician will check to make sure the medicine is working as it should and will decide whether it is still needed. Blood tests and other medical tests may be ordered to help the physician monitor the drug's effectiveness and check for side effects.

For most people, cholesterol-reducing drugs are just one part of a whole program for lowering cholesterol levels. Other important elements of the program may include weight loss, exercise, special diets, and changes in other habits. The medication should never be viewed as a substitute for other measures ordered by the physician. Cholesterol-reducing drugs will not cure problems that cause high cholesterol; they will only help control cholesterol levels.

People over 60 years of age may be unusually sensitive to the effects of some cholesterol-reducing drugs. This may increase the chance of side effects.

Anyone who is taking an HMG-CoA reductase inhibitor should notify the health care professional in charge before having any surgical or dental procedures or receiving emergency treatment.

Special conditions

People who have certain medical conditions or who are taking certain other medications may have problems if they take cholesterol-reducing drugs. Before taking these drugs, the prescribing physician should be informed of any of the following conditions:

ALLERGIES

Anyone who has had unusual reactions to cholesterol-reducing drugs in the past should inform the prescribing physician before taking the drugs again. The physician also should be told about any allergies to foods, dyes, preservatives, or other substances.

PREGNANCY

Studies of laboratory animals have shown that giving high doses of gemfibrozil during pregnancy increases the risk of birth defects and other problems, including death of the unborn baby. The effects of this drug have not been studied in pregnant women. Women who are pregnant or who may become pregnant should check with their physicians before using gemfibrozil.

Cholesterol-reducing drugs in the group known as HMG-CoA reductase inhibitors (such as lovastatin, fluvastatin, pravastatin and simvastatin) should not be taken by women who are pregnant or who plan to become pregnant soon. By blocking the production of cholesterol, these drugs prevent a fetus from developing properly. Women who are able to bear children should use an effective birth control method while taking these drugs. Any woman who becomes pregnant while taking these drugs should check with her physician immediately.

Cholestyramine and colestipol will not directly harm an unborn baby, because these drugs are not taken into the body. However, the drugs may keep the mother's body from absorbing vitamins that she and the baby need. Pregnant women who take these drugs should ask their physicians whether they need to take extra vitamins.

BREASTFEEDING

Because cholestyramine and colestipol interfere with the absorption of vitamins, women who use these drugs while breastfeeding should ask their physicians if they need to take extra vitamins.

Women who are breastfeeding should talk to their physicians before using gemfibrozil. Whether this drug passes into breast milk is not known. But because animal studies suggest that it may increase the risk of some types of cancer, women should carefully consider the safety of using it while breastfeeding.

HMG-CoA reductase inhibitors (such as lovastatin, pravastatin, fluvastatin and simvastatin) should not be used by women who are breastfeeding their babies.

OTHER MEDICAL CONDITIONS

Cholesterol-reducing drugs may make some medical problems worse. Before using these drugs, people with any of these medical conditions should make sure their physicians are aware of their conditions:

* stomach problems, including stomach ulcer

* constipation

* hemorrhoids

* gallstones or gallbladder disease

* bleeding problems

* underactive thyroid

* heart or blood vessel disease

In addition, people with kidney or liver disease may be more likely to have blood problems or other side effects when they take certain cholesterol-reducing drugs. And some drugs of this type may actually raise cholesterol levels in people with liver disease.

Patients with any of the following medical conditions may develop problems that could lead to kidney failure if they take HMG-CoA reductase inhibitors:

* treatments to prevent rejection after an organ transplant

* recent major surgery

* seizures (convulsions) that are not well controlled

People with phenylketonuria (PKU) should be aware that sugar-free formulations of some cholesterol-reducing drugs contain phenylalanine in aspartame. This ingredient can cause problems in people who have phenylketonuria.

USE OF CERTAIN MEDICINES

Cholesterol-reducing drugs may change the effects of other medicines. Patients should not take any other medicine that has not been prescribed or approved by a physician who knows they are taking cholesterol-reducing drugs.

Side effects

Gemfibrozil

Studies in animals and humans suggest that gemfibrozil increases the risk of some types of cancer. The drug may also cause gallstones or muscle problems. Patients who need to take this medicine should ask their physicians for the latest information on its benefits and risks.

Patients taking gemfibrozil should check with a physician immediately if any of these side effects occur:

* fever or chills

* severe stomach pain with nausea and vomiting

* pain in the lower back or side

* pain or difficulty when urinating

* cough or hoarseness

HMG-CoA reductase inhibitors

These drugs may damage the liver or muscles. Patients who take the drugs should have blood tests to check for liver damage as often as their physician recommends. Any unexplained pain, tenderness or weakness in the muscles should be reported to the physician at once.

All cholesterol-reducing drugs

Minor side effects such as heartburn, indigestion, belching, bloating, gas, nausea or vomiting, stomach pain, dizziness and headache usually go away as the body adjusts to the drug and do not require medical treatment unless they continue or they interfere with normal activities.

Patients who have constipation while taking cholesterol-reducing drugs should bring the problem to a physician's attention as soon as possible.

Additional side effects are possible. Anyone who has unusual symptoms while taking cholesterol-reducing drugs should get in touch with his or her physician.

Interactions

Cholesterol-reducing drugs may interact with other medicines. When this happens, the effects of one or both of the drugs may change or the risk of side effects may be greater. Anyone who takes cholesterol-reducing drugs should let the physician know all other medicines he or she is taking and should ask whether the possible interactions can interfere with drug therapy. Examples of possible interactions are listed below.

Some cholesterol-reducing drugs may prevent the following medicines from working properly:

* thyroid hormones

* water pills (diuretics)

* certain antibiotics taken by mouth, such as tetracyclines, penicillin G and vancomycin

* the beta-blocker Inderal, used to treat high blood pressure

* digitalis heart medicines

* phenylbutazone, a nonsteroidal anti-inflammatory drug

Taking some cholesterol-reducing drugs with blood thinners (anticoagulants) may increase the chance of bleeding.

Combining HMG-CoA reductase inhibitors with gemfibrozil, cyclosporine (Sandimmune) or niacin may cause or worsen problems with the kidneys or muscles.

Key Terms

Cell
The basic unit that makes up all living tissue.

Cholesterol
Fatty substance found in tissue. Necessary to maintain a healthy body.

Enzyme
A type of protein, produced in the body, that brings about or speeds up chemical reactions.

Hormone
A substance that is produced in one part of the body, then travels through the bloodstream to another part of the body where it has its effect.

Phenylketonuria
(PKU) A genetic disorder in which the body lacks an important enzyme. If untreated, the disorder can lead to brain damage and mental retardation.

Pituitary gland
A pea-sized gland at the base of the brain that produces many hormones that affect growth and body functions.

Taste of Future?

"Ice cream is the nectar of the gods. This is a fat-free nectar." According to USA Today, that's what its reporter Pat Guy had to say about the new frozen dessert Simple Pleasures.

Mark Memmott of the same paper was less enthusiastic. "The chocolate leaves a rather unpleasant aftertaste," he said. "I wouldn't serve it to my dog. I'd give it to the cat. I don't like the cat." Editor Ray Goldbacher's verdict was more middle-of-the-road: "I don't think anyone will mistake this for super-premium ice cream, but it's not bad."

Pronouncements on the taste of this new dessert varied similarly among others present at the press conference held in February 1990 to introduce the product to the public.

What's all the fuss about? It's about ice cream without fat. Ice cream without guilt. (Well, maybe some guilt even though it's fat-free, it's not calorie-free.)

Simple Pleasures is a frozen dessert made with Simplesse, the first fat substitute approved by the Food and Drug Administration. In fact, legally, Simple Pleasures cannot be called ice cream because FDA's standards of identity require that ice cream contain at least 10 percent butterfat. Both Simple Pleasures and Simplesse are products of NutraSweet Co., a subsidiary of Monsanto Co. of St. Louis, Mo. (NutraSweet also makes aspartame, the sugar substitute widely used in low-calorie beverages and other products.)

Simplesse is promoted as a competitor for premium ice creams. In petitioning FDA for approval of Simplesse, NutraSweet compared the fat, cholesterol and caloric content of a super-premium vanilla ice cream containing 16 percent butterfat with a frozen dessert using Simplesse. A 4-ounce serving of the ice cream provided 19 grams of fat, 97 milligrams of cholesterol, and 274 calories, whereas the same size serving of Simple Pleasures contained less than 1 gram of fat, 14 milligrams of cholesterol, and 120 calories. Regular ice cream, with approximately 10 percent fat, contains about 7 grams of fat, 30 milligrams of cholesterol, and 135 calories per 4-ounce serving. (Simple Pleasures is not yet available in vanilla because, the company says, it hasn't yet been able to get the taste just right. It now offers toffee crunch, chocolate, strawberry, coffee, peach, and rum raisin.)
Simplesse is made from egg white and milk protein blended and heated in a process called microparticulation, in which the protein is shaped into microscopic round particles that roll easily over one another. The aim of the process is to create the feel of a creamy liquid with the texture of fat.

It works. Because its components have long been used as foods, FDA, on Feb. 23,1990, affirmed Simplesse as "generally recognized as safe" (GRAS) for use as a thickener or texturizer in frozen dessert products. Safety studies were not required.

NutraSweet plans to seek FDA approval for use of Simplesse in additional products, such as mayonnaise, salad dressing, yogurt, dips, sour cream, butter, margarine, and cheese spreads. Simplesse cannot be used in cooking because baking or frying causes it to lose its creaminess. NutraSweet says, however, that "products made with Simplesse can be enjoyed with many hot foods." For example, it can be used in an imitation butter spread on toast or in a sour cream-type sauce used to top a baked potato.

NutraSweet estimates that full use of Simplesse has the potential to decrease total dietary fat consumption by Americans by 14 percent and dietary cholesterol intake by 5 percent.

Other fat substitutes are under development or awaiting FDA approval. Kraft General Foods has petitioned the agency for GRAS approval of Trailblazer, which, like Simplesse, is made from egg and milk protein processed to mimic the "mouth feel" of fat.

Procter and Gamble's fat substitute Olestra, however, is a different matter. Developed for use in hot foods as well as cold, it is a new substance that, according to the company, is "almost a carbon copy of regular fat, but with a molecule of sugar at its core instead of glycerine, and up to eight fatty acids attached to the core instead of the customary three."

Because it is a new molecular structure that does not break down to its component parts during digestion, Olestra must be approved as a new food additive rather than as a GRAS substance, which means that studies must be done to ensure its safety.

Procter and Gamble says its product looks, tastes, feels, and behaves like fat. It cooks without breaking down under heat, yet it cannot be digested and absorbed, so it passes through the body "contributing no calories, no cholesterol, and no fat." The company is asking for approval of Olestra for deep-frying savory snacks such as chips and puffs made from potatoes and corn.

Health- and weight-conscious consumers are expected to welcome fat-free products that taste like the real thing. In fact, a recent survey by the Calorie Control Council, an association of low-calorie and diet food manufacturers, found that 57 percent of adult Americans believe there is a need for fat substitutes.

According to the 1988 Surgeon General's Report on Nutrition and Health, high intake of fat is associated with increased risk for obesity, some types of cancer (breast, colon, prostate, rectum, ovaries, and endometrium), and possibly gallbladder disease. Studies also show strong evidence of a relationship between high saturated fat intake and a high blood cholesterol level, which is a risk factor for coronary heart disease.

The report also states that because obesity is a risk factor for several chronic diseases, it is important to maintain a desirable weight. Obesity increases the risk of high blood pressure and, consequently, stroke. It also increases blood cholesterol and may, by itself, be a risk factor for coronary heart disease.

Because fat contributes nine calories per gram, fat substitution would significantly reduce the calorie content of a food. Excess calories from fat are readily stored and cause weight gain.

A 1985 national survey by the U.S. Department of Agriculture found that fat contributed 34 percent of total calorie intake for children ages 1 to 5, 36 percent for men ages 19 to 50, and 37 percent for women ages 19 to 50. The National Cholesterol Education Program of the National Heart, Lung, and Blood Institute, along with other health groups, recommends that all healthy Americans 2 and older limit their total daily fat intake to no more than 30 percent of total calories and that less than 10 percent of the total calories should be from saturated fat. Cholesterol should be kept to less than 300 milligrams per day, and the total calorie intake should be what is needed to reach or maintain a desirable weight. (People with certain illnesses or conditions may have different requirements.)

It remains to be seen, however, whether consumers will, indeed, become healthier by using products with fat substitutes. According to the June 15,1990, issue of The Medical Letter, a professional publication on drugs and therapeutics, no clinical studies have shown that use of either Simplesse or Trailblazer leads to weight reduction or decreases blood lipid (fat) concentrations.

Moreover, some nutritionists are concerned that people who eat products made with fat substitutes will feel freer to eat more of other high-fat foods, rationalizing that they are "saving" on those made with substitutes. Another possibility experts anticipate is that people will eat more fat-free double-dip ice cream cones, leaving less room for the more nutritious foods they need.

A more basic, as yet unanswered, question is whether nonfat foods will satisfy as well as the traditional foods they replace and, therefore, whether they will really help people reduce fat consumption.

Lisa Lefferts, staff scientist with the Washington-based consumer advocacy group Center for Science in the Public Interest, points to the experience with sugar substitutes: "We're eating four times the amount of sugar substitutes as we were in 1975, but sugar consumption has gone up as well, so clearly sugar substitutes are not substituting for sugar." Lefferts says that the effect of fat substitutes on the diet is unclear. "Fat substitutes such as Simplesse are a step in the right direction," she says, "but we would encourage that their use be monitored in order to assess their true impact."

FDA, too, has questions about the impact of fat substitutes in the food supply. "There are two categories of fat substitutes to consider," says Walter Glinsmann, M.D., associate director for clinical nutrition. "Products like Simplesse are processed from substances already in the diet, and they are digested and used by the body in the same way as the original substances. Others, like Olestra, are new, undigestible molecules never before in the food supply."

The possible health effects of consuming large amounts of a novel substance must be carefully researched and reviewed before such a product can be marketed. "When you consider that fat intake is about 35 to 40 percent of the daily caloric intake and that half of that fat is derived from foods in which the fat can be replaced with a substitute, you need to take a hard look at the potential health effects," Glinsmann cautions.

Some of the questions to be considered are:

* If the materials are absorbed in the body even in very small amounts are they toxic?
* If they are not absorbed, how do they affect gastrointestinal functions? For example, could they interfere with the absorption of nutrients or drugs?
* Are the substitutes suitable for general use or only for subpopulations of the general public?

The financial impact of fat substitutes may be easier to predict than the health and dietary effects. In February 1990, The Wall Street Journal reported that some estimates have Simplesse becoming a $500-million-a-year or bigger business by the mid-199Os. It is not surprising that still more firms, in addition to Kraft and Procter and Gamble, are entering the race for these consumer dollars.

Type 2 Diabetes

Definition

Type 2 diabetes is a life-long disease marked by high levels of sugar in the blood. It occurs when the body does not respond correctly to insulin, a hormone released by the pancreas. Type 2 diabetes is the most common form of diabetes.

See also:

* Diabetes
* Type 1 diabetes
* Gestational diabetes

Alternative Names

Noninsulin-dependent diabetes; Diabetes - type 2
Causes, incidence, and risk factors

Diabetes is caused by a problem in the way your body makes or uses insulin. Insulin is needed to move glucose (blood sugar) into cells, where it is used for energy.

If glucose does not get into the cells, the body cannot use it for energy. Too much glucose will then remain in the blood, causing the symptoms of diabetes.

There are several types of diabetes. This article focuses on type 2, which is usually accompanied by obesity and insulin resistance.

Insulin resistance means that insulin produced by your pancreas cannot get inside fat and muscle cells to produce energy. Since the cells are not getting the insulin they need, the pancreas produces more and more. Over time, abnormally high levels of sugar build up in the blood. This is called hyperglycemia. Many people with insulin resistance have hyperglycemia and high blood insulin levels at the same time. People who are overweight have a higher risk of insulin resistance, because fat interferes with the body's ability to use insulin.

Type 2 diabetes usually occurs gradually. Most people with the disease are overweight at the time of diagnosis. However, type 2 diabetes can also develop in those who are thin, especially the elderly.

Family history and genetics play a large role in type 2 diabetes. Low activity level, poor diet, and excess body weight (especially around the waist) significantly increase your risk for type 2 diabetes.

Other risk factors include:

* Race/ethnicity (African-Americans, Hispanic-Americans, and Native Americans all have high rates of diabetes)
* Age greater than 45 years
* Previously identified impaired glucose tolerance by your doctor
* High blood pressure
* HDL cholesterol of less than 35 mg/dL or triglyceride level of greater than 250 mg/dL
* History of gestational diabetes

Symptoms

Often, people with type 2 diabetes have no symptoms at all. If you do have symptoms, they may include:

* Increased thirst
* Increased urination
* Increased appetite
* Fatigue
* Blurred vision
* Frequent or slow-healing infections
* Erectile dysfunction

Signs and tests

Type 2 diabetes is diagnosed with the following blood tests:

* Fasting blood glucose level -- diabetes is diagnosed if higher than 126 mg/dL on 2 occasions.
* Random (non-fasting) blood glucose level -- diabetes is suspected if higher than 200 mg/dL and accompanied by the classic symptoms of increased thirst, urination, and fatigue (this test must be confirmed with a fasting blood glucose test).
* Oral glucose tolerance test -- diabetes is diagnosed if glucose level is higher than 200 mg/dL after 2 hours.

Treatment

The first goals are to eliminate the symptoms and stabilize your blood glucose levels. The ongoing goals are to prevent long-term complications and prolong your life. The primary treatment for type 2 diabetes is exercise and diet.

LEARN THESE SKILLS

You should learn basic diabetes management skills. They will help prevent complications and the need for medical care. These skills include:

* How to test and record your blood glucose (see blood glucose monitoring)
* What to eat and when
* How to take medications, if indicated
* How to recognize and treat low and high blood sugar
* How to handle sick days
* Where to buy diabetes supplies and how to store them

It may take several months to learn the basic skills. Always continue to educate yourself about the disease and its complications, as well as how to control and live with diabetes. Over time, stay current on new research and treatment.

SELF-TESTING

Regular self-testing of your blood sugar tells you how well your combination of diet, exercise, and medication are working. Tests are usually done before meals and at bedtime. More frequent testing may be needed when you are sick or under stress.

A device called a glucometer can provide an exact blood sugar reading. There are different types of devices. Usually, you prick your finger with a small needle called a lancet, which gives you a tiny drop of blood. You place the blood on a test strip, and put the strip into the device. Results are available within 30 to 45 seconds.

A health care provider or diabetes educator will help set up an appropriate testing schedule for you. You will also be taught how to respond to different ranges of glucose values obtained when you self-test.

The results of the test can be used to adjust meals, activity, or medications to keep blood sugar levels in an appropriate range. Testing provides valuable information for the health care provider and identifies high and low blood sugar levels before serious problems develop.

Accurate record keeping of test results will help you and your health care provide plan how to best control your diabetes.

DIET AND WEIGHT CONTROL

Meal planning includes choosing healthy foods, eating the right amount of food, and eating meals at the right time. You should work closely with your health care provider to learn how much fat, protein, and carbohydrates you need in your diet. Your specific meal plans need to be tailored to your food habits and preferences.

Managing your weight and eating a well-balanced diet are important. Some people with type 2 diabetes can stop medications after intentional weight loss, although the diabetes is still present. A registered dietitian can be helpful in determining your specific, individual dietary needs. (See diabetes diet.)

REGULAR PHYSICAL ACTIVITY

Regular exercise is important for everyone, but especially if you have diabetes. Regular exercise helps control the amount of glucose in the blood. It also helps burn excess calories and fat so you can manage your weight.

Exercise improves overall health by improving blood flow and blood pressure. It decreases insulin resistance even without weight loss. Exercise also increases the body's energy level, lowers tension, and improves your ability to handle stress.

The following should be considered when starting an exercise routine:

* Check with your health care provider before starting an exercise program.
* Choose an enjoyable physical activity that is appropriate for the current fitness level.
* Exercise every day, and at the same time of day, if possible.
* Monitor blood glucose levels at home before and after exercise.
* Carry food that contains a fast-acting carbohydrate in case blood glucose levels get too low during or after exercise.
* Wear a diabetes identification bracelet and carry change or a cell phone for a phone call in case of emergency.
* Drink extra fluids that do not contain sugar before, during, and after exercise.
* Changes in exercise intensity or duration may require modification of your diet or medication to keep blood glucose levels in an appropriate range.

MEDICATION

When diet and exercise do not help maintain normal or near-normal blood glucose levels, your doctor may prescribe medication. Some of the most common types are listed below. They are taken by mouth.

* Oral sulfonylureas (like glimepiride, glyburide, and tolazamide) trigger the pancreas to make more insulin.
* Biguanides (Metformin) tell the liver to decrease its production of glucose, which increases glucose levels in the blood stream.
* Alpha-glucosidase inhibitors (such as acarbose) decrease the absorption of carbohydrates from the digestive tract, thereby lowering the after-meal glucose levels.
* Thiazolidinediones (such as rosiglitazone) help insulin work better at the cell site. In essence, they increase the cell's sensitivity (responsiveness) to insulin. Rosiglitazone may increase the risk of heart problems. Talk to your doctor.
* Meglitinides (including repaglinide and nateglinide) trigger the pancreas to make more insulin in response to how much glucose is in the blood.

If you continue to have poor blood glucose control despite lifestyle changes and taking medicines by mouth, your doctor will prescribe insulin. Insulin may also be prescribed if you have had a bad reaction to other medicines. Insulin must be injected under the skin using a syringe and cannot be taken by mouth.

Insulin preparations differ in how fast they start to work and how long they work. Your healthcare provider will determine the appropriate type of insulin to use and will tell you what time of day to use it.

More than one type may be mixed together in an injection to achieve the best control of blood glucose. Usually injections are needed one to four times a day. Your doctor or diabetes educator will show you how to give yourself an injection.

FOOT CARE

People with diabetes are prone to foot problems. Diabetes can cause damage to nerves, which means you may not feel an injury to the foot until a large sore or infection develops. Diabetes can also damage blood vessels, which makes it harder for the body to fight infection.

To prevent injury to the feet, a person with diabetes should adopt a daily routine of checking and caring for the feet as follows:

* Check your feet every day, and report sores or changes and signs of infection.
* Wash feet every day with lukewarm water and mild soap, and dry them thoroughly.
* Soften dry skin with lotion or petroleum jelly.
* Protect feet with comfortable, well-fitting shoes.
* Exercise daily to promote good circulation.
* See a podiatrist for foot problems, or to have corns or calluses removed.
* Remove shoes and socks during a visit to the health care provider to remind them to examine your feet.
* Stop smoking because it worsens blood flow to the feet.

CONTINUING CARE

A person with type 2 diabetes should have a visit with a diabetes care provider every 3 months. A complete examination includes:

* Glycosylated hemoglobin (HbA1c) is a 3-month average of your blood glucose level. This test measures how much glucose has been sticking to red blood cells and other cells. A high HbA1c is an indicator of risk for long-term complications. Currently, the ADA recommends an HbA1c of less than 7% to protect oneself from complications.
* Blood pressure check
* Foot and skin examination
* Ophthalmoscopy examination
* Neurological examination

The following evaluations should be done at least once a year:

* Random microalbumin (urine test for protein)
* BUN and serum creatinine
* Serum cholesterol, HDL, and triglycerides
* ECG
* Dilated retinal exam

Support Groups

For additional information, see diabetes resources.
Expectations (prognosis)

The risk of long-term complications from diabetes can be reduced. If you control your blood glucose and blood pressure, you can reduce your risk of death, stroke, heart failure, and other complications. Reduction of HbA1c by even 1% can decrease your risk for complications by 25%.
Complications

Emergency complications include diabetic coma.

Long-term complications include:

* Diabetic retinopathy (eye disease)
* Diabetic nephropathy (kidney disease)
* Diabetic neuropathy (nerve damage)
* Peripheral vascular disease (damage to blood vessels/circulation)
* High cholesterol, high blood pressure, atherosclerosis, and coronary artery disease

Calling your health care provider

Call your health care provider immediately if you have:

* Trembling
* Weakness
* Drowsiness
* Headache
* Confusion
* Dizziness
* Double vision
* Lack of coordination

These symptoms can rapidly progress to emergency conditions (such as convulsions, unconsciousness, or hypoglycemic coma).
Prevention

Everyone over 45 should have blood glucose checked at least every 3 years. Regular testing of random blood glucose should begin at a younger age and be performed more often if you are at particular risk for diabetes.

Maintain a healthy body weight and keep an active lifestyle to help prevent the onset of type 2 diabetes.

Pregnancy Implications

Glyburide was not found to significantly cross the placenta in vitro and was not found in the cord serum infants of mothers taking glyburide for gestational diabetes mellitus (GDM). Reported teratogenic effects may be due to poorly controlled maternal diabetes; abnormal blood glucose levels in the mother are associated with a higher incidence of congenital abnormalities. Nonteratogenic effects such as hypoglycemia in the neonate have been associated with maternal glyburide use. The manufacturer recommends that if glyburide is used during pregnancy, it should be discontinued at least 2 weeks before the expected delivery date. Although studies have shown positive outcomes using glyburide for the treatment of GDM, use may not be appropriate for all women. When compared to insulin for the treatment of GDM, as the severity of GDM increased, the success rate of treatment decreased. It should be noted that studies using glyburide for the treatment of GDM have initiated treatment after the period of organogenesis. Insulin is considered the drug of choice for the control of diabetes mellitus during pregnancy.Reproduction studies differ by manufacturer labeling. Because adverse events were not observed in animal reproduction studies, one manufacturer classifies glyburide as pregnancy category B. Because adverse events were noted in animal studies during the period of lactation, another manufacturer classifies glyburide as pregnancy category C.

Some Other drugs may affect Glyburide

Many other medicines may increase or decrease the effects of glyburide or affect your condition. Before taking glyburide, tell your doctor if you are taking any of the following medicines:

* aspirin or another salicylate such as magnesium/choline salicylate (Trilisate), salsalate (Disalcid, others), choline salicylate (Arthropan), magnesium salicylate (Magan), or bismuth subsalicylate (Pepto-Bismol);
* a nonsteroidal anti-inflammatory drug (NSAID) such as ibuprofen (Motrin, Advil, Nuprin, others), ketoprofen (Orudis, Orudis KT, Oruvail), diclofenac (Voltaren, Cataflam), etodolac (Lodine), indomethacin (Indocin), nabumetone (Relafen), oxaprozin (Daypro), naproxen (Anaprox, Naprosyn, Aleve), and others;
* a sulfa-based drug such as sulfamethoxazole-trimethoprim (Bactrim, Septra), sulfisoxazole (Gantrisin), or sulfasalazine (Azulfidine);
* a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil);
* a beta-blocker such as propranolol (Inderal), atenolol (Tenormin), acebutolol (Sectral), metoprolol (Lopressor), and others;
* a diuretic (water pill) such as hydrochlorothiazide (HCTZ, Hydrodiuril), chlorothiazide (Diuril), and others;
* a steroid medicine such as prednisone (Deltasone, Orasone, others), methylprednisolone (Medrol, others), prednisolone (Prelone, Pediapred, others), and others;
* a phenothiazine such as chlorpromazine (Thorazine), fluphenazine (Prolixin, Permitil), prochlorperazine (Compazine), promethazine (Phenergan), and others;
* phenytoin (Dilantin);
* isoniazid (Nydrazid); or
* prescription, over-the-counter, or herbal cough, cold, allergy, or weight loss medications.

You may require a dosage adjustment or special monitoring if you are taking any of the medicines listed above.

Drugs other than those listed here may also interact with glyburide or affect your condition. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines, including vitamins, minerals, and herbal products.

Long Term Safety of Glyburide for Diabetes Mellitus

Pioglitazone is an oral antidiabetic agent of the thiazolidinedione class indicated for use in patients with type 2 diabetes mellitus as an adjunct to diet and exercise or in combination with a sulfonylurea, metformin, or insulin when diet and exercise alone do not result in adequate glycemic control. Thiazolidinediones act on peroxisome proliferator-activated receptors (PPARs), which regulate glucose, lipid, and protein metabolism and influence cell proliferation, differentiation, and apoptosis. Through selective agonism of PPAR-g receptors, thiazolidinediones inhibit hepatic glucogenesis and increase insulin sensitivity in muscle and adipose tissue, lowering glucose levels.3 Because thiazolidinediones do not stimulate insulin secretion but enhance the effects of circulating insulin, the antihyperglycemic effect can be achieved only in the presence of insulin.

In addition to glycemic control, selected thiazolidinediones have been shown to have a beneficial effect on lipid profiles. In support of these findings, several randomized controlled trials have demonstrated improved glycemic control and favorable lipid-altering effects with once-daily pioglitazone or with a combination of pioglitazone plus metformin, a sulfonylurea, repaglinide, or insulin.[4-9] In addition, a recent head-to-head comparison trial of the thiazolidinediones pioglitazone and rosiglitazone demonstrated comparable effects on glycemic control, although pioglitazone significantly lowered triglyceride levels, increased high-density lipoprotein cholesterol levels, and decreased the number of small, dense low-density lipoprotein cholesterol particles compared with rosiglitazone.

Although thiazolidinediones have been associated with weight gain, edema, and slight reductions in hemoglobin and hematocrit levels (as a result of plasma volume expansion), several reports indicate that these adverse events are generally mild to moderate and infrequently lead to discontinuation of pioglitazone or rosiglitazone. Neither pioglitazone nor rosiglitazone has been associated with hepatotoxicity, which is linked to the thiazolidinedione troglitazone.

Oral drugs of the sulfonylurea class, such as glyburide, stimulate insulin secretion by binding to and blocking adenosine 5¢-triphosphate- dependent potassium channels in β-cell membranes. This action increases intracellular calcium concentrations, inducing insulin secretion. Because the therapeutic effect of sulfonylureas depends on their insulin secretory action, development of hypoglycemia is associated with their use.

Type 2 diabetes mellitus is a lifelong disorder requiring long-term treatment. Because, to our knowledge, no long-term safety and efficacy data comparing glyburide with pioglitazone have been collected yet, this study was conducted to determine whether long-term treatment with glyburide versus pioglitazone is safe and effective in achieving and maintaining glycemic control in patients with recently diagnosed type 2 diabetes mellitus inadequately controlled with diet and exercise.

Stop taking glyburide and seek emergency medical attention if you experience an allergic reaction (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives).

Other, less serious side effects from glyburide result mostly from blood sugar levels that are either too high or too low. You should be familiar with the symptoms of both high and low blood sugar levels and know how to treat both conditions. Also, be sure your family and close friends know how to help you in an emergency situation.

Low blood sugar may occur when too much glyburide is taken; when meals are missed or delayed; if you exercise more than usual; during illness, especially with vomiting or diarrhea; if you take other medications; after drinking alcohol; and in other situations.

Hypoglycemia or Low blood sugar has the following symptoms:

* shaking;
* headache;
* cold sweats;
* pale, cool skin;
* anxiety; and
* difficulty concentrating.

Keep hard, sugary candy; chocolate; fruit juice; or glucose tablets on hand to treat episodes of low blood sugar.

Increased blood sugar may occur when not enough glyburide is taken; if you eat significantly more food than usual; if you exercise less than usual; if you take other medications; during fever or other illness; and in other situations.

Hyperglycemia or High blood sugar has the following symptoms:

* increased thirst,
* increased hunger, and
* increased urination.

There may be an increased risk of death due to cardiovascular (heart and blood vessels) complications with the use of glyburide when compared to the treatment of diabetes with diet or diet plus insulin. The long-term use of glyburide should be discussed with your doctor.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.

Type2 Diabetes

Description
An in-depth report on the causes, diagnosis, treatment, and prevention of type 2 diabetes.
Alternative Names
Maturity Onset Diabetes; Noninsulin-dependent Diabetes Mellitus
Medications

The American Heart Association now recommends that patients should aim for the following test results for intensive control of glucose levels:

* Fasting plasma glucose concentrations below 110 mg/dL.
* Glycolated hemoglobin (HbA1c) levels of less than 7%. Controlling HbA1c is the most important factor for reducing the risk of complications in patients with diabetes. According to one 2000 study, a 1% reduction in people with elevated glycolated hemoglobin levels lowers the risk for complications by 21%.

Evidence clearly supports strict glycemic control for reducing complications in the nervous system and blood vessels that occur in both type 1 and type 2 diabetes. Although to date tight control of blood glucose has not proven to reduce mortality rates from all causes or cardiovascular diseases in patients with type 2 diabetes, evidence is increasing that intensive control has benefits for the heart as well--although they may not be evident as rapidly.

It is may be difficult for patients with type 2 diabetes to control their blood sugar levels--particularly if they are overweight. On the positive side, metformin (Glucophage), an oral anti-hypoglycemic agent, has many benefits--it helps control blood glucose levels, does not produce weight gain, and also has heart benefits. In comparison with other diabetic agents, including insulin, it is the only proven drug to improve survival rates. A number of oral agents are also available that are beneficial, alone or in combinations. Insulin therapy is often eventually required as natural insulin reserves become depleted.

Managing risk factors for heart disease and stroke, particularly strict control of blood pressure, may more important for improving survival than strict control of blood glucose levels in these patients. Such goals also seem to be more attainable for many patients with type 2 diabetics.

Oral Anti-hyperglycemic Agents (OHAs). Many oral anti-hyperglycemic agents (OHAs) are now available to help patients with for type 2 diabetes control their blood sugar levels. Most of these agents are aimed at using or increasing sensitivity to the patient's own natural stores of insulin. Metformin is the only agent to date that achieves lower mortality rates:

* Biguanides (metformin). Increase tissue sensitivity to available insulin. Metformin also has beneficial effects on cholesterol, blood pressure, and clotting factors. It does not cause weight gain or hypoglycemia. Metformin produces lower mortality rates than other drugs, including insulin, and should be considered as first-line therapy for most type 2 patients who are insulin resistant.
* Sulfonylureas (examples include glyburide, glipizide, and glimepiride). Stimulate insulin secretion.
* Meglitinides (repaglinide, nateglinide). Stimulate insulin secretion. These newer agents are better than sulfonylureas in controlling glucose spikes after meals.
* Thiazolidinediones (pioglitazone and rosiglitazone). Reduce insulin resistance. These agents improve cholesterol levels and may reduce the risk for blood clots. However, they can cause swelling from fluid build-up, which can worsen heart failure or even possibly precipitate it. They also may injure the liver. The drugs have not been intensively studied, and some experts believe they should not be used except in clinical studies.
* Alpha-glucosidase inhibitors (acarbose and miglitol). Slow intestinal absorption of carbohydrates. Have only modest effects and have gastrointestinal side effects.

Combinations of these agents, particularly with metformin, are often used to increase effectiveness. For example, combinations of rosiglitazone and metformin (Avandamet) and glyburide and metformin (Glucovance) are proving to be very effective. Glucovance may be particularly beneficial for patients with unhealthy cholesterol levels and poor control of their blood sugar levels. Some experts recommend the combination as first-line treatment.

Adding Insulin Replacement. Insulin replacement is usually required as natural insulin reserves are depleted. It is typically started it combination with an oral agent. Eventually, some people may need to go on full insulin replacement.
Metformin (a Biguanide)

Metformin (Glucophage) is a biguanide, which appears to work by reducing glucose production in the liver and by making tissues more sensitive to insulin. It is now be considered by many experts to be the first choice for most type 2 patients who are insulin resistant, particularly if they are overweight. Metformin achieves lower mortality rates from diabetes and all causes than other drugs. In one comparison study, it achieved the lowest mortality rates (8%) compared to insulin (28%), a sulfonylurea (16%), and a thiazolidinedione (14%). Combinations with insulin-secreting drugs, other insulin-sensitizing drugs, or insulin itself are particularly effective.

Metformin does not cause hypoglycemia or add weight, so it is particularly well suited for obese type 2 patients. (In some studies, in fact, patients lost weight.) Metformin also appears to have beneficial effects on cholesterol and lipid levels and may be heart protective. Some research, in fact, has suggested that it significantly reduces the risk for heart attack. It is also the first choice for children who need oral agents and is proving to be very effective for women with polycystic ovaries and insulin resistance.

Side Effects. Side effects include the following:

* A metallic taste.
* Gastrointestinal problems, including nausea, and diarrhea.
* It may also reduce absorption of vitamin B12 and folic acid, which are important for protection against heart disease.
* There have been some reports of lactic acidosis, a potentially life-threatening condition, particularly in people with risk factors for it. Major studies, however, found no greater risk with metformin than with any of the other drugs used for type 2 diabetes.

Certain people should not use this drug, including anyone with congestive heart failure or kidney or liver disease. It is rarely suitable for adults over 80.
Sulfonylureas

Sulfonylureas are oral drugs that stimulate the pancreas to release insulin. They are also first-line oral agents. For adequate control of blood glucose levels, the drugs should only be taken 20 to 30 minutes before a meal. A number of brands are available, including chlorpropamide (Diabinese), tolazamide (Tolinase), acetohexamide (Dymelor), glipizide (Glucotrol), tolbutamide (Orinase), glimepiride (Amaryl), glyburide or glibenclamide outside the US (DiaBeta, Micronase), and gliclazide.

Most patients can take sulfonylureas for seven to 10 years before they lose effectiveness. Combinations with small amounts of insulin or with other drugs (such as metformin or a thiazolidinedione) may extend their benefits. In fact, a combination of glyburide and metformin in one pill (Glucovance) is now available. Glucovance may be particularly beneficial for patients with unhealthy cholesterol levels and poor control of their blood sugar levels. Some experts recommend the combination as first-line treatment.

Also encouraging was a 2000 study of patients with severe type 2 diabetes reporting that combinations of insulin with either chlorpropamide or glipizide (two different sulfonylureas) achieved better glucose control over the long term than insulin alone.

Side Effects and Complications. In general, sulfonylureas should not be used by women who are pregnant or nursing or by individuals who are allergic to sulfa drugs. Side effects include the following:

* Weight gain. Some sulfonylureas, such as glimepiride, may produce less weight gain than others.
* Water retention.
* Although sulfonylureas pose a lower risk for hypoglycemia than insulin does, the hypoglycemia produced by sulfonylureas may be prolonged and dangerous. The newer sulfonylureas, such as glimipiride, appear to have about one tenth the risk of hypoglycemia than do older sulfonylureas.
* Some may pose a slight risk for cardiac events.

Sulfonylureas interact with many other drugs, and patients should be sure to inform their physician of any medications they are taking, including alternative or over-the-counter drugs.
Meglitinides

Meglitinides stimulate beta cells to produce insulin. They include repaglinide (Prandin), nateglinide (Starlix), and mitiglinide. These agents are rapidly metabolized and short acting and if taken before every meal, they actually mimic the normal effects of insulin after eating. Patients, then, can vary their meal times with this drug. (Nateglinide appears to work more quickly and is shorter-acting than repaglinide). These agents may be particularly effective in combination with metformin or other agents. And they may be good agents for people with potential kidney problems.

Side Effects. Side effects include diarrhea and headache. As with the sulfonylureas, repaglinide poses a slightly increased risk for cardiac events. (Newer agents, such as nateglinide, may pose less of a risk.) People with heart failure or liver disease should use them with caution and be monitored.
Thiazolidinedione

Thiazolidinediones include rosiglitazone (Avandia) and pioglitazone (Actos). They improve insulin sensitivity by activating certain genes involved in fat synthesis and carbohydrate metabolism. These drugs are usually taken once or twice per day; however, it may take several days before the patient notices any results from them and several weeks before they take full effect. Thiazolidinediones do not cause hypoglycemia when used alone, although they are usually taken in combination with oral agents or insulin.

In some studies, thiazolidinediones have produced favorable effects on the heart, including reducing blood pressure and preventing blood clots. Pioglitazone improves triglyceride and HDL levels. (Rosiglitazone has mixed effects on lipid levels.) Of importance, some evidence suggests that these agents may preserve beta-cell function and, if used early, may help prevent progression of diabetes. This effect has not been observed with other standard oral agents.

Side Effects Nevertheless, thiazolidinediones can have serious side effects. They tend to increase fluid-build up, which can cause or worsen heart failure in some patients. Combinations with insulin increase the risk. They should not be used at all in patients with existing heart failure and should be used cautiously in those with risk factors for heart failure. Any patient who experiences sudden weight gain, water retention, or shortness of breath should call their physicians immediately.

Thiazolidinediones can cause also anemia and, as with other oral agents, can cause moderate weight gain. There have been a few reports of liver injury. At this time some experts believe thiazolidinediones should not be used routinely for managing type 2 diabetes but only in the context of clinical studies.
Alpha-Glucosidase Inhibitors

Alpha-glucosidase inhibitors, including acarbose (Precose, Glucobay) and miglitol (Glyset) reduce glucose levels by interfering with the absorption of starch in the small intestine. Acarbose tends to lower insulin levels after meals, a particular advantage, since higher levels of insulin after meals are associated with an increased risk for heart disease. Some evidence suggests that early use of these agents may reduce heart risk factors, including high blood pressure. A 2002 study using acarbose also suggested that these agents might even delay the development of type 2 diabetes in high-risk individuals. Alpha-glucosidase inhibitors are not as effective alone as other single oral drugs, but combinations, such as with metformin, insulin, or a sulfonylurea, increase their effectiveness.

Side Effects. These medications need to be taken with meals. Unfortunately, about a third of patients to stop taking the drug because of flatulence and diarrhea, particularly after high-carbohydrate meals. The drug may also interfere with iron absorption.

Alpha-glucosidase inhibitors do not cause hypoglycemia when used alone, but combinations with other drugs do. In such cases, it is important that the patient receive a solution that contains glucose or lactose, not table sugar. This is because acarbose inhibits the breakdown of complex sugar and starches, which includes table sugar.
Insulin Replacement

Issues Involves with Insulin Replacement. Insulin replacement is the best treatment for strict control of blood glucose and is required as natural insulin reserves are depleted. Because type 2 diabetes is progressive, most patients eventually require insulin, typically starting it in combination with an oral agent. However, when a single oral agent fails to control blood sugar it is not clear whether it is better to add insulin replacement or to add a second or third oral agent. A 2003 study reported that three oral agents were as effective as insulin plus an oral agent, but the costs are significantly higher. Some experts advocate using insulin as early as possible for optimal control.

However, in patients who still have insulin reserves, there is some concern that extra natural insulin will have adverse effects, including hypoglycemia, weight gain, and heart complications. It is still not clear if insulin replacement will improve survival rates compared to oral agents, notably metformin.

One approach that might solve some of these problems is to combine insulin with metformin, which achieves blood glucose control without added weight gain. Newer forms of insulin analogues, such as glargine, may be specifically helpful for people with type 2 diabetes and reduce the risk for hypoglycemia.

Fortunately, studies to date have not reported any adverse cardiac effects in patients with type 2 diabetes who are taking insulin. In fact, insulin has been associated, in some cases, with improvement in heart risk factors. More research is needed to clarify these important issues.

Forms of Insulin. Experts are working toward administering insulin so that it closely mimics the daily pattern of insulin, which responds to blood sugar levels by surging after meals and then falling to a steady base level afterward. To achieve this, physicians may use two insulin types:

* Fast-Acting Insulins for Surges. Insulin lispro and insulin aspart are fast-acting insulins. They mimic insulin's response to food intake. They are taken before meals, and their short action reduces the risk for hypoglycemia afterward.
* Slower Insulins for Base Levels. Intermediate forms (including NPH and lente) and long-acting forms (insulin glargine, ultralente insulin) have been developed to provide a steady level of insulin throughout the day. To date, glargine (Lantus) seems to be the most successful in achieving this goal in type 2 diabetes.

Noninjected forms of insulin are under investigation and may be particularly beneficial for type 2 diabetes. For example, preprandial inhaled insulin, or INH, is used with an inhaler, and Oralin is administered using an oral spray that is absorbed in the cheek lining. In one study, INH was added to oral agents administration and inhaled before meals. After 12 weeks it was more effective in controlling blood glucose, although patients gained weight and had a great incidence in hypoglycemia.

[For more detailed information on insulin therapy, see Well-Connected Report #9, Diabetes: Type 1.]
Investigative Agents

Incretins. Incretins are hormones that are released from the intestine and enhance insulin secretion. Glucagon-like insulinotropic peptide, or GLP-1 (Betatropin), is an incretin under investigation. It appears to help metabolize glucose and reduce appetite. Betatropin is administered using injections. Early studies report that it is effective in controlling blood glucose levels and has also been associated with weight reduction. A transmucosal tablet (placed between the lip and gum) is also under investigation and is showing benefits.

Pramlintide. Pramlintide (Symlin), known as an amylin analog, is derived from a natural hormone that acts in concert with the body's insulin in the pancreas to control hyperglycemia. It slows stomach emptying and delays absorption of nutrients in the intestine. It therefore prevents the surge in blood sugar that typically occurs after meals. Some studies indicate that in combination with insulin it helps control glucose levels, importantly after meals, without increasing the risk for hypoglycemia or increasing weight when added to insulin regimens. It is being considered for approval for both type 1 and type 2 insulin-dependent diabetes. One possible adverse effect is a delay in stomach emptying, which is already a complication of diabetes in some patients with neuropathy.

D-Chiro-Inositol. D-chiro-inositol (INS-1) is an investigational agent that increases sensitivity to insulin. It is showing promise in treating people with less severe diabetes and women with polycystic ovary syndrome. More research is underway.

Ciliary Neurotrophic Factor. An agent derived from ciliary neurotrophic factor (Axokine) signals the brain to suppress appetite. It is proving to be effective in achieving weight loss, and also improves cholesterol, lipid, and glucose levels regardless of food intake. The agent, then, may be particularly helpful for people with type 2 diabetes. It is currently in late trials.

Exenatide. Exenatide (Heloderma) is derived from the venom of the Gila monster. Animal and laboratory studies suggest that it enhances insulin secretion and slows stomach emptying. It may also have some protective effects on beta cells. Early studies are reporting reductions in HbA1C when used in combination with metformin, sulfonylureas, or both.

Glucovance

Drug Description
DESCRIPTION

GLUCOVANCE ® (Glyburide and Metformin HCl Tablets) contains two oral antihyperglycemic drugs used in the management of type 2 diabetes, glyburide and metformin hydrochloride.

Glyburide is an oral antihyperglycemic drug of the sulfonylurea class. The chemical name for glyburide is 1-[[ p-[ 2-( 5-chloro-o-anisamido) ethyl] phenyl] sulfonyl]-3-cyclohexylurea. Glyburide is a white to off-white crystalline compound with a molecular formula of C 23 H 28 ClN 3 O 5 S and a molec-ular weight of 494.01. The glyburide used in GLUCOVANCE has a particle size distribution of 25% undersize value not more than 6 m, 50% undersize value not more than 7 -10 m, and 75% undersize value not more than 21 m.

Metformin hydrochloride is an oral antihyperglycemic drug used in the management of type 2 dia-betes. Metformin hydrochloride (N, N-dimethylimidodicarbonimidic diamide monohydrochloride) is not chemically or pharmacologically related to sulfonylureas, thiazolidinediones, or -glucosidase inhibitors. It is a white to off-white crystalline compound with a molecular formula of C 4 H 12 ClN 5 (monohydrochloride) and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.

GLUCOVANCE is available for oral administration in tablets containing 1.25 mg glyburide with 250 mg metformin hydrochloride, 2.5 mg glyburide with 500 mg metformin hydrochloride, and 5 mg glyburide with 500 mg metformin hydrochloride. In addition, each tablet contains the following inactive ingredients: microcrystalline cellulose, povidone, croscarmellose sodium, and magne-sium stearate. The tablets are film coated, which provides color differentiation.

Glyburide

GENERIC NAME: glyburide
BRAND NAMES: Micronase, Diabeta, Glynase

DRUG CLASS AND MECHANISM: Glyburide is an oral glucose lowering-drug in a class of diabetes medicines called sulfonylureas. Glyburide lowers the sugar level by stimulating insulin secretion in the pancreas. Insulin is a hormone which lowers the blood sugar level.

Approximately 90% of patients with diabetes have type 2 or non-insulin dependent diabetes mellitus. Type 2 diabetes usually occurs in adulthood, and is associated with obesity and a strong family history of the disease. Sugar (glucose) intolerance is related to impaired insulin secretion by the pancreas and resistance to insulin at the cell level.

PRESCRIPTION: Yes

GENERIC AVAILABLE: Yes

PREPARATIONS: Tablets; 1.25mg, 1.5mg, 2.5mg, 3mg, 5mg.

STORAGE: Glyburide should be stored at room temperature in a tight container.

PRESCRIBED FOR: Glyburide is used in type 2 diabetes to help lower and control blood sugars in those not controlled by diet alone. Studies have shown that strict sugar control in diabetics decreases the risks of eye, kidney, and nerve damage. Oral sulfonylureas are used in type 2 diabetics after a trial on a strict diabetic diet and usually before insulin is tried.

DOSING: Glyburide may be taken with or without food. Since glyburide is metabolized by the liver and excreted by the kidneys, dosages may need to be lowered in patients with liver or kidney dysfunction.

DRUG INTERACTIONS: All sulfonylureas can cause low blood sugar (hypoglycemia). Therefore, glyburide must be used cautiously in patients with kidney or liver problems, and those with poor food intake, using alcohol, or participating in heavy exercise, as well as in patients taking other glucose-lowering drugs. Drug interactions causing hypoglycemia can occur with nonsteroidal anti-inflammatories, sulfa drugs, coumadin, miconazole, fluoroquinolone antibiotics, and beta-blocking drugs. High glucose reactions (hyperglycemia) can occur with thiazide diuretics, corticosteroids, thyroid medicines, estrogens, niacin, dilantin, and calcium channel blocking drugs.

PREGNANCY: Glyburide is not recommended during pregnancy. Use of glyburide during the 2nd and 3rd term of pregnancy does not appear to affect the fetus, but use of glyburide during pregnancy should be discussed with a physician

NURSING MOTHERS: Glyburide should not be used by breast-feeding mothers.

SIDE EFFECTS: Minor side effects include nausea, heartburn, and bloating. Skin rashes can occur and cause itching, hives, or a diffuse measles-like rash. Rare but serious side effects include hepatitis, jaundice, and a low sodium concentration.

Glyburide Effective for Managing Gestational Diabetes

Glyburide may control gestational diabetes unresponsive to diet therapy.

According to a new report. "Glyburide is a reasonable alternative to insulin therapy for women diagnosed with gestational diabetes and who fulfill the criteria we used in our study," says,Dr. Gavin F. Jacobson.

Dr. Jacobson, from Kaiser Permanente Northern California, San Francisco, and colleagues compared glyburide and insulin treatment in nearly 600 women with singleton pregnancies who had gestational diabetes diagnosed by oral glucose tolerance test between 12 and 34 weeks gestation, a fasting plasma glucose of 140 mg/dL or less, and who failed diet therapy.

Women treated with glyburide had significantly lower mean fasting and postprandial blood sugar levels, the authors report in the July issue of the American Journal of Obstetrics and Gynecology. Maternal hypoglycemia was rare with both treatments but more common in the glyburide group (0.20%) than in the insulin group (0.08%).

Twenty-eight women (12%) in the glyburide group were switched to insulin, the report indicates, including 14 for poor control and 8 for side effects attributed to hypoglycemia.

Most maternal and neonatal outcomes were similar between treatments, the researchers note. Preeclampsia was more common in the glyburide group, and neonates in the glyburide group were more likely to receive phototherapy.

Neonates in the insulin group, however, were more likely to be admitted to the neonatal intensive care unit, the results indicate. There were no neonatal deaths, lethal anomalies, or exchange transfusions in either treatment group, the investigators report. Four infants in each group had congenital anomalies.

"Women should be switched to insulin if they are unable to achieve adequate glycemic control on glyburide," Dr. Jacobson advised.

Also, he emphasized, "It is important women (treated with glyburide) receive all the other standard prenatal, intrapartum, and postpartum care that would have been provided if they were on insulin, including frequency of visits, counseling, and antenatal surveillance."

The study findings show that "glyburide can be used to achieve good glycemic control in a large clinical setting in the majority of women with gestational diabetes unresponsive to dietary management," write Dr. Celeste Durnwald and Dr. Mark B. Landon from The Ohio State University Medical Center, Columbus, in a related editorial. "Larger trials will also be of benefit in describing clinical characteristics associated with glyburide failure."

Dr. Jacobson added: "We are currently looking at the use of glyburide to treat a subgroup of women diagnosed with gestational diabetes in a nontraditional manner, specifically women diagnosed by a very high 1 hour GLT (>200mg/dl) and an elevated fasting (>105 mg/dl),"