ORAL DIABETES MEDICATIONS UPDATE

by Peter J. Nebergall, PhD

Photo:� Peter and cat.� Caption:� Peter J. Nebergall, PhD

����������� Currently there are an estimated 16 million diabetics in the United States.� Perhaps 5 to 10 percent are insulin-dependent; the rest are type 2 diabetics, controlling their condition with diet, exercise, insulin, and oral diabetes medications.

����������� "Oral diabetes medications" are not insulin pills; rather five classes of drugs designed to improve the body's utilization of what insulin is still present.� These are:� The sulfonylureas, repaglinide, metformin, the �glitazones�, and acarbose.

����������� Most of today's "diabetes pills" are sulfonylureas, a class of chemicals that stimulate the pancreas to produce more insulin, effectively lowering blood glucose levels.� Type 2 diabetics, those who need better management than diet and exercise can provide alone, often turn to these medications:� tolbutamide, chlorpropamide, tolazamide, glyburide, glipizide, and glimepiride, for effective self-management.� The sulfonylureas are effective �insulin secretagogues,� but only for as long as the impaired pancreas maintains some part of its insulin-making capacity.

����������� But the sulfonylureas grow ever less effective with the passage of time.� They drive the failing pancreas to greater effort, but the patient may well require ever-increasing doses to maintain good diabetes control.� All this time, the pancreas is continuing to fail, and at some point, no further increase in medication will be effective; the pancreas isn't doing its job.� This patient needs to start injecting insulin.� When the islet cells of the pancreas cease producing sufficient insulin, insulin must be injected.

����������� Repaglinide (trade name Prandin), the second medication on our list, is a completely new chemical formulation.� Prandin resembles the sulfonylureas in its mechanism of action, in that it stimulates the release of pancreatic insulin, improving blood sugar control (and is of no use in type 1 diabetes, where pancreatic insulin is not present).� But it differs from the sulfonylureas in several ways:

*��������� Prandin is short-acting, with quick onset and fast excretion, allowing more freedom in the timing of meals (dosages can be taken 0 to 30 minutes before mealtime).

*��������� Unlike the sulfonylureas, Prandin is excreted via the liver.� Individuals with renal insufficiency (kidney disease) should use caution ("dosage for each patient should be individualized, to achieve optimal clinical response" says the manufacturer), but even ESRD�end stage renal disease--is not a contraindication for Prandin.

*��������� Individuals with hepatic (liver) impairment should proceed with caution, and with longer intervals between dosages, as the drug will take longer to clear the body.

����������� Metformin (trade name Glucophage), the third oral diabetes medication on our list, works to raise the body's sensitivity to its own insulin.� Used for decades in Europe, it can be prescribed alone or with the sulfonylureas.� Metformin helps the type 2 diabetic make better use of the insulin he or she has left.� Like the sulfonylureas, it becomes useless when the pancreas ceases producing insulin.

����������� The �glitazones� (medically the thiazolidinediones):� Actos, from Takeda Pharmaceuticals; Avandia, from Smith-Kline Beecham; and now-banned Rezulin, from Parke-Davis, are the fourth class of oral medication.� These medications directly attack the problem of insulin resistance, the increasing inability to process insulin, that is the chief component of type 2 diabetes.� In tests, they have enabled many diabetics to reduce volume and frequency of insulin injections.� A few were able to discontinue insulin injections entirely.

����������� Initially, the glitazones were tested and approved for use with insulin-using type 2 diabetics.� As tests continued, it became clear they were also effective blood glucose reducers, either alone (in combination with diet and exercise), or in combination with a sulfonylurea, for type 2 diabetics who did not need insulin (although not a replacement for the sulfonylureas).� Other applications and combinations may well follow.

����������� Rezulin was the first of the class to be approved, and was very widely prescribed.� It did its job very well, but collected a history of hepatic (liver) side effects.� Doctors were asked to closely monitor their Rezulin-using patients.� Much of the liver damage proved temporary, with normal function restored upon cessation of Rezulin therapy, but there were cases of serious permanent damage, and more than 60 deaths.� Early this year, the Food and Drug Administration asked Parke-Davis to remove Rezulin from the market.

����������� At this time, there is no evidence that Actos (pioglitazone hydrochloride) or Avandia (rosiglitazone maleate) cause the same permanent liver damage damage, but doctors have been advised to follow the same liver-monitoring routines as for Rezulin, in case a similar pattern of damage appears.

����������� Acarbose (trade name Precose, from Bayer), the fifth of the "oral meds" on our list, is completely different.� A carbohydrase inhibitor, it temporarily suppresses the digestive enzymes which turn carbohydrates into glucose, slowing digestion and glucose absorption, keeping glucose levels more even.� More a management tool than an antidote to insulin shortage, Acarbose helps some diabetics keep a more constant blood glucose level.� A "temperamental" medication, it has many side effects, and is less than universal in its utility.� New Glyset, from Pharmacia-UpJohn, appears to work in the same manner.

Problems

����������� Unfortunately, oral medications are often eventually insufficient.� Many type 2 diabetics, diagnosed as young adults, at first successfully control their condition with diet and exercise, but find they need the pills as they grow older.� A number of years (and dosage increases) later, these diabetics have reached the limit of what oral medications can do for them; they are "maxed out," and really need to start injecting insulin, to keep their blood glucose at a safe level.� (Note: �Regular, frequent blood glucose monitoring and HbA1c testing will show if you have reached the point where you should begin insulin therapy.)

����������� Here we encounter what the drug companies call "psychological insulin resistance."� Some of this is plain old fear of sticking yourself with needles-nurtured by memories from our childhood in the bad old days of dull-as-nails reusable syringes!� Many men would rather face a bayonet.� But some doctors contribute to the problem when they don't make it clear to the patient what the high glucose levels (consequent to remaining on now-useless oral medications) will bring in their wake, or worse, when they assume their patient would resist commencing regular insulin injections-so they don't even suggest it.� Yes, insulin is a powerful medication, with risks if used incorrectly-but what in this world DOESN'T have risks if used incorrectly?� The risks of remaining on oral diabetes medications once pancreatic insulin has diminished or ceased entirely are far greater than the risks of taking insulin.

Oral Insulin?

����������� Recent reports have mentioned insulin administration by mouth.� The nature of insulin, and of human digestion, make oral administration of insulin ineffective for blood glucose management--the insulin is digested before it can reach the bloodstream.� The oral insulin administration here noted is taking place as part of several diabetes prevention trials.� In one example, individuals considered at high risk for developing diabetes (but not yet "diabetic") are given oral insulin in an effort to misdirect their body's autoimmune attack on the Beta cells of the pancreas.� Oral insulin, very "investigational" at this time, is not currently an option for blood glucose management.

The Future

����������� Amylin Pharmaceuticals, Inc., has continued work on their Extendin-4 (AC2993), an analog of the hormone GLP-1, glucagon-like-peptide.� This investigational diabetes drug has shown a number of potentially therapeutic effects.� Extendin-4 appears to stimulate insulin secretion, except during periods of hypoglycemia (dangerously low blood sugars).� It appears to modulate gastric emptying, slowing the entry of ingested nutrients into the blood.� It appears it may lessen food consumption in obese animals, leading to reduction of body weight.� Most important, it has resulted in "near normalization of glucose control in animal models of type 2 diabetes."

����������� Researchers at Johns Hopkins are testing aminoguanidine, a new medication that may prevent or reduce some of the ramifications of diabetes.� Swedish and American researchers are testing still another, APO A1 MILANO, that may help reduce diabetic heart disease.� Inhaled insulin (for nasal administration) is being tested in the U.S. and U.K., and may someday supplant injection.� Vitrase, from Advanced Corneal Systems, a drug that may help clear vitreous hemorrhage, is currently in FDA clinicals.� Trental (pentoxifyline, from Hoechst Marion Roussel) is now available to treat "intermittent claudication," a painful circulatory ailment and frequent companion of diabetic peripheral neuropathy.� Some doctors are prescribing the antidepressant Paxil or the antiseizure medication Neurontin to treat neuropathy symptoms.� ACE inhibitors, a class of blood pressure medications like Capoten (Captopril), have been proven to deter and retard diabetic kidney complications.� Other oral medications are constantly being evaluated for possible diabetic applications, and some will make it to the pharmacy shelf.

����������� Many of these are new, investigational or just-licensed prescription medications.� Talk to your doctor about them.� I list them here as an example of how unbelievably rapid is the pace of change.� Where will we be two years from now?� We'll be doing even better!