REVIEW OF ORAL DIABETES MEDICATIONS

by Peter J. Nebergall, PhD

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

Oral medications are not insulin pills, rather four classes of drugs designed to improve the body's utilization of what insulin is still present. These are: The sulfonylureas, metformin, troglitazone, and acarbose.

Most "diabetes pills" are sulfonylureas, a class of chemicals that stimulate the pancreas to produce more insulin, effectively lowering blood glucose levels. Type II diabetics, those who need better management than diet and exercise can provide, often turn to these medications: tolbutamide, chlorpropamide, tolazamide, glyburide, glipizide, and new glimepiride for effective self-management. The sulfonylureas are effective, but only so long as the pancreas maintains some 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. At some point, no further increase in medication will be effective; the pancreas isn't doing its job, and the patient needs to start injecting insulin. When the islet cells of the pancreas stop making sufficient insulin, insulin must be injected.

Metformin, the second of the oral diabetes medications, 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 II diabetic make better use of the insulin he or she has left. Like the sulfonylureas, it becomes useless when the pancreas ceases producing adequate insulin.

Troglitazone (trade name Rezulin, from Parke-Davis) is the third oral medication. Rezulin directly attacks the problem of insulin resistance, the increasing inability to process insulin, that is the chief component of type II diabetes. In tests, Rezulin enabled many diabetics to reduce volume and frequency of insulin injections. A few were able to discontinue insulin injections entirely.

Initially, Rezulin was tested and approved for use with insulin-using type II diabetics. As tests continued, it became clear that it was also an effective blood glucose reducer either alone (in combination with diet and exercise) or in combination with a sulfonylurea, for type II diabetics who did not need insulin (although not a replacement for the sulfonylureas). On August 4, 1997, the Food and Drug Administration approved Rezulin for these new uses.

As with other oral diabetes medications, Rezulin's effectiveness depends on the presence of insulin. If sufficient insulin is not present, it must be injected, and Rezulin therapy will not change that fact. Where insulin supply rather than insulin resistance is the issue (as in type I diabetes), Rezulin therapy offers nothing. Investigations continue, and new uses may come with time. "Because of its mechanism of action," states Parke-Davis, "Rezulin is active only in the presence of insulin. Therefore, Rezulin should not be used in type I diabetes or for the treatment of diabetic ketoacidosis."

Published data state that although degree of renal insufficiency has no effect on Rezulin dosage, persons with hepatic (liver) disease should exercise caution. Other data warn that in premenopausal anovulatory women, Rezulin therapy may result in resumption of ovulation, and risk of pregnancy. There is further recommendation to proceed with caution if the individual is taking antirejection drugs such as cyclosporine or tacrolimus.

Acarbose, the fourth of the current "oral meds" is completely different. A carbohydrase inhibitor, it temporarily suppresses the digestive enzymes which turn carbohydrate 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.

Problems

Unfortunately, oral medications are often eventually insufficient. Many type II 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. (Note: Regular, frequent blood glucose monitoring 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. 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

Researchers at Johns Hopkins are testing aminoguanidine, a new medication that may prevent or reduce some of the ramifications of diabetes. Ergo Scientific Company's Ergoset, currently in Phase III clinicals, appears to reduce the high plasma lipid levels common in type II diabetes, and thus the risk of diabetic heart disease. Swedish and American researchers are testing still another (APO A1 MILANO, covered in VOICE Volume 10, Number 4) that may help reduce diabetic heart disease. Aerosol spray insulin (for nasal administration) is being tested, and may someday supplant injection. Trental (pentoxifyline, from Hoechst Marion Roussel) is now available to treat "intermittent claudication," a painful circulatory ailment and frequent companion of peripheral neuropathy. 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. Change is coming quickly.