Oral Diabetes Medications Update

by Peter J. Nebergall, PhD

This article appeared in Voice of the Diabetic, Volume 17, Number 4, Fall 2002 Edition, published by the Diabetes Action Network of the National Federation of the Blind. Updated July 2004.

Currently there are an estimated 18 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 several classes of drugs designed to improve the body's utilization of what insulin is still present, and to alter the digestion of sugars and carbohydrates. Prominent are: The sulfonylureas, the meglitinides (repaglinide/Prandin and nateglinide/Starlix), the biguanides (metformin,) the "glitazones", and the alpha-glucosidase inhibitors (glyset 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 inevitably grow ever less effective with the passage of time. They drive the failing pancreas to greater effort, producing needed insulin, 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 simply isn't doing its job any longer. This patient needs to start injecting insulin. When the islet cells of the pancreas cease producing sufficient insulin, insulin must be injected. This is a normal and predictable part of type 2 diabetes--not a "defeat."

Repaglinide (trade name Prandin), and its sister nateglinide (trade name Starlix), the second class of medications on our list, are a completely new chemical formulation. Prandin and Starlix resemble the sulfonylureas in mechanism of action, in that they stimulate the release of pancreatic insulin, improving blood sugar control (and are of no use in type 1 diabetes, where pancreatic insulin is not present). But they differ from the sulfonylureas in several ways:

  • Prandin and Starlix are 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 and Starlix are 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 Prandin's manufacturer), but even ESRD--end stage renal disease--is not a contraindication for Prandin or Starlix.
  • 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; it is not a substitute for insulin.

Glucovance is a special case. A mix of metformin and the sulfonylurea glyburide, it represents convenient combination therapy. Being part metformin, it carries metformin's cautions: against heavy consumption of alcohol, against use when chronic kidney problems are present, and against use by pregnant women. Its clinical effects are the same as those of metformin taken with a sulfonylurea.

The "glitazones" (medically the thiazolidinediones): Actos, from Takeda Pharmaceuticals; Avandia, from Smith-Kline Beecham; and now-banned Rezulin, from Parke-Davis, make up 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. Several years ago, 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.

The Alpha-Glucosidase Inhibitors: Acarbose (trade name Precose, from Bayer), and Glyset (trade name Miglitol, from Pharmacia/Pfizer) the fifth class of the "oral meds" on our list, are completely different. Carbohydrase inhibitors, they temporarily suppress the digestive enzymes which turn carbohydrates into glucose, slowing digestion and glucose absorption, keeping glucose levels more even. More dietary management tool than antidote to insulin shortage, these meds help some diabetics keep a more constant blood glucose level. "Temperamental" medications, they can have many side effects, and less than universal in its utility.


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? A "completely safe" medication would have to be a powerless one, and 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, in "pill" form, ineffective for blood glucose management--the insulin is digested before it can reach the bloodstream. However, several different groups are pursuing variations of inhaled insulin, and at least two of these are in late clinicals - and may prove sufficient to pass FDA regulatory oversight. There are no "oral" or "buccal" insulins" available for prescription--yet. I believe there shortly will be - as many experts are working on this problem.

I note that in several diabetes prevention trials, individuals considered at high risk for developing diabetes (but not yet "diabetic") were given oral insulin in an effort to misdirect their body's autoimmune attack on the Beta cells of the pancreas. So far, that strategy has not produced positive findings.

The Future

Progress is coming thick and fast. There is research on Glucagon-Like-Peptide (GLP1), and ongoing studies of Simlyn/Amylin, and much more. Each month brings news of new FDA filings, approvals, and breakthroughs. Change is the rule.

Good work is being done with "combination therapy," where two known ingredients are combined into a new medication more effective than either component. We've mentioned Glucovance, but there is also work being done with blood pressure medications, combining an ACE inhibitor with a calcium channel blocker. Other oral medications are constantly being evaluated for possible diabetic applications, and some will make it to the pharmacy shelf.

Talk to your doctor about these new, just-licensed prescription medications. 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!