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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.

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? 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!