Oral Diabetes Medications Update

Oral Diabetes Medications Update

ORAL DIABETES MEDICATIONS UPDATE
by 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,
troglitazone, 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 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 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).
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.
Troglitazone (trade name Rezulin, from Parke-Davis) is the fourth
oral medication. Rezulin directly attacks the problem of insulin resistance,
the increasing inability to process insulin, that is the chief component of
type 2 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 2 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 2 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. Other
applications may well follow.
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 1 diabetes),
Rezulin therapy as yet offers nothing. Investigations continue. "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
1 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, as there have been reports of individuals sustaining liver
damage from this medication. Although statistical incidence is small, the potential
is there—talk to your doctor. Parke-Davis (the manufacturer) now recommends
regular testing of liver function, and cessation of Rezulin use if hepatic impairment
is discovered.
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 (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. (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 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
Researchers at Johns Hopkins are testing aminoguanidine, a new
medication that may prevent or reduce some of the ramifications of diabetes.
Amylin Pharmaceuticals (whose investigational injectable, pramlintide, may help
type 2 diabetics), is testing Extendin-4, an insulin stimulant for type 2 diabetics
(like the sulfonylureas), but one that appears to shut off its action during
periods of hypoglycemia. Clinical tests are just beginning.
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. Avandia (rosiglitazone),
new from Smith Kline Beecham, now in the final stages of FDA approval, is similar
to Rezulin. 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. Change is coming
quickly.