Chapter
14: Oral Hypoglycemic Agents /
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If diet and exercise
are not adequate to bring your blood sugar readings
under control, the next level of treatment to consider
is blood sugar–lowering pills, known as oral hypoglycemic
agents (OHAs). For people who still have sufficient
insulin-producing capacity, OHAs alone may provide
the extra help they need to reach their blood sugar
target. Some insulin-resistant individuals who produce
little or no insulin on their own may find two particular
OHAs useful in reducing their doses of injected insulin.
Although there are several
OHAs currently on the market, at this writing I routinely
prescribe only one of them. By the time you read this,
however, a new agent, troglitazone, will be available.*
I expect to prescribe it at least as much as I do.
Metformin and Troglitazone—The
OHAs of Choice
The great advantage
of metformin and troglitazone over all other OHAs
is that they help to reduce blood sugar by making
the body's tissues more sensitive to insulin, whether
it's the body's own or injected. This is a benefit
that can't be underestimated. Not only is it a boon
to those trying to get their blood sugars under control,
but it's also quite useful to those who are obese
and simultaneously trying to get their weight under
control. By helping to reduce the amount of insulin
in the bloodstream at any given time, these two drugs
can help in controlling the powerful fat-building
properties of insulin. I have many patients who are
not diabetic but have come to me for treatment of
their obesity. Metformin has been a real plus to the
weight-loss efforts of some because of its ability
to curtail insulin resistance. I expect the same benefits
from troglitazone.
Some obese diabetic patients
come to me who are injecting very large doses of insulin
because their obesity makes them highly insulin-resistant.
These high doses of insulin cause a lot of fat-building
to take place, and weight loss becomes proportionately
more difficult. Metformin and troglitazone make these
patients more sensitive to the insulin they're injecting.
In one case I had a patient taking 27 units of insulin
at bedtime, even though he was on our low-carbohydrate
diet. After he started on metformin, he was able to
cut the dose to about 20 units. This is still a very
high dose, but the metformin facilitated the reduction.
Both OHAs have also been
shown to improve a number of measurable cardiac risk
factors, including lipid profile, serum fibrinogen,
blood pressure, and even abnormal thickening of the
heart muscle itself. In addition, metformin has been
found to inhibit the destructive binding of glucose
to proteins throughout the body—independent of its
effect upon blood sugar.
Most of the other OHA drugs
on the market, the old sulfonylureas, only work if
you are still producing some insulin on your own.
They operate by stimulating the pancreas to produce
more insulin, which can directly cause your remaining
pancreatic beta cells to break down over a period
of years. The higher their doses, the more likely
will be beta cell burnout. They do not decrease the
body's requirements for—or increase its sensitivity
to—insulin. They also stimulate insulin production
whether the body needs it or not, so there's the constant
risk of hypoglycemia. Therefore, the only case in
which I still prescribe a sulfonylurea is if a patient's
blood sugars cannot be controlled by diet alone and
for some reason he's likely to live less than five
years—and he is terrified of insulin injections. Otherwise,
the harm that sulfonylureas can do simply outweighs
any benefit. There's a new sulfonylurea OHA being
marketed in the United States which the manufacturer
and several published studies claim lowers insulin
resistance and serum insulin levels. This product,
glimepiride (Amaryl, Parke-Davis), also stimulates
beta cells to produce insulin. It is therefore the
only sulfonylurea I will prescribe for special situations.
At present, I only have one patient who is a "special
situation." Thus far, when given the choice,
all my other patients have chosen insulin or insulin
in combination with metformin.
Who is a Likely Candidate
for Metformin or Troglitazone?
Generally speaking,
these OHAs are natural choices for a Type II diabetic
who despite a low-carbohydrate diet cannot get his
weight down or his blood sugars into normal ranges.
The blood sugar elevation may be limited to a particular
time of the day, it may be during the night, or it
may entail a slight elevation all day. We base our
prescription on the individual's blood sugar profiles.
If even on our diet, blood sugar exceeds 300 mg/dl
at any time of the day, I'll immediately prescribe
insulin and won't even attempt to use these agents,
except to eventually reduce doses of injected insulin.
If your blood sugar is higher upon arising than at
bedtime, we'd give you metformin or troglitazone at
bedtime. If your blood sugar goes up after a particular
meal, we'd give you the OHA about 2 hours before that
meal. Since food enhances the absorption of troglitazone,
we might give this drug with the meal.
Getting Started: some
typical OHA Protocols
Let's say you're
a Type II diabetic and through weight loss, exercise,
and diet, you pretty much have your blood sugars within
your target range. Still, your blood sugar profiles
show a regular elevation in the mornings after a low-carbohydrate
breakfast, probably due to the dawn phenomenon.
In order to get your blood
sugars into normal ranges, we'd start you out on a
progressive dose. Overall, metformin has a very low
side-effects profile, with the exception of gastrointestinal
distress—queasiness, nausea, diarrhea, or a slight
bellyache—in as many as a third of the people who
try it. Most people who experience such distress,
however, find that their discomfort diminishes as
they become accustomed to the medication. Only a very
few patients can't tolerate it at all. (Some patients,
particularly obese patients who are anxious to achieve
weight loss that metformin can facilitate, will ignore
any initial gastrointestinal distress and use an antacid
drug such as Pepcid or Tagamet for relief. Others,
who may only experience relatively mild discomfort,
are willing to tolerate it for a few weeks just to
get things rolling.) Gastrointestinal side effects
have not been reported for troglitazone.
In any case, metformin
takes about 2 hours to start working. Although the
literature says that it peaks 2 hours after that,
we find that it literally lasts all night if you take
it at bedtime. It comes in two dosage strengths—500
mg and 850 mg unscored tablets. It's my practice always
to start patients on the lowest possible dose—so in
the above case we'd set you up with a pill cutter
and have you take half a 500 mg tablet immediately
after breakfast. Studies show that troglitazone starts
working after 30 minutes, peaks in about 2–3 hours,
and stops working after about 48 hours. Because it
remains in the blood for so long, after dosing for
a few days it will reduce insulin resistance all day
long. It is supplied as 200 mg and 400 mg unscored,
coated tablets that probably should not be broken
with a pill cutter. The maximum recommended dose is
600 mg per day.
Note that even though it
takes 2 hours for metformin to begin working, and
your blood sugar elevation is after breakfast, we'd
still start you off by having you take the medication
immediately after breakfast. We do this in order to
reduce the likelihood of gastrointestinal discomfort.
Many people don't have any discomfort when they take
metformin on a full stomach. Troglitazone, on the
other hand, can be taken before meals from the start,
without distress, but it may not be fully absorbed
without food.
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