15
Oral Insulin-Sensitizing Agents, Insulin-Mimetic Agents, and Amylin
Analog
GETTING STARTED: SOME TYPICAL PROTOCOLS
Let’s say you’re a type 2 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.
Of the medications I’ve described here, the most rapid to start acting
is rosiglitazone, which, although it reaches peak levels in the bloodstream
in about an hour, probably achieves its full effect after about 2 hours.
So you might take a starting dose of 4 mg upon arising and then eat
breakfast 1–2 hours later. If this is only partly effective, the dose
can be increased to two 4 mg tablets or one 8 mg tablet (the maximum
recommended daily dose). If this is somewhat effective, but 2 hours
after breakfast your blood sugars are still above target, you might
add a sustained-release dose of metformin before you go to bed.
This type of metformin achieves its peak blood levels after about 7
hours. A starting point would be one 500 mg tablet at bedtime. If this
still doesn’t get your blood sugars into target range, then you could
increase the dose gradually, perhaps by one more tablet at bedtime for
a week and so on, until you reach a maximum of 4 tablets a night or
you hit your target. I always recommend the least possible dosage—partly
due to the Laws of Small Numbers, but also because of the reduction
of likelihood for potential side effects. With metformin, if you build
up your dosage slowly, it lessens the possibility of gastrointestinal
discomfort that about one-third of users of the older,more-rapid-acting
version experience.
In some cases, blood sugar levels either increase overnight or increase
during the first 2 hours after you arise. The latter situation is most
likely due to the dawn phenomenon. Either situation may respond to timed-release
versions of metformin (Glucophage XR in the United States) with or without
ALA plus evening primrose oil, all taken at bedtime, using the doses
described above. If need be, pioglitazone may also be added at bedtime.
Tablets of pioglitazone are sold in 15 mg and 45 mg doses. The maximum
daily dose is 45 mg. Another possibility that would warrant oral medication
would be if your blood sugar levels increased after lunch or dinner.
We could possibly
cover the problem meal with rosiglitazone by taking it 1–2 hours before
eating.
WILL THESE MEDICATIONS CAUSE HYPOGLYCEMIA?
Sulfonylurea OHAs carry the very real possibility of causing dangerously
low blood sugars, which is one of the reasons I never prescribe them.
However, this is only remotely likely with the insulin-sensitizing and
insulin-mimetic agents listed above.None of them interferes with the
self-regulating system of a pancreas that can still make its own insulin.
If your blood sugar drops too low, your body will most likely just stop
making insulin automatically. Sulfonylureas and similar
drugs, on the other hand, because they stimulate insulin production
whether the body needs it or not, can cause hypoglycemia. Although the
manufacturer and the scientific literature claim that
metformin does not cause hypoglycemia, I did have a single patient who
experienced hypoglycemia. She was very obese but only very mildly diabetic,
and I was giving her metformin to reduce insulin resistance to facilitate
weight loss. When I put her on metformin, her blood sugars went too
low (but not dangerously)—down into the 60s.While it’s possible for
any drug to have nearly any effect on a given individual, this was the
only case I’ve seen of hypoglycemia with metformin, and I was using
it in a patient who was only mildly diabetic. Her insulin resistance
was causing her to make a lot of insulin. Why the metformin brought
her down so low was probably related to her difficulty storing insulin.
So there may be some very slight risk of hypoglycemia with the insulin
sensitizers or insulin mimetics, but this is not at all comparable
to the great risk with the sulfonylureas and similar medications. One
warning, however. The body cannot turn off injected insulin, so if you
are taking insulin plus either of these agents, hypoglycemia is possible.
WHAT IF THESE AGENTS DON’T BRING BLOOD SUGARS INTO LINE?
If these agents are not adequate to normalize blood sugars completely,
chances are there is something awry in the diet or exercise portion
of your treatment program. The most likely culprit for continued elevated
blood sugars is that the carbohydrate portion of your diet is not properly
controlled. So the first step is to examine your diet again to see if
that’s where the problem lies.With many patients, this is a matter of
carbohydrate craving. If this is the case and your carbohydrate craving
is overwhelming, I’d recommend that you reread Chapter 13 and consider
pursuing one of the techniques described there. If diet is not the culprit,
then the next thing—no matter how obese or resistant to exercise you
might be—would be to try to get you started on
a strenuous exercise program. If even this doesn’t do the trick, we’ll
certainly use injected insulin.
It’s also worth keeping in mind that infection or illness can seriously
impair your efforts at blood sugar normalization. If your blood sugar
levels are way out of line even with the use of insulin, you might also
consider talking to your physician about potential underlying infection,
especially in the mouth (see pages 97–98).
DISADVANTAGES OF INSULIN SENSITIZERS AND INSULIN MIMETICS
Although insulin mimetics and insulin-sensitizing agents are some of
the best tools we have for controlling blood sugars, they are not without
their difficulties. Since alpha lipoic acid and evening primrose oil
are not prescription drugs in most countries (Germany is a notable exception),
they are not covered by most health insurance. Alpha lipoic acid is
not inexpensive; at this writing, a supply of 60 Alpha Lipoic Sustain
300 mg tablets costs about $30–$40.
ALA reduces body stores of biotin, a substance that aids in the utilization
of protein and a variety of other nutrients, so when you take alpha
lipoic acid, you might be wise to take biotin supplements also. Your
biotin intake should theoretically equal about 1 percent of your alpha
lipoic acid intake, so if you are taking 1,800 mg ALA per day, in theory
you would take about 18 mg of biotin. Most of my patients who use alpha
lipoic acid don’t take more than about 15 mg biotin per day, and they
experience no apparent adverse effects. Most preparations come only
in 1 mg strengths.* You can take the biotin once daily.
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 the non– timed-release
version. Most people who experience such discomfort, however, find that
it diminishes as they become accustomed to the medication. Only a very
few patients can’t tolerate it at all. (Some patients, particularly
obese people who are anxious to achieve the 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.) Rare cases
of diarrhea have been reported long after the start of metformin therapy.
They were reversed by discontinuation of the medication. I have not
observed gastrointestinal side effects associated with the use of thiazolidinediones
or slow-release metformin.
Metformin’s predecessor, phenformin, was, in the 1950s, associated
with a potentially life-threatening condition called lactic acidosis.
This occurred in a small number of patients who were already suffering
from heart failure or advanced liver or kidney disease. Although I have
read of only three instances of lactic acidosis associated with metformin,
the FDA advises against using it in individuals with these conditions.
Metformin has been reported to lower vitamin B-12 stores in
about one-third of users. This effect can be prevented by taking a calcium
supplement (see page 175).*
*Trotta’s Pharmacy now carries 5 mg doses of biotin. I recommend 3–4
doses daily when using the above doses of ALA.
The two thiazolidinediones currently available in the United States
both have potential for minor problems. Pioglitazone is cleared from
the bloodstream by the liver, utilizing the same enzyme it utilizes
to clear many other common medications. The competition for this enzyme
can leave dangerously elevated blood levels of some of these drugs.
If you are taking one or more of these competing medications, such as
some antidepressants, antifungal agents, certain antibiotics,
and others, you should likely not be using pioglitazone. You should
check the package insert for potential drug interactions and talk to
your physician and pharmacist.
Rosiglitazone and pioglitazone can cause a small amount of fluid retention
in some people. The consequence of this is a dilution of red blood cell
count and mild swelling in the legs. I’ve seen three such cases. There
can also be a small weight gain due to the retained water, not to fat.
This water retention has caused a few instances of heart failure in
individuals taking one of these medications plus insulin. In the United
States, the FDA has therefore recommended that doses of these agents
not exceed 4 mg and 30 mg per day, respectively, for people who inject
insulin. I have treated many insulin users with them and have seen slight
swelling of the legs in only three cases.When this occurred, I discontinued
the medication immediately. There also have been very
rare cases of reversible liver damage associated with both rosiglitazone
and pioglitazone.† A study reported in Endocrine Practice in 2001 showed
a significant increase in serum triglyceride levels for users of rosiglitazone
but not pioglitazone.
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