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Chapter 14: Oral Hypoglycemic Agents
If diet and exercise are not adequate to bring your blood sugar readings under control, the nextlevel 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 mayprovide the extra help they need to reach their blood sugar target. Some insulin-resistantindividuals who produce little or no insulin on their own may find two particular OHAs useful inreducing their doses of injected insulin.
Although there are several OHAs currently on the market, at this writing I routinely prescribeonly one of them. By the time you read this, however, a new agent, troglitazone, will beavailable.* 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 toreduce blood sugar by making the body's tissues more sensitive to insulin, whether it's the body'sown or injected. This is a benefit that can't be underestimated. Not only is it a boon to thosetrying to get their blood sugars under control, but it's also quite useful to those who are obese andsimultaneously trying to get their weight under control. By helping to reduce the amount ofinsulin in the bloodstream at any given time, these two drugs can help in controlling the powerfulfat-building properties of insulin. I have many patients who are not diabetic but have come to mefor treatment of their obesity. Metformin has been a real plus to the weight-loss efforts of somebecause 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 becausetheir 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 andtroglitazone make these patients more sensitive to the insulin they're injecting. In one case I hada 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 veryhigh 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 theheart muscle itself. In addition, metformin has been found to inhibit the destructive binding ofglucose 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 stillproducing some insulin on your own. They operate by stimulating the pancreas to produce moreinsulin, which can directly cause your remaining pancreatic beta cells to break down over aperiod of years. The higher their doses, the more likely will be beta cell burnout. They do notdecrease the body's requirements for—or increase its sensitivity to—insulin. They also stimulateinsulin 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 sugarscannot 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 simplyoutweighs any benefit. There's a new sulfonylurea OHA being marketed in the United Stateswhich the manufacturer and several published studies claim lowers insulin resistance and seruminsulin levels. This product, glimepiride (Amaryl, Parke-Davis), also stimulates beta cells toproduce insulin. It is therefore the only sulfonylurea I will prescribe for special situations. Atpresent, I only have one patient who is a "special situation." Thus far, when given the choice, allmy 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 bloodsugar elevation may be limited to a particular time of the day, it may be during the night, or itmay entail a slight elevation all day. We base our prescription on the individual's blood sugarprofiles. If even on our diet, blood sugar exceeds 300 mg/dl at any time of the day, I'llimmediately prescribe insulin and won't even attempt to use these agents, except to eventuallyreduce doses of injected insulin. If your blood sugar is higher upon arising than at bedtime, we'dgive you metformin or troglitazone at bedtime. If your blood sugar goes up after a particularmeal, we'd give you the OHA about 2 hours before that meal. Since food enhances theabsorption 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 muchhave your blood sugars within your target range. Still, your blood sugar profiles show a regularelevation in the mornings after a low-carbohydrate breakfast, probably due to the dawnphenomenon.
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 gastrointestinaldistress—queasiness, nausea, diarrhea, or a slight bellyache—in as many as a third of the peoplewho try it. Most people who experience such distress, however, find that their discomfortdiminishes 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 thatmetformin can facilitate, will ignore any initial gastrointestinal distress and use an antacid drugsuch as Pepcid or Tagamet for relief. Others, who may only experience relatively milddiscomfort, are willing to tolerate it for a few weeks just to get things rolling.) Gastrointestinalside effects have not been reported for troglitazone.
In any case, metformin takes about 2 hours to start working. Although the literature says that itpeaks 2 hours after that, we find that it literally lasts all night if you take it at bedtime. It comesin two dosage strengths—500 mg and 850 mg unscored tablets. It's my practice always to startpatients on the lowest possible dose—so in the above case we'd set you up with a pill cutter andhave you take half a 500 mg tablet immediately after breakfast. Studies show that troglitazonestarts working after 30 minutes, peaks in about 2–3 hours, and stops working after about 48hours. Because it remains in the blood for so long, after dosing for a few days it will reduceinsulin resistance all day long. It is supplied as 200 mg and 400 mg unscored, coated tablets thatprobably should not be broken with a pill cutter. The maximum recommended dose is 600 mgper day.
Note that even though it takes 2 hours for metformin to begin working, and your blood sugarelevation is after breakfast, we'd still start you off by having you take the medicationimmediately after breakfast. We do this in order to reduce the likelihood of gastrointestinaldiscomfort. 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 itmay not be fully absorbed without food.
We'd then have you check your blood sugars before lunch. If your blood sugar was lower butstill elevated, after a few days, we'd gradually increase the dosage by half a pill (if metformin)until we got your prelunch blood sugars into your target range. To do this, we could go as high asfive 500 mg metformin tablets. (Metformin ceases having any cumulative effect after 2,500 mg.)If you were to experience gastrointestinal discomfort at any dose, we'd revert back to the priordose for three or four weeks and then increase it more slowly.
Once we determined what dose of metformin got your blood sugar normalized, we'd start to shiftthe dose to before breakfast—immediately upon arising. In shifting doses, we'd again work insmall increments. Let's say we had found that it took three 500 mg tablets to get your bloodsugars to within your target range. You'd shift the dose by starting to take half a tabletimmediately upon arising, and the other 2H tablets immediately after eating. After a week,provided you didn't experience any intestinal distress, we'd shift another half a pill toimmediately upon arising, and so on until you were taking all 3 when you got up.
If, after moving a portion of your dose—say, 1 1/2 tablets—you started experiencinggastrointestinal distress, we'd shift half a tablet back to after breakfast. Some people can takeseveral weeks to acclimate to metformin, so we'd let the regimen stand for a few days beforewe'd try moving it again. We've done this with numerous patients, and it works for most (thoughnot all) without any undue discomfort. This cautious tapering up of dose is not necessary fortroglitazone, which is unlikely to cause gastrointestinal side effects.
This is how we'd get your postbreakfast blood sugar elevation under control. Let's look at someother instances where these drugs can be useful.
Let's say you wake up in the morning with a higher blood sugar than when you went to sleep—not an especially elevated blood sugar, just higher than when you went to bed. This would tellme that you need some kind of help overnight. I have many patients whose blood sugars don't goup after meals but do go up overnight. The cause of the rise in blood sugars may be slowdigestion of dinner while you're asleep, or may be due to the dawn phenomenon. Whatever thecase, you'd still need something to help. Here we'd have you take metformin or troglitazone atbedtime. I'd prefer the troglitazone because it appears to be longer-acting. Again, it takes 2 hoursfor metformin to start working, 30 minutes for troglitazone, but both drugs appear to work formost of the night.
There's a good chance that your stomach will be empty at bedtime, so you stand a higher risk ofdeveloping gastrointestinal distress from metformin. As before, we'd start you with a low doseand bring it up slowly if you showed gastrointestinal distress, or rapidly if you didn't. Over time,as we discovered the proper dose, your blood sugar profiles would, we hope, show that yourfasting blood sugar in the morning was the same as at bedtime because of the metformin ortroglitazone.
Another instance when we'd start you on these drugs would be if you showed an elevated bloodsugar at bedtime. This would reflect the effects of dinner, and to get that under control, we'dwant you on one of them before dinner. Again, with metformin, we'd start you out on thesmallest possible dose immediately after dinner and eventually shift the dose to precede themeal. If you were also showing overnight blood sugar rises, we'd first work on the dinner dose.
Of course, the same protocol can be applied to lunch if blood sugars are routinely elevated beforedinner. Many of my patients take metformin before each meal and at bedtime.
Certainly if metformin were to cause gastrointestinal distress, we now have the option ofswitching to troglitazone. It is very possible that for some individuals we'd use both medications— perhaps metformin before meals and troglitazone at bedtime, or vice versa.
Will These Medications Cause Hypoglycemia?
Some OHAs—specifically the sulfonylureas—carry the very real possibility of causingdangerously low blood sugars, but this is only remotely likely with troglitazone or metformin.
This is because their mode of action is to increase your sensitivity to insulin. Neither agentinterferes with the self-regulating system of a pancreas that can still make its own insulin. If yourblood sugar drops too low, your body will just stop making insulin automatically. Sulfonylureas,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 causehypoglycemia, I did have a single patient who experienced hypoglycemia. She was very obesebut only very mildly diabetic, and I was giving her metformin to reduce insulin resistance andfacilitate weight loss. When I put her on metformin, her blood sugars went too low—down into the 60s. While it's possible for any drug to have nearly any effect on a given individual, this wasthe only case I've seen of hypoglycemia with metformin, and I was using it in a patient who wasonly mildly diabetic. Her insulin resistance was causing her to make a lot of insulin, but why themetformin brought her down so low I can't explain.
So there may be some very slight risk of hypoglycemia with troglitazone or metformin, but thisis not at all comparable to the great risk with the sulfonylureas. One warning, however. The bodycannot 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 neither of these drugs is adequate to normalize blood sugars completely, chances are there issomething awry in the diet or exercise portion of your treatment program. The most likely culpritfor continued elevated blood sugars is that the carbohydrate portion of your diet is somehow notproperly controlled. So the first step is to examine your diet again to see if that's where theproblem lies. With many patients, this is a matter of carbohydrate craving, patients eatingrestricted foods. If this is the case, if your carbohydrate craving is so overwhelming, I'drecommend that you look at appetite-suppressing medication as a way of getting uncontrollablecraving into line. If diet is not the culprit, then the next thing—no matter how obese or resistantto exercise you might be—would be to try to get you started on a strenuous exercise program. Ifeven this doesn't do the trick, we'll certainly use injected insulin. Another far-out possibility (Isay far-out because I haven't tried it yet) would be to use both metformin and troglitazonetogether.


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