your body wiU most likelyjust stop making insulin automaticaUy.
Sul fonylureas and simUar drugs, on the other hand, because they stimu late 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 patient who ex periencedhypoglycemia.
Shewasveryobese but onlyvery mUdly dia betic, and I was giving her metformin to reduce insulin resistance to facUitate weight loss.
When I put her on metformin, her blood sugars went too low (but not dangerously) , down into the 60s.
So there may be some very sUght risk of hypoglycemia with the insulin sensitizers or insulin mimetics, but this is not at aU compara ble to the great risk with the sulfonylureas and simUar medications.
One warning, however.
The body cannot turn off injected insulin, so if you are taking insulin plus any of these oral agents,hypoglycemia is possible.
WHAT IF THESE AGENTS DON'T BRING BLOOD SUGARS INTO LINE?
If these agentsare not adequateto normalizeblood sugarscompletely, chances are there is something awry in the diet or exercise portion of your treatment program.
The most likely culprit for continued ele vated blood sugarsis that the carbohydrate portion of your diet is not properly controUed.
So the first step is to examine your diet again to see if that's where the problem Ues.
With many patients, this is a mat ter 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 techniquesdescribed there.
If diet is not the culprit, then the next thing , no matter how obese or resis tant 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'U certainlyuse injectedinsulin.
It's also worth keeping in mind that infection or illness can seri ouslyimpair your efforts at blood sugarnormalization.
If your blood sugarlevels areway out of lineeven with the useof insulin, you might also consider talking to your physician about potential underlying in fection, especiaUy in the mouth (see pages 100-101).
OralInsulin-Sensitizing Agents, Insulin-Mimetic Agents, and OtherOptions 243
DISADVANTAGES OF INSULIN SENSITIZERS AND INSULIN MIMETICS
Although insuUn mimeticsand insuUn-sensitizing agents are some of the best tools we havefor controUing blood sugars,they are not with out their difficulties.
Since alpha Upoic acid and evening primrose oU are not prescription drugs in most countries (Germany is a notable exception), they are not covered by most health insurance.
Alpha Upoic acid is not inexpensive; at this writing, a supply of 180Insulow 100 mg tablets costs about $30.
ALA reduces body stores of biotin, a substance that aids in the uti lization of protein and a varietyof other nutrients, so when you take alpha Upoic acid, you might be wiseto take biotin supplements also, unless you are taking Insulow,which already contains biotin.
Yourbi otin intake should theoreticaUy equal about 1 percent of your alpha Upoic acidintake,so if you are taking1,800 mgALA per day, in theory youwouldtake about 18mg of biotin.
Mostof mypatients who use al pha Upoic 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.
Metformin has a very low side-effects profile, with the exception of gastrointestinal distress , queasiness, nausea, diarrhea, or a slight beUyache , in as many as a third of the people who try the non- extended-release version.
Most people who experience such discom fort, however, find that it diminishes as they become accustomed to the medication.
Only a very few patients can't tolerate it at aU. (Some patients, particularly obese people who are anxious to achieve the weight loss that metformin can facUitate, wiU ignore any initial gas trointestinal distress and use an antacid drug such as Pepcid or Taga met for reUef.
Others, who may only experience relatively mUd discomfort, are wiUing to tolerate it for a few weeks just to get things roUing.) Rare casesof diarrhea have been reported long after the start of metformin therapy.
They were reversed by discontinuation of the medication.
I havenot observedgastrointestinal side effects associated with the use of thiazolidinediones or extended-release metformin.
Metformin's predecessor, phenformin, was,in the 1950s, associated with a potentiaUy life-threateningcondition calledlactic acidosis.
This occurred in a smaU number of patients who were already suffering fromheart faUure or advanced Uver or kidney disease.
AlthoughI have
244 Treatment
read of only a few instances of lactic acidosis associated with met formin, the FDAadvises against using it in individuals with these con ditions.
Metformin has been reported to lower vitamin B-12 stores in about one-third of users.
This effectcanbe preventedby taking a cal cium supplement (see page 179).* The two thiazoUdinediones currently avaUable in the United States both have potential for minor problems.
PiogUtazone is cleared from the bloodstream by the liver, utilizing the same enzyme it utilizes to clear many other common medications.
The competition for this en zyme 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 piogUtazone.
You should check the package insert for potential drug interactions and talk to your physicianand pharmacist.
RosigUtazone and especiaUy piogUtazone can cause a smaU amount of fluid retention in some people.The consequence of this is a dilution of redblood ceU count and mUd swelling in the legs.
I've seena number of such cases.
There can alsobe a smaU weight gain due to the retained water, not to fat.
This water retention has been associated with a few in stances of heart faUure in individuals taking one of these medications plus insulin.
In the United States, the FDA hastherefore recommended that doses of these agents not exceed 4 mg and 30 mg per day, respec tively, for peoplewho inject insulin.
I havetreated many insulin users with them and have seen sUght swelling ofthe legsin some cases.
When this occurred, I discontinued the medication immediately.
There also have been very rare cases of reversible Uver damage associated with both rosigUtazone and piogUtazone.* A study reported in Endocrine Practice in 2001 showeda significant increase in serum triglyceride lev els for users of rosigUtazone but not piogUtazone.
On the other hand, piogUtazone hasbeen shownto improveUpid profiles (LDL, HDL,and triglycerides), whUe rosigUtazone cancause a sUght impairment.
A deficit of vitamin B-12 can increase serum levels of the renal disease risk fac tor homocysteine. It would therefore be wise for your physician to check your serum homocysteine everysix months whileyou are using metformin. *Even though reports of Uver toxicityare far fewer than with some commonly used medications such as niacin and the so-caUed statins, it's a good idea for users of these insulin sensitizers to have their blood tested for liver enzymes annuaUy.
Oral Insulin-SensitizingAgents, Insulin-Mimetic Agents, andOther Options 245
Because of the possibUity of fluid retention, neither medication should be used by patients with significant cardiac, lung, or kidney disease, or with any degreeof heart failure. I usuaUy start people on rosigUtazone to avoid potential competi tion for clearance by the liver with other drugs another physician might prescribe in the future.
USING MULTIPLE AGENTS
Metformin works principaUy by lowering insuUn resistance in the liver.
It also impairs, somewhat, the absorption of carbohydrate bythe intestine.
Thiazolidinediones principaUy affect muscleand fat, and to a lesser degree the liver.
Thus, if metformin does not fuUy normalize blood sugars, it makes sense to add one of the thiazoUdinediones , and vice versa.
Since rosigUtazone and piogUtazone workby the same mechanisms, it makes little sense to use both in the same individual.
The FDA suggests that doses of piogUtazone not exceed 30 mg daUy when taken with metformin.
Since ALA and eveningprimrose oU work as insulin mimetics, it is certainly appropriate to add these to any combination of the other agents.
OTHER CONSIDERATIONS
Thethiazolidinediones do not have theirfuU bloodsugar-lowering ef fects on the daytheyarestarted.
PiogUtazone achieves its fuU potency after a few weeks, and rosigUtazone mayrequire up to twelve weeks.
When bloodsugars are much higher than the targets that I set,both metformin and the thiazoUdinediones can cause the pancreas to in crease its insulin production in response to glucose.
Because of the lower blood sugars that wesee, this effect becomes insignificant.
Vitamin A supplementation has been shown to lower insulin resis tance (as does vitamin E)* in doses of about 25,000 IU daUy.
Since slightly higher doses of vitamin AarepotentiaUy very toxic, and doses as low as 5,000 IU can cause calcium loss from bone, I would consider
*Vitamin Eshouldonlybe usedin the forms called gamma tocopherol or mixed tocopherols.
246 Treatment
only moderate doses of its nontoxic precursor, beta carotene, for this purpose.
Studies have shown that magnesium deficiency can cause insuUn resistance.
It would therefore be a sensible idea for physicians to test type 2 diabetics for red blood ceU magnesium (not serum magne sium) levels.
If the level is low, magnesium supplementation should help.
I recommend a product caUed slow-mag in smaU doses that can be increased if the test remains low after one month.
Excessive doses can causediarrhea.
Sinceredblood ceU magnesium is not a perfect in dicator of blood magnesium stores, and since magnesium supple ments are benign to peoplewith normalkidneys (except fordiarrhea), it is appropriate to use magnesium supplements as a test to see if blood sugars decUne.
Doses as high as700 mg daUy are common for adults.
SimUarly, zinc deficiency can cause diminished production of lep tin, a hormone that impedes overeating and weight gain.
Such defi ciency can also impair functioning of the thyroid gland.
It is thus wise for aU type 2 patients to ask their physicians to test their serum zinc levels and to prescribe zinc supplementation if warranted.
FoUow-up serum zinc levels should be measured to ensure that normal levels are not exceeded.
Compounds ofthe heavymetalvanadiumhavebeen shown to lower insulin resistance, reduce appetite, and possibly also act as insuUn- mimetic agents.
They are quite potent in lowering blood sugars, but there's a catch.Vanadium compounds work by inhibiting the enzyme tyrosine phosphatase, which is essential to many vital biochemical processes in the body.
The possibUity is quite real that this inhibi tion can be damaging.
Since clinical trials in humans have not ex ceeded three weeks in duration, long-term freedom from adverse ef fects has yet to be documented.
Some users of vanadium compounds have experienced gastrointestinal irritation.
Although vanadyl sulfate is widely avaUable in health food stores as a dietary supplement and has been used for years without anyreports of adverse effectsin med icaljournals, I tentatively recommend that it be avoided until more is known.*
Except by commercial pilotswho must avoidinsuUn (seepage247).
OralInsulin-Sensitizing Agents, Insulin-Mimetic Agents, and OtherOptions 247