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.
*A deficit of vitamin B-12 can increase serum levels of the cardiac risk factor homocysteine. It would therefore be wise for your physician to check your serum homocysteine every six months while you are using metformin. †Even though reports of liver toxicity are far fewer than with some commonly used medications such as niacin and the so-called statins, it’s a good idea for users of these insulin sensitizers to have their blood tested for liver enzymes every three to six months.
I usually start people on rosiglitazone to avoid potential competition for clearance by the liver with other drugs another physician might prescribe in the future.
USING MULTIPLE AGENTS
Metformin works principally by lowering insulin in the liver. Thiazolidinediones principally affect muscle and fat, and to a lesser degree the liver. Thus, if metformin does not fully normalize blood sugars, it makes sense to add one of the thiazolidinediones—and vice versa. Since rosiglitazone and pioglitazone work by the same mechanisms, it makes little sense to use both in the same individual. The FDA suggests that doses of pioglitazone not exceed 30 mg daily when taken with
metformin.
Since ALA and evening primrose oil work as insulin mimetics, it is certainly appropriate to add these to any combination of the other agents.
OTHER CONSIDERATIONS
The thiazolidinediones do not have their full blood sugar–lowering effects on the day they are started. Pioglitazone achieves its full potency after a few weeks, and rosiglitazone may require up to twelve weeks. When blood sugars are much higher than the targets that I set, both metformin and the thiazolidinediones can cause the pancreas to increase its insulin production in response to glucose. Because of the lower blood sugars that we see, this effect becomes insignificant.
Vitamin A supplementation has been shown to lower insulin resistance (as does vitamin E) in doses of about 25,000 IU daily. Since slightly higher doses of vitamin A are potentially toxic, and doses as low as 5,000 IU can cause calcium loss from bone, I would only consider its nontoxic precursor, beta carotene, for this purpose.
Studies have shown that magnesium deficiency can cause insulin resistance. It would therefore be a sensible idea for physicians to test type 2 diabetics for red blood cell magnesium (not serum magnesium) levels. If the level is low, magnesium supplementation should help. I recommend a product called slow-mag in small doses that can be increased if the test remains low after one month. Excessive doses can cause diarrhea.
Similarly, zinc deficiency can cause diminished production of leptin, a hormone that impedes overeating and weight gain. Such deficiency can also impair functioning of the thyroid gland. It is thus wise for all type 2 patients to ask their physicians to test their serum zinc levels and to prescribe zinc supplementation if warranted.
Compounds of the heavy metal vanadium have been shown to lower insulin resistance, reduce appetite, and possibly also act as insulinmimetic 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 possibility is quite real that this inhibition can be damaging. Since clinical trials in humans have not exceeded three weeks in duration, long-term freedom from adverse effects has yet to be documented. Some users of vanadium compounds have experienced gastrointestinal irritation. Although vanadyl sulfate is widely available in health food stores as a dietary supplement and has been used for years without any reports of adverse effects in medical journals, I tentatively recommend that it be avoided until more is known.
