Insulin altering agents

By treating the insulin resistance, PCOS may be also treated, possibly reversed. While preliminary studies have been very encouraging, there is much to be learned. A major benefit of these medications is that the entire spectrum of problems arising in PCOS appears to be improved. Additionally, this appears to be accomplished at relatively low risk, inconvenience, and cost. It should be noted that since these medications are currently approved solely for the treatment of diabetes, they must be considered experimental for sole treatment of PCOS. But then, there is no therapy that is approved for the treatment of PCOS, only its symptoms.

It is still very unsettled which PCOS patient may derive benefit from these medications. With some PCOS patients these medications have successfully restored normal menstruation and even fertility even the absence of the insulin resistance. They may be a useful alternative when other therapies have failed, or benefit appears to exceed risk. The primary drug of choice because of its safety profile is metformin. Rosiglitazone (Avandia) and pioglitazone (Actos) are usually second lines drugs used when metformin can not be tolerated, or is ineffective in reducing insulin levels. At least some weight loss is common with metformin, while the “glitazones” have been repotted to cause weight gain, at least in diabetics.

Metformin (Glucophage)

An FDA advisory subcommittee voted unanimously in March, 1994 that Metformin be approved for the treatment of insulin resistance and type 2 (insulin resistant) diabetes that cannot be controlled by diet alone. It had the strong endorsement of the American Diabetes Association and is presently used in more than 80 countries. By September, 1996 more than one million U.S. patients had been prescribed the medication. Now there are as many as seven million on the drug.

Metformin enhances the body’s sensitivity to insulin and inhibits glucose production from the liver without the risk of hypoglycemia. It does not lower blood glucose levels, but acts to improve the body’s sensitivity to insulin without effecting insulin secretion. There is new evidence that suggests that metformin may also have a direct activity on androgen production by the ovary. Metformin use in some with PCOS has shown weight loss, improved lipid profiles, lowering of blood pressure, lowered androgen levels, increased sensitivity to clomiphene, restoration or improvement in menstruation, pregnancy and improved pregnancy outcome. About 50 percent of PCOS patients taking metformin note improvement in well being and energy level. Trials are underway to see if metformin may postpone or prevent the development of diabetes in individuals at risk. The preliminary result are promising. Overall, metformin appears to have an excellent safety profile. Because problems that might arise form metformin use are a major source of inquiry, an extended listed is given below.

Gastrointestinal disturbance 
Gastrointestinal (GI) upset and a tendency toward looser stools or more frequent bowel movements are reported in at least one third of users. These problems are much more common in the initial month of use and can be decreased by starting at lower doses and taking the medications less frequently. GI problems are most often experienced after a meal rich in fats or sugars. If there is recurrent vomiting or persistent diarrhea, a physician should be consulted.

In warning patients about the side effects of metformin, there are several analogies I use that are more or less correct. The first is that metformin is similar to Antibuse given to alcoholics that causes a quite severe reaction when alcohol is used. The same will often occur while on metformin if a “Big Mac attack” is launched. If the thought of a piece of chocolate cake, or an order of French fries becomes a little repulsive due to resulting intestinal problems, one is less likely to partake of the evil.

The early stages of metformin use afford a reasonable chance for behavior modification. An additional analogy of metformin action is that it regulates the body’s need for glucose. If more is taken in than needed, the excess will be “dumped.” That dumping can be the source of the GI side effects. And the third analogy used is that Metformin adjusts the carburetor on the body’s engine. It is running on too rich a fuel and by “leaning out” the mixture, performance is increased.

None of these examples may be scientifically correct, but taken together I believe they accurately portray an assessment of the actions of metformin and the reason for the GI side effects. It may be less than kind. I am not opposed to responding to complaints of GI side effects after initiation of therapy with the comment, “Good. It’s working.” Certainly the side effects can be so severe that the medication must be discontinued and a physician should be immediately informed if a problem is perceived. Clearly, metformin is not a “one size fits all” drug. Those who continue to have persistent GI symptoms after the first month of use should reexamine their diet.

Generalized feeling of unwellness 
It seems that about 30 to 40 percent of patients on metformin really feel better. They may have mild GI effects; overall the energy level is increased and their appetite is decreased. They appear to almost be addicted to the drug. Another 30 to 40 percent are more in the “take it or leave it” category. They see or feel advancement in some areas, maybe a little decline in others, and often no real change one way or the other. A third group of 10 to 20 percent feel poorly on metformin with a number of varied complaints. Common sense would dictate that the medication be stopped in this group.

Blood Monitoring 
Metformin is cleared from the body by the kidneys. One half of the drug has been removed in 6 hours and another 50 precent in the next 6 hours. If there is a reduction in kidney function, the clearance of metformin is slowed and can build up in the body. Renal (kidney) function is tested by measurement of blood urea nitrogen (BUN) and creatinine levels in the blood and repeated yearly. A complete blood count (CBC) and comprehensive biochemistry panel including tests for liver and kidney function should be drawn at onset of therapy and at least yearly.

Lactic acidosis 
Lactic acidosis is a potentially fatal disorder that has been reported to complicate a small number of cases of metformin use. The reported incidence of lactic acidosis is 3/100,000 using the drug for one year. Some have argued that there is no risk in healthy individuals and that the problem only occurs in those already compromised by other illnesses and/or medication use. For now we should be vigilant. The symptoms of lactic acidosis are hyperventilation, slow and erratic pulse, weakness, muscle pain, sleepiness, and feeling of extreme unwellness. It will not just happen; there will be warning signs. There is some fear that if we no longer consider it a possibility and fail to inform our patients, then the one case might occur that could be prevented.

X-ray dye 
Metformin should be stopped at the time of, or just prior, to a procedure using X- ray dye containing iodine. The kidneys clear X-ray dye and rare cases of diminished kidney function have occurred because of the dye. Since the kidney clears metformin, it could cause a build-up of metformin and potentially increase the risk of lactic acidosis. The procedures that use iodinated dye include the hysterosalpingogram (HSG) in evaluation of infertility, intravenous pyleogram (VIP) often to exclude a kidney stone or evaluate the urinary tract for recurrent infection and abnormalities, evaluation for gall bladder disease (cholangiogram), tests to evaluate for blood clots, coronary artery function (angiogram), and CT / MRI scans. Metformin can be safely started in 48 hours if there have been no problems with the procedures.

The same rationale for withholding metformin before procedures using X-ray dye, can be said for surgery. Metformin should be discontinued until a regular diet and fluid intake has resumed.

Alcohol use 
A social drink or two should pose no problems, but since alcohol may worsen lactic acid metabolism, excessive intake should be avoided.

Liver disease 
Again it’s the lactic acid problem. Metformin is not metabolized by the liver but individuals with markedly altered liver (hepatic) function may be at increased risk of lactic acidosis.

Exercise and dehydration 
Prolonged aggressive exercise may cause of build up of lactic acid. Aggressive exercise routines should be discussed. Kidney function can also be altered by dehydration. Metformin should be withheld if there is not adequate fluid intake.

Vitamin absorption 
Use of metformin may alter the body’s capacity to absorb vitamins from the digestive system, specifically vitamin B-12. A daily multivitamin and with increased calcium supplementationis a good idea.

It must be emphasized that the risk in pregnancy is unknown. Metformin been given a class B rating by the Federal Drug Administration (FDA), indicating expected safety, but with insufficient data to identify a harmful effect. Studies in laboratory animals have not shown an alteration in fertility, an increase in rate of pregnancy loss, or birth defects. The medication has been used in a small number of pregnant patients with no apparent adverse events. At present, it is generally recommended that Metformin be discontinued, if pregnancy is established. Recent studies have shown that metformin may reduce the possibility of miscarriage. A pregnancy test should be performed with breast tenderness, or other subjective signs of pregnancy. It appears that use in pregnancy is increasing. In the future, these drugs potentially could be used in pregnancy to prevent or treat gestational diabetes. It is important to note that maternal diabetes has been associated with increased rates of early pregnancy loss and birth defects. Metformin is excreted in milk and use during nursing is questionable.

Metformin is available in 500, 850 and 1000 mg tablets. The initial PCOS studies were performed using 500 mg of metformin three times daily. Because the midday dose is the hardest to remember, most now recommend twice daily dosing at either 500 to 1000 mg for PCOS. The maximum dose under all circumstance is 2550 mg (850 mg three times a day). Most often a once a day dose is used for about a week then increased at weekly intervals to minimize GI side effects. There is now an extended release form of Glucophage. Glucophage XR is available only in 500 mg tablets that are quite large. Many find a great convenience in once a day dosing and there is advantage of more evenly sustained levels and perhaps fewer side effects. Because of the lower dose and larger size the tablet, higher doses may still be better given as split doses.

Glitazones increase the number of fat cells (adipocytes) in the body. This may, in part, account for the minor weight gain seen in some individuals as opposed to weight loss often seen, at least initially, with metformin.

Since all glitazones are metabolized in the liver, the drug will be cleared more slowly in patients with liver disease. This doesn’t mean the drug cannot be used; however, more aggressive monitoring is needed.

The side effects are few and mild with the most common being fluid retention. At least in diabetes, there is a weight gain of two to 10 pounds. This is thought to be evidence of improved metabolism.

Treatment during mid- to late gestation was associated with fetal death and growth retardation in rats and rabbits when more than four times the usual human dose was given. There was no increase in birth defects even at very high doses. There is insufficient information to determine positive or negative effects in human pregnancy and most advise against use in pregnancy. In diabetics who achieve pregnancy while taking glitazones it may be better to continue the medications, but the risks should be carefully weighed. The manufacturers say that the glitazones should not be given to nursing mothers.

Rosiglitazone comes in 2, 4 and 8 mg tablets (maximum dose 8 mg) and is taken orally once or twice a day. For diabetic management the recommended does is 4 mg daily. For pioglitazone the dose is 15 mg once daily, increasing to a maximum dose of 45 mg daily. For PCOS, lower doses may be tried, especially if metformin is already being used. Although the incidence of liver toxicity is low, it is advised that ALT (alanine aminotransaminase- a liver enzyme) levels be performed before starting therapy and every other month for the first year of use.

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