[If you've been reading other pages on this website about metabolic syndrome, you may have already seen many of the links below; sorry about any loops you find yourself taking... JP].
There are three reasons to read about this medication (at least):
(Update June 2007: a possible fourth reason has recently been described by several bipolar experts, who note that medications for diabetes could have protective effects on the brainMcIntyre --particularly in patients who have illnesses where a shrinking of connections between brain cells, or sometimes even loss of these neurons in particular brain regions, is thought to be part of the underlying problem, as is now the case in mood disorders (see my series of essays on brain chemistry for more on this)).
Metformin was used recently as an "antidote" to weight gain induced by several different medications.Morrison It was remarkable effective in that one, small, uncontrolled (no placebo group) study -- meaning that these results should be interpreted with caution. Fifteen of the 19 patients lost weight, and some who continued metformin lost 10-30 pounds. [Update February 2007: another article came out recently with a larger group of adolescent patients, and a control group. Again, the results were quite striking..Klein Overall, there was no weight loss, but the placebo group continued to gain weight, leading to a quite striking difference. Insulin resistance, thought to be related to "metabolic syndrome", which goes along with the weight gain and represents a significant risk for cardiovascular disease, also did not increase in the metformin group, while increasing in the placebo group.
Someone asked me recently at a meeting about metformin, and I mentioned that my early experience with about 10 patients had not been very impressive. However, on the basis of this new study, I think trying it again for patients who are stuck on an atypical antipsychotic may be warranted. In this more recent study, patients had been on their atypical antipsychotics for months, and were even sometimes on other weight gain inducing medications such as lithium or Depakote. Perhaps they did not show any weight-loss because they were all adolescents, and should be growing (age range 10 to 17). They were clearly different from the control group, both statistically and in terms of clinically meaningful differences. For example, over four months, the control group gained about 10 pounds, while the metformin group gained none.
There are other reasons to be interested in this medication. A patient wrote me who had responded 20 years ago to the precursor of metformin (phenformin, removed from the market quickly because of risks which are fortunately much lower in metformin; see Lactic Acidosis below). She had "foggy mindedness" and difficulty concentrating which responded dramatically to phenformin. Note that she had "mental" symptoms, but was given a medication which affects insulin, and she got better. Her 3 children all had symptoms suggestive of Bipolar II, one diagnosed as such, and all 3 seemed to benefit from phenformin. Here's her letter, if you're interested (used by permission).
Her experience and that of her children illustrates how this medication may actually be a treatment in itself for complex mental health symptoms. For more on that possibility, read the essay on Metabolic Syndrome -- Causes Mental Health Symptoms?
Metformin is a medication given for the treatment of diabetes. Sometimes it is used for people who only have "insulin resistance". In this condition, people have difficulty responding to their own insulin. As a result, the body releases even more insulin trying to make up for this problem. However, insulin has many effects around the body.
One of these insulin effects may change a person's "metabolism" in very profound ways. Excess insulin can induce something called "metabolic syndrome". In younger women, this is sometimes recognized through infertility, or growing excess hair, and in that setting is called "Polycystic Ovarian Syndrome" (PCOS). Not everyone who has insulin resistance gets PCOS or metabolic syndrome, or diabetes – but many do.
Metformin can decrease this "insulin resistance". It can restore fertility. It can decrease excess hair growth and other body changes. In some cases this medication can decrease abdominal obesity, or at least assist people in their efforts to control their weight. In some people it can suppress appetite somewhat. It is now being tested for use with medications that commonly increase appetite and weight.
There are 3 main problems associated with this medication. We'll look at each in turn:
Lactic Acidosis (revised 9/2008)
In this condition the kidneys fail to clear out a normal product of muscle metabolism, lactate. LA occurs in roughly 5-9 people for every 100,000 treated; it has been fatal for half those affected, or roughly 2-5 deaths per 100,000. However, if your kidneys are working normally (and you don't drink a lot of alcohol), the odds on having this problem are even lower. In fact, there is even some debate as to whether metformin alone causes LA at all.Lalau
Since the relationship between metformain and LA was discovered, several risk factors, noted below, have been discovered. Of the very few who've had metformin-associated LA with no risk factors, noneMisbin have died, according to one review; although there is one reported case on a metformin-lactic acidosis webpage. In other words, if people don't have these risk factors, there is very little risk from taking this medication.
Here are the risk factors to be aware of: by far the biggest one is kidney disease. This is easily detected with routine lab tests (guidelines, 2007). After this, comes liver disease as shown in similarly routine tests. Metformin should not be used after surgery (or for planned cases, shortly before surgery either; ask your doctor), as that has been associated with developing lactic acidosis. If you have congestive heart failure, more caution is required using this medication. Using alcohol while taking this medication substantially increases the risk of having LA. Click for symptoms of lactic acidosis.
Between 10 and 30% of people taking metformin have a decrease in their B12 levels. B-12 is a vitamin required for production of red blood cells, so if you're low, one of the ways this can show up is "anemia" -- too few red blood cells. The cells you do make actually come out too big in this situation, so it's pretty easy to recognize this problem. A simple blood test will easily reveal this anemia and identify B-12 deficiency as a likely culprit.
However, B-12 deficiency can show up in some other ways even without the anemia. If you need it later, here's a list. You should alert your primary care physician that you're on metformin, as a yearly simple blood count will reveal the problem in the vast majority of casesFiliossi and the condition is easily treated with B12 (but it must be injected; oral medication will not solve the problem). There are recent reports of preventing the deficiency from developing while people are taking metformin by giving routine doses of calcium,Baumann but this has a risk of kidney stones so should also be supervised by your primary care physician.
You should stop this medication if you have surgery, and begin taking it again when you are eating normal foods. Do not allow a contrast agent for a radiology procedure (e.g. a kidney test called an IVP) to be given while you are taking this medication; discuss how to handle any need for that test with your doctor.
Finally, some reports, but not all, caution against use of metformin along with certain medications that are handled by the kidney, called "cationic drugs".Calabrese, Klepser You should review your other medications with your doctor and pharmacist regarding this issue. Lithium is actually such a cation, but there are no clear reports of problems with lithium and metformin together (manufacturer's database, consulted October 2002).
This medication very frequently causes diarrhea and sometimes nausea. You can try to decrease this problem by taking the medication only with meals. Using the generic metformin, you can cut the 500 mg pill in half when you first begin, which seems to help quite a bit. There is an "extended release" version, though this might cost you more; it does help limit these side effects, however. The XR version cannot be cut.
One of my experienced medicine colleagues says that taking the medication all at once with your largest meal, rather than spreading it out in smaller doses through the day, can decrease the diarrhea problem. The other trick she taught me: go up on the dose slowly, increasing by one pill (or even a half a pill) only every week or so. Most people can handle this medication if they go up slowly enough. Nearly every patient of mine who's tried metformin could handle even the generic (not slow release) if they went up slowly enough. Sometimes they had to go up only 1/2 pill a month, though.
For other basic information, including other side effects -- which in my experience so far are not common -- see this summary from the National Library of Medicine (a great source regarding any medication).
How to start
The following information is what I tell my own patients. It is your responsibility to review this with your physician. Do not do this on your own. Your physician may have a different, perhaps better way of doing this.
Generic 500mg pill
Start with 1/2 of a 500 mg pill once a day with meals. Increase by 1/2 pill steps every several weeks, once you're not having diarrhea! If you have trouble with nausea, or diarrhea, decrease to the previous dose and wait you're not having such symptoms before you try increasing again. Increase to a total of two 500 mg pills per day, which can be taken all at once with your largest meal of the day. From there we talk about how high to go.
Trade-name extended release pills (Glucophage XR)
Start with one pill per day at your largest meal. Add 1 pill every several weeks. Take the first two at the same meal; after that, when adding the third pill, split the dose: one with one meal, two tablets with a bigger meal. Follow the same instructions above, decreasing the dose then increasing again, if you're having side effect problems. You may split the dose and take one pill with breakfast/lunch/dinner, if you get better results that way.
The highest dose is usually one gram twice a day (two 500 mg pills in the morning, and two again in the evening, with meals). You'll probably be directed to keep increasing the dose until:
- your symptoms are clearly responding;
- you're getting an intolerable side effect (decrease to the previous dose);
- you reach 1 gram twice a day.