Editor’s Note: This is the second post in our miniseries about diabetes drugs. Tune in on August 21 for the next installment.
Metformin (brand names Glucophage, Glucophage XR, Riomet, Fortamet, Glumetza) is a member of a class of medicines known as biguanides. This type of medicine was first introduced into clinical practice in the 1950’s with a drug called phenformin. Unfortunately, phenformin was found to be associated with lactic acidosis, a serious and often fatal condition, and was removed from the U.S. market in 1977.
This situation most likely slowed the approval of metformin, which was not used in the U.S. until 1995. (By comparison, metformin has been used in Europe since the 1960’s.) The U.S. Food and Drug Administration (FDA) required large safety studies of metformin, the results of which demonstrated that the development of lactic acidosis as a result of metformin therapy is very rare. (A finding that has been confirmed in many other clinical trials to date.) Of note, the FDA officer involved in removing phenformin from the market recently wrote an article highlighting the safety of metformin.
Metformin works primarily by decreasing the amount of glucose made by the liver. It does this by activating a protein known as AMP-activated protein kinase, or AMPK. This protein acts much like an “energy sensor,” setting off cellular activities that result in glucose storage, enhanced entry of glucose into cells, and decreased creation of fatty acids and cholesterol.
A secondary effect of the enhanced entry of glucose into cells is improved glucose uptake and increased storage of glycogen (a form of glucose) by the muscles. Additionally, the decrease in fatty acid levels brought about by metformin may indirectly improve insulin resistance and beta cell function. As a result, both glucose and insulin levels in people with Type 2 diabetes decrease with metformin therapy.
The joint guidelines issued by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) for the treatment of people with Type 2 diabetes call for metformin to be used as the first-line drug therapy along with lifestyle interventions (a healthful diet and exercise). Large reviews of multiple studies have shown decreases in HbA1c (an indication of blood glucose control over the previous 2–3 months) from 1% to 2% in people using metformin. In the large United Kingdom Prospective Diabetes Study (UKPDS), metformin was associated with better health outcomes than various other therapies, including chlorpropamide (brand name Diabinese), glibenclamide, also known as glyburide, (DiaBeta and others), or insulin, and was additionally associated with less weight gain and fewer episodes of hypoglycemia (low blood glucose). In fact, the UKPDS is one of the major studies that lead the ADA and EASD to place metformin as the first-line therapy.
Metformin is available as a stand-alone pill and is also available in combination pills with several other types of oral medicines. Various studies have evaluated metformin in combination with glyburide, nateglinide (Starlix), pioglitazone (Actos), insulin, and acarbose (Precose). In all of these studies, there were better health outcomes associated with the combined therapies compared to each of the therapies used alone. Notably, the combination of metformin and insulin not only demonstrated a reduction in HbA1c in studies, but also a reduction in the insulin dose.
Moreover, in various trials using metformin, triglyceride (a type of blood fat) levels have been reduced by approximately 10% to 20%, with an additional reduction in LDL (“bad”) cholesterol.
Metformin has also been used for the treatment of polycystic ovary syndrome (PCOS), although this is not an FDA-approved use.
Metformin is eliminated from the body by the kidneys and has a half-life of 6 hours, meaning that roughly 94% of the drug is removed from the body in 24 hours. It is prescribed in doses from 500 milligrams to 2,000 milligrams and is given 1–3 times daily. It is usually started at a dose of 500 milligrams and slowly raised every one to two weeks to the maximum dose that can be tolerated without side effects. (Doses above 2,000 milligrams have not been shown to be any more effective than a 2,000-milligram dose.)
The major side effects of metformin are gastrointestinal and include an increase in the frequency of bowel movements, diarrhea, nausea, and abdominal pain. These effects may be reduced by taking metformin with meals, as well as by starting off at a low dose that is slowly increased. Some evidence suggests that using an extended-release form of metformin may also decrease gastrointestinal side effects.
Minor side effects of this medicine include a metallic taste and decreased absorption of vitamin B12. As mentioned above, the development of lactic acidosis with this medicine is rare and has been estimated at roughly 4–9 cases per 100,000 people. To prevent the occurrence of lactic acidosis, the use of metformin is not recommended for those older than 80 years old, and for people who have mild kidney dysfunction, congestive heart failure, or a previous history of acidosis, among several other conditions.
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Excellent article. I am a metformin user and found that a good nutrition and exercise program in combination with the drug is the answer for me. Metformin alone and a sedentary lifestyle just did not work for me. Lots of great information concisely presented! Thanks!
Posted by Bob | Aug 19, 2009 at 12:29 pmIf you take Metformin with any type of stomach disorder, i.e. anyone who takes Nexium, Prilosec and the like have a very high probability of having real trouble with the drug. It caused severe stomach pain, nausea to the point of vomiting, and then hard heavy bowel pain as it went on through the body. People need to be told about these possible side effects.
Posted by Mary Strayer | Aug 19, 2009 at 12:48 pmAfter taking 500mg of Metformin for a few months, my doctor doubled my daily dose. Within 3-4 days of this change, I began to have significant pains in my lower back and in all limbs, to the point that I was unable to sleep due to the pain. After another week of this, I dropped back to the previous doze, and the severe pain went away. A few months later, upon the advice of my doctor, I again tried to go back to 1000mg, with the same side effect, and the same results. This was repeated one more time. My doctor indicates that this should not be happening and may not be related to Metformin.
Is this a unique side effect, or one of the known possible side effects? Are there any items that correlate well with this side effect?
Any feedback would be appreciated.
Posted by Ron | Aug 19, 2009 at 7:59 pmThe symptoms that you are reporting may be consistent just with metformin itself. There are no reported cases of interactions of metformin and PPIs (acid blocking drugs) like Prilosec as far as I could find in the literature. There also is no known plausible mechanism for their interaction. This does not mean that it could not be possible. If your health-care provider believes that there might be an interaction occurring, he could report this to the FDA Medwatch program.
The symptoms of back pain you experienced with metformin have not been commonly reported in the medical literature. Of course the classic challenge and re-challenge approach that you tried with metformin is highly suggestive that your symptoms might be related to metformin. Once again, if your health-care provider believes that there might be an interaction occurring, he could report this to the FDA Medwatch program.
For details about metformin, see http://packageinserts.bms.com/pi/pi_glucophage.pdf
Posted by Mark T. Marino | Aug 20, 2009 at 10:25 pmI was first diagnosed with diabetes at age 12. I was diet controlled until perimenapause. I am extremely medication sensitive and failed the first medication trial of Avandia. I have an allergy to sulfa so that immediately eliminated a large number of medications. My doctor started me on Metformin 500 mg/d and as the years have gone on I am now at the max 1000mg bid. This drug has been my miracle drug. Up until last year it was used solely. I have had no side effects from this drug. I must also reveal that I am very good about my responsibility when it comes to diet and exercise.
Posted by Nancy Russell | Aug 22, 2009 at 10:53 amOne caution for aging diabetics- keep a close eye and attention to gum disease. I have just had total mouth gum surgery and my a1c has gone done 1 point!
I have been taking Metformin (1000mg @ 1 pill 2x daily) for the last few years and have had difficulty getting the A1C down below 7.5. About 5-6 months ago my doc added Glipizide (5mg @ 1 pill 2x daily)and my last A1C dropped to 6.0. I’m waiting for my next test.
Posted by Daniel G. Emilio | Sep 04, 2009 at 2:00 pmRon,
I wonder if the higher doses brought on episodes of kidney stones. I have experienced this from time to time.
Ask your doctor to check your kidneys out? Especially if the pain you experience is in the love-handle area.
Cheers
Posted by Melody | Sep 06, 2009 at 12:16 amI AM ALSO ON METFORMIN AND HAVE THE BACK PAIN AND UPSET STOMACH. THE UPSET STOMACH WAS CURED THANKS TO MY HUSBAND, AND GINGER ROOT CAPSULES WHICH YOU CAN BUY AT WAL-MART .THE BACK PAIN I AM STILL WORKING ON. MY DR. TELLS ME THAT IT IS NOT THE MEDS CAUSING THIS PROBLEM THAT IT IS IN MY HEAD. I AM GOING TO LOOK FOR AN HERBALIST
Posted by betty from las vegas | Sep 06, 2009 at 10:59 pmI have been a diabetic for the last 3 years and have been on metformin 500mg twice a day. Not much of an exerciser but better diet control has seen me keep my A1C at just below 6.0. I don’t like the mild nausea like symptoms brought on by the drug but its a small price to pay.
Posted by Bathmanathan | Sep 15, 2009 at 6:03 amI have been a diabetic for the last 3 years and I’ve tried a bunch of different glucometers. I found a site that actually compares the available products and reviews them. Pretty interesting:
Posted by bg233 | Sep 18, 2009 at 11:25 amI was diagnosed in November of 2007 with an A1c of 11.3 and a fasting bg of 285.
My doc started me on 1,000mg of Metformin twice a day. He added 4mg of Glimepiride twice daily shortly after because although the Metformin had stabilized my BG, it hadn’t dropped it enough.
By April of 2008 my A1c was down to 6.0! Three tests since then (I’m due for another blood test in October) have been: 6.0, 5.7 & 6.0. My average bg ranges from low 80’s to low 90’s.
I have had NO complications of any sort.
Posted by Phil | Sep 26, 2009 at 3:19 pmI have been a diabetic for 16 years. When I was first diagnosed with diabetes, I was put on Gliberide but it didn’t work. Now, I’m on 500 mg Metformin along with 1 mg Glimepiride, take 30 units (twice per day) of Humalog 75/25, and my A1c is down to 6.9. On some days, insulin injections can be painful at times and I do change injection sites. Another thing I dislike with the insulin injection is weight gain. I’m hoping in the near future, an insulin patch will be on the market.
Posted by Kimmie K. | Nov 16, 2009 at 8:30 amI have been taking Metformin along with Lantus injections for several years. I am pleased with the results, but I would like to know why the makers of Metformin cannot do something about the terrible odor that the medicine gives off. Each time the bottle is opened the smell is awful. I hope they are working on this problem.
Posted by Peggy Mason | Nov 16, 2009 at 8:53 amThank u so much for your article on Metformin. I have been taking this medication since being diagnosed in 2006/August. I was grosely overweight and since changing my eating habits, etc., I have lost 54 lbs. and feel emensely better. My dose of Metformin is the ER at 500mg. of which I take 3x per day.
Thank goodness for this medication. It interacts well with my other meds. and my blood work is stellar.
Thank you for your article.
Pat
Posted by Patricia B. Davino | Nov 16, 2009 at 10:05 amI was diagnosed with type 2 diabetes in 1999, and I controlled it with diet and exercise, and seemed to be doing well with my tight control, until 2008, when my son got married and graduated from law school, good stress, but stress as you know increases blood sugar readings. Nunmbers in the 6 range, doctor put me on Metformin 500×2 daily. Initially numbers dropped to 6.0, then after several months went up to 6.7. I also had an episode of blood in my urine in Feb 08, diagnosed with urinary tract infection, wonder if it was kidney stones. Not sure if metformin was the culprit with the incident.
Posted by Bev | Nov 16, 2009 at 10:15 amI’m on 2000 mg of the XL Metformin. I always take it with dinner, all at one time but am now wondering if I should split it up. Any suggestions?
Posted by Debbie | Nov 16, 2009 at 7:01 pmThis is a great article about Metformin. I am consuming a combination of Metformin 250mg plus Glibenclamide 1.25mg under trade name “Glucovence” from Merck, in the past 2 years. If the Metformin is consumed less than 500mg on daily basis, do you think that will bring any effective result in controlling the blood glucose? Thank you for your reply.
Posted by Phillips Gunawan | Nov 18, 2009 at 7:21 amPeggy, my Metformin does not have an odor in the least bit. You might try asking your pharmacist or physician about the smell your pills give off upon opening the bottle. You could have a bad batch. Good luck!
Posted by Kim | Nov 21, 2009 at 8:18 pmThere is a clear dose response relationship with metformin, which means that the higher the dose, the greater the effect, on average. So on average, 500 mg once a day will provide less of an effect on HbA1c than 2,000 mg once a day. While the average response is important in clinical trials, what is most important is how the drug works for any individual. A general principle to follow is to take the lowest dose that provides the desired result, since this obtains the desired clinical results while minimizing side effects and potentially cost. When metformin is used in combination, the doses are often lower than those needed when the drug is used alone. So if your HbA1c, fasting blood glucose, and other tests are fine, there would be no need to change; if not, then consider reevaluation by your health-care provider.
I am attaching the link to studies that evaluated different metformin dosing regimens. In general, there is not much evidence for the superiority of once a day versus several times a day. Most physicians prescribe split doses to reduce gastrointestinal side effects, but on the other hand, multiple daily doses tend to reduce compliance (it is sometimes hard to remember to take multiple daily doses).
http://www.japi.org/may2005/O-441.pdf.
Clinical Therapeutics Volume 25, Issue 2, February 2003, Pages 515–529
Posted by Mark Marino | Nov 24, 2009 at 10:41 pmI have recently tried metformin again probably for about the 4th time… this time I had a severe reaction…Have gone back to Glimepride and a low carb diet…When I first got diabetes my doctor gave me this diet….After having a reading of 410, at the end of three months, he took me off all blood sugar, and blood pressure medicine….That lasted a couple of years until all of my bad eating habits and lack of stuctual exercize slowly came back…Well with quite a bit of stress that I have this year I am at that level and worse again(13)…these numbers were about two to three weeks ago ..now after deciding that I really needed to take charge of my life again and knowing that we cannnot afford to probably do the medicne that will probably take of the problam the most efficiently…..I have brought my sugar levels back down to the acceptable range and after acouple more weeks hope to put them right were they belong and with the Lord’s help in giving me strength to do this just maybe get off of the pills all together….Okay this is basicly the diet my old doctor gave me…THIS IS TO STAY OFF INSULIN AND TO GET OFF PILLS…… just about all the vegetables I want …no white foods, such as rice, potatoes, pasta, bread ….no food with sugar….lean beef with little fat (small portions), lean pork….. Best of all poultry and fish ( you can eat almost as much as you like of these) …but remember this: white flour seems to be bad for a diebetic…actually there was nothing on the diet about fruit…but I found out that you have to have fruit…what I’ve found out: apples are the best as far as controlling your sugar, than mellens and just all of the rest have quite a bit of sugar…Healthy snacks are cauliflower and low moisture motzerella cheese..These are probably the only white foods are that are exceptable…leafy vegetables seem to be the best for reversing the diebetes, poultry, and turkey in paticular, fish and chicken are also good..I have more problem with the white stuff staying in the body longer than anything…..THIS DIET IS FOR PEOPLE THAT ARE NOT ON INSULIN…If you are on insulin you need to talk to your doctor.
Posted by Pat | Nov 25, 2009 at 7:52 amI had been taking Metformin successfully for nearly 4 years, when its effectiveness started to decrease and my blood sugar started to rise during the overnight fasting period. (I’m told this is quite common–that Metformin often loses its strength when taken in high doses over a long period. I take max dose of 4 500-m tablets a day.) My biggest problem is a very high “dawn effect” wherein my blood sugar peaks during sleep at night, so I need a counteractive during that time. I kept taking Metformin, but Glimepiride (generic Amaryl) was prescribed with it–one at breakfast, one at dinner and a double whammy at midnight when I retire (always with milk/food). That’s done the trick, and my latest A1C is 6.7, back below 7. Metformin users may be dismayed to find it not working like it used to. This is common over a period. The next step is to add an insulin-producing stimulant to it. Don’t worry–Metformin plus a supplement will often work.
Posted by John (Greenman) | Nov 30, 2009 at 11:11 pmMetformin does have a fishy smell. The only one out there that did not…is no longer available. It was by Apotek and it is gone.
I gag at the thought of it let alone the smell. It makes me want to toss the medication in the toilet. It makes me angry that I’m forced to swallow something so vile. Why can’t they make it more palatable? It’s disgusting. The major pharmacies that I have contacted looking for Apotek said it is what it is…no options. They understand but there are no suggested solutions accept hold the nose and gulp it down. I want to vomit…I want to cry…I want to scream. It’s not fair!! Arghhhhhhhhhhh!
Posted by Bonnie Bell | Dec 30, 2009 at 8:24 pmI have been taking Metfomin for a couple of years. My blood sugar has been reasonable. However, about four months ago the Metforman began reeking with odor and concurrently my blood sugar went up and has remained about 30 to 40 points higher with no change in healthy diet. I am concerned not only about the smell but the effectiveness of the product. Something is wrong. My prescription comes from TEVA based in Israel. Where are the different capsuls made? What is being done about correcting the issue?
Posted by D. Combs | Feb 24, 2010 at 11:17 am