Metformin Page Rewritten

Page Changed: Metformin

I have rewritten this page to emphasize the research findings of the past few years. Metformin's mode of action is emphasized as is the weight of data pointing to metformin's strong cardioprotective and anti-cancer properties. I have eliminated the long discussion of the DPP trial because the preponderance of evidence suggests now that starting metformin very early has long term benefits that extend beyond the actual lowering of blood sugar. In fact, the evidence suggests very strongly to me that lowering blood sugar by no means the most useful function that metformin performs. Its real value is in activating AMP-kinase and in stopping the liver from synthesizing the liver fat which increases insulin resistance.

Here is the updated text of the page:

Though many people find that they can bring their blood sugar back into the normal range simply by limiting their carbohydrate intake, blood sugar control is not a short term project. When you have abnormal blood sugars you will have to spend the rest of your life keeping them under control, and not everyone is willing or even able to stick with a restrictive diet for the rest of their lives.

For this reason, most doctors assume that dietary changes will not solve their patient's blood sugar problems. So immediately after diagnosing diabetes they prescribe what are known as oral anti-diabetic drugs. Chief among these is metformin.

You may well be asking, if these drugs are effective, why bother with complex and restrictive dietary regimens?

Effective, But Not Effective Enough

Unfortunately, the catch lies in how you define "effective." Just as research has shown that the current criteria for diagnosing diabetes ignore the blood sugar levels at which damage occurs, other research shows that none of these drugs brings blood sugar levels down to anywhere near normal levels. So while an oral anti-diabetic drug might be "effective" by the FDA definition of the term, that effect might only be to lower a diabetic person's fasting blood sugar from a dangerously high 250 mg/dl (13.8 mmol/L) to an only slightly less dangerous 180 mg/dl (10 mmol/L) --a level which is still high enough to encourage the development of serious complications. Even when prescribed for people whose blood sugar is only impaired, as we will see, these drugs may only lower the OGTT 2-hour reading by 20 or 30 mg/dl (1.1 or 1.7 mmol/L)--which still leaves their blood sugars higher than a damaging 140 mg/dl (7.8 mmol/L) most of the day.

So metformin alone will not be likely to bring your blood sugars back into the normal range.

An Add-On not a Substitute for Dietary Control

But--and here's the silver lining--if you are unable to get your blood sugars back into the normal range with diet alone, but are willing to modify your diet, the addition of metformin may be what it takes to push your blood sugar levels that last bit of the way needed to normalize them.

Facts about Metformin

Metformin is the generic name of the drug also marketed as Glucophage. It has been used to control diabetic blood sugars since the 1970s in Europe. It was also the subject of a detailed study intended to see whether it could prevent impaired glucose tolerance from progressing to actual diabetes.

Diabetes Prevention Program Research Group; Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin.NEJM , Volume 346:393-403 February 7, 2002 Number 6

Metformin is available in an extended release form, Metformin ER (Glucophage XR) which is supposed to be a bit easier on the digestive system.

Metformin is a cheap generic drug. Because of it's long track record for safety, it is supposed to be the first drug doctors prescribe, Unfortunately, because of the marketing efforts of the drug companies, this doesn't always happen. All too often, doctors prescribe metformin in the form of combination pills like Janumet that cost 15 times what metformin alone costs and include relatively untested drugs that have serious side effects. You will do much better and be much safer taking the plain generic metformin rather than one of these combos. In addition, the combo pills because they include drugs whose dosage is fixed make it impossible to adjust the metformin dose to the one that is right for you. Metformin is a drug where the effective dose may vary greatly with your body size.

In the course of 2010 a series of studies emerged that document quite convincingly that Metformin alone among the diabetes drugs has "side effects" that include a dramatically lower risk of death from heart disease and a strong anti-cancer effect. In addition, Metformin helps with weight loss and appears to stop the progress of fatty liver. This makes it the one oral antidiabetes drug I recommend to people with both full fledged diabetes and prediabetes.

What Metformin Does

Metformin Inhibits the Liver's Production of Glucose

There is some scholarly debate about what exactly it is that Metformin does, but most researchers agree that in most people Metformin suppresses the production of glucose in the liver.

If you'll remember, it is the liver's tendency to dump additional glucose into the blood stream when first phase insulin response is weak or missing that can cause blood sugar to shoot up after a meal. The liver may also dump glucose in the blood stream early in the morning when fasting insulin levels are low. (To read more on this topic, visit How Blood Sugar Deteriorates)

Metformin may lower fasting blood sugar by limiting the liver's production of glucose rather than by making cells more sensitive to insulin.

A mouse study published on May 15, 2009 suggests that Metformin works to lower blood sugar by directly stimulating a gene in the liver which is how it shuts off glucose production. Rather than by improving insulin sensitivity, it bypasses the broken insulin signaling.

Metformin and Insulin Suppress Hepatic Gluconeogenesis through Phosphorylation of CREB Binding Protein Ling He et al,, Cell Volume 137, Issue 4, 635-646, 15 May 2009. doi:10.1016/j.cell.2009.03.016

This study is explained in layman's language here:

New Information on how Metformin works. Diabetes in Control May 27, 2009.

Metformin Appears to Stimulate Glucose Uptake in Muscles via AMPK Activation

Though Metformin appears to increase the amount of glucose absorbed into cells this effect is observable mostly when blood sugar is high.

Mechanism of Metformin action in obese and lean noninsulin-dependent diabetic subjects. DeFronzo RA, Barzilai N, Simonson DC. J Clin Endocrinol Metab. 1991 Dec;73(6):1294-301

Research suggests that Metformin may stimulate glucose uptake by muscles and inhibit glucose production by the liver by activating an enzyme, AMP-activated protein kinase which is present in muscle, liver, and heart cells. This enzyme is usually activated when exercise has burnt off cellular energy stores. So in a way, Metformin seems to trick the body into thinking it has exercised. This may be why it can slightly elevate levels of lactate--the substance that makes your muscles ache the day after an exercise session.

Metformin Increases AMP-Activated Protein Kinase Activity in Skeletal Muscle of Subjects With Type 2 Diabetes. Nicolas Musi, Michael F. Hirshman, Jonas Nygren, Monika Svanfeldt, Peter Bavenholm, Olav Rooyackers, Gaochao Zhou, Joanne M. Williamson, Olle Ljunqvist, Suad Efendic, David E. Moller, Anders Thorell, and Laurie J. Goodyear; Diabetes 51: 2074-2081

Metformin's Activation of AMPK Blocks The Liver's Ability to Synthesize Triglycerides and Promotes Fat Burning.

For an exhaustive look at how metformin's impact on AMP-kinase works in rat tissues (and probably human tissues), read this full text study:

Role of AMP-activated protein kinase in mechanism of metformin actionZhou et al. J. Clin. Invest. 108(8): 1167-1174 (2001). doi:10.1172/JCI13505.

This study found that

metformin activates AMPK in hepatocytes [liver cells]; as a result, acetyl-CoA carboxylase (ACC) activity is reduced [ACC promotes the creation of triglycerides], fatty acid oxidation is induced [i.e. fat is burned], and expression of lipogenic enzymes is suppressed [lipogenic enzymes are needed to create triglycerides].

It also found that glucose uptake in muscles by metformin required the activation of AMPK. When it was blocked the uptake did not happen.

AMPK activation is also known to increase the breakdown of glycogen, which may be why some low carbers have observed that their glycogen stores appear already depleted when they embark on a low carb diet, so they don't lose the glycogen-associated water weight at the start of the diet that dieters lose who are not taking metformin. It may also be why when theu carb up they don't gain a lot of instant water weight either.

It is this impact of metformin on the liver, which is independent of its impact on glucose absorption that probably explains why metformin often causes modest weight loss, especially when it is first taken. It also explains why it makes weight loss maintenance much easier even in insulin sensitive dieters such as myself. Blocking the synthesis of fats and promoting the burning of fat at the liver (and possibly muscles) makes it much harder to gain weight.

Stimulation of AMPK May Be Why Metformin Appears Cardioprotective

AMPK has also been shown to have a protective effect on the heart. This review describes how AMPK may protect the body during heart attacks.

AMP-Activated Protein Kinase Conducts the Ischemic Stress Response Orchestra Lawrence H. Young. Circulation. 2008;117:832-840
doi: 10.1161/CIRCULATIONAHA.107.713115

Metformin May Boost GLP-1 Level

GLP-1 is an incretin hormone secreted in the gut which appears to stimulate insulin release when blood sugars rise and limit glucagon production at the same time. While Byetta and Januvia are promoted as being incretin drugs, some little known research suggests that metformin may also raise the level of GLP-1 in the body. The good news is that unlike Januvia it does this without inhibiting DPP-4, a tumor suppressive drug.

Enhanced secretion of glucagon-like peptide 1 by biguanide compounds. Yasuda N et al. Biochem Biophys Res Commun. 2002 Nov 15;298(5):779-84.

UKPDS 20 Year Follow-up Study Shows Excellent Metformin Effect

The follow-up to the huge UKPDS study presented at the EASD conference in Sept 2008 followed for 20 year what happened to people who had been prescribed either a sulfonylurea drug or metformin at diagnosis. This study was one where people attempted to achieve the barely adequate blood sugar goal of a 7% A1c. Over the second ten years of the study, it was reported that few people in the study taking any drug were able to attain an A1c as low as even 7%--primarily because they were also urged to eat a very high carb/low fat diet.

Nevertheless, after twenty years, as reported by Medpage Today right after the conference found that at 20 years after the start of the study,

Patients treated with metformin had a >21% reduction in risk of any diabetes endpoint (P=0.01), a 30% reduction in risk of diabetes-related death (P=0.01), a 33% reduction in risk of MI (P=0.005), and a 27% reduction in risk of all cause mortality (P=0.002).

Of course, in this population, because of the very high blood sugars people maintained, the total rate of complications, heart attack and death was very high, so even the 33% reduction of risk left a risk far higher than you or I would wish to expose ourselves to.

Metformin May Fight Cancer

Intriguing data emerged in 2009 suggesting that metformin has cancer fighting abilities that go beyond its ability to lower insulin resistance.

Now new data from a British epidemiological study suggests that metformin may exert an anti-cancer effect. The study is:

New Users of Metformin Are at Low Risk of Incident Cancer: A cohort study among people with type 2 diabetes. Gillian Libby et al. Diabetes Care September 2009 vol. 32 no. 9 1620-1625.doi: 10.2337/dc08-2175

The study made use of medical records collected in Tayside, Scotland UK. The researchers compared 4085 people with type 2 diabetes who were new users of metformin in 1994–2003 to a group of people with diabetes diagnosed the same year who were not given metformin.

The result was that

Cancer was diagnosed among 7.3% of 4,085 metformin users compared with 11.6% of 4,085 comparators, with median times to cancer of 3.5 and 2.6 years, respectively (P < 0.001). The unadjusted hazard ratio (95% CI) for cancer was 0.46 (0.40–0.53).

This association held up even when adjusted for "sex, age, BMI, A1C, deprivation, smoking, and other drug use."

This result is intriguing, though it makes me want to ask, "What kept the doctors from prescribing metformin to the second group, the one that had so much more cancer?" Until we know the answer to that question, it is impossible to screen out the possibility that the same factor that kept doctors from prescribing the usual first line treatment for Type 2 diabetes might have also promoted cancer.

However, a mouse study supports the idea that it is metformin, not an outside factor at play here. Researchers found that metformin appears to stop breast cancer stem cells from growing in mice. You can read about this study in this article.

Science Daily: Diabetes Drug Kills Cancer Stem Cells in Combination Treatment in Mice.

More evidence that metformin is protective against cancer emerged in a second study of 1,353 people with diabetes that lasted almost ten years. It was conducted in the Netherlands as part of the ZODIAC study and published in Februrary 2010. This study found that the cancer risk of people with diabetes taking metformin was identical to that of the population at large which was not the case with those who were not taking metformin. This is significant because people with diabetes have long been known to have a higher risk of cancer.

Metformin Associated With Lower Cancer Mortality in Type 2 Diabetes: ZODIAC-16 Gijs W.D. Landman et al.Diabetes Care Diabetes Care February 2010 vol. 33 no. 2 322-326. doi: 10.2337/dc09-1380

Metformin May Be Protective Against Heart Disease

This idea has been floating around for years, though there wasn't definitive proof of it. A relatively small study published in March 2009 supports the idea.

Long-term Effects of Metformin on Metabolism and Microvascular and Macrovascular Disease in Patients With Type 2 Diabetes Mellitus. Kooy et all. Archives of Internal Medicine, 169 (6), 616-625 DOI: 19307526

A presentation at the 2009 European Association for the Study of Diabetes (EASD) described research which may point to why metformin is so effective.

You can read about it here:

Diabetes in Control: Metformin Improves Endothelial Function in Type 2 Diabetes

This study examined a series of factors associated with endothelial function--i.e. the function of the linings of the blood vessels. It demonstrated significant improvements in the 196 patients who took metformin over a period of up to 4.3 years.

Compared to those on placebo plus insulin those on metformin experienced highly significant drops in plasma levels of von Willebrand factor (vWf), soluble vascular adhesion molecule-1 (sVCAM-1), tissue-type plasminogen activator (t-PA) antigen, plasminogen activator inhibitor-1 (PAI-1), C-reactive protein (CRP), and soluble intercellular adhesion molecule-1 (sICAM-1).

The drop in C-Reactive Protein--a measure strongly linked to the risk of inflammation-related heart attack was 17%.

Since all the other oral drugs prescribed for diabetes have either been linked to increased heart attacks (sulfonylureas) or produce heart failure (Avandia and Actos) this data should reinforce the idea that metformin is the safest of the oral diabetic drugs and the one most likely to improve health outcomes long term.

Metformin Lowers Risk of All Kinds of Fatal Outcomes

A study presented at the 2010 ADA Scientific Sessions analyzed records of "19,699 patients over age 45 who had diabetes as well as documented cardiovascular disease or other atherothrombotic risk factors." It found:

patients on metformin had a significant 33% reduction in the risk of death compared with those not on the drug (95% CI 0.59 to 0.75, P less than 0.001). After adjustment with the propensity score, there was still a significant 24% reduction in death (95% CI 0.65 to 0.89, P less than 0.001).

The "propensity score" was a way of adjusting for other drugs given to control heart disease.

Diabetes in Control: ADA: Mortality Lower with Metformin

Metformin Started Early Far More Effective than Metformin Started Later

A study published of 1,799 Kaiser patients who were able to lower their A1c below 7.5% using Metformin found that when patients were started on Metformin immediately after diagnosis, they were able to stay at an A1c lower than 7% for longer than did patients whose doctors waited a year before starting them on the drug.

Secondary Failure of Metformin Monotherapy in Clinical Practice
Jonathan B. Brown. Diabetes Care Diabetes Care March 2010 vol. 33 no. 3 501-506 doi: 10.2337/dc09-1749

A more detailed discussion of this study can be found here:

Diabetes in Control: Early Treatment Doubles Chance of Success for People with Diabetes

This is important. Many people with diabetes resist taking a drug thinking that it is better to attempt to lower blood sugar with diet or exercise alone. Because the action Metformin is different from the effect of cutting carbs or exercising, this may be a mistake. It may be better to start metformin along with other approaches as soon as you receive a diagnosis of abnormal blood sugar (including a diagnosis of pre-diabetes) rather than waiting.

There's No Research Data about the Effect of Combining Metformin with Carb Restriction

Unfortunately, all studies of Metformin published to date have been performed with people who were encouraged to eat a high carbohydrate diet. So there is no definitive information about what happens when Metformin is combined with a low carbohydrate diet.

Anecdotal Evidence

Postings on newsgroups suggest that people who have a lot of weight to lose who stall out above their desired weight while on a long-term low carb diet often start losing again when they add Metformin to their diet regimen, if they continue to keep their carbohydrate intake low.

Women with PCOS have also found that the addition of Metformin to their regimen may improve both weight loss and fertility.

Metformin may prevent weigth gain independent of insulin resistance by blocking the liver's synthesis of triglycerides. It also appears to prevent the liver from storing glucose in the form of glycogen which leads to less ability to dump glucose inappropriately.

I have observed that when I am taking metformin while eating a very low carb diet and I raise my carbohydrate intake above the level that usually refills glycogen resulting in an instant water weight gain I do not see the water weight fluctuation I see when I am not taking it. I speculate that this indicates that metformin somehow interferes with the normal liver glycogen function.

In addition, studies of people with Type 1 diabetes find that metformin will lower the amount of insulin they need to use.

The Benefits of Metformin Therapy During Continuous Subcutaneous Insulin Infusion Treatment of Type 1 Diabetic Patients Laurent Meyer et. al. Diabetes Care 25:2153-2158, 2002.

The addition of metformin in type 1 diabetes improves insulin sensitivity, diabetic control, body composition and patient well-being. Moon, RJ. Diabetes Obes Metab. 2007 Jan;9(1):143-5.

What You Need To Know About Taking Metformin

Metformin takes about 3 days to kick in and 3 weeks to achieve its maximum effect. Because it can cause intense gastric problems, it's advisable to start out with a low dose and work up. Most people don't see an effect on blood sugars until they are taking between 1,000 and 1,500 mg a day. Larger people may need to take the full dose (2250 to 2500 mg depending on whether it is metformin ER or Metformin)

Timing when you take your metformin will often subtly change the impact it has on your blood sugar because even the ER form does not result in a completely smooth activity curve. Taking metformin ER it at night will often result in a stronger effect on fasting blood sugar but less action at dinner. Taking Metformin in the morning may give best coverage on lunch, decent coverage for dinner but result in the highest fasting blood sugars and the most stomach discomfort. You can experiement with the time you take metformin as long as you NEVER take more than the prescribed dose during a 24 hour period.

Side Effects

Gastric Distress

The most common side effects of Metformin are nausea, diarrhea, heartburn and gas. That's why it's been nicknamed "metfartin" by people who post on Web bulletin boards. These unpleasant digestive system symptoms often go away after a few weeks, but not always. Some people are unable to take Metformin because of the persistence of these symptoms.

The extended release form of metformin (metformin ER) often relieves gastric symptoms. Many of us find that taking metformin ER in the early afternoon after we have eaten several meals may eliminate heartburn or the stomach irritation that occurs when it is taken on a relatively empty stomach.

If your problem is gas or diarrhea, try eating less starch. These symptoms are caused by undigested starches reaching the gut where they are fermented by helpful bacteria.

Can Metformin Cause Low Blood Sugar?

Metformin is not supposed to cause dangerous hypos. A very few people have found that it causes their blood sugar to drop low enough to make them uncomfortable. This may be because of the phenomenon called False Hypo. You can read about false hypos HERE.

Lactic Acidosis?

Metformin is chemically similar to an earlier drug, Phenformin which was taken off the market bwascause it caused a fatal side effect, lactic acidosis. There is some debate about whether or not Metformin also causes this symptom.

An epidemiological study in Canada found 10 cases of hospitalization for lactic acidosis in a population of 11,797 patients who had been prescribed Metformin.

Incidence of lactic acidosis in Metformin users. Stang M, Wysowski DK, Butler-Jones D. Diabetes Care , Jun 1999, 22(6) p925-7

One review of data from published studies suggests that this frequency is a normal incidence in all populations--including those not taking the drug and probably not related to taking the drug.

Risk of fatal and nonfatal lactic acidosis with Metformin use in type 2 diabetes mellitus: systematic review and meta-analysis. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE.Arch Intern Med. 2003 Nov 24;163(21):2594-602.

Further confirmation that Metformin does not cause lactic acidosis at a rate higher than occurs in people NOT taking the drug was found in a study of 50,048 people with diabetes taking either metformin or a sulfonylurea drug. This study found that lactic acidosis was extremely rare, occurring at the rate of "3.3 cases per 100,000 person-years among metformin users and 4.8 cases per 100,000 person-years among users of sulfonylureas." In all cases the lactic acidosis appeared to be caused by "concurrent comorbidity" which means another medical problem--usually kidney disease.

Metformin, Sulfonylureas, or Other Antidiabetes Drugs and the Risk of Lactic Acidosis or Hypoglycemia: A nested case-control analysis. Michael Bodmer et. at. Diabetes Care 31:2086-2091, 2008.

The symptoms of lactic acidosis include malaise, muscle aches, and gastric distress that comes on after a person has gotten over the initial problems associated with taking Metformin. It is possible that the incidence of lactic acidosis is higher than the statistics suggest because doctors are aware of it and take patients off the drug if they begin to exhibit symptoms.

Because they are more likely to developed lactic acidosis, people with kidney damage, liver damage, or congestive heart failure should not take Metformin. Lactic Acidosis can also occur with dehydration in people who have otherwise normal kidney and liver function. If you develop a truly dehydrating condition like severe diarrhea, stop your metformin until you recover.

Stop Metformin Before X-rays with Contrast Medium

The combination of metformin plus iodine-based contrast medium can cause kidney failure in people with marginal kidnety function. The current recommendation in the prescribing information for metformin is:

Radiologic studies involving the use of iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography and computed tomography (CT) scans with intravascular contrast materials) - Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving GLUCOPHAGE [metformin]...Therefore, in patients in whom any such study is planned, GLUCOPHAGE should be discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstated only after renal function has been re-evaluated and found to be normal.

According to the nephrologist who pointed me to these guidelines, kidney function should be evaluated using a serum creatinine test.

Avoid Alcohol While Taking Metformin

Because of a fear that drinking alcohol, which temporarily paralyzes the liver, may enhance the risk of lactic acidosis, people taking Metformin are advised not to drink more than a very small amount of alcohol.

Metformin May Deplete Vitamin B-12 and Folate

Metformin has one more significant side effect. It may deplete Vitamin B-12 because it may alter the ability of the body to absorb vitamin B-12 from the gut. If this is the case, oral supplementation will not help. You would need to have Vitamin B-12 shots to address this deficiency.

Typically it takes about 10 years for low Vitamin B-12 levels to develop, but if you are already marginal for Vitamin B-12 or have other issues with your ability to absorb nutrients this might happen earlier. Your doctor should periodically test your Vitamin B-12 levels if you are taking Metformin.

Low vitamin B-12 causes a form of neuropathy that can be confused with diabetic neuropathy but which is something different.

Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. Wulffele MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B, Donker AJ, Stehouwer CD.J Intern Med. 2003 Nov;254(5):455-63.