Metformin is a prescription drug that successfully treats type 2 diabetes. Metformin is also approved for improving fertility in women with polycystic ovarian syndrome (PCOS) and has many other benefits and “off-label” uses, such as insulin resistance and even cancer. However, metformin also has several adverse side effects and should be taken with caution.
What Is Metformin?
Metformin is classified as a biguanide. It’s used as a first-line drug treatment for type 2 diabetes and PCOS. Doctors may prescribe it for its “off-label” use in people with conditions such as insulin resistance and even cancer. It is the most commonly prescribed anti-diabetic medication in the world [1].
Mechanism of Action
Metformin adjusts cellular energy consumption by targeting the liver, preventing it from creating more sugar (glucose), and inhibiting a hormone (glucagon) responsible for increasing blood sugar levels. It also decreases the absorption of glucose in the gut and increases insulin sensitivity [2, 3].
The effect of metformin on blood sugar levels can be attributed to AMPK, an enzyme that controls the production and storage of energy in cells by regulating when muscle cells should increase their sugar uptake from the blood [4].
Recently, attention has shifted to non-AMPK mechanisms, often involving mitochondria, the parts of cells responsible for energy production [5].
Uses of Metformin
Approved Uses
1) Treating and Preventing Type 2 Diabetes
Type 2 diabetes coexists with insulin resistance and patients develop extremely high blood sugar levels. Metformin lowers blood sugar, preventing permanent organ damage, which could eventually lead to dysfunction and failure [6, 7].
Metformin exerts its effects through AMPK, which initiates the uptake of sugar from the blood into muscles. Metformin has been shown to increase AMPK, which leads to more sugar being taken from the blood into tissues. As a result, the drug lowers blood sugar concentrations [4].
On the other hand, mitochondria are responsible for cellular energy production. Metformin may decrease blood sugar by inhibiting the production of new glucose (gluconeogenesis) from noncarbohydrates such as lactate, glycerol, and some amino acids [8].
A clinical trial on over 3,000 people at risk of developing type 2 diabetes showed that those treated with metformin had a 31% lower occurrence of type 2 diabetes compared to placebo. Metformin was somehow more effective in preventing diabetes in patients with relatively high BMI and blood sugar levels [9].
2) PCOS Symptoms
Polycystic ovarian syndrome (PCOS) is a hormonal disorder often aggravated by obesity and insulin resistance. Metformin treats PCOS symptoms, such as irregular ovulation or menstrual cycles, and the excess of insulin in the body [10].
It has also been shown to treat other PCOS symptoms by reducing BMI and testosterone levels [11].
Furthermore, metformin assists fertility and increases the chance of successful pregnancy and reduces the risk of early miscarriage, gestational diabetes, and inflammation associated with PCOS [12].
Off-Label Uses
1) Insulin Resistance
Insulin resistance is one of the major factors contributing to the development of type 2 diabetes but is also observed in PCOS and as a side effect of HIV therapy [13, 14, 15, 16].
Metformin improved insulin sensitivity in cell-based and animal studies and decreased the effects of insulin resistance in diabetic patients [17, 18, 19].
Moreover, a clinical trial of 25 HIV patients with lipodystrophy, a condition in which the body is unable to generate fat tissue, showed that metformin reduced the risk of abnormally high insulin levels in the blood [20].
A small trial on 10 people showed that metformin improved insulin sensitivity produced by exercise [21].
In insulin-resistant rats, the combination of metformin and electroacupuncture increased insulin sensitivity through the activation of an enzyme that mediates insulin’s activity (GLUT4) [22].
2) Cancer
Metformin prevented the growth and spreading of certain cancers in over 300,000 patients with type 2 diabetes. The proposed mechanism of this effect is through a known tumor-suppressant gene (LKB1), which activates AMPK [23].
A meta-analysis on nearly 20,000 patients with type 2 diabetes and over 70,000 unaffected by the disease found that the incidence of a form of liver cancer (hepatocellular carcinoma) was twice as high for non-diabetic patients than for diabetics on metformin [24].
Another meta-analysis found a 60% reduction of the risk of another type of liver cancer (intrahepatic cholangiocarcinoma) in diabetic patients using metformin. This study also associated metformin use with a 50 to 85% reduction in the risk of pancreatic, colorectal, breast, and lung cancers [25, 26].
Metformin was also associated with a reduced incidence of lung (by 29%) and respiratory system cancer (by 15%). However, the lack of distinction between smoker and non-smoker patients may be a limitation of this meta-analysis [27].
Metformin has also been proposed to play a direct role in stunting cancerous tumor growth, although more evidence is needed to determine the mechanism of action [2].
A retrospective study involving 302 diabetic patients with pancreatic cancer showed a longer survival rate, higher chances of two-year survival, and lower risk of death when treated with metformin [28].
The combination of metformin with chemotherapeutic drugs has been suggested as a treatment for breast cancer because it also reduced resistance to chemotherapy [29].
Numerous clinical studies spanning a variety of cancers indicated that metformin may not only have a preventative effect on the development of cancer, but also a positive effect on disease progression [30].
However, a retrospective database study performed on over 80,000 diabetic patients indicated that metformin was not linked to reduced cancer risk, implying that previous observational studies were biased [31].
3) Protecting the Heart
Often, one of the main risk factors for heart disease is an imbalance in blood sugar. Metformin reduces blood sugar levels and enhances its uptake from the blood into the muscles by decreasing insulin resistance [32].
Metformin decreased irregularities in the heartbeat (atrial fibrillation) in a study of over 645,000 patients with type 2 diabetes. Cell-based studies also showed that metformin lowered oxidative stress and overall damage to heart muscle cells [33].
Metformin also decreases irregular heartbeat or sudden death due to heart complications in diabetic rats [34].
One study involving nearly 20,000 diabetic patients with increased blood clotting indicated that metformin increased the survival rate after two years [35].
In a study of 25 HIV patients, metformin lowered BMI, waist circumference, and blood insulin levels, all of which are risk factors for heart disease [20].
Although metformin was found to be safe to use after a heart attack, it failed to improve this condition in a clinical trial on almost 400 people [36, 37].
4) Lowering Cholesterol
Metformin lowered the levels of “bad” low-density lipoprotein (LDL) cholesterol in the body in a study on almost 2,000 people [38].
In a small trial on 24 non-diabetic patients with high cholesterol, it reduced total and LDL-cholesterol levels. This reduction was stronger with higher doses of metformin [39].
A meta-analysis of over 3,000 patients showed that metformin reduced total and LDL cholesterol in patients with type 2 diabetes. However, it did not affect blood pressure, HDL cholesterol, and blood fat (triglyceride) levels [40].
5) Weight Loss
In a clinical trial on 46 middle-aged women with high insulin relative to blood sugar levels and weight gain, metformin along with a special diet helped sustain weight loss [41].
Metformin also decreased waist circumference and body mass index (BMI) in 19 HIV-infected patients with an abnormal distribution of body fat (lipodystrophy) [20].
However, metformin had no effect on weight loss after giving birth in another trial on 114 women with gestational diabetes [42].
6) Erectile Dysfunction
Several animal and human studies on men with erectile dysfunction and insulin resistance, obesity, or diabetes showed that metformin improved erectile dysfunction [43, 44, 45, 46].
Uses without Evidence
Aging
A number of studies in animals and cells have suggested that metformin may slow the aging process, probably in part through AMPK activation [47, 48, 49, 50].
Gentamicin (Antibiotic) Damage
Gentamicin is an antibiotic that produces serious damage to the kidneys and the auditory system [51].
In several animal studies, metformin protected and treated the damage to the kidneys done by gentamicin [52, 53, 54].
Other animal and cell-based studies showed that metformin may also protect against hearing loss caused by gentamicin [55, 56].
Side Effects of Metformin
The most common side effects of metformin are related to gut complications and include upset stomach, nausea, vomiting, diarrhea, lightheadedness, or a metallic taste in the mouth [35].
In general, older patients may be at an increased risk for some of its side effects, such as lactic acidosis or low blood sugar, due to other factors [35].
However, other more severe side effects should be taken into account. Consult your doctor if these effects are severe or mild but persistent and carefully follow their recommendations.
1) Lactic Acidosis
Lactic acidosis is a condition in which lactic acid builds up in the body, altering pH balance and potentially leading to complications [57].
Because metformin reduces the breakdown of lactate to glucose, the drug may induce lactic acidosis if it accumulates significantly. Metformin’s exact mechanism of action in doing so is unknown. More frequently, the combination of this drug and an underlying health condition may trigger lactic acidosis [58].
Patients with the following conditions have an increased risk of lactic acidosis induced by metformin:
- Infections
- Recent surgery
- Kidney or liver damage
- History of heart disease
- Respiratory failure
- Excessive alcohol consumption or dehydration
Also, elderly patients are especially at risk for developing lactic acidosis [59, 35].
Symptoms of lactic acidosis include [35]:
- Muscle aches
- Drowsiness
- Exhaustion
- Chills
- Dizziness
- Shortness of breath
- Nausea and vomiting
- Diarrhea and Stomach pain
- Irregular or slow heartbeat
- Cold, blue skin
2) Low Blood Sugar (Hypoglycemia)
Metformin, itself, does not lead to a state of critically low blood sugar. However, in combination with other risk factors like heavy alcohol drinking (or dehydration), the use of other drugs for diabetes, insufficient calorie intake, or bouts of heavy exercise, it may increase the chances of developing this condition [35].
Nevertheless, a meta-analysis of pregnant women with diabetes showed that metformin poses a lower threat of low blood sugar occurrence in newborns compared to insulin [60].
3) Vitamin B12 Deficiency
Studies have linked metformin to vitamin B12 deficiencies, depending on the dose taken [61].
With increased metformin dosage, the incidence of vitamin B12 deficiency also increased. One study of 465 people reported that 30% of those using metformin had poor vitamin B12 absorption and its level in the body was 14 to 30% lower than that of an average person [62].
This deficiency is corrected by using vitamin B12 supplements [63].
4) Cognitive Impairments
A case-control study of over 7,000 patients with Alzheimer’s disease showed that, compared to insulin treatments, sulfonylureas, and thiazolidinediones, metformin was associated with an increased incidence of Alzheimer’s [64].
However, another study on approximately 1,500 people showed that the cognitive impairment associated with metformin may be alleviated with vitamin B12 and calcium supplements [65].
Metformin Warnings
1) X-Ray & CT Scans
X-ray studies and CT scans frequently use contrast media, which may induce kidney damage and lead to lactic acidosis.
A study of 98 patients taking metformin showed that the risk of developing kidney damage (contrast-induced nephropathy) due to contrast media injection is minimal unless the patient has previous kidney failure [66, 67].
2) Use During Pregnancy and Breastfeeding
A review of several studies showed that metformin does not have any acute negative effects on pregnancy outcomes. However, there is not enough evidence regarding its prolonged use during pregnancy. Pregnant women should always consult their doctors about the potential risks of using metformin [68].
Moreover, several human studies have shown that metformin may decrease the relative risks of pregnancy complications, miscarriage, premature birth, and early pregnancy loss in women with polycystic ovarian syndrome [69, 70, 71, 72].
Because regulating their blood sugar and insulin levels is crucial to pregnant women, the benefits of taking metformin generally outweigh the risks.
A study of seven women taking metformin immediately after giving birth showed that, although traces of the drug were found in the milk, they were too low to have any effects on the blood sugar levels of the babies [73].
3) Patients with Liver Cirrhosis
Cirrhosis is the replacement of healthy liver tissue with scar tissue caused by chronic damage. A decreased oxygen concentration in blood traveling from the heart to the body (arterial hypoxemia) has been found in approximately one-third of patients with chronic liver damage [74].
Because this condition involves decreased blood flow, it heightens the risk of developing lactic acidosis, a serious potential complication of metformin [75, 59, 35].
4) Patients with Kidney Disease
Metformin may decrease kidney function in diabetics with co-existing kidney disease [76].
Drug Interactions of Metformin
To help avoid interactions, your doctor should manage all of your medications carefully. Be sure to tell your doctor about all medications, vitamins, or herbs you’re taking. Talk to your healthcare provider to find out how metformin might interact with something else you are taking.
The dose of metformin varies depending on what it is being used to treat, the age of the patient, and any previous health conditions or factors that could potentially interfere with or amplify the drug’s effect. There are a host of medications thought to theoretically decrease metformin effectiveness (absorption in the gut and uptake in the liver), but most are thought not to do so in a clinically significant manner [1].
Below are some exceptions.
1) Other Diabetes Medications
Sitagliptin (Januvia), a dipeptidyl peptidase-4 (DPP-4) inhibitor, and repaglinide (Prandin), a meglitinide, can both decrease the effectiveness of metformin by inhibiting its absorption in the gut and uptake in the liver [1].
2) Antibiotics
The antibiotic trimethoprim may also decrease the effectiveness of metformin by inhibiting its absorption in the gut and uptake in the liver [1].
3) Anticancer Drugs
Like the previously mentioned drugs, anticancer medications such as imatinib, nilotinib, gefitinib, and erlotinib (tyrosine kinase inhibitors) may decrease the effectiveness of metformin by inhibiting metformin’s absorption in the gut and uptake in the liver [1].
4) Oral Contraceptives
Although the combination of oral contraceptives and metformin has not been documented to cause any harm, a study on 41 women showed that oral contraceptives decrease metformin’s insulin-sensitizing effects [77].
5) Other Drugs
Other medications such as disopyramide, dipyridamole, imipramine, tacrine, orphenadrine, and cimetidine are also thought to inhibit metformin’s absorption in the gut and uptake in the liver [1].
6) Alcohol
Heavy alcohol use leads to dehydration and causes a lowered level of oxygen in the blood. This increases a patient’s risk of lactic acidosis, one of the metformin’s most common side effects. Frequent drinking also decreases blood sugar, which may lead to complications when combined with metformin [35].
What to Know About Using Metformin
Forms and Dosage of Metformin
Metformin is available in immediate-release and extended-release formulations. Doses are in the 500 to 2,550 mg range and are usually taken with food twice daily (immediate-release) or once daily (extended-release). It can also be taken in combination with certain anti-diabetic medications (rosiglitazone and metformin – Avandamet, glyburide, and metformin – Glucovance) [3].
Follow your doctor’s instructions carefully. Take metformin as recommended and do not change its dose and frequency or stop taking it without your doctor’s approval. Talk to your doctor if your condition doesn’t improve or if it worsens.
Metformin Compared with Other Antidiabetic Medications
Compared to insulin and sulfonylureas (glyburide, glimepiride, glipizide, chlorpropamide), metformin shows a lower incidence of weight gain and fewer instances of critically lowered blood sugar (which can lead to health complications) [78].
Rosiglitazone (Avandia) is more effective than both metformin and sulfonylurea in the delay of type 2 diabetes onset but has more adverse side effects than metformin (including weight gain, increased “bad” cholesterol levels, swelling in certain areas of the body, and decreased red blood cells) [79].
A review of 347 human studies indicated that metformin did not pose a higher risk of lactic acidosis in comparison to other treatments for diabetes or placebo. However, this study did not take into account patients at a specially high risk of the condition [80].
Diabetic patients taking either metformin or sulfonylureas have a similar risk of developing cancer [81].
Sulfonylureas can increase the risk of Parkinson’s disease in patients with type 2 diabetes. This effect is often neutralized by the addition of metformin to the treatment [82].
