Metformin is a prescription drug that successfully treats type 2 diabetes. Metformin also has many other benefits and “off-label” uses, such as its use in cancer and polycystic ovarian syndrome (PCOS) treatment. However, metformin also has several adverse side effects and should be taken with caution.

What is Metformin?

Metformin is classified as a biguanide is used as a first-line drug treatment for type 2 diabetes, and is also used “off-lable” for insulin resistance, PCOS, and even cancer. It is the most commonly prescribed anti-diabetic medication in the world [1].

Metformin 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 [23].

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

1) Treats and Prevents 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. It has been shown that metformin increases AMPK, which leads to more sugar being taken from the blood into tissues thus lowering 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 study (randomized controlled trial) of at-risk prediabetic patients showed that patients treated with metformin had a 31% lower occurrence of type 2 diabetes, compared to placebo. The study also pointed out that it was somehow more effective in preventing diabetes in patients with relatively high BMI and blood sugar levels [9].

2) Improves 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 [10, 11, 12, 13].

Metformin improves insulin sensitivity in cell-based and animal studies and decreases the effects of insulin resistance in diabetic patients [14, 15, 16].

Moreover, a randomized study 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 [17].

A study performed on 10 patients showed that metformin improved insulin sensitivity produced by exercise [18].

Another study on insulin-resistant rats showed that the combination of metformin and electroacupuncture increased insulin sensitivity through the activation of an enzyme that mediates insulins activity (GLUT4) [19].

3) Treats Symptoms of PCOS

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 [20].

It has also been shown to treat other PCOS symptoms by reducing BMI and testosterone levels [21].

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 [22].

4) May Help Prevent and Treat Cancer

Metformin prevented 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 genet (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 showed a 50 to 85% reduction in the risk of pancreatic, colorectal, breast, and lung cancers [25, 26].

Metformin also reduces the risk of lung (by 29%) and respiratory system cancer (by 15%). However, the lack of distinction between cancer patients who smoked and who did not be a limitation of this meta-analysis [27].

It is assumed that it may also 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 reduces resistance to chemotherapy [29].

Numerous clinical studies spanning a variety of cancers indicated that not only does metformin have a preventative effect on the development of cancer, but it also has a positive effect on disease progression [30].

However, a retrospective database study performed on over 80,000 diabetic patients indicated that metformin was not tied to reduced cancer risk, implying that previous observational studies were biased [31].

5) Protects 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].

It is safe to use after experiencing a heart attack [33].

In a study of 25 HIV patients, it was found that metformin lowered BMI, waist circumference, and blood insulin levels, all risk factors for heart disease [17].

Metformin decreased the 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 [34].

One study involving nearly 20,000 diabetic patients with increased blood clotting indicated that metformin increased the survival rate after two years, compared to controls [35].

Metformin also decreases irregular heartbeat or sudden death due to heart complications in diabetic rats [36].

6) Lowers Cholesterol

Metformin lowers the levels of “bad” low-density lipoprotein (LDL) cholesterol in the body [37].

A study (randomized controlled study) of 24 non-diabetic patients with high cholesterol showed that it reduced total and LDL-cholesterol levels, compared to controls, and this reduction was stronger with higher doses of metformin [38].

A meta-analysis of over 3,000 patients showed that while metformin does not affect blood pressure, HDL cholesterol, and blood fat (triglyceride) levels in patients with type 2 diabetes, it reduces total and LDL cholesterol [39].

7) Causes Weight Loss

In a study (double-blind randomized controlled trial) of middle-aged women with high insulin relative to blood sugar levels and weight gain, metformin along with diet helped sustain weight loss [40].

Metformin also decreased waist circumference and body mass index (BMI) in 19 HIV-infected patients with abnormal distribution of body fat (lipodystrophy) [17].

However, another pilot randomized study of 114 women with diabetes (gestational) found that it had no effect on the subjects’ weight loss after giving birth [41].

8) May Improve Erectile Dysfunction

Several animal and human studies on men with erectile dysfunction and insulin resistance, obesity, or diabetes showed that metformin improved erectile dysfunction [42, 43, 44, 45].

9) May Slow Aging

A number of studies have suggested that metformin may slow the aging process, probably in part through AMPK activation [46, 47, 48, 49].

May Protect Against Gentamicin (Antibiotic) Damage

Gentamicin is an antibiotic that produces serious damage to the kidneys and the auditory system [50].

In several animal studies, metformin protected and treated the damage to the kidneys done by gentamicin [51, 52, 53].

Other animal and cell-based studies showed that metformin may also protect against hearing loss caused by gentamicin [54, 55].

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 more at risk for some of its side effects, such as lactic acidosis or low blood sugar, due to other factors that can increase the risk of developing these conditions [35].

However, other more severe side effects should be taken into account:

1) Can Cause Lactic Acidosis

Lactic acidosis is a condition in which lactic acid builds up in the body, altering pH balance, which can lead to complications [56].

Because metformin reduces the breakdown of lactate to glucose, if the drug accumulates significantly, it may induce lactic acidosis. Metformin’s exact mechanism for action in doing so is unknown. More frequently, the combination of this drug and an underlying health condition may trigger lactic acidosis [57].

Patients with the following conditions have an increased risk of lactic acidosis induced by metformin:

Infections, recent surgery, kidney or liver damage, a history of heart disease, respiratory failure, and excessive alcohol consumption/dehydration, among others.

Also, elderly patients are especially at risk for developing lactic acidosis [58, 35].

Symptoms of lactic acidosis include muscle aches, drowsiness, and exhaustion, chills, dizziness, shortness of breath, nausea, diarrhea, vomiting, stomach pain, irregular or slow heartbeat, and cold, blue skin [35].

2) May Contribute to 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 (dehydration), the use of other drugs for diabetes, insufficient calorie intake, or bouts of heavy exercise may heighten the chances of developing this condition [35].

However, 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 [59].

3) May Lead to Vitamin B12 Deficiency

Studies have linked metformin to vitamin B12 deficiencies, depending on the dose taken [60].

It was found that 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 [61].

This deficiency is corrected using vitamin B12 supplements [62].

4) May Increase the Risk of 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 increased the risk of developing Alzheimer’s [63].

However, another study on approximately 1,500 people showed that the cognitive impairment associated with metformin is alleviated with vitamin B12 and calcium supplements [64].

Metformin Warnings

1) X-Ray & CT Scans Are Safe for Most Patients Using Metformin

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 there is a minimal risk of developing kidney damage (contrast-induced nephropathy) due to contrast media injection unless the patient has previous kidney failure, in which case the development of lactic acidosis is possible [65, 66].

2) Metformin Use During Pregnancy

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 [67].

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 [68, 69, 70, 71]. Basically, it is more important for women to regulate there glucose and insulin levels properly in pregnancy, than to avoid metformin.

3) Metformin Is Likely Safe While Breastfeeding

A study of seven women taking metformin immediately after they gave birth showed that although traces of the drug were found in the milk, they had no effects on the infant’s’ blood sugar levels, and were deemed insignificant [72].

4) Metformin May Pose a Risk to 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 correlated with approximately one-third of patients with chronic liver damage [73].

Because this condition involves decreased blood flow, it heightens the risk of developing lactic acidosis, a serious potential complication of metformin caused by the buildup of lactic acid [74, 58, 35].

5) Metformin May Pose a Risk to Patients with Kidney Disease

Metformin may decrease kidney function in diabetics with co-existing kidney disease [75].

Drug Interactions of Metformin

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) Anti-cancer Drugs

Like the previously mentioned drugs, anti-cancer 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 retrospective study on 41 subjects has shown that oral contraceptives decrease metformin’s insulin-sensitizing effects, compared to metformin treatment alone [76].

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 Intake Counteracts Metformin Effects

Heavy alcohol use leads to dehydration and causes a lowered level of oxygen in the blood, increasing 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 in combination with metformin [35].

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 with the immediate-release and once daily with the extended-release. It is also included in combination with other anti-diabetic medications in certain medications (rosiglitazone and metformin – Avandamet, glyburide and metformin – Glucovance) [3].

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) [77].

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) [78].

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 especially at risk for the condition [79].

Diabetic patients taking either metformin or sulfonylureas have a similar risk of developing cancer [80].

Sulfonylureas can increase the risk of Parkinson’s disease for patients with type 2 diabetes. This effect is often neutralized by the addition of metformin to treatment [81].

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