- ACRONYMS AND DEFINITIONS
- A1C - Hemoglobin A1C
- AASLD - American Association for the Study of Liver Diseases
- ACR - American College of Radiology
- ADA - American Diabetes Association
- CrCl - Creatinine clearance
- ER - Extended release
- FBS - fasting blood sugar
- FDA - U.S. Food and Drug Admin
- GFR - Glomerular filtration rate
- GI - Gastrointestinal
- Glucose - Blood sugar
- IR - Immediate release
- Met - Metformin
- NASH - Nonalcoholic steatohepatitis
- PCOS - Polycystic ovary syndrome
- RCT - Randomized controlled trial
- DRUGS IN CLASS
- Standard-release metformin
- Glucophage®
- Riomet® solution
- Metformin extended-release
- Fortamet®
- Glucophage XR®
- Glumetza®
- Combination products with DPP-4 inhibitors
- Janumet® (metformin + sitagliptin)
- Janumet® XR (metformin extended-release + sitagliptin)
- Jentadueto® (metformin + linagliptin)
- Jentadueto® XR (metformin extended-release + linagliptin)
- Kazano® (metformin + alogliptin)
- Kombiglyze™ XR (metformin extended-release + saxagliptin)
- Combination products with glitazones
- Actoplus Met® (metformin + pioglitazone)
- Actoplus Met XR® (metformin extended-release + pioglitazone)
- Avandamet® (metformin + rosiglitazone)
- Combination products with meglitinides
- PrandiMet® (metformin + repaglinide)
- Combination products with SGLT2 inhibitors
- Invokamet® (metformin + canagliflozin)
- Invokamet® XR (metformin extended-release + canagliflozin)
- Segluromet® (metformin + ertugliflozin)
- Synjardy® (metformin + empagliflozin)
- Synjardy® XR (metformin extended-release + empagliflozin)
- Xigduo™ XR (metformin extended-release + dapagliflozin)
- Combination products with sulfonylureas
- Glucovance® (metformin + glyburide)
- Metaglip® (metformin + glipizide)
- Combination product with a SGLT2 inhibitor and a DPP-4 inhibitor
- Trijardy® XR (empagliflozin + linagliptin + metformin ER)
- MECHANISM OF ACTION
- Metformin
- Metformin is part of a drug class called biguanides
- Metformin does not stimulate the secretion of insulin
- In the past, metformin was sometimes called an "insulin sensitizer" because it was thought to increase the body's sensitivity to insulin
- Recent research has shown that the main action of metformin is to inhibit gluconeogenesis in the liver
- Metformin lowers blood sugars through the following cellular actions:
- Metformin selectively inhibits the mitochondrial isoform of glycerophosphate dehydrogenase, an enzyme that catalyzes the conversion of glycerophosphate to dihydroxyacetone phosphate (DHAP)
- Through a series of enzymatic steps, decreasing DHAP levels lead to a reduction in the amount of cytosolic pyruvate, a precursor for gluconeogenesis
- The use of glycerol and lactate as gluconeogenic precursors drops, and glycerol and lactate levels build up in the plasma [27]
- TYPE 2 DIABETES
- Blood sugar effects
- The effects of metformin on blood sugars were evaluated in the Cochrane meta-analysis detailed below
- STUDY
- Metformin vs Comparator (A1C):
- Metformin lowered the A1C level an average of 0.97% [95%CI -1.25 to -0.69] more than placebo (N=1587)
- Metformin lowered the A1C level an average of 1.06% [95%CI -1.89 to -0.22] more than diet therapy (N=914)
- Metformin lowered the A1C level an average of 0.14% [95%CI -0.28 to -0.01] more than sulfonylureas (N=2376)
- Metformin lowered the A1C level an average of 0.28% [95%CI -0.52 to -0.03] more than glitazones (N=260)
- Metformin lowered the A1C level an average of 0.16% [95%CI -0.36 to 0.03] more than meglitinides (N=413)
- Metformin lowered the A1C level an average of 0.26% [95%CI -1.40 to 0.89] more than alpha-glucosidase inhibitors (N=223)
- Metformin vs Comparator (FBS):
- Metformin lowered the FBS an average of 15.7 mg/dl [95%CI -20.3 to -11] more than placebo (N=1587)
- Metformin lowered the FBS an average of 2.9 mg/dl [95%CI -4.86 to -0.90] more than sulfonylureas (N=2409)
- Metformin lowered the FBS an average of 37.4 mg/dl [95%CI -87.7 to 12.8] more than diet therapy (N=814)
- Metformin lowered the FBS an average of 2.7 mg/dl [95%CI -1.6 to 7.0] less than glitazones (N=260) [2]
- Body weight effects
- Metformin appears to have a neutral effect on weight when compared to placebo or diet
- Other diabetes medications (insulin, sulfonylureas, glitazones) are prone to cause weight gain [2,3]
- Lipid effects
- Metformin appears to have a neutral effect on lipid parameters when compared to placebo or diet
- Other diabetes medications (sulfonylureas, glitazones) may have a negative effect on lipid parameters when compared to metformin [2,3]
- TYPE 2 DIABETES | Clinical outcomes
- Overview
- The United Kingdom Prospective Diabetes Study (UKPDS) was a large study that compared dietary advice to sulfonylureas or insulin in patients with newly-diagnosed T2DM. The primary outcomes for the study were the incidence of microvascular and macrovascular disease.
- A substudy of the UKPDS study compared metformin to diet and insulin/sulfonylurea therapy. It is one of the few studies that have looked at clinical outcomes with metformin. Results from the study are detailed below.
- The UKPDS 34 trial enrolled 1704 overweight, newly-diagnosed type 2 diabetics
Main inclusion criteria
- Age 25 - 65 years
- Fasting blood sugar > 108 mg/dl after 3 months of diet therapy without symptoms of hyperglycemia
- Body weight > 120% of ideal body weight
Main exclusion criteria
- SCr > 1.98 mg/dl
- Myocardial infarction within past year
- Current angina or heart failure
- > 1 major vascular event
- Retinopathy requiring laser treatment
Baseline characteristics
- Average age 53 years
- Average weight - 189 lbs (86 kg)
- Average BMI - 31.4
- Average HgA1C - 7.2%
Randomized treatment groups
- Group 1 (342 patients) - Metformin with a target dose of 2550 mg/day
- Group 2 (411 patients) - Diet therapy
- Group 3 (951 patients) - Other therapy (sulfonylurea or insulin)
- The goal of therapy was to obtain a fasting blood sugar < 108 mg/dl
- If blood sugars were not controlled in any group, then therapy from another group could be added
Primary outcomes:
- 1. - Composite of any diabetes-related clinical endpoint (sudden death, death from hyperglycemia or hypoglycemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous hemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction)
- 2. - Diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hypoglycemia, or hyperglycemia, and sudden death)
- 3. - All-cause mortality
Results
Duration: Median of 10.7 years | ||||
Outcome | Metformin | Diet therapy | Sulfonylurea or Insulin | Comparisons |
---|---|---|---|---|
Primary outcome #1 (events per 1000 patient-years) | 29.8 | 43.3 | 40.1 | 1 vs 2 p=0.0023 | 3 vs 2 p=0.46 | 1 vs 3 p=0.0034 |
Primary outcome #2 (events per 1000 patient-years) | 7.5 | 12.7 | 10.3 | 1 vs 2 p=0.017 | 3 vs 2 p=0.19 | 1 vs 3 p>0.05 |
All-cause mortality (events per 1000 patient-years) | 13.5 | 20.6 | 18.9 | 1 vs 2 p=0.011 | 3 vs 2 p=0.49 | 1 vs 3 p=0.021 |
Myocardial infarction (events per 1000 patient-years) | 11 | 18 | 14.4 | 1 vs 2 p=0.01 | 3 vs 2 p=0.11 | 1 vs 3 p>0.05 |
Median A1C during follow-up | 7.4% | 8% | 7.4% | N/A |
|
Findings: Since intensive glucose control with metformin appears to decrease the risk of diabetes-related endpoints in overweight diabetic patients, and is associated with less weight gain and fewer hypoglycaemic attacks than are insulin and sulfonylureas, it may be the first-line pharmacological therapy of choice in these patients.
- Summary
- There are few good studies that have compared clinical outcomes between metformin and other diabetes interventions
- In the small UKPDS 34 study, metformin was superior to diet therapy for all of the primary outcomes albeit at a lower average HgA1C value. Metformin was superior to insulin or sulfonylurea therapy on two of the primary outcomes even though the groups achieved similar HgA1C values. The UKPDS 34 study is often cited as evidence to support metformin as a first-line agent in type 2 diabetes.
- Metformin is a good first-line agent in most patients because it is cheap, safe, and does not cause hypoglycemia or weight gain
- TYPE 2 DIABETES | ADA recommendations
- Metformin is the recommended first-line agent for patients with type 2 diabetes who do not have contraindications
- See ADA type 2 diabetes treatment recommendations for more
- TYPE 2 DIABETES | Prevention
- POLYCYSTIC OVARY DISEASE (PCOS)
- Polycystic ovary disease (PCOS)
- PCOS is a syndrome characterized by cystic ovaries, insulin resistance, infertility (anovulation), high levels of testosterone, and obesity. Because metformin can improve insulin resistance, it can be used to treat the symptoms of PCOS.
- A Cochrane meta-analysis that compared the effects of metformin to placebo, clomiphene, and oral contraceptives is detailed below.
- STUDY
- Fertility outcomes
- Metformin had the following effects when compared to placebo or no treatment:
- Metformin increased the odds of becoming pregnant by 3.86
- Two very small studies (total 50 patients) found no difference in the live birth rates for women on metformin
- Metformin increased the odds of ovulation by 2.12
- Metformin increased the odds of having an improved menstrual pattern by 1.72
- Compared to clomiphene:
- Metformin was inferior to clomiphene for ovulation rates and pregnancy rates [6]
- Metabolic outcomes
- Metformin had the following effects when compared to placebo or no treatment:
- Metformin did not have a significant effect on body weight
- Metformin did not have a significant effect on fasting insulin levels
- Metformin had a small significant effect on fasting blood sugar levels
- Metformin did not have a significant effect on lipid parameters (cholesterol, triglycerides, etc.)
- Metformin lowered serum testosterone levels significantly [6]
- Metformin compared to oral contraceptives (birth control pills)
- Oral contraceptives and metformin were equally effective at treating hirsutism (male-pattern hair growth)
- Oral contraceptives were significantly better than metformin in improving menstrual cycles
- Oral contraceptives were significantly better than metformin in lowering testosterone levels [7]
- Endocrine Society recommendations
- Hormone contraceptives (e.g. oral contraceptives, patch, vaginal ring) are the recommended first-line treatment for menstrual abnormalities and hirsutism/acne
- Clomiphene is the recommended first-line treatment for infertility
- Metformin is recommended for women who have type 2 diabetes of glucose intolerance
- Metformin is recommended as a second-line therapy for menstrual irregularities in women who cannot take hormone contraceptives
- Metformin is recommended as adjuvant therapy for infertility to prevent ovarian hyperstimulation syndrome (OHSS) in women with PCOS undergoing in vitro fertilization (IVF) [30]
- Summary
- Oral contraceptives are the preferred first-line medication for PCOS in women who do not wish to become pregnant
- Oral contraceptives are more effective than metformin for controlling menstrual cycles and lowering testosterone levels
- Clomiphene is more effective than metformin in treating infertility
- Metformin may be beneficial in women who wish to become pregnant, women who are at high-risk for developing diabetes, and women who do not wish to take clomiphene
- FATTY LIVER DISEASE (NASH)
- Overview
- Fatty liver disease is often associated with insulin resistance and diabetes. Because of this, there has been interest in using metformin to treat the condition.
- A handful of very small studies have compared metformin to control for various NASH outcomes. In general, there is insufficient data to draw any firm conclusions from these studies.
- One relatively larger study that only enrolled children was published in 2011. The results of that study are detailed below.
- A JAMA study enrolled 173 patients (ages 8 - 17 years) with nonalcoholic fatty liver disease
Main inclusion criteria
- Age 8 - 17 years
- Nonalcoholic fatty liver disease defined by a liver biopsy demonstrating more than 5% steatosis within a 6-month period before randomization
- ALT > 60 U/L for 1 - 6 months before and at the time of randomization
Main exclusion criteria
- Diabetes
- Cirrhosis
- Inborn errors of metabolism
- Viral hepatitis
Baseline characteristics
- Average age 13 years
- Hispanic ethnicity - 61%
- Average ALT - 123 U/L
- Average BMI - 34
- Average % body fat - 43%
- Definite NASH - 42%
- Average NAFLD activity score - 4.6
Randomized treatment groups
- Group 1 (58 patients) - Vitamin E 400 IU twice a day for 96 weeks
- Group 2 (57 patients) - Metformin 500 mg twice a day for 96 weeks
- Group 3 (58 patients) - Placebo twice a day for 96 weeks
Primary outcome: Sustained reduction in alanine aminotransferase (ALT) defined as 50% or
less of the baseline level or 40 U/L or less at visits every 12 weeks from 48 to 96 weeks of treatment
Results
Duration: 96 weeks | ||||
Outcome | Vitamin E | Metformin | Placebo | Comparisons |
---|---|---|---|---|
Primary outcome | 26% | 16% | 17% | 1 vs 3 p=0.26 | 2 vs 3 p=0.83 |
Average decrease in ALT at 96 weeks | 48 U/L | 41.7 U/L | 35.2 U/L | 1 vs 3 p=0.07 | 2 vs 3 p=0.40 |
Decrease in NAFLD activity score | 1.8 | 1.1 | 0.7 | 1 vs 3 p=0.02 | 2 vs 3 p=0.25 |
|
Findings: Neither vitamin E nor metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with pediatric NAFLD
- Professional recommendations
- SIDE EFFECTS
- Gastrointestinal side effects
- Gastrointestinal (GI) side effects with metformin are common
- GI side effects tend to improve after several weeks of use
Common metformin GI side effects | |
---|---|
Side effect | % of patients |
Diarrhea | 10 - 40% |
Nausea | 7 - 14% |
Gas | 3 - 6% |
- Measures to limit GI side effects
- Start with a lower dose and increase gradually over several weeks
- Take doses with meals
- If doses are unequal (ex. 500 mg in AM and 1000 mg in PM), take larger dose with evening meal [1, 12, 13]
- Extended-release metformin
- Extended-release metformin is sometimes touted as having fewer GI side effects than immediate-release metformin
- A study that compared metformin ER to metformin IR found no significant difference in the incidence of diarrhea and nausea between the two. See metformin extended-release for more.
- Low blood sugar (hypoglycemia)
- Metformin does not stimulate insulin secretion
- Metformin does not cause low blood sugar when taken by itself
- When metformin is taken with other medications that can cause low blood sugar (ex. insulin, sulfonylureas), it may increase the risk of hypoglycemia
- Lactic acidosis
- Metformin is part of a class of drugs called biguanides
- A previous biguanide called phenformin was brought to market in the 1970s
- Phenformin was associated with a serious, life-threatening condition called lactic acidosis, and it was eventually taken off the market
- Risk factors for lactic acidosis include many common conditions in diabetics like decreased kidney function, heart attack, respiratory diseases, heart failure, and liver disease
- When metformin was introduced, the FDA was wary of lactic acidosis because of the problems with phenformin, so the prescribing information for metformin stated that it was contraindicated in these conditions
- Since its release in 1995, metformin has been a very popular drug that has been prescribed to millions of patients
- Being so widely prescribed, metformin has inevitably been taken by many patients with the original contraindications
- Despite this, an increase in the incidence of lactic acidosis has not been observed
- This has led many to question the contraindications that were originally placed on the drug
- Three studies that looked at metformin and the risk of lactic acidosis are summarized below
- STUDY
- Design: Registry cohort study (N=75,413; length = 5.7 years) in diabetics with a postdiagnosis serum creatinine measurement
- Exposure: Metformin vs Other DM meds. A sensitivity analysis was done comparing new metformin users to new sulfonyurea users.
- Primary outcome: Hospitalization with acidosis
- Results:
- Primary outcome: Metformin use was associated with an increased risk of acidosis only in patients with GFR < 30 ml/min (adjusted HR 2.07, 95%CI [1.33-3.22]). Results were consistent when new metformin users were compared with new sulfonylurea users
- Findings: In 2 real-world clinical settings, metformin use was associated with acidosis only at eGFR less than 30 mL/min/1.73 m2. Our results support cautious use of metformin in patients with type 2 diabetes and eGFR of at least 30 mL/min/1.73 m2
- STUDY
- A Cochrane meta-analysis evaluated the incidence of lactic acidosis in trials involving metformin and found the following:
- Out of 347 trials with a cumulative exposure of 70,490 patients on metformin for one year, there were no cases of lactic acidosis
- Of the trials that measured serum lactic acid levels, there was no difference between metformin users and placebo
- 324 of the trials in the review allowed for patients with at least one contraindication to metformin to be included in their trial [14]
- Findings: There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments.
- STUDY
- A trial in the European Journal of Internal Medicine randomized 393 diabetics who were taking metformin to either stop metformin or continue it
- The patients all had at least one relative contraindication to metformin therapy including heart failure, heart disease, liver disease, COPD, and kidney disease
- The average serum creatinine in the group that continued metformin was 1.84 mg/dl
- After 4 years of therapy, the following was seen:
- There were no cases of lactic acidosis in either group
- There was no difference in serum lactic acid levels between the groups [15]
- Findings: Diabetic patients who are treated with metformin and who tolerate the drug well may continue taking it, even when mild renal impairment develops, possibly up to serum creatinine levels of 220 µmol/l. There is also no apparent reason why patients with CHD, CHF, and COPD should discontinue metformin.
- Summary
- Metformin has been used safely in many patients who have one of the original contraindications to its use
- Unlike phenformin, there is no good evidence that it increases the risk of lactic acidosis
- Vitamin B12 deficiency
- Metformin can decrease the absorption of vitamin B12 from the intestine leading to B12 deficiency
- Several studies that looked at the association of metformin with vitamin B12 deficiency are summarized below. Recommendations from the ADA and manufacturer are also presented.
- STUDY
- Participants in the DPP were assigned to placebo (n=1082) or metformin (n=1073) for 3.2 years, followed by open-label metformin in the metformin group for 9 years
- During follow-up, the following was seen:
- Low B12 (≤ 203 pg/mL) occurred more often in the metformin group than the placebo group at 5 years (4.3 vs 2.3%, p=0.02) but not at 13 years (7.4 vs 5.4%, p=0.12)
- Combined low and borderline-low B12 (≤ 298 pg/mL) was more common in the metformin group at 5 years (19.1 vs 9.5%, p<.01) and 13 years (20.3 vs 15.6%, p=0.02)
- Years of metformin use was significantly associated with increased risk of B12 deficiency (OR 1.13, 95% CI [1.06 - 1.20])
- Anemia was more common in the metformin group but did not differ by B12 level
- Neuropathy was more common in the metformin group with low B12 levels [28]
- Findings: Long-term use of metformin in DPPOS was associated with biochemical B12 deficiency and anemia. Routine testing of vitamin B12 levels in metformin-treated patients should be considered.
- STUDY
- A trial in the British Medical Journal randomized diabetics on insulin to metformin 850 mg three times a day (n=196) or placebo (n=194)
- The average B12 level at baseline was 513 pg/ml
- After 4.3 years of therapy, the following effects were seen:
- Patients on metformin had an average decrease in B12 levels of 19% compared to placebo (95% CI [-24% to -14%], p<0.001)
- The absolute risk of vitamin B12 deficiency (defined as B12 level < 200 pg/ml) was 7.2% higher in the metformin group than in the placebo group (95% CI [2.3% - 12.1%] p=0.004),
- The absolute risk of low vitamin B12 levels (defined as B12 level of 200 pg/ml - 300 pg/ml) was 11.2% higher in the metformin group than in the placebo group (95% CI [4.6% - 17.9%], p=0.001) [18]
- Findings: Long-term treatment with metformin increases the risk of vitamin B12 deficiency, which results in raised homocysteine concentrations. Vitamin B-12 deficiency is preventable; therefore, our findings suggest that regular measurement of vitamin B-12 concentrations during long term metformin treatment should be strongly considered.
- Professional recommendations
- ADA recommendations
- The ADA DM treatment guidelines state that long-term use of metformin may be associated with biochemical vitamin B12 deficiency, and periodic measurement of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anemia or peripheral neuropathy [29]
- Metformin package insert
- The metformin package insert recommends that hematologic parameters (CBC) be measured on an annual basis and B12 levels be measured every 2 - 3 years [1]
- Summary
- The ideal screening protocol for vitamin B12 deficiency in patients on metformin has not been determined
- Patients at high risk for B12 deficiency who have been taking metformin for a significant period of time (≥ 2 years) should be screened for B12 deficiency
- Risk factors for Vitamin B12 deficiency include the following:
- Advanced age
- Pernicious anemia
- Vegetarian diet
- Chronic proton pump inhibitor use (e.g. Prilosec®, Prevacid®, Nexium®)
- Chronic gastrointestinal disorders (e.g. Crohn's disease, celiac disease, bowel resection, gastritis)
- Ovulation and pregnancy
- High blood insulin levels can inhibit ovulation
- Women with insulin resistance have high insulin levels and often do not ovulate
- Insulin-sensitizing drugs like metformin may cause a decrease in insulin levels, and women who were not ovulating may start to ovulate
- This can lead to pregnancy
- Women taking metformin should be aware that metformin may increase their chances of becoming pregnant [1]
- Anemia / decreased hemoglobin
- In some randomized controlled trials, patients treated with metformin had a decrease in hemoglobin levels and a higher risk of anemia when compared to controls. In metformin-treated patients, hemoglobin levels decreased within months of initiating therapy, and were on average, 0.40 - 0.50 g/dL lower than controls after 3 years of treatment.
- While metformin is known to cause vitamin B12 deficiency, the anemia seen in the trials was not consistent with this etiology because of its early onset (depletion of vitamin B12 stores typically takes years) and the fact that the average MCV also decreased in the metformin group.
- In summary, it's unknown how metformin may cause this type of anemia, but it should be considered as a possible cause when a workup fails to identify another source [32]
- CONTRAINDICATIONS
- Kidney disease - metformin should not be used in patients with CrCl < 30 ml/min
- Known hypersensitivity
- Acute or chronic metabolic acidosis - including diabetic ketoacidosis
- Iodinated contrast - metformin should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. See iodinated contrast for more.
- PRECAUTIONS
- Kidney disease
- When metformin was first marketed, there was concern that it may cause lactic acidosis like phenformin, a previous biguanide (see lactic acidosis). The original prescribing information stated that it was contraindicated in patients with a serum creatinine ≥ 1.5 mg/dl in males and ≥ 1.4 mg/dl in females.
- After marketing, metformin was so widely prescribed that it was inevitably taken by many patients with kidney disease. Despite this, an increase in lactic acidosis cases was not observed.
- In 2016, the FDA loosened its recommendations on prescribing metformin in patients with kidney disease. Other professional societies have also published less stringent guidelines. Dosing guidance in renal disease from 3 organizations is detailed below.
- FDA recommendations for prescribing metformin in kidney disease
- Obtain a GFR before prescribing metformin and at least annually thereafter. Check more frequently in patients at risk for kidney disease (e.g. elderly).
- Metformin is contraindicated in patients with a GFR < 30 ml/min
- Starting metformin in patients with a GFR of 30 - 45 ml/min is not recommended
- If GFR falls to 30 - 45 ml/min in a patient taking metformin, assess the risk/benefit of continuing metformin
- Canadian Diabetes Association recommendations
- Use metformin with caution in patients with GFR 30 - 60 ml/min
- Metformin is not to be used in patients with GFR < 30 ml/min
- Australian Diabetes Society recommendations
- Use metformin with caution in patients with GFR 30 - 45 ml/min
- Metformin is not to be used in patients with GFR < 30 ml/min [16]
- Liver disease
- Metformin's prescribing information states that it should be avoided in patients with clinical or laboratory evidence of liver disease because significant hepatic impairment increases the risk of lactic acidosis. Many diabetics have fatty liver disease, and metformin has been used safely in this population for years. Metformin has even been studied as a treatment for this condition.
- Patients with cirrhosis should avoid metformin. Metformin appears to be safe in patients with milder forms of liver disease. [21, 23]
- Heart failure
- Heart failure is a risk factor for lactic acidosis
- Metformin prescribing information states that it is contraindicated in patients who have heart failure "requiring drug treatment." In practice, many patients with heart failure have received metformin.
- A cohort study that looked at outcomes among patients with heart failure taking metformin is detailed below along with the ADA recommendations
- STUDY
- A cohort study in Diabetes Care looked at a Saskatchewan medical database and compared outcomes in diabetics with heart failure based on whether they were prescribed a sulfonylurea, metformin, or a combination (metformin + sulfonylurea)
- After an average follow-up of 2.5 years, the following was seen:
- Metformin therapy was associated with a 30% relative risk reduction for death when compared to sulfonylurea therapy
- Combination therapy was associated with a 39% relative risk reduction for death when compared to sulfonylurea therapy [26]
- Findings: Metformin, alone or in combination, in subjects with heart failure and type 2 diabetes was associated with lower morbidity and mortality compared with sulfonylurea monotherapy
- ADA recommendations
- The ADA 2019 diabetes guidelines state that patients with type 2 diabetes who have stable congestive heart failure may use metformin if the estimated GFR remains > 30 mL/min. Metformin should be avoided in unstable or hospitalized patients with congestive heart failure. [29]
- Acute heart attack
- Heart attacks increase the risk of lactic acidosis
- Metformin's prescribing information states that it should be discontinued in patients suffering a heart attack
- There are no large, randomized studies that have evaluated the use of metformin in patients who have suffered an acute heart attack
- A small registry study in Diabetic Medicine found that in practice, patients on metformin who suffer a heart attack are often left on metformin with no apparent adverse effect [22]
- Hypoxia
- Acutely-ill patients with hypoxia are at increased risk for lactic acidosis and should have their metformin withheld
- Examples include patients who are septic, in respiratory distress, cardiovascular shock, acute kidney failure, etc. [1]
- Alcoholism
- Heavy alcohol use can cause elevated lactic acid levels
- Theoretically, heavy alcohol use combined with metformin could increase the risk of lactic acidosis [1]
- Advanced age
- As people age, their kidney function naturally declines
- The prescribing guidelines for metformin recommend that patients ≥ 80 years old have their kidney function monitored frequently and that metformin not be used at its maximum dose [1]
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- Metformin
- Alcohol - alcohol may potentiate the effect of metformin on lactate metabolism. Patients should not drink excessively while taking metformin.
- Colesevelam (Welchol™) - colesevelam has been shown to increase levels of metformin extended-release. Monitor for side effects when combining.
- Carbonic anhydrase inhibitors - carbonic anhydrase inhibitors cause a decrease in serum bicarbonate and induce nonanion gap, hyperchloremic metabolic acidosis. This may increase the risk of lactic acidosis.
- Examples of drugs that inhibit carbonic anhydrase include:
- Topiramate (Topamax®)
- Acetazolamide (Diamox®)
- Zonisamide (Zonegran®)
- Dichlorphenamide
- Cephalexin (Keflex®) - cephalexin may increase blood levels of metformin. The significance of this interaction is unclear.
- OCT2/MATE inhibitors - metformin is an OCT2 substrate. OCT2/MATE inhibitors may increase systemic exposure to metformin thus increasing the risk for lactic acidosis.
- Metabolism and clearance
- Metformin does not undergo liver metabolism
- OCT2 - substrate
- METFORMIN EXTENDED-RELEASE
- Overview
- Metformin extended-release is a long-acting version of metformin that is typically dosed less frequently than metformin. It has also been touted as having fewer GI side effects than standard-release metformin.
- The study detailed below compared the glycemic effects and incidence of GI side effects between metformin IR and metformin ER
- See converting between metformin IR and ER for recommendations on switching between the different formulations
- A Diabetes Care study enrolled 706 patients with type 2 diabetes
Main inclusion criteria
- Type 2 diabetes
- Treatment-naïve or treatment with oral medications
- HgA1C 7 - 12% (treatment-naïve) or 6.5 - 10% (receiving treatment)
Main exclusion criteria
- Insulin therapy
- Receiving steroids, niacin, or isoniazid
- History of gastrointestinal disease
- History of retinopathy, neuropathy, or proteinuria
- Serum creatinine > 1.5 mg/dl (male), > 1.4 mg/dl (female)
Baseline characteristics
- Average age 54 years
- Average BMI - 33.5
- Average duration of diabetes - 4.2 years
- Average HgA1C ∼ 8.4%
- Treatment at study entry: Drug naïve - 48% | Metformin only - 25% | Sulfonylurea only - 16% | Metformin + sulfonylurea - 8%
Randomized treatment groups
- Group 1 (178 patients) - Metformin ER 1500 mg once daily for 24 weeks
- Group 2 (182 patients) - Metformin ER 500 mg in the AM and 1000 mg in the PM for 24 weeks
- Group 3 (172 patients) - Metformin ER 2000 mg once daily for 24 weeks
- Group 4 (174 patients) - Metformin IR 500 mg in the AM and 1000 mg in the PM for 24 weeks
- There was a 6-week washout period for patients receiving prior drug treatment
- All patients started therapy at 1000 mg/day and were titrated to their assigned dose over 2 - 3 weeks
- Placebo tablets were given to the once daily groups to maintain blinding
Primary outcomes:
- 1. Differences between groups in change in HgA1C values from baseline (adjusted for differences at baseline)
- 2. Incidence of GI side effects
Results
Duration: 24 weeks | |||||
Outcome | Group 1 | Group 2 | Group 3 | Group 4 | Comparisons |
---|---|---|---|---|---|
Primary outcome (A1C decrease from baseline) | 0.73% | 0.74% | 1.06% | 0.70% | Group 3 was significantly better than Group 4 |
Diarrhea (during 1000 mg/day dosing) | 6.9% | 8.3% | 8.9% | 10.5% | IR vs ER groups, p>0.05 |
Nausea (during 1000 mg/day dosing) | 2.9% | 3.9% | 2.4% | 8.2% | IR vs ER groups, p<0.05 |
Diarrhea (during entire study) | 14.2% | 18.2% | 15.8% | 14.4% | IR vs ER groups, p>0.05 |
Nausea (during entire study) | 9.7% | 7.7% | 8.2% | 10.9% | IR vs ER groups, p>0.05 |
Findings: Once- or twice-daily extended-release metformin was as safe and effective as twice-daily immediate-release metformin and provided continued glycemic control for up to 24 weeks of treatment.
- Summary
- Based on the RCT above, metformin ER has similar glycemic effects as metformin IR
- As far as GI side effects are concerned, metformin ER had less nausea during initial dosing, but there was no significant difference in diarrhea over the entire trial
- Converting between metformin ER and metformin IR
- The maximum recommended daily dose of the metformin extended-release products is lower than that of immediate-release metformin
- When switching from immediate-release metformin to extended-release formulations, the dose should remain the same as long as it does not exceed the maximum recommended daily dose of the extended-release product
Maximum daily dose for metformin formulations | |
---|---|
Drug | Maximum daily dose |
Metformin IR (Glucophage®) | 2550 mg |
Metformin ER (Glucophage XR®) | 2000 mg |
Fortamet® | 2500 mg |
Glumetza® | 2000 mg |
- METFORMIN AND RADIOLOGICAL CONTRAST
- Iodinated contrast
- The iodinated contrast given during many radiological procedures (ex. CAT scans) can be toxic to the kidneys
- Since metformin is primarily excreted by the kidneys, there is concern that iodinated contrast could damage the kidneys causing metformin levels to rise and lactic acidosis to ensue
- Metformin's prescribing information gives recommendations for patients who are to receive iodinated contrast while taking metformin. The American College of Radiology has also issued guidelines. Both sets of recommendations are detailed below.
Manufacturer recommendations for metformin and iodinated contrast |
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Discontinue metformin at the time of or before an iodinated contrast imaging procedure in the following patients:
|
ACR recommendations for metformin and iodinated contrast |
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Category I
|
Category II
|
Category III
|
Comorbidities include:
|
- MRI studies with gadolinium
- Metformin does not have to be stopped prior to or after MRI studies with gadolinium (at usual doses) [24]
- LONG-TERM SAFETY
- Metformin is one of the most widely prescribed medications in the world
- It has been prescribed in Europe since the 1950s and in the U.S. since 1995
- It has proven to be safe and effective
- DOSING
- BIBLIOGRAPHY
- 1 - Metformin PI
- 2 - PMID 16034881
- 3 - PMID 21403054
- 4 - PMID 9742977
- 5 - PMID 21471135
- 6 - PMID 20091537
- 7 - PMID 20091537
- 8 - PMID 18945255
- 9 - PMID 17253544
- 10 - PMID 21105109
- 11 - PMID 21521847
- 12 - PMID 16567811
- 13 - Fortamet PI
- 14 - PMID 20393934
- 15 - PMID 12384131
- 16 - PMID 21617112
- 17 - PMID 18945920
- 18 - PMID 20488910
- 19 - PMID 17030830
- 20 - PMID 17823192
- 21 - PMID 12651978
- 22 - PMID 11472468
- 23 - PMID 11045142
- 24 - American College of Radiology manual on contrast media v7 2010
- 25 - PMID 18955635
- 26 - PMID 16186261
- 27 - PMID 25317875
- 28 - PMID 26900641 - DPP B12 study
- 29 - ADA Standards of Medical Care in Diabetes (2019)
- 30 - PMID 24151290 - Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline (2013)
- 31 - PMID 30992795 - The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance From the American Association for the Study of Liver Diseases, Hepatology (2018)
- 32 - PMID 32801130 - Risk of Anemia With Metformin Use in Type 2 Diabetes: A MASTERMIND Study, Diabetes Care (2020)