METFORMIN














Blood sugar effects
  • The effects of metformin on blood sugars were evaluated in the Cochrane meta-analysis detailed below
STUDY
Metformin for Type 2 Diabetes, Cochrane meta-analysis (2005) [PubMed abstract]
  • 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

Lipid effects



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.
UKPDS 34 trial - Metformin vs Diet vs Sulfonylurea or Insulin for Diabetic Outcomes, Lancet (1998) [PubMed abstract]
  • 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
  • The sulfonylurea or insulin group had greater weight gain than the other 2 groups

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









Polycystic ovary disease (PCOS)
Overview
  • 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
Metformin for PCOS, Cochrane meta-analysis (2010) [PubMed abstract]
  • 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



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.
TONIC trial - Metformin vs Vitamin E vs Placebo for NASH, JAMA (2011) [PubMed abstract]
  • 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
  • NAFLD activity score (0 to 8) is based on liver histology with higher scores indicating more severe disease
  • Incidence of adverse events were similar between the 3 groups

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
AASLD recommendations
  • Metformin is not recommended for treating NASH in adult patients
  • Metformin at 500 mg twice-daily offers no benefit to children with NAFLD and thus should not be prescribed to specifically treat NAFLD or NASH. The effect of metformin administered at a higher dose is not known. [31]
StraightHealthcare analysis
  • There are a limited number of good trials that have evaluated the effects of metformin in fatty liver disease
  • The available evidence does not support the use of metformin in patients with fatty liver disease
  • Weight loss appears to convey the most consistent beneficial effect
  • Overweight patients with fatty liver disease should pursue weight loss aggressively



Gastrointestinal side effects
Overview
  • 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)

Lactic acidosis
Overview
  • 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
Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney Function, JAMA Intern Med (2018) [PubMed abstract]
  • Design: Registry cohort study (N=75,413; length = 5.7 years) in diabetics with new prescription for metformin or sulfonylurea
  • Exposure: Metformin
  • 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])
  • 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
Risk of lactic acidosis in trials involving metformin, Cochrane meta-analysis (2010) [PubMed abstract]
  • 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
Metformin in Patients with Contraindications to its Use, European Journal of Internal Medicine (2002) [PubMed abstract]
  • 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
Overview
  • 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
Diabetes Prevention Program study (DPP) secondary analysis, JCEM (2016) [PubMed abstract]
  • 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
Metformin vs Placebo for B12 deficiency, BMJ (2010) [PubMed abstract]
  • 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
  • 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]
  • The metformin package insert states that certain individuals (those with inadequate B12 intake or absorption) may want to check B12 levels every 2 - 3 years
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






Kidney disease
Overview
  • Because of concerns over lactic acidosis (see lactic acidosis above), metformin's prescribing information used to state that it was contraindicated in patients with kidney disease (defined as serum creatinine ≥ 1.5 mg/dl in males, and ≥ 1.4 mg/dl in females)
  • Metformin has been so widely prescribed that it has inevitably been taken by many patients with significant kidney disease. Despite this, an increase in the incidence of lactic acidosis has not been observed
  • In 2016, the FDA loosened its recommendations on prescribing metformin in patients with kidney disease
FDA recommendations for prescribing metformin in kidney disease
  • Obtain a GFR before prescribing metformin and at least annually thereafter. In patients at risk for kidney disease (e.g. elderly), check more frequently.
  • 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
Summary
  • There is no conclusive evidence that metformin increases the risk of lactic acidosis
  • Metformin is so widely prescribed that a significant number of patients with contraindications have received the medication with no increase in lactic acidosis incidence [16]
  • In 2016, the FDA updated metformin's prescribing information to reflect its many years of safe prescribing
  • The FDA's guidelines are now more in line with other professional organizations, including the ones listed below
  • The Canadian Diabetes Association recommends the following:
    • 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
  • The Australian Diabetes Society recommends the following:
    • 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
Overview
  • Advanced liver disease is a risk factor for lactic acidosis
  • Metformin's prescribing information states that it should generally be avoided in patients with clinical or laboratory evidence of liver disease
  • A large number of diabetics have fatty liver disease and elevated liver enzymes
  • Metformin has been used safely in these patients for years
  • There are case reports of lactic acidosis in patients with advanced liver disease (cirrhosis) on metformin, but no large studies have reviewed metformin use in this population [21, 23]
Summary
  • Metformin is safe in most patients with mild-to-moderate liver disease
  • It is not known if metformin is safe in patients with advanced liver disease
  • The manufacturer makes no dosage recommendations in liver disease

Heart failure
Overview
  • 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
Clinical Outcomes in Patients with Heart Failure Taking Metformin, Diabetes Care (2005) [PubMed abstract]
  • 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

Hypoxia

Alcoholism

Advanced age



Metformin

  • Alcohol - alcohol may potentiate the effect of metformin on lactate metabolism. Do 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.
  • 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.




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
Metformin Immediate-release (IR) vs Metformin Extended-release (ER), Diabetes Care (2006) [PubMed abstract]
  • 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





Manufacturer recommendations for metformin and iodinated contrast
Discontinue metformin at the time of or before an iodinated contrast imaging procedure in the following patients:
  • Patients with GFR 30 - 60 ml/min
  • Patients with a history of liver disease
  • Patients with a history of alcoholism
  • Patients with a history of heart failure
  • Patients who will receive intra-arterial iodinated contrast
Recheck GFR 48 hours after procedure and restart metformin if kidney function is stable

ACR recommendations for metformin and iodinated contrast
Category I
  • Patients with normal kidney function (GFR > 60 ml/min) and no known comorbidities (see comorbidities below)
    • Discontinue metformin at the time of the study (not before)
    • Patient should hold metformin for 48 hours after study is done
    • Patient can restart metformin without checking serum creatinine
Category II
  • Patients with normal kidney function (GFR > 60 ml/min) and one or more comorbidities (see comorbidities below)
    • Discontinue metformin at the time of the study (not before)
    • Patient should hold metformin for 48 hours after study is done
    • Patients who are stable and have no other acute risk factors for kidney failure (ex. aminoglycoside therapy, major surgery, acute heart failure, sepsis, multiple radiological procedures, etc.) can restart metformin without checking a serum creatinine
    • Patients who have other acute risk factors for kidney failure should have a serum creatinine checked before restarting metformin
Category III
  • Patients with known kidney disease (GFR < 60 ml/min)
    • Discontinue metformin at the time of the study (not before)
    • Patient should hold metformin for 48 hours after study is done
    • Metformin should not be restarted until kidney function is verified with serum creatinine or GFR [24]
Comorbidities include:
  • Liver disease
  • Alcohol abuse
  • Heart failure
  • Heart attack or peripheral vascular disease
  • Severe infection or sepsis