METFORMIN


















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.













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




Common metformin GI side effects
Side effect % of patients
Diarrhea 10 - 40%
Nausea 7 - 14%
Gas 3 - 6%





















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.



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