What Should You Know Before Starting Metformin?
Before starting metformin, your doctor should check your kidney function (eGFR), vitamin B12 level, and liver function. Take metformin with food to reduce stomach upset. Start at a low dose (500 mg once or twice daily) and gradually increase over 2 to 4 weeks to minimize gastrointestinal side effects. Extended-release formulations cause fewer GI symptoms and can be taken once daily.
Metformin requires kidney function assessment before initiation because it is excreted unchanged by the kidneys. The ADA and FDA recommend that metformin can be started safely with an eGFR of 45 mL/min or higher, used with dose reduction at an eGFR of 30 to 45 mL/min (maximum 1,000 mg per day), and should be discontinued if eGFR falls below 30 mL/min. Kidney function should be rechecked at least annually, and more frequently in patients with declining renal function. Liver function tests should be checked before starting, though metformin is generally safe in mild to moderate liver disease.
Gradual dose escalation is the key to tolerability. A typical titration schedule starts at 500 mg once daily with the evening meal for the first week, increases to 500 mg twice daily (morning and evening) in the second week, and continues increasing by 500 mg per week until the target dose is reached (typically 1,000 to 2,000 mg per day). Extended-release metformin (Glucophage XR, Fortamet, Glumetza) is taken once daily with the evening meal and has a significantly lower rate of GI side effects. If immediate-release metformin causes persistent GI problems, switching to extended-release often resolves the issue.
The FDA allows metformin use at eGFR 30 to 45 mL/min with dose reduction, and recommends discontinuation below eGFR 30 mL/min
How Does Metformin Work to Lower Blood Sugar?
Metformin lowers blood sugar through three primary mechanisms: it reduces glucose production by the liver (its dominant effect), improves insulin sensitivity in muscle and fat tissue, and decreases intestinal glucose absorption. Unlike sulfonylureas or insulin, metformin does not directly stimulate insulin secretion and therefore has very low risk of causing hypoglycemia.
The liver is the primary target of metformin's glucose-lowering action. In type 2 diabetes, the liver produces excess glucose through gluconeogenesis (creating new glucose from non-carbohydrate sources) and glycogenolysis (releasing stored glucose), particularly overnight and between meals. Metformin suppresses hepatic gluconeogenesis by activating AMP-activated protein kinase (AMPK), a cellular energy sensor that inhibits the enzymes responsible for glucose synthesis. This mechanism explains why metformin is particularly effective at reducing fasting blood glucose and addresses a key pathophysiological defect in type 2 diabetes. Studies show that metformin reduces hepatic glucose output by approximately 25 to 30 percent.
Metformin also improves peripheral insulin sensitivity, meaning that muscle and fat cells respond better to the insulin your pancreas produces. This effect helps lower postprandial (after-meal) blood sugar levels. Additionally, metformin appears to reduce the amount of glucose absorbed from food in the intestines and may favorably alter the gut microbiome. The combined effect of these mechanisms typically reduces A1C by 1.0 to 1.5 percentage points. Importantly, metformin's glucose-lowering effect is glucose-dependent: it primarily reduces elevated glucose levels without pushing them below normal, which is why monotherapy with metformin rarely causes hypoglycemia.
Studies show metformin reduces hepatic glucose output by approximately 25 to 30 percent through AMPK activation
What Are the Side Effects of Metformin?
The most common metformin side effects are gastrointestinal: nausea, diarrhea, abdominal cramping, bloating, flatulence, and a metallic taste. These affect 20 to 30 percent of patients, are usually dose-related, and typically improve within 2 to 4 weeks. Serious side effects including lactic acidosis and vitamin B12 deficiency are rare but require monitoring.
Gastrointestinal side effects are the primary reason patients discontinue metformin, with approximately 5 to 10 percent of patients unable to tolerate it at any dose. Starting at a low dose, increasing gradually, and taking with meals significantly reduces GI symptoms. Switching from immediate-release to extended-release formulations reduces GI side effects by approximately 50 percent. If metformin is stopped and restarted, the gradual dose escalation should be repeated. Some gastroenterologists believe that metformin may alter the gut microbiome, which partially explains its GI effects and may also contribute to its therapeutic benefits.
Long-term metformin use decreases vitamin B12 absorption in approximately 5 to 10 percent of patients. Vitamin B12 deficiency can cause peripheral neuropathy that mimics diabetic neuropathy, megaloblastic anemia, and cognitive changes. The ADA recommends periodic vitamin B12 monitoring, especially in patients on long-term metformin, those with anemia, and those with neuropathy symptoms. Supplementation with vitamin B12 resolves the deficiency. Lactic acidosis, the most feared complication, is exceedingly rare (estimated 3 to 10 per 100,000 patient-years) and occurs almost exclusively in patients with contraindications such as severe renal impairment, hepatic failure, or conditions causing tissue hypoxia.
Lactic acidosis from metformin is estimated at 3 to 10 per 100,000 patient-years and almost exclusively occurs with contraindicated conditions
What Is the Correct Dosing for Metformin?
Metformin dosing starts low and increases gradually. Typical starting dose is 500 mg once or twice daily with meals. The dose is increased by 500 mg every 1 to 2 weeks to a target of 1,000 to 2,000 mg per day divided into two doses. Maximum dose is 2,550 mg per day for immediate-release and 2,000 mg per day for extended-release.
The relationship between metformin dose and glucose lowering follows a dose-response curve that plateaus around 2,000 mg per day. Studies show that 1,500 mg daily provides about 80 percent of the maximum glucose-lowering effect, with only modest additional benefit from increasing to 2,000 or 2,550 mg daily. For this reason, many clinicians target 2,000 mg daily as the optimal dose that balances efficacy with tolerability. Metformin should always be taken with food — immediate-release is typically split into two or three doses with meals, while extended-release is taken once daily with the evening meal.
Dose adjustments are needed in certain situations. For patients with moderate kidney impairment (eGFR 30 to 45 mL/min), the maximum dose should be limited to 1,000 mg per day. Metformin should be temporarily discontinued 48 hours before elective procedures using iodinated contrast dye and restarted 48 hours after, once kidney function is confirmed stable. During acute illness, particularly conditions that may affect kidney function or cause dehydration (vomiting, diarrhea, severe infection), consider temporarily holding metformin. Elderly patients may require lower doses due to age-related decline in kidney function.
What Drug Interactions Should You Watch for With Metformin?
Important metformin interactions include alcohol (increases lactic acidosis risk), iodinated contrast dye (temporary discontinuation required), carbonic anhydrase inhibitors like topiramate (increase metformin levels), cimetidine (competes for renal excretion), and certain drugs that affect kidney function. Always inform your healthcare providers about all medications and supplements you take.
Alcohol consumption with metformin requires caution because both alcohol and metformin independently affect lactate metabolism. Excessive alcohol intake increases the risk of lactic acidosis, particularly when combined with metformin. The ADA recommends limiting alcohol to moderate amounts (no more than one drink per day for women, two for men) and avoiding binge drinking. Alcohol can also cause delayed hypoglycemia by impairing hepatic gluconeogenesis, which is particularly relevant when metformin is combined with insulin or sulfonylureas.
Iodinated contrast dye used in CT scans and certain imaging procedures can temporarily impair kidney function, increasing the risk of metformin-associated lactic acidosis. Current guidelines from the American College of Radiology recommend holding metformin at the time of or before the procedure in patients with eGFR below 30 mL/min, and restarting 48 hours later after confirming stable kidney function. For patients with eGFR of 30 to 60 mL/min, the decision depends on the clinical situation. Other interactions include carbonic anhydrase inhibitors (topiramate, zonisamide, acetazolamide) which can increase metformin blood levels and lactic acidosis risk, and cimetidine which competes with metformin for renal tubular secretion.
What Are the Benefits of Metformin Beyond Blood Sugar?
Metformin offers benefits beyond glucose lowering. The UKPDS trial demonstrated a 42 percent reduction in diabetes-related death and 36 percent reduction in all-cause mortality in overweight patients treated with metformin. It is weight-neutral, improves lipid profiles, and has emerging evidence for potential benefits in cancer prevention and aging.
The cardiovascular benefits of metformin were established by UKPDS 34, which showed that metformin therapy in overweight patients with type 2 diabetes significantly reduced the risk of diabetes-related death by 42 percent, all-cause mortality by 36 percent, and myocardial infarction by 39 percent compared to conventional (diet-only) therapy. These benefits were disproportionately greater than what would be expected from glucose lowering alone, suggesting that metformin has direct cardiovascular protective effects. These findings, published in the Lancet in 1998, are the primary reason metformin is recommended as first-line therapy regardless of weight or baseline A1C.
Emerging research suggests metformin may have additional benefits. Observational studies have associated metformin use with reduced cancer incidence (particularly colorectal, breast, and liver cancers), though randomized trial data are limited. Metformin activates AMPK, a key metabolic regulator involved in cellular energy metabolism, autophagy, and inflammation, which may explain its broad biological effects. The TAME (Targeting Aging with Metformin) trial is investigating whether metformin can delay aging-related diseases in non-diabetic older adults. Metformin also modestly improves lipid profiles, reducing total cholesterol and LDL cholesterol by approximately 5 to 10 percent.
UKPDS 34 showed metformin reduced diabetes-related death by 42 percent and all-cause mortality by 36 percent in overweight patients
Can Metformin Be Used for Purposes Other Than Diabetes?
Metformin is used off-label for several conditions. The ADA recommends it for diabetes prevention in high-risk individuals with prediabetes. It is also used for polycystic ovary syndrome (PCOS) to improve insulin resistance and restore ovulation. Research is investigating potential roles in cancer prevention, aging, and nonalcoholic fatty liver disease.
The Diabetes Prevention Program established metformin's role in preventing type 2 diabetes, showing a 31 percent risk reduction in adults with prediabetes. The ADA recommends considering metformin for prediabetes in select populations: adults aged 25 to 59 with BMI over 35, women with prior gestational diabetes, and individuals with rising A1C despite lifestyle modifications. In PCOS, metformin improves insulin resistance, reduces androgen levels, and can restore regular ovulation and menstrual cycles. While not FDA-approved for PCOS, the Endocrine Society includes metformin as a treatment option for metabolic features of PCOS.
Active research areas include metformin for nonalcoholic fatty liver disease (NAFLD), where it may reduce liver fat and inflammation; cancer prevention, where the AMPK activation pathway may inhibit cancer cell growth; and anti-aging, as the landmark TAME trial tests whether metformin can delay age-related diseases in non-diabetic individuals. These applications remain investigational, and metformin should not be taken for these purposes outside of clinical trials or without physician oversight. The low cost (approximately 4 to 10 dollars per month for generic formulations), favorable safety profile, and decades of clinical experience make metformin one of the most thoroughly studied medications in medicine.
The DPP showed metformin reduced the risk of developing type 2 diabetes by 31 percent in adults with prediabetes
When Should Metformin Be Stopped or Changed?
Consider stopping or adjusting metformin if eGFR drops below 30 mL/min, if you develop severe liver disease, before surgery or procedures with contrast dye, during acute illness causing dehydration or kidney stress, or if GI side effects are intolerable despite trying extended-release. Never stop metformin without consulting your doctor.
The most common reason for switching from metformin is inadequate glycemic control rather than side effects. If A1C remains above target after 3 months of maximum tolerated metformin dose, the ADA and EASD consensus recommends adding a second agent. The choice depends on individual factors: GLP-1 receptor agonists (semaglutide, liraglutide) for patients with cardiovascular disease or obesity, SGLT2 inhibitors (empagliflozin, dapagliflozin) for patients with heart failure or chronic kidney disease, and other options including DPP-4 inhibitors, sulfonylureas, thiazolidinediones, or insulin based on cost, hypoglycemia risk, and patient preference.
Metformin should be temporarily discontinued before major surgical procedures, during acute illness with risk of dehydration or kidney injury, and 48 hours before and after procedures using iodinated contrast dye. It should be permanently discontinued if eGFR falls below 30 mL/min, in severe hepatic insufficiency, in active alcohol abuse, or in conditions predisposing to lactic acidosis including sepsis, shock, and severe heart failure. If switching from metformin, the replacement medication should overlap with metformin until the new medication reaches therapeutic levels, unless metformin must be stopped immediately for safety reasons.
The ADA and EASD consensus report recommends adding a second agent if A1C remains above target after 3 months of maximum tolerated metformin
