From the Guidelines
The starting dose of metformin should be 500 mg once daily with the evening meal, as recommended by the most recent guidelines. This approach helps minimize gastrointestinal side effects, which are common when beginning metformin therapy 1. The dose can be increased to 500 mg twice daily (morning and evening with meals) after one week with good tolerance, and further titration can occur gradually, usually by adding 500 mg weekly as needed and tolerated, up to a maximum of 2000-2500 mg daily divided into two or three doses.
Key Considerations
- Extended-release formulations (Metformin XR) may be started at 500 mg once daily with the evening meal and can be increased more gradually, potentially improving tolerability.
- Taking metformin with food is important as it reduces gastrointestinal side effects.
- For patients with renal impairment (eGFR 30-45 mL/min), a lower starting dose and maximum dose are recommended, while metformin is contraindicated when eGFR falls below 30 mL/min, as stated in the KDIGO 2022 clinical practice guideline for diabetes management in chronic kidney disease 1.
Monitoring and Adjustments
- Monitor eGFR in patients treated with metformin, and increase the frequency of monitoring when the eGFR is <60 ml/min per 1.73 m2.
- Adjust the dose of metformin when the eGFR is <45 ml/min per 1.73 m2, and for some patients when the eGFR is 45–59 ml/min per 1.73 m2, as recommended by the KDIGO 2022 guideline 1.
- Monitor patients for vitamin B12 deficiency when they are treated with metformin for more than 4 years.
Dosing Approach
The suggested approach in dosing metformin based on the level of kidney function is as follows:
| eGFR | ≥ 60 | 45–59 | 30–44 |
|---|---|---|---|
| Subsequent dose adjustment | Continue same dose | Consider dose reduction in certain conditions (see text) | Halve the dose |
| This gradual titration approach maximizes tolerance while allowing the medication to effectively lower blood glucose by reducing hepatic glucose production and improving peripheral insulin sensitivity. |
From the FDA Drug Label
The recommended starting dose of metformin hydrochloride tablets are 500 mg orally twice a day or 850 mg once a day, given with meals. The starting dose of metformin is 500 mg orally twice a day or 850 mg once a day, given with meals 2.
- The dose can be increased in increments of 500 mg weekly or 850 mg every 2 weeks on the basis of glycemic control and tolerability.
- The maximum dose is 2550 mg per day, given in divided doses.
From the Research
Metformin Starting Dose
- The starting dose of metformin is not explicitly stated in the provided studies, but the doses used in the studies can be used as a reference.
- In the study 3, the doses of metformin XR used were 500 mg once daily, 1000 mg once daily, 1500 mg once daily, 2000 mg once daily, and 1000 mg twice daily.
- In the study 4, the maximum dose of metformin XR used was 2000 mg/day.
- In the study 5, the maximum daily dose of metformin recommended for patients with normal kidney function, CKD stage 2, 3a, 3b, and 4 were 2250,1700,1250,1000, and 500 mg, respectively.
- The study 6 mentions that the mean daily doses of metformin-XR and immediate-release metformin were 1258 mg (range 500-2500 mg) and 1282 mg (range 500-2550 mg), respectively.
Dose-Response Relationship
- The study 3 shows a clear dose-response relationship for metformin XR at doses up to 1500 mg, with treatment differences vs. placebo of -0.6% (500 mg once daily), -0.7% (1000 mg once daily), and -1.0% (1500 mg once daily).
- The study 7 also shows that metformin DR administered once-daily in the morning had 28% lower bioavailability compared to either once-daily in the evening or twice-daily, although the glucose-lowering effects were maintained.