Short answer: Glipizide extended-release (Glucotrol XL) is a sulfonylurea taken once a day with breakfast; metformin is a biguanide taken with meals.12 Low blood sugar is the main glipizide risk. Diarrhea and nausea are the most common metformin side effects, and metformin carries a boxed warning for lactic acidosis. Neither label reports a trial of one against the other.
| Glipizide XL (Glucotrol XL) | Metformin | |
|---|---|---|
| Drug class | Sulfonylurea1 | Biguanide2 |
| Approved for | Blood sugar control in adults with type 2 diabetes1 | Blood sugar control in adults and children 10 and older with type 2 diabetes2 |
| How taken | Once daily with breakfast or the first main meal; swallowed whole1 | With meals, in divided doses; swallowed whole2 |
| Starting dose | 5 mg once daily; 2.5 mg at higher risk of low blood sugar1 | Adults: 500 mg twice a day or 850 mg once a day2 |
| Maximum | 20 mg once daily1 | 2,550 mg a day for adults; 2,000 mg for children2 |
| Low blood sugar | 3.4% of 580 people in trials; 2.6% stopped because of it1 | Rare on its own, per the Patient Information; more likely with insulin or a sulfonylurea2 |
| Most common side effects | Dizziness 6.8% vs 5.8% on placebo; diarrhea 5.4% vs 0%1 | Diarrhea 53% vs 12% on placebo; nausea or vomiting 26% vs 8%2 |
| Missed dose | No rule in the label1 | Take the next dose as prescribed; no extra dose the next day2 |
| Boxed warning | None1 | WARNING: LACTIC ACIDOSIS2 |
The Glucotrol XL label warns that all sulfonylureas can cause severe low blood sugar, more so with other diabetes medicines, in older or frail people, or with too little food, hard exercise or alcohol. It also lists red blood cell breakdown in G6PD deficiency, the class warning on heart-related deaths seen with tolbutamide in the older UGDP study, and bowel blockage with severe gut narrowing, because the tablet shell does not dissolve. People allergic to sulfonamide derivatives do not take it.1
The metformin label's main warning is lactic acidosis. Kidney function is checked before starting and at least yearly; metformin is not used with an eGFR below 30, is not started at 30 to 45, and is paused around some contrast scans and while food and fluids are restricted for surgery. It can also lower vitamin B12, which dropped below normal in about 7% in 29-week trials.2 These numbers come from separate trials with different people, lengths and methods, so they are not a head-to-head comparison.
This page uses the Glucotrol XL label; it says people on immediate-release glipizide may switch to it once daily at the nearest equivalent total daily dose.1 Which, if either, fits is for your prescriber. More detail: Glucotrol XL side effects, metformin side effects, the Glucotrol XL and metformin dosing schedules, the metformin missed-dose page, the glipizide and metformin guides, and Glimepiride vs glipizide: how do the two sulfonylureas differ?.