From the Guidelines
Metformin alone rarely causes hypoglycemia in patients with type 2 diabetes, as it primarily works by reducing glucose production in the liver and improving insulin sensitivity, rather than directly increasing insulin secretion. According to the most recent and highest quality study, metformin is effective and safe, and reduces risks of microvascular complications, cardiovascular events, and death 1.
Mechanism of Action and Hypoglycemia Risk
Metformin's mechanism of action is distinct from other glucose-lowering medications, as it does not directly increase insulin secretion, thereby reducing the risk of hypoglycemia. However, when metformin is combined with other medications such as insulin or sulfonylureas, the risk of hypoglycemia increases.
Risk Factors for Metformin-Associated Hypoglycemia
Risk factors for metformin-associated hypoglycemia include:
- Missed meals
- Excessive alcohol consumption
- Intense exercise
- Renal impairment
- Advanced age
- Drug interactions
Management of Hypoglycemia
If a patient experiences hypoglycemic symptoms while taking metformin, they should consume 15-20 grams of fast-acting carbohydrates (like glucose tablets or juice), wait 15 minutes, and recheck blood glucose. For prevention, patients should maintain regular meal schedules, monitor blood glucose regularly, adjust medication doses appropriately during increased physical activity, and avoid excessive alcohol.
Clinical Considerations
Healthcare providers should consider dose reductions of insulin or sulfonylureas when adding metformin to a treatment regimen, rather than reducing the metformin dose itself, as metformin is not the primary driver of hypoglycemic risk. The principal side effects of metformin are gastrointestinal intolerance, which can be mitigated by gradual dose titration, and the drug is cleared by renal filtration, with very high circulating levels associated with lactic acidosis, although this complication is very rare 1.
Patient-Centered Approach
A patient-centered approach to choosing appropriate pharmacologic treatment of blood glucose should consider efficacy and key patient factors, including important comorbidities, hypoglycemia risk, effects on body weight, side effects, cost, and patient preferences 1. Lifestyle modifications that improve health should be emphasized along with any pharmacologic therapy.
From the FDA Drug Label
Metformin hydrochloride tablets rarely cause hypoglycemia (low blood sugar) by themselves. However, hypoglycemia can happen if you do not eat enough, if you drink alcohol, or if you take other medicines to lower blood sugar. Inform patients that hypoglycemia may occur when metformin hydrochloride tablets is coadministered with oral sulfonylureas and insulin.
Metformin and Hypoglycemia: Metformin hydrochloride tablets rarely cause hypoglycemia by themselves. However, the risk of hypoglycemia increases when metformin is taken with other medicines that lower blood sugar, such as oral sulfonylureas and insulin. Additionally, hypoglycemia can occur if the patient does not eat enough or drinks alcohol. 2 2
- Key Points:
- Metformin rarely causes hypoglycemia on its own
- Hypoglycemia risk increases with concomitant use of other blood sugar-lowering medicines
- Hypoglycemia can also occur with inadequate food intake or alcohol consumption
From the Research
Relationship Between Metformin and Hypoglycemia
- Metformin rarely causes hypoglycemia when used as labeled 3, 4
- Hypoglycemia is rarely associated with accidental or suicidal overdose of metformin, metabolic dysfunction, exercise, missed meal, acute illness, or the initiation of additional antidiabetic medication 3
- Metformin-associated hypoglycemia may occur with no obvious trigger, and the risk could be mitigated by a switch to metformin extended-release (Met XR) 3
- The combination of DPP-4 inhibition and metformin has been shown to be highly tolerable with a very low risk of hypoglycemia 5
Case Reports of Metformin-Associated Hypoglycemia
- A case report of a patient who developed symptomatic hypoglycemia while being treated with a therapeutic dose of metformin 6
- The patient's hypoglycemic episodes resolved within days after discontinuing metformin and the chronic daytime fatigue and somnolence significantly improved 6
Comparison of Metformin with Other Antidiabetic Drugs
- Metformin monotherapy was superior to placebo and comparable to sulfonylureas in reducing fasting plasma glucose and glycosylated hemoglobin levels in patients with non-insulin-dependent diabetes mellitus (NIDDM) uncontrolled by diet 4
- Sulfonylureas and glinides were associated with higher rates of hypoglycemia than with placebo when added to maximal metformin therapy 7
- Glucagon-like peptide-1 analogs, alpha-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors were associated with weight loss or no weight change, and had a lower risk of hypoglycemia compared to sulfonylureas and glinides 7