From the Guidelines
Metformin alone does not cause hypoglycemia, as it works by reducing glucose production in the liver and improving insulin sensitivity without directly increasing insulin levels. According to the most recent and highest quality study 1, metformin is effective and safe, and it reduces risks of microvascular complications, cardiovascular events, and death. The study also states that metformin, compared with sulfonylureas, has beneficial effects on A1C, is weight neutral, does not cause hypoglycemia, and reduces cardiovascular mortality.
The mechanism of metformin means that it typically doesn't drive blood sugar below normal ranges when used as monotherapy. However, hypoglycemia can occur in specific situations: when metformin is combined with other diabetes medications (especially insulin or insulin secretagogues), during prolonged fasting, with excessive alcohol consumption, or with intense exercise without adequate caloric intake. Patients with kidney or liver impairment may also be at higher risk since these conditions can affect metformin clearance and glucose regulation.
Key points to consider when taking metformin include:
- Recognizing hypoglycemia symptoms (shakiness, sweating, confusion, dizziness)
- Keeping fast-acting carbohydrates available
- Regular blood glucose monitoring, especially when starting metformin or adjusting dosages
- Being aware of the potential for increased risk of vitamin B12 deficiency and worsening of symptoms of neuropathy with long-term metformin use, as suggested by 1 and 1.
It's essential to follow the guidelines and recommendations provided by the most recent study 1 to minimize the risk of hypoglycemia and other potential side effects associated with metformin use.
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.
Metformin can rarely cause hypoglycemia by itself, but the risk increases when combined with other factors such as:
- Not eating enough
- Drinking alcohol
- Taking other medicines to lower blood sugar 2
From the Research
Metformin and Hypoglycemia
- Metformin is known to ameliorate hyperglycemia by improving peripheral sensitivity to insulin, and reducing gastrointestinal glucose absorption and hepatic glucose production 3.
- Unlike sulfonylureas, metformin does not stimulate insulin secretion, aggravate hyperinsulinemia, or cause hypoglycemia or weight gain when administered as monotherapy 3.
- However, there have been cases reported where metformin has been associated with hypoglycemia, particularly when combined with other medications such as ACE inhibitors and NSAIDs 4.
- A study found that metformin does not usually cause hypoglycemia when administered as monotherapy, but the risk of hypoglycemia may increase when combined with other blood glucose-lowering agents 4.
Comparison with Other Antidiabetic Agents
- A systematic review and meta-analysis found that insulins, DPP-4 inhibitors, GLP-1 analogues, and thiazolidinediones all produced statistically significant reductions in hemoglobin A1c in combination with metformin and a sulphonylurea, but the risk of hypoglycemia varied across treatments 5.
- Another study found that sulfonylureas, when prescribed as the initiating monotherapy for the treatment of type 2 diabetes, are associated with a 4.5-fold increase in the risk of severe hypoglycemia compared to metformin 6.
- A retrospective cohort study found that baseline rates of hypoglycemia varied across initial second-line antidiabetic medication classes, and that DPP-4 inhibitors, SGLT-2 inhibitors, and TZDs were associated with lower adjusted rates of hypoglycemia compared to sulfonylureas 7.
Key Findings
- Metformin is generally considered to be a safe and effective treatment for type 2 diabetes, with a low risk of hypoglycemia when administered as monotherapy 3, 4.
- However, the risk of hypoglycemia may increase when metformin is combined with other blood glucose-lowering agents, such as sulfonylureas, ACE inhibitors, and NSAIDs 4, 5, 6, 7.
- The choice of second-line therapy after metformin should take into account the risk of hypoglycemia and other glycemic outcomes, as well as the individual patient's needs and medical history 7.