Which diabetes drugs cause hypoglycemia?

Diabetes is typically characterized by too high blood glucose, but hypoglycemia is the result of too low blood glucose. So how does hypoglycemia happen in diabetics?

One word: insulin.

Most of the time, if a diabetic person has hypoglycemia, the problem was caused by too high of an insulin dose or not enough food around the time of an insulin dose. It's much easier to make this mistake than you would think: when the body starts to get low on glucose, the first thing the brain usually does is release extra epinephrine, causing the tell-tale tremors, palpitations, and feels like anxiety. But if the brain doesn't release as much epinephrine as it should, then the person will have little way of knowing there's a problem, particularly if they've been desensitized to hypoglycemia.

As mentioned above, among diabetes drugs, insulin is responsible for far more incidents of hypoglycemia than any other drug.

Metformin, the front-line treatment for most diabetics, does not typically cause hypoglycemia.

In contrast, sulfonylureas (including Amaryl and Gliclazide) were shown to cause hypoglycemia almost three times as often as metformin.

Thiazolidinediones (including Actos and Avandia) do not appear to cause hypoglycemia on their own, but they do cause it when used with other antidiabetic drugs.

Glucagon-like peptide–1 (GLP-1) agonists (including Byetta and Victoza) do not appear to increase the risk of hypoglycemia.

Dipeptidyl peptidase-4 (DPP-4) inhibitors (including Januvia and Onglyza) can cause severe hypoglycemia when used with sulfonylureas, but they do not seem to cause it on their own.

All in all, the science suggests that, other than insulin, sulfonylureas are the only diabetes drug likely to cause hypoglycemia. This makes sense, given that they work by directly stimulating the production of insulin in the pancreas. In contrast, the other drugs are a bit more removed by the process.