Biguanides, particularly metformin (Glucophage), are insulin sensitizers that enhance glucose uptake, thereby reducing insulin resistance. Unlike sulfonylureas, metformin doesn't prompt insulin secretion, which helps to curb hypoglycemia risk. Metformin is beneficial in treating conditions like polycystic ovary syndrome due to its insulin-resistance reduction capability. The drug's primary action involves curtailing hepatic gluconeogenesis, a significant contributor to high blood glucose levels in type 2 diabetes. Furthermore, it slows intestinal sugar absorption and boosts peripheral glucose usage, potentially leading to weight loss through appetite suppression.

Metformin is the recommended initial treatment for type 2 diabetes by the American Diabetes Association (ADA), either as a standalone medication or combined with other agents or insulin. However, combining it with insulin may lead to hypoglycemia, requiring dose adjustments. Metformin's adverse effects, predominantly gastrointestinal, like nausea, vomiting, and diarrhea, can be mitigated by gradual dosage increase and mealtime administration. It's contraindicated in cases of renal dysfunction, acute myocardial infarction, sepsis, and situations potentially leading to acute renal failure. Vitamin B12 deficiency is a potential long-term side effect.

Another class of insulin sensitizers, Thiazolidinediones (TZDs), including pioglitazone (Actos) and rosiglitazone (Avandia), don't stimulate insulin release from pancreatic β cells, averting hyperinsulinemia risk. TZDs function as peroxisome proliferator-activated receptor-γ (PPARγ) agonists, enhancing insulin sensitivity in various tissues. They can be used alone or combined with other glucose-lowering agents or insulin. The ADA recommends pioglitazone as a secondary or tertiary agent for type 2 diabetes treatment, while rosiglitazone usage is limited due to potential cardiovascular risks. Both drugs are well absorbed orally, bind to serum albumin, and undergo extensive metabolism. TZDs can cause weight gain and osteopenia and increase bladder cancer risk, particularly with pioglitazone. They should be avoided in patients with severe heart failure.