Glucose-lowering treatment of type 2 diabetes. Part II--Glucose-lowering drugs after metformin: a choice based largely on adverse effects.

Metformin alone is the glucose-lowering drug of first choice for patients with type 2 diabetes. None of the other glucose-lowering drugs available in 2014 have any proven efficacy in preventing diabetes complications. How important are adverse effects in the choice of glucose-lowering alternatives to metformin for patients with type 2 diabetes? What about their effects on HbA1c levels? To answer these questions, we conducted a review of the literature using the standard Prescrire methodology. Sulphonylureas have been in use for many years. These drugs lower HbA1c levels by an average of 1.5% when used alone, and by 0.8% to 1% when added to metformin. All sulphonylureas can cause dose-related hypoglycaemia. Available data do not rule out a tangible increase or decrease in cardiovascular mortality among patients treated with sulphonylureas. Comparative data suggest that the combination of metformin + sulphonylurea increases overall mortality. Human insulins have also been in use for many years. A daily injection of long-acting insulin, added to on-going oral glucose-lowering therapy, lowers HbA1c by 0.7% to 2.5% on average but causes weight gain and increases the risk of hypoglycaemia. It cannot be ruled out that insulin may increase the risk of certain cancers. Alpha-glucosidase inhibitors have a weak glucose-lowering effect. The average decline in HbA1c is about 0.7%, which is not sufficient to offset the gastrointestinal disorders caused by these drugs. The glucose-lowering effect of repaglinide is similar to that of sulphonylureas. Repaglinide can cause hypoglycaemia, particularly when co-administered with inhibitors of some cytochrome P450 isoenzymes. Glitazones have a clearly unfavourable harm-benefit balance, potentially causing fractures, heart failure, other cardiovascular events, bladder cancer. Gliptins lower HbA1c by 0.7% on average but can provoke anaphylactic reactions, Stevens-Johnson syndrome, and infections. Saxagliptin may increase the risk of fractures and heart failure. The long-term adverse effects of gliptins are poorly documented and may include an increased risk of pancreatic cancer. These risks are not offset by any proven clinical efficacy; patients should therefore not be exposed to these drugs. When they are combined with metformin, two injectable GLP-1 analogues, exenatide and liraglutide, have a glucose-lowering potency similar to one or two daily insulin injections. They have the advantage of inducing weight loss, without increasing the risk of hypoglycaemia. Gastrointestinal adverse effects such as nausea are frequent at the beginning of treatment. A possible increase in the risk of pancreatitis, pancreatic cancer and thyroid cancer has not been ruled out. Gliflozins reduce HbA1c by 0.6-0.7% on average. These drugs are already known to have a burdensome adverse effect profile despite their relatively recent market introduction. There are also safety signals concerning serious long-term adverse effects. Patients should not be exposed to these risks.