Clinical Evidence Handbook

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Glycemic Control in Type 2 Diabetes (Drug Treatments)

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Am Fam Physician. 2014 May 15;89(10):820-822.

This clinical content conforms to AAFP criteria for continuing medical education (CME). See CME Quiz Questions.

Author disclosure: Guy E.H.M. Rutten has received fees for speaking and unrestricted grants for investigator-initiated studies from Novo Nordisk, Merck, and Sanofi-Aventis. He has also received consultancy fees from Novo Nordisk, Merck, Novartis, Eli Lilly, and Sanofi-Aventis. He is also the coauthor of several reviews referenced in this review. The other authors declare that they have no competing interests.

Diabetes mellitus affects about 6.5% of persons 20 to 79 years of age worldwide. In 2010, an estimated 285 million persons had diabetes, more than 85% of whom had type 2 diabetes.

Type 2 diabetes is often associated with obesity, hypertension, and dyslipidemia, which are all powerful predictors of cardiovascular disease. For that reason, the treatment of type 2 diabetes requires a multifactorial approach, including lifestyle advice, treatment of hypertension, and lowering of lipid levels.

Without adequate blood glucose–lowering treatment, blood glucose levels may rise progressively over time in persons with type 2 diabetes. Microvascular and macrovascular complications may develop.

Metformin reduces A1C levels effectively compared with placebo.

  • The UK Prospective Diabetes Study (UKPDS), a randomized controlled trial, found that metformin may be moderately protective against mortality and cardiovascular morbidity, but further high-quality studies are needed.

  • We found no evidence to suggest that metformin increases the risk of lactic acidosis.

Sulfonylureas reduce A1C levels by 1% compared with placebo, and they may reduce microvascular complications compared with diet alone. They can cause weight gain and hypoglycemia. One review found that the risk of hypoglycemia was highest with glibenclamide compared with other second-generation sulfonylureas.

The effectiveness of the combination of metformin and a sulfonylurea on mortality and morbidity is unknown.

Meglitinides reduce A1C levels by about 0.4% to 0.9% compared with placebo, but robust data are sparse.

Alpha-glucosidase inhibitors reduce A1C levels by about 0.8% compared with placebo. We found no reports of dangerous adverse effects.

Thiazolidinediones reduce A1C levels by 1.0% compared with placebo but may increase the risk of congestive heart failure and bone fractures. Rosiglitazone increases the risk of myocardial infarction.

  • Drug alert: Rosiglitazone has been withdrawn from the market in many countries because the benefits of treatment are no longer thought to outweigh the risks.

Dipeptidyl-peptidase-4 inhibitors reduce A1C levels by about 0.6% to 0.7% compared with placebo. We found no long-term data on effectiveness and safety.

Glucagon-like peptide-1 analogues reduce A1C levels compared with placebo and result in weight loss. We found no long-term data on effectiveness and safety.

Combined oral drug treatment may reduce A1C levels more than monotherapy, but it increases the risk of hypoglycemia.

Insulin improves glycemic control in persons with inadequate control of A1C who are taking oral drug treatment, but it is associated with weight gain and an increased risk of hypoglycemia.

Adding metformin to insulin may reduce A1C levels compared with insulin alone, with less weight gain.

Insulin analogues, short-acting, long-acting, and combined in various regimens, seem no more effective than conventional (human) insulin in reducing A1C levels. However, in persons presenting with recurrent hypoglycemic episodes, long-acting insulin analogues may be preferred over human insulin.

Long-acting insulin analogues seem equally effective at reducing A1C levels.

There is lack of evidence about the effectiveness of various insulin analogue regimens after once-daily, long-acting insulin has failed.

The effectiveness of insulin basal bolus regimens is not well established.

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Clinical Questions

What are the effects of blood glucose–lowering medications in adults with type 2 diabetes?


Metformin (may be moderately protective against mortality and cardiovascular morbidity; reduces A1C levels more effectively than placebo and is comparably effective to sulfonylureas, alpha-glucosidase inhibitors, meglitinides, and insulin)

Sulfonylureas (lower the occurrence of microvascular disease; reduce A1C levels more effectively than placebo, may be marginally more effective than alpha-glucosidase inhibitors, and comparably effective to metformin, meglitinides, TZDs, and dipeptidyl-peptidase-4 inhibitors)

Likely to be beneficial

Alpha-glucosidase inhibitors (acarbose, miglitol only; alpha-glucosidase inhibitors) (reduction of A1C: more effective than placebo, may be comparably effective to metformin, meglitinides, and dipeptidyl-peptidase-4 inhibitors, and may be slightly less effective than sulfonylureas; no evidence for an effect on disease-related mortality or morbidity)

Dipeptidyl-peptidase-4 inhibitors (reduction of A1C: more effective than placebo, may be comparably effective to sulfonylureas and alpha-glucosidase inhibitors, but may be less effective than metformin and TZDs; evidence on long-term effects is lacking)

Glucagon-like peptide-1 analogues (reduction of A1C: more effective than placebo,

EDITOR'S NOTE: Glibenclamide is called glyburide in the United States. Gliclazide is not available in the United States.


SEARCH DATE: February 2010

Adapted with permission from Gorter KJ, Alexander van de Laar FA, Janssen PG, Houweling ST, Rutten GE. Diabetes: glycaemic control in type 2 (drug treatments). Clin Evid Handbook. December 2013:150–151. Please visit for full text and references.

This is one in a series of chapters excerpted from the Clinical Evidence Handbook, published by the BMJ Publishing Group, London, U.K. The medical information contained herein is the most accurate available at the date of publication. More updated and comprehensive information on this topic may be available in future print editions of the Clinical Evidence Handbook, as well as online at (subscription required).

A collection of Clinical Evidence Handbook published in AFP is available at

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