ACP Guideline Addresses Pharmacotherapy of Type 2 Diabetes

Laurie Barclay, MD

February 6, 2012 — Metformin should be the initial drug for most patients with type 2 diabetes refractory to lifestyle modifications, with a second drug added if needed, according to a new clinical practice guideline from the American College of Physicians (ACP), published online February 6 in the Annals of Internal Medicine.

The new recommendations are based on a systematic evidence review and comparative efficacy analysis of FDA-approved oral medications for the treatment of type 2 diabetes (metformin, sulfonylureas, meglitinides, thiazolidinediones, DPP-4 inhibitors, and GLP-1 receptor antagonists).

"We found that most diabetes medications reduced blood sugar levels to a similar degree," lead author Amir Qaseem, MD, FACP, PhD, MHA, director of clinical policy at the ACP, said in a news release. "However, metformin is more effective compared to other type 2 diabetes drugs in reducing blood sugar levels when used alone and in combination with other drugs. In addition, metformin reduces body weight and improves cholesterol profiles."

The guideline authors searched MEDLINE (updated through December 2010), EMBASE, and the Cochrane Central Register of Controlled Trials for trials that compared diabetes drugs head-to-head and were published in English-language journals between 1966 and April 2010. The researchers assessed clinical outcomes including death from any cause, cardiovascular disease and death, cerebrovascular morbidity, neuropathy, nephropathy, and retinopathy. The ACP clinical practice guidelines grading system allowed grading of the recommendations and underlying evidence.

Specific recommendations in the new guidelines are:

• Recommendation 1: When diet, exercise, weight loss, and other lifestyle modifications have not adequately improved hyperglycemia, clinicians should add oral pharmacologic therapy in patients with type 2 diabetes (grade: strong recommendation, high-quality evidence).
• Recommendation 2: For most patients with type 2 diabetes, initial pharmacologic therapy should be monotherapy with metformin (grade: strong recommendation; high-quality evidence).
• Recommendation 3: When lifestyle modifications and monotherapy with metformin fail to control hyperglycemia, clinicians should add a second drug to metformin (grade: strong recommendation; high-quality evidence).

Overall adverse effects were fewer with metformin than with sulfonylureas, and high-quality evidence showed that risk for dangerous levels of hypoglycemia was higher with sulfonylureas than with metformin or thiazolidinediones. In addition, the combination of metformin plus sulfonylureas is associated with 6-fold greater risk for hypoglycemia than the combination of metformin plus thiazolidinediones. When used as monotherapy, the risk for hypoglycemia with metformin and thiazolidinediones was similar, based on moderate-quality evidence.

Evidence was insufficient regarding any efficacy difference among various medications across subgroups of adults based on age, sex, or race.

The ACP recommended generic metformin because of its better efficacy and fewer adverse effects than most other available medications, lack of associated weight gain, and lower cost.

"It was difficult to draw conclusions about the comparative effectiveness of type 2 diabetes medications on all-cause and cardiovascular mortality, cardiovascular and cerebrovascular morbidity, and microvascular outcomes because of low-quality or insufficient evidence," the guideline authors write.

"Metformin is associated with an increased risk for gastrointestinal side effects. Thiazolidinediones are associated with an increased risk for heart failure, and both rosiglitazone and pioglitazone are contraindicated in patients with serious heart failure."

The ACP also has produced a summary of the guideline for patients.

Financial support for the development of this guideline came exclusively from the ACP operating budget. One author has disclosed that he has been a consultant for ECRI; has received grants from the Agency for Healthcare Research and Quality, the US Department of Veterans Affairs, and the Centers for Medicare and Medicaid Services; and is an employee of the US Department of Veterans Affairs. The other authors have disclosed no relevant financial relationships.

Ann Intern Med. 2012;156:218-231.

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