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Am Fam Physician. 2007;75(7):1051-1052

Author disclosure: Nothing to disclose.

Clinical Question

What is the most effective oral monotherapy for glycemic control in patients with type 2 diabetes?

Evidence-Based Answer

There is no clearly superior oral agent for glycemic control in patients with type 2 diabetes. (Strength of Recommendation [SOR]: C)

Metformin (Glucophage) has shown additional benefit when compared with other treatments (including insulin) for diabetes-related outcomes and all-cause mortality and should be considered the agent of choice for initial monotherapy, particularly in obese patients. (SOR: A)

Evidence Summary

A systematic review of 63 randomized controlled trials (RCTs) compared A1C reductions among the five classes of oral agents.1 The studies met the following criteria: study period of at least three months, enrollment of at least 10 subjects, and reported A1C reduction. Two groups of trials—monotherapy head-to-head studies (23 trials) and monotherapy versus placebo studies (31 trials)—were compared. A1C reductions were similar among studies with comparable numbers of subjects and lengths of follow-up (Table 11). Head-to-head trials comparing two or more drugs also showed similar effectiveness for reducing A1C.1

The United Kingdom Prospective Diabetes Study included 4,075 newly diagnosed patients with type 2 diabetes who had A1C levels of 7.5 to 10.7 percent.2 After three months of diet therapy, subjects were randomized to four groups: insulin, sulfonylurea, metformin, or continued diet therapy. Only 50 percent of the patients in any group had A1C levels of less than 7 percent after three years, and only 25 percent had levels of less than 7 percent after nine years.2

Glycemic control is not the ultimate goal of diabetes treatment; the focus should be on which medications best reduce morbidity and mortality. A Cochrane review that included 29 trials and 5,259 participants looked at intensive glucose control with metformin.3 Metformin showed greater benefits for all-cause mortality (P = .03) and diabetes-related outcomes (P = .009) when compared with sulfonylurea, placebo, diet, thiazolidinedione, insulin, meglitinides, and glucosidase inhibitors.3

Medication class (number of trials)Study lengthNumber of subjectsRanges of A1C reductions (%)
Sulfonylurea (4)12 weeks to 10 years204 to 3,8670.9 to 2.5
Alpha glucosidase inhibitor (12)16 weeks to 2 years40 to 4950.4 to 1.3
Metformin (7)11 weeks to 10.7 years27 to 7530.8 to 3.0
Meglitinide (4)12 to 24 weeks93 to 7010.6 to 1.7
Thiazolidinedione (4)24 to 26 weeks402 to 9591.1 to 1.6

A systematic review of alpha-glucosidase inhibitors found no clear evidence that they reduce morbidity or mortality.4

Recommendations from Others

The American Diabetes Association recommends that patients with type 2 diabetes maintain an A1C of less than 7 percent. They do not recommend any specific medications for therapy.5

The Institute for Clinical Systems Improvement reports that the single best choice for oral therapy for type 2 diabetes has not been determined.6 The guideline also states that the United Kingdom Prospective Diabetes Study provides strong evidence that metformin in monotherapy may offer advantages for obese patients with type 2 diabetes with respect to morbidity and mortality. The guideline aconsiders sulfonylurea a good choice for monotherapy because it is relatively inexpensive and generally well tolerated.6

Clinical Commentary

Oral therapy for diabetes has long been an issue of “This is how I was trained” for physicians. Early on, sulfonylureas were the only choice. When metformin arrived on the scene in the 1990s, it brought more choice, and with the introduction of thiazolidinediones, meglitinides, and glucosidase inhibitors, the situation is even less clear. Achieving glucose and A1C goals remains one of the aims of diabetic therapy, but the bottom line should be reduction in morbidity and mortality.

Monotherapy with metformin is therefore appealing for several reasons: (1) it is generally well tolerated and its side effects are usually easy to manage; (2) the risk of hypoglycemia is minimal; and (3) it has direct effects on insulin resistance. With evidence of benefit in total morbidity and mortality over other oral antidiabetic agents, metformin seems a good choice for monotherapy when a single agent is effective.

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