Comparing Medications for Type 2 Diabetes: What's Known

Charles P. Vega, MD


August 30, 2011

In This Article

Current Trial

Researchers examined articles published in major medical databases prior to April 2010. All research focused on nonpregnant adults aged 18 or older. Researchers did not include alpha-glucosidase inhibitors due to their record of poor efficacy and high rate of gastrointestinal side effects. In addition, colesevelam was not reviewed because it was too new to the market.

Research lasting less than 3 months or including fewer than 40 patients was excluded from the analysis. The authors focused on outcomes of individual medication classes beyond glycemic control, and there was also a thorough evaluation of adverse events.

The literature search garnered 140 randomized controlled trials and 26 observational studies. Most of the studies were done in Europe and the United States. Only 25 studies examined diabetes therapy for 2 years or more, 95 articles were supported by pharmaceutical companies, and most trials excluded older adults. Moreover, participants in the collective research did not reflect the racial and ethnic diversity of adults with diabetes in the United States.

Unfortunately, there were little data comparing different medications regarding important clinical outcomes. However, some studies suggested that all-cause mortality and cardiovascular mortality were lower with metformin compared with sulfonylureas. The risk for bias in these studies was moderate. One clinical trial involving a total of 4447 patients examined cardiovascular events as a primary outcome in comparing different regimens of oral medications for diabetes.[5] The combination of rosiglitazone with metformin or a sulfonylurea was noninferior to the combination of metformin plus a sulfonylurea for cardiovascular death, myocardial infarction, or stroke. However, heart failure promoting hospitalization or death was more common during treatment with rosiglitazone.

In 2 trials, pioglitazone reduced the urinary albumin-creatinine ratio more than metformin. However, there was no quality research assessing differential effects of diabetes medications on neuropathy or retinopathy.

Most trials compared different medication regimens based on their efficacy in glycemic control. In general, all forms of monotherapy reduced A1c values by approximately 1%. Metformin appeared more effective than dipeptidyl peptidase-4 (DPP-4) inhibitors in this outcome.

One study of 4360 patients that had a median follow-up duration of 4 years found that the rates of monotherapy failure with rosiglitazone, metformin, and glyburide were 15%, 21%, and 34%, respectively.[6] However, glyburide therapy was associated with a lower risk for cardiovascular events compared with rosiglitazone in this particular trial.

Combination therapy improved A1c levels compared with monotherapy by approximately 1%. In general, there was little to recommend one combination of diabetes medications over another based on efficacy in glycemic control alone. There was weak evidence that metformin plus a glucagon-like peptide-1 (GLP-1) agonist reduced A1c levels more than metformin plus a DPP-4 inhibitor.

Given the lack of data regarding efficacy against major clinical events and similar effectiveness in reducing A1c levels among different diabetes medications, secondary effects of these drugs are particularly important. In the current review, sulfonylureas were found to increase body weight, but not to the degree that thiazolidinediones did. GLP-1 agonists reduced weight more than sulfonylureas, and adding a DPP-4 inhibitor to metformin had no significant effect on body weight.

Metformin modestly reduces low-density lipoprotein (LDL) cholesterol and triglyceride levels, while mildly increasing levels of high-density lipoprotein (HDL) cholesterol. In contrast, the thiazolidinediones can increase LDL cholesterol levels. However, pioglitazone also may raise HDL cholesterol levels.

In terms of safety, sulfonylureas were found to increase the risk for hypoglycemia by a factor of 4 compared with metformin alone. The risk for hypoglycemia associated with sulfonylurea therapy increased even more when these drugs were used in combination with metformin. Thiazolidinediones were noted to promote higher rates of fracture, particularly in the limbs, compared with metformin.

In pooled analyses of randomized controlled trials, thiazolidinediones did not promote significantly higher risks for heart failure compared with metformin or sulfonylureas. However, there was a general trend in all included research suggesting a higher risk for heart failure with thiazolidinediones. Gastrointestinal side effects were quite common during treatment with metformin, with an incidence of approximately 30% overall.


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