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Safety and efficacy of oral medications for type 2 diabetes
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The Agency for Healthcare Research and Quality commissioned a systematic review of the safety and efficacy of oral agents for type 2 diabetes. This review summarizes all available head-to-head comparisons with regard to intermediate end points and other clinically relevant outcomes.
The researchers identified 216 studies and two systematic reviews that met their criteria for inclusion. This column serves to highlight some of the findings of this manuscript.
The newest agents (those affecting the incretin system) were not included in the Agency for Healthcare Research and Quality review because of a lack of trials to date. The results were recently published and are assessed in the following section.
Mortality, micro- and macrovascular outcomes
The researchers found little comparative evidence relating to the effectiveness of oral agents on all-cause mortality, cardiovascular morbidity and mortality, peripheral arterial disease, neuropathy, retinopathy or nephropathy. The small number of head-to-head trials on specific outcomes and small number of events did not allow for definitive conclusions. The ADOPT study results became available after this review was completed. In this trial, glyburide was associated with a lower incidence of cardiovascular events (1.8%) compared with metformin (3.2%) and rosiglitazone (3.4%). The patients in the glyburide group had lower rates of congestive heart failure and nonfatal myocardial infarction. Forty percent of patients were lost to follow-up in this study.
An interim analysis of the RECORD trial also was recently published. This analysis revealed a hazard ratio of 1.08 (95% CI, 0.89-1.31) for hospitalization or death from cardiovascular disease for rosiglitazone plus metformin or a sulfonylurea compared with metformin plus a sulfonylurea. There are, however, limitations to this analysis, including a lack of power to detect differences.
Effects on intermediate outcomes
 James R. Taylor |
The researchers identified stronger evidence relating to oral agents’ effect on improving intermediate outcomes. Thiazolidinediones, second-generation sulfonylureas and metformin all reduced HbA1c by about 1% when used as monotherapy. Repaglinide HbA1c reductions were comparable with reductions from sulfonylureas. Combination therapies (metformin plus a TZD or a sulfonylurea, a sulfonylurea plus a TZD) produced additional HbA1c reductions of 0.62% to 1.0% as compared with monotherapy. Based on indirect comparisons, nateglinide and the á-glucosidase inhibitors reduced HbA1c by about 0.5%.
None of the oral medications had a significant effect on blood pressure. The largest difference was a 3 mmHg greater reduction in systolic BP with TZDs as compared with sulfonylureas, although this finding was not statistically significant.
Varying effects on lipids were observed with the oral medications. When compared with sulfonylureas, metformin reduced LDL by 10 mg/dL and triglycerides by about 9 mg/dL, and slightly increased HDL by 0.2 mg/dL. TZDs increased LDL by an average of 10 mg/dL and HDL by 3 mg/dL to-5 mg/dL. Rosiglitazone increased triglycerides by 10 mg/dL and pioglitazone decreased them by an average of 26 mg/dL as compared with metformin. Sulfonylureas had little effect on LDL when compared with acarbose or repaglinide. Acarbose and repaglinide reduced triglycerides by an average of 10 mg/dL to 30 mg/dL when compared with sulfonylureas.
TZDs and repaglinide increased weight by 1 kg to 5 kg when compared with sulfonylureas. Metformin did not cause weight gain when compared with the other agents or with placebo.
Comparative safety
Second-generation sulfonylureas consistently caused more hypoglycemic episodes than did metformin or TZDs. Glyburide demonstrated a slightly higher hypoglycemic risk as compared with other second-generation sulfonylureas. It is also worth noting that hypoglycemia rates were higher (absolute risk differences of 8% to 14%) with combinations that included a sulfonylurea as compared with either metformin or sulfonylurea monotherapy.
The researchers found that metformin produced more gastrointestinal problems than TZDs, second-generation sulfonylureas or repaglinide. Gastrointestinal symptoms with acarbose were similar to those experienced with metformin.
TZDs, second-generation sulfonylureas and metformin all had similar rates of significant elevations of aminotransferase levels. As expected, compared with other oral agents, TZDs increased risk for congestive heart failure (absolute risk difference of 0.7% to 2.2%) and peripheral edema (absolute risk difference of 2% to 21%).
Summary
Unfortunately, as the researchers point out, definitive comparative evidence of oral agents’ effects on macrovascular and microvascular outcomes is lacking. Thus, at this time, we must rely on intermediate markers, adverse effects and cost when selecting oral medications for patients with type 2 diabetes. The researchers wrote that metformin was equal to or better than other agents when considering these issues. This is in agreement with the current American Diabetes Association recommendations. Second-generation sulfonylureas, TZDs, á-glucosidase inhibitors and meglitinides all are reasonable second-line therapies. They all have similar benefit-to-risk profiles, although sulfonylureas offer cost savings. Long-term comparative studies focusing on macrovascular and microvascular outcomes are needed to further clarify treatment decisions.
James R. Taylor, PharmD, CDE, is a Clinical Associate Professor in the Department of Pharmacy Practice at the University of Florida.
For more information:
- Bolen S, Feldman L, Vassy J, et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 2007;147:386-399.