Systematic Review: Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes Mellitus

The prevalence and morbidity associated with type 2 diabetes mellitus continue to increase in the United States and elsewhere (1, 2). Several studies of the treatment of type 2 diabetes suggest that improved glycemic control reduces microvascular risks (37). In contrast, the effects of treatment on macrovascular risk are more controversial (3, 4, 8, 9), and the comparative effects of oral diabetes agents on clinical outcomes are even less certain. As newer oral agents, such as thiazolidinediones and meglitinides, are increasingly marketed, clinicians and patients must decide whether they prefer these generally more costly medications over older agents, such as sulfonylureas and metformin. Systematic reviews and meta-analyses of oral diabetes agents have attempted to fill this gap (1019), but few have compared all agents with one another (18, 19). The few investigations that have compared all oral agents focused narrowly on individual outcomes, such as hemoglobin A1c level (18) or serum lipid levels (19). No systematic review has summarized all available head-to-head comparisons with regard to the full range of intermediate end points (including hemoglobin A1c level, lipid levels, and body weight) and other clinically important outcomes, such as adverse effects and macrovascular risks. Therefore, the Agency for Healthcare Research and Quality commissioned a systematic review to summarize the comparative benefits and harms of oral agents that are used to treat type 2 diabetes. Methods Data Sources and Selection We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from inception to January 2006 for original articles. We also searched these databases until November 2005 for systematic reviews. We reviewed reference lists of related reviews and original data articles, hand-searched recent issues of 15 medical journals, invited experts to provide additional citations, reviewed selected medications from the U.S. Food and Drug Administration (FDA) Web site, and reviewed unpublished data from several pharmaceutical companies and public registries of clinical trials. Our search strategy for the bibliographic databases combined terms for type 2 diabetes and oral diabetes agents and was limited to English-language articles and studies in adults. The search for systematic reviews was similar but included terms for study design as well. We selected studies that included original data on adults with type 2 diabetes and assessed benefits or harms of FDA-approved oral diabetes agents that were available in the United States as of January 2006. To facilitate head-to-head comparisons of drug classes, we included drugs not on the U.S. market if members of their class were in use and had not been banned (voglibose, gliclazide, and glibenclamide). We also included studies of combinations of therapies that are commonly used, such as combinations of metformin, second-generation sulfonylureas, and thiazolidinediones. We excluded studies that evaluated combinations of 3 oral diabetes agents, and we also excluded first-generation sulfonylureas, because few clinicians prescribe these medications. We sought studies that reported on major clinical outcomes (for example, all-cause mortality, cardiovascular morbidity and mortality, and microvascular outcomes) or any of the following intermediate end points or adverse events: hemoglobin A1c level, body weight, systolic and diastolic blood pressure, high-density lipoprotein (HDL) cholesterol level, low-density lipoprotein (LDL) cholesterol level, triglyceride level, hypoglycemia, gastrointestinal problems, congestive heart failure, edema or hypervolemia, lactic acidosis, elevated aminotransferase levels, liver failure, anemia, leukopenia, thrombocytopenia, allergic reactions requiring hospitalization or causing death, and other serious adverse events. For intermediate end points, we included only randomized, controlled trials, which were abundant. For major clinical end points and adverse events, we considered observational studies as well as trials, because fewer randomized trials assessed these end points. We excluded studies that followed patients for less than 3 months (the conventional threshold for determining effects on hemoglobin A1c) or had fewer than 40 patients. Figure 1 shows the search and selection process, and the full technical report (available at effectivehealthcare.ahrq.gov/repFiles/OralFullReport.pdf) provides a more detailed description of the study methods (20). Figure 1. Study flow diagram. Data Extraction and Quality Assessment One investigator used standardized forms to abstract data about study samples, interventions, designs, and outcomes, and a second investigator confirmed the abstracted data. Two investigators independently applied the Jadad scale to assess some aspects of the quality of randomized trials (21). We considered observational studies and nonrandomized trials to provide weaker evidence than randomized trials, and we did not use a standardized scoring system to assess their quality (22). We used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) working group definitions to grade the overall strength of the evidence as high, moderate, low, very low, or insufficient (23). Data Synthesis and Analysis We first performed a qualitative synthesis based on scientific rigor and type of end point. In general, we described the UKPDS (United Kingdom Prospective Diabetes Study) separately, because this large randomized, controlled trial differed from other trials in design, end points, and duration. When data were sufficient (that is, obtained from at least 2 randomized, controlled trials) and studies were relatively homogeneous in sample characteristics, study duration, and drug dose, we conducted meta-analyses for the following intermediate outcomes and adverse effects: hemoglobin A1c level, weight, systolic blood pressure, LDL cholesterol level, HDL cholesterol level, triglyceride level, and hypoglycemia. For trials with more than 1 dosing group, we chose the dose that was most comparable with other trials and most clinically relevant. We combined drugs into drug classes only when similar results were found across individual drugs. We could not perform formal meta-analyses for microvascular or macrovascular outcomes, mortality, and adverse events other than hypoglycemia because of methodological diversity among the trials or insufficient numbers of trials. We used a random-effects model with the DerSimonian and Laird formula to derive pooled estimates (posttreatment weighted mean differences for intermediate outcomes and posttreatment absolute risk differences for adverse events) (24). We tested for heterogeneity among the trials by using a chi-square test with set to 0.10 or less and an I 2 statistic greater than 50% (25). If heterogeneity was found, we conducted meta-regression analyses by using study-level characteristics of double-blinding, study duration, and dose ratio (calculated as the dose given in the study divided by the maximum approved dose of drug). The full report contains data on indirect comparisons, in which 2 interventions are compared through their relative effect against a common comparator (20). We tested for publication bias by using the tests of Begg and Mazumdar (26) and Egger and colleagues (27). All statistical analyses were done by using STATA Intercooled, version 8.0 (Stata, College Station, Texas). Role of the Funding Source The Agency for Healthcare Research and Quality suggested the initial questions and provided copyright release for this manuscript but did not participate in the literature search, data analysis, or interpretation of the results. Results Comparative Effectiveness of Oral Diabetes Agents in Reducing the Risk for Microvascular and Macrovascular Outcomes and Death We found no definitive evidence about the comparative effectiveness of oral diabetes agents on all-cause mortality, cardiovascular mortality or morbidity, peripheral arterial disease, neuropathy, retinopathy, or nephropathy (Table 1). For each head-to-head comparison on specific outcomes, the number of randomized trials (3 trials) and the absolute number of events were small (20). The few observational studies were limited in quantity, consistency, and adjustment for key confounders. Table 1. Evidence of the Comparative Effectiveness of Oral Diabetes Medications on Mortality, Microvascular and Macrovascular Outcomes, and Intermediate End Points Since our review, 2 high-profile comparative randomized trials with about 4 years of follow-up have been published, providing data on cardiovascular outcomes (28, 29). In ADOPT (A Diabetes Outcome Progression Trial) (28), the incidence of cardiovascular events was lower with glyburide than with rosiglitazone or metformin (1.8%, 3.4%, and 3.2%, respectively; P< 0.05). This effect was mainly driven by fewer congestive heart failure events and a lower rate of nonfatal myocardial infarction events in the glyburide group. Loss to follow-up was high (40%) and was disproportionate among the groups and therefore may account for some differences among groups. The interim analysis of the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes) study reported that rosiglitazone plus metformin or a sulfonylurea compared with metformin plus a sulfonylurea had a hazard ratio of 1.08 (95% CI, 0.89 to 1.31) for the primary end point of hospitalization or death from cardiovascular disease (29). The hazard ratio was driven by more congestive heart failure in the rosiglitazone plus metformin or sulfonylurea group than in the control group of metformin plus sulfonylurea (absolute risk, 1.7% vs. 0.8%, respectively). In KaplanMeier curves, the risk for hospitalization or death from myocardial infarction was slightly lower in the control group than in the rosiglitazone group, but the difference was not statistically significant. A limitation of