Systematic Review: Glucose Control and Cardiovascular Disease in Type 2 Diabetes

Context The relative benefits and harms of intensive versus conventional glucose control for type 2 diabetes are controversial. Contribution This review of 5 large trials found that, compared with conventional control, intensive glucose control reduced the risk for cardiovascular disease (mostly nonfatal myocardial infarction) but not for cardiovascular death or all-cause mortality, and increased risk for severe hypoglycemia. Trial design, achieved control, and findings were heterogeneous: Early trials suggested possible decreased risk for death with intensive control, whereas some more recent trials suggested possible increased risk for death with more stringent control. Caution The investigators did not evaluate costs. They pooled summary findings from trials rather than individual data from patients. The Editors The prevalence of type 2 diabetes is increasing globally (13). Epidemiologic evidence indicates that diabetes is a major risk factor for cardiovascular disease (CVD), and recent data suggest that the CVD burden attributable to diabetes is on the rise (47). Clinical trials have shown that intensive glucose control reduces the risk for microvascular complications among patients with type 2 diabetes, but its effect on CVD, including coronary heart disease (CHD), stroke, and peripheral arterial disease, is uncertain (810). Early data from the UKPDS (United Kingdom Prospective Diabetes Study) 34 suggested a protective effect of improved glucose control on CVD, CVD deaths, and all-cause mortality (11). However, within the past year, 3 large randomized, controlled trials have reported conflicting results (1214). Although ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) and VADT (Veterans Affairs Diabetes Trial) found no effect of intensive glucose control on major cardiovascular events (13, 14), ACCORD (Action to Control Cardiovascular Disease in Diabetes) identified an increased risk for death from cardiovascular causes and total mortality associated with intensive glucose control (12). On the basis of these results, a recent article by Montori and colleagues suggested that additional research is needed to confirm or refute the importance of tight glucose control (15). Thus, recommendations for health care providers regarding optimal hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes remain unclear. Because of the early termination of ACCORD and fewer events than anticipated in ADVANCE and VADT, there is real concern that these studies were underpowered to capture the true effects of intensive glucose control on CVD risk (1214). Therefore, we conducted a meta-analysis of randomized, controlled trials to examine the effects of intensive glucose control on CVD among patients with type 2 diabetes. Furthermore, we examined the separate effects of intensive glucose control on all-cause mortality, CVD mortality, CHD, congestive heart failure (CHF), stroke, and peripheral artery disease. In an effort to explain incongruities among trial results, we conducted subgroup analyses and examined the occurrence of severe hypoglycemia. Methods Data Sources and Searches We developed and followed a standard protocol for all steps of the review. Investigators searched the MEDLINE database (January 1950 through April 2009) using the Medical Subject Headings cardiovascular diseases; coronary disease; stroke; peripheral vascular diseases; hypoglycemic agents; and diabetes mellitus, type 2, as well as the keywords coronary heart disease, glucose control, and glycemic control. We restricted the search to randomized, controlled trials conducted among human adults (age 19 years), with no language restrictions. We also manually searched references cited in the published original reports and contacted experts in the field. Study Selection Two investigators independently reviewed the contents of 341 abstracts or full-text manuscripts identified through the literature search to determine whether they met the eligibility criteria. Studies were eligible for inclusion if 1) the study was a randomized, controlled trial; 2) the study compared intensive glucose control with conventional treatment, with a priori specification of glycemic goals for the intensive and conventional glucose control groups; 3) clinical CVD was the primary end point; 4) the study sample size was 500 patients or more; and 5) the study participants had type 2 diabetes mellitus. Reviewers resolved disagreements about study inclusion or exclusion by consensus and by referring to the original reports. Data Extraction and Quality Assessment Study investigators independently abstracted data in duplicate using a standardized data collection form. Reviewers did not contact authors to request additional information. Reviewers abstracted characteristics of each trial and its participants. Reviewers critically appraised methodological characteristics of trials, such as randomization procedures, blinded assessment of outcomes, adjudication procedures for outcomes, and follow-up rates, but did not use a scoring system to formally rate study quality of the individual trials (Appendix Table 1). Appendix Table 1. Assessment of Methodological Characteristics Reviewers recorded the following as the main outcomes of interest: number of clinical CVD, CHD, stroke, and CHF events, along with cardiovascular deaths and all-cause mortality, for the intensive and conventional glucose control groups. Reviewers also recorded single end points, including nonfatal myocardial infarction, fatal myocardial infarction, nonfatal stroke, fatal stroke, and peripheral artery disease. In addition, reviewers recorded the number of severe hypoglycemic events for each trial group. Because definitions of certain composite outcomes varied between trials, each outcome is defined for each trial in Appendix Table 2. Appendix Table 2. Definitions of Composite Outcomes for Each Trial Data Synthesis and Analysis We examined the relationship between intensive glucose control and risk for all study outcomes using relative risk and risk difference measures. We calculated the relative risks in each trial on the basis of the number of events in the intensive glucose control and conventional treatment groups and used these estimates for pooling analyses. To estimate the risk difference, we first calculated the annual absolute risk for an event in participants in each trial group by dividing the number of events in each trial group by the corresponding number of person-years (estimated as median treatment time number of participants in the trial group). We then multiplied the annual absolute risk by 5 to estimate the 5-year risk among participants in each trial group. We calculated the risk difference for each trial by subtracting the 5-year risk in the conventional glucose control group from the 5-year risk in the intensive glucose control group. We logarithmically transformed the relative risks and risk differences and their corresponding standard errors to stabilize the variance and normalize their distribution. We pooled relative risks and risk differences using both fixed-effects and DerSimonian and Laird random-effects models (16). We used inverse variance weighting to calculate fixed- and random-effects summary estimates. We assessed heterogeneity formally by using the Dersimonian and Laird Q test, considering any P value less than 0.100 as evidence of heterogeneity, and by examining the I 2 quantity. Although fixed- and random-effects models yielded similar findings, we detected between-study heterogeneity for several study outcomes (severe hypoglycemia, cardiovascular deaths, all-cause mortality, and fatal myocardial infarction). Because of this heterogeneity and trial differences in median diabetes duration of participants, achieved HbA1c levels, and therapeutic regimens, we present results from the random-effects models. We conducted a prestated subgroup analysis to examine the effects of intensive glucose control on all study outcomes. We then compared the relative risks for CVD, CHD, CHF, stroke, cardiovascular deaths, all-cause mortality, and severe hypoglycemia, as well as fatal and nonfatal myocardial infarction, fatal and nonfatal stroke, and peripheral artery disease between the early UKPDS trials (8, 11) and the 3 more recent ACCORD, ADVANCE, and VADT trials (1214). We conducted all analyses by using Stata software, version 9.2 (Stata Corp, College Station, Texas). Role of the Funding Source This study was funded in part by a career development award from the National Heart, Lung, and Blood Institute and by an award from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The funding sources played no role in the study design; collection, analysis, and interpretation of the data; writing of the report; or decision to submit the paper for publication. Results Figure 1 depicts the study selection process. We excluded 2 trials, the Kumamoto Study (n = 110) and the Veterans Affairs (VA) Diabetes Feasibility Trial (n = 153), because of small sample sizes (9, 17). The VA Diabetes Feasibility Trial was a pilot study that examined whether intensive glucose control could be effectively sustained in patients with type 2 diabetes and was a precursor to the subsequent VADT. The Kumamoto Study examined the effects of intensive glucose control on microvascular complications of diabetes. The current meta-analysis included a total of 5 trials conducted among 27 802 participants (8, 1114). Table 1 presents the characteristics of the 5 randomized, controlled trials and trial participants. The number of trial participants ranged from 753 to 11 140, while intervention duration ranged from 3.4 to 10.7 years. The UKPDS 33 and 34 recruited participants with newly diagnosed diabetes. Those inclusion criteria differed from those of ADVANCE, ACCORD and VADT, whose participants had an average duration of diabetes ranging