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Effect of Intensive Versus Standard Blood Glucose Control in Patients With Type 2 Diabetes Mellitus in Different Regions of the World: Systematic Review and Meta-analysis of Randomized Controlled Trials

Background Regional variation in type 2 diabetes mellitus care may affect outcomes in patients treated with intensive versus standard blood glucose control. We sought to evaluate these differences between North America and the rest of the world. Methods and Results Databases were searched from their inception through December 2013. Randomized controlled trials comparing the effects of intensive therapy with standard therapy for macro- and microvascular complications in adults with type 2 diabetes mellitus were selected. We calculated summary odds ratios (ORs) and 95% CIs with the random-effects model. The analysis included 34 967 patients from 17 randomized controlled trials (7 in North America and 10 in the rest of the world). There were no significant differences between intensive and standard therapy groups for all-cause mortality (OR 1.03, 95% CI 0.93 to 1.13) and cardiovascular mortality (OR 1.09, 95% CI 0.90 to 1.32). For trials conducted in North America, intensive therapy compared with standard glycemic control resulted in significantly higher all-cause mortality (OR 1.21, 95% CI 1.05 to 1.40) and cardiovascular mortality (OR 1.41, 95% CI 1.05 to 1.90) than trials conducted in the rest of the world (all-cause mortality OR 0.93, 95% CI 0.85 to 1.03; interaction P=0.006; cardiovascular mortality OR 0.89, 95% CI, 0.79 to 1.00; interaction P=0.007). Analysis of individual macro- and microvascular outcomes revealed no significant regional differences; however, the risk of severe hypoglycemia was significantly higher in trials of intensive therapy in North America (OR 3.52, 95% CI 3.07 to 4.03) compared with the rest of the world (OR 1.45, 95% CI 0.85 to 2.47; interaction P=0.001). Conclusion Randomization to intensive glycemic control in type 2 diabetes mellitus patients was associated with increases in all-cause mortality, cardiovascular mortality, and severe hypoglycemia in North America compared with the rest of the world. Further investigation into the pathobiology or patient variability underlying these findings is warranted.

I ntensive glycemic control has been suggested as a possible modality of therapy for prevention of cardiovascular (CV) events in patients with type 2 diabetes mellitus (T2DM). 1,2 The American Diabetes Association guidelines recommend a glycated hemoglobin (HbA1c) level of ≤7% as a target for nonpregnant adults with T2DM. 3 Based on the mortality benefit in a subgroup of overweight patients receiving metformin in the UK Prospective Diabetes Study (UKPDS), much attention has been focused on intensive glycemic control for prevention of CV events. 4,5 The benefit of such a strategy, however, has not been replicated in dedicated trials. [6][7][8][9] Intensive control in trials conducted in Europe and the Asia-Pacific region did not reduce (or increase) CV events. 6,7 In contrast, North American trials of intensive control resulted in increased mortality with this strategy. 8,9 Several recent meta-analyses of intensive and standard glycemic control trials did not find any mortality benefit with intensive therapy and reported either limited or no benefit for other macro-and microvascular events 10-14 ; however, there was high heterogeneity among trial results for all-cause and CV mortality, and the reason for these suggested differences in trial results were not fully explained. Previous reports have highlighted regional and race/ethnicity differences in CV risk-factor profiles among patients with T2DM. [15][16][17][18][19][20] Significant regional variations in the efficacy of intensive antiplatelet treatment were recently observed in randomized controlled trials (RCTs) of acute coronary syn-drome. 21,22 Regional variation for major macro-or microvascular disease in patients with T2DM was also seen in 1 RCT. 23 We performed a systematic review and meta-analysis of RCTs to examine regional variation in the efficacy and safety of intensive glycemic control treatment in T2DM patients.

Data Sources and Searches
We systematically searched PubMed, Cochrane Central, Embase, EBSCO, and Web of Science databases since their inception through December 2013, using the following key words: diabetes mellitus, type 2 diabetes, cardiovascular diseases, glucose, HbA1c, and/or glucose control, glycemic  control, tight glucose control, intensive therapy, intensive glucose lowering, intensive blood glucose control, The search was restricted to randomized clinical trials, and we did not apply any language restrictions. Considering the meta-analytic study design, institutional review board approval and informed consent were not required for this project.

Study Selection and Data Extraction
Two authors (P.S. and S.C.) reviewed the identified publications for eligibility and extracted data independently. Eligibility for inclusion was predefined as randomized clinical trials that recruited patients with T2DM who were aged ≥18 years and that assessed the efficacy of intensive blood glucose control versus a standard treatment (placebo or less intensive glycemic control treatment) and reported all-cause or CV mortality data. We excluded trials in which intensive therapy was applied as an acute intervention or in acute care setting.
The primary outcome was all-cause mortality, and secondary outcomes included CV mortality, major macrovascular events (composite major macrovascular outcomes, nonfatal myocardial infarction, and stroke), major microvascular events (composite microvascular outcomes, new or worsening nephropathy, new or worsening retinopathy, neuropathy and peripheral vascular disease), and severe hypoglycemic events. Risk of bias was assessed using the components recommended by the Cochrane Collaboration. 24

Categorization of Included Randomized Trials
Among the included trials, 7 were conducted in North America (NA) 8,9,25-32 and 10 4-7,33-42 were conducted in the rest of the world (ROW), including 5 in Europe 4-6,33-37 and 3 in Asia. [38][39][40][41] All except 1 European trial 34 were multinational or were conducted in Western Europe. Fifteen trials were published in English, 1 was published in Russian, 34 and 1 was published in Chinese. 41 For our primary analysis, we included data based on initial planned follow-up. Three trials had a factorial design. 4 28,29 ; data from these 2 trials were combined. Separate analysis excluding data from these 2 UGDP trials was performed because phenformin and tolbutamide are no longer in use. The UGDP 1982 trial 30 used insulin as intensive therapy; we regarded this as a separate trial from UGDP 1975-1976. Data from the UKPDS 33 and 34 trials were combined. 4,5 In the ROW group, intensive glycemic control was part of a multimodal multifactorial intervention in 3 RCTs, 36,40,41 and there was no predefined difference in glycemic targets in 2 RCTs. 6,35 Four trials reported long-term follow-up data after the initial published report. 25,33,37,39 Data Synthesis and Analyses Analyses were performed according to standard guidelines by intention to treat. 43 Summary odds ratios (ORs) and 95% CIs were calculated with the random-effects model. 44 The random-effects method described by DerSimonian (1986) 44 incorporates an assumption that the different studies are estimating different but related intervention effects. The method is based on the inverse-variance approach and adjusts the study weights according to the extent of variation, or heterogeneity, among the varying intervention effects. Because we included trials with differently sized patient populations, and there were apparent differences in baseline characteristics and intervention strategies, the randomeffects method is more appropriate in this situation. Heterogeneity was assessed with the I 2 statistic, 45 which seeks to determine whether genuine differences underlie the results of the studies (heterogeneity) or whether the variation in findings is compatible with chance alone (homogeneity). We considered I 2 <25% as low heterogeneity and I 2 >75% as high, with a Cochran Q statistic (P≤0.1) considered significant for each outcome. Any potential differential association of intensive therapy in patients from NA and the ROW was then tested using a test for interaction, with P<0.05 considered statistically significant. Publication bias was estimated visually with funnel plots and the weighted regression test of Egger. Additional subgroup analyses categorizing trials conducted in Europe, Western Europe, and Asia were explored. We performed the following sensitivity analyses: excluding studies with a multimodal treatment strategy or multifactorial intervention, excluding the largest trial in both groups (NA and ROW), repeating the analysis with longest available follow-up data of the trials, excluding trials using hypoglycemic agents not currently available, and limiting to trials with low risk of bias. Four trials reported long-term follow-up data after initial published report (ACCORD, 8,25 UKPDS, 4,5 Steno-2, 36,37 Kumamoto 39 ). According to trial protocols, intensive therapy was discontinued after the initial planned follow-up period, and patients in both arms of the trials were followed up without any active intensive intervention. We also conducted metaregression analysis adjusting for potential confounders in our multivariable model, including age, baseline duration of diabetes, baseline proportion with prior CV events, baseline HbA1c, change in HbA1c in the intensive arm, and duration of follow-up. All tests were 2-tailed, with P<0.05 considered significant. We used Review Manager (RevMan), version 5.2.3 (Cochrane Collaboration, 2012) and Stata 11.2 (StataCorp LP) software for analyses.

Characteristics of Included Trials and Patients
The mean duration of diabetes at the entry level was 5.2 years (range 0 to 11.5 years) for the trials conducted in NA and 5.4 years (range 0 to 12.0 years) for the trials conducted in the ROW. Initial (baseline) mean HbA1C level for NA was 10.6% compared with 8.1% for the ROW. Mean duration of follow-up for trials was 5.1 years in NA and 4.1 years in the ROW. The mean decrease in HbA1c level in the intensive group was 2.20% and 0.83% for trials conducted in NA and in the ROW, respectively. Mean age of participants was 57.1 years for trials in NA and 56.6 years in the ROW. The percentage of male patients in the intensive group for trials conducted in NA was 56.9% and 57.4% in the ROW. Baseline mean fasting plasma glucose level for NA was 9.9 mmol/L compared with 8.0 mmol/L for the ROW (Tables 1 through 3).
Major trials in NA mainly followed an intensive strategy by maximizing doses of oral agents followed by an introduction of insulin (VADT); 9 1 major trial allowed for an individualized approach at the discretion of the investigators (ACCORD). 8 Major trials in the ROW started with oral agents, and insulin was added if patients were not at the glycemic target, according to details described in Table 1. In 1 trial, PROactive, 6 the comparison was simply pioglitazone to placebo.

Outcomes
There was no significant differences between the intensive and standard therapy groups for all-cause mortality (OR 1.03, 95% CI 0.93 to 1.13) and CV mortality (OR 1.09, 95% CI 0.90 to 1.32). A significant interaction was found between the effect of intensive versus standard blood glucose therapy and region (NA versus the ROW) for all-cause mortality (interaction P=0.006) and CV mortality (interaction P=0.0072), suggesting that the effect of intensive therapy was not uniform across the world; intensive therapy was associated with harm in NA but not in the ROW.

North America
Analysis of the data from trials conducted in NA (7 trials, total of 13 287 patients) showed that intensive therapy compared with standard treatment resulted in significantly higher all-cause mortality among T2DM patients (summary OR 1.21, 95% CI 1.05 to 1.40, P=0.007, I 2 =0%) (Figure 2). There were 519  (Figure 3). Again, a trend of higher CV mortality with intensive therapy was observed in almost all NA trials (except UGDP 1982 and Veteran Affairs 1995).   Europe, Western Europe, and Asia also did not show an increase in all-cause mortality with intensive therapy (interaction P=0.51) in comparison with the baseline for the ROW. Data pooled from the 10 RCTs conducted outside NA consistently showed no increased risk for CV mortality with intensive compared with standard therapy (OR 0.89, 95% CI 0.79 to 1.00, P=0.05, I 2 =0%) (Figure 3). Our analysis for different regions of the ROW for Europe, Western Europe, and Asia also did not show an increase in CV mortality with intensive therapy (interaction P=0.75).

Regional Differences in Macro-and Microvascular Outcomes
No significant differences were observed for macrovascular outcomes between NA and the ROW including composite major macrovascular outcomes (interaction P=0.72), nonfatal myocardial infarction (interaction P=0.79), and nonfatal stroke (interaction P=0.75). The risk of microvascular complications also was not significantly different between NA and the ROW for composite microvascular outcomes (interaction P=0.06), new or worsening nephropathy (interaction P=0.06), new or worsening retinopathy (interaction P=0.74), neuropathy (interaction P=0.09), and peripheral vascular disease (interaction P=0.82). In contrast, there was a significant difference in severe hypoglycemic events, with higher rates among patients assigned to intensive therapy in NA (OR 3.52, 95% CI 3.07 to 4.03) but not in the ROW (OR 1.45, 95% CI 0.85 to 2.47; interaction P=0.001) ( Tables 4 and 5 and Figures 4 through 8).

Regional Differences With Longer Follow-up
We performed sensitivity analyses including data from the longest reported follow-up in all trials. Inclusion of these additional data extended follow-up by 5.2 years. Data from trials conducted in NA consistently showed significantly higher all-cause mortality (OR 1.18, 95% CI 1.05 to 1.34, P=0.008, I 2 =0%) and CV mortality (OR 1.35, 95% CI 1.02 to 1.79, P=0.04, I 2 =45%) for intensive compared with standard therapy. Regional differences between NA and the ROW were statistically significant, with the longest follow-up data for allcause mortality (interaction P=0.0007). In contrast, analysis of long-term data from the ROW trials revealed significantly lower all-cause mortality with intensive therapy (OR 0.88, 95% CI 0.78 to 0.99, P=0.04, I 2 =27%). The largest trial from the ROW reporting long-term data, UKPDS, did not report separate data for CV mortality ( Figure S1).

Sensitivity Analyses
There was no meaningful difference in the results under various other sensitivity analyses exploring the robustness of the data by region for all-cause mortality ( Figures S2 and S3) and CV mortality ( Figures S4 and S5). Results limited to trials with low risk of bias were also consistent with our primary analysis ( Figure S6). Meta-regression analysis did not detect any confounding factors or effect modifiers in regional variation of results for mortality. No evidence of publication bias was observed ( Figure S7).

Discussion
Previous meta-analyses of RCTs of intensive versus standard blood glucose therapy among T2DM patients demonstrated high between-study heterogeneity for mortality outcomes that was insufficiently explained based on differences in patient population alone. 11,13 In this present analysis, we demonstrated that the heterogeneity in results among 17 global RCTs that studied almost 35 000 T2DM participants may derive from patient or treatment-pattern differences, specifically between NA and other regions of the world. There were no major differences between trials conducted in NA and the ROW for mean age, mean duration of diabetes at the entry level, and mean duration of follow-up. Baseline mean HbA1c levels in trials conducted in NA were higher (10.6%) compared with the ROW (8.07%), and mean reductions in HbA1c level in the intensive group were higher in NA (2.20% in NA and 0.83% in ROW). There was no major difference in the treatment regimens used in the trials conducted in NA and the ROW.
Most of the trials used oral agents as primary therapy, and insulin was added in cases in which target A1c was not achieved by maximal doses of oral agents. The pooled analysis from trials conducted in NA showed significantly higher all-cause mortality, CV mortality, and severe hypoglycemia with versus without intensive glycemic treatment. In contrast, when data were pooled from trials conducted in the ROW, no significant increase in death or severe hypoglycemia was observed between intensive and standard treatment groups. In fact, when analyzed within each region separately, we could not detect any statistical heterogeneity between study results for mortality (I 2 =0% for both NA and ROW), which suggested that once region was considered, outcomes were consistent despite variation in trial size. No significant differences were observed for major macro-and microvascular outcomes with intensive therapy between NA and the ROW. Our findings suggest the possibility that the observed differences in mortality and severe hypoglycemia across trials may be associated with underlying design differences in targeting more intensive glycemic control between trials from NA and the ROW, regional variation in background care, or other factors.

Findings in Context With Prior Reviews and Metaanalyses
Previous meta-analyses of trials conducted globally concluded that there was no definite benefit or harm with intensive therapy for all-cause or CV mortality. [10][11][12][13][14] Significant between-trial differences in outcomes persisted after several adjusted analyses, 11,13 and the reason behind this observed heterogeneity could not be fully explained. 11 Our analyses suggest that the effect of intensive therapy was not uniform worldwide and that potential harm (mortality) with intensive therapy may be specific to North American trials, an observation not seen in trials conducted in other regions of the world.

Regional Variation in Intensive Versus Standard Glycemic Control in Diabetes and Outcomes
It is unclear if the differential mortality effect seen across regions may be related to type, dose, or style of introduction of antidiabetic therapies preferentially used in trials from different parts of the world. 4,5,7,8,15,16 Although there was no standardized definition of intensive therapy, most trials used oral hypoglycemic agents followed by insulin therapy to titrate intensive control and usual therapy in the control arm; however, there was some variation in therapy, as shown in Table 1. Differences in outcomes may also be related to differences in trial design, such as studying patients with established versus new-onset T2DM or studying elderly and younger patients, 2 groups in which efficacy and safety may be more challenging to discern due to competing risks for all-cause mortality. 46 Both ACCORD 8 and VADT 9 included comparatively older patients and participants with long history of diabetes. In addition, the ACCORD and VADT trials specified an HbA1c target of <6.0%, which was much lower than targets in the studies organized in the ROW. In contrast, long-term follow-up data from UKPDS, which included younger participants with new-onset T2DM, reported a mortality benefit with intensive therapy 33 ; however, meta-regression analysis adjusting for age, duration of diabetes, and baseline HbA1c did not reveal any significant attenuation of the effect of intensive therapy on mortality in NA. Nevertheless, because intensive glycemic control did not demonstrate superiority over standard therapy for composite macrovascular events, with mixed results for microvascular events, in either North American RCTs or those conducted in the ROW, current evidence does not support routine intensive glycemic control in patients with T2DM.

Study Limitations
This study has potential limitations inherent to meta-analyses. Retrospective pooling of data from trials conducted in different time periods, with different designs, treatment strategies, targets of glycemic control, patient populations, definitions of outcomes, length of the interventions, and duration of follow-up, are inherently exploratory. Because this study used published data only, we could not explore results using individual patient data. Consequently, our results should be considered hypothesis generating and should be confirmed. We included trials without predefined differences in glycemic targets and trials using multimodal treatment strategies; however, our results remain unchanged when excluding these trials. Diagnostic criteria used for T2DM also varied over time and among trials. Many of the included trials were not double-blinded, and some of them were not designed or powered to assess our predefined primary outcome. We included the ADVANCE trial in the ROW group, although 4% participants were recruited from Canada. There were no participants from the United States, and separate outcomes data for the population from Canada have not been reported. The definition of intensive therapy is not standardized, and different trials used different definitions of intensive therapy and the target of HbA1C. Future studies to assess an effect of treatment intensity should standardize methods to define intensive therapy and the eligible population that maximizes safety while allowing the opportunity to assess for effectiveness.

Conclusion
Intensive therapy compared with standard glycemic control in patients with T2DM was associated with increased all-cause and CV mortality and severe hypoglycemia in North American RCTs but not in those conducted in the ROW. Regional differences in clinical outcomes may be an artifact that resulted from subtle design differences among trials primarily conducted in NA in contrast with the ROW, particularly with regard to the choice of glycemic target and mean age of the populations studied. Nevertheless, a potential differential regional effect on mortality and hypoglycemia merits further investigation into whether our findings may be a reflection of targeting more intense glycemic control, differences in clinical risk profiles, genetic susceptibility, or differences in disease management protocols.

Author Contributions
Chatterjee and Sardar conceived the analysis. Sardar, Udell and Chatterjee acquired, analyzed, interpreted the data and designed the study with guidance and active participation from Bansilal, Mukherjee and Farkouh. Sardar and Chatterjee drafted the initial manuscript and Udell, Bansilal, Farkouh and Mukherjee critically revised the manuscript for important intellectual content. Mukherjee and Farkouh provided study supervision. The authors accept full responsibility for the content of this article.