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

Abstract

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.

Keywords: cardiovascular mortality; diabetes mellitus; intensive glycemic control.

Figure 1

Search strategy and selection of clinical trials included in systematic review and meta-analysis according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist.

Figure 2

All-cause mortality with intensive therapy for type 2 diabetes mellitus for North America and the rest of the world. ACCORD indicates Action to Control Cardiovascular Risk in Diabetes Study; ADVANCE, Action in Diabetes and Vascular disease—PreterAx and DiamicroN MR Controlled Evaluation; M-H, Mantel-Haenszel; PROactive, PROspective pioglitAzone Clinical Trial In macroVascular Events; REMBO, Rational Effective Multicomponent Therapy in the Struggle Against DiaBetes Mellitus in Patients With COngestve Heart Failure; UGDP, University Group Diabetes Program; UKPDS, United Kingdom Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial.

Figure 3

Cardiovascular mortality with intensive therapy for type 2 diabetes mellitus for North America and the rest of the world. ACCORD indicates Action to Control Cardiovascular Risk in Diabetes Study; ADVANCE, Action in Diabetes and Vascular disease—PreterAx and DiamicroN MR Controlled Evaluation; M-H, Mantel-Haenszel; PROactive, PROspective pioglitAzone Clinical Trial In macroVascular Events; REMBO, Rational Effective Multicomponent Therapy in the Struggle Against DiaBetes Mellitus in Patients With COngestve Heart Failure; UGDP, University Group Diabetes Program; UKPDS, United Kingdom Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial.

Figure 4

Macrovascular outcomes in North America: composite macrovascular (A), nonfatal myocardial infarction (B), and nonfatal stroke (C). ACCORD indicates Action to Control Cardiovascular Risk in Diabetes Study; M-H, Mantel-Haenszel; UGDP, University Group Diabetes Program; VADT, Veterans Affairs Diabetes Trial.

Figure 5

Microvascular outcomes in North America: composite microvascular (A), new or worsening nephropathy (B), new or worsening retinopathy (C), neuropathy (D), peripheral vascular disease (E). ACCORD indicates Action to Control Cardiovascular Risk in Diabetes Study; M-H, Mantel-Haenszel; UGDP, University Group Diabetes Program; VADT, Veterans Affairs Diabetes Trial.

Figure 6

Macrovascular outcomes in the rest of the world: composite macrovascular (A), nonfatal myocardial infarction (B), and nonfatal stroke (C). ADVANCE indicates Action in Diabetes and Vascular disease—PreterAx and DiamicroN MR Controlled Evaluation; M-H, Mantel-Haenszel; PROactive, PROspective pioglitAzone Clinical Trial In macroVascular Events; UKPDS, United Kingdom Prospective Diabetes Study.

Figure 7

Microvascular outcomes in rest of the world: composite microvascular (A), new or worsening nephropathy (B), new or worsening retinopathy (C), neuropathy (D), peripheral vascular disease (E). ADVANCE indicates Action in Diabetes and Vascular disease—PreterAx and DiamicroN MR Controlled Evaluation; M-H, Mantel-Haenszel; PROactive, PROspective pioglitAzone Clinical Trial In macroVascular Events; UKPDS, United Kingdom Prospective Diabetes Study.

Figure 8

Risk of hypoglycemia with intensive therapy in North America (A) and the rest of the world (B). ADVANCE indicates Action in Diabetes and Vascular disease—PreterAx and DiamicroN MR Controlled Evaluation; M-H, Mantel-Haenszel; PROactive, PROspective pioglitAzone Clinical Trial In macroVascular Events; UKPDS, United Kingdom Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial.