Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial

Abstract

Background: Hyperglycaemia is associated with increased risk of cardiovascular complications in people with type 2 diabetes. We investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in people with type 2 diabetes.

Methods: ACCORD was a parallel-group, randomised trial done in 77 clinical sites in North America. People with diabetes, high HbA(1c) concentrations (>7.5%), and cardiovascular disease (or >or=2 cardiovascular risk factors) were randomly assigned by central randomisation to intensive (target haemoglobin A(1c) [HbA(1c)] of <6.0%) or standard (7.0-7.9%) glycaemic therapy. In this analysis, the prespecified composite outcomes were: dialysis or renal transplantation, high serum creatinine (>291.7 micromol/L), or retinal photocoagulation or vitrectomy (first composite outcome); or peripheral neuropathy plus the first composite outcome (second composite outcome). 13 prespecified secondary measures of kidney, eye, and peripheral nerve function were also assessed. Investigators and participants were aware of treatment group assignment. Analysis was done for all patients who were assessed for microvascular outcomes, on the basis of treatment assignment, irrespective of treatments received or compliance to therapies. ACCORD is registered with ClinicalTrials.gov, number NCT00000620.

Findings: 10 251 patients were randomly assigned, 5128 to the intensive glycaemia control group and 5123 to standard group. Intensive therapy was stopped before study end because of higher mortality in that group, and patients were transitioned to standard therapy. At transition, the first composite outcome was recorded in 443 of 5107 patients in the intensive group versus 444 of 5108 in the standard group (HR 1.00, 95% CI 0.88-1.14; p=1.00), and the second composite outcome was noted in 1591 of 5107 versus 1659 of 5108 (0.96, 0.89-1.02; p=0.19). Results were similar at study end (first composite outcome 556 of 5119 vs 586 of 5115 [HR 0.95, 95% CI 0.85-1.07, p=0.42]; and second 1956 of 5119 vs 2046 of 5115, respectively [0.95, 0.89-1.01, p=0.12]). Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Seven secondary measures at study end favoured intensive therapy (p<0.05).

Interpretation: Microvascular benefits of intensive therapy should be weighed against the increase in total and cardiovascular disease-related mortality, increased weight gain, and high risk for severe hypoglycaemia.

Funding: US National Institutes of Health; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; National Eye Institute; Centers for Disease Control and Prevention; and General Clinical Research Centers.

Figure A1

Kaplan-Meier curves for the microvascular secondary composite outcome (development of renal failure or retinal photocoagulation or vitrectomy to treat retinopathy, or score >2.0 on MNSI) by glycemia arm. Panel A: data until transition of intensive glycemia arm to standard therapy. Panel B: all data through end of study. Hazard ratios adjusted for baseline history of clinical cardiovascular disease and second trial treatment arm assignment.

Figure A2

Kaplan-Meier curves for microvascular outcome Neph-1 (development of microalbuminuria) by glycemia arm. Panel A: data until transition of intensive glycemia arm to standard therapy. Panel B: all data through end of study. Hazard ratios adjusted for baseline history of clinical cardiovascular disease and second trial treatment arm assignment.

Figure A3

Kaplan-Meier curves for microvascular outcome Neph-2 (development of macroalbuminuria) by glycemia arm. Panel A: data until transition of intensive glycemia arm to standard therapy. Panel B: all data through end of study. Hazard ratios adjusted for baseline history of clinical cardiovascular disease and second trial treatment arm assignment.

Figure A4

Kaplan-Meier curves for microvascular outcome Neph-3 (development of renal failure, renal transplant, or serum creatinine > 291.7 micomol/L) by glycemia arm. Panel A: data until transition of intensive glycemia arm to standard therapy. Panel B: all data through end of study. Hazard ratios adjusted for baseline history of clinical cardiovascular disease and second trial treatment arm assignment.

Figure A5

Kaplan-Meier curves for microvascular outcome Neph-4 (doubling of serum creatinine or more than 20 mL/min/1.73m² decrease in estimated GFR) by glycemia arm. Panel A: data until transition of intensive glycemia arm to standard therapy. Panel B: all data through end of study. Hazard ratios adjusted for baseline history of clinical cardiovascular disease and second trial treatment arm assignment.

Figure A6

Kaplan-Meier curves for microvascular renal composite outcome Neph-5 (development of any of three conditions Neph-2, Neph-3, or Neph-4) by glycemia arm. Panel A: data until transition of intensive glycemia arm to standard therapy. Panel B: all data through end of study. Hazard ratios adjusted for baseline history of clinical cardiovascular disease and second trial treatment arm assignment.

Figure A7

Kaplan-Meier curves for microvascular outcome Eye-1 (retinal photocoagulation or vitrectomy to treat retinopathy) by glycemia arm. Panel A: data until transition of intensive glycemia arm to standard therapy. Panel B: all data through end of study. Hazard ratios adjusted for baseline history of clinical cardiovascular disease and second trial treatment arm assignment.

Figure A8

Kaplan-Meier curves for microvascular outcome Eye-2 (surgery for cataract extraction) by glycemia arm. Panel A: data until transition of intensive glycemia arm to standard therapy. Panel B: all data through end of study. Hazard ratios adjusted for baseline history of clinical cardiovascular disease and second trial treatment arm assignment.

Figure A9

Kaplan-Meier curves for microvascular outcome Eye-3 (three line change in visual acuity) by glycemia arm. Panel A: data until transition of intensive glycemia arm to standard therapy. Panel B: all data through end of study. Hazard ratios adjusted for baseline history of clinical cardiovascular disease and second trial treatment arm assignment.

Figure A10

Kaplan-Meier curves for microvascular outcome Eye-4 (severe vision loss) by glycemia arm. Panel A: data until transition of intensive glycemia arm to standard therapy. Panel B: all data through end of study. Hazard ratios adjusted for baseline history of clinical cardiovascular disease and second trial treatment arm assignment.

Figure A11

Kaplan-Meier curves for microvascular outcome Neuro-1 (score of >2.0 on the Michigan Neuropathy Screening Instrument) by glycemia arm. Panel A: data until transition of intensive glycemia arm to standard therapy. Panel B: all data through end of study. Hazard ratios adjusted for baseline history of clinical cardiovascular disease and second trial treatment arm assignment.

Figure A12

Kaplan-Meier curves for microvascular outcome Neuro-2 (loss of vibratory sensation) by glycemia arm. Panel A: data until transition of intensive glycemia arm to standard therapy. Panel B: all data through end of study. Hazard ratios adjusted for baseline history of clinical cardiovascular disease and second trial treatment arm assignment.

Figure A13

Kaplan-Meier curves for microvascular outcome Neuro-3 (loss of ankle jerk during Jendrassic maneuver) by glycemia arm. Panel A: data until transition of intensive glycemia arm to standard therapy. Panel B: all data through end of study. Hazard ratios adjusted for baseline history of clinical cardiovascular disease and second trial treatment arm assignment.

Figure A14

Kaplan-Meier curves for microvascular outcome Neuro-4 (loss light-touch sensation) by glycemia arm. Panel A: data until transition of intensive glycemia arm to standard therapy. Panel B: all data through end of study. Hazard ratios adjusted for baseline history of clinical cardiovascular disease and second trial treatment arm assignment.

Figure 1

Distribution of randomisation assignment of participants to the ACCORD glycemia, blood pressure and lipid trials.

Figure 2

CONSORT diagram depicting flow of participants through screening and randomisation in ACCORD trial.

Figure 3

Kaplan-Meier curves for the microvascular primary composite outcome (development of renal failure or retinal photocoagulation or vitrectomy to treat retinopathy) by glycemia arm. Panel A: data until transition of intensive glycemia arm to standard therapy. Panel B: all data through end of study. Hazard ratios adjusted for baseline history of clinical cardiovascular disease and second trial treatment arm assignment.

Figure 4

Hazard ratios comparing intensive to standard glycemia arm assignment for each microvascular outcome utilizing data until transition of intensive glycemia arm to standard therapy. Hazard ratios adjusted for baseline clinical cardiovascular disease history and second trial treatment arm assignment. Horizontal bars represent 95% confidence intervals.

Figure 5

Hazard ratios comparing intensive to standard glycemia arm assignment for each microvascular outcome utilizing data through end of study. Hazard ratios adjusted for baseline history of clinical cardiovascular disease and second trial treatment arm assignment. Horizontal bars represent 95% confidence intervals.

Figure 6

Mean serum creatinine levels ± two standard errors of the mean by glycemia treatment arm and follow-up visit.