Effects of intensive glucose lowering in type 2 diabetes

The Action to Control Cardiovascular Risk in Diabetes Study Group.
N Engl J Med.2008;358(24):2545-2559. 

A relationship exists between glycated hemoglobin (A1c) and cardiovascular (CV) risk in patients with type 2 diabetes. Targeting A1c levels with therapeutic treatments may reduce this risk, but there is insufficient data regarding the risks and benefits using current available therapies. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study investigated the effects of intensive glucose-lowering therapy on CV event reduction among patients with type 2 diabetes and either risk factors for, or established, cardiovascular disease.  

Participants (n=10,251) had a median A1c level of 8.1%, and 35% had experienced a previous CV event. They were randomized to one of two treatment arms: intensive therapy, targeting a normal (non-diabetic range) A1c level <6.0% (n=5,128), or standard therapy, targeting an A1c level of 7.0% to 7.9% (n=5,123). Participants received glucose-lowering therapy for A1c goal attainment. Use of all FDA-approved diabetes agents, including metformin (a biguanide), insulin, sulfonylureas, and thiazolidinediones, was allowed. Participants were also randomized into two large substudies: one to test more aggressive vs standard antihypertensive therapy (n=4,473) and the other to test simvastatin monotherapy vs simvastatin plus fenofibrate to control lipid levels (n=5,518). The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from CV causes. Secondary outcomes included death from any cause.  


  • Median A1c levels were 6.4% (interquartile range [IQR], 6.1–7.0) in the intensive-therapy group and 7.5% (IQR, 7.0–8.1) in the standard-therapy group at Year 1. These levels were maintained throughout follow-up.
  • The primary outcome occurred among 352 patients in the intensive-therapy group vs 371 in the standard-therapy group (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.78–1.04; P=0.16).
  • Secondary outcomes occurred among 257 patients in the intensive-therapy group versus 203 patients in the standard-therapy group (HR, 1.22; 95% CI, 1.01–1.46; P=0.04). Between-group differences in the rate of death appeared to begin after 1 year of treatment and continued throughout follow-up.
  • Subjects in the intensive-therapy group had higher rates of hypoglycemia requiring medical assistance (10.5% vs 3.5% standard therapy; P<0.001), weight gain >10 kg (27.8% vs 14.1%; P<0.001), and fluid retention (70.1% vs 66.8%; P<0.001).
  • In February 2008, the intensive-therapy regimen was discontinued after a mean of 3.5 years of follow-up due to increased total mortality. Patients in the intensive-therapy arm were subsequently transferred to the standard-therapy group. The hypertension and lipid arms of ACCORD are projected to conclude in mid-2009.

Intensive therapy targeting normal A1c levels for 3.5 years caused an increase in mortality and no significant reductions in the rate of major CV events.  



September 2012 

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Last Modified: 1/9/2013