ArticlesEffect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial
Introduction
Epidemiological studies of type 2 diabetes have shown that high blood glucose concentrations, as established by measurement of haemoglobin A1c (HbA1c) concentration, are associated with an increased risk of diabetic retinopathy, nephropathy, and neuropathy.1, 2, 3, 4, 5, 6 Results of several clinical trials aimed at reducing HbA1c concentrations have shown that intensive glycaemic control in patients with type 2 diabetes is associated with a reduction in microvascular complications (mostly in albuminuria).7, 8, 9, 10
The glycaemia arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial11 was an investigation of the effects on cardiovascular events of intensive versus standard glycaemia control therapy for hyperglycaemia in a large population with type 2 diabetes.12 Besides the primary composite cardiovascular endpoint, the ACCORD trial had predefined secondary endpoints to assess the effect of intensive glycaemia therapy on incidence and progression of retinopathy, nephropathy, and neuropathy.
ACCORD targeted near-normal glycaemia in people with longstanding type 2 diabetes (mean 10 years) and cardiovascular disease or high cardiovascular risk. The intensive therapy aimed to reduce HbA1c values to less than 6·0%, whereas the standard therapy sought to keep values between 7·0% and 7·9%, with a mean of 7·5%.11 As reported,11 HbA1c concentrations achieved with the intensive therapy were much lower than those achieved in UKPDS7 and VADT,13 and were similar to those in the ADVANCE trial,9 which reported results from people with a similar duration of diabetes as in ACCORD. HbA1c concentrations in the standard treatment group in ACCORD were lower than those achieved in UKPDS and VADT, and were similar to those reported in ADVANCE. For participants with surveillance for one or more microvascular outcomes, the intensive glycaemia control was stopped in February, 2008, after a median of 3·7 years (IQR 2·7–4·3) of follow-up because of an increase in all-cause mortality.14 However, these participants continued in the trial with the standard therapy for the planned remainder of the median 5·0 years (4·2–5·7) of follow-up to June, 2009.
Here, we report results of predefined secondary microvascular outcomes at transition of patients from intensive to standard therapy, and at the end of the full duration of the trial. The effect of glycaemia control strategies on diabetic retinopathy including fundus photography in a subset of patients is the protocol-defined main microvascular endpoint in ACCORD, and is published separately as the ACCORD-EYE study.15
Section snippets
Study design and participants
We recruited volunteers who had type 2 diabetes mellitus, HbA1c concentrations of 7·5% or more, and were aged 40–79 years with history of cardiovascular disease or 55–79 years with anatomical evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or at least two risk factors for cardiovascular disease (dyslipidaemia, hypertension, being a smoker, or obesity). Exclusion criteria included frequent or recent serious hypoglycaemic events, unwillingness to monitor
Results
10 251 participants were assigned to therapy. 1174 participants were randomly assigned in the vanguard phase with an additional 9077 randomised during the main trial. Figure 2 shows the process of screening and randomisation. Participants had a median age of 62 years (IQR 57–67), and type 2 diabetes for around 10 years. Table 2, Table 3 show continuous and categorical baseline participant characteristics by glycaemia intervention group assignment. When the ACCORD intensive glycaemia control was
Discussion
We recorded no significant effect of intensive glycaemia therapy on the two prespecified composite microvascular outcomes—1) advanced renal or eye complications, or 2) these two outcomes or peripheral neuropathy.
Microvascular complications including nephropathy, retinopathy, and neuropathy are an important source of morbidity in patients with type 2 diabetes. Analysis of available epidemiological evidence suggests that hyperglycaemia is an important contributor to development and progression of
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