Elsevier

The Lancet

Volume 376, Issue 9739, 7–13 August 2010, Pages 419-430
The Lancet

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

https://doi.org/10.1016/S0140-6736(10)60576-4Get rights and content

Summary

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 HbA1c concentrations (>7·5%), and cardiovascular disease (or ≥2 cardiovascular risk factors) were randomly assigned by central randomisation to intensive (target haemoglobin A1c [HbA1c] 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 μmol/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. Six 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.

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

References (30)

  • Y Ohkubo et al.

    Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study

    Diabetes Res Clin Pract

    (1995)
  • R Klein et al.

    The Wisconsin epidemiologic study of diabetic retinopathy

    Arch Ophthalmol

    (1984)
  • IM Stratton et al.

    UKPDS50: risk factors for incidence and progression of retinopathy in type II diabetes over 6 years from diagnosis

    Diabetologia

    (2001)
  • DJ Ballard et al.

    Epidemiology of persistent proteinuria in type II diabetes mellitus. Population-based study in Rochester, Minnesota

    Diabetes

    (1988)
  • X. Urinary albumin excretion over 3 years in diet-treated type 2, (non-insulin-dependent) diabetic patients, and association with hypertension, hyperglycaemia and hypertriglyceridaemia

    Diabetologia

    (1993)
  • AI Adler et al.

    Risk factors for diabetic peripheral sensory neuropathy. Results of the Seattle prospective diabetic foot study

    Diabetes Care

    (1997)
  • IM Stratton et al.

    Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study

    BMJ

    (2000)
  • Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

    Lancet

    (1998)
  • Intensive blood glucose and vascular outcomes in patients with type 2 diabetes

    N Engl J Med

    (2008)
  • T Moritz et al.

    Veterans affairs diabetes trial-corrections

    N Eng J Med

    (2009)
  • HC Gerstein et al.

    Glycemia treatment strategies in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial

    Am J Cardiol

    (2007)
  • JB Buse et al.

    Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods

    Am J Cardiol

    (2007)
  • W Duckworth et al.

    Glucose control and vascular complications in veterans with type 2 diabetes

    N Engl J Med

    (2009)
  • HC Gerstein et al.

    Effects of intensive glucose lowering in type 2 diabetes

    N Engl J Med

    (2008)
  • Chew EY, Ambrosius WT, Davis MD, et al. Effects of medical therapies on retinopathy progression in Type 2 diabetes. N...
  • Cited by (0)

    Members listed at end of paper

    View full text