Elsevier

The Lancet

Volume 384, Issue 9958, 29 November–5 December 2014, Pages 1936-1941
The Lancet

Articles
Effects of intensive glycaemic control on ischaemic heart disease: analysis of data from the randomised, controlled ACCORD trial

https://doi.org/10.1016/S0140-6736(14)60611-5Get rights and content

Summary

Background

Hyperglycaemia could substantially increase the risk of ischaemic heart disease in patients with type 2 diabetes. We investigated whether intensive lowering of glucose concentrations affects risk.

Methods

We assessed 10 251 adults aged 40–79 years with established type 2 diabetes, mean glycated haemoglobin A1c (HbA1c) concentration of 67 mmol/mol (8·3%), and risk factors for ischaemic heart disease enrolled in the ACCORD trial. Participants were assigned to intensive or standard therapy (target HbA1c less than 42 or 53–63 mmol/mol [less than 6·0% or 7·0–7·9%], respectively). We assessed fatal or non-fatal myocardial infarction, coronary revascularisation, unstable angina, and new angina during active treatment (mean 3·7 years) plus a further mean 1·2 years. This trial is registered with ClinicalTrials.gov, number NCT00000620.

Findings

Myocardial infarction was less frequent in the intensive than in the standard therapy group during active treatment (hazard ratio [HR] 0·80, 95% CI 0·67–0·96; p=0·015) and overall (0·84, 0·72–0·97; p=0·02). Findings were similar for combined myocardial infarction, coronary revascularisation, and unstable angina (active treatment HR 0·89, 95% CI 0·79–0·99, overall 0·87 0·79–0·96) and for coronary revascularisation alone (0·84, 0·75–0·94) and unstable angina alone (0·81, 0·67–0·97) during full follow-up. With lowest achieved HbA1C concentrations included as a time-dependent covariate, all hazards became non-significant.

Interpretation

Raised glucose concentration is a modifiable risk factor for ischaemic heart disease in middle-aged people with type 2 diabetes and other cardiovascular risk factors.

Funding

National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, National Eye Intitute, and Centers for Disease Control and Prevention.

Introduction

People with type 2 diabetes have a two to three times higher incidence of ischaemic heart disease than people without diabetes, even when other risk factors are taken into account.1, 2 Reasons for this difference are unclear. Diabetes, however, is defined on the basis of raised glucose concentrations.3 As the incidence of ischaemic heart disease increases with increasing glycated haemoglobin A1c (HbA1c) concentrations,4 glucose concentrations might be an important contributing factor. This possibility is supported by the finding that 10 years of intensive compared with standard glucose-lowering therapy reduces the 20-year risk of myocardial infarction by 15% in people with newly diagnosed type 2 diabetes.5 Additionally, a meta-analysis of four large trials showed 15% reduced incidence of total myocardial infarction (95% CI 6–24) during a mean follow-up period of 4·4 years.6

The ACCORD trial was a large North American trial of intense versus standard glucose-lowering therapy in people with established type 2 diabetes and additional risk factors for cardiovascular disease. As previously reported the intervention had a non-significant effect on the primary composite cardiovascular outcome. The incidence of non-fatal myocardial infarction, however, was decreased, whereas the risk of death, particularly from cardiovascular causes, was increased. The effect on cardiovascular mortality remains unexplained. Exploratory analyses have so far identified no relation with severe hypoglycaemia,7 the degree or speed of glucose lowering,8 or other potential factors.9, 10, 11 The reduced rate of ischaemic heart disease in ACCORD was not explored. Here we report the effects of the ACCORD glucose-lowering interventions on indices of ischaemic heart disease, including fatal and non-fatal myocardial infarction and unstable and new-onset angina, and the degree to which change in HbA1c concentration accounts for any of these effects.

Section snippets

Design

The design and results of the ACCORD trial have been published previously.12, 13 Briefly, 10 251 men and women aged 40–79 years with established type 2 diabetes (mean duration 10 years), a mean gHbA1c concentration of 67 mmol/mol (8·3%), and either previous cardiovascular events or risk factors for cardiovascular disease were recruited from 77 clinical centres in the USA and Canada. Participants were randomly allocated to either intensive glucose-lowering therapy, with a target HbA1c

Results

No significant differences were seen between groups for baseline characteristics, or for blood pressure, LDL cholesterol and creatinine concentrations, or use of cardiovascular drugs during follow-up (table). Patients were followed up for a mean of 3·7 years until the date of transition, and a mean of 4·8 years until the end of full follow-up. Greater numbers of all classes of glucose-lowering drugs and combinations had been used in the intensive treatment group than in the standard group at

Discussion

Intensive therapy was associated with significant reductions in the 5-year incidence of ischaemic heart disease (13%), any myocardial infarction (16%), non-fatal myocardial infarction (19%), coronary revascularisation (16%), and unstable angina (19%). These analyses were not prespecified in the ACCORD protocol, but our findings are consistent with those from other large outcomes trials where intensive glucose-lowering therapy reduced the incidence of fatal and non-fatal myocardial infarction in

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