ArticlesEffect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials
Introduction
Type 2 diabetes mellitus is a well established risk factor for cardiovascular disease. Several observational studies have shown a positive correlation between measures of glycaemic control and both cardiovascular outcomes and microvascular disease, independent of risk factors known to cluster with diabetes.1, 2, 3 Consequently, randomised controlled trials have aimed to assess whether more intensive control of glucose reduces long-term clinical events and lengthens lifetime compared with standard treatment. By contrast with the substantial benefits to microvascular outcomes,4, 5 individually these trials have failed to show consistent beneficial effects on cardiovascular events.5, 6, 7, 8
Such inconsistent evidence has resulted in the American Heart Association, the American College of Cardiology, and the American Diabetes Association providing a conservative class IIb recommendation with level of evidence A9 for the benefit of glycaemic control on cardiovascular disease. However, individually these trials might have been underpowered to show clinical benefit—especially if event rates were lower than were expected because of improved control of risk factors; duration of treatment was shorter than was needed to show a clinical benefit;10 or differences in glycaemic control between patient groups were too small to show any benefit. To address such uncertainties, we quantitatively assessed whether intensive glucose-lowering treatment in individuals with type 2 diabetes mellitus resulted in a reduction of cardiovascular events and all-cause mortality. We present data from a meta-analysis of randomised controlled clinical trials, which aimed to assess the effect of differential glycaemic control on cardiovascular outcomes.
Section snippets
Data sources
We searched Medline, Cochrane Central, and EmBase for articles published in English from January, 1970, to January, 2009, with terms related to diabetes and vascular outcomes (eg, “cardiovascular diseases”, “diabetes mellitus”, “glucose”, and “HbA1c”). We restricted the search to randomised controlled trials. This search provided 2439 articles, which were further screened for inclusion from titles, abstracts, or full texts, or a combination of these. We supplemented the electronic search from
Results
Table 1 shows the study design, baseline demographic characteristics of participants, duration of follow-up, and mean HbA1c concentration in the five randomised controlled trials. The criteria for diagnosis of type 2 diabetes and eligibility for the studies are shown on webappendix p 2. 33 040 participants were enrolled from predominantly western populations (table 1). UKPDS4, 7 enrolled individuals within 1 year after diagnosis, whereas the remaining four studies enrolled participants with
Discussion
This meta-analysis of five relevant randomised controlled trials has shown consistently that intensive glucose-lowering treatment has cardiovascular benefit compared with standard treatment for individuals with type 2 diabetes. During about 5 years of treatment, reduction of HbA1c concentration by 0·9% resulted in a significant 17% reduction in events of non-fatal myocardial infarction, a significant 15% reduction in events of coronary heart disease, and a non-significant 7% reduction in events
References (31)
- et al.
Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial
Lancet
(2005) - et al.
Effects of pioglitazone on major adverse cardiovascular events in high-risk patients with type 2 diabetes: results from PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive 10)
Am Heart J
(2008) - et al.
Design of the cooperative study on glycemic control and complications in diabetes mellitus type 2: Veterans Affairs Diabetes Trial
J Diabetes Complications
(2003) - et al.
Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus: meta-analysis of randomized trials
Am Heart J
(2006) - et al.
Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial
Lancet
(1998) - et al.
Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European Prospective Investigation of Cancer and Nutrition (EPIC-Norfolk)
BMJ
(2001) - et al.
Predictors of 10-year macrovascular and overall mortality in patients with NIDDM: the Munich General Practitioner Project
Diabetologia
(1996) - 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)- et al.
Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes
N Engl J Med
(2008)
The University Group Diabetes Program. A statistician looks at the mortality results
JAMA
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)
Lancet
Effects of intensive glucose lowering in type 2 diabetes
N Engl J Med
Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association
Circulation
10-year follow-up of intensive glucose control in type 2 diabetes
N Engl J Med
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These authors contributed equally