Associations between circulating markers of dysglycaemia and coronary heart disease (CHD) risk in people without diabetes have not been reliably characterised. We report new data from a prospective study and a systematic review to help quantify these associations.
Methods and Findings
Fasting and post-load glucose levels were measured in 18,569 participants in the population-based Reykjavik study, yielding 4,664 incident CHD outcomes during 23.5 y of mean follow-up. In people with no known history of diabetes at the baseline survey, the hazard ratio (HR) for CHD, adjusted for several conventional risk factors, was 2.37 (95% CI 1.79–3.14) in individuals with fasting glucose ≥7.0 mmol/l compared to those <7 mmol/l. At fasting glucose values below 7 mmol/l, adjusted HRs were 0.95 (0.89–1.01) per 1 mmol/l higher fasting glucose and 1.03 (1.01–1.05) per 1 mmol/l higher post-load glucose. HRs for CHD risk were generally modest and nonsignificant across tenths of glucose values below 7 mmol/l. We did a meta-analysis of 26 additional relevant prospective studies identified in a systematic review of Western cohort studies that recorded fasting glucose, post-load glucose, or glycated haemoglobin (HbA1c) levels. In this combined analysis, in which participants with a self-reported history of diabetes and/or fasting blood glucose ≥7 mmol/l at baseline were excluded, relative risks for CHD, adjusted for several conventional risk factors, were: 1.06 (1.00–1.12) per 1 mmol/l higher fasting glucose (23 cohorts, 10,808 cases, 255,171 participants); 1.05 (1.03–1.07) per 1 mmol/l higher post-load glucose (15 cohorts, 12,652 cases, 102,382 participants); and 1.20 (1.10–1.31) per 1% higher HbA1c (9 cohorts, 1639 cases, 49,099 participants).
In the Reykjavik Study and a meta-analysis of other Western prospective studies, fasting and post-load glucose levels were modestly associated with CHD risk in people without diabetes. The meta-analysis suggested a somewhat stronger association between HbA1c levels and CHD risk.
Please see later in the article for the Editors' Summary
Among people diagnosed with type 2 diabetes mellitus (the commonest type of diabetes worldwide), poor management or lack of appropriate treatment can lead to long-term complications resulting from persistently high sugar levels in the blood. The long-term complications of type 2 diabetes are generally divided into two main groups: microvascular problems (such as nerve damage, kidney disease, and eye disorders), and macrovascular disease (such as heart disease, strokes, and peripheral vascular disease). A major goal of diabetes treatment is to keep glucose control as normal as possible through diet, weight control, exercise, and pharmacological treatments. However, it is unclear whether the link between high blood sugar and macrovascular disease (principally heart disease and strokes) also holds for people who have slightly higher than normal blood sugar levels, but in whom this level does not reach the diabetic threshold. Some previous research studies have suggested that a continuous relationship exists between blood sugar level and the risk of heart disease across the spectrum, i.e., below the diabetic threshold as well as above it. If such a relationship were confirmed this might have important implications for the management of high blood sugar levels even among people who would not normally meet the usual definition for a diagnosis of diabetes (the “diabetic threshold”).
Why Was This Study Done?
Studies which examine the risk of serious, but relatively common, outcomes (such as a nonfatal heart attack or fatal heart disease), often suffer from insufficient statistical power: a large number of participants need to be recruited, and followed up over a long time, to find out whether certain factors measured at baseline (e.g., fasting glucose) are indeed associated with a particular outcome (e.g., heart attack) or not during follow up. Given the inconclusive nature of some previous studies in this area, the researchers who carried out this work wanted to gather evidence from a large prospective cohort, and a reappraisal of all existing evidence, in relation to the possible link between high blood sugar and risk of heart disease in people without diabetes.
What Did the Researchers Do and Find?
In this study, the researchers report results from a prospective population-based study (in which participants are followed forward in time) from Reykjavik, Iceland. In the study, men and women without history of heart disease aged between 31 and 57 in 1966 were first invited to join the cohort, and were followed forward in time using national registries that recorded deaths (and causes of death), and incidence of heart disease. A total of 8,888 male and 9,681 female participants were recruited. At baseline, laboratory measurements were taken to record blood sugar levels using two different methods: fasting blood glucose and post-load glucose. Among the group of participants, 4,664 people were recorded as having either a nonfatal heart attack or fatal heart disease, during approximately 23 years of follow-up. In addition, the researchers attempted to identify from the published medical literature previous prospective studies conducted in Western populations that had looked at the association between blood sugar levels and risk of coronary heart disease. They requested, and obtained, re-analyses of data conducted in accordance with a common protocol for most of the identified studies and then analysed these, together with the results of the Reykjavik cohort, to produce a summary estimate (meta-analysis) of the association between blood sugar levels and risk of coronary heart disease in people without diabetes.
In the Reykjavik cohort, the researchers confirmed an increased risk of coronary heart disease among individuals with blood sugar above the diabetic threshold, as compared to those below it. However, when they looked at blood sugar in people below the diabetic threshold, they found no evidence that higher levels were strongly linked with greater risk of coronary heart disease. This held for both methods of measuring blood sugar levels (fasting and post-load).
In the meta-analysis, the researchers obtained data for 27 different studies, comprising 303,961 participants and 16,982 cases of heart disease. In this meta-analysis, very small increases in risk of heart disease were found with higher levels of blood sugar, when measured using fasting blood glucose or post-load glucose. However, studies using glycated haemoglobin (a measure of average sugar levels over the past 1–3 months or so) found this measure to be associated with a somewhat higher risk of heart disease.
What Do these Findings Mean?
In this prospective cohort and wider meta-analysis, the researchers did not find evidence of a strong or continuous association between blood sugar levels and risk of heart disease amongst people without diabetes. The prospective study, and analysis of other cohorts, was large, but only looked at participants of European decent, so it is not clear whether the findings will also hold for non-European groups.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000278.
Information is available from the US National Diabetes Information Clearinghouse about diabetes, heart disease, and stroke
Centers for Disease Control provides information for the public and professionals about diabetes on their diabetes minisite
Medline Plus encyclopedia has an entry about coronary heart disease