Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies

Abstract

Background: Uncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We aimed to quantify these associations for a wide range of circumstances.

Methods: We undertook a meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration. We combined within-study regressions that were adjusted for age, sex, smoking, systolic blood pressure, and body-mass index to calculate hazard ratios (HRs) for vascular disease.

Findings: Analyses included data for 698 782 people (52 765 non-fatal or fatal vascular outcomes; 8.49 million person-years at risk) from 102 prospective studies. Adjusted HRs with diabetes were: 2.00 (95% CI 1.83-2.19) for coronary heart disease; 2.27 (1.95-2.65) for ischaemic stroke; 1.56 (1.19-2.05) for haemorrhagic stroke; 1.84 (1.59-2.13) for unclassified stroke; and 1.73 (1.51-1.98) for the aggregate of other vascular deaths. HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers. HRs for coronary heart disease were higher in women than in men, at 40-59 years than at 70 years and older, and with fatal than with non-fatal disease. At an adult population-wide prevalence of 10%, diabetes was estimated to account for 11% (10-12%) of vascular deaths. Fasting blood glucose concentration was non-linearly related to vascular risk, with no significant associations between 3.90 mmol/L and 5.59 mmol/L. Compared with fasting blood glucose concentrations of 3.90-5.59 mmol/L, HRs for coronary heart disease were: 1.07 (0.97-1.18) for lower than 3.90 mmol/L; 1.11 (1.04-1.18) for 5.60-6.09 mmol/L; and 1.17 (1.08-1.26) for 6.10-6.99 mmol/L. In people without a history of diabetes, information about fasting blood glucose concentration or impaired fasting glucose status did not significantly improve metrics of vascular disease prediction when added to information about several conventional risk factors.

Interpretation: Diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and non-linearly associated with risk of vascular disease.

Funding: British Heart Foundation, UK Medical Research Council, and Pfizer.

Figure 1

Hazard ratios (HRs) for vascular outcomes in people with versus those without diabetes at baseline Analyses were based on 530 083 participants. HRs were adjusted for age, smoking status, body-mass index, and systolic blood pressure, and, where appropriate, stratified by sex and trial arm. 208 coronary heart disease outcomes that contributed to the grand total could not contribute to the subtotals of coronary death or non-fatal myocardial infarction because there were fewer than 11 cases of these coronary disease subtypes in some studies. *Includes both fatal and non-fatal events.

Figure 2

Hazard ratios (HRs) for coronary heart disease and ischaemic stroke in people with versus those without diabetes at baseline, by individual characteristics HRs were adjusted as described in figure 1. BMI=body-mass index. *Bottom third=<23·8 kg/m² (mean 21·7 kg/m²); middle third=23·8–<27 kg/m² (mean 25·3 kg/m²); and top third=≥27 kg/m² (mean 30·7 kg/m²). †Bottom third=<123 mm Hg (mean 113 mm Hg); middle third=123–<141 mm Hg (mean 132 mm Hg); and top third=≥141 mm Hg (mean 157 mm Hg).

Figure 3

Hazard ratios (HRs) for coronary heart disease and ischaemic stroke in people with versus those without diabetes, progressively adjusted for baseline levels of conventional risk factors Analyses were based on 264 353 participants (11 848 cases) for coronary heart disease and 157 315 participants (2858 cases) for ischaemic stroke with complete information on all covariates listed. BMI=body-mass index.

Figure 4

Hazard ratios (HRs) for coronary heart disease and ischaemic stroke by baseline fasting blood glucose concentration Analyses were based on 279 290 participants (14 814 cases) for coronary heart disease (CHD) and 175 542 participants (1754 cases) for ischaemic stroke. Participants without known diabetes at baseline were classified into groups of fasting glucose (CHD: <4·0, 4·0–4·5, 4·5–5·0, 5·0–5·5, 5·5–6·0, 6·0–6·5, 6·5–7·0, 7·0–7·5, and >7·5 mmol/L; ischaemic stroke: <4·5, 4·5–5·0, 5·0–5·5, 5·5–6·0, 6·0–7·0, and >7·0 mmol/L). HRs were adjusted as described in figure 1 and are plotted against mean fasting blood glucose in each group. Reference group for both outcomes is 5·0–5·5 mmol/L.

Figure 5

Hazard ratios (HRs) for coronary heart disease by clinically defined categories of baseline fasting blood glucose concentration Analyses were based on 279 290 participants (14 814 cases). HRs were adjusted as described in figure 1. HR (95% CI) in people with fasting glucose 5·60–6·99 mmol/L was 1·12 (1·06–1·18). *Reference group.

Figure 6

Comparison of hazard ratios (HRs) for coronary heart disease by long-term average concentrations of fasting blood glucose concentration, total (and non-HDL) cholesterol, and systolic blood pressure, in a common set of participants Analyses were done in participants with no known history of diabetes at baseline. Analyses of fasting blood glucose concentration, total cholesterol, and systolic blood pressure were based on 140 624 participants (10 667 cases). For fasting blood glucose, participants were classified into groups of baseline fasting concentrations, as described in figure 4. For the other factors presented, participants were classified according to baseline values as follows: total cholesterol, <4·5, 4·5–5·1, 5·1–5·7, 5·7–6·3, 6·3–6·9, 6·9–7·5, 7·5–8·1, 8·1–8·7, ≥8·7 mmol/L; non-HDL cholesterol, <3, 3–3·6, 3·6–4·2, 4·2–4·8, 4·8–5·4, 5·4–6·0, 6·0–6·6, 6·6–7·2, ≥7·2 mmol/L; systolic blood pressure: <110, 110–120, 120–130, 130–140, 140–150, 150–160, 160–170, 170–180, ≥180 mm Hg). These categories approximately correspond to those used for fasting blood glucose concentration (ie, increments of half the SD of each factor). HRs were adjusted, where appropriate, for age, smoking status, BMI, systolic blood pressure, total cholesterol and fasting blood glucose, and stratified, where appropriate, by sex and trial arm. HRs were plotted against the mean value in each group. Long-term average values were calculated with information from serial measurements. The reference group for each factor is the category with the lowest HR. *Analyses of non-HDL cholesterol were based on a subset of 71 224 participants (4290 cases).