Q J Med 1999; 92: 207-210
© 1999 Association of Physicians
Fasting plasma glucose and subsequent macrovascular disease after 10 years follow-up: a collaborative study on two populations
From the Department of Epidemiology and Public Health, Queen's University of Belfast, Belfast, and the 1 MRC Epidemiology Unit (S Wales), Llandough Hospital, Penarth, UK
Received 9 October 1998 and in revised form 5 February 1999
Dr J.W.G. Yarnell, Department of Epidemiology and Public Health, Queen's University of Belfast, Mulhouse Building, Royal Victoria Hospital Site, Grosvenor Road, Belfast BT12 6BJ
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The American Diabetes Association recently proposed a new, lower, cut-point of 7.0 mmol/l for diagnosis of diabetes mellitus. We examined data from the Caerphilly and Speedwell cohorts to determine possible cut-points of fasting plasma glucose for increased risk of subsequent ischaemic heart disease (IHD). Men (n=4860) from the general population of a town in South Wales and a practice-based population in Bristol aged 45–63 years were first examined in 1979–83, and re-examined at intervals, and these data relate to follow-up at about 10 years (120 months, Caerphilly) (112 months, Speedwell). Clinically recognized diabetics (n=94) experienced a higher mortality rate and an excess number of major IHD events. Among non-diabetics, mean blood glucose was 5.0 mmol/l and a significant excess of major IHD events occurred above this point even when the data were fully adjusted for all other IHD risk factors. Risk of major IHD was greatest for non-diabetic men with plasma glucose levels between 7.0 and 7.7 mmol/l. Under 7.0 mmol/l, the excess event rate was modest, however. Glucose levels were not associated with excess all-cause mortality among these non-diabetic men. These data, based on the excess risk of macrovascular disease experienced by a British cohort of non-diabetic men, accord with the proposals to base the diagnosis of diabetes on a cut point of 7.0 rather than 7.8 mmol/l.
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Introduction |
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The American Diabetes Association recently reported the findings of its expert committee on the diagnosis and classification of diabetes mellitus.1 Their principal recommendation is that, for epidemiological studies, estimates of diabetes prevalence and incidence should be based on a fasting plasma glucose (FPG) of 126 mg/dl or less (7.0 mmol/l). The World Health Organization definition2 was based on a cut-point of
140 mg/dl (7.8 mmol) for FPG or a 2-h plasma glucose of 200 mg/dl (11.1 mmol/l) in a standard oral glucose tolerance test. Evidence relating to the threshold values for glucose at which subsequent risk of macrovascular disease was increased was obtained from two longitudinal studies—the Baltimore Longitudinal Study of Aging3 from the United States and from the Paris Prospective Study.4 A recent report from the European Diabetes Epidemiology Study Group5 examined the effect on the prevalence of diabetes mellitus of adopting the diagnostic criterion proposed by the American Diabetes Association in populations from eight European countries; their report noted a high rate of disagreement in the classification of diabetes based on the two different diagnostic criteria. They proposed that prospective data should be examined to evaluate risk of subsequent disease in subjects classified by each method. The present report provides evidence for fasting plasma glucose from British surveys—the Caerphilly and Speedwell collaborative study, in which men were first examined in 1979–83.
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Study populations
In Caerphilly, a 100% sample of men was selected from within a defined area. They were aged between 45 and 59 years when first examined. A total of 2512 men were seen—89% of the 2818 found to be eligible. In Speedwell, a 100% sample of men was selected from the age-sex registers of 16 general practitioners working from two neighbouring health centres. The men chosen were aged 45–59 years when chosen, immediately before the study began in 1978; thus they were aged between 45 and 63 years when first examined. A total of 2348 men were seen during the following 3 years, 92% of those eligible. The combined cohort thus numbers 4860 men.
Survey methods and follow-up procedure
The two studies had a common core protocol and common training procedures for medical and non-medical observers. These have been described in detail elsewhere.6,7 Briefly, at recruitment, the men attended an afternoon or evening clinic at which a standard medical and smoking history was obtained; the London School of Hygiene and Tropical Medicine Chest Pain questionnaire was administered; height was measured using Holtain stadiometers and weight was recorded using calibrated beam balances. Blood pressure was recorded by trained medical observers using Hawksley `random zero' sphygmomanometers for the majority of observations. A standardized 12-lead electrocardiogram (ECG) was recorded. ECGs were coded using the Minnesota coding system8 by two experienced observers. Men were asked whether or not they had ever been diagnosed as having diabetes. They then returned, after an overnight fast, to an early morning clinic where a blood sample was taken with minimal venous stasis. Fasting samples were obtained from 4641 men.
The results reported in this paper refer to the second follow-up in Caerphilly. This was at a nearly constant interval of 120 months (SD 6 months). In Speedwell results related to the third follow-up and the mean interval was 112 months (SD 3 months).
At each follow-up the Chest Pain Questionnaire was again administered, and a further ECG recorded. The Chest Pain Questionnaire was extended to include questions about hospitalization for severe chest pain. These, together with Hospital Activity Analysis notifications of admissions coded as 410 to 414—ischaemic heart disease (IHD) in the 9th revision of the International Classification of Diseases (ICD)—were used as the basis for a search of hospital notes for events which satisfied the World Health Organization (WHO) criteria for definite acute myocardial infarction.9 For men who had died before the end of follow-up, a copy of the death certificate was automatically received from the National Health Service Central Register. From this information, three categories of incident IHD events were defined: IHD death, clinical non-fatal myocardial infarction and electrocardiographic myocardial infarction, as previously described.6,7 A major IHD event was defined as one or more of the three possible outcomes described above.
Laboratory methods
All blood samples were taken with minimum haemostasis after an overnight fast. Plasma glucose was measured for both studies in the same laboratory using a Beckman Astra 8 analyser at Frenchay Hospital, Bristol. This analyser used the oxygen rate method10 to measure glucose and a Beckman standard for reference values. The laboratory participated in the South-West Regional Hospitals' Quality Control scheme which provides common standards for laboratory parameters. The normal fasting plasma glucose values were in the standard range 4.0–6.0 mmol/l. A 5% sample of subjects provided a duplicate blood sample for glucose determination. This was presented blindly to the laboratory, and the overall coefficient of variation of the duplicate pairs was <5%. Laboratory methods and their accuracy for the plasma lipids have been reported in detail previously.7
Statistical methods
Analysis of events during follow-up used multiple logistic regression with the occurrence, or not, of a major IHD event as the principal outcome variable. Men with evidence of IHD when first examined were not excluded from the analyses, but their increased risk was allowed for by including pre-existing IHD as a factor in the regression model. In this instance a broad epidemiological definition of pre-existing IHD was used; men with severe chest pain and/or angina on the Chest Pain questionnaire and/or probable or possible ECG ischaemia according to the Whitehall criteria.11 Death from any cause was also analysed as a separate outcome variable. Risks for men in different categories of blood glucose level were compared in the logistic model by a likelihood ratio 
2 test and by a 2 test for linear trend across the categories.
Any possible difference in incidence between the two study areas, for example, arising from their slightly different lengths of follow-up, was allowed for by including area as a two-level factor in the logistic model. The assumption that the IHD risk associated with various glucose levels in the two areas was the same was tested by including interactions with area in the model; none was found to be statistically significant. No time-to-event was available for incidence cases of IHD defined by significant changes in the Minnesota ECG codes. Time-to-event analyses were not performed for this reason and because the average length of follow-up was nearly constant within each area.
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Results |
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Ninety-four subjects said that they had been given a diagnosis of diabetes by their general practitioner or a consultant physician prior to our baseline examination. Of these 44 were receiving dietary advice only, 25 were taking oral hypoglycaemics and 22 used insulin; there was no information for the remaining three. Table 1
shows the subsequent all-cause mortality and incidence of IHD (fatal and non-fatal IHD events) in these diabetics and in non-diabetics. Mortality and incident IHD were significantly higher in diabetics than in non-diabetics, and diabetics who received medical therapy were at higher risk than those on diet only.
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The mean age of diabetics and non-diabetics was similar, but the mean body mass index of the known non-insulin-dependent diabetics (27.0 kg/m2) was significantly higher than that of non-diabetics (25.9 kg/m2).
For the purposes of the present analysis, unrecognized diabetics were included among the non-diabetic subjects since no intervention would have been offered prior to baseline examination. All further analyses are based on 4511 non-diabetic men in the combined cohort who had a fasting glucose measurement.
Multiple logistic regression analyses were performed in order to assess the excess risk associated with various glucose levels, independent of other risk factors. The following variables were included as potential confounders: age, smoking habit (never, ex- or current), pre-existing IHD, diastolic blood pressure, body mass index, total cholesterol, HDL-cholesterol and log triglyceride. Table 2 shows that, using a value of <5 mmol/l as a baseline, subjects with higher values than this showed increased risk of subsequent IHD when adjusting for all other major risk factors (2=10.8, df=4; p=0.03). A trend in increased risk of IHD is apparent (2=7.23, df=1; p=0.0007) although the relative odds are greatest in men with glucose levels which were between 7.0 and 7.8; men with higher levels had a rather lower estimated risk, but this was non-significantly different from risk in the former group. The pooled risk for men with glucose levels of 7.0 mmol/l and above was 1.93 (95% CI 1.05–3.57).
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Discussion |
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These data support the common finding of excess mortality from all causes and increased risk of IHD among men with diabetes. Mortality and incident IHD were also increased among previously unrecognized diabetics according to the current WHO criteria of fasting glucose levels of 7.8 mmol/l or above, although this did not achieve formal statistical significance, possibly due to small numbers. As has been reported elsewhere,9–12 there is evidence of increased risk of IHD in non-diabetics with above-average glucose levels. A recent report13 based on British prospective studies suggests that excess mortality due to cardiovascular disease is due to the association of non-insulin-dependent diabetes mellitus with other cardiovascular risk factors, and a review of studies14 summarized the evidence that hyperglycaemia was an independent cardiovascular risk factor as `weak and inconsistent' in non-diabetic subjects. A more recently published analysis15 of 20-year prospective data from three populations found that increased mortality (particularly from IHD) occurred mainly above a cut-point of 6.88 mmol/l (97.5 percentile) in data fully adjusted for other cardiovascular risk factors. This agrees closely with our findings that increased incidence of IHD occurs mainly above 7.0 mmol/l, among 1.7% of the men.
Among these present data, there is a statistically significant increase in risk of IHD at glucose levels above 5.0 mmol/l but the highest risk is found between 7.0 and 7.7 mmol/l. The trend in risk above 5.0 mmol/l is reasonably consistent, however, but is not maintained at levels of 7.8 mmol/l and above. One possible explanation for this is that general practitioners were notified about patients whose levels were above 7.8 mmol/l; thus preventive measures may have been instituted which may have affected outcome. Alternatively, this may be due to a chance effect and, as can be seen in Table 2
, the small numbers produce wide confidence intervals.
As Table 2 shows, 40% of this population of non-diabetic men have a fasting glucose above 5.0 mmol/l, and thus show increased risk of subsequent IHD on the basis of their fasting glucose, independently of other cardiovascular risk factors. The risks from 5.0 to 7.0 mmol/l appear small, however. The suggestion that the WHO threshold should be reduced to 7.0 mmol/l is consistent with these data.
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References |
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1. American Diabetes Association Expert Committee. Report on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 20:1183–97.[Web of Science][Medline]
2. World Health Organisation Study Group. Diabetes mellitus. WHO Tech Rep Ser 1985; No. 727.
3. Andres R, et al. quoted in reference 1 as personal communication (1997).
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DECODE Study Group on behalf of the European Diabetes Epidemiology Study Group. Will new diagnostic criteria for diabetes mellitus change phenotype of patients with diabetes? Reanalysis of European epidemiological data. Br Med J 1998; 317:371–5.
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WHO MONICA Project (prepared by Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, Arveiler D, Rajakangas A-M, Pajak A).Myocardial Infarction and Coronary Deaths in the World Health Organization MONICA Project. Registration procedures, event rates, and case-fatality rates in 38 Populations from 21 countries in four continents. Circulation 1994; 90:583–612.
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Yarnell JWG, Patterson CC, Bainton D, Sweetnam PM. Is metabolic syndrome a discrete entity in the general population? Evidence from the Caerphilly and Speedwell population studies. Heart 1998; 79:248–52.
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