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(Non-Insulin-Dependent) Diabetes Mellitus and Cardiovascular Disease - Putative Association Via Common Antecedents; Further Evidence from the Whitehall Study

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(Non-Insulin-Dependent) Diabetes Mellitus and Cardiovascular Disease - Putative Association Via Common Antecedents; Further Evidence from the Whitehall Study Diabetologia (1988) 31:737-740 Diabetologia Springer-Verlag 1988 Type 2 (non-insulin-dependent) diabetes mellitus and cardiovascular disease - putative association via common antecedents; further evidence from the Whitehall Study R. J. Jarrett t and M.J. Shipley 2 1 Division of Community Health, United Medical and Dental Schools of Guy's and St. Thomas's Hospitals (Guy's Campus), and 2 Division of Medical Statistics and Epidemiology, London School of Hygiene and Tropical Medicine, U.K. Summary. Fifteen year mortality rates are reported for men creasing duration of diabetes. With adjustment for other risk participating in the Whitehall Study in 1968-70. Subjects factors, relative risks were similar in newly diagnosed and were divided into four groups - normoglycaemic (centiles previously diagnosed diabetic men. There was no significant 1-95 of the blood glucose distribution: n=17,05t), glucose linear trend of adjusted relative risks with duration of diabe- intolerant (centiles96-100: n=999), newly diagnosed dia- tes when all diabetic men were pooled and person years at betic patients (n= 56) and previously diagnosed diabetic pa- risk calculated. The lack of effect of duration upon relative tients (n= 121) treated with diet + tablets. Relative risks for risk together with other observations suggests common, pos- all causes mortality- and from coronary and cardiovascular sibly genetic, antecedents of both Type 2 (non-insulin-de- disease deaths were calculated. Age adjusted relative risks pendent) diabetes and coronary heart disease. were highest in the newly diagnosed diabetic patients and were also increased in glucose intolerant and previously di- Key words: Type 2 (non-insulin-dependent)diabetes mellitus, agnosed diabetic men (p< 0.05), but did not increase with in- diabetes duration, cardiovascular disease mortality. It is commonly believed that the increased risk of car- creased risk of cardiovascular disease [5], and in men diovascular disease (CVD) associated with Type2 who were normoglycaemic. (non-insulin-dependent) diabetes mellitus is due to the metabolic abnormalities of the latter condition. This view has been challenged [1, 2] and an alternative hy- Subjects and methods pothesis proposed that CVD and Type 2 diabetes mel- litus are associated disorders, possibly linked geneti- In the Whitehall Study, cardio-respiratory screening of male civil cally [1]. There are several lines of evidence, but a prin- servants working in London was carried out between 1967 and 1969. cipal one lies in the absence of an association between The methods of the study have been previously reported [6]. Men duration of diabetes and the risk of CVD in contrast to known to be diabetic could participate in the screening survey, but were not required to take the oral glucose load. Information on du- the demonstrable and consistently strong association ration of diabetes and the kind of treatment was sought on the ques- between duration of diabetes and microvascular dis- tionnaire completed by each participant. Non-diabetic men drank ease; in particular diabetic retinopathy [3]. However, 50 g glucose in the morning after an overnight fast and capillary there are few prospective studies with relevant data, blood was taken 2 h later for blood glucose measurement. Those with levels above tl.0mmol/1, subsequently approved by the one of the exceptions being the Whitehall Study, in W. H. O. Study Group on Diabetes Mellitus [7] as a suitable epidemi- which 10-year mortality rates from all causes, CVD ological definition of diabetes, were referred to their general practi- and coronary heart disease (CHD) were not related to tioner as probably diabetic, and are designated as newly diagnosed duration of disease in 121 subjects with previously di- diabetic patients. Additional measurements included height, weight, agnosed Type 2 diabetes mellitus who participated in blood pressure and capillary plasma cholesterol. Smoking habits and employment grade were derived from the questionnaire. Elec- the survey [4]. The present paper presents data on mor- trocardiographs were recorded and coded according to the Min- tality at 15 years of follow up and also compares mor- nesota Code [8]. tality rates in the previously known diabetic subjects Positive ECG signs (Whitehall criteria) were taken as one or with those in the newly diagnosed diabetic men, in more of the following Minnesota Code items: Q/QS waves men in the upper 5 percentiles of the distribution of (codes 1.1-1.3); S-T depressions (codes 4,I-4.4); T-wave inversion or flattening (codes 5.1-5.3); left bundle-branch block (7.1). 2 h post-load blood glucose levels (5.4-11.0mmol/1), The records of the men held at the National Health Service Cen- referred to as 'glucose-intolerant', who also have an in- tral Register were identified and flagged. Thus, notification of a 738 R.J. Jarrett and M.J. Shipley: Type 2 (non-insulin-dependent) diabetes mellitus and cardiovascular disease Table I. Age adjusted mortality rates (per 1000 person years), number of deaths and relative risks with 95% confidence intervals Glycaemia Popu- All causes Coronary heart disease All cardiovascular disease group lation Rate No. RR Rate No. RR Rate No. RR deaths (95% CI) deaths (95% CI) deaths (95% CI) Normoglycaemic 17,051 12.2 2774 1.0 4.7 1084 1.0 6.4 1458 1.0 Glucose 999 15.9 239 1.3 6.7 101 1.4 8.8 134 1.4 intolerant (1.1; 1.5) (1.2; 1.8) (1.2; 1.7) Newly diagnosed 56 39.8 30 2.6 28.1 17 3.9 31.5 20 3.7 diabetic patient (1.8; 3.7) (2.4; 6.4) (2.1 ; 5.2) Known duration of diabetes at examination: ~<2 years 35 23.7 12 1.7 9.9 5 1.9 13.2 7 1.9 (1.0; 3.0) (0.8; 4.5) (0.9; 4.0) 3-6 years 43 31.6 20 2.2 13.9 8 2.4 17.7 12 2.6 (1.4; 3.5) (1.2; 4.8) (1.5; 4.5) >7 years 43 25.7 15 1.8 12.2 8 2.6 12.2 8 1.9 (1.1;3.0) (1.3; 5.1) (0.9; 3.7) RR= relative risk; 95% CI =95% confidence interval Table 2. Relative risks with 95% confidence intervals controlling for major risk factors Glycaemia group All causes Coronary heart disease All cardiovascular disease Relative risk 95% CI Relative risk 95% CI Relative risk 95% CI Normoglycaemic 1.0 1.0 - 1.0 Glucose intolerant 1.2 (1.0, 1.4) 1.2 (1.0, 1.5) 1.2 (1.0, 1.5) Newly diagnosed 2.0 (1.4, 2.9) 2.6 (1.6, 4.2) 2.2 (1.4, 3.5) diabetic patient Known duration of diabetes at examination: ~<2 years 2.0 (1.1, 3.8) 2.3 (0.9, 6.1) 2,5 (1.1, 5.6) 3-6 years 2.0 (1.2, 3.3) 2.2 (1.1, 4.7) 2.4 (1.3, 4.4) />7 years 1.8 (1.0, 3.1) 2.5 (1.2, 5.4) 1.9 (0.9, 3.9) death was made whether or not diabetes mellitus was mentioned on formed which allow for this time dependence and so are more sensi- the death certificate. Copies of death certificates were obtained, cod- tive to detecting an association with duration of diabetes. Briefly, the ing being carried out by the staff of the Registrar General according person years for each subject were divided into the categories cur- to the International Classification of Disease (ICD) (8th Revision). rent age at risk and duration of diabetes which allowed adjusted The results presented are for men aged 40-64 years at entry. relative risks to be calculated [9, 10]. Statistical analysis Results Mortality rates were calculated using person years at risk and adjust- Table 1 presents the age-adjusted mortality rates and ment for age was carried out by direct standardisation, using the relative risks for all causes of death, CHD - ICD total population as standard. The data were also analysed by fitting models as described by Berry [9] using the statistical package GLIM codes (410-414) and CVD - ICD codes (390-458). The [10]. This allowed age adjusted relative risks and confidence intervals calculations of relative risks are in relation to mortality to be calculated from the fitted models. Adjustment for other major amongst men in centiles 1-95 (2h blood glucose risk factors was done using Cox's proportional hazards regression <5.4mmol/1) of the blood glucose distribution, model [11]. These initial analyses divided the diabetic patients into referred to subsequently as 'normoglycaemic'. The tertiles according to the distribution of duration of diabetes at the Survey examination. However, as follow-up increases so each sub- known diabetic men are divided into tertiles of dis- ject's duration of diabetes increases. Further analyses were per- tribution of duration at the Survey examination - R. J. Jarrett and M.J. Shipley: Type 2 (non-insulin-dependent) diabetes mellitus and cardiovascular disease 739 Table 3. Person years at risk, numbers of deaths, relative risk and 95% confidence intervals by duration of diabetes in known Type 2 (non-in- sulin-dependent) and newly diagnosed diabetic groups combined Duration of Person- All causes Coronary heart disease All cardiovascular disease diabetes years at risk No. RR 95% CI No. RR 95% CI No. RR 95% CI deaths deaths deaths < 5 years 408 6 1.0 - 4 1.0 - 4 1.0 - 5- 571 21 2.0 (0.8, 5.0) 12 1.8 (0.6, 5.7) 16 2.2 (0.7, 6.7) 10 537 25 2.0 (0.8, 5.2) 10 1.3 (0.4, 4.5) 13 1.5 (0.5, 5.0) 15- 256 13 2.5 (0.9, 6.9) 8 2.6 (0.7, 9.6) 10 3.1 (0.9, 10.6) >/20 270 5 0.9 (0.3, 3.2) 1 0.3 (0.0, 3.2) 1 0.3 (0.0, 2.8) Chi-square test for: Heterogeneity of 6.85 CO=0.15) 7.38 CO=0.12) 11.oo Co=o.o3) relative risks (4 dot) Linear trend in 0.00 Co> 0.5) 0.07 Co> 0.5) 0.16 (/,>0.5) relative risks (1 dot) Relative risks adjusted for major mortality risk factors; dof - degrees of freedom ~2years, 3-6years and 1>7 years.
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