Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom prospective diabetes study

British Medical Journal, March 14, 1998 by R.C. Turner, H. Millns, H.A.W. Neil, I.M. Stratton, S.E. Manley, D.R. Matthews, R.R. Holman

Introduction

Patients with type 2 diabetes mellitus have a twofold to threefold increased incidence of diseases related to atheroma,[1] and those who present in their 40s and 50s have a twofold increased total mortality.[2] In the United Kingdom the incidence of macrovascular complications in patients with type 2 diabetes mellitus is twice that of microvascular disease.[3] The greater mortality in patients with type 2 diabetes mellitus than in the general population cannot be explained only by the presence of the three classic risk factors for coronary artery disease--that is, smoking, hypertension, and an increased plasma cholesterol concentration.[4]

Previous prospective studies of patients with type 2 diabetes mellitus had comparatively few patients and cardiovascular end points.[5-11] Many of these studies have not measured the concentration of low density lipoprotein cholesterol, potentially the most important lipid fraction.[12, 13]

We report a prospective study of white patients with recently diagnosed type 2 diabetes mellitus. After entry to the United Kingdom prospective diabetes study[14] patients were assessed for baseline risk factors after initial treatment by diet for 3 months. The association of coronary artery disease with baseline risk factors has been assessed irrespective of subsequent treatments.

Subjects and methods

Patients

Between 1977 and 1991, 5102 patients aged 25 to 65 years with type 2 diabetes mellitus based on a fasting plasma glucose concentration [is greater than] 6 mmol/l on two occasions were recruited to the study[14]; 4775 (94%) had fasting plasma glucose values [is greater than] 7.0 mmol/l, which is consistent with the American Diabetic Association's definition of diabetes. Of the 7108 patients originally referred for entry to the study, 2006 (28%) were excluded. These were of a similar age and sex and had a similar fasting plasma glucose concentration as those patients included in the study. The main reasons for exclusion were myocardial infarction in the previous year, current angina or heart failure, accelerated hypertension, proliferative or preproliferative retinopathy, renal failure with a plasma creatinine concentration [is greater than] 175 [Mu] mol/l, other life threatening disease such as cancer, an illness requiring systemic steroids, an occupation which precluded insulin treatment, language difficulties, or ketonuria [is greater than] 3 mmol/l suggestive of insulin dependent diabetes mellitus.

The study was approved by the ethics committee in each of the 23 centres: Radcliffe Infirmary, Oxford; Royal Infirmary, Aberdeen; General Hospital, Birmingham; St George's Hospital and Hammersmith Hospital, London; City Hospital, Belfast; North Staffordshire Royal Infirmary, Stoke on Trent; Royal Victoria Hospital, Belfast; St Helier Hospital, Carshalton; Whittington Hospital, London; Norfolk and Norwich Hospital; Lister Hospital, Stevenage; Ipswich Hospital; Ninewells Hospital, Dundee; Northampton Hospital; Torbay Hospital; Peterborough General Hospital; Scarborough Hospital; Derbyshire Royal Infirmary; Manchester Royal Infirmary; Hope Hospital, Salford; Leicester General Hospital; Royal Devon and Exeter Hospital. All patients gave their informed consent to take part in the study.

The initial treatment by diet for 3 months was completed by 4178 white patients,[14] with a mean loss of 5 kg body weight, but only 867 (16.9%) were able to achieve a near normal fasting plasma glucose concentration of [is less than] 6 mmol/l. Cardiovascular disease was evident in 381 (7.5%) patients, of whom 58 (15.2%) had previous myocardial infarction, 144 (37.8%) a definite electrocardiographic Q wave abnormality on Minnesota coding, 7 (1.8%) angina, 1 (0.3%) heart failure, 120 (31.5%) intermittent claudication, and 51 (13.4%) a previous stroke or transient ischaemic attack. Only 2693 (70.9%) of the 3797 datasets could be analysed for all variables, as biochemical measurements were not undertaken until 1981, and some patients had no valid data for one or more of the other variables. Sufficient data were available from 3055 (80.5%) patients for the final Cox model analysis, and 2161 (56.9%) patients had ophthalmic photographic data available for the assessment of the effect of retinopathy.

After the initial treatment diet, patients were randomly allocated to different treatments according to the protocol of the United Kingdom prospective diabetes study.[14] This paper does not include any reference to treatment allocations, actual treatment, or diabetes control during the 10 years of follow up.

Follow up, identification, and classification of end points

Patients were seen every three months in the clinics, and any events that were clinically important were noted. To ascertain whether predetermined criteria for the end points were attained two independent doctors received full information on the patients but without details of treatment.[14] Any discrepancies between the two doctors were adjudicated by two independent senior doctors. All end points were coded according to ICD-9 (international classification of disease, 9th revision).[15]