UKPDS 59: Hyperglycemia and Other Potentially Modifiable Risk Factors for Peripheral Vascular Disease in Type 2 Diabetes AMANDA I. ADLER, MD, PHD 1 RICHARD J. STEVENS, PHD 1 ANDREW NEIL, FRCP 2 IRENE M. STRATTON, MSC 1 ANDREW J. M. BOULTON, FRCP 3 RURY R. HOLMAN, FRCP 1 FOR THE U.K. PROSPECTIVE DIABETES STUDY GROUP OBJECTIVE — To determine the role of hyperglycemia in prospective analyses of peripheral vascular disease (PVD) in type 2 diabetes, taking into account other potential risk factors. RESEARCH DESIGN AND METHODS — Potential risk factors for the development of PVD were examined in 3,834 of 5,102 individuals enrolled in the U.K. Prospective Diabetes Study (UKPDS) without PVD at diagnosis of diabetes, followed for 6 years, and for whom relevant data were available. PVD was defined as two of the following: ankle-arm blood pressure index 0.8, absence of both dorsalis pedis and posterior tibial pulses to palpation in one or both legs, and intermittent claudication. Logistic regression was used to estimate the association between potential risk factors measured 3– 4 months after diagnosis of diabetes and incident PVD. The prevalence of PVD at 3-year intervals to 18 years was determined. RESULTS — Hyperglycemia, assessed as HbA 1c , was associated with an increased risk for incident PVD, independent of other risk factors including age, increased systolic blood pressure, reduced HDL cholesterol, smoking, prior cardiovascular disease, peripheral sensory neuropathy, and retinopathy. Each 1% increase in HbA 1c was associated with a 28% increased risk of PVD (95% CI 12– 46), and each 10-mmHg increase in systolic blood pressure with a 25% increase in risk (95% CI 10 – 43). CONCLUSIONS — Hyperglycemia, as well as smoking, dyslipidemia, and blood pressure are potentially modifiable risk factors for the development of PVD. Diabetes Care 25:894 – 899, 2002 P eripheral vascular disease (PVD), defined as lower extremity arterial atherosclerosis, is a significant com- plication of type 2 diabetes. PVD, as with other manifestations of cardiovascular disease, is more common in individuals with type 2 diabetes than in the general population (1,2). Diabetes increases the risk of PVD progression (3), and PVD in patients with diabetes increases the risk of death (4,5) and lower extremity amputa- tion (6). Of patients with PVD, those with diabetes have longer hospital stays and consume a greater percentage of re- sources (7). Because PVD is more common in di- abetes, and hyperglycemia is the defining characteristic of diabetes, it is logical that hyperglycemia may play a role in the de- velopment of PVD in diabetes. However, no prospective study has identified hyper- glycemia as an independent risk factor for PVD in type 2 diabetes. A cross-sectional association between HbA 1c and periph- eral artery disease has been shown (8,9). Blood glucose, but not HbA 1c , was signif- icant in a small prospective study in uni- variate analyses only (10). This study sought to define the role of hyperglycemia in the development of incident PVD, tak- ing into account other potential risk fac- tors that might confound an association. Identification of hyperglycemia and other risk factors for PVD would permit detec- tion of individuals at high risk and guide strategies for prevention, as few therapeu- tic options exist for PVD. We have used data from the U.K. Prospective Diabetes Study (UKPDS) to identify risk factors measured shortly after diagnosis of type 2 diabetes for the development of PVD at 6 years after diabetes. We have also esti- mated the prevalence of PVD up to 18 years after the diagnosis of diabetes. RESEARCH DESIGN AND METHODS Subjects The UKPDS recruited 5,102 individuals with newly diagnosed type 2 diabetes, aged 25– 65 years, from 23 centers in the U.K. between 1977 and 1991. The meth- ods and main results of the study, which was designed primarily to evaluate the ef- fect of improved glycemic control on dia- betic complications, have been published (11). Of the 5,063 white, South Asian, and Afro-Caribbean subjects, 4,987 had data for the measurement of PVD avail- able at diagnosis of diabetes. A total of 3,834 individuals who did not have PVD initially were reexamined at 6 years. Patients not followed to 6 years were slightly older (52.6 vs. 51.9 years), had ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From the 1 Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.; the 2 Division of Public Health and Primary Health Care, Institute of Health Sciences, University of Oxford, Oxford, U.K.; and the 3 Department of Medicine, University of Manchester, Manchester, U.K. Address correspondence and reprint requests to Dr. A. I. Adler, Diabetes Trials Unit, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, U.K. E-mail: amanda.adler@dtu.ox.ac.uk. Received for publication 28 August 2001 and accepted in revised form 10 February 2002. Abbreviations: AAI, ankle-arm index; DBP, diastolic blood pressure; DP, dorsalis pedis; ESR, erythrocyte sedimentation rate; PT, posterior tibial; PVD, peripheral vascular disease; SBP, systolic blood pressure; UKPDS, U.K. Prospective Diabetes Study. A table elsewhere in this issue shows conventional and Syste `me International (SI) units and conversion factors for many substances. Pathophysiology/Complications ORIGINAL ARTICLE 894 DIABETES CARE, VOLUME 25, NUMBER 5, MAY 2002