Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes Nish Chaturvedi, Anne-Katrin Sjolie, Judith M Stephenson, Heidemarie Abrahamian, Marc Keipes, Allesandro Castellarin, Zeljka Rogulja-Pepeonik, John H Fuller, and the EUCLID Study Group* EARLY REPORT Introduction Retinopathy eventually develops in 70–100% of people with type 1 diabetes (insulin-dependent diabetes mellitus) and remains a common cause of visual impairment and eventual blindness. 1–3 The only intervention that prevents development and slows progression of retinopathy is tight glycaemic control. 4 However, this approach is not wholly effective, and other interventions must be sought. Blood pressure is an important risk factor for the development of retinopathy. 5–7 Antihypertensive therapy, especially inhibitors of angiotensin-converting enzyme (ACE), slow the progression of nephropathy, 8,9 but whether these agents have a beneficial effect on retinopathy is much less clear. Previous randomised controlled trials of these drugs in people with type 1 diabetes either did not collect standardised data on retinopathy status, 9 or did not have sufficient power 10,11 to show an effect.We report the retinopathy results from the EUCLID (EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus) study. 12 Methods The EUCLID study was a double-blind, randomised, parallel- design clinical trial of lisinopril, an ACE inhibitor, and placebo in 18 European centres, in 530 patients. Men and women with type 1 diabetes 13 aged 20–59 years were recruited if resting blood pressure was 75–90 mm Hg diastolic, and 155 mm Hg or less systolic. Most of the patients were normoalbuminuric (albumin- excretion rate <20 μg/min); 15% were microalbuminuric (albumin-excretion rate 20–200 μg/min). Trained photographers took retinal photographs of two 45–50° fields of each eye—macula temporal and disc nasal—at baseline and at 24 months. Slides were sent to London, UK, and then to Aarhus, Denmark, for classification on a five-level scale. AKS assessed all photographs according to the EURODIAB protocol, based on the modified Airlie House classification. 14 She had no access to information about patients, except study number. Concordance between the EURODIAB and other methods of grading is high. 14 Three centres (Bucharest, Krakow, and Watford) did not have retinal cameras and did not participate in the retinopathy section of the study. Therefore, photographs were taken in 409 patients, 354 of whom had photographs at baseline and follow-up. Patients were re-examined at 1, 3, 6, 12, 18, and 24 months. Blood samples were taken every 6 months to measure glycated haemoglobin (HbA 1c ). Patients were started on 10 mg lisinopril or matching placebo daily at randomisation. The dose was increased to 20 mg if diastolic blood pressure was more than 75 mm Hg at 3 months. HbA 1c was estimated in London by EIA with a monoclonal antibody raised against HbA 1c (Dako Ltd, Ely, UK); the normal range for this assay is 2·9–4·8%. 15 We estimated that 500 patients would be needed to show a difference between groups in urinary albumin excretion rate, the primary endpoint. Retinopathy was a secondary endpoint, and we estimated the statistical power of the trial to detect a treatment difference in degree of retinopathy. The WESDR showed that retinopathy progressed over 4 years in 48% of Summary Background Retinopathy commonly occurs in people with type 1 diabetes. Strict glycaemic control can decrease development and progression of retinopathy only partially. Blood pressure is also a risk factor for microvascular complications. Antihypertensive therapy, especially with inhibitors of angiotensin-converting enzyme (ACE), can slow progression of nephropathy, but the effects on retinopathy have not been established. We investigated the effect of lisinopril on retinopathy in type 1 diabetes. Methods As part of a 2-year randomised double-blind placebo-controlled trial, we took retinal photographs at baseline and follow-up (24 months) in patients aged 20–59 in 15 European centres. Patients were not hypertensive, and were normoalbuminuric (85%) or microalbuminuric. Retinopathy was classified from photographs on a five-level scale (none to proliferative). Findings The proportion of patients with retinopathy at baseline was 65% (117) in the placebo group and 59% (103) in the lisinopril group (p=0·2). Patients on lisinopril had significantly lower HbA 1c at baseline than those on placebo (6·9% vs 7·3 p=0·05). Retinopathy progressed by at least one level in 21 (13·2%) of 159 patients on lisinopril and 39 (23·4%) of 166 patients on placebo (odds ratio 0·50 [95% CI 0·28–0·89], p=0·02). This 50% reduction was the same when adjusted for centre and glycaemic control (0·55 [0·30–1·03], p=0·06). Lisinopril also decreased progression by two or more grades (0·27 [0·07–1·00], p=0·05), and progression to proliferative retinopathy (0·18 [0·04–0·82], p=0·03). Progression was not associated with albuminuric status at baseline. Treatment reduced retinopathy incidence (0·69 [0·30–1·59], p=0·4). Interpretation Lisinopril may decrease retinopathy progression in non-hypertensive patients who have type 1 diabetes with little or no nephropathy. These findings need to be confirmed before changes to clinical practice can be advocated. Lancet 1998; 351: 28–31 28 THE LANCET • Vol 351 • January 3, 1998 Early Report *Listed at end of paper EURODIAB, Department of Epidemiology and Public Health, University College London, London WC1E 6BT, UK (N Chaturvedi MRCP, J M Stephenson MD, J H Fuller FRCP); Aarhus University Hospital, Aarhus, Denmark (A-K Sjolie MD); Hospital Vienna Lainz and L Boltzmann-Institute for Nutrition and Metabolic Diseases, Vienna, Austria (H Abrahamian MD); Maladies du Metabolisme et de la Nutrition, Luxembourg (M Keipes MD); Università de Verona, Verona, Italy (A Castellarin MD); and Vuk Vrhovac Institute, Zagreb, Croatia (Z Rogulja-Pepeonik MD) Correspondence to: Dr Nish Chaturvedi (e-mail: nish@public-health.ucl.ac.uk)