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van Sloten TT, Stehouwer CD. No need to change guidelines for diabetic retinopathy and renin-angiotensin system inhibitors. Lancet Diabet Endocrinol 2015; 3: 231–32. Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010; 362: 1575–85. Chaturvedi N, Porta M, Klein R, et al. Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet 2008; 372: 1394–402. Sjolie AK, Klein R, Porta M, et al. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial. Lancet 2008; 372: 1385–93.

Authors’ reply Hans-Henrik Parving and Frederik Persson recommend the use of renin– angiotensin system (RAS) inhibitors for the primary and secondary prevention of retinopathy in patients with diabetes and normal blood pressure. They argue that RAS inhibitors do not significantly lower blood pressure in these individuals and are not associated with serious side-effects, as shown by the DIRECT-1 and DIRECT-2 trials.1,2 However, the DIRECT trials included healthy individuals without cardiovascular disease (DIRECT-1) or a group with a very low prevalence of cardiovascular disease (1–2%; DIRECT-2). We agree that RAS inhibitors might be beneficial for the prevention and treatment of retinopathy in such individuals. However, it remains to be seen whether this is also true in the real world and in individuals with more comorbidities. Furthermore, the optimum duration and intensity of treatment are unclear, as are the subgroups of patients most likely to benefit from the use of RAS inhibitors, both in terms of their retinopathy and clinical profile. For example, the DIRECT trials suggested that only early-stage retinopathy improves with RAS inhibition, whereas the metaanalysis3 of Bin Wang and colleagues suggests that RAS inhibitors are beneficial in both early and advanced stages of retinopathy. We conclude that more data and a meta-analysis of individual participant data are needed 316

to address these contradictions before RAS inhibitors can be recommended for the prevention and treatment of retinopathy in normotensive individuals. We declare no competing interests.

Thomas T van Sloten, *Coen D A Stehouwer [email protected] Department of Internal Medicine (TTvS, CDAS), Department of Cardiovascular Research Institute Maastricht (TTvS, CDAS), and School for Nutrition, Toxicology and Metabolism (TTvS), Maastricht University Medical Centre, Maastricht 6202 AZ, Netherlands 1

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Chaturvedi N, Porta M, Klein R, et al, for the DIRECT Programme Study Group Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet 2008; 372: 1394–402. Sjolie AK, Klein R, Porta M, et al, for the DIRECT Programme Study Group. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial. Lancet 2008; 372: 1385–93. Wang B WF, Zhang Y, Zhao SH, Zhao WJ, Yan SL, Wang YG. Beneficial effect of renin-angiotensin system inhibitors on diabetic retinopathy: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2015; 3: 263–74.

Cardiovascular disease risk in type 1 diabetes Rachel Huxley and colleagues1 reported that type 1 diabetes confers a higher relative risk for all-cause mortality, incident stroke, fatal renal disease, fatal cardiovascular disease, and in particular incident coronary heart disease in women than in men. We have a few comments that might be of interest. Extensive evidence in this area refers mostly to type 2 diabetes and generally suggests that, relative to their counterparts without diabetes, women with diabetes are at a higher relative cardiovascular disease risk than are men. However, absolute risk (ie, when comparing men with diabetes with women with diabetes) might not differ.2,3 During assessment of sex differences in the relation between glycaemia and cardiovascular disease risk, what matters is not

whether women with diabetes are at higher relative risk of cardiovascular disease than are men, but whether women are at higher absolute risk, for any given level of glycaemia. In view of the apparent susceptibility of women to the effects of hyperglycaemia, as suggested by Huxley and coworkers,1 should glycaemic thresholds for diabetes be lower in women than in men? To resolve this possibility, definitive studies are needed that relate absolute risk for microvascular or macrovascular disease in women and men to actual levels of glycaemia, whether measured by fasting blood glucose or by HbA1c. The same arguments also apply when comparing cardiovascular disease risk factors: at any given level of glycaemia, do women have a worse risk factor profile than do men? Few studies clearly address these issues.2 Except for sex differences in cardiovascular disease risk factors for both type 1 and type 2 diabetes,4 another variable to consider is that women with diabetes are suboptimally treated compared with men regarding lipid and blood pressure targets.2,5 This factor, along with the effect of the duration of diabetes, should also be taken into account when interpreting studies of cardiovascular disease risk differences between the sexes. We declare no competing interests.

*Panagiotis Anagnostis, Ian F Godsland [email protected] Division of Endocrinology, Police Medical Center of Northern Greece, Thessaloniki 54640, Greece (PA); and Diabetes Endocrinology and Metabolic Medicine, Faculty of Medicine, Imperial College London, St Mary’s Campus, London, UK (IFG) 1

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Huxley RR, Peters SAE, Mishra GD, Woodward M. Risk of all-cause mortality and vascular events in women versus men with type 1 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2015; 3: 198–206. Anagnostis P, Majeed A, Johnston DG, Godsland IF. Cardiovascular risk in women with type 2 diabetes mellitus and prediabetes: is it indeed higher than men? Eur J Endocrinol 2014; 171: R245–55.

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Kalyani RR, Lazo M, Ouyang P, et al. Sex differences in diabetes and risk of incident coronary artery disease in healthy young and middle-aged adults. Diabetes Care 2014; 37: 830–38. Collier A, Ghosh S, Hair M, Waugh N. Gender differences and patterns of cardiovascular risk factors in type 1 and type 2 diabetes: a population-based analysis from a Scottish region. Diabet Med 2015; 32: 42–46. Kautzky-Willer A, Stich K, Hintersteiner J, et al. Sex-specific-differences in cardiometabolic risk in type 1 diabetes: a cross-sectional study. Cardiovasc Diabetol 2013; 12: 78.

Authors’ reply We agree with the comments made by Panagiotis Anagnostis and Ian Godsland, that sex differences in the relative risk of type 1 diabetes on allcause mortality should be interpreted in terms of the absolute mortality risk in women and men. However, as we stated in our Article,1 results are presented in terms of relative rather than absolute risk differences since risk is represented as a ratio rather than as a difference. Thus, to compare risks and relative risks through their ratios is both mathematically consistent and logical. Further, an averaged pooled mortality risk difference and the difference in these differences between the sexes has little clinical merit. By comparison, the pooled sex-specific standardised mortality ratios and their ratio are reasonable estimations of individual outcomes and are robust to variations in underlying baseline risk.2

In our study, we explored whether the generally higher background mortality reported in men than in women was driving the observed excess relative risk in women with type 1 diabetes. If true, the relative effect of type 1 diabetes on risk of all-cause mortality would be more extreme in women than in men in populations in which background mortality is higher in men than in women and, conversely, converge when background mortality is similar in both sexes. In our analysis, which we have since updated to include additional data from the National Diabetes Audit3 and the Scottish Registry Linkage study,4 the pooled ratio of the standardised mortality ratios was 1·34 (95% CI 1·30–1·50). In studies in which mortality in men was more than 10% higher than in women, the summary estimate was 1·13 (0·97–1·31); in studies in which background mortality was 0–10% higher in men than in women it was 1·59 (1·24–2·05); and in studies in which mortality was higher in women than in men the estimate was 1·86 (1·13–3·08). Thus, these data lend no support to the argument proffered by the respondents and indeed are contrary to what would be expected if the observed excess risk was chiefly an artefact of the data.

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Although our meta-analysis provides convincing evidence of a sex difference in the risk of all-cause mortality associated with type 1 diabetes, the mechanisms underlying this difference are unknown. We thank Anagnostis and Godsland for their thoughtful suggestions for future studies aiming to clarify why diabetes poses a greater hazard to women than to men. We declare no competing interests.

*Rachel R Huxley, Sanne A E Peters, Gita D Mishra, Mark Woodward [email protected] School of Public Health, University of Queensland, Herston, Brisbane, QLD 4006, Australia (RH, GDM); The George Institute for Global Health, Nuffield Department of Population Health, University of Oxford, Oxford, UK (SAEP, MW); The George Institute for Global Health, University of Sydney, Sydney, NSW, Australia (MW); and Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA (MW) 1

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Huxley RR, Peters SA, Mishra GD, Woodward M. Risk of all-cause mortality and vascular events in women versus men with type 1 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2015; 3: 198–206 Woodward M, Huxley RR. Increased risk of coronary heart disease in female smokers— Authors’ reply. Lancet 2012; 379: 803. Health and Social Care Information Centre. National diabetes audit 2011–2012. Report 2: complications and mortality. http://www. hscic.gov.uk/catalogue/PUB12738/nati-diabaudi-11-12-mort-comp-rep.pdf (accessed March 23, 2015). Livingstone SJ, Looker HC, Hothersall EJ, et al. Risk of cardiovascular disease and total mortality in adults with type 1 diabetes: Scottish registry linkage study. PLoS Med 2012; 9: e1001321.

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Cardiovascular disease risk in type 1 diabetes.

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