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real world to the point that they alone would be sufficient to permanently reverse sustained obesity, which is in large part (but certainly not entirely) biologically mediated. Finally, we do not state or believe that “any treatment of obesity should include direct biological intervention”, but we do maintain that lifestyle interventions alone are unlikely to be sufficient to reverse obesity long-term for most individuals with sustained obesity. The data from Julian Shield’s laboratory, although valuable, do not refute this contention, which is consistent with decades of data from well conducted behavioural trials.5 Changing lifestyle behaviours is foundational for successful obesity treatment, and the biological changes brought about by pharmacotherapy and surgery are translated through behaviour (eg, reduced caloric consumption, choice of healthier food, reduced speed of eating). The fact that a behavioural change such as slowing the rate of consumption leads to a biological change such as reductions in ghrelin is interesting but does not suggest that such interventions alone would be sufficient to combat obesity on a population level. CNO reports grants from Accera, and non-financial support from ProBar. AGT reports non-financial support from Nutrisystem. RFK reports personal fees from Vivus, Takeda, and Novo Nordisk and grants from Weight Watchers. TAW reports personal fees from Nutrisystem, Orexigen Pharmaceutical, Novo Nordisk, Boehringer Ingelheim, Guilford Press, and Shire Pharmaceutical and grants from Novo Nordisk, Weight Watchers, and NutriSystem.

*Christopher N Ochner, Adam G Tsai, Robert F Kushner, Thomas A Wadden [email protected] Mount Sinai Adolescent Health Center, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, Box 1005, New York, NY 10128, USA (CNO); New York Obesity Nutrition Research Center, Columbia University Medical Center, New York, NY, USA (CNO); Departments of Internal Medicine and Metabolic-Surgical Weight Management, Kaiser Permanente of Colorado, Denver, CO, USA (AGT); Division of General Internal Medicine, University of Colorado School of Medicine, Aurora, CO, USA (AGT); Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA (RFK); Center for Lifestyle Medicine,

Northwestern Medical Faculty Foundation, Chicago, IL, USA (RFK); and Center for Weight and Eating Disorders, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA (TAW) 1

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Ford AL, Bergh C, Södersten P, et al. Treatment of childhood obesity by retraining eating behaviour: randomised controlled trial. BMJ 2010; 340: b5388. Ochner CN, Tsai AG, Kushner RF, Wadden TA. Treating obesity seriously: when recommendations for lifestyle change confront biological adaptations. Lancet Diabetes Endocrinol 2015; 3: 232–34. Ochner CN, Barrios DM, Lee CD, Pi-Sunyer FX. Biological mechanisms that promote weight regain following weight loss in obese humans. Physiol Behav 2013; 120: 106–13. Arner P, Spalding KL. Fat cell turnover in humans. Biochem Biophys Res Commun 2010; 396: 101–04. Dombrowski SU, Knittle K, Avenell A, Araújo-Soares V, Sniehotta FF. Long term maintenance of weight loss with non-surgical interventions in obese adults: systematic review and meta-analyses of randomised controlled trials. BMJ 2014; 348: g2646.

Effects of RAS inhibitors on diabetic retinopathy In their meta-analysis,1 Bin Wang and colleagues included 21 randomised clinical trials with 13 823 patients with type 1 or 2 diabetes. Groups of patients that received renin–angiotensin system (RAS) inhibitors had significantly lower risk for development and progression of diabetic retinopathy, and a higher possibility for regression of diabetic retinopathy. Sensitivity analyses substantiated the data. The normotensive patients had the best treatment responses and highly significant improvements in each of the three aforementioned endpoints. A Comment2 by Thomas T van Sloten and Coen DA Stehouwer that assessed the meta-analysis1 by Wang and colleagues suggested: “No need to change guidelines for diabetic retinopathy and renin-angiotensin system inhibitors”. The main reason for this conclusion was the concern about side-effects due to blood pressure lowering in normotensive patients with diabetes. However, the data presented by the authors suggesting “evidence of greatly increased risk of serious adverse events including

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(orthostatic) hypotension, syncope, and hyperkalaemia” are based on the ACCORD blood pressure trial.3 This trial investigated hypertensive patients with diabetes who took an average of 3·4 blood pressure-lowering drugs. The ACCORD blood pressure trial was a study of a treatment strategy to achieve specific systolic blood pressure goals, rather than an assessment of any specific drug regimen. By contrast, RAS inhibitors were not being used to treat blood pressure in normotensive patients with diabetes, as assumed in the meta-analysis1 by Wang and colleagues, but rather to partly block the damaging effects of RAS on the initiation and progression of diabetic retinopathy. Inhibition of RAS has little or no effect on blood pressure in normotensive patients, as documented in the studies included in the meta-analysis. Furthermore, the DIRECT study4,5—the largest study of the meta-analysis, which assessed 5224 patients with type 1 and 2 diabetes—the number of serious adverse events, the number of patients who discontinued treatment due to adverse events, and the number of deaths were similar in the normotensive or hypertensive patients given either RAS inhibitors or placebo. The aforementioned findings clearly suggest a strong need to change guidelines for diabetic retinopathy and RAS inhibitors. HHP reports having equity in Merck and Novo Nordisk and receiving consulting and lecture fees from AstraZeneca, Abbott, Novartis, and Reata. FP is employed by Steno Diabetes Center, a nonprofit institution owned by Novo Nordisk. FP has also received lecture fees from Novo Nordisk, Novartis, Eli Lilly, Boehringer Ingelheim, as well as advisory honoraria from Bristol-Myers Squibb and AstraZeneca.

Hans-Henrik Parving, *Frederik Persson [email protected] Department of Medical Endocrinology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark (H-HP); Aarhus University, Aarhus, Denmark (HP); and Steno Diabetes Center, Gentofte 2820, Denmark (FP) 1

Wang B, Wang F, Zhang Y, et al. Effects of RAS inhibitors on diabetic retinopathy: a systematic review and meta-analysis. Lancet Diabet Endocrinol 2015; 3: 263–74.

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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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