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real world, despite their best efforts, patients consumed more than three times as much salt as instructed; this was reflected by urinary sodium, which was reduced from 224 mmol per day with baseline treatment to 148 mmol per day on a sodium restricted diet. Nevertheless, substantial clinical benefits were noted, with reductions in both blood pressure and proteinuria. Thus, the findings of this crossover trial5 show that modest reduction of dietary sodium in a real-world setting can have important clinical benefits. These results suggest that drastic sodium restriction—which is impractical in free-living society—is not necessary, and that modest dietary sodium reduction, which could be obtained by preferential use of fresh foods and vegetables rather than processed foods, can lead to important changes in blood pressure and proteinuria. Thus, the key message from this study is that modest dietary sodium reduction, coupled with a full dose of an ACE inhibitor and an appropriate dose of a thiazide diuretic, can be effective in lowering blood pressure and proteinuria, even in patients who are older, with mild reductions in eGFR and clinical proteinuria. Importantly, the study was done in a largely middle-aged population (mean age 65 years) with only a modest reduction in estimated glomerular filtration rate (eGFR; 65 mL/min) who had clinical proteinuria at baseline (711 mg per day). Whether this approach would be effective in patients with more substantial reduction in renal function or a greater amount of proteinuria is unknown. Secondary analyses of clinical trials6 suggest that patients with diabetic nephropathy who consume less salt have fewer associated renal and cardiovascular events. Modest dietary salt restriction as in this study could conceivably reduce levels and cardiovascular events. Importantly, some side-effects of salt restriction were noted in the present trial.5 The investigators recorded

orthostatic complaints with sodium restriction, diuretic treatment, or both; increases in serum creatinine were also noted and would need close monitoring. Previous work7 of the investigators showed that reninangiotensin system inhibition (with an angiotensin receptor blocker), a thiazide diuretic, and modest dietary salt restriction can be beneficial in patients with nondiabetic kidney disease with clinical proteinuria7. Thus, the results of this clinical trial5 should encourage physicians to use modest salt reduction as part of a strategy to slow the progression of renal disease in patients with diabetes. Matthew R Weir Nephrology Division, Department of Medicine, University of Maryland School of Medicine, 22 South Greene Street, N3W143, Baltimore, MD 21201, USA [email protected] I have received personal fees from Amgen, Keryx, Lexicon, Janssen, Novartis, AbbVie, Bristol-Myers Squibb, Relypsa, and Genzyme. 1

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de Zeeuw D, Remuzzi G, Parving HH, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004; 65: 2309–20. de Zeeuw D, Remuzzi G, Parving HH, et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 2004; 110: 921–27. Eijkelkamp WB, Zhang Z, Remuzzi G, et al. Albuminuria is a target for renoprotective therapy independent from blood pressure in patients with type 2 diabetic nephropathy: post hoc analysis from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial. J Am Soc Nephrol 2007; 18: 1540–46. Holtkamp FA, de Zeeuw D, de Graeff PA, et al. Albuminuria and blood pressure, independent targets for cardioprotective therapy in patients with diabetes and nephropathy: a post hoc analysis of the combined RENAAL and IDNT trials. Eur Heart J 2011; 32: 1493–99. Kwakernaak AJ, Krikken JA, Binnenmars SH, et al. Effects of sodium restriction and hydrochlorothiazide added to RAAS blockade efficacy in diabetic nephropathy: a randomised clinical trial. Lancet Diabetes Endocrinol 2014; published online March 5. http://dx.doi.org/10.1016/S22138587(14)70030-0. Lambers Heerspink HJ, Holtkamp FA, Parving HH, et al. Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers. Kidney Int 2012; 82: 330–37. Vogt L, Waanders F, Boomsma F, de Zeeuw D, Navis G. Effects of dietary sodium and hydrochlorothiazide on the antiproteinuric efficacy of losartan. J Am Soc Nephrol 2008; 19: 999–1007.

How should patients with adrenal incidentalomas be followed up? Published Online January 29, 2014 http://dx.doi.org/10.1016/ S2213-8587(13)70190-6 See Articles page 396

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Increased widespread use of diagnostic imaging means that incidental discovery of adrenal masses, without previous clinical suspicion of adrenal disease, is becoming more common, with a prevalence of about 4% in radiological studies.1,2 These so-called adrenal incidentalomas pose various diagnostic and therapeutic

challenges and are expensive to manage because they need regular clinical, hormonal, and radiological follow-up. Long-term studies are necessary to define their potential effect on morbidity and mortality, because these outcomes have not yet been adequately addressed.1,2 This information would allow stratification www.thelancet.com/diabetes-endocrinology Vol 2 May 2014

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risk.6 This risk seems to be higher in patients with either subclinical Cushing’s syndrome or an intermediate phenotype than in those with non-secreting tumours.8 However, people with non-secreting adrenal masses also seem to be at higher cardiometabolic risk than healthy controls matched for age, sex, and BMI.6 These data suggest that all patients with adrenal incidentalomas might need clinical monitoring for cardiometabolic risk. Moreover, the pattern of hormonal secretion can evolve, although rarely, and adrenal incidentalomas originally classified as non-secreting might progress to hypersecreting tumours,9 raising the clinical issue of hormonal follow-up. In The Lancet Diabetes and Endocrinology, Di Dalmazi and coworkers10 report the results of their long-term (mean 7·5 [SD 3·2] years) follow-up study of the natural history of non-secreting adrenal incidentalomas, masses with an intermediate phenotype, and adrenal tumours associated with subclinical Cushing’s syndrome. The study findings underline that the degree of hormonal dysfunction can worsen during follow-up: subclinical cortisol hypersecretion developed in some patients with non-secreting tumours at baseline, and some patients with an intermediate phenotype developed subclinical Cushing’s syndrome during follow-up. Di Dalmazi and colleagues grouped together patients with subclinical Cushing’s syndrome and those with an intermediate phenotype at baseline and defined three risk categories: stable non-secreting; stable intermediate phenotype or subclinical Cushing’s syndrome; and worsening (non-secreting to intermediate phenotype or subclinical Cushing’s syndrome, or intermediate phenotype to subclinical Cushing’s syndrome). The frequency of cardiovascular events was higher in patients with stable intermediate phenotype or subclinical Cushing’s syndrome than in those with stable non-secreting masses (16·7% vs 6·7%; p=0·04). Furthermore, mild alterations of cortisol secretion, even without clinical symptoms and signs of hypercortisolism, were associated with increased mortality. In patients with a worsening phenotype, more cardiovascular events were recorded than in individuals with stable non-secreting masses (28·4% vs 6·7%; p=0·02). Di Dalmazi and coworkers are the first researchers to determine over a long follow-up period, albeit in a retrospective analysis, the frequency of new cardiovascular events and rates of cardiovascular-specific

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of patients into different categories of risk, enabling individualised management that could cut costs and diminish a patient’s psychological discomfort linked to excessive worry about a disease that might remain asymptomatic for their lifetime. When an adrenal incidentaloma is identified, the first objective is to exclude the presence of malignant disease, for which early surgery is recommended. Surgical adrenal removal might represent the only chance of cure for patients with adrenocortical cancer, a rare but aggressive malignant disease.3 The second major aim is to verify the presence of overt adrenal hormone hypersecretion, for which surgery is also recommended. A surgical approach offers the chance for rapid resolution of the clinical syndrome and complications associated with adrenal diseases, such as Cushing’s syndrome,1,2 which has been associated with increased morbidity and mortality.4,5 However, optimum management of benign, non-secreting adrenal incidentalomas is not well defined. The risk of progression to malignant disease over time is low, but, in view of the importance of early surgery for adrenocortical cancer, radiological follow-up is generally recommended.1,2 Most adrenal incidentalomas are benign adrenocortical tumours that either do not secrete cortisol or at least do not secrete an amount adequate to trigger an overt endocrine syndrome.1,2,6 However, a wide range of intermediate clinical and biochemical phenotypes attributable to subclinical cortisol hypersecretion (subclinical Cushing’s syndrome) have been described and are associated with increased morbidity.7 The exact definition of subclinical Cushing’s syndrome is unclear because scant data exist to support risk stratification of morbidity according to the degree of subclinical cortisol hypersecretion. Currently, the most commonly used definition of subclinical Cushing’s syndrome is an absence of cortisol inhibition with the 1 mg overnight dexamethasone suppression test (DST) without specific symptoms and signs of overt hypercortisolism. A concentration of cortisol post DST that is higher than 138 nmol/L defines subclinical Cushing’s syndrome, whereas a value lower than 50 nmol/L virtually excludes the disorder; an area of uncertainty—defined as intermediate phenotype—includes post-DST cortisol values of 50–138 nmol/L.1 Accumulating evidence suggests that patients with adrenal incidentalomas have increased cardiometabolic

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and all-cause mortality in patients with adrenal incidentalomas. They stratified individuals according to the degree of subclinical cortisol hypersecretion and the presence or not of a worsening phenotype. However, they did not stratify risk in patients according to baseline characteristics or include healthy controls matched for age, sex, and BMI. Their findings support the importance of long-term hormonal follow-up for clinical management of all patients with adrenal incidentalomas. Furthermore, clinical monitoring of cardiometabolic risks seems to be important in these patients, particularly in those with subclinical Cushing’s syndrome and intermediate phenotype adrenal incidentalomas, for whom medical or surgical intervention could be needed. Long-term prospective studies are needed to assess the frequency of new cardiovascular events and mortality in patients with adrenal incidentalomas, stratified according to the degree of subclinical hormone hypersecretion at baseline, compared with controls matched for age, sex, and BMI.

We declare that we have no conflicts of interest. 1 2 3

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Terzolo M, Stigliano A, Chiodini I, et al. AME position statement on adrenal incidentaloma. Eur J Endocrinol 2011; 164: 851–70. Young WF Jr. The incidentally discovered adrenal mass. N Engl J Med 2007; 356: 601–10. Baudin E, Leboulleux S, Al Ghuzlan A, et al. Therapeutic management of advanced adrenocortical carcinoma: what do we know in 2011? Horm Cancer 2011; 2: 363–71. Pivonello R, De Martino MC, De Leo M, Lombardi G, Colao A. Cushing’s syndrome. Endocrinol Metab Clin North Am 2008; 37: 135–49. Graversen D, Vestergaard P, Stochholm K, Gravholt CH, Jorgensen JO. Mortality in Cushing’s syndrome: a systematic review and meta-analysis. Eur J Intern Med 2012; 23: 278–82. Peppa M, Koliaki C, Raptis SA. Adrenal incidentalomas and cardiometabolic morbidity: an emerging association with serious clinical implications. J Intern Med 2010; 268: 555–66. Tauchmanova L, Rossi R, Biondi B, et al. Patients with subclinical Cushing’s syndrome due to adrenal adenoma have increased cardiovascular risk. J Clin Endocrinol Metab 2002; 87: 4872–78. Di Dalmazi G, Vicennati V, Rinaldi E, et al. Progressively increased patterns of subclinical cortisol hypersecretion in adrenal incidentalomas differently predict major metabolic and cardiovascular outcomes: a large cross-sectional study. Eur J Endocrinol 2012; 166: 669–77. Barzon L, Sonino N, Fallo F, Palu G, Boscaro M. Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol 2003; 149: 273–85. Di Dalmazi G, Vicennati V, Garelli S, et al. Cardiovascular events and mortality in patients with non-secreting adrenal incidentalomas and subclinical Cushing’s syndrome: a 15-year retrospective study. Lancet Diabetes Endocrinol 2014; published online Jan 29. http://dx.doi.org/10.1016/S2213-8587(13)70211-0.

*Rosario Pivonello, Maria Cristina De Martino, Annamaria Colao Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II, Naples, Italy [email protected]

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Targeting non-alcoholic fatty liver disease through 11-βHSD1 inhibition

Published Online February 17, 2014 http://dx.doi.org/10.1016/ S2213-8587(14)70028-2 See Articles page 406

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With the epidemic surge of obesity and diabetes worldwide, excessive liver fat is becoming increasingly common. Although for most patients fatty liver is a benign condition, a sizeable proportion develop non-alcoholic steatohepatitis—a progressive disorder associated with liver-related mortality, cirrhosis, and liver cancer.1 In patients who do not successfully implement diet and lifestyle changes, pharmacotherapy that aims to prevent liver disease progression is necessary, yet few pharmacological agents have been tested within well-designed development programmes. Most patients with non-alcoholic steatohepatitis are insulin resistant and have increased adipose tissue mass. This expansion triggers uncontrolled lipolysis from visceral adipose tissue, which results in increased delivery of fatty acids to the liver, de-novo hepatic lipogenesis

stimulated by hyperinsulinaemia, and deregulated hepatic glucose production.1 In itself, esterified fat does not damage the liver; however, lipotoxic intermediates trigger the hepatic inflammation, cell injury, and fibrosis that characterise non-alcoholic steatohepatitis. Cellular toxicity of free cholesterol, endotoxinaemia, hypoxia, and altered innate immunity also contribute to liver damage. The agents used up to now within well designed clinical trials tested two distinct approaches: a broad, non-specific antioxidant (vitamin E)2 and insulin sensitisers—such as glitazones2—with predominantly extrahepatic actions. Glitazones restore adipose tissue insulin sensitivity, expandability, adiponectin secretion and, only as a consequence of these effects, reduce liver fat and associated lipotoxic species. Both agents were moderately effective, although large, confirmatory trials are lacking. www.thelancet.com/diabetes-endocrinology Vol 2 May 2014

How should patients with adrenal incidentalomas be followed up?

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