Correspondence
2
3
4
5
Soisson V, Brailly-Tabard S, Helmer C, et al. A J-shaped association between plasma testosterone and risk of ischemic arterial event in elderly men: the French 3C cohort study. Maturitas 2013; 75: 282–88. Yeap BB, Alfonso H, Chubb SAP, et al. In older men an optimal plasma testosterone is associated with reduced all-cause mortality and higher dihydrotestosterone with reduced ischemic heart disease mortality, while estradiol levels do not predict mortality. J Clin Endocrinol Metab 2014; 99: E9–18. Tan R, Cook KR, Reilly WG. Testosterone therapy is not associated with higher risk of myocardial infarction or stroke: the low T experience. American Association of Clinical Endocrinologists Annual Meeting 2014; May 13–18, 2014; Las Vegas, NV, USA. Abstract 1353. Muraleedharan V, Marsh H, Kapoor D, et al. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol 2013; 169: 1–10.
Author’s reply The letters from T Hugh Jones and Schooling and Xu discuss continuing controversies in testosterone replacement therapy in men, further highlighting the need for a large randomised controlled trial to assess the risks for testosterone therapy in men. Although such a trial might not be definitive, the current knowledge deficit makes both clinicians and patients reliant on inconsistent expert opinion for treatment decision making, with experts citing selected, poorer quality data. 1 Although the resource investment would be considerable, a large trial would likely reap large economic benefits, as recently shown by the Women’s Health Initiative, from which the return on each US$1 invested is about $140.2 Jones argues that testosterone replacement therapy improves survival and reduces cardiovascular events in men. He makes the important point that the clinical syndrome of male hypogonadism needs both symptoms and low serum testosterone concentrations,1 and symptoms of hypogonadism were not assessed in either of the recent studies linking testosterone replacement therapy and increased cardiovascular morbidity. This weakness is an inherent problem with reliance on large databases for patient
information and is often a weakness of observational studies. A welldesigned clinical trial in symptomatic men with low testosterone is crucial to support the assertion that testosterone replacement therapy benefits cardiovascular morbidity and survival. By contrast, Schooling and Xu argue that available data do not support a benefit for testosterone replacement therapy, an issue being addressed by a 1 year randomised trial of 800 men with symptomatic low testosterone3 that is funded by the US National Institutes of Health. Clearly, findings will provide important data. However, meta-analyses of shorter trials have reported conflicting conclusions about cardiovascular events and testosterone replacement.4,5 Importantly, the recent meta-analysis by Xu and colleagues5 was not limited to studies of only men with low testosterone, making the conclusions less clinically relevant for clinicians using published treatment guidelines. Such contradictory analyses show the need for better data for evidence-based medicine in the treatment of male hypogonadism. I have received non-financial support from Besins and from Abvie, outside the submitted work.
Stephanie T Page [email protected] Endocrinology and Diabetes, Harborview Medical Center, Division of Metabolism and Endocrinology, University of Washington, Seattle, WA 98195, USA 1
2
3
4
5
Bhasin S, Cunningham GR, Hayes FJ, et al, for the Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95: 2536–59. Roth JA, Etzioni R, Waters TM, et al. Economic return from the Women’s Health Initiative estrogen plus progestin clinical trial: a modeling study. Ann Intern Med 2014; 160: 594–602. Snyder PJ, Ellenberg SS, Cunningham GR, et al. The Testosterone trials: seven coordinated trials of testosterone treatment in elderly men. Clin Trials 2014; 11: 362–375. Fernández-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab 2010; 95: 2560–75. Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med 2013; 11: 108.
www.thelancet.com/diabetes-endocrinology Vol 2 August 2014
High serum cholesterol: a missed risk factor for chronic kidney disease mortality We appreciate the global coverage, comprehensive analytical methods, and meaningful conclusions of Majid Ezzati and colleagues’ report assessing mortality burden due to metabolic risk factors in major non-communicable diseases.1 However, we would like to underline an important shortcoming in their assumption that cholesterol is not a risk factor for mortality due to chronic kidney disease, thus implying that no deaths are attributable to atherosclerotic renovascular disease. Atherosclerotic renovascular disease is a fairly common disorder in elderly people, with relevant clinical consequences (table). Estimates of disease epidemiology vary greatly according to methods used for diagnosis and studied population. Prominent atherosclerotic renovascular disease was documented in as many as 7% of individuals aged 65 years and older with no history of kidney disease in a USA population-based study using renal duplex sonography.5 In a similarly aged population and time period, an analysis of an administrative database that accounted only to formal International Classification of Diseases, ninth revison, and Current Procedural Terminology codes, prevalence was 0·54% and incidence was 3·7 per 1000 patient-years.4 Among patients with other atherosclerotic diseases, diabetes, or hypertension, prevalence of atherosclerotic renovascular disease could reach up to 40%.3 Of note, the high mortality could be attributable to the independent effect of the renal disease, not only to its coexistence with other atherosclerotic lesions. Indeed, evidence is available to show that the presence of atherosclerotic renovascular disease in patients with coronary or peripheral artery disease more than doubles the risk of death, 613
Correspondence
Rate in patients with ARVD
Rate in US general Medicare population
Gradual loss of kidney function with development of chronic kidney disease*
24·6%
End-stage renal disease incidence (per 1000 patient-years)†
28·8%
1·3%
History of acute kidney injury*
10·3%
0·8%
Hypertension (often resistant)*
2·3%
90·8%
53·4%
Flash pulmonary oedema due to episodes of acute exacerbations of congestive heart failure
Almost 8%;can be ameliorated by renal artery revascularisation
Unknown
Death (per 1000 patient-years)†
166·3%
63·3%
ARVD=atherosclerotic renovascular disease. *Prevalence. †Incidence.
Table: Relevant clinical consequences of ARVD2–4
and the degree of renal artery stenosis predicts survival in individuals with atherosclerotic renovascular disease.3 Therefore, we believe that consideration of high serum cholesterol as a risk factor for development of renal artery atherosclerosis and atherosclerotic renovascular disease is crucial for the precise estimation of mortality and morbidity due to chronic kidney disease, and to accurately document the proportion of deaths attributable to different metabolic risk factors in further revisions from the Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration. GR has recieved payment to his institution from Abbvie, Alexion Pharmaceuticals, Bayer Healthcare, and Novertis Pharma. BB and NP declare no competing interests.
*Boris Bikbov, Norberto Perico, Giuseppe Remuzzi, on behalf of the Global Burden of Disease Study Genitourinary Disease Expert Group [email protected] Chair of Nephrology, AI Evdokimov Moscow State University of Medicine and Dentistry, Moscow 127463, Russia (BB); Department of Nephrology Issues of Transplanted Kidney, Academician VI Shumakov Federal Research Center of Transplantology and Artificial Organs, Moscow, Russia (BB); Moscow City Nephrology Center, Moscow City Hospital 52, Moscow, Russia (BB); Istituto di Ricerche Farmacologiche Mario Negri (IRCCS), Bergamo, Italy (NP, GR); and Unit of Nephrology, Dialysis and Transplantation, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy (GR) 1
614
The Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration. Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: a comparative risk assessment. Lancet Diabetes Endocrinol 2014; published online May 17. http://dx. doi:10.1016/S2213-8587(14)70102-0.
with the progression of chronic kidney disease remains mixed,4,5 and randomised trials6,7 showed no effect of statins on end-stage renal diseases. In summary, the association between high cholesterol and atherosclerotic renovascular disease is hypothesised, rather than confirmed, and there is no convincing or probable evidence on the presence of a causal association or its magnitude. We declare no competing interests.
2
3
4
5
Kalra PA, Guo H, Kausz AT, et al. Atherosclerotic renovascular disease in United States patients aged 67 years or older: risk factors, revascularization, and prognosis. Kidney Int 2005; 68: 293–301. Chrysochou C, Kalra PA. Epidemiology and natural history of atherosclerotic renovascular disease. Prog Cardiovasc Dis 2009; 52: 184–95. Ritchie J, Green D, Chrysochou C, Chalmers N, Foley RN, Kalra PA. High-risk clinical presentations in atherosclerotic renovascular disease: prognosis and response to renal artery revascularization. Am J Kidney Dis 2014; 63: 186–97. Hansen KJ, Edwards MS, Craven TE, et al. Prevalence of renovascular disease in the elderly: a population-based study. J Vasc Surg 2002; 36: 443–51.
Authors’ reply
*Majid Ezzati, Goodarz Danaei, on behalf of the Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group [email protected] MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK (ME); and Department of Global Health and Poulation, and Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA 1
2
In our analysis of death attributable to cardiometabolic risk factors, 1 we used disease outcomes with convincing or probable evidence of a causal association, which amounted to evidence of an association from randomised trials or from multiple well-done prospective studies. 2 Furthermore, quantification of the number of deaths attributable to risk factors requires data on the magnitude of the causal association, often a relative risk. Atherosclerotic renovascular disease does not currently meet either of these requirements. The report3 cited as evidence of an association by Bikbov and colleagues states “although intuitively hyperlipidaemia should be associated with increased ARVD [atherosclerotic renovascular disease] prevalence, there are no reports that confirm this relationship in the literature”. Evidence from prospective cohort studies for whether serum lipids are associated
3
4
5.
6
7
The Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration. Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: a comparative risk assessment. Lancet Diabetes Endocrinol 2014; published online May 17. http://dx.doi:10.1016/ S2213-8587(14)70102-0. Singh GM, Danaei G, Farzadfar F, et al. The age-specific quantitative effects of metabolic risk factors on cardiovascular diseases and diabetes: a pooled analysis. PLoS One 2013; 8: e65174. Chrysochou C, Kalra PA. Epidemiology and natural history of atherosclerotic renovascular disease. Prog Cardiovasc Dis 2009; 52: 184–95. Rahman M, Yang W, Akkina S, et al. Relation of Serum Lipids and Lipoproteins with Progression of CKD: The CRIC Study. Clin J Am Soc Nephrol 2014; 9: 1190–98. Baragetti A, Norata GD, Sarcina C, et al. High density lipoprotein cholesterol levels are an independent predictor of the progression of chronic kidney disease. J Intern Med 2013; 274: 252–62. Margolis KL, Davis BR, Baimbridge C, et al. Long-term follow-up of moderately hypercholesterolemic hypertensive patients following randomization to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). J Clin Hypertens 2013; 15: 542–54. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011; 377: 2181–92.
www.thelancet.com/diabetes-endocrinology Vol 2 August 2014
2
3
4
5
Soisson V, Brailly-Tabard S, Helmer C, et al. A J-shaped association between plasma testosterone and risk of ischemic arterial event in elderly men: the French 3C cohort study. Maturitas 2013; 75: 282–88. Yeap BB, Alfonso H, Chubb SAP, et al. In older men an optimal plasma testosterone is associated with reduced all-cause mortality and higher dihydrotestosterone with reduced ischemic heart disease mortality, while estradiol levels do not predict mortality. J Clin Endocrinol Metab 2014; 99: E9–18. Tan R, Cook KR, Reilly WG. Testosterone therapy is not associated with higher risk of myocardial infarction or stroke: the low T experience. American Association of Clinical Endocrinologists Annual Meeting 2014; May 13–18, 2014; Las Vegas, NV, USA. Abstract 1353. Muraleedharan V, Marsh H, Kapoor D, et al. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol 2013; 169: 1–10.
Author’s reply The letters from T Hugh Jones and Schooling and Xu discuss continuing controversies in testosterone replacement therapy in men, further highlighting the need for a large randomised controlled trial to assess the risks for testosterone therapy in men. Although such a trial might not be definitive, the current knowledge deficit makes both clinicians and patients reliant on inconsistent expert opinion for treatment decision making, with experts citing selected, poorer quality data. 1 Although the resource investment would be considerable, a large trial would likely reap large economic benefits, as recently shown by the Women’s Health Initiative, from which the return on each US$1 invested is about $140.2 Jones argues that testosterone replacement therapy improves survival and reduces cardiovascular events in men. He makes the important point that the clinical syndrome of male hypogonadism needs both symptoms and low serum testosterone concentrations,1 and symptoms of hypogonadism were not assessed in either of the recent studies linking testosterone replacement therapy and increased cardiovascular morbidity. This weakness is an inherent problem with reliance on large databases for patient
information and is often a weakness of observational studies. A welldesigned clinical trial in symptomatic men with low testosterone is crucial to support the assertion that testosterone replacement therapy benefits cardiovascular morbidity and survival. By contrast, Schooling and Xu argue that available data do not support a benefit for testosterone replacement therapy, an issue being addressed by a 1 year randomised trial of 800 men with symptomatic low testosterone3 that is funded by the US National Institutes of Health. Clearly, findings will provide important data. However, meta-analyses of shorter trials have reported conflicting conclusions about cardiovascular events and testosterone replacement.4,5 Importantly, the recent meta-analysis by Xu and colleagues5 was not limited to studies of only men with low testosterone, making the conclusions less clinically relevant for clinicians using published treatment guidelines. Such contradictory analyses show the need for better data for evidence-based medicine in the treatment of male hypogonadism. I have received non-financial support from Besins and from Abvie, outside the submitted work.
Stephanie T Page [email protected] Endocrinology and Diabetes, Harborview Medical Center, Division of Metabolism and Endocrinology, University of Washington, Seattle, WA 98195, USA 1
2
3
4
5
Bhasin S, Cunningham GR, Hayes FJ, et al, for the Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95: 2536–59. Roth JA, Etzioni R, Waters TM, et al. Economic return from the Women’s Health Initiative estrogen plus progestin clinical trial: a modeling study. Ann Intern Med 2014; 160: 594–602. Snyder PJ, Ellenberg SS, Cunningham GR, et al. The Testosterone trials: seven coordinated trials of testosterone treatment in elderly men. Clin Trials 2014; 11: 362–375. Fernández-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab 2010; 95: 2560–75. Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med 2013; 11: 108.
www.thelancet.com/diabetes-endocrinology Vol 2 August 2014
High serum cholesterol: a missed risk factor for chronic kidney disease mortality We appreciate the global coverage, comprehensive analytical methods, and meaningful conclusions of Majid Ezzati and colleagues’ report assessing mortality burden due to metabolic risk factors in major non-communicable diseases.1 However, we would like to underline an important shortcoming in their assumption that cholesterol is not a risk factor for mortality due to chronic kidney disease, thus implying that no deaths are attributable to atherosclerotic renovascular disease. Atherosclerotic renovascular disease is a fairly common disorder in elderly people, with relevant clinical consequences (table). Estimates of disease epidemiology vary greatly according to methods used for diagnosis and studied population. Prominent atherosclerotic renovascular disease was documented in as many as 7% of individuals aged 65 years and older with no history of kidney disease in a USA population-based study using renal duplex sonography.5 In a similarly aged population and time period, an analysis of an administrative database that accounted only to formal International Classification of Diseases, ninth revison, and Current Procedural Terminology codes, prevalence was 0·54% and incidence was 3·7 per 1000 patient-years.4 Among patients with other atherosclerotic diseases, diabetes, or hypertension, prevalence of atherosclerotic renovascular disease could reach up to 40%.3 Of note, the high mortality could be attributable to the independent effect of the renal disease, not only to its coexistence with other atherosclerotic lesions. Indeed, evidence is available to show that the presence of atherosclerotic renovascular disease in patients with coronary or peripheral artery disease more than doubles the risk of death, 613
Correspondence
Rate in patients with ARVD
Rate in US general Medicare population
Gradual loss of kidney function with development of chronic kidney disease*
24·6%
End-stage renal disease incidence (per 1000 patient-years)†
28·8%
1·3%
History of acute kidney injury*
10·3%
0·8%
Hypertension (often resistant)*
2·3%
90·8%
53·4%
Flash pulmonary oedema due to episodes of acute exacerbations of congestive heart failure
Almost 8%;can be ameliorated by renal artery revascularisation
Unknown
Death (per 1000 patient-years)†
166·3%
63·3%
ARVD=atherosclerotic renovascular disease. *Prevalence. †Incidence.
Table: Relevant clinical consequences of ARVD2–4
and the degree of renal artery stenosis predicts survival in individuals with atherosclerotic renovascular disease.3 Therefore, we believe that consideration of high serum cholesterol as a risk factor for development of renal artery atherosclerosis and atherosclerotic renovascular disease is crucial for the precise estimation of mortality and morbidity due to chronic kidney disease, and to accurately document the proportion of deaths attributable to different metabolic risk factors in further revisions from the Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration. GR has recieved payment to his institution from Abbvie, Alexion Pharmaceuticals, Bayer Healthcare, and Novertis Pharma. BB and NP declare no competing interests.
*Boris Bikbov, Norberto Perico, Giuseppe Remuzzi, on behalf of the Global Burden of Disease Study Genitourinary Disease Expert Group [email protected] Chair of Nephrology, AI Evdokimov Moscow State University of Medicine and Dentistry, Moscow 127463, Russia (BB); Department of Nephrology Issues of Transplanted Kidney, Academician VI Shumakov Federal Research Center of Transplantology and Artificial Organs, Moscow, Russia (BB); Moscow City Nephrology Center, Moscow City Hospital 52, Moscow, Russia (BB); Istituto di Ricerche Farmacologiche Mario Negri (IRCCS), Bergamo, Italy (NP, GR); and Unit of Nephrology, Dialysis and Transplantation, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy (GR) 1
614
The Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration. Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: a comparative risk assessment. Lancet Diabetes Endocrinol 2014; published online May 17. http://dx. doi:10.1016/S2213-8587(14)70102-0.
with the progression of chronic kidney disease remains mixed,4,5 and randomised trials6,7 showed no effect of statins on end-stage renal diseases. In summary, the association between high cholesterol and atherosclerotic renovascular disease is hypothesised, rather than confirmed, and there is no convincing or probable evidence on the presence of a causal association or its magnitude. We declare no competing interests.
2
3
4
5
Kalra PA, Guo H, Kausz AT, et al. Atherosclerotic renovascular disease in United States patients aged 67 years or older: risk factors, revascularization, and prognosis. Kidney Int 2005; 68: 293–301. Chrysochou C, Kalra PA. Epidemiology and natural history of atherosclerotic renovascular disease. Prog Cardiovasc Dis 2009; 52: 184–95. Ritchie J, Green D, Chrysochou C, Chalmers N, Foley RN, Kalra PA. High-risk clinical presentations in atherosclerotic renovascular disease: prognosis and response to renal artery revascularization. Am J Kidney Dis 2014; 63: 186–97. Hansen KJ, Edwards MS, Craven TE, et al. Prevalence of renovascular disease in the elderly: a population-based study. J Vasc Surg 2002; 36: 443–51.
Authors’ reply
*Majid Ezzati, Goodarz Danaei, on behalf of the Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group [email protected] MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK (ME); and Department of Global Health and Poulation, and Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA 1
2
In our analysis of death attributable to cardiometabolic risk factors, 1 we used disease outcomes with convincing or probable evidence of a causal association, which amounted to evidence of an association from randomised trials or from multiple well-done prospective studies. 2 Furthermore, quantification of the number of deaths attributable to risk factors requires data on the magnitude of the causal association, often a relative risk. Atherosclerotic renovascular disease does not currently meet either of these requirements. The report3 cited as evidence of an association by Bikbov and colleagues states “although intuitively hyperlipidaemia should be associated with increased ARVD [atherosclerotic renovascular disease] prevalence, there are no reports that confirm this relationship in the literature”. Evidence from prospective cohort studies for whether serum lipids are associated
3
4
5.
6
7
The Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration. Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: a comparative risk assessment. Lancet Diabetes Endocrinol 2014; published online May 17. http://dx.doi:10.1016/ S2213-8587(14)70102-0. Singh GM, Danaei G, Farzadfar F, et al. The age-specific quantitative effects of metabolic risk factors on cardiovascular diseases and diabetes: a pooled analysis. PLoS One 2013; 8: e65174. Chrysochou C, Kalra PA. Epidemiology and natural history of atherosclerotic renovascular disease. Prog Cardiovasc Dis 2009; 52: 184–95. Rahman M, Yang W, Akkina S, et al. Relation of Serum Lipids and Lipoproteins with Progression of CKD: The CRIC Study. Clin J Am Soc Nephrol 2014; 9: 1190–98. Baragetti A, Norata GD, Sarcina C, et al. High density lipoprotein cholesterol levels are an independent predictor of the progression of chronic kidney disease. J Intern Med 2013; 274: 252–62. Margolis KL, Davis BR, Baimbridge C, et al. Long-term follow-up of moderately hypercholesterolemic hypertensive patients following randomization to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). J Clin Hypertens 2013; 15: 542–54. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011; 377: 2181–92.
www.thelancet.com/diabetes-endocrinology Vol 2 August 2014
