- Email: [email protected]
Estimating cardiovascular disease risk in diabetes
Estimating cardiovascular disease risk in diabetes
younger than 40 years in 1994 mostly had type 1 diabetes, whereas type 2 disease predominated in those older than 40 years. We declare that we have no conflict of interest.
We agree with many of Gillian Booth and colleagues’ conclusions (July 1, p 29),1 but are concerned about some methodological shortcomings that might have affected key interpretations. Type 2 diabetes is asymptomatic for many years; thus, many “nondiabetic” individuals might in fact have had diabetes. Many patients who have a myocardial infarction have undiagnosed type 2 diabetes.2 How were these facts taken into account? People with diabetes often have “silent” myocardial infarctions without chest pain. How did this possibility affect diagnostic accuracy? Substituting all-cause mortality for mortality from cardiovascular disease is likely to substantially affect absolute risk figures. One aim of Booth and colleagues’ study was to determine the age at which people can be expected to move into a high absolute risk category for cardiovascular disease. But since the measure of absolute risk used includes non-cardiovasculardisease deaths, the calculated ages at which these transitions occur are younger than if Booth and colleagues had been able to restrict their analysis to the appropriate cardiovascular disease deaths. It is not possible for a reader to estimate the extent of this difference, but it is clearly very important because all the interventions (mainly lipid-lowering therapy) that would be used in highrisk patients are directed at reducing cardiovascular disease risk. No attempt was made to discriminate between type 1 and type 2 diabetes (two fundamentally different diseases) although hospital records with International Classification of Diseases codes E10 and E11 probably could have provided clues. One trivial explanation contributing to Booth and colleagues’ findings could be that people with diabetes who were www.thelancet.com Vol 368 September 30, 2006
*Åke Sjöholm, Paul Z Zimmet, Jonathan E Shaw [email protected] Karolinska Institutet, Department of Internal Medicine, Stockholm South Hospital, SE-11883 Stockholm, Sweden (AS); and International Diabetes Institute, Melbourne, Victoria, Australia (PZZ, JES) 1
2
Booth GL, Kapral MK, Fung K, Tu JV. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study. Lancet 2006; 368: 29–36. Norhammar A, Tenerz A, Nilsson G, et al. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet 2002; 359: 2140–44.
Gillian Booth and colleagues1 deserve praise for their further insights into the complex relation between cardiovascular risk, diabetes mellitus, and age. They point out that they are unable to adjust for several factors including hypertension, hypercholesterolaemia, and smoking, but I would like to emphasise another important variable that has been hitherto neglected: ethnicity. Previous epidemiological studies in the UK have shown a significantly increased mortality in the south Asian diabetic population, with upwards of 70% of mortality related to cardiovascular disease.2 Conversely, a Canadian case control series postmyocardial infarction showed a higher proportion of diabetes in south Asians (43·4% vs 28·2%, p<0·001).3 As well as possible underlying pathological mechanisms, there is evidence of differences in access to health care in these groups. Although cardiovascular risk in south Asians and other ethnic groups is recognised as an important area, this is yet to be seen in clinical research and practice. A study of cardiovascular cohort studies revealed that only 15 of 72 North American and European
studies assessed non-white ethnic minority groups.4 This is undoubtedly a complex issue that requires further unravelling as well We do not have the as increased attention. An eloquent example of such attention is the study rights to reproduce of the contribution of smoking to this image on the web. ethnic inequalities in mortality in the Maori population in New Zealand.5 The role of ethnicity should be considered both in clinical practice and research if we are to push the boundaries similarly in the rest of the world. I declare that I have no conflict of interest.
Nij Bhala [email protected] University Hospital of Coventry and Warwick, Walsgrave, Coventry CV2 2DX, UK 1
2
3
4
5
Booth GL, Kapral MK, Fung K, Tu JV. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study. Lancet 2006; 368: 29–36. Swerdlow AJ, Laing SP, Dos Santos Silva I, et al. Mortality of South Asian patients with insulintreated diabetes mellitus in the United Kingdom: a cohort study. Diabet Med 2004; 21: 845–51. Gupta M, Doobay AV, Singh N, et al. Risk factors, hospital management and outcomes after acute myocardial infarction in South Asian Canadians and matched control subjects. CMAJ 2002; 166: 717–22. Ranganathan M, Bhopal R. Exclusion and Inclusion of nonwhite ethnic minority groups in 72 North American and European cardiovascular cohort studies. PLoS Med 2006; 3: e44. Blakely T, Fawcett J, Hunt D, Wilson N. What is the contribution of smoking and socioeconomic position to ethnic inequalities in mortality in New Zealand? Lancet 2006; 368: 44–52.
Gillian Booth and colleagues1 convincingly show that diabetes confers a risk of cardiovascular disease equivalent to ageing 15 years. However, the second part of their conclusion, that younger people with diabetes (age 40 years or younger) do not seem to be at high risk of cardiovascular disease, could be misleading. Booth and colleagues’ definition of high risk of cardiovascular disease is an event rate of 20 or more per 1000 person-years or an event rate equivalent to that associated with previous myocardial infarction. Considering that age is one of the most important independent predictors
e-mail submissions to [email protected]
1149
Science Photo Library
Correspondence
Correspondence
of cardiovascular disease events2 and that the number of cardiovascular risk factors increases with advancing age, it is obvious that young people with one or two strong cardiovascular risk factors will not reach the “high risk” level in absolute terms. The early stages of diabetes in young people are characterised by subtle disturbances in various metabolic profiles including lipids, alterations in haemodynamics, and increased inflammation, which result in organ damage and culminate in cardiovascular disease and clinical events.3 Booth and colleagues could show that being diabetic in the second and third decade is associated with a 12–38-fold risk of myocardial infarction compared with being non-diabetic and of a similar age. Likewise, the risk of death within the same category of age is 6–7-fold higher in diabetic than non-diabetic individuals.1 The difference in risk between diabetics and non-diabetics is much higher in lower age-groups than higher age-groups. When considering younger diabetics as a “low risk” category we miss the opportunity to prevent the evolution of future cardiovascular disease and clinical events.4 We declare that we have no conflict of interest.
*Johann Auer, Gudrun Lamm, Bernd Eber [email protected] Department of Cardiology, General Hospital Wels, Grieskirchnerstrasse 42, A-4600 Wels, Austria 1
2
3
4
1150
Booth GL, Kapral MK, Fung K, Tu JV. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study. Lancet 2006; 368: 29–36. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report. Circulation 2002; 106: 3143–421. Sjöholm A, Nystrom T. Endothelial inflammation in insulin resistance. Lancet 2005; 365: 610–12. Schurgin S, Rich S, Mazzone T. Increased prevalence of significant coronary artery calcification in patients with diabetes. Diabetes Care 2001; 24: 335–38.
Authors’ reply Use of administrative health-care databases enabled us to examine the effect of age on cardiovascular risk in a very large population-based sample; however, these data do have some important limitations. In reply to Åke Sjöholm and colleagues, individuals who were diagnosed with diabetes at any point during our follow-up (eg, during a cardiovascular event) were excluded from the non-diabetic comparison group, but asymptomatic people who remained undiagnosed were not. Exclusion of these undiagnosed patients from our diabetic cohort might have led to higher estimates of cardiovascular disease within this population. Inclusion of noncardiovascular deaths in our definition of cardiovascular disease probably had a similar effect. However, alternative approaches resulting in lower absolute event rates would have lent further support to our contention that not all groups with diabetes are at high risk of cardiovascular events. Silent myocardial infarction is another outcome that cannot be ascertained from administrative data. Although silent events might be an important outcome, many published studies have excluded them in favour of harder endpoints. The algorithm we used to identify acute myocardial infarction was previously validated and shown to have a diagnostic accuracy of 96%.1 The preponderance of type 1 over type 2 diabetes in younger groups could contribute to the lower rate of cardiovascular disease among diabetic individuals younger than 40 years. We were unable to examine the effect of diabetes subtype on cardiovascular risk in our analysis. Although the 10th version of the International Classification of Diseases uses E10 and E11 codes to define diabetes subtypes, this version was adopted by the Canadian Institute for Health Information hospital discharge database in 2002—after the end of
our study period. However, fewer than 3% of individuals younger than 40 years who enter our diabetes database do so on the basis of hospital-derived diabetes claims, rendering this datasource unreliable for that purpose. Similarly, our health records do not collect information on ethnicity. We agree with Nij Bhala that ethnicity can be an important predictor of cardiovascular events. Our study identifies a need for further research into more precise ways to estimate cardiovascular risk in populations with diabetes that consider age, diabetes subtype, disease duration, ethnicity, and other important risk factors. The relative importance of lifetime versus short-term cardiovascular risk in determining the need for riskmodifying agents, as raised by Johann Auer and colleagues, is a matter of debate.2 Our findings do not suggest that all young people with diabetes be considered as “low” or “moderate” risk but confirm that the absolute risk is not uniformly high in this subgroup. 10-year estimates are commonly used by clinical practice guidelines to define cardiovascular risk, with some guidelines calling for an individualised approach to risk reduction even in the diabetic population.3 Our findings support individualisation of therapy in younger populations with diabetes when considering short-term prevention strategies. We declare that we have no conflict of interest.
*Gillian L Booth, Moira K Kapral, Jack V Tu [email protected] Division of Endocrinology and Metabolism, St Michael’s Hospital, Toronto, Ontario M5C 2T2, Canada 1
2
3
Tu JV, Naylor CD, Austin P. Temporal changes in the outcomes of acute myocardial infarction in Ontario, 1992–1996. CMAJ 1999; 161: 1257–61. Grundy SM. Diabetes and coronary risk equivalency. What does it mean? Diabetes Care 2006; 29: 457–58. McIntosh A, Hutchinson A, Feder G, et al. Clinical guidelines and evidence review for type 2 diabetes: lipids management. Sheffield: ScHARR, University of Sheffield: 2002. http:// www.nice.org.uk/page.aspx?o=264875.
www.thelancet.com Vol 368 September 30, 2006
younger than 40 years in 1994 mostly had type 1 diabetes, whereas type 2 disease predominated in those older than 40 years. We declare that we have no conflict of interest.
We agree with many of Gillian Booth and colleagues’ conclusions (July 1, p 29),1 but are concerned about some methodological shortcomings that might have affected key interpretations. Type 2 diabetes is asymptomatic for many years; thus, many “nondiabetic” individuals might in fact have had diabetes. Many patients who have a myocardial infarction have undiagnosed type 2 diabetes.2 How were these facts taken into account? People with diabetes often have “silent” myocardial infarctions without chest pain. How did this possibility affect diagnostic accuracy? Substituting all-cause mortality for mortality from cardiovascular disease is likely to substantially affect absolute risk figures. One aim of Booth and colleagues’ study was to determine the age at which people can be expected to move into a high absolute risk category for cardiovascular disease. But since the measure of absolute risk used includes non-cardiovasculardisease deaths, the calculated ages at which these transitions occur are younger than if Booth and colleagues had been able to restrict their analysis to the appropriate cardiovascular disease deaths. It is not possible for a reader to estimate the extent of this difference, but it is clearly very important because all the interventions (mainly lipid-lowering therapy) that would be used in highrisk patients are directed at reducing cardiovascular disease risk. No attempt was made to discriminate between type 1 and type 2 diabetes (two fundamentally different diseases) although hospital records with International Classification of Diseases codes E10 and E11 probably could have provided clues. One trivial explanation contributing to Booth and colleagues’ findings could be that people with diabetes who were www.thelancet.com Vol 368 September 30, 2006
*Åke Sjöholm, Paul Z Zimmet, Jonathan E Shaw [email protected] Karolinska Institutet, Department of Internal Medicine, Stockholm South Hospital, SE-11883 Stockholm, Sweden (AS); and International Diabetes Institute, Melbourne, Victoria, Australia (PZZ, JES) 1
2
Booth GL, Kapral MK, Fung K, Tu JV. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study. Lancet 2006; 368: 29–36. Norhammar A, Tenerz A, Nilsson G, et al. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet 2002; 359: 2140–44.
Gillian Booth and colleagues1 deserve praise for their further insights into the complex relation between cardiovascular risk, diabetes mellitus, and age. They point out that they are unable to adjust for several factors including hypertension, hypercholesterolaemia, and smoking, but I would like to emphasise another important variable that has been hitherto neglected: ethnicity. Previous epidemiological studies in the UK have shown a significantly increased mortality in the south Asian diabetic population, with upwards of 70% of mortality related to cardiovascular disease.2 Conversely, a Canadian case control series postmyocardial infarction showed a higher proportion of diabetes in south Asians (43·4% vs 28·2%, p<0·001).3 As well as possible underlying pathological mechanisms, there is evidence of differences in access to health care in these groups. Although cardiovascular risk in south Asians and other ethnic groups is recognised as an important area, this is yet to be seen in clinical research and practice. A study of cardiovascular cohort studies revealed that only 15 of 72 North American and European
studies assessed non-white ethnic minority groups.4 This is undoubtedly a complex issue that requires further unravelling as well We do not have the as increased attention. An eloquent example of such attention is the study rights to reproduce of the contribution of smoking to this image on the web. ethnic inequalities in mortality in the Maori population in New Zealand.5 The role of ethnicity should be considered both in clinical practice and research if we are to push the boundaries similarly in the rest of the world. I declare that I have no conflict of interest.
Nij Bhala [email protected] University Hospital of Coventry and Warwick, Walsgrave, Coventry CV2 2DX, UK 1
2
3
4
5
Booth GL, Kapral MK, Fung K, Tu JV. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study. Lancet 2006; 368: 29–36. Swerdlow AJ, Laing SP, Dos Santos Silva I, et al. Mortality of South Asian patients with insulintreated diabetes mellitus in the United Kingdom: a cohort study. Diabet Med 2004; 21: 845–51. Gupta M, Doobay AV, Singh N, et al. Risk factors, hospital management and outcomes after acute myocardial infarction in South Asian Canadians and matched control subjects. CMAJ 2002; 166: 717–22. Ranganathan M, Bhopal R. Exclusion and Inclusion of nonwhite ethnic minority groups in 72 North American and European cardiovascular cohort studies. PLoS Med 2006; 3: e44. Blakely T, Fawcett J, Hunt D, Wilson N. What is the contribution of smoking and socioeconomic position to ethnic inequalities in mortality in New Zealand? Lancet 2006; 368: 44–52.
Gillian Booth and colleagues1 convincingly show that diabetes confers a risk of cardiovascular disease equivalent to ageing 15 years. However, the second part of their conclusion, that younger people with diabetes (age 40 years or younger) do not seem to be at high risk of cardiovascular disease, could be misleading. Booth and colleagues’ definition of high risk of cardiovascular disease is an event rate of 20 or more per 1000 person-years or an event rate equivalent to that associated with previous myocardial infarction. Considering that age is one of the most important independent predictors
e-mail submissions to [email protected]
1149
Science Photo Library
Correspondence
Correspondence
of cardiovascular disease events2 and that the number of cardiovascular risk factors increases with advancing age, it is obvious that young people with one or two strong cardiovascular risk factors will not reach the “high risk” level in absolute terms. The early stages of diabetes in young people are characterised by subtle disturbances in various metabolic profiles including lipids, alterations in haemodynamics, and increased inflammation, which result in organ damage and culminate in cardiovascular disease and clinical events.3 Booth and colleagues could show that being diabetic in the second and third decade is associated with a 12–38-fold risk of myocardial infarction compared with being non-diabetic and of a similar age. Likewise, the risk of death within the same category of age is 6–7-fold higher in diabetic than non-diabetic individuals.1 The difference in risk between diabetics and non-diabetics is much higher in lower age-groups than higher age-groups. When considering younger diabetics as a “low risk” category we miss the opportunity to prevent the evolution of future cardiovascular disease and clinical events.4 We declare that we have no conflict of interest.
*Johann Auer, Gudrun Lamm, Bernd Eber [email protected] Department of Cardiology, General Hospital Wels, Grieskirchnerstrasse 42, A-4600 Wels, Austria 1
2
3
4
1150
Booth GL, Kapral MK, Fung K, Tu JV. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study. Lancet 2006; 368: 29–36. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report. Circulation 2002; 106: 3143–421. Sjöholm A, Nystrom T. Endothelial inflammation in insulin resistance. Lancet 2005; 365: 610–12. Schurgin S, Rich S, Mazzone T. Increased prevalence of significant coronary artery calcification in patients with diabetes. Diabetes Care 2001; 24: 335–38.
Authors’ reply Use of administrative health-care databases enabled us to examine the effect of age on cardiovascular risk in a very large population-based sample; however, these data do have some important limitations. In reply to Åke Sjöholm and colleagues, individuals who were diagnosed with diabetes at any point during our follow-up (eg, during a cardiovascular event) were excluded from the non-diabetic comparison group, but asymptomatic people who remained undiagnosed were not. Exclusion of these undiagnosed patients from our diabetic cohort might have led to higher estimates of cardiovascular disease within this population. Inclusion of noncardiovascular deaths in our definition of cardiovascular disease probably had a similar effect. However, alternative approaches resulting in lower absolute event rates would have lent further support to our contention that not all groups with diabetes are at high risk of cardiovascular events. Silent myocardial infarction is another outcome that cannot be ascertained from administrative data. Although silent events might be an important outcome, many published studies have excluded them in favour of harder endpoints. The algorithm we used to identify acute myocardial infarction was previously validated and shown to have a diagnostic accuracy of 96%.1 The preponderance of type 1 over type 2 diabetes in younger groups could contribute to the lower rate of cardiovascular disease among diabetic individuals younger than 40 years. We were unable to examine the effect of diabetes subtype on cardiovascular risk in our analysis. Although the 10th version of the International Classification of Diseases uses E10 and E11 codes to define diabetes subtypes, this version was adopted by the Canadian Institute for Health Information hospital discharge database in 2002—after the end of
our study period. However, fewer than 3% of individuals younger than 40 years who enter our diabetes database do so on the basis of hospital-derived diabetes claims, rendering this datasource unreliable for that purpose. Similarly, our health records do not collect information on ethnicity. We agree with Nij Bhala that ethnicity can be an important predictor of cardiovascular events. Our study identifies a need for further research into more precise ways to estimate cardiovascular risk in populations with diabetes that consider age, diabetes subtype, disease duration, ethnicity, and other important risk factors. The relative importance of lifetime versus short-term cardiovascular risk in determining the need for riskmodifying agents, as raised by Johann Auer and colleagues, is a matter of debate.2 Our findings do not suggest that all young people with diabetes be considered as “low” or “moderate” risk but confirm that the absolute risk is not uniformly high in this subgroup. 10-year estimates are commonly used by clinical practice guidelines to define cardiovascular risk, with some guidelines calling for an individualised approach to risk reduction even in the diabetic population.3 Our findings support individualisation of therapy in younger populations with diabetes when considering short-term prevention strategies. We declare that we have no conflict of interest.
*Gillian L Booth, Moira K Kapral, Jack V Tu [email protected] Division of Endocrinology and Metabolism, St Michael’s Hospital, Toronto, Ontario M5C 2T2, Canada 1
2
3
Tu JV, Naylor CD, Austin P. Temporal changes in the outcomes of acute myocardial infarction in Ontario, 1992–1996. CMAJ 1999; 161: 1257–61. Grundy SM. Diabetes and coronary risk equivalency. What does it mean? Diabetes Care 2006; 29: 457–58. McIntosh A, Hutchinson A, Feder G, et al. Clinical guidelines and evidence review for type 2 diabetes: lipids management. Sheffield: ScHARR, University of Sheffield: 2002. http:// www.nice.org.uk/page.aspx?o=264875.
www.thelancet.com Vol 368 September 30, 2006