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Diabetes mellitus and risk of sudden cardiac death: A systematic review and meta-analysis
International Journal of Cardiology 177 (2014) 535–537
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Diabetes mellitus and risk of sudden cardiac death: A systematic review and meta-analysis☆ Francesco Zaccardi a,b,⁎, Hassan Khan b, Jari A. Laukkanen c a b c
Internal Medicine and Diabetes Care Unit, Catholic University School of Medicine, Rome, Italy Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, United Kingdom Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
a r t i c l e
i n f o
Article history: Received 27 June 2014 Accepted 17 August 2014 Available online 26 August 2014 Keywords: Diabetes mellitus Sudden cardiac death Meta-analysis Diabetic autonomic neuropathy Cardiovascular disease
Sudden cardiac death (SCD), generally defined as unexpected death occurring within a short period of time after the onset of symptoms, accounts for 50% of all cardiovascular disease (CVD)-related deaths and its incidence has been estimated to be between 180,000 and 250,000 annually in the US [1]. Risk factors for nonsudden CVD events and SCD are similar; however, other factors have been proposed, such as the sympato-vagal imbalance [2]. This observation would suggest a particularly high incidence of SCD in individuals with diabetes mellitus (DM) who are predisposed to autonomic dysfunction, mainly with increasing duration of the disease and exposure to uncontrolled dysglycemia [3]. DM approximately doubles the risk of a wide range of vascular diseases including coronary heart disease (CHD) and stroke [4]. However, the impact of diabetes on the risk of SCD has not been reliably quantified because individual studies have typically not recorded many occurrences of this condition, as they tend to be less frequent or less well studied than CHD or stroke. Furthermore, it is not clear whether the risk of SCD in DM differs by population groups such as by gender or pre-existing vascular disease (VD).
☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Servizio di Diabetologia, Policlinico Gemelli, L.go A. Gemelli, 00168 Roma, Italy. Tel.: +39 630154112; fax: +39 630157232. E-mail address: [email protected] (F. Zaccardi).
http://dx.doi.org/10.1016/j.ijcard.2014.08.105 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
To help clarify the current evidence, we have conducted a systematic review and meta-analysis of data from observational studies that reported on diabetes mellitus and risk of SCD. Methods are described in the supplementary material. Overall 18 studies were identified (eFigure 1) and 14 were included in the meta-analysis (in 3 studies it was not possible to obtain relevant estimates from the published report or correspondence and one study reported data on the same population but with a shorter follow-up); references and details are provided in the supplementary material. Study characteristics and quality score assessed using the Newcastle– Ottawa Scale are reported in Table 1 and eTables 1 and 2. Of the 14 studies included (involving a total of 5647 SCD cases and 346,356 participants), 10 studies were prospective in design (median followup 11.6 years) and 4 were case–control studies; eleven were based in the US or Europe and 3 in Japan, Australia and China. Diagnosis of diabetes was generally based on biochemical measurements or self-reported, while SCD definitions varied among studies mainly due to the specification of the time frame between onset of acute symptoms and death. All the studies, except one, adjusted at least for age, sex (when appropriate) and for conventional cardiovascular risk factors such as blood pressure, dyslipidemia and smoking status (Table 1 and eTable1). The random-effects meta-analysis comparing DM versus non-diabetic subjects and combining maximally adjusted RR of SCD was 2.18 (95% CI: 1.89, 2.52; p b 0.001) (Fig. 1 and eFigure 2), with a moderate level of heterogeneity across the studies (I2 = 42% [95% CI: 0, 69], p = 0.049); there was no evidence of publication bias (eFigure 3; Egger's p = 0.116). RRs of SCD did not significantly differ according to several clinical and study characteristics such as level of adjustment, duration of follow-up, gender, number of cases recorded, inclusion of individuals with pre-existing VD at baseline and study design (Fig. 1). In sensitivity analyses, RRs of SCD were not different comparing studies that have [11–15, 18, 19, 21–24] or have not [16, 17, 20] used a clear definition of the time-frame between the onset of the symptoms and SCD (meta-regression p = 0.237); similarly, no difference was found comparing studies with only self-reported diagnosis of diabetes [11, 16, 22, 23] to those including self-reported, biochemical or antidiabetic drug diagnostic criteria [12–15, 17–21, 24] (meta-regression p = 0.090). Our results suggested a two-fold higher risk of SCD in DM compared to non-DM subjects; this finding was consistent across several clinical
536
F. Zaccardi et al. / International Journal of Cardiology 177 (2014) 535–537
Table 1 Characteristics of the studies included in the meta-analysis. First author [Ref.]
Year
Albert [11] Balkau [12] Bertoia [13] Burke [14] Curb [15] Escobedo [16] Jouven [17] Junttila [18] Kataoka [19] Kucharska-Newton [20] Laukkanen [21] Sexton [22] Wannamethee [23] Yeung [24]
2003 1999 2012 2002 1995 1997 2005 2010 2003 2009 2013 1997 1995 2012
Designa
PC PC PC CC PC CC CC PC PC PC PC CC PC PC
Location
US France US US US US US Germany Japan US Finland Australia UK China
No. of Participants
Cases (%)
Men (%)
Age mean (yrs)
Follow-up (yrs)
Prevalent VDc
Adjustment levelh
121,701 6539 161,808 774 8006 4726 5840 3276 8917 13,978 2140 306 7735 610
244 (0.20) 92 (1.41) 418 (0.26) 206 (26.61) 347 (4.33) 1415 (29.94) 2040 (34.93) 83 (2.53) 56 (0.63) 209 (1.50) 175 (8.18) 102 (33.33) 117 (1.51) 143 (23.44)
0 100 0 80b 100 49e 70e 77 55 43e 100 100 100 74
30–55d 48 63 51b 45–68d N25 67 60 60 54 53 25–74d 40–59d 65
22 17.5 10.8 NAg 23 NAg NAg 4 6.5 12.4 19 NAg 8 5
Both No No/bothf Both No Yes/nof Yes/no/bothf Yes Both No Both No Both Yes
++ ++ ++ +++ +++ + + +++ +++ ++ ++ ++ +++ –
Notes: References of the studies are reported in the supplementary material. +, adjusted for age, sex (when appropriate), 1 or 2 cardiovascular risk factors. ++, adjusted for age, sex (when appropriate), 3 cardiovascular risk factors (not left ventricular hypertrophy and/or ECG variables). +++, adjusted for age, sex (when appropriate), 3 cardiovascular risk factors plus left ventricular hypertrophy and/or ECG variables. Cardiovascular risk factors are reported in Supplementary eTable 1. a PC, prospective cohort; CC, case control. b Data available only for cases. c Vascular Disease, either macrovascular [acute or previous MI, angina or coronary revascularization] or microvascular [retinopathy or nephropathy] disease. d Range. e Analysis stratified by gender: Males/females/both sexes. f Analysis stratified by prevalent cardiovascular disease; “Both” indicates that also unstratified analysis is reported. g NA, not applicable. h –, adjusted for not specified covariates.
and study level characteristics, such as gender and history of VD, and did not differ according to the definitions of SCD or DM. SCD continues to be a relevant public health problem as the large majority of events occur outside the hospital and in individuals
without a previous clinical diagnosis of CVD; therefore, the identification of markers of SCD for risk stratification is of great interest. Although SCD and CVD share generally the same risk factors, in recent years an increase in the SCD-to-CVD events ratio has been
Fig. 1. Overall and subgroup-specific relative risk of sudden cardiac death comparing diabetes vs nondiabetes. Legend: ⁎ + adjusted for age, sex (when appropriate), 1 or 2 cardiovascular risk factors ++ adjusted for age, sex (when appropriate), 3 cardiovascular risk factors (not left ventricular hypertrophy and/or ECG variables) +++ adjusted for age, sex (when appropriate), 3 cardiovascular risk factors plus left ventricular hypertrophy and/or ECG variables. ^ Prospective studies only $ Two studies had data stratified for both gender and prevalent VD; one for prevalent VD only and one for gender only (Table 1). RR: Relative Risk; CI: Confidence Interval; p(Het): p for heterogeneity of estimates between groups; VD: Vascular Disease, either macrovascular (acute or previous MI, angina or coronary revascularization) or microvascular (retinopathy or nephropathy) disease.
F. Zaccardi et al. / International Journal of Cardiology 177 (2014) 535–537
observed, suggesting that other mechanism(s) could be potentially implicated [1]. Several potential biological mechanisms might explain the association between DM and SCD. First, while a multifactorial control of DMassociated CVD risk factors (particularly blood pressure and dyslipidemia) can significantly reduce CVD risk in DM, recent trials have cast doubt on a beneficial effect of tight glucose control for the prevention of CVD [5], stimulating the research of the other mechanism(s) that may dilute the benefit of intensive glucose control. An increased risk of hypoglycaemic episodes has been suggested as a potential mechanism to explain this apparent lack of efficacy, as hypoglycaemic events are more frequent in intensive-treated diabetic subjects and they have long been associated with arrhythmic abnormalities [5]. A meta-analysis of about a million diabetic subjects has indeed evidenced a strong association between severe hypoglycaemic episodes and CVD risk [6] and, more recently, a specific increase of SCD events has been reported in intensively treated type 2 DM subjects [7]. Second, diabetic autonomic neuropathy (DAN) might be another potential mechanism, as subjects with DAN have a high prevalence of electrocardiographic abnormalities and an increased risk of SCD [8]. Moreover, subjects with DAN have also an increased risk of hypoglycaemia. A third possible mechanism is the so-called “diabetic cardiomyopathy”: structural changes in the myocardium/interstitium of diabetic heart have been described, and these modifications have been associated with SCD [9]. Lastly, although many studies have been adjusted for conventional CHD risk factors, the higher risk of SCD in DM could be due to a concomitant increased risk of CHD. Our study has several strengths and limitations. First, to our knowledge this is the first attempt to reliably summarise the evidence on the association between DM and SCD; second, we extracted data according to standardised protocol and on several variables that enable clinically relevant sub-group analyses; third, the generalisability of our findings has been enhanced by the involvement of ~340,000 participants who, with the exception of three studies (that selected people with a previous history of myocardial infarction or only post-menopausal women), have been selected from the general population (i.e., participants not selected on the basis of pre-existing characteristic or disease at baseline). Although we were not able to include 3 studies in our meta-analysis, these represent only 4% of the total number of cases included in the current report. Moreover, SCD and DM were differently defined across studies; yet, no significant heterogeneities were evident according to their definitions. We also lacked access to individual participant data and therefore we could not adjust consistently for potential confounding factors across all studies. In conclusion, the results of this study evidenced a two-fold higher risk of SCD in subjects with DM and further emphasize the need of a better definition of the interrelationship between DM, CVD and SCD [10].
537
Author contribution F.Z. conceived the idea, performed literature search, analysed data and wrote the paper. H.K. contributed to data analysis and wrote the paper. J.A.L. performed literature search and reviewed the paper. All authors approved the final submitted version of the manuscript. Funding None. Duality of interest The authors report no relationships that could be construed as a conflict of interest. Acknowledgements We thank Dr Emanuele Di Angelantonio (Cardiovascular Epidemiology Unit, Cambridge University, UK) for his helpful comments. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2014.08.105. References [1] Adabag AS, Luepker RV, Roger VL, Gersh BJ. Sudden cardiac death: epidemiology and risk factors. Nat Rev Cardiol 2010;7:216–25. [2] Volders PG. Novel insights into the role of the sympathetic nervous system in cardiac arrhythmogenesis. Heart Rhythm 2010;7:1900–6. [3] Vinik AI, Erbas T, Casellini CM. Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. J Diabetes Investig 2013;4:4–18. [4] Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010;375:2215–22. [5] Terry T, Raravikar K, Chokrungvaranon N, Reaven PD. Does aggressive glycemic control benefit macrovascular and microvascular disease in type 2 diabetes? Insights from ACCORD, ADVANCE, and VADT. Curr Cardiol Rep 2012;14:79–88. [6] Goto A, Arah OA, Goto M, Terauchi Y, Noda M. Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. BMJ 2013; 347:f4533. [7] The ORIGIN Trial Investigators. Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial. Eur Heart J 2013;34:3137–44. [8] Spallone V, Ziegler D, Freeman R, et al. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 2011;27:639–53. [9] Chugh SS, Kelly KL, Titus JL. Sudden cardiac death with apparently normal heart. Circulation 2000;102:649–54. [10] Vasiliadis I, Kolovou G, Mavrogeni S, Nair DR, Mikhailidis DP. Sudden cardiac death and diabetes mellitus. J Diabetes Complications 2014;28:573–9.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Diabetes mellitus and risk of sudden cardiac death: A systematic review and meta-analysis☆ Francesco Zaccardi a,b,⁎, Hassan Khan b, Jari A. Laukkanen c a b c
Internal Medicine and Diabetes Care Unit, Catholic University School of Medicine, Rome, Italy Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, United Kingdom Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
a r t i c l e
i n f o
Article history: Received 27 June 2014 Accepted 17 August 2014 Available online 26 August 2014 Keywords: Diabetes mellitus Sudden cardiac death Meta-analysis Diabetic autonomic neuropathy Cardiovascular disease
Sudden cardiac death (SCD), generally defined as unexpected death occurring within a short period of time after the onset of symptoms, accounts for 50% of all cardiovascular disease (CVD)-related deaths and its incidence has been estimated to be between 180,000 and 250,000 annually in the US [1]. Risk factors for nonsudden CVD events and SCD are similar; however, other factors have been proposed, such as the sympato-vagal imbalance [2]. This observation would suggest a particularly high incidence of SCD in individuals with diabetes mellitus (DM) who are predisposed to autonomic dysfunction, mainly with increasing duration of the disease and exposure to uncontrolled dysglycemia [3]. DM approximately doubles the risk of a wide range of vascular diseases including coronary heart disease (CHD) and stroke [4]. However, the impact of diabetes on the risk of SCD has not been reliably quantified because individual studies have typically not recorded many occurrences of this condition, as they tend to be less frequent or less well studied than CHD or stroke. Furthermore, it is not clear whether the risk of SCD in DM differs by population groups such as by gender or pre-existing vascular disease (VD).
☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Servizio di Diabetologia, Policlinico Gemelli, L.go A. Gemelli, 00168 Roma, Italy. Tel.: +39 630154112; fax: +39 630157232. E-mail address: [email protected] (F. Zaccardi).
http://dx.doi.org/10.1016/j.ijcard.2014.08.105 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
To help clarify the current evidence, we have conducted a systematic review and meta-analysis of data from observational studies that reported on diabetes mellitus and risk of SCD. Methods are described in the supplementary material. Overall 18 studies were identified (eFigure 1) and 14 were included in the meta-analysis (in 3 studies it was not possible to obtain relevant estimates from the published report or correspondence and one study reported data on the same population but with a shorter follow-up); references and details are provided in the supplementary material. Study characteristics and quality score assessed using the Newcastle– Ottawa Scale are reported in Table 1 and eTables 1 and 2. Of the 14 studies included (involving a total of 5647 SCD cases and 346,356 participants), 10 studies were prospective in design (median followup 11.6 years) and 4 were case–control studies; eleven were based in the US or Europe and 3 in Japan, Australia and China. Diagnosis of diabetes was generally based on biochemical measurements or self-reported, while SCD definitions varied among studies mainly due to the specification of the time frame between onset of acute symptoms and death. All the studies, except one, adjusted at least for age, sex (when appropriate) and for conventional cardiovascular risk factors such as blood pressure, dyslipidemia and smoking status (Table 1 and eTable1). The random-effects meta-analysis comparing DM versus non-diabetic subjects and combining maximally adjusted RR of SCD was 2.18 (95% CI: 1.89, 2.52; p b 0.001) (Fig. 1 and eFigure 2), with a moderate level of heterogeneity across the studies (I2 = 42% [95% CI: 0, 69], p = 0.049); there was no evidence of publication bias (eFigure 3; Egger's p = 0.116). RRs of SCD did not significantly differ according to several clinical and study characteristics such as level of adjustment, duration of follow-up, gender, number of cases recorded, inclusion of individuals with pre-existing VD at baseline and study design (Fig. 1). In sensitivity analyses, RRs of SCD were not different comparing studies that have [11–15, 18, 19, 21–24] or have not [16, 17, 20] used a clear definition of the time-frame between the onset of the symptoms and SCD (meta-regression p = 0.237); similarly, no difference was found comparing studies with only self-reported diagnosis of diabetes [11, 16, 22, 23] to those including self-reported, biochemical or antidiabetic drug diagnostic criteria [12–15, 17–21, 24] (meta-regression p = 0.090). Our results suggested a two-fold higher risk of SCD in DM compared to non-DM subjects; this finding was consistent across several clinical
536
F. Zaccardi et al. / International Journal of Cardiology 177 (2014) 535–537
Table 1 Characteristics of the studies included in the meta-analysis. First author [Ref.]
Year
Albert [11] Balkau [12] Bertoia [13] Burke [14] Curb [15] Escobedo [16] Jouven [17] Junttila [18] Kataoka [19] Kucharska-Newton [20] Laukkanen [21] Sexton [22] Wannamethee [23] Yeung [24]
2003 1999 2012 2002 1995 1997 2005 2010 2003 2009 2013 1997 1995 2012
Designa
PC PC PC CC PC CC CC PC PC PC PC CC PC PC
Location
US France US US US US US Germany Japan US Finland Australia UK China
No. of Participants
Cases (%)
Men (%)
Age mean (yrs)
Follow-up (yrs)
Prevalent VDc
Adjustment levelh
121,701 6539 161,808 774 8006 4726 5840 3276 8917 13,978 2140 306 7735 610
244 (0.20) 92 (1.41) 418 (0.26) 206 (26.61) 347 (4.33) 1415 (29.94) 2040 (34.93) 83 (2.53) 56 (0.63) 209 (1.50) 175 (8.18) 102 (33.33) 117 (1.51) 143 (23.44)
0 100 0 80b 100 49e 70e 77 55 43e 100 100 100 74
30–55d 48 63 51b 45–68d N25 67 60 60 54 53 25–74d 40–59d 65
22 17.5 10.8 NAg 23 NAg NAg 4 6.5 12.4 19 NAg 8 5
Both No No/bothf Both No Yes/nof Yes/no/bothf Yes Both No Both No Both Yes
++ ++ ++ +++ +++ + + +++ +++ ++ ++ ++ +++ –
Notes: References of the studies are reported in the supplementary material. +, adjusted for age, sex (when appropriate), 1 or 2 cardiovascular risk factors. ++, adjusted for age, sex (when appropriate), 3 cardiovascular risk factors (not left ventricular hypertrophy and/or ECG variables). +++, adjusted for age, sex (when appropriate), 3 cardiovascular risk factors plus left ventricular hypertrophy and/or ECG variables. Cardiovascular risk factors are reported in Supplementary eTable 1. a PC, prospective cohort; CC, case control. b Data available only for cases. c Vascular Disease, either macrovascular [acute or previous MI, angina or coronary revascularization] or microvascular [retinopathy or nephropathy] disease. d Range. e Analysis stratified by gender: Males/females/both sexes. f Analysis stratified by prevalent cardiovascular disease; “Both” indicates that also unstratified analysis is reported. g NA, not applicable. h –, adjusted for not specified covariates.
and study level characteristics, such as gender and history of VD, and did not differ according to the definitions of SCD or DM. SCD continues to be a relevant public health problem as the large majority of events occur outside the hospital and in individuals
without a previous clinical diagnosis of CVD; therefore, the identification of markers of SCD for risk stratification is of great interest. Although SCD and CVD share generally the same risk factors, in recent years an increase in the SCD-to-CVD events ratio has been
Fig. 1. Overall and subgroup-specific relative risk of sudden cardiac death comparing diabetes vs nondiabetes. Legend: ⁎ + adjusted for age, sex (when appropriate), 1 or 2 cardiovascular risk factors ++ adjusted for age, sex (when appropriate), 3 cardiovascular risk factors (not left ventricular hypertrophy and/or ECG variables) +++ adjusted for age, sex (when appropriate), 3 cardiovascular risk factors plus left ventricular hypertrophy and/or ECG variables. ^ Prospective studies only $ Two studies had data stratified for both gender and prevalent VD; one for prevalent VD only and one for gender only (Table 1). RR: Relative Risk; CI: Confidence Interval; p(Het): p for heterogeneity of estimates between groups; VD: Vascular Disease, either macrovascular (acute or previous MI, angina or coronary revascularization) or microvascular (retinopathy or nephropathy) disease.
F. Zaccardi et al. / International Journal of Cardiology 177 (2014) 535–537
observed, suggesting that other mechanism(s) could be potentially implicated [1]. Several potential biological mechanisms might explain the association between DM and SCD. First, while a multifactorial control of DMassociated CVD risk factors (particularly blood pressure and dyslipidemia) can significantly reduce CVD risk in DM, recent trials have cast doubt on a beneficial effect of tight glucose control for the prevention of CVD [5], stimulating the research of the other mechanism(s) that may dilute the benefit of intensive glucose control. An increased risk of hypoglycaemic episodes has been suggested as a potential mechanism to explain this apparent lack of efficacy, as hypoglycaemic events are more frequent in intensive-treated diabetic subjects and they have long been associated with arrhythmic abnormalities [5]. A meta-analysis of about a million diabetic subjects has indeed evidenced a strong association between severe hypoglycaemic episodes and CVD risk [6] and, more recently, a specific increase of SCD events has been reported in intensively treated type 2 DM subjects [7]. Second, diabetic autonomic neuropathy (DAN) might be another potential mechanism, as subjects with DAN have a high prevalence of electrocardiographic abnormalities and an increased risk of SCD [8]. Moreover, subjects with DAN have also an increased risk of hypoglycaemia. A third possible mechanism is the so-called “diabetic cardiomyopathy”: structural changes in the myocardium/interstitium of diabetic heart have been described, and these modifications have been associated with SCD [9]. Lastly, although many studies have been adjusted for conventional CHD risk factors, the higher risk of SCD in DM could be due to a concomitant increased risk of CHD. Our study has several strengths and limitations. First, to our knowledge this is the first attempt to reliably summarise the evidence on the association between DM and SCD; second, we extracted data according to standardised protocol and on several variables that enable clinically relevant sub-group analyses; third, the generalisability of our findings has been enhanced by the involvement of ~340,000 participants who, with the exception of three studies (that selected people with a previous history of myocardial infarction or only post-menopausal women), have been selected from the general population (i.e., participants not selected on the basis of pre-existing characteristic or disease at baseline). Although we were not able to include 3 studies in our meta-analysis, these represent only 4% of the total number of cases included in the current report. Moreover, SCD and DM were differently defined across studies; yet, no significant heterogeneities were evident according to their definitions. We also lacked access to individual participant data and therefore we could not adjust consistently for potential confounding factors across all studies. In conclusion, the results of this study evidenced a two-fold higher risk of SCD in subjects with DM and further emphasize the need of a better definition of the interrelationship between DM, CVD and SCD [10].
537
Author contribution F.Z. conceived the idea, performed literature search, analysed data and wrote the paper. H.K. contributed to data analysis and wrote the paper. J.A.L. performed literature search and reviewed the paper. All authors approved the final submitted version of the manuscript. Funding None. Duality of interest The authors report no relationships that could be construed as a conflict of interest. Acknowledgements We thank Dr Emanuele Di Angelantonio (Cardiovascular Epidemiology Unit, Cambridge University, UK) for his helpful comments. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2014.08.105. References [1] Adabag AS, Luepker RV, Roger VL, Gersh BJ. Sudden cardiac death: epidemiology and risk factors. Nat Rev Cardiol 2010;7:216–25. [2] Volders PG. Novel insights into the role of the sympathetic nervous system in cardiac arrhythmogenesis. Heart Rhythm 2010;7:1900–6. [3] Vinik AI, Erbas T, Casellini CM. Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. J Diabetes Investig 2013;4:4–18. [4] Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010;375:2215–22. [5] Terry T, Raravikar K, Chokrungvaranon N, Reaven PD. Does aggressive glycemic control benefit macrovascular and microvascular disease in type 2 diabetes? Insights from ACCORD, ADVANCE, and VADT. Curr Cardiol Rep 2012;14:79–88. [6] Goto A, Arah OA, Goto M, Terauchi Y, Noda M. Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. BMJ 2013; 347:f4533. [7] The ORIGIN Trial Investigators. Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial. Eur Heart J 2013;34:3137–44. [8] Spallone V, Ziegler D, Freeman R, et al. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 2011;27:639–53. [9] Chugh SS, Kelly KL, Titus JL. Sudden cardiac death with apparently normal heart. Circulation 2000;102:649–54. [10] Vasiliadis I, Kolovou G, Mavrogeni S, Nair DR, Mikhailidis DP. Sudden cardiac death and diabetes mellitus. J Diabetes Complications 2014;28:573–9.