Compared to those without diabetes mellitus (DM), people with DM are at about twice the risk for sudden cardiac death (SCD).^1-4 Because DM is associated with increased morbidity and mortality, especially due to a higher risk for concomitant coronary artery disease (CAD) and congestive heart failure (CHF),⁵ the association between DM and an increased risk for SCD may not come as a surprise to those caring for people with DM. However, it is important to recognize that the risk of SCD in DM is related to many factors beyond CAD and CHF, and there remains much to be explored in terms of risk factors for SCD in DM which might allow for preventive strategies. This is especially true for identifying risk factors for SCD among young people with DM, who may not have yet manifested comorbid cardiovascular diseases. Researchers from Denmark compared young patients in that country (age 1-49 years; median (IQR) 33 (24-43) years)) without DM to those with DM and showed that young people with DM had higher all-cause mortality (4-fold) and mortality due to cardiac diseases (8-fold). The authors suggest that future studies should look specifically at rates of SCD in this population,⁶ This group has now performed this investigation into SCD, which is the focus of this ACC expert analysis.⁷

While there are limited data in this area, prior studies have suggested that SCD is an important cause of death among young people with DM. For example, analysis of data from the Oregon Sudden Unexpected Death Study examined sudden cardiac arrest (SCA) of all ages between 2002-2015 and then looked specifically at SCA between ages 5-34 years. Of 3775 cardiac arrests in all ages, 5% (186 cases) were in the 5-34 year age group. In this young age group, the prevalence of DM was 9.2% with 58% of patients having at least one traditional cardiovascular risk factor (obesity, DM, hypertension, hyperlipidemia, smoking).⁸ An Australian series of 1914 deaths among people ≤ 40 years with type 1 diabetes mellitus (T1DM) reported that these individuals were four times more likely to experience sudden unexpected death compared to those without DM.⁹

In the current study by Lynge and colleagues, the authors examined death certificates and other information to assess if SCD was the cause of death. They also assessed for diabetes treatment status by utilizing pharmacy records (i.e. filling prescriptions for one or more glucose-lowering prescription drugs). They then compared SCD rates between those with and without DM. Detailed information regarding cause of death are routinely recorded in Denmark and Denmark keeps a comprehensive registry of drug prescriptions filled by citizens. This allows for the generation of a large, granular dataset and indeed a major strength of this analysis is the size of the cohort with 14,294 deaths among people aged 1-49 years over a 10-year period (27.1 million person-years). Among these deaths in young people, 1363 (10%) were due to sudden cardiac death. A total of 669 (or 5%) of the deaths occurred in people with DM and 118 of the deaths in those with DM were attributed to SCD (18% of deaths among those with DM). Thus, the incidence rate of SCD was much higher among young people with DM versus without DM: about 8-9 times higher among those 1-35 years, and about 6 times higher among those 36-49 years. SCD was the most common cause of death overall among young people with DM, even compared with endocrine disorders (e.g. diabetic ketoacidosis and hypoglycemia) and death due to non-sudden cardiovascular disease (defined as death due to a confirmed or likely cardiac etiology that was not sudden and unexpected) (Figure 1). Those who died due to SCD and had DM were generally older than those without DM who died due to SCD (median (IQR) 43 (35-47) years versus 37 (29-45) years, p <0.001).⁷

Figure 1

Why do young people with DM suffer from SCD more often than those without DM? The authors attempt to answer this question using the detailed death certificate data available in Denmark, along with the findings of medicolegal external exams and autopsies which were only performed in about 1/3 of cases of SCD in those with DM (less often than in those without DM). Among the 38 autopsies performed in people with DM who had experienced SCD, in the younger age group (1-35 years) the most common underlying cause of SCD was sudden arrhythmic death syndrome (SADS) (n=7, 54%), and in the older age group (36-49 years) the most common underlying cause of SCD was CAD (n=16, 64%).⁷

Thus, it is clear that the treatment of traditional risk factors to prevent concomitant diseases like CAD is crucial, but what else can be done to prevent SCD? One avenue might be to give greater attention to risk for SADS, defined as death presumably due to a primary electrical etiology in a structurally normal heart, including death related to long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT) and Brugada syndrome. Post-mortem genetic testing has found important variants in 13% of SADS cases, primarily causing CPVT and LQTS.¹⁰ Thus, increased genetic testing both in the deceased and among living relatives could help to detect some preventable cases of SCD in those with DM. Other causes of SCD are more unique to DM, especially the roles of cardiac autonomic neuropathy (CAN) and hypoglycemia. Both CAN and hypoglycemia affect the QT interval and might predispose to ventricular arrhythmias. In CAN, due to effects of hyperglycemia over time, there is less parasympathetic output. Increased sympathetic output to the heart leads to higher heart rates with less day/night variation, and may also affect repolarization, leading to QT prolongation. Hypoglycemia contributes to higher sympathetic output, and also has direct effects at QT prolongation.⁹ Other mechanisms which may explain SCD risk in DM include myocardial ischemia (including "silent ischemia"), potassium abnormalities, and a decreased ventilatory response to hypoxia and hypercapnia.⁷

The fact that patients with DM are already at risk for QT prolongation due to CAN and hypoglycemia relates to another major, actionable conclusion by Lynge and colleagues: 25% of cases of those with DM who died due to SCD had filled prescriptions of proarrhythmic drugs within 90 days of death. This suggests that providers might help to prevent SCD in people with DM simply by choosing to prescribe medications that do not carry risk for QT prolongation. Since commonly used drugs like antibiotics and antiemetics may have QT prolonging effects, and may be prescribed by providers from multiple specialties, it is critical that all providers understand the baseline risk of those with diabetes for QT prolongation and avoid prescribing drugs which may cause QT prolongation.

With regard to study limitations, Lynge and colleagues suggest that one limitation relates to the way in which they identified cases of DM and estimated DM duration. Because a diagnosis of DM was based entirely on whether a person had ever filled a prescription for an anti-diabetes medication, their analysis may be underestimating the total population with DM. Also, their method for distinguishing T1DM from T2DM was based entirely on the prescription drug record, with T1DM defined as an individual having filled only prescriptions for insulin or insulin-analogues. Their methods may have also led to underestimating DM duration which was relatively short (median duration of T1DM was 13.9 years and of T2DM was 3.9 years). Also, patient-level data, such as glucose levels, are unknown, which could have prognostic significance. For example, prior research suggests that risk of death may be related to degree of hyperglycemia, but not other risk factors (such as systolic blood pressure and lipids).¹¹ Additionally, despite the death records kept in Demark, there is still uncertainty about the exact cause of death in some patients.

For future studies, additional large datasets are needed with detailed clinical information, including data regarding use of anti-diabetes pharmacotherapy, duration of diabetes diagnosis and treatment, and control of hyperglycemia and other risk factors (i.e. inclusion of lab values). Also, data from other areas of the world, involving patients with different demographic characteristics would be useful. Perhaps registry data could be combined by multiple countries to explore this topic further. Another important focus of future research will be on the use of certain anti-diabetes medications to reduce SCD risk. Recent clinical trials have demonstrated the potential for sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists to reduce cardiovascular events in patients with DM, and there is significant interest in determining whether these drug classes have anti-arrhythmic properties.^12-14 For example, SGLT2 inhibitors have many proposed anti-arrhythmic mechanisms, including possible suppression of the sympathetic nervous system and magnesium sparing diuresis.^13-17 As we continue to learn more about the potential anti-arrhythmic effects of agents from these drug classes, increased use of these medications, including among younger people with DM, could prove to be an important part of a strategy to reduce the risk of SCD.

In conclusion, the report by Lynge and colleagues finds that SCD is a common cause of death among young people with DM and highlights the need for increased awareness regarding risk of SCD among providers caring for young patients with DM. In addition to the importance of measuring and treating traditional modifiable risk factors (blood pressure, lipids, glucose) to prevent micro- and macrovascular complications and mitigating the risk of SCD as a complication of CAD and CHF, providers must be aware that SCD occurs in the absence of CAD and CHF and may be related to factors such as SADS, CAN, hypoglycemia, and possibly iatrogenic effects of QT prolonging medications.

References

1. Aune D, Schlesinger S, Norat T, Riboli E. Diabetes mellitus and the risk of sudden cardiac death: a systematic review and meta-analysis of prospective studies. Nutr Metab Cardiovasc Dis 2018;28:543-56.
2. Zaccardi F, Khan H, Laukkanen JA. Diabetes mellitus and risk of sudden cardiac death: a systematic review and meta-analysis. Int J Cardiol 2014;177:535-7.
3. Jouven X, Lemaitre RN, Rea TD, Sotoodehnia N, Empana JP, Siscovick DS. Diabetes, glucose level, and risk of sudden cardiac death. Eur Heart J 2005;26:2142-7.
4. Junttila MJ, Kiviniemi AM, Lepojarvi ES, et al. Type 2 diabetes and coronary artery disease: preserved ejection fraction and sudden cardiac death. Heart Rhythm 2018;15:1450-6.
5. Wilkinson MJ, Zadourian A, Taub PR. Heart failure and diabetes mellitus: defining the problem and exploring the interrelationship. Am J Cardiol 2019;124: Suppl 1:S3-S11.
6. Svane J, Lynge TH, Pedersen-Bjergaard U, et al. Cause-specific mortality in children and young adults with diabetes mellitus: a Danish nationwide cohort study. Eur J Prev Cardiol 2019. [Epub ahead of print].
7. Lynge TH, Svane J, Pedersen-Bjergaard U, et al. Sudden cardiac death among persons with diabetes aged 1-49 years: a 10-year nationwide study of 14 294 deaths in Denmark. Eur Heart J 2019. [Epub ahead of print].
8. Jayaraman R, Reinier K, Nair S, et al. Risk factors of sudden cardiac death in the young: multiple-year community-wide assessment. Circulation 2018;137:1561-70.
9. Hsieh A, Twigg SM. The enigma of the dead-in-bed syndrome: challenges in predicting and preventing this devastating complication of type 1 diabetes. J Diabetes Complications 2014;28:585-7.
10. Lahrouchi N, Raju H, Lodder EM, et al. Utility of post-mortem genetic testing in cases of sudden arrhythmic death syndrome. J Am Coll Cardiol 2017;69:2134-45.
11. Rao Kondapally Seshasai S, Kaptoge S, Thompson A, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011;364:829-41.
12. Ang R, Mastitskaya S, Hosford PS, et al. Modulation of cardiac ventricular excitability by GLP-1 (Glucagon-Like Peptide-1). Circ Arrhythm Electrophysiol 2018;11:e006740.
13. Garg V, Verma S, Connelly K. Mechanistic insights regarding the role of SGLT2 inhibitors and GLP1 agonist drugs on cardiovascular disease in diabetes. Prog Cardiovasc Dis 2019;62:349-57.
14. Kubota Y, Yamamoto T, Tara S, et al. Effect of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: rationale. Diabetes Ther 2018;9:2107-16.
15. Inzucchi SE, Zinman B, Wanner C, et al. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res 2015;12:90-100.
16. Toto RD, Goldenberg R, Chertow GM, et al. Correction of hypomagnesemia by dapagliflozin in patients with type 2 diabetes: a post hoc analysis of 10 randomized, placebo-controlled trials. J Diabetes Complications 2019;33:107402.
17. Tang H, Zhang X, Zhang J, et al. Elevated serum magnesium associated with SGLT2 inhibitor use in type 2 diabetes patients: a meta-analysis of randomised controlled trials. Diabetologia 2016;59:2546-51.

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Atherosclerotic Disease (CAD/PAD), EP Basic Science, Genetic Arrhythmic Conditions, Lipid Metabolism

Keywords: Metabolic Syndrome, Coronary Artery Disease, Cardiovascular Diseases, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Diabetic Ketoacidosis, Prescription Drugs, Risk Factors, Brugada Syndrome, Autopsy, Death Certificates, Cause of Death, Lipids, Prognosis, Anti-Bacterial Agents, Blood Pressure, Glucose, Magnesium, Antiemetics, Insulin, Anti-Arrhythmia Agents, Anti-Arrhythmia Agents, Hypercapnia, Heart Rate, Prevalence, Hyperlipidemias

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