Non-classical risk factors for sudden cardiac arrest in type 2 diabetes

Aims: Indicators of sudden cardiac arrest (SCA) risk are poorly understood, specifically in the absence of cardiovascular disease (CVD). This study assessed longitudinal associations with SCA of clinical characteristics recorded in primary care in people with type 2 diabetes (T2D), with and without CVD.

Methods: This is a case-control study with SCA case subjects with T2D from the Amsterdam Resuscitation Studies (ARREST) out of hospital SCA registry in the Dutch Noord-Holland region (2010–2020), and up to five matched (age, sex, T2D, general practitioner [GP] practice) non-SCA control subjects. Clinical measurements, medication use, and medical history from GPs’ electronic health care records were collected. Univariable and multivariable time-dependent Cox regression (hazard ratios, 95% confidence intervals) were used.

Results: 689 SCA case subjects (63.4% male, mean age of 72.2±11.2 years in the year before the index date) and 3320 non-SCA control subjects (63.5% male, mean age 72.1±10.5 years at the same time) were included. Compared with control, case subjects were more often smokers and less often normal weight; had higher fasting glucose, total and LDL cholesterol, triglycerides, albuminuria; had lower HDL cholesterol and eGFR; used more insulin, antihypertensive and QTc-prolonging medications; and more frequently had a history of atrial fibrillation, tachycardia/ectopic beats, and conduction disorders, microvascular complications, or CVD (53.5% vs. 39.5%). In multivariable models, low fasting glucose (<4.5 mmol/mol: 1.91 [1.00-3.64]), heart failure (1.91 [1.55-2.35]), antihypertensive (1.80 [1.39-2.33]), glucose lowering (oral only: 1.32 [1.06-1.63]; insulin only: 2.31 [1.71-3.12]; oral and insulin: 1.64 [1.21-2.22]), and QTc-prolonging prokinetic (1.78 [1.27-2.50]), antibiotic (1.35 [1.05-1.73]), and antipsychotic (2.10 [1.42-3.09]) medication were associated with SCA in the total sample. In subgroup effect modification analyses, QTc-prolonging antibiotic (1.82 [1.26-2.63]) and antipsychotic (3.10 [2.09-4.59]) medication use was associated with SCA only in those without CVD.

Conclusions: In T2D, low fasting glucose and QTc-prolonging prokinetic, antibiotic, or antipsychotic medication use and a history of heart failure were associated with an up to twofold increased SCA risk. Tests for effect modification by CVD history indicated that insulin-only use even increased SCA risk threefold in those without CVD and that antibiotics with QTc-prolonging properties or antipsychotic medication use exclusively increased SCA risk in those without CVD by up to threefold.

Comments: The study confirms the role in SCA of established cardiovascular risk factors and heart failure in T2D thus supporting the importance of cardiovascular risk management. However, a residual risk was not explained by CVD related factors. Actually, the link with low fasting glucose and QTc-prolonging medication is less known, although this latter was reported previously in the general population (Straus SM et al Eur Heart J 2005;26(19):2007-12), with the highest risk for antipsychotic medication, followed by prokinetics and antibiotics.

Despite the limitations due to the missing values from routine care data and the observational case-control design, the prospective collection of data, the five matched control subjects from the same GP practice and calendar time period to control for variables of interest provide strength to the results. History of overall neuropathy was included among the microvascular complications (which independently increased the risk of SCA in those without CVD) whereas autonomic neuropathy was not evaluated, although it was suggested by the authors as a possible player in those with CVD.

The role of autonomic dysfunction in the susceptibility to drug-induced QTc prolongation or to hypoglycaemia risk would have deserved to be considered in those without CVD. Finally, this study emphasizes that physicians should be aware of the hazards of too strict glycaemic control and prescription of QTc-prolonging medication, including prokinetics.

Carla Greco

Reference: Harms PP, van Dongen LH, Bennis F, Swart KMA, Hoogendoorn M, Beulens JWJ, Tan HL, Elders PPJM, Blom MT; RESCUED Investigators. Associations of Clinical Characteristics With Sudden Cardiac Arrest in People With Type 2 Diabetes With and Without Cardiovascular Disease: A Longitudinal Case-Control Study Using Routine Primary Care Data. Diabetes Care. 2025 Jan 1;48(1):125-135. doi: 10.2337/dc24-0715. PMID: 39556475.

🔗 https://diabetesjournals.org/care/article/48/1/125/157476/Associations-of-Clinical-Characteristics-With