Insulin, Not Diabetes, May Increase Thromboembolic Risk in Atrial Fibrillation

In patients with atrial fibrillation (AF) treated with anticoagulation, diabetes without insulin did not appear to increase thromboembolic risk, according to the results of the European Prevention of Thromboembolic Events-European Registry in Atrial Fibrillation (PREFER AF) study, published in the Journal of the American College of Cardiology.

A total of 5717 patients with AF from 7 countries (Austria, France, Germany, Italy, Spain, Switzerland, and the United States) were included in PREFER AF. Of these patients, 1288 (22.5%) had diabetes, and 288 (22.4%) of the patients with diabetes were receiving insulin treatment.

Regardless of insulin status, patients with diabetes had increased prevalence of systemic hypertension, congestive heart failure, prior transient ischemic attack/stroke/thromboembolism, vascular disease, chronic renal impairment, left atrial enlargement, chronic obstructive pulmonary disease, and body mass index higher than 30 kg/m² compared with patients without diabetes. Patients who were receiving insulin treatment had higher use of vitamin K antagonists plus antiplatelet therapy (16.7% vs 9.6%; P =.0002) at baseline and 1 year (71.5% vs 62.9%; P =.0036).

The primary end point of PREFER AF was stroke/systemic embolism incidence at 1-year follow-up according to diabetes status (no diabetes, noninsulin-requiring diabetes, or insulin-requiring diabetes), according to the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE-AF-TIMI 48) definitions.

At 1 year, the incidence of stroke/systemic embolism was 2 per 100 patients/year in the overall population. Insulin-requiring diabetes was associated with a higher risk for the primary end point compared with no diabetes (5.2 per 100 patients/year vs 1.9 per 100 patients/year; hazard ratio [HR], 2.89; 95% CI, 1.67-5.02; P =.0002) and noninsulin-requiring diabetes (5.2 per 100 patients/year vs 1.8 per 100 patients/year; HR, 2.96; 95% CI, 1.49-5.87; P =.0019). In addition, stroke/systemic embolism rates were not different between insulin-requiring diabetes and no diabetes (HR, 0.97; 95% CI, 0.58-1.61; P =.90). Patients who were receiving insulin also tended to have an increased prevalence of sustained (persistent or permanent) AF (80% vs 76% in noninsulin-requiring diabetes compared with 67% of patients without diabetes).

The correlation between insulin-requiring diabetes and higher rates of thromboembolic events remained significant even after the addition of various risk factors as covariates to the Cox proportional hazard regression model. Of the 15 covariates, 2 had statistically significant interactions in a comparison between insulin-requiring diabetes and noninsulin-requiring diabetes; specifically, the relative increase of thromboembolic events related to insulin therapy was higher in patients with congestive heart failure and in patients who were receiving antithrombotic therapy at baseline.

Furthermore, high rates of stroke/systemic embolism were still present in patients with insulin-requiring diabetes who had received anticoagulation at baseline (5.1 per 100 patients/year vs 6.1 per 100 patients/year in those without anticoagulation). Patients’ daily insulin dose did not appear to affect thromboembolic risk.

In patients without diabetes or noninsulin-requiring diabetes (n = 4354) with a CHA₂DS₂-VASc score higher than 1, the rate of stroke/systemic embolism was 2.0% at 1 year.

“The surprising finding of our study was the strikingly similar incidence of thromboembolic events at 1 year in patients with diabetes but without insulin treatment compared with patients without diabetes,” the researchers noted.

“[A]ccording to our data, it is the need for insulin therapy, rather than the presence of diabetes per se,” they concluded, “that seems to be an independent factor affecting the occurrence of AF-related stroke/systemic embolism during follow-up.”

Study Limitations

• The researchers could not determine the thromboembolic risk of the untreated patients included or the risk associated with specific antithrombotic therapies. 
• Residual confounding cannot be ruled out. 
• Because of the study size, the researchers could not stratify the thromboembolic risk for patients with diabetes receiving insulin therapy according to different CHA₂DS₂-VASc scores (1 vs >1).
• A uniform definition of diabetes may not have been used, and no data were available on specific criteria for initiating insulin therapy or on glycemic control.

Disclosures: Dr Patti reports financial relationships with Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Daiichi-Sankyo, Eli Lilly, AstraZeneca, and Merck Sharp & Dohme. Dr Lucema is an employee of Daiichi-Sankyo Europe and Dr Romeo is an employee of Daiichi-Sankyo Italy. Dr Renda reports financial relationships with Boehringer Ingelheim, Daiichi-Sankyo, and Bayer. Dr Le Heuzey reports financial relationships with Sanofi, Bristol-Myers Squibb, Pfizer, Meda, Boehringer Ingelheim, Merck Sharp & Dohme, Bayer, Servier, AstraZeneca, Novartis, and Daiichi-Sankyo. Dr Zamorano reports financial relationships with Sanofi, Servier, and Daiichi-Sankyo. Dr Kirchhof reports financial relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, 3M Medica, MEDA Pharma, Medtronic, Merck, Otsuka, Pfizer, Sanofi, Servier, Siemens, Takeda, and St. Jude Medical. Dr de Caterina reports financial relationships with Sanofi, Boehringer Ingelheim, Bayer, Bristol-Myers Squibb, Pfizer, Daiichi-Sankyo, Novartis, and Merck Sharp & Dohme. 

Reference

Patti G, Lucerna M, Cavallari I, et al. Insulin-requiring vs noninsulin-requiring diabetes and thromboembolic risk in patients with atrial fibrillation: PREFER in AF. J Am Coll Cardiol. 2017;69(4):409-419. doi:10.1016/j.jacc.2016.10.069