Diabetes mellitus and atrial fibrillation: Upstream treatment mitigates downstream complications

Suneet Mittal, MD, is Director, Electrophysiology Laboratory, The St. Luke’s-Roosevelt Hospital Center, Columbia University College of Physicians & Surgeons, New York, NY.

Published on Nov 17, 2008

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The incidence of atrial fibrillation (AF), which is the most frequently encountered sustained cardiac arrhythmia, is increasing in the United States.¹ Numerous risk factors have been implicated in the development of AF, including nonmodifiable risk factors such as age and the patient’s sex, modifiable risk factors such as obesity and smoking history, and disease-specific risk factors such as hypertension, diabetes, heart failure, coronary and valvular heart disease (particularly mitral regurgitation), and thyroid disease.^2-5 Because AF and diabetes mellitus have reached epidemic levels worldwide, it is particularly important to examine the relationship between these entities.

The VALUE (Valsartan Antihypertensive Long-term Use Evaluation) trial compared the effect of the angiotensin-II receptor blocker valsartan with the calcium-channel blocker amlodipine on cardiac mortality.⁶ In this study, a total of 15,245 patients from 31 nations were followed for 4.2 years until a prespecified number of patients (n = 1450) had a primary cardiac event.⁷ New-onset AF (as assessed by an annual electrocardiogram [ECG]) was a prespecified secondary outcome. Aksnes and colleagues provide a post hoc analysis of this trial and examine the relationship between the development of diabetes mellitus and new-onset AF.⁸ They found that patients with new-onset diabetes mellitus were significantly more likely (hazard ratio [HR], 1.49) to develop AF than those without diabetes; new-onset diabetes was defined as evidenced by study investigators, included those who used antidiabetic drugs during the trial, and those who had a fasting glucose concentration of 7 mmol/L (126 mg/dL) or above in a blood sample at the end of the trial. The most significant finding was that the development of AF translated into a significantly greater risk of developing heart failure (HR, 3.56) and stroke (HR, 1.96).

Would “upstream” treatment of high-risk patients mitigate adverse outcomes?
It is apparent that in hypertensive patients, manipulation of the rennin- angiotensin-aldosterone system using either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ARBs) can make a difference.^9,10 One particularly important benefit is the reduction in the risk of developing de novo AF, particularly with ARBs.¹¹ For example, the LIFE (Losartan Intervention for End Point Reduction in Hypertension) study evaluated 9193 patients aged 55 years to 80 years with treated or untreated hypertension and compared the effect of an ARB (losartan) with a beta-blocker (atenolol) on an end point of cardiovascular morbidity (myocardialinfarction and stroke) andmortality.¹² Both groups showeda similar reduction in blood pressure.Of the 8851 patients withoutAF at baseline, new-onset AFoccurred in 150 patients receivinglosartan versus 221 patientsreceiving atenolol after at least 4years of follow-up, representing a33% reduction in the risk of developingAF in patients treatedwith losartan. Similar findingswere observed in the VALUE trial,where the incidence of new-onsetAF (paroxysmal and persistent)was 16% lower in the valsartanarm (3.67% vs 4.34% in the amlodipinearm; P = .044).⁶

Where do we go from here?
First, future trials need to do a better job of screening for AF. Studies to date have relied on annual ECGs, which clearly underestimate the true burden of AF, especially in patients with paroxysmal AF. Second, in addition to using ARBs in hypertensive patients, those at high risk for developing diabetes mellitus need to be counseled on the protective effects of exercise, weight loss, smoking cessation, and lipid-lowering therapies (fish oils and statins) on the development of AF. Only by taking a multifactorial approach can we hope to reduce the burden of AF and its “downstream” complications like heart failure, stroke, and death.

References

1. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001;285(18):2370-2375.

2. Aksnes TA, Flaa A, Strand A, Kjeldsen SE. Prevention of new-onset atrial fibrillation and its predictors with angiotensin II-receptor blockers in the treatment of hypertension and heart failure. J Hypertens. 2007;25(1):15-23.

3. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial fibrillation: the Framingham study. N Engl J Med. 1982;306(17):1018-1022.

4. Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol. 1998;82(8A):2N-9N.

5. Healey JS, Connolly SJ. Atrial fi brillation: hypertension as a causative agent, risk factor for complications, and potential therapeutic target. Am JCardiol. 2003;91(10A):9G-14G.

6. Julius S, Kjeldsen SE, Weber M, et al; VALUE Trial Group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363(9426):2022-2031.

7. Schmieder RE, Kjeldsen SE, Julius S, McInnes GT, Zanchetti A, Hua TA; VALUE Trial Group. Reduced incidence of new-onset atrial fibrillation with angiotensin II receptor blockade: the VALUE trial. J Hypertens. 2008; 26(3):403-411.

8. Aksnes TA, Tjugen TB, Schmieder RE, Kjeldsen SE, Julius S. Impact of diabetes development on atrial fibrillation in hypertensives. Cardiology Review. 2008;25(11):44-47.

9. Shi Y, Li D, Tardif JC, Nattel S. Enalapril effects on atrial remodeling and atrial fibrillation in experimental congestive heart failure. Cardiovasc Res. 2002;54(2):456-461.

10. Kumagai K, Nakashima H, Urata H, Gondo N, Arakawa K, Saku K. Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation. J Am Coll Cardiol. 2003;41(12):2197-2204.

11. Healey JS, Baranchuk A, Crystal E, et al. Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis. J Am Coll Cardiol. 2005;45(11):1832-1839.

12. Wachtell K, Lehto M, Gerdts E, et al. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: the Losartan Intervention For End Point Reduction in Hypertension (LIFE) study. J Am Coll Cardiol. 2005;45(5):712-719.