Atrial fibrillation with diabetes, heart failure or kidney disease

Diabetes and atrial fibrillation often coexist, which significantly increases the morbidity and mortality of patients
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When diabetic patients with atrial fibrillation are combined with macrovascular complications (heart failure or kidney disease), the condition is even more dangerous
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This article summarizes the mechanisms, risks and best management strategies of such patients for readers
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Patients at risk of heart failure or heart failure 1.
Increased risk of heart failure Diabetes patients with increased risk of aging
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The prevalence of diabetes in patients with heart failure is approximately 30%-40%, and is similar in heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF)
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The risk of HFrEF or HFpEF in diabetic patients increases, and it increases with age
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 In addition, heart failure itself is a risk factor for the development of diabetes, which is likely to be related to insulin resistance
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Heart failure can increase the risk of hospitalization, cardiovascular death and all-cause death in diabetic patients due to heart failure, and HFrEF has the strongest predictive value for diabetes
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Due to loss of atrial pulsation and impaired left ventricular filling, diabetic patients are at increased risk of developing acute heart failure during new onset of atrial fibrillation
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Atrial fibrillation and acute heart failure often coexist and aggravate each other
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 Because diabetes can significantly increase short-term risks including hospital death, rehospitalization due to heart failure, and all-cause death within one year, the presence of diabetes can amplify the risk of acute heart failure
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 In addition to the direct adverse effects of insulin resistance and hyperglycemia on left ventricular dysfunction, the main risk factors that promote the development of heart failure in diabetic patients also include coronary heart disease (CAD), chronic kidney disease (CKD) and hypertension
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Since left ventricular diastolic dysfunction is closely related to insulin resistance and hyperglycemia, it is very common in diabetic patients and has been observed in pre-diabetic patients
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HFpEF is the most common type of heart failure in diabetic patients (about 75%), and its prevalence is higher in diabetic patients with risk factors such as elderly, female, and hypertension
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In addition, randomized controlled trials have shown that, regardless of whether the patient has diabetes, guideline-directed drug therapy (GDMT) and device therapy are equally effective for patients with heart failure
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 2.
Drug therapy β-blockers play a vital role in the onset and symptom control of atrial fibrillation, and it is the pillar part of strategy B in the "ABC" management strategy of atrial fibrillation (B: better through heart rate and rhythm control Control symptoms), which is completely related to the heart rate control of atrial fibrillation patients with diabetes
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However, although the therapeutic benefit strongly supports the widespread use of β-blockers in sinus rhythm diabetic patients with HFrEF, its prognostic benefit in patients with atrial fibrillation is still questioned
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Therefore, once the condition of patients with acute heart failure is stable, β-blockers should be used cautiously in the hospital
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 Non-dihydropyridine calcium channel blockers (verapamil or diltiazem) can be used as a substitute for β-blockers for the heart rate control of patients with atrial fibrillation and the treatment of hypertension in patients with or without HFpEF , But HFrEF patients are forbidden
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In addition, since it can inhibit the inhibitory effect of P-glycoprotein and cytochrome P450 3A4 enzyme, the interaction between verapamil and diltiazem and DOAC should be considered
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In addition, it can lead to increased DOAC blood drug levels, thereby increasing the risk of bleeding
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 In patients with permanent atrial fibrillation and heart failure symptoms, low-dose digoxin can be used for treatment because its quality of life improvement at 6 months is similar to that of bisoprolol
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 Existing evidence from clinical studies in recent decades shows that hypoglycemic therapy has only a moderate benefit on the risk of large vessel outcomes and heart failure-related outcomes in diabetic patients
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However, in recent years, clinical studies of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA), as well as the results of several important cardiovascular outcome trials have been announced.
Leading to fundamental changes
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In particular, it is proved that SGLT2 inhibitors can significantly reduce the risk of hospitalization for heart failure in T2DM patients at high risk of cardiovascular disease
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 Patients at risk of chronic kidney disease or chronic kidney disease 1.
Diabetic nephropathy In addition to atrial fibrillation and its complications and stroke risk factors, diabetes is also associated with an increased risk of kidney disease
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Nearly 30%-40% of diabetic patients will develop diabetic nephropathy or CKD, accompanied by increased proteinuria, decreased renal function, and increased risk of cardiovascular disease
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In most parts of the world, diabetes is the main cause of renal failure, accounting for about 50% of patients with renal failure, but most patients with diabetes and CKD die of cardiovascular events before renal failure
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 In addition, diabetic nephropathy seems to have a familial tendency, and many gene variants are associated with diabetic nephropathy, although the main single-gene effect has not been clarified
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In addition to high blood sugar, high blood pressure and smoking are also risk factors for CKD in diabetic patients
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Risk markers also include oxidative stress, endothelial dysfunction, inflammation, uric acid and dyslipidemia
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  Figure 1 High-risk factors leading to chronic kidney disease in diabetic patients In diabetic patients, the comprehensive treatment of chronic kidney disease includes life>
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For the risk of kidney and cardiovascular disease, renin-angiotensin system (RAS) inhibitors can be used to manage blood pressure, including the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB)
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In addition, blood lipids and blood sugar management are also crucial
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 In T2DM patients, the use of SGLT2 inhibitors has a protective effect on renal function
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They also have beneficial effects on cardiovascular disease and heart failure
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 2.
Anticoagulation-related nephropathy In patients with atrial fibrillation and CKD undergoing anticoagulation therapy, the risk of bleeding increases, and the risk of anticoagulation-related nephropathy also increases
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The latter is a newly discovered form of acute kidney injury.
Excessive anticoagulation can cause a large number of glomerular hemorrhages.
Kidney biopsy shows a large number of renal tubules filled with red blood cells and red blood cell casts
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The glomeruli may show changes, but they are not sufficient to explain glomerular hemorrhage
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  Figure 2 Possible mechanism of changes in renal function in patients with anticoagulation treatment Note: PAR: Protease activated receptors Although anticoagulation-related nephropathy may occur due to any anticoagulation drugs (including VKAs and DOACs), it is incompatible with warfarin (INR>3).
) Over-application is particularly relevant
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Elderly patients with diabetes and diabetic nephropathy are more likely to develop anticoagulation-related nephropathy, which may trigger the onset of acute kidney injury in patients with atrial fibrillation more frequently than before
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In turn, these acute kidney injury events will also accelerate the progression of CKD and are associated with increased mortality
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 Both diabetes and CKD increase the risk of stroke and other cardiovascular complications in patients with atrial fibrillation, and DOAC therapy is better than warfarin
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It is recommended that patients with significantly impaired renal function (CrCl<30 ml/min) should be treated with reduced doses of rivaroxaban, apixaban or idoxaban (CrCl: 15-30 ml/min), but CrCl<25– Patients with 30 ml/min were not included in randomized controlled trials
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 The US Food and Drug Administration (FDA) approved dabigatran 75 mg twice daily for patients with CrCl<30 ml/min, but it has not been verified in prospective trials and has not been approved in Europe
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 If the INR is within the treatment range (TTR)> 70%, but with the increased risk of bleeding, anticoagulant nephropathy, and vascular calcification, the damage may outweigh the benefit
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Therefore, before studies have clarified the best anticoagulation strategy for patients with kidney disease, individualized assessment of risks and benefits must be carried out
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 3.
Vascular calcium chemistry theory In the pathophysiological mechanism of increasing vascular calcification, diabetes and CKD have complementary effects, which can lead to the decline of renal function in patients with diabetes and CKD
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In addition to glucose-related pathways in diabetic patients, factors such as CKD-related calcium and phosphorus balance disorders, uremic toxin accumulation and severe vitamin K deficiency are also related to the pathogenesis of vascular calcification
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 In patients with atrial fibrillation undergoing anticoagulant therapy, especially those with diabetic nephropathy, the use of warfarin can aggravate vascular calcification, including calcification of the renal vascular bed, resulting in deterioration of renal function in these patients
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In contrast, DOAC (such as rivaroxaban) has a different mode of action.
Not only does it have no side effects, it can even provide protection against vascular damage and decreased renal function by reducing vascular inflammation, remodeling, and inflammation
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 In addition, observational studies have shown that compared with DOACs, patients undergoing warfarin treatment progress faster in kidney disease
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Studies have shown that compared with warfarin users, rivaroxaban treatment is associated with a lower risk of acute kidney injury events and stage 5 CKD or hemodialysis
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 4.
Renal function test Because patients have a higher risk of kidney disease, all patients with diabetes must be screened for complications during regular follow-up.
The patient's urinary albumin excretion is measured annually to assess renal function and control blood pressure
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When the renal function is worse, the measurement frequency is higher.
When the renal function is less than 60 ml/min/1.
73 m2, it is recommended to check the renal function once a month
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For diabetic patients with rapidly declining kidney function, more frequent testing may be required
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 Since decreased renal function increases the risk of bleeding, it is particularly important to test renal function and electrolytes (such as hyperkalemia) in patients with diabetes and atrial fibrillation receiving anticoagulant therapy
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 Yimaitong compiled from: Laurent Fauchier, Giuseppe Boriani, Joris R de Groot, et al.
Medical therapies for prevention of cardiovascular and renal events in patients with atrial fibrillation and diabetes mellitus.
EP Europace.
2021; 23(12): 1873– 1891.