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A new target in the fight against atrial fibrillation – obesity

By Dr Dermot McCaffrey - 24th Sep 2023

Atrial fibrillation

Atrial fibrillation (AF) is the most common arrhythmia and can have devastating consequences, namely  embolic stroke, which has significantly worse long-term outcomes compared to ischaemic or hypertension-related lacunar stroke. The burden of AF is increasing both due to an ageing population and the increased burden of obesity in Ireland. We cannot reverse the natural ageing process, but we have tools to reverse obesity, both non-pharmacological and, more recently, by effective pharmacological treatments, namely glucagon-like peptide 1 receptor agonists (GLP-1 RA) semaglutide and liraglutide.

Ireland has one of the highest levels of obesity in Europe, with over 60 per cent of adults and over one-in-five children and young people living with overweight and obesity (2019, Healthy Ireland). Obesity should be viewed as a facilitating causal agent interacting with other risk factors; eg, hypertension, family history, LDL (low-density lipoprotein) cholesterol, diabetes, smoking, etc, to increase a person’s overall cardiovascular risk, rather than being causative itself.

The associations and causes of AF are many, but are mostly related to raised right or left atrial pressure. The strongest AF association is increasing age, with a prevalence of 0.1 per cent in those aged <55 years old and 9.0 per cent in those >80 years old. Anything that increases left atrial pressure can provoke AF; eg, hypertension, valvular heart disease (especially mitral stenosis), and heart failure with a high left ventricular end diastolic pressure. Increases in right atrial pressure that can precipitate AF include a pulmonary embolus, pneumonia or any chronic pulmonary disease, eg, COPD or pulmonary fibrosis. Sleep apnoea causes wide nocturnal variations in pulmonary arterial pressure and can provoke AF.

Obese patients with a body mass index (BMI) of >30kg/m2 are more likely than those with a BMI of <25kg/m2 to develop AF. The Framingham Heart Study (www.framinghamheartstudy.org/) showed a 5 per cent increase in AF risk for every one unit increase in BMI. The case report (see below) woman’s BMI rose from 42-to-49kg/m2 over four years, so her AF risk increased significantly; up to 35 per cent.

Pericardial fat has inflammatory properties and studies have shown that patients with AF have a higher pericardial fat volume compared to controls, independent of left atrial area.

BMI, which is a person’s weight in kilograms divided by the square of their height in metres, is not a measure of body composition, ie, body muscle and fat content, but does correlate well with cardiovascular disease (CVD) and all-cause mortality so is useful for risk prediction.

Long-term weight loss is associated with a reduction of AF burden, as seen in the LEGACY study (Long-term effect of goal-directed weight management on AF cohort: A five-year follow-up study),1 where those with a 10 per cent weight loss had a six-fold greater probability of AF-free survival compared to those without effective weight loss over a five-year follow-up.

Weight reduction should be an intervention target in this obese patient group. Although we do not have trial data proving that weight loss will improve AF-free survival, trials with semaglutide are currently enrolling which should answer this question; ie, the SELECT trial.2 

We can invoke the ‘vicious cycle’ vs the ‘positive cycle’ concept, ie, the more weight lost, the better sleep quality, less hypertension, more refreshed and thus more energy to exercise, which should result in further weight loss, and therefore the positive cycle continues.

However, diet, exercise, and behavioural changes are ineffective in producing sustained weight loss. There was only a 2.4 per cent weight loss in the placebo arm of the Step 1 trial.3

Question: Can we now offer patients effective weight loss treatment, which might influence their AF burden and potentially, reduce their stroke risk?

The GLP-1 RA drugs such as semaglutide s/c weekly and liraglutide s/c daily are effective in causing weight loss in patients with obesity (BMI >30) or those who are overweight BMI ≥27kg/m2 with at least one weight-related co-morbidity.

The semaglutide studies are summarised below:

Step 1 trial looked at semaglutide in adults who were overweight or obese and showed a 15 per cent weight reduction compared to 2.4 per cent in the placebo group from baseline to 68 weeks with the maximum weight loss seen by one year. See Figure 2.3

Step 2 trial compared semaglutide 1.0mg vs 2.4mg with the mean weight loss of 7 per cent vs 10 per cent, respectively.4

Only the lower semaglutide 1.0mg dose is currently available in Ireland. Semaglutide 2.4mg (Wegovy) should be available later this year and this dose has been approved by the European Medicines Agency (EMA) with an indication for weight loss in this patient population.

Step 4 trial looked at what happens after stopping semaglutide 2.4mg after 20 weeks and showed that patients regain 7 per cent of their initial weight.5 This study suggests the GLP-1 RA need to be taken long-term unless there is significant behavioural change to maintain the weight loss achieved.

Step 8 trial  was a head-to-head study comparing semaglutide 2.4mg s/c weekly vs liraglutide 3.0mg s/c daily and showed better weight loss with semaglutide, 16 vs 6.4 per cent, respectively, which equated to a 15kg vs 7kg weight loss.6

The SELECT trial, which is currently recruiting,  is a large cardiovascular outcomes trial looking at 17,500 patients on semaglutide 2.4mg compared to placebo.2 Hopefully, this will answer both the primary outcome of time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stoke. The trial should be completed this month (September 2023). There are many secondary outcomes, but although AF-free survival is not included on the www.clinicaltrials.gov website, this question should be clarified in late 2024.

Case report:

New discharge medications – Ms SM was discharged on bisoprolol 2.5mg, apixaban 5mg bd, Micardis Plus 40/12.5mg, and an up-titrating dose of semaglutide. If she reaches the mean weight loss seen in the Step 2 trial, that would equate to 9.7kg loss, but, anecdotally, patients have lost 10-to-15 per cent, which would result in a 20kg loss, which would get her weight down to her 2019 pre-Covid weight of 120kg.

Who can be prescribed GLP-1 RA?
(excluding diabetic indication)

Anyone with obesity or overweight ≥27kg/m2 with one weight-related co-morbidity who have not met their weight-loss goals using comprehensive lifestyle intervention alone are entitled to GLP-1 RA treatment.

Reimbursement: Only diabetic patients with HbA1c ≥48 (R:20-42) are currently reimbursed by the HSE for GLP-1 RA for their diabetic management, with weight loss as a secondary benefit. However, non-diabetic obese patients are not entitled for reimbursement, with pharmacy costs of €120-to-€150 per month. There are ongoing supply chain problems in Ireland so it is important to ensure there is adequate supply before starting the up-titration regime.

*Ozempic prescription: Semaglutide 0.25mg s/c week x four weeks, then 0.5mg s/c week x four weeks then 1.0mg s/c week. Note: The results of the Step 4 trial show patients regain 7 per cent of the weight lost upon cessation of therapy so treatment is currently recommended for long-term use.5

*Victosa prescription: Liraglutide is also not currently reimbursed for weight-loss management only. However, if the patient is pre-diabetic, liraglutide is currently approved by the HSE for reimbursement if pre-diabetic with a BMI >35kg/m2 and with a high-risk of CVD. However, it is important to note the dose available in Ireland is 1.8mg not the weight-loss dose of 2.4mg.

To meet HSE reimbursement criteria for liraglutide, the physician must be registered with the PCRS (Primary Care Reimbursement Service) and must upload the patient’s recent HbA1c, LDL and 24-hour ABPM report to confirm the high CV risk profile before the drug will be approved.

Assuming the patient meets the criteria, the liraglutide prescription is 0.6mg s/c daily x four weeks, 1.2mg daily x four weeks, and then 1.8mg daily long-term if tolerated.

A one-year course of GLP-1 RA may cost €1,500-to-€1,800 and if effective, patients may be unable to afford to continue the treatment with resumption of their obesity status.

Obesity disproportionately affects those of lower socioeconomic means who are least able to avail of these effective weight-loss treatments.

The cost of obesity on society is immeasurable, but includes lost work days, fatigue, poor sleep, OSA, worse Covid-19 outcomes, development of diabetes and hypertension, and orthopaedic complications, eg, knee replacement, etc. However, the association of obesity and AF with the risk of an embolic stroke is the most concerning cost, both on society and in individual terms.

The fact that we now have EMA-approved treatments for obesity, but which are only available for those patients who can afford them is an ethical challenge for healthcare providers and those responsible for the purse strings.

But waiting for patients to develop complications of obesity, namely diabetes and hypertension, before reimbursement appears to be short-sighted and costly in the medium- to long-term.

We await the results of the SELECT trial with interest, but in the meantime, we can only advise our obese patients of limited financial means to change their diet, exercise more, and hopefully lose weight, knowing that the likelihood of them achieving a clinically-relevant weight reduction is slim, if you can pardon the pun.

*Opinions are those of the author alone.

Case report

Ms SM, a 63-year-old woman, presented to the emergency department with a six-hour history of dizziness, palpitations, breathlessness, and chest tightness. Her husband had a heart rhythm app as he had an ablation three years ago. The rhythm monitor confirmed a fast AF rate of 136bpm.

She has a past history of hypertension, hypothyroidism, and dyslipidaemia as well as a remote smoking history. She is not diabetic (HbA1c 40), but she is morbidly obese – weight 138kg, height 168cm with a BMI of 49kg/m2. Of note, she weighed 120kg with a BMI of 42.5 in 2019 pre-Covid-19.

She has obstructive sleep apnoea (OSA), and has been on CPAP (continuous positive airway pressure) for five years. No family history of premature coronary disease. She drinks 12 units/week and walks regularly, but at a slow pace due to breathlessness and painful arthritic knees.

There was no secondary precipitant for her AF such as any recent surgery, alcohol, thyrotoxicosis, infection, infarction, pulmonary embolus, etc, and she has no family history of AF.

Usual medications: Micardis Plus (combination tablet of telmisartan and hydrochlorothiazide for treatment of hypertension) 40/12.5mg and eltroxin 100mcg daily. She was comfortable at rest, blood pressure (BP) 110/70mmHg, AF rate 126bpm. JVP (jugular venous pressure) not elevated. Chest clear. No murmurs. No oedema.

Pathology showed a normal NTproBNP 118pg/mL (R:0-300) excluding heart failure (but note she is on a thiazide diuretic and is obese, which can both lower NTproBNP), normal troponin <14ng/mL, Hb 12.4g/dL, normal renal function eGFR 78ml, normal TFTS on levothyroxine, normal D-dimers, and CRP.

ECG confirmed fast AF rate of 112bpm with normal R wave progression.

Diagnosis: New-onset fast AF in a 63-year-old woman with morbid obesity, OSA, and hypertension. CHADsVASc score 2 due to her gender and hypertension.

Management: Rate control with beta blockers for her palpitations and shortness of breath; stroke prevention with anticoagulation, apixaban 5mg bd. Her Micardis Plus was withheld and she reverted spontaneously to sinus rhythm that evening and was discharged the following day.

Her trans-thoracic echo showed sinus rhythm 64bpm, normal LV size and systolic function, LVEF 60 per cent, normal valves, and normal LA area.

Plan: Follow-up in three months with patient self-monitoring for any breakthrough AF on her husband’s app.

Discharge medications: Micardis Plus 40/12.5mg, Eltroxiin, bisoprolol 2.5mg, and Eliquis 5mg bd.

Question: In the absence of an obvious precipitant, what can we do
to prevent further AF?

Hypertension: There is strong evidence from the SPRINT trial that intensive BP control reduces the risk of developing AF by 26 per cent. This study compared a target systolic BP <120mmHg to a target systolic BP <140mmHg.

Our patient is on Micardis Plus, so if her BP was elevated as an outpatient, she could have 24-hour ambulatory blood pressure monitoring (ABPM) with a large cuff to clarify if she has optimal BP control.

OSA can cause secondary hypertension so we can check her CPAP readings, and in this case her AHI (Apnoea-Hypoapnoea Index) scores were acceptable.

What role did obesity play and if she can lose weight, can she reduce her future AF burden?

References

Pathak RK, Middeldorp ME, Meredith M, Mehta AB, Mahajan R, Wong CX, et al. Long-term effect of goal-directed weight management in an atrial fibrillation cohort: A long-term follow-up study (LEGACY). J Am Coll Cardiol. 2015 May 26;65(20):2159-69

Semaglutide effects on heart disease and stroke in patients with overweight or obesity (SELECT) trial. ClinicalTrials.Gov Identifier: NCT03574597. Available at: www.clinicaltrials.gov/ct2/show/NCT03574597

Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. STEP 1 Study Group. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021 Mar 18;384(11):989-1002

Davies M, Færch L, Jeppesen OK, Pakseresht A, Pedersen SD, Perreault L, et al. STEP 2 Study Group. Semaglutide 2·4mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): A randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. 2021 Mar 13;397(10278):971-984

Rubino D, Abrahamsson N, Davies M, Hesse D, Greenway FL, Jensen C, et al. Effect of continued weekly subcutaneous semaglutide vs Placebo on weight loss maintenance in adults with overweight or obesity: The STEP 4 randomised clinical trial. JAMA. 2021;325(14):1414–1425

Rubino DM, Greenway FL, Khalid U, O’Neil PM, Rosenstock J, Rasmus Sørrig, MD, PhD3, et al. Effect of weekly subcutaneous semaglutide vs Daily liraglutide on body weight in adults with overweight or obesity without diabetes: The STEP 8 randomised clinical trial. JAMA. 2022;327(2):138–150

Dr Dermot McCaffrey, Consultant Cardiologist and Heart Failure Specialist,
Beacon Hospital Dublin, and Associate Clinical Professor in Medicine, UCD

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