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• W3200528051 abstract "HomeCirculation: Heart FailureVol. 14, No. 9Pharmacologic Weight Loss for Heart Failure With Preserved Ejection Fraction Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessArticle CommentaryPDF/EPUBPharmacologic Weight Loss for Heart Failure With Preserved Ejection FractionGetting to the Core of the Problem Daniel N. Silverman, MD and Sheldon E. Litwin, MD Daniel N. SilvermanDaniel N. Silverman https://orcid.org/0000-0002-9000-0631 Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston (D.N.S., S.E.L.). Division of Cardiology, Department of Medicine, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC (D.N.S., S.E.L.). Search for more papers by this author and Sheldon E. LitwinSheldon E. Litwin Correspondence to: Sheldon Litwin, MD, Alicia Spaulding-Paolozzi Endowed Chair in Cardiovascular Imaging Medical University of South Carolina, 25 Courtenay Dr, Charleston, SC 29425. Email E-mail Address: [email protected] https://orcid.org/0000-0002-5887-8161 Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston (D.N.S., S.E.L.). Division of Cardiology, Department of Medicine, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC (D.N.S., S.E.L.). Search for more papers by this author Originally published14 Sep 2021https://doi.org/10.1161/CIRCHEARTFAILURE.121.008554Circulation: Heart Failure. 2021;14Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: September 14, 2021: Ahead of Print Obesity has a strong and graded association with incident heart failure (HF).1 The association is much stronger for HF with preserved ejection fraction (HFpEF) than for HF with reduced ejection fraction.2 The rising proportion of HFpEF is likely fueled by the increasing prevalence and severity of obesity3 and the associated features of the metabolic syndrome.Neurohormonal antagonism in patients with HFpEF has not shown convincing benefit. Individual components of the proposed obesity-HFpEF phenotype,4 such as increased blood volume and increased epicardial fat, are not clearly actionable targets. Hence, a call for more targeted, phenotype-specific therapies has been made.5 Current guidelines for HFpEF suggest management of comorbid conditions—most of which are consequences of obesity (eg, diabetes, hypertension, sleep disordered breathing, inflammation, etc)—while surprisingly little effort has been made to directly deal with obesity itself. Here, we propose the initiation of effective, low-cost pharmacological anti-obesity agents as a targeted therapy for durable weight loss in HFpEF. Successful weight reduction may facilitate increased physical activity, one of the few interventions that has been proven effective in HFpEF.Potential Methods of Weight ManagementLifestyle ModificationLifestyle approaches typically include initiation of hypocaloric diet with various changes in dietary composition. Such changes generally produce small to moderate amounts of weight loss,6 and the magnitude of change is typically not in the range of 7% to 10% body weight reduction, which seems to be necessary to attenuate consequences of obesity such as atrial fibrillation or nonalcoholic fatty liver disease.7,8 Addition of a formal physical activity program may improve the amount of weight loss, but physical activity by itself generally does not produce much weight loss. Unfortunately, weight loss achieved through lifestyle changes is rarely sustained beyond 6 to 12 months.Bariatric SurgeryPatients with severe obesity who undergo bariatric surgery have ≈40% to 50% reductions in the rate of incident HF after several years of follow-up.9 Despite the potential large benefits of these procedures, insurance coverage is not universal, the up-front cost is relatively high, there are short-term and long-term risks, and weight regain is relatively common. A recent prospective single-center study evaluating the effects of bariatric surgery in 12 female patients with HFpEF revealed improved quality of life measures.10 Furthermore, there are plausible mechanisms that could lead to clinical benefit in patients with HFpEF following bariatric surgery.11Pharmacological Weight LossAnti-obesity medications have been stigmatized because of past issues. Most notorious was the experience with phentermine/fenfluramine (also known as phen-fen). Fenfluramine was ultimately withdrawn from the market in 1997 after it was discovered that it was associated with valvular damage and pulmonary hypertension.12 Other agents, including sibutramine and rimonabant, were withdrawn because of association with adverse cardiovascular effects and increased depression and suicide, respectively. It may come as no surprise, then, that health care providers do not readily reach for anti-obesity medications.Over the past decade, multicenter, randomized clinical trials including thousands of patients have shown consistently greater weight loss efficacy with the addition of pharmacological therapy to lifestyle modification. With all currently approved medications, patients receiving anti-obesity pharmacotherapy were more likely to achieve the goal of >5% body weight reduction, and improvement in cardiovascular risk factors when compared with lifestyle modification alone.Patients and many health care providers are unaware that safe and effective prescription weight-loss medications exist and that these medications can be used concurrently in the treatment of their HF. Similarly, physicians—and cardiologists in general—lack familiarity with weight-loss medications, their side effect profiles, efficacy, medication interactions, and safety profile. Compounding this ignorance, practitioners may be stricken with a therapeutic nihilism once obesity is present, with the general impression that efforts to facilitate weight loss are futile.Until recently, the combination of low dose phentermine and topiramate has shown the greatest magnitude of safe, effective weight loss.13 This pair of medications in tandem—phentermine an adrenergic stimulant and topiramate an antiepileptic—synergistically target and suppress distinct appetite regulatory pathways.14 Using low doses of each was intended to minimize side effects. Two large, randomized control trials studied a combination of phentermine and a long-acting topiramate (Qsymia), and the collective data obtained from the >4000 study subjects showed a dose-dependent reduction in weight of >10% and improvement in multiple cardiovascular risk factors.13,15 Most importantly, there were no adverse cardiac events in any treatment groups. Only minor side effects were observed and heart rate increased by only 1 to 2 beats per minute and blood pressure decreased. Gratifyingly, durable weight loss persisted at 2 years of follow-up. Recent studies using the injectable GLP-1 (glucagon-like peptide-1) agonist, semaglutide, have shown weight loss in the range of 15% body weight, leading to FDA approval of this agent.16The relatively high costs of all the recently approved anti-obesity medications poses a significant barrier to their use. Nonetheless, phentermine alone has been available since 1959. It is currently the most widely prescribed anti-obesity agent. Current package labeling suggests it should only be given for 3 months. However, it is known that obesity is a chronic condition and several studies have shown weight regain soon after discontinuation of anti-obesity medications.17 Although it has not been specifically studied, a combination of generic phentermine and topiramate offers an attractive first-line option that is low cost, and nearly as effective as semaglutide in terms of the magnitude of weight loss.Phentermine/topiramate has advantages over other available anti-obesity medications, beyond cost. Compared with naltrexone/bupropion, it can be used in patients who need opiates for pain relief. The GLP-1 receptor agonists liraglutide and semaglutide are administered by injection and require high dosing for weight loss. Lorcascerin has demonstrated cardiovascular safety, but it was removed from the market due to concerns about excess cancer.18 The lipase-inhibitor Orlistat is relatively ineffective in terms of expected weight loss and is limited by gastrointestinal side effects.19 Finally, the dual actions of phentermine/topiramate target one of the most challenging drivers of weight gain and resistance to weight loss: the psychological component of hunger.14Case StudiesExample 1A 44-year-old female with diabetes and severe obesity had a history of HF post-partum. She underwent Roux-en-Y gastric bypass with over 100 lb weight loss (282 lbs, with body mass index [BMI], 53.5 kg/m2, to 174 lbs, BMI, 31.8 kg/m2) by 1-year post-surgery with accompanying improvement in exertional tolerance. She unfortunately experienced steady weight gain thereafter reaching nearly presurgical weight levels by 3 years post-operatively (255 lbs, BMI, 46.6 kg/m2). She had recurrent symptoms of HF and had invasive exercise hemodynamics showing pulmonary capillary wedge pressure rising to >30 mm Hg during supine bicycle ergometry. She was provided lifestyle counseling and prescribed phentermine 15 mg daily along with topiramate 25 mg twice daily. In the ensuing year, she lost over 55 lbs, reaching a nadir of 197 lbs (BMI, 36.1 kg/m2) or 22.7% weight loss. Following this, she had markedly increased exertional tolerance, reduced blood pressure, decreased diuretic dosing, and reduced hemoglobin A1C.Example 2A 65-year-old male with severe obesity (225 lbs, BMI, 35 kg/m2), a history of coronary artery disease with prior coronary artery bypass surgery, difficult to control hypertension, and HFpEF with NYHA class III symptoms was initiated on generic phentermine and topiramate. Over the course of the following year, he experienced steady weight loss down to 168 lbs (BMI, 25.6 kg/m2) with discontinuation of 2 antihypertensive medications, improvement in tolerance to physical activity with NYHA class II functional class symptoms, and reduction in diuretic dosing by half.ConclusionsThe prescription of proven anti-obesity medications in conjunction with lifestyle change, particularly generic phentermine and topiramate, offers the potential to cost-effectively produce clinically meaningful weight loss, to allow for durable weight maintenance, and ultimately to facilitate increased activity and healthier lifestyle. In our experience, these medications seem to be safe in patients with HFpEF and are financially attainable for most. Newer anti-obesity medications also seem very promising although cost considerations may limit their use.16 Direct treatment of obesity offers the potential for a bridge to activity, one of the primary measures of success in heart failure—and especially HFpEF—treatment.Disclosures None.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Disclosures, see page 1034.Correspondence to: Sheldon Litwin, MD, Alicia Spaulding-Paolozzi Endowed Chair in Cardiovascular Imaging Medical University of South Carolina, 25 Courtenay Dr, Charleston, SC 29425. Email [email protected]eduReferences1. Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, Kannel WB, Vasan RS. Obesity and the risk of heart failure.N Engl J Med. 2002; 347:305–313. doi: 10.1056/NEJMoa020245CrossrefMedlineGoogle Scholar2. Savji N, Meijers WC, Bartz TM, Bhambhani V, Cushman M, Nayor M, Kizer JR, Sarma A, Blaha MJ, Gansevoort RT, et al.. 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Sjöström L, Rissanen A, Andersen T, Boldrin M, Golay A, Koppeschaar HP, Krempf M. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group.Lancet. 1998; 352:167–172. doi: 10.1016/s0140-6736(97)11509-4CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails September 2021Vol 14, Issue 9Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.121.008554PMID: 34517721 Originally publishedSeptember 14, 2021 Keywordshypertensionheart failureinflammationweight lossobesityPDF download Advertisement SubjectsDiet and NutritionHeart FailureObesityRisk FactorsSecondary Prevention" @default.
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• W3200528051 title "Pharmacologic Weight Loss for Heart Failure With Preserved Ejection Fraction: Getting to the Core of the Problem" @default.
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