Advances in metabolic modulators as therapeutic agents for heart failure

doi:10.3969/j.issn.1674-8115.2025.12.009

Abstract

Abstract:

Heart failure is a complex clinical syndrome resulting from structural and functional impairments of the heart, leading to diminished cardiac output and an inability to fulfill the body's metabolic requirements. Perturbations in myocardial energy metabolism represent a central hallmark of heart failure, characterized by altered substrate utilization, mitochondrial dysfunction, and elevated oxidative stress, all of which contribute critically to disease progression. Given the fundamental role of metabolic homeostasis in sustaining cardiac performance, pharmacological agents that target metabolic pathways, collectively termed metabolic modulators, have gained prominence as promising therapeutic strategies for heart failure. For instance, fatty acid oxidation inhibitors such as perhexiline act by suppressing carnitine palmitoyltransferase Ⅰ/Ⅱ (CPT1/2), thereby reducing fatty acid β-oxidation and improving the efficiency of cardiac energy metabolism. Similarly, 3-ketoacyl-coenzyme A thiolase (3-KAT) inhibitors, such as trimetazidine, enhance glucose oxidation, thereby improving myocardial energy supply. Sodium-glucose cotransporter 2 (SGLT2) inhibitors (e.g., empagliflozin) not only exert hypoglycemic effects but also confer cardioprotective benefits through pleiotropic mechanisms, although their detailed metabolic actions remain under investigation. Furthermore, mitochondrial-targeting peptides, such as elamipretide, preserve mitochondrial integrity and function by stabilizating cardiolipin, thereby providing additional cardioprotection. Although several metabolic modulators have demonstrated encouraging results in preclinical and early clinical studies, their long-term efficacy and safety profiles await validation in large-scale randomized trials. This review synthesizes recent advances in the development of metabolic modulators for heart failure, providing insights into basic research and the translation of clinical treatments.

Key words: heart failure, energy metabolism, mitochondria, pharmacotherapy

CLC Number:

R541.6

DU Tailai, HUANG Zhanpeng. Advances in metabolic modulators as therapeutic agents for heart failure[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(12): 1636-1643.

TrendMD

References 74

[1]	LOPASCHUK G D, KARWI Q G, TIAN R, et al. Cardiac energy metabolism in heart failure[J]. Circ Res, 2021, 128(10): 1487-1513.
[2]	NEUBAUER S. The failing heart: an engine out of fuel[J]. N Engl J Med, 2007, 356(11): 1140-1151.
[3]	BERGMAN G, ATKINSON L, METCALFE J, et al. Beneficial effect of enhanced myocardial carbohydrate utilisation after oxfenicine (L-hydroxyphenylglycine) in angina pectoris[J]. Eur Heart J, 1980, 1(4): 247-253.
[4]	DRAKE-HOLLAND A J, PASSINGHAM J E. The effect of Oxfenicine on cardiac carbohydrate metabolism in intact dogs[J]. Basic Res Cardiol, 1983, 78(1): 19-27.
[5]	BACHMANN E, WEBER E. Biochemical mechanisms of oxfenicine cardiotoxicity[J]. Pharmacology, 1988, 36(4): 238-248.
[6]	SCHMIDT-SCHWEDA S, HOLUBARSCH C. First clinical trial with etomoxir in patients with chronic congestive heart failure[J]. Clin Sci (Lond), 2000, 99(1): 27-35.
[7]	HOLUBARSCH C J F, ROHRBACH M, KARRASCH M, et al. A double-blind randomized multicentre clinical trial to evaluate the efficacy and safety of two doses of etomoxir in comparison with placebo in patients with moderate congestive heart failure: the ERGO (etomoxir for the recovery of glucose oxidation) study[J]. Clin Sci (Lond), 2007, 113(4): 205-212.
[8]	SCHWARZER M, FAERBER G, RUECKAUER T, et al. The metabolic modulators, Etomoxir and NVP-LAB121, fail to reverse pressure overload induced heart failure in vivo[J]. Basic Res Cardiol, 2009, 104(5): 547-557.
[9]	ASHRAFIAN H, HOROWITZ J D, FRENNEAUX M P. Perhexiline[J]. Cardiovasc Drug Rev, 2007, 25(1): 76-97.
[10]	LEE L, CAMPBELL R, SCHEUERMANN-FREESTONE M, et al. Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment[J]. Circulation, 2005, 112(21): 3280-3288.
[11]	ABOZGUIA K, ELLIOTT P, MCKENNA W, et al. Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy[J]. Circulation, 2010, 122(16): 1562-1569.
[12]	BEADLE R M, WILLIAMS L K, KUEHL M, et al. Improvement in cardiac energetics by perhexiline in heart failure due to dilated cardiomyopathy[J]. JACC Heart Fail, 2015, 3(3): 202-211.
[13]	CAPPOLA T P. Perhexiline: lessons for heart failure therapeutics[J]. JACC Heart Fail, 2015, 3(3): 212-213.
[14]	KANTOR P F, LUCIEN A, KOZAK R, et al. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase[J]. Circ Res, 2000, 86(5): 580-588.
[15]	FRAGASSO G, SALERNO A, LATTUADA G, et al. Effect of partial inhibition of fatty acid oxidation by trimetazidine on whole body energy metabolism in patients with chronic heart failure[J]. Heart, 2011, 97(18): 1495-1500.
[16]	MOMEN A, ALI M, KARMAKAR P K, et al. Effects of sustained-release trimetazidine on chronically dysfunctional myocardium of ischemic dilated cardiomyopathy: six months follow-up result[J]. Indian Heart J, 2016, 68(6): 809-815.
[17]	JATAIN S, KAPOOR A, SINHA A, et al. Metabolic manipulation in dilated cardiomyopathy: assessing the role of trimetazidine[J]. Indian Heart J, 2016, 68(6): 803-808.
[18]	TUUNANEN H, ENGBLOM E, NAUM A, et al. Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated cardiomyopathy[J]. Circulation, 2008, 118(12): 1250-1258.
[19]	WINTER J L, CASTRO P F, QUINTANA J C, et al. Effects of trimetazidine in nonischemic heart failure: a randomized study[J]. J Card Fail, 2014, 20(3): 149-154.
[20]	CHANDLER M P, STANLEY W C, MORITA H, et al. Short-term treatment with ranolazine improves mechanical efficiency in dogs with chronic heart failure[J]. Circ Res, 2002, 91(4): 278-280.
[21]	SABBAH H N, CHANDLER M P, MISHIMA T, et al. Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, improves left ventricular function in dogs with chronic heart failure[J]. J Card Fail, 2002, 8(6): 416-422.
[22]	UNDROVINAS N A, MALTSEV V A, BELARDINELLI L, et al. Late sodium current contributes to diastolic cell Ca²⁺ accumulation in chronic heart failure[J]. J Physiol Sci, 2010, 60(4): 245-257.
[23]	NIE J L, DUAN Q L, HE M Y, et al. Ranolazine prevents pressure overload-induced cardiac hypertrophy and heart failure by restoring aberrant Na⁺ and Ca²⁺ handling[J]. J Cell Physiol, 2019, 234(7): 11587-11601.
[24]	WILLIAMS S, POURRIER M, MCAFEE D, et al. Ranolazine improves diastolic function in spontaneously hypertensive rats[J]. Am J Physiol Heart Circ Physiol, 2014, 306(6): H867-H881.
[25]	COPPINI R, FERRANTINI C, YAO L N, et al. Late sodium current inhibition reverses electromechanical dysfunction in human hypertrophic cardiomyopathy[J]. Circulation, 2013, 127(5): 575-584.
[26]	MURRAY G L, COLOMBO J. Ranolazine preserves and improves left ventricular ejection fraction and autonomic measures when added to guideline-driven therapy in chronic heart failure[J]. Heart Int, 2014, 9(2): 66-73.
[27]	MAIER L S, LAYUG B, KARWATOWSKA-PROKOPCZUK E, et al. RAnoLazIne for the treatment of diastolic heart failure in patients with preserved ejection fraction: the RALI-DHF proof-of-concept study[J]. JACC Heart Fail, 2013, 1(2): 115-122.
[28]	WANG T, MCDONALD C, PETRENKO N B, et al. Estrogen-related receptor α (ERRα) and ERRγ are essential coordinators of cardiac metabolism and function[J]. Mol Cell Biol, 2015, 35(7): 1281-1298.
[29]	SCHILLING J, KELLY D P. The PGC-1 cascade as a therapeutic target for heart failure[J]. J Mol Cell Cardiol, 2011, 51(4): 578-583.
[30]	XU W Y, BILLON C, LI H, et al. Novel pan-ERR agonists ameliorate heart failure through enhancing cardiac fatty acid metabolism and mitochondrial function[J]. Circulation, 2024, 149(3): 227-250.
[31]	MONTAIGNE D, BUTRUILLE L, STAELS B. PPAR control of metabolism and cardiovascular functions[J]. Nat Rev Cardiol, 2021, 18(12): 809-823.
[32]	LEGCHENKO E, CHOUVARINE P, BORCHERT P, et al. PPARγ agonist pioglitazone reverses pulmonary hypertension and prevents right heart failure via fatty acid oxidation[J]. Sci Transl Med, 2018, 10(438): eaao0303.
[33]	DAMBROVA M, MAKRECKA-KUKA M, VILSKERSTS R, et al. Pharmacological effects of meldonium: biochemical mechanisms and biomarkers of cardiometabolic activity[J]. Pharmacol Res, 2016, 113(Pt B): 771-780.
[34]	HAYASHI Y, KIRIMOTO T, ASAKA N, et al. Beneficial effects of MET-88, a γ-butyrobetaine hydroxylase inhibitor in rats with heart failure following myocardial infarction[J]. Eur J Pharmacol, 2000, 395(3): 217-224.
[35]	NAKANO M, KIRIMOTO T, ASAKA N, et al. Beneficial effects of MET-88 on left ventricular dysfunction and hypertrophy with volume overload in rats[J]. Fundam Clin Pharmacol, 1999, 13(5): 521-526.
[36]	KIRIMOTO T, NOBORI K, ASAKA N, et al. Beneficial effect of MET-88, a γ-butyrobetaine hydroxylase inhibitor, on energy metabolism in ischemic dog hearts[J]. Arch Int Pharmacodyn Ther, 1996, 331(2): 163-178.
[37]	STATSENKO M E, SHILINA N N, TURKINA S V. Use of meldonium in the combination treatment of patients with heart failure in the early postinfarction period[J]. Ter Arkh, 2014, 86(4): 30-35.
[38]	STATSENKO M E, BELENKOVA S V, SPOROVA O E, et al. The use of mildronate in combined therapy of postinfarction chronic heart failure in patients with type 2 diabetes mellitus[J]. Klin Med (Mosk), 2007, 85(7): 39-42.
[39]	MASOUD W G T, USSHER J R, WANG W, et al. Failing mouse hearts utilize energy inefficiently and benefit from improved coupling of glycolysis and glucose oxidation[J]. Cardiovasc Res, 2014, 101(1): 30-38.
[40]	BERSIN R M, STACPOOLE P W. Dichloroacetate as metabolic therapy for myocardial ischemia and failure[J]. Am Heart J, 1997, 134(5 Pt 1): 841-855.
[41]	WANG P P, LLOYD S G, CHATHAM J C. Impact of high glucose/high insulin and dichloroacetate treatment on carbohydrate oxidation and functional recovery after low-flow ischemia and reperfusion in the isolated perfused rat heart[J]. Circulation, 2005, 111(16): 2066-2072.
[42]	KATO T, NIIZUMA S, INUZUKA Y, et al. Analysis of metabolic remodeling in compensated left ventricular hypertrophy and heart failure[J]. Circ Heart Fail, 2010, 3(3): 420-430.
[43]	BØGH N, HANSEN E S S, OMANN C, et al. Increasing carbohydrate oxidation improves contractile reserves and prevents hypertrophy in porcine right heart failure[J]. Sci Rep, 2020, 10(1): 8158.
[44]	BERSIN R M, WOLFE C, KWASMAN M, et al. Improved hemodynamic function and mechanical efficiency in congestive heart failure with sodium dichloroacetate[J]. J Am Coll Cardiol, 1994, 23(7): 1617-1624.
[45]	LEWIS J F, DACOSTA M, WARGOWICH T, et al. Effects of dichloroacetate in patients with congestive heart failure[J]. Clin Cardiol, 1998, 21(12): 888-892.
[46]	AIZAWA K, IKEDA A, TOMIDA S, et al. A potent PDK4 inhibitor for treatment of heart failure with reduced ejection fraction[J]. Cells, 2023, 13(1): 87.
[47]	BEI Y H, ZHU Y J, ZHOU J W, et al. Inhibition of Hmbox1 promotes cardiomyocyte survival and glucose metabolism through Gck activation in ischemia/reperfusion injury[J]. Circulation, 2024, 150(11): 848-866.
[48]	HORTON J L, DAVIDSON M T, KURISHIMA C, et al. The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense[J]. JCI Insight, 2019, 4(4): e124079.
[49]	DENG Y, XIE M D, LI Q, et al. Targeting mitochondria-inflammation circuit by β-hydroxybutyrate mitigates HFpEF[J]. Circ Res, 2021, 128(2): 232-245.
[50]	PACKER M, ANKER S D, BUTLER J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure[J]. N Engl J Med, 2020, 383(15): 1413-1424.
[51]	MCMURRAY J J V, SOLOMON S D, INZUCCHI S E, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction[J]. N Engl J Med, 2019, 381(21): 1995-2008.
[52]	ANKER S D, BUTLER J, FILIPPATOS G, et al. Empagliflozin in heart failure with a preserved ejection fraction[J]. N Engl J Med, 2021, 385(16): 1451-1461.
[53]	NASSIF M E, WINDSOR S L, BORLAUG B A, et al. The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial[J]. Nat Med, 2021, 27(11): 1954-1960.
[54]	GHEZZI C, LOO D D F, WRIGHT E M. Physiology of renal glucose handling via SGLT1, SGLT2 and GLUT2[J]. Diabetologia, 2018, 61(10): 2087-2097.
[55]	XIE Y F, WEI Y J, LI D, et al. Mechanisms of SGLT2 inhibitors in heart failure and their clinical value[J]. J Cardiovasc Pharmacol, 2023, 81(1): 4-14.
[56]	PANDEY A K, BHATT D L, PANDEY A, et al. Mechanisms of benefits of sodium-glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction[J]. Eur Heart J, 2023, 44(37): 3640-3651.
[57]	WU X Q, LIU H, BROOKS A, et al. SIRT6 mitigates heart failure with preserved ejection fraction in diabetes[J]. Circ Res, 2022, 131(11): 926-943.
[58]	KOLIJN D, PABEL S, TIAN Y N, et al. Empagliflozin improves endothelial and cardiomyocyte function in human heart failure with preserved ejection fraction via reduced pro-inflammatory-oxidative pathways and protein kinase Gα oxidation[J]. Cardiovasc Res, 2021, 117(2): 495-507.
[59]	FERRANNINI E, MARK M, MAYOUX E. CV protection in the EMPA-REG OUTCOME trial: a "thrifty substrate" hypothesis[J]. Diabetes Care, 2016, 39(7): 1108-1114.
[60]	MUDALIAR S, ALLOJU S, HENRY R R. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis[J]. Diabetes Care, 2016, 39(7): 1115-1122.
[61]	LOPASCHUK G D, VERMA S. Empagliflozin's fuel hypothesis: not so soon[J]. Cell Metab, 2016, 24(2): 200-202.
[62]	VERMA S, RAWAT S, HO K L, et al. Empagliflozin increases cardiac energy production in diabetes: novel translational insights into the heart failure benefits of SGLT2 inhibitors[J]. JACC Basic Transl Sci, 2018, 3(5): 575-587.
[63]	HO K L, KARWI Q G, WAGG C, et al. Ketones can become the major fuel source for the heart but do not increase cardiac efficiency[J]. Cardiovasc Res, 2021, 117(4): 1178-1187.
[64]	ALLEN M E, PENNINGTON E R, PERRY J B, et al. The cardiolipin-binding peptide elamipretide mitigates fragmentation of cristae networks following cardiac ischemia reperfusion in rats[J]. Commun Biol, 2020, 3(1): 389.
[65]	ZHANG L, FENG M W, WANG X J, et al. Peptide Szeto-Schiller 31 ameliorates doxorubicin-induced cardiotoxicity by inhibiting the activation of the p38 MAPK signaling pathway[J]. Int J Mol Med, 2021, 47(4): 63.
[66]	YEH J N, SUNG P H, CHIANG J Y, et al. Early treatment with combination of SS31 and entresto effectively preserved the heart function in doxorubicin-induced dilated cardiomyopathic rat[J]. Biomed Pharmacother, 2021, 141: 111886.
[67]	CHATFIELD K C, SPARAGNA G C, CHAU S, et al. Elamipretide improves mitochondrial function in the failing human heart[J]. JACC Basic Transl Sci, 2019, 4(2): 147-157.
[68]	DAUBERT M A, YOW E, DUNN G, et al. Novel mitochondria-targeting peptide in heart failure treatment: a randomized, placebo-controlled trial of elamipretide[J]. Circ Heart Fail, 2017, 10(12): e004389.
[69]	BUTLER J, KHAN M S, ANKER S D, et al. Effects of elamipretide on left ventricular function in patients with heart failure with reduced ejection fraction: the PROGRESS-HF phase 2 trial[J]. J Card Fail, 2020, 26(5): 429-437.
[70]	WONG A K F, SYMON R, ALZADJALI M A, et al. The effect of metformin on insulin resistance and exercise parameters in patients with heart failure[J]. Eur J Heart Fail, 2012, 14(11): 1303-1310.
[71]	LARSEN A H, JESSEN N, NØRRELUND H, et al. A randomised, double-blind, placebo-controlled trial of metformin on myocardial efficiency in insulin-resistant chronic heart failure patients without diabetes[J]. Eur J Heart Fail, 2020, 22(9): 1628-1637.
[72]	YANG J, HOLMAN G D. Long-term metformin treatment stimulates cardiomyocyte glucose transport through an AMP-activated protein kinase-dependent reduction in GLUT4 endocytosis[J]. Endocrinology, 2006, 147(6): 2728-2736.
[73]	SCHERNTHANER G, BRAND K, BAILEY C J. Metformin and the heart: update on mechanisms of cardiovascular protection with special reference to comorbid type 2 diabetes and heart failure[J]. Metabolism, 2022, 130: 155160.
[74]	中国医师协会心血管内科医师分会, 中国心衰中心联盟, 《慢性心力衰竭“新四联”药物治疗临床决策路径专家共识》工作组, 等. 慢性心力衰竭“新四联”药物治疗临床决策路径专家共识[J]. 中国循环杂志, 2022, 37(8): 769-781.
	Chinese College of Cardiovascular Physicians, Chinese Heart Failure Center Alliance, The Task Force for Expert Consensus Decision Pathway for Quadruple Pharmacotherapy Management of Chronic Heart Failure, et al. Expert consensus on decision-making pathway for quadruple pharmacotherapy management of chronic heart failure[J]. Chinese Circulation Journal, 2022, 37(8): 769-781.