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Cardiovascular effects of antiobesity drugs: are the new medicines all the same?

International Journal of Obesity Supplements volume 10, pages 14–26 (2020)Cite this article

Abstract

Waiting for a definite answer from well-designed randomized prospective clinical trials, the impact of the new antiobesity drugs -liraglutide, bupropion/naltrexone, phentermine/topiramate and lorcaserin- on cardiovascular outcomes remains uncertain. What has been learned from previous experience with older medicines is that antiobesity drugs may influence cardiovascular health not only causing weight reduction but also through direct actions on the cardiovascular system. Therefore, in the present review, we examine what is known, mainly from preclinical investigations, about the cardiovascular pharmacology of the new antiobesity medicines with the aim of highlighting potential mechanistic differences. We will show that the two active substances of the bupropion/naltrexone combination both exert beneficial and unwanted cardiovascular effects. Indeed, bupropion exerts anti-inflammatory effects but at the same time it does increase heart rate and blood pressure by potentiating catecholaminergic neurotransmission, whereas naltrexone reduces TLR4-dependent inflammation and has potential protective effects in stroke but also impairs cardiac adaption to ischemia and the beneficial opioid protective effects mediated in the endothelium. On the contrary, with the only exception of a small increase in heat rate, liraglutide only exerts favorable cardiovascular effects by protecting myocardium and brain from ischemic damage, improving heart contractility, lowering blood pressure and reducing atherogenesis. As far as the phentermine/topiramate combination is concerned, no direct cardiovascular beneficial effect is expected for phentermine (as this drug is an amphetamine derivative), whereas topiramate may exert cardioprotective and neuroprotective effects in ischemia and anti-inflammatory and antiatherogenic actions. Finally, lorcaserin, a selective 5HT2C receptor agonist, does not seem to exert significant direct effects on the cardiovascular system though at very high concentrations this drug may also interact with other serotonin receptor subtypes and exert unwanted cardiovascular effects. In conclusion, the final effect of the new antiobesity drugs on cardiovascular outcomes will be a balance between possible (but still unproved) beneficial effects of weight loss and “mixed” weight-independent drug-specific effects. Therefore comparative studies will be required to establish which one of the new medicines is more appropriate in patients with specific cardiovascular diseases.

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References

  1. Di Angelantonio E, Bhupathiraju ShN, Wormser D, Gao P, Kaptoge S. Global BMI Mortality Collaboration et al. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet.2016;388:776–86.

    PubMed  Google Scholar 

  2. Ma C, Avenell A, Bolland M, Hudson J, Stewart F, Robertson C, et al. Effects of weight loss interventions for adults who are obese on mortality, cardiovascular disease, and cancer: systematic review and meta-analysis. BMJ. 2017;359:j4849.

    PubMed  PubMed Central  Google Scholar 

  3. Carbone S, Lavie CJ, Arena R. Obesity and heart failure: focus on the obesity paradox. Mayo Clin Proc. 2017;92:266–79.

    PubMed  Google Scholar 

  4. LeBlanc EL, Patnode CD, Webber EM, Redmond N, Rushkin M, O’Connor EA. Behavioral and pharmacotherapy weight loss interventions to prevent obesity-related morbidity and mortality in adults: an updated systematic review for the U.S. Preventive Services Task Force. Rockville (MD): Agency for Healthcare Research and Quality (US); 2018. AHRQ Publication No. 18-05239-EF-1 September 201, https://www.ncbi.nlm.nih.gov/books/NBK532379/pdf/Bookshelf_NBK532379.pdf.

  5. Nissen SE, Wolski KE, Prcela L, Wadden T, Buse JB, Bakris G, et al. Effect of naltrexone-bupropion on major adverse cardiovascular events in overweight and obese patients with cardiovascular risk factors: a randomized clinical trial. JAMA. 2016;315:990–1004.

    CAS  PubMed  Google Scholar 

  6. Killian LM, Docherty JR. Cardiovascular stimulant actions of bupropion in comparison to cocaine in the rat. Eur J Pharmacol. 2014;735:32–7.

    CAS  PubMed  Google Scholar 

  7. Cremers B, Schmidt KI, Maack C, Schäfers HJ, Böhm M. Catecholamine release in human heart by bupropion. Eur J Pharmacol. 2003;467:169–71.

    CAS  PubMed  Google Scholar 

  8. Caillier B, Pilote S, Castonguay A, Patoine D, Ménard-Desrosiers V, Vigneault P, et al. QRS widening and QT prolongation under bupropion: a unique cardiac electrophysiological profile. Fundam Clin Pharmacol. 2012;26:599–608.

    CAS  PubMed  Google Scholar 

  9. Beyens MN, Guy C, Mounier G, Laporte S, Ollagnier M. Serious adverse reactions of bupropion for smoking cessation: analysis of the French Pharmacovigilance Database from 2001 to 2004. Drug Saf. 2008;31:1017–26.

    CAS  PubMed  Google Scholar 

  10. Martins LC, Ferreira-Melo SE, Sabha M, Coelho OR, Yugar-Toledo JC, Quinaglia T, et al. Acute effects of pharmacotherapies in blood pressure in normotensive moderate smokers. Blood Press. 2009;18:255–60.

    CAS  PubMed  Google Scholar 

  11. Thase ME, Haight BR, Johnson MC, Hunt T, Krishen A, Fleck RJ, et al. A randomized, double-blind, placebo-controlled study of the effect of sustained-release bupropion on blood pressure in individuals with mild untreated hypertension. J Clin Psychopharmacol. 2008;28:302–7.

    CAS  PubMed  Google Scholar 

  12. Balit CR, Lynch CN, Isbister GK. Bupropion poisoning: a case series. Med J Aust. 2003;178:61–3.

    PubMed  Google Scholar 

  13. Brustolim D, Ribeiro-dos-Santos R, Kast RE, Altschuler EL, Soares MB. A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice. Int Immunopharmacol. 2006;6:903–7.

    CAS  PubMed  Google Scholar 

  14. Tsai JH, Kuo CH, Yang P, Cheng KH, Wang PW, Chen CC, et al. Effects of antidepressants on IP-10 production in LPS-activated THP-1 human monocytes. Int J Mol Sci. 2014;15:13223–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Ahmed M, El-Bakly WM, Zaki AM, abd Alzez LF, El serafi O. Bupropion effects on high-fat diet-induced steatohepatitis and endothelial dysfunction in rats: role of tumour necrosis factor-alpha. J Pharm Pharmacol. 2014;66:793–801.

    CAS  PubMed  Google Scholar 

  16. Camacho Á, McClelland RL, Delaney JA, Allison MA, Psaty BM, Rifkin DE, et al. Antidepressant use and subclinical measures of atherosclerosis: the multi-ethnic study of atherosclerosis. J Clin Psychopharmacol. 2016;36:340–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Wittert G, Hope P, Pyle D. Tissue distribution of opioid receptor gene expression in the rat. Biochem Biophys Res Commun. 1996;218:877–81.

    CAS  PubMed  Google Scholar 

  18. Holaday JW. Cardiovascular effects of endogenous opiate systems. Annu Rev Pharmacol Toxicol. 1983;23:541–94.

    CAS  PubMed  Google Scholar 

  19. Tanaka K, Kersten JR, Riess ML. Opioid-induced cardioprotection. Curr Pharm Des. 2014;20:5696–705.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Schultz JE, Hsu AK, Gross GJ. Morphine mimics the cardioprotective effect of ischemic preconditioning via a glibenclamide-sensitive mechanism in the rat heart. Circ Res. 1996;78:1100–4.

    CAS  PubMed  Google Scholar 

  21. Tong G, Sun Z, Wei X, Gu C, Kaye AD, Wang Y, et al. U50,488H postconditioning reduces apoptosis after myocardial ischemia and reperfusion. Life Sci. 2011;88:31–8.

    CAS  PubMed  Google Scholar 

  22. Tomai F, Crea F, Gaspardone A, Versaci F, Ghini AS, Ferri C, et al. Effects of naloxone on myocardial ischemic preconditioning in humans. Am Coll Cardiol. 1999;33:1863–9.

    CAS  Google Scholar 

  23. Li R, Wong GT, Wong TM, Zhang Y, Xia Z, Irwin MG. Intrathecal morphine preconditioning induces cardioprotection via activation of delta, kappa, and mu opioid receptors in rats. Anesth Analg. 2009;108:23–9.

    CAS  PubMed  Google Scholar 

  24. Schultz JJ, Hsu AK, Gross GJ. Ischemic preconditioning and morphine induced cardioprotection involve the delta (d)-opioid receptor in the intact rat heart. J Mol Cell Cardiol. 1997;29:2187–95.

    CAS  PubMed  Google Scholar 

  25. Maslov LN, Naryzhnaia NV, Tsibulnikov SY, Kolar F, Zhang Y, Wang H, et al. Role of endogenous opioid peptides in the infarct size-limiting effect of adaptation to chronic continuous hypoxia. Life Sci. 2013;93:373–9.

    CAS  PubMed  Google Scholar 

  26. Zhang SZ, Wang NF, Xu J, Gao Q, Lin GH, Bruce IC, et al. κ-opioid receptors mediate cardioprotection by remote preconditioning. Anesthesiology. 2006;105:550–6.

    CAS  PubMed  Google Scholar 

  27. Xu YC, Li RP, Xue FS, Cui XL, Wang SY, Liu GP, et al. κ-Opioid receptors are involved in enhanced cardioprotection by combined fentanyl and limb remote ischemic postconditioning. J Anesth. 2015;29:535–43.

    PubMed  Google Scholar 

  28. He SF, Jin SY, Yang W, Pan YL, Huang J, Zhang SJ, et al. Cardiac μ-opioid receptor contributes to opioid-induced cardioprotection in chronic heart failure. Br J Anaesth. 2018;121:26–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Bolte C, Newman G, Schultz Jel J. Kappa and delta opioid receptor signaling is augmented in the failing heart. J Mol Cell Cardiol. 2009;47:493–503.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Yatani A, Imai N, Himura Y, Suematsu M, Liang CS. Chronic opiate-receptor inhibition in experimental congestive heart failure in dogs. Am J Physiol. 1997;272(1 Pt 2):H478–84.

    CAS  PubMed  Google Scholar 

  31. Arbit B, Marston N, Shah K, Lee EL, Aramin H, Clopton P, et al. Prognostic usefulness of proenkephalin in stable ambulatory patients with heart failure. Am J Cardiol. 2016;117:1310–4.

    CAS  PubMed  Google Scholar 

  32. Oldroyd KG, Gray CE, Carter R, Harvey K, Borland W, Beastall G, et al. Activation and inhibition of the endogenous opioid system in human heart failure. Br Heart J. 1995;73:41–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Baskin DS, Hosobuchi Y. Naloxone reversal of ischaemic neurological deficits in man. Lancet. 1981;2:272–5.

    CAS  PubMed  Google Scholar 

  34. Hosobuchi Y, Baskin DS, Woo SK. Reversal of induced ischemic neurologic deficit in gerbils by the opiate antagonist naloxone. Science. 1982;215:69–71.

    CAS  PubMed  Google Scholar 

  35. Baskin DS, Hosobuchi Y, Grevel JC. Treatment of experimental stroke with opiate antagonists. Effects on neurological function, infarct size, and survival. J Neurosurg. 1986;64:99–103.

    CAS  PubMed  Google Scholar 

  36. Yang L, Wang H, Shah K, Karamyan VT, Abbruscato TJ. Opioid receptor agonists reduce brain edema in stroke. Brain Res. 2011;1383:307–16.

    CAS  PubMed  Google Scholar 

  37. Gooshe M, Abdolghaffari AH, Aleyasin AR, Chabouk L, Tofigh S, Hassanzadeh GR, et al. Hypoxia/ischemia a key player in early post stroke seizures: modulation by opioidergic and nitrergic systems. Eur J Pharmacol. 2015;746:6–13.

    CAS  PubMed  Google Scholar 

  38. Wang X, Sun ZJ, Wu JL, Quan WQ, Xiao WD, Chew H, et al. Naloxone attenuates ischemic brain injury in rats through suppressing the NIK/IKKα/NF-κB and neuronal apoptotic pathways. Acta Pharmacol Sin. 2019;40:170–9.

    CAS  PubMed  Google Scholar 

  39. Anttila JE, Albert K, Wires ES, Mätlik K, Loram LC, Watkins LR, et al. Post-stroke intranasal (+)-naloxone delivery reduces microglial activation and improves behavioral recovery from ischemic injury. eNeuro. 2018;18:5. pii: ENEURO.0395-17.2018.

  40. Wang X, Zhang Y, Peng Y, Hutchinson MR, Rice KC, Yin H, et al. Pharmacological characterization of the opioid inactive isomers (+)-naltrexone and (+)-naloxone as antagonists of toll-like receptor 4. Br J Pharmacol. 2016;173:856–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Cozzolino D, Sasso FC, Cataldo D, Gruosso D, Giammarco A, Cavalli A, et al. Acute pressor and hormonal effects of beta-endorphin at high doses in healthy and hypertensive subjects: role of opioid receptor agonism. J Clin Endocrinol Metab. 2005;90:5167–74.

    CAS  PubMed  Google Scholar 

  42. Faden AI, Holaday JW. Opiate antagonists: a role in the treatment of hypovolemic shock. Science. 1979;205:317–8.

    CAS  PubMed  Google Scholar 

  43. Schobel HP, Oren OM, Mark AL, Ferguson DW. Naloxone potentiates cardiopulmonary baroreflex sympathetic control in normal humans. Circ Res. 1992;70:172–83.

    CAS  PubMed  Google Scholar 

  44. Stefano GB, Hartman A, Bilfinger TV, Magazine HI, Liu Y, Casares F, et al. Presence of the mu3 opiate receptor in endothelial cells. Coupling to nitric oxide production and vasodilation. J Biol Chem. 1995;270:30290–3.

    CAS  PubMed  Google Scholar 

  45. Sun X, Ma S, Zang YM, Lu SY, Guo HT, Bi H, et al. Vasorelaxing effect of U50,488H in pulmonary artery and underlying mechanism in rats. Life Sci. 2006;78:2516–22.

    CAS  PubMed  Google Scholar 

  46. Tian F, Zheng XY, Li J, Zhang SM, Feng N, Guo HT, et al. κ-Opioid receptor stimulation improves endothelial function via Akt-stimulated NO production in hyperlipidemic rats. Sci Rep. 2016;6:26807.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhou X, Wang D, Zhang Y, Zhang J, Xiang D, Wang H. Activation of κ-opioid receptor by U50,488H improves vascular dysfunction in streptozotocin-induced diabetic rats. BMC Endocr Disord. 2015;15:7.

    PubMed  PubMed Central  Google Scholar 

  48. Liu J, Wei S, Tian L, Yan L, Guo Q, Ma X. Effects of endomorphins on human umbilical vein endothelial cells under high glucose. Peptides. 2011;32:86–92.

    PubMed  Google Scholar 

  49. Zhao J, Zhang Q, Liu J, Tian L, Huang W, Quan J, et al. Effect of Endomorphins on HUVECs Treated by ox-LDL and Its Related Mechanisms. J Diabetes Res. 2016;2016:9741483.

    PubMed  PubMed Central  Google Scholar 

  50. Chiurchiù V, Izzi V, D’Aquilio F, Vismara D, Carotenuto F, Catanzaro G, et al. Endomorphin-1 prevents lipid accumulation via CD36 down-regulation and modulates cytokines release from human lipid-laden macrophages. Peptides. 2011;32:80–5.

    PubMed  Google Scholar 

  51. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Davies MJ, Aronne LJ, Caterson ID, Thomsen AB, Jacobsen PB, Marso SP, et al. Liraglutide and cardiovascular outcomes in adults with overweight or obesity: A post hoc analysis from SCALE randomized controlled trials. Diabetes Obes Metab. 2018;20:734–9.

    CAS  PubMed  Google Scholar 

  53. Nauck MA, Meier JJ, Cavender MA, Abd El Aziz M, Drucker DJ. Cardiovascular actions and clinical outcomes with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Circulation. 2017;136:849–70.

    CAS  PubMed  Google Scholar 

  54. Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation. 2008;117:2340–50.

    CAS  PubMed  Google Scholar 

  55. Lim S, Kim KM, Nauck MA. Glucagon-like peptide-1 receptor agonists and cardiovascular events: class effects versus individual patterns. Trends Endocrinol Metab. 2018;29:238–48.

    CAS  PubMed  Google Scholar 

  56. Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004;109:962–5.

    CAS  PubMed  Google Scholar 

  57. Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes. 2005;54:146–51.

    CAS  PubMed  Google Scholar 

  58. Noyan-Ashraf MH, Momen MA, Ban K, Sadi AM, Zhou YQ, Riazi AM, et al. GLP1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes. 2009;58:975–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Chen WR, Chen YD, Tian F, Yang N, Cheng LQ, Hu SY, et al. Effects of liraglutide on reperfusion injury in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Imaging. 2016;9:e005146.

    PubMed  Google Scholar 

  60. Bose AK, Mocanu MM, Carr RD, Yellon DM. Glucagon like peptide-1 is protective against myocardial ischemia/reperfusion injury when given either as a preconditioning mimetic or at reperfusion in an isolated rat heart model. Cardiovasc Drugs Ther. 2005;19:9–11.

    PubMed  Google Scholar 

  61. Basalay MV, Mastitskaya S, Mrochek A, Ackland GL, Del Arroyo AG, Sanchez J, et al. Glucagon-like peptide-1 (GLP1) mediates cardioprotection by remote ischaemic conditioning. Cardiovasc Res. 2016;112:669–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Bose AK, Mocanu MM, Carr RD, Yellon DM. Myocardial ischaemia-reperfusion injury is attenuated by intact glucagon like peptide-1 (GLP1) in the in vitro rat heart and may involve the p70s6K pathway. Cardiovasc Drugs Ther. 2007;21(Aug):253–6.

    CAS  PubMed  Google Scholar 

  63. Qiao H, Ren H, Du H, Zhang M, Xiong X, Lv R. Liraglutide repairs the infarcted heart: The role of the SIRT1/Parkin/mitophagy pathway. Mol Med Rep. 2018;17:3722–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhang Y, Zhou H, Wu W, Shi C, Hu S, Yin T, et al. Liraglutide protects cardiac microvascular endothelial cells against hypoxia/reoxygenation injury through the suppression of the SR-Ca(2+)-XO-ROS axis via activation of the GLP1R/PI3K/Akt/survivin pathways. Free Radic Biol Med. 2016;95:278–92.

    CAS  PubMed  Google Scholar 

  65. Clarke SJ, Giblett JP, Yang LL, Hubsch A, Zhao T, Aetesam-Ur-Rahman M, et al. GLP1 is a coronary artery vasodilator in humans. J Am Heart Assoc. 2018;7:e010321.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Qi Q, Lu L, Li H, Yuan Z, Chen G, Lin M, et al. Spatiotemporal delivery of nanoformulated liraglutide for cardiac regeneration after myocardial infarction. Int J Nanomedicine. 2017;12:4835–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Yang X, Liang Z. Efficacy of liraglutide intervention in myocardial infarction: a meta-analysis of randomized controlled trials. Herz. 2018. https://doi.org/10.1007/s00059-018-4748-5.

  68. Gros R, You X, Baggio LL, Kabir MG, Sadi AM, Mungrue IN. et al. Cardiac function in mice lacking the glucagon-like peptide-1 receptor. Endocrinology.2003;144:2242–52.

    CAS  PubMed  Google Scholar 

  69. Wallner M, Kolesnik E, Ablasser K, Khafaga M, Wakula P, Ljubojevic S, et al. Exenatide exerts a PKA-dependent positive inotropic effect in human atrial myocardium: GLP1R mediated effects in human myocardium. J Mol Cell Cardiol. 2015;89:365–75.

    CAS  PubMed  Google Scholar 

  70. Nikolaidis LA, Elahi D, Hentosz T, Doverspike A, Huerbin R, Zourelias L, et al. Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation. 2004;110:955–61.

    CAS  PubMed  Google Scholar 

  71. Noyan-Ashraf MH, Shikatani EA, Schuiki I, Mukovozov I, Wu J, Li RK, et al. A glucagon-like peptide-1 analog reverses the molecular pathology and cardiac dysfunction of a mouse model of obesity. Circulation. 2013;127:74–85.

    CAS  PubMed  Google Scholar 

  72. Ji Y, Zhao Z, Cai T, Yang P, Cheng M. Liraglutide alleviates diabetic cardiomyopathy by blocking CHOP-triggered apoptosis via the inhibition of the IRE-α pathway. Mol Med Rep. 2014;9:1254–8.

    CAS  PubMed  Google Scholar 

  73. Leonardini A, D’Oria R, Incalza MA, Caccioppoli C, Andrulli, Buccheri V, et al. GLP1 receptor activation inhibits palmitate-induced apoptosis via ceramide in human cardiac progenitor cells. J Clin Endocrinol Metab. 2017;102:4136–47.

    PubMed  Google Scholar 

  74. Arturi F, Succurro E, Miceli S, Cloro C, Ruffo M, Maio R, et al. Liraglutide improves cardiac function in patients with type 2 diabetes and chronic heart failure. Endocrine. 2017;57:464–73.

    CAS  PubMed  Google Scholar 

  75. Jorsal A, Kistorp C, Holmager P, Tougaard RS, Nielsen R, Hänselmann A, et al. Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)-a multicentre, double-blind, randomised, placebo-controlled trial. Eur J Heart Fail. 2017;19:69–77.

    CAS  PubMed  Google Scholar 

  76. Margulies KB, Hernandez AF, Redfield MM, Givertz MM, Oliveira GH, Cole R, et al. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. JAMA. 2016;316:500–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Briyal S, Shah S, Gulati A. Neuroprotective and anti-apoptotic effects of liraglutide in the rat brain following focal cerebral ischemia. Neuroscience. 2014;281:269–81.

    CAS  PubMed  Google Scholar 

  78. Wang MD, Huang Y, Zhang GP, Mao L, Xia YP, Mei YW, et al. Exendin-4 improved rat cortical neuron survival under oxygen/glucose deprivation through PKA pathway. Neuroscience. 2012;226:388–96.

    CAS  PubMed  Google Scholar 

  79. Zhu H, Zhang Y, Shi Z, Lu D, Li T, Ding Y, et al. The neuroprotection of liraglutide against ischaemia-induced apoptosis through the activation of the PI3K/AKT and MAPK pathways. Sci Rep. 2016;6:26859.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Ma X, Lin W, Lin Z, Hao M, Gao X, Zhang Y, et al. Liraglutide alleviates H2O2-induced retinal ganglion cells injury by inhibiting autophagy through mitochondrial pathways. Peptides. 2017;92:1–8.

    CAS  PubMed  Google Scholar 

  81. Chen Y, Zhang X, He J, Xie Y, Yang Y. Delayed administration of the glucagon-like peptide 1 analog liraglutide promoting angiogenesis after focal cerebral ischemia in mice. J Stroke Cerebrovasc Dis. 2018;27:1318–25.

    PubMed  Google Scholar 

  82. Yu M, Moreno C, Hoagland KM, Dahly A, Ditter K, Mistry M, et al. Antihypertensive effect of glucagon-like peptide 1 in Dahl salt sensitive rats. J Hypertens. 2003;21:1125–35.

    CAS  PubMed  Google Scholar 

  83. Zhao X, Huang K, Zheng M, Duan J. Effect of liraglutide on blood pressure: a meta-analysis of liraglutide randomized controlled trials. BMC Endocr Disord. 2019;19:4.

    PubMed  PubMed Central  Google Scholar 

  84. Baggio LL, Ussher JR, McLean BA, Cao X, Kabir MG, Mulvihill EE, et al. The autonomic nervous system and cardiac GLP1 receptors control heart rate in mice. Mol Metab. 2017;6:1339–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Golpon HA, Puechner A, Welte T, Wichert PV, Feddersen CO. Vasorelaxant effect of glucagon-like peptide-(7-36)amide and amylin on the pulmonary circulation of the rat. Regul Pept. 2001;102:81–6.

    CAS  PubMed  Google Scholar 

  86. Richter G, Feddersen O, Wagner U, Barth P, Göke R, Göke B. GLP1 stimulates secretion of macromolecules from airways and relaxes pulmonary artery. Am J Physiol. 1993;265:L374–L381.

    CAS  PubMed  Google Scholar 

  87. Wei R, Ma S, Wang C, Ke J, Yang J, Li W, et al. Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP1 receptor-dependent manner. Am J Physiol Endocrinol Metab. 2016;310:E947–E957.

    PubMed  Google Scholar 

  88. Green BD, Hand KV, Dougan JE, McDonnell BM, Cassidy RS, Grieve DJ. GLP1 and related peptides cause concentration-dependent relaxation of rat aorta through a pathway involving KATP and cAMP. Arch Biochem Biophys. 2008;478:136–42.

    CAS  PubMed  Google Scholar 

  89. Kim M, Platt MJ, Shibasaki T, Quaggin SE, Backx PH, Seino S, et al. GLP1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med. 2013;19:567–75.

    CAS  PubMed  Google Scholar 

  90. Oeseburg H, de Boer RA, Buikema H, van der Harst P, van Gilst WH, Silljé HH. Glucagon-like peptide 1 prevents reactive oxygen species-induced endothelial cell senescence through the activation of protein kinase A. Arterioscler Thromb Vasc Biol. 2010;30:1407–14.

    CAS  PubMed  Google Scholar 

  91. Gaspari T, Liu H, Welungoda I, Hu Y, Widdop RE, Knudsen LB, et al. A GLP1 receptor agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE−/− mouse model. Diab Vasc Dis Res. 2011;8:117–24.

    PubMed  Google Scholar 

  92. Nystrom T, Gutniak MK, Zhang Q, Zhang F, Holst JJ, Ahren B, et al. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab. 2004;287:E1209–E1215.

    PubMed  Google Scholar 

  93. Dai Y, Dai D, Wang X, Ding Z, Li C, Mehta JL. GLP1 agonists inhibit ox-LDL uptake in macrophages by activating protein kinase A. J Cardiovasc Pharmacol. 2014;64:47–52.

    CAS  PubMed  Google Scholar 

  94. Bruen R, Curley S, Kajani S, Crean D, O’Reilly ME, Lucitt MB, et al. Liraglutide dictates macrophage phenotype in apolipoprotein E null mice during early atherosclerosis. Cardiovasc Diabetol. 2017;16:143.

    PubMed  PubMed Central  Google Scholar 

  95. Goto H, Nomiyama T, Mita T, Yasunari E, Azuma K, Komiya K, et al. Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces intimal thickening after vascular injury. Biochem Biophys Res Commun. 2011;405:79–84.

    CAS  PubMed  Google Scholar 

  96. Jojima T, Uchida K, Akimoto K, Tomotsune T, Yanagi K, Iijima T, et al. Liraglutide, a GLP1 receptor agonist, inhibits vascular smooth muscle cell proliferation by enhancing AMP-activated protein kinase and cell cycle regulation, and delays atherosclerosis in ApoE deficient mice. Atherosclerosis. 2017;261:44–51.

    CAS  PubMed  Google Scholar 

  97. Ritchey ME, Harding A, Hunter S, Peterson C, Sager PT, Kowey PR, et al. Cardiovascular safety during and after use of phentermine and topiramate. J Clin Endocrinol Metab. 2019;104:513–22.

    PubMed  Google Scholar 

  98. Rothman RB, Hendricks EJ. Phentermine cardiovascular safety. Am J Emerg Med. 2009;27:1010–3.

    PubMed  Google Scholar 

  99. Noh MR, Kim SK, Sun W, Park SK, Choi HC, Lim JH, et al. Neuroprotective effect of topiramate on hypoxic ischemic brain injury in neonatal rats. Exp Neurol. 2006;201:470–8.

    CAS  PubMed  Google Scholar 

  100. Yang Y, Shuaib A, Li Q, Siddiqui MM. Neuroprotection by delayed administration of topiramate in a rat model of middle cerebral artery embolization. Brain Res. 1998;804:169–76.

    CAS  PubMed  Google Scholar 

  101. Tian Y, Guo SX, Li JR, Du HG, Wang CH, Zhang JM, et al. Topiramate attenuates early brain injury following subarachnoid haemorrhage in rats via duplex protection against inflammation and neuronal cell death. Brain Res. 2015;1622:174–85.

    CAS  PubMed  Google Scholar 

  102. Cure E, Cure MC, Tumkaya L, Kalkan Y, Aydin I, Kirbas A, et al. Topiramate ameliorates abdominal aorta cross-clamping induced liver injury in rats. Saudi J Gastroenterol. 2014;20:297–303.

    PubMed  PubMed Central  Google Scholar 

  103. Wang Z, Huang S, Sheng Y, Peng X, Liu H, Jin N, et al. Topiramate modulates post-infarction inflammation primarily by targeting monocytes or macrophages. Cardiovasc Res. 2017;113:475–87.

    CAS  PubMed  Google Scholar 

  104. Dionisio L, Jose De Rosa M, Bouzat C, Esandi Mdel C. An intrinsic gabaergic system in human lymphocytes. Neuropharmacology. 2011;60:513–9.

    CAS  PubMed  Google Scholar 

  105. Bhat R, Axtell R, Mitra A, Miranda M, Lock C, Tsien RW, et al. Inhibitory role for GABA in autoimmune inflammation. Proc Natl Acad Sci USA. 2010;107:2580–5.

    CAS  PubMed  Google Scholar 

  106. Yang Y, Lian YT, Huang SY, Yang Y, Cheng LX, Liu K. GABA and topiramate inhibit the formation of human macrophage-derived foam cells by modulating cholesterol-metabolism-associated molecules. Cell Physiol Biochem. 2014;33:1117–29.

    CAS  PubMed  Google Scholar 

  107. Manzini S, Busnelli M, Parolini C, Minoli L, Ossoli A, Brambilla E, et al. Topiramate protects apoE-deficient mice from kidney damage without affecting plasma lipids. Pharmacol Res. 2018;141:189–200.

    PubMed  Google Scholar 

  108. Salameh TS, Shah GN, Price TO, Hayden MR, Banks WA. Blood-brain barrier disruption and neurovascular unit dysfunction in diabetic mice: protection with the mitochondrial carbonic anhydrase inhibitor topiramate. J Pharmacol Exp Ther. 2016;359:452–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Bohula EA, Wiviott SD, McGuire DK, Inzucchi SE, Kuder J, Im K, et al. Cardiovascular safety of lorcaserin in overweight or obese patients. N Engl J Med. 2018;379:1107–17.

    CAS  PubMed  Google Scholar 

  110. Julius D, MacDermott AB, Axel R, Jessell JM. Molecular characterization of a functional cDNA encoding the serotonin 1C receptor. Science. 1988;241:558–64.

    CAS  PubMed  Google Scholar 

  111. Jordan D. Vagal control of the heart: central serotonergic (5-HT) mechanisms. Exp Physiol. 2005;90:175–81.

    CAS  PubMed  Google Scholar 

  112. Ferreira HS, Oliveira E, Faustino TN, Silva Ede C, Fregoneze JB. Effect of the activation of central 5-HT2C receptors by the 5-HT2C agonist mCPP on blood pressure and heart rate in rats. Brain Res. 2005;1040:64–72.

    PubMed  Google Scholar 

  113. Hamik A, Peroutka SJ. 1-(m-chlorophenyl)piperazine (mCPP) interactions with neurotransmitter receptors in the human brain. Biol Psychiatry. 1989;25:569–75.

    CAS  PubMed  Google Scholar 

  114. Nozulak J, Kalkman HO, Floersheim P, Hoyer D, Schoeffter P, Buerki HR. (+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo[1,7- bc][2,6]-naphthyridine: a 5-HT2C/2B receptor antagonist with low 5-HT2A receptor affinity. J Med Chem.1995;38:28–33.

    CAS  PubMed  Google Scholar 

  115. Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, et al. Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature. 1995;374:542–6.

    CAS  PubMed  Google Scholar 

  116. Calama E, Morán A, Ortiz De Urbina AV, Martin ML, San Roman L. m-CPP, a 5-HT2C receptor agonist that modifies the perfusion pressure of the hindquarter vascular bed of anesthetized rat. Pharmacology. 2005;73:70–5.

    CAS  PubMed  Google Scholar 

  117. Fernández MM, Morán A, Martín ML, San Román L. Mesenteric vasoconstrictor responses to 5-hydroxytryptamine in the in situ blood autoperfused rat mesentery:involvement of 5-HT2B and/or 5-HT2C receptor activation. Eur J Pharmacol. 2000;40:221–7.

    Google Scholar 

  118. Zhang B, Liu Y, Luo Y, Niu W, Li ZC. Alteration of serotonin 2C receptor expression in the aorta and the pulmonary artery in rats exposed to hypoxia. Chin J Physiol. 2008;51:338–47.

    CAS  PubMed  Google Scholar 

  119. Morán A, Ortiz de Urbina AV, Martín ML, García M, Rodriguez-Barbero A, Dorado F, et al. Characterization of contractile 5-hydroxytryptamine receptor subtypes in the in situ autoperfused kidney in the anaesthetized rat. Eur J Pharmacol. 2008;592:133–7.

    PubMed  Google Scholar 

  120. Cataldi M, Muscogiuri G, Savastano S, Barrea L, Guida B, Taglialatela M, et al. Gender-related issues in the pharmacology of new anti-obesity drugs. Obes Rev. 2019;20:375–84.

    PubMed  Google Scholar 

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Acknowledgements

Obesity Programs of nutrition, Education, Research and Assessment (OPERA) group members served as collaborators and approved the final version of the manuscript: Colao Annamaria, Savastano Silvia, Barrea Luigi, Muscogiuri Giovanna, Alviggi Carlo, Angrisani Luigi, Annunziata Giuseppe, Beguinot Francesco, Belfiore Annamaria, Belfiore Antonino, Bellastella Giuseppe, Biondi Bernadette, Bonaduce Domenico, Bordoni Laura, Brasacchio Caterina, Capaldo Brunella, Caprio Massimiliano, Cataldi Mauro, Cignarelli Angelo, Cittadini Antonello, Conforti Alessandro, Cuomo Rosario, De Placido Giuseppe, De Siena Marina, Di Carlo Costantino, Di Luigi Luigi, Di Nisio Andrea, Di Renzo Laura, Di Somma Carolina, Docimo Ludovico, Donini Lorenzo Maria, Federici Massimo, Foresta Carlo, Gabbianelli Rosita, Gambineri Alessandra, Gastaldelli Amalia, Giallauria Francesco, Giardiello Cristiano, Gnessi Lucio, Guida Brunella, Laudisio Daniela, Lenzi Andrea, Macchia Paolo Emidio, Manno Emilio, Marzullo Paolo, Migliaccio Silvia, Muratori Fabrizio, Musella Mario, Nardone Gerardo, Nicasto Vincenzo, Piazza Luigi, Pilone Vincenzo, Pivari Francesca, Pivonello Rosario, Pugliese Gabriella, Riccardi Gabriele, Ritieni Alberto, Salzano Ciro, Sanduzzi Alessandro, Sbraccia Paolo, Sesti Giorgio, Soldati Laura, Taglialatela Maurizio, Trimarco Bruno, Tuccinardi Dario.

Funding

The 2019 OPERA meeting was organized by Panta Rei Srl and sponsored by Novo Nordisk, Therascience, Bruno Pharma, Merck, Savio Pharma Italia Srl, IBSA Institut Biochimique SA, Bioitalia Srl, Cohesion Pharmaceutical, and Specchiasol Srl. Publication of this article as part of a supplement was sponsored by Panta Rei Srl, Naples, Italy. The meeting sponsors and organizer did not have access to the manuscripts and the authors maintained control of the content.

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Authors and Affiliations

  1. Department of Neuroscience, Reproductive Sciences and Dentistry, Division of Pharmacology, Federico II University of Naples, Naples, Italy

    Mauro Cataldi

  2. Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy

    Angelo Cignarelli

  3. Department of Translational Medical Sciences, Internal Medicine (Metabolic and Cardiac Rehabilitation Unit), Federico II University of Naples, Naples, Italy

    Francesco Giallauria

  4. Department of Clinical Medicine and Surgery, Unit of Endocrinology, Federico II University Medical School of Naples, Via Sergio Pansini 5, 80131, Naples, Italy

    Giovanna Muscogiuri, Luigi Barrea, Silvia Savastano & Annamaria Colao

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  1. Mauro Cataldi
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  3. Francesco Giallauria
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  4. Giovanna Muscogiuri
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  7. Annamaria Colao
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on behalf of Obesity Programs of nutrition, Education, Research and Assessment (OPERA) Group

Contributions

The authors’ responsibilities were as follows: MC, AC, and FG: were responsible for the concept of this paper and drafted the manuscript; GM, LB, SS and AC: provided a critical review of the paper. OPERA Group members participated to the revision of the manuscript. All authors and OPERA Group Members contributed to and agreed on the final version of the manuscript.

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Correspondence to Mauro Cataldi.

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Conflict of interest

AC received lecture fees from Eli Lilly, Novo Nordisk, Sanofi Aventis, Astra Zeneca, Bruno farmaceutici, Roche. The remaining authors have nothing to disclose.

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On February 13, 2020, after the present manuscript completed its review process, FDA requested the withdrawal of lorcaserin from the market because of evidence from the CAMELLIA-TIMI 61clinical trial that poteintial risk of cancer could outweigh benefits.

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Cataldi, M., Cignarelli, A., Giallauria, F. et al. Cardiovascular effects of antiobesity drugs: are the new medicines all the same?. Int J Obes Supp 10, 14–26 (2020). https://doi.org/10.1038/s41367-020-0015-3

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