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Review

Liraglutide for the prevention of major adverse cardiovascular events in diabetic patients

Pages 377-387 | Received 04 Nov 2018, Accepted 02 May 2019, Published online: 17 May 2019

References

  • Rawshani A, Rawshani A, Franzen S, et al. Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2018 Aug 16;379(7):633–644.
  • American Diabetes Association. 10. Cardiovascular disease and risk management: Standards of Medical Care in Diabetesd2019. Diabetes Care 2019;42(Suppl.1): S103–S123 © 2018 by theAmerican Diabetes Association.
  • Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Oct 4;41:2669–2701.
  • Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American association of clinical endocrinologists and American college of endocrinology on the comprehensive type 2 diabetes management algorithm–2016 executive summary. Endocr Pract. 2016 Jan;22(1):84–113.
  • Ostergaard L, Frandsen CS, Madsbad S. Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus: a review. Expert Rev Clin Pharmacol. 2016;9(2):241–265.
  • Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012 Dec;8(12):728–742.
  • Nauck MA, Kleine N, Orskov C, et al. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993 Aug;36(8):741–744.
  • Nauck MA, Heimesaat MM, Behle K, et al. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab. 2002 Mar;87(3):1239–1246.
  • Jelsing J, Vrang N, Hansen G, et al. Liraglutide: short-lived effect on gastric emptying – long lasting effects on body weight. Diabetes Obes Metab. 2012 Jun;14(6):531–538.
  • Meier JJ, Gallwitz B, Salmen S, et al. Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes. J Clin Endocrinol Metab. 2003 Jun;88(6):2719–2725.
  • Drucker DJ. The cardiovascular biology of glucagon-like peptide-1. Cell Metab. 2016 Jul 12;24(1):15–30.
  • Hermansen K, Baekdal TA, During M, et al. Liraglutide suppresses postprandial triglyceride and apolipoprotein B48 elevations after a fat-rich meal in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, cross-over trial. Diabetes Obes Metab. 2013 Nov;15(11):1040–1048.
  • Kumarathurai P, Anholm C, Larsen BS, et al. Effects of liraglutide on heart rate and heart rate variability: a randomized, double-blind, placebo-controlled crossover study. Diabetes Care. 2017 Jan;40(1):117–124.
  • Lau J, Bloch P, Schaffer L, et al. Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J Med Chem. 2015 Sep 24;58(18):7370–7380.
  • Nauck MA, Petrie JR, Sesti G, et al. A phase 2, randomized, dose-finding study of the novel once-weekly human GLP-1 analog, semaglutide, compared with placebo and open-label liraglutide in patients with type 2 diabetes. Diabetes Care. 2016 Feb;39(2):231–241.
  • Holst JJ, Madsbad S. Semaglutide seems to be more effective the other GLP-1Ras. Ann Transl Med. 2017 Dec;5(24):505.
  • Madsbad S. Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists. Diabetes Obes Metab. 2016 Apr;18(4):317–332.
  • Madsbad S, Kielgast U, Asmar M, et al. An overview of once-weekly glucagon-like peptide-1 receptor agonists–available efficacy and safety data and perspectives for the future. Diabetes Obes Metab. 2011 May;13(5):394–407.
  • Agerso H, Jensen LB, Elbrond B, et al. The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia. 2002 Feb;45(2):195–202.
  • Knudsen LB, Nielsen PF, Huusfeldt PO, et al. Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem. 2000 May 4;43(9):1664–1669.
  • Madsbad S. Exenatide and liraglutide: different approaches to develop GLP-1 receptor agonists (incretin mimetics)–preclinical and clinical results. Best Pract Res Clin Endocrinol Metab. 2009 Aug;23(4):463–477.
  • Ostergaard L, Frandsen CS, Dejgaard TF, et al. Fixed-ratio combination therapy with GLP-1 receptor agonist liraglutide and insulin degludec in people with type 2 diabetes. Expert Rev Clin Pharmacol. 2017 Jun;10(6):621–632.
  • Pratley RE, Nauck MA, Barnett AH, et al. Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study. Lancet Diabetes Endocrinol. 2014 Apr;2(4):289–297.
  • Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet. 2018;392(10157):1519-1529.
  • Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017 Sep 28;377(13):1228–1239.
  • Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844.
  • Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016 Jul 28;375(4):311–322.
  • Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015 Dec 3;373(23):2247–2257.
  • Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet. 2014 Oct 11;384(9951):1349–1357.
  • Pratley RE, Aroda VR, Lingvay I, et al. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol. 2018 Apr;6(4):275–286.
  • Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008 Oct 9;359(15):1577–1589.
  • Zoungas S, Arima H, Gerstein HC, et al. Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials. Lancet Diabetes Endocrinol. 2017 Jun;5(6):431–437.
  • Kumarathurai P, Anholm C, Fabricius-Bjerre A, et al. Effects of the glucagon-like peptide-1 receptor agonist liraglutide on 24-h ambulatory blood pressure in patients with type 2 diabetes and stable coronary artery disease: a randomized, double-blind, placebo-controlled, crossover study. J Hypertens. 2017;35(5):1070-1078.
  • Zhao X, Huang K, Zheng M, et al. Effect of liraglutide on blood pressure: a meta-analysis of liraglutide randomized controlled trials. BMC Endocr Disord. 2019 Jan 7;19(1):4.
  • Fonseca VA, DeVries JH, Henry RR, et al. Reductions in systolic blood pressure with liraglutide in patients with type 2 diabetes: insights from a patient-level pooled analysis of six randomized clinical trials. J Diabetes Complications. 2014 May;28(3):399–405.
  • Tonneijck L, Smits MM, Muskiet MH, et al. Renal effects of DPP-4 inhibitor sitagliptin or GLP-1 receptor agonist liraglutide in overweight patients with type 2 diabetes: A 12-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2016 Nov;39(11):2042–2050.
  • Tonneijck L, Muskiet MHA, Smits MM, et al. Postprandial renal haemodynamic effect of lixisenatide vs once-daily insulin-glulisine in patients with type 2 diabetes on insulin-glargine: an 8-week, randomised, open-label trial. Diabetes Obes Metab. 2017 Dec;19(12):1669–1680.
  • Skov J, Dejgaard A, Frokiaer J, et al. Glucagon-like peptide-1 (GLP-1): effect on kidney hemodynamics and renin-angiotensin-aldosterone system in healthy men. J Clin Endocrinol Metab. 2013 Apr;98(4):E664–E671.
  • Plutzky J, Garber A, Falahati A, et al. Reductions in lipids and CV risk markers in patients with type 2 diabetes treated with liraglutide: a meta-analysis. Can J Diabetes. 2009;33(3):209–210.
  • Dallinga-Thie GM, Nieuwdorp M. GLP1, an important regulator of intestinal lipid metabolism. Arterioscler Thromb Vasc Biol. 2015 May;35(5):1048–1049.
  • Engelbrechtsen L, Lundgren J, Wewer Albrechtsen NJ, et al. Treatment with liraglutide may improve markers of CVD reflected by reduced levels of apoB. Obes Sci Pract. 2017 Dec;3(4):425–433.
  • Pujadas G, Drucker DJ. Vascular biology of glucagon receptor superfamily peptides: mechanistic and clinical relevance. Endocr Rev. 2016 Dec;37(6):554–583.
  • Hogan AE, Gaoatswe G, Lynch L, et al. Glucagon-like peptide 1 analogue therapy directly modulates innate immune-mediated inflammation in individuals with type 2 diabetes mellitus. Diabetologia. 2014 Apr;57(4):781–784.
  • Lim S, Lee GY, Park HS, et al. Attenuation of carotid neointimal formation after direct delivery of a recombinant adenovirus expressing glucagon-like peptide-1 in diabetic rats. Cardiovasc Res. 2017 Feb;113(2):183–194.
  • Nagashima M, Watanabe T, Terasaki M, et al. Native incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice. Diabetologia. 2011 Oct;54(10):2649–2659.
  • Iacobellis G. Local and systemic effects of the multifaceted epicardial adipose tissue depot. Nat Rev Endocrinol. 2015 Jun;11(6):363–371.
  • Iacobellis G, Mohseni M, Bianco SD, et al. Liraglutide causes large and rapid epicardial fat reduction. Obesity (Silver Spring). 2017 Feb;25(2):311–316.
  • Baggio LL, Yusta B, Mulvihill EE, et al. GLP-1 Receptor Expression Within the Human Heart. Endocrinology. 2018 Apr 1;159(4):1570–1584.
  • Ussher JR, Drucker DJ. Cardiovascular biology of the incretin system. Endocr Rev. 2012 Apr;33(2):187–215.
  • Ussher JR, Baggio LL, Campbell JE, et al. Inactivation of the cardiomyocyte glucagon-like peptide-1 receptor (GLP-1R) unmasks cardiomyocyte-independent GLP-1R-mediated cardioprotection. Mol Metab. 2014 Aug;3(5):507–517.
  • Ban K, Noyan-Ashraf MH, Hoefer J, et al. 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 May 6;117(18):2340–2350.
  • Lonborg J, Kelbaek H, Vejlstrup N, et al. Exenatide reduces final infarct size in patients with ST-segment-elevation myocardial infarction and short-duration of ischemia. Circ Cardiovasc Interv. 2012 Apr;5(2):288–295.
  • Chen WR, Hu SY, Chen YD, et al. Effects of liraglutide on left ventricular function in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Am Heart J. 2015 Nov;170(5):845–854.
  • Chen WR, Chen YD, Tian F, et al. Effects of liraglutide on reperfusion injury in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Imaging. 2016 Dec;9(12).
  • Chen WR, Shen XQ, Zhang Y, et al. Effects of liraglutide on left ventricular function in patients with non-ST-segment elevation myocardial infarction. Endocrine. 2016 Jun;52(3):516–526.
  • Margulies KB, Hernandez AF, Redfield MM, et al. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. Jama. 2016 Aug 2;316(5):500–508.
  • Jorsal A, Kistorp C, Holmager P, 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 Jan;19(1):69–77.
  • Kumarathurai P, Anholm C, Nielsen OW, et al. Effects of the glucagon-like peptide-1 receptor agonist liraglutide on systolic function in patients with coronary artery disease and type 2 diabetes: a randomized double-blind placebo-controlled crossover study. Cardiovasc Diabetol. 2016 Jul 26;15(1):105.
  • Dai Y, Mehta JL, Chen M. Glucagon-like peptide-1 receptor agonist liraglutide inhibits endothelin-1 in endothelial cell by repressing nuclear factor-kappa B activation. Cardiovasc Drugs Ther. 2013 Oct;27(5):371–380.
  • Wei R, Ma S, Wang C, et al. Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner. Am J Physiol Endocrinol Metab. 2016 Jun 1;310(11):E947–E957.
  • Nandy D, Johnson C, Basu R, et al. The effect of liraglutide on endothelial function in patients with type 2 diabetes. Diab Vasc Dis Res. 2014;Nov;11(6):419–430.
  • Rizzo M, Rizvi AA, Patti AM, et al. Liraglutide improves metabolic parameters and carotid intima-media thickness in diabetic patients with the metabolic syndrome: an 18-month prospective study. Cardiovasc Diabetol. 2016 Dec 3;15(1):162.
  • Kushima H, Mori Y, Koshibu M, et al. The role of endothelial nitric oxide in the anti-restenotic effects of liraglutide in a mouse model of restenosis. Cardiovasc Diabetol. 2017 Oct 2;16(1):122.
  • Devin JK, Pretorius M, Nian H, et al. Dipeptidyl-peptidase 4 inhibition and the vascular effects of glucagon-like peptide-1 and brain natriuretic peptide in the human forearm. J Am Heart Assoc. 2014 Aug 26;3:4.
  • Nomoto H, Miyoshi H, Furumoto T, et al. A comparison of the effects of the GLP-1 analogue liraglutide and insulin glargine on endothelial function and metabolic parameters: a randomized, controlled trial sapporo athero-incretin study 2 (SAIS2). PLoS One. 2015;10(8):e0135854.
  • Smits MM, Tonneijck L, Muskiet MH, et al. GLP-1-based therapies have no microvascular effects in type 2 diabetes mellitus: an acute and 12-week randomized, double-blind, placebo-controlled trial. Arterioscler Thromb Vasc Biol. 2016 Oct;36(10):2125–2132.
  • Faber R, Zander M, Pena A, et al. Effect of the glucagon-like peptide-1 analogue liraglutide on coronary microvascular function in patients with type 2 diabetes - a randomized, single-blinded, cross-over pilot study. Cardiovasc Diabetol. 2015 Apr 22;14:41.
  • Stefanadis C, Antoniou CK, Tsiachris D, et al. Coronary atherosclerotic vulnerable plaque: current perspectives. J Am Heart Assoc. 2017 Mar 17;6(3).
  • Gaspari T, Welungoda I, Widdop RE, et al. The GLP-1 receptor agonist liraglutide inhibits progression of vascular disease via effects on atherogenesis, plaque stability and endothelial function in an ApoE(-/-) mouse model. Diab Vasc Dis Res. 2013 Jul;10(4):353–360.
  • Tashiro Y, Sato K, Watanabe T, et al. A glucagon-like peptide-1 analog liraglutide suppresses macrophage foam cell formation and atherosclerosis. Peptides. 2014;54:19–26.
  • Stefan N, Haring HU, Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. Lancet Diabetes Endocrinol. 2019;7(4):313-324.
  • Pyke C, Heller RS, Kirk RK, et al. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology. 2014 Apr;155(4):1280–1290.
  • Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016 Feb 13;387(10019):679–690.
  • Bethel MA, Patel RA, Merrill P, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol. 2018 Feb;6(2):105–113.
  • Muskiet MHA, Tonneijck L, Huang Y, et al. Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2018 Nov;6(11):859–869.
  • Verma S, Bhatt DL, Bain SC, et al. Effect of liraglutide on cardiovascular events in patients with type 2 diabetes mellitus and polyvascular disease: results of the LEADER trial. Circulation. 2018 May 15;137(20):2179–2183.
  • Gilbert MP, Bain SC, Franek E, et al. Effect of liraglutide on cardiovascular outcomes in elderly patients: a post Hoc analysis of a randomized controlled trial. Ann Intern Med. 2018 Dec 4. doi: 10.7326/M18-1569. [Epub ahead of print].
  • Marso SP, Nauck MA, Monk FT, et al. Myocardial infarction subtypes in patients with type 2 diabetes mellitus and the effect of liraglutide therapy (from the LEADER trial). Am J Cardiol. 2018 Jun 15;121(12):1467–1470.
  • Nauck MA, Tornoe K, Rasmussen S, et al. Cardiovascular outcomes in patients who experienced a myocardial infarction while treated with liraglutide versus placebo in the LEADER trial. Diab Vasc Dis Res. 2018 Sep;15(5):465–468.
  • Hallen J. Troponin for the estimation of infarct size: what have we learned? Cardiology. 2012;121(3):204–212.
  • Zinman B, Marso SP, Christiansen E, et al. Outcomes, and death: the LEADER experience. Diabetes Care. 2018 Aug;41(8):1783–1791.
  • Mann JFE, Orsted DD, Brown-Frandsen K, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med. 2017 Aug 31;377(9):839–848.
  • Svanstrom H, Ueda P, Melbye M, et al. Use of liraglutide and risk of major cardiovascular events: a register-based cohort study in Denmark and Sweden. Lancet Diabetes Endocrinol. 2019 Feb;7(2):106–114.
  • Vilsboll T, Bain SC, Leiter LA, et al. Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy. Diabetes Obes Metab. 2018 Apr;20(4):889–897.
  • Gerstein HC, Colhoun HM, Dagenais GR, et al. Design and baseline characteristics of participants in the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial on the cardiovascular effects of dulaglutide. Diabetes Obes Metab. 2018 Jan;20(1):42–49.
  • Bjerre KL, Madsen LW, Andersen S, et al. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology. 2010 Apr;151(4):1473–1486.
  • Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugs–FDA and EMA assessment. N Engl J Med. 2014 Feb 27;370(9):794–797.
  • Hegedus L, Moses AC, Zdravkovic M, et al. GLP-1 and calcitonin concentration in humans: lack of evidence of calcitonin release from sequential screening in over 5000 subjects with type 2 diabetes or nondiabetic obese subjects treated with the human GLP-1 analog, liraglutide. J Clin Endocrinol Metab. 2011 Mar;96(3):853–860.
  • Steinberg WM, Buse JB, Ghorbani MLM, et al. Amylase, lipase, and acute pancreatitis in people with type 2 diabetes treated with liraglutide: results from the LEADER randomized trial. Diabetes Care. 2017 Jul;40(7):966–972.
  • Nauck MA, Jensen TJ, Rosenkilde C, et al. Neoplasms reported with liraglutide or placebo in people with type 2 diabetes: results from the LEADER randomized trial. Diabetes Care. 2018 Aug;41(8):1663–1671.
  • le Roux CW, Astrup A, Fujioka K, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet. 2017 Apr 8;389(10077):1399–1409.
  • Smits MM, Tonneijck L, Muskiet MH, et al. Biliary effects of liraglutide and sitagliptin, a 12-week randomized placebo-controlled trial in type 2 diabetes patients. Diabetes Obes Metab. 2016 Dec;18(12):1217–1225.
  • Eng C, Kramer CK, Zinman B, et al. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet. 2014 Dec 20;384(9961):2228–2234.
  • Gough SC, Bode BW, Woo VC, et al. One-year efficacy and safety of a fixed combination of insulin degludec and liraglutide in patients with type 2 diabetes: results of a 26-week extension to a 26-week main trial. Diabetes Obes Metab. 2015 Oct;17(10):965–973.
  • Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2015 Mar;58(3):429–442.
  • Davies M, Pieber TR, Hartoft-Nielsen ML, et al. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. Jama. 2017 Oct 17;318(15):1460–1470.
  • O’Neil PM, Birkenfeld AL, McGowan B, et al. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet. 2018 Aug 25;392(10148):637–649.
  • Brandt SJ, Muller TD, DiMarchi RD, et al. Peptide-based multi-agonists: a new paradigm in metabolic pharmacology. J Intern Med. 2018;284(6):581-602.
  • Tschop MH, Finan B, Clemmensen C, et al. Unimolecular polypharmacy for treatment of diabetes and obesity. Cell Metab. 2016 Jul 12;24(1):51–62.
  • Frias JP, Nauck MA, Van J, et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet. 2018;392(10160):2180-2193.

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