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Horm Metab Res 2023; 55(01): 7-24
DOI: 10.1055/a-1971-6965
Review

Repurposing of Drugs for Cardiometabolic Disorders: An Out and Out Cumulation

Rufaida Wasim
1   Pharmacology, Integral University, Lucknow, India
,
Tarique Mahmood Ansari
2   Faculty of Pharmacy, Integral University, Lucknow, India
,
Mohammed Haris Siddiqui
3   Bioengineering, Integral University, Lucknow, India
,
Farogh Ahsan
1   Pharmacology, Integral University, Lucknow, India
,
Arshiya Shamim
1   Pharmacology, Integral University, Lucknow, India
,
Aditya Singh
4   Pharmaceutics, Integral University, Lucknow, India
,
Mohammad Shariq
5   Pharmacy, Integral University, Lucknow, India
,
Aamir Anwar
5   Pharmacy, Integral University, Lucknow, India
,
Aquib Rehanullah Siddiqui
5   Pharmacy, Integral University, Lucknow, India
,
Saba Parveen
1   Pharmacology, Integral University, Lucknow, India
› Author Affiliations
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Abstract

Cardiometabolic disorders (CMD) is a constellation of metabolic predisposing factors for atherosclerosis such as insulin resistance (IR) or diabetes mellitus (DM), systemic hypertension, central obesity, and dyslipidemia. Cardiometabolic diseases (CMDs) continue to be the leading cause of mortality in both developed and developing nations, accounting for over 32% of all fatalities globally each year. Furthermore, dyslipidemia, angina, arrhythmia, heart failure, myocardial infarction (MI), and diabetes mellitus are the major causes of death, accounting for an estimated 19 million deaths in 2012. CVDs will kill more than 23 million individuals each year by 2030. Nonetheless, new drug development (NDD) in CMDs has been increasingly difficult in recent decades due to increased costs and a lower success rate. Drug repositioning in CMDs looks promising in this scenario for launching current medicines for new therapeutic indications. Repositioning is an ancient method that dates back to the 1960s and is mostly based on coincidental findings during medication trials. One significant advantage of repositioning is that the drug’s safety profile is well known, lowering the odds of failure owing to undesirable toxic effects. Furthermore, repositioning takes less time and money than NDD. Given these facts, pharmaceutical corporations are becoming more interested in medication repositioning. In this follow-up, we discussed the notion of repositioning and provided some examples of repositioned medications in cardiometabolic disorders.

Keywords

cardiometabolic disorders - cardiovascular disease - diabetes mellitus - drug repositioning - new drug development


Publication History

Received: 24 July 2022

Accepted after revision: 18 October 2022

Article published online:
04 January 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Mullard A. Drug repurposing programmes get lift off. Nat Rev Drug Discov 2012; 11: 505-506
    CrossrefPubMedGoogle Scholar
  • 2 Chong CR, Sullivan DJ. New uses for old drugs. Nature 2007; 448: 645-646
    CrossrefPubMedGoogle Scholar
  • 3 Cha Y, Erez T, Reynolds IJ. et al. Drug repurposing from the perspective of pharmaceutical companies. Br J Pharmacol 2018; 175: 168-180
    PubMedGoogle Scholar
  • 4 Aggarwal S, Verma SS, Aggarwal S. Drug repurposing for breast cancer therapy: Old weapon for new battle. Semin Cancer Biol 2021; 68: 8-20
    CrossrefPubMedGoogle Scholar
  • 5 Hubsher G, Haider M, Okun M. Amantadine: The journey from fighting flu to treating Parkinson disease. Neurology 2012; 78: 1096-1099
    CrossrefPubMedGoogle Scholar
  • 6 Yang J, Griffin W, Li Y. et al. Understanding drug repurposing from the perspective of biomedical entities and their evolution: bibliographic research using aspirin. JMIR Med Inform 2020; 8: e16739
    CrossrefPubMedGoogle Scholar
  • 7 Colombo D, Ammirati E. Cyclosporine in transplantation – A history of converging timelines. J Boil Regul Homeost Agents 2012; 25: 493-504
    PubMedGoogle Scholar
  • 8 Varothai S, Bergfeld WF. Androgenetic alopecia: an evidence-based treatment update. Am. J Clin Dermatol 2014; 15: 217-230
    CrossrefPubMedGoogle Scholar
  • 9 Ross DM, Hughes TP. Cancer treatment with kinase inhibitors: What have we learnt from imatinib?. Br J Cancer 2004; 90: 12-19
    CrossrefPubMedGoogle Scholar
  • 10 Ferreira LG, Andricopulo AD. Drug repositioning approaches to parasitic diseases: a medicinal chemistry perspective. Drug Discov Today 2016; 21: 1699-1710
    CrossrefPubMedGoogle Scholar
  • 11 Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov 2014; 3: 673-683
    CrossrefPubMedGoogle Scholar
  • 12 Cao C, Moult J. GWAS and drug targets. BMC Genom 2014; 15: S5
    CrossrefPubMedGoogle Scholar
  • 13 Campillos M, Kuhn M, Gavin AC. et al. Drug target identification using side-effect similarity. Science 2008; 321: 263-266
    CrossrefPubMedGoogle Scholar
  • 14 Tam V, Patel N, Turcotte M. et al. Benefits and limitations of genome-wide association studies. Nat Rev Genet 2019; 20: 467-484
    CrossrefPubMedGoogle Scholar
  • 15 Nabirotchkin S, Peluffo AE, Rinaudo P. et al. Next-generation drug repurposing using human genetics and network biology. Curr Opin Pharmacol 2020; 51: 78-92
    CrossrefPubMedGoogle Scholar
  • 16 Miller IN, Cronin-Golomb A. Gender differences in Parkinson’s disease: clinical characteristics and cognition. Mov Disord 2010; 25: 2695-2703
    CrossrefPubMedGoogle Scholar
  • 17 Shu L, Blencowe M, Yang X. Translating GWAS findings to novel therapeutic targets for coronary artery disease. Front Cardiovasc Med 2018; 5: 1-9
    PubMedGoogle Scholar
  • 18 Bullock C, Cornia N, Jacob R. et al. DockoMatic 2.0: high throughput inverse virtual screening and homology modeling. J Chem Inf Model 2013; 53: 2161-2170
    CrossrefPubMedGoogle Scholar
  • 19 King MD, Long T, Pfalmer DL. et al. SPIDR: Small-molecule peptide-influenced drug repurposing. BMC Bioinform 2018; 19: 138
    CrossrefPubMedGoogle Scholar
  • 20 Chong CR, Chen X, Shi L. et al. A clinical drug library screen identifies astemizole as an antimalarial agent. Nat Chem Biol 2006; 2: 415-416
    CrossrefPubMedGoogle Scholar
  • 21 Appleby BS, Cummings JL. Discovering new treatments for Alzheimer’s disease by repurposing approved medications. Curr Top Med Chem 2013; 13: 2306-2327
    CrossrefPubMedGoogle Scholar
  • 22 Shah B, Modi P, Sagar SR. In silico studies on therapeutic agents for COVID-19: drug repurposing approach. Life Sci 2020; 20: 117652
    CrossrefPubMedGoogle Scholar
  • 23 World Health Organization. Global action plan for the prevention and control of noncommunicable diseases 2013–2020. 2013 https://www.who.int/publications/i/item/9789241506236
    PubMed
  • 24 Alkerwi A, Albert A, Guillaume M. Cardiometabolic syndrome www. intechopen.com. (Accessed: July 22 2022)
    PubMed
  • 25 Global status report on noncommunicable diseases 2014: attaining the nine global noncommunicable diseases targets; a shared responsibility. WHO, Geneva, 2015 https://apps.who.int/iris/bitstream/handle/10665/148114/9789241564854_eng.pdf
    PubMed
  • 26 World Health Organization. Cardiovascular Diseases (CVDs). [Fact Sheet 317 (updated March 2013)]. Retrieved June 2022; 9:2013 http://www.who.int/mediacentre/factsheets/fs317/en/
    PubMed
  • 27 Centers for Disease Control and Prevention (CDC). Heart disease and stroke prevention: Addressing the nationGÇÖs leading killers. At a glance 2009. 2013. Available from: http://www.cdc.gov/nccdphp/publications/AAG/pdf/dhdsp.pdf
    PubMed
  • 28 Parker J, Hashmi O, Dutton D. et al. Levels of vitamin D and cardiometabolic disorders: systematic review and meta-analysis. Maturitas 2010; 65: 225-236
    CrossrefPubMedGoogle Scholar
  • 29 Grundy SM, Benjamin IJ, Burke GL. et al. Diabetes and cardiovascular disease a statement for healthcare professionals from the American Heart Association. Circulation 1999; 100: 1134-1146
    CrossrefPubMedGoogle Scholar
  • 30 Castro JP, El-Atat FA, McFarlane SI. et al. Cardiometabolic syndrome: pathophysiology and treatment. Curr Hypertens Rep 2003; 5: 393-401
    CrossrefPubMedGoogle Scholar
  • 31 Catherine AS, Matthew W, Orville K. Metabolic effects of the incretin mimetic exenatide in the treatment of type 2 diabetes. Vasc Health Risk Manag 2006; 2: 69-77
    CrossrefPubMedGoogle Scholar
  • 32 van Genugten RE, Moller-Goede DL, van Raalte DH. et al. Extra-pancreatic effects of incretin-based therapies: potential benefit for cardiovascular-risk management in type 2 diabetes. Diabet Obes Metab 2013; 15: 593-606
    CrossrefPubMedGoogle Scholar
  • 33 Monami M, Dicembrini I, Nardini C. et al. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials. Diabet Obes Metab 2014; 16: 38-47
    CrossrefPubMedGoogle Scholar
  • 34 Best JH, Hoogwerf BJ, Herman WH. et al. Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the LifeLink database. Diabet Care 2011; 34: 90-95
    CrossrefPubMedGoogle Scholar
  • 35 Wang B, Zhong J, Lin H. et al. Blood pressure-lowering effects of GLP-1 receptor agonists exenatide and liraglutide: a meta-analysis of clinical trials. Diabet Obes Metab 2013; 15: 737-749
    CrossrefPubMedGoogle Scholar
  • 36 Robinson LE, Holt TA, Rees K. et al. Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: systematic review and meta-analysis. BMJ Open 2013; 3: piie001986
    CrossrefPubMedGoogle Scholar
  • 37 Filippatos TD, Elisaf MS. Effects of glucagon-like peptide-1 receptor agonists on renal function. World J Diabet 2013; 4: 190-201
    CrossrefPubMedGoogle Scholar
  • 38 Nystrom T, Gonon AT, Sjoholm A. et al. Glucagon-like peptide-1 relaxes rat conduit arteries via an endothelium-independent mechanism. Regul Pept 2005; 125: 173-177
    CrossrefPubMedGoogle Scholar
  • 39 Sivertsen J, Rosenmeier J, Holst JJ. et al. The effect of glucagon-like peptide 1 on cardiovascular risk. Nat Rev Cardiol 2012; 9: 209-222
    CrossrefPubMedGoogle Scholar
  • 40 Kim M, Platt MJ, Shibasaki T. et al. GLP-1 receptor activation and epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med 2013; 19: 567-575
    CrossrefPubMedGoogle Scholar
  • 41 Skov J, Holst JJ, Gotze JP. et al. Glucagon-like peptide-1: effect on pro-atrial natriuretic peptide in healthy males. Endocrine Connect 2014; 3: 11-16
    CrossrefPubMedGoogle Scholar
  • 42 Koska J, Schwartz EA, Mullin MP. et al. Improvement of postprandial endothelial function after a single dose of exenatide in individuals with impaired glucose tolerance and recent-onset type 2 diabetes. Diabet Care 2010; 33: 1028-1030
    CrossrefPubMedGoogle Scholar
  • 43 Nikolaidis LA, Elahi D, Hentosz T. et al. Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circ 2004; 110: 955-961
    CrossrefPubMedGoogle Scholar
  • 44 Nikolaidis LA, Mankad S, Sokos GG. et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circ 2004; 109: 962-965
    CrossrefPubMedGoogle Scholar
  • 45 Sokos GG, Nikolaidis LA, Mankad S. et al. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Cardiac Failure 2006; 12: 694-699
    CrossrefPubMedGoogle Scholar
  • 46 Noyan-Ashraf MH, Momen MA, Ban K. et al. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes. 2009; 58: 975-983
    CrossrefPubMedGoogle Scholar
  • 47 Liu Q, Anderson C, Broyde A. et al. Glucagon-like peptide-1 and the exenatide analogue ac3174 improve cardiac function, cardiac remodeling, and survival in rats with chronic heart failure. Cardiovasc Diabetol 2010; 9: 76
    CrossrefPubMedGoogle Scholar
  • 48 Wohlfart P, Linz W, Hubschle T. et al. Cardioprotective effects of lixisenatide in rat myocardial ischemia-reperfusion injury studies. J Trans Med 2013; 11: 84
    CrossrefPubMedGoogle Scholar
  • 49 Lonborg J, Vejlstrup N, Kelbaek H. et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J 2012; 33: 1491-1499
    CrossrefPubMedGoogle Scholar
  • 50 Courreges JP, Vilsboll T, Zdravkovic M. et al. Beneficial effects of once-daily liraglutide, a human glucagon-like peptide-1 analogue, on cardiovascular risk biomarkers in patients with type 2 diabetes. Diabet Med J Br Diabet Assoc 2008; 25: 1129-1131
    CrossrefPubMedGoogle Scholar
  • 51 Bunck MC, Diamant M, Eliasson B. et al. Exenatide affects circulating cardiovascular risk biomarkers independently of changes in body composition. Diabet Care 2010; 33: 1734-1737
    CrossrefPubMedGoogle Scholar
  • 52 Tibble CA, Cavaiola TS, Henry RR. Longer acting GLP-1 receptor agonists and the potential for improved cardiovascular outcomes: a review of current literature. Expert Rev Endocrinol Metab 2013; 8: 247-259
    CrossrefPubMedGoogle Scholar
  • 53 Available at: http://ClinicalTrials.gov
    PubMed
  • 54 Miller AA, Spencer SJ. Obesity and neuroinflammation: a pathway to cognitive impairment. Brain Behav Immun 2014; 42: 10-21
    CrossrefPubMedGoogle Scholar
  • 55 de la Monte SM. Relationships between diabetes and cognitive impairment. Endocrinol Metab Clin North Am. 2014; 43: 245-267
    CrossrefPubMedGoogle Scholar
  • 56 Holst JJ, Burcelin R, Nathanson E. Neuroprotective properties of GLP-1: theoretical and practical applications. Curr Med Res Opin 2011; 27: 547-558
    CrossrefPubMedGoogle Scholar
  • 57 Holscher C. Central effects of GLP-1: new opportunities for treatments of neurodegenerative diseases. J Endocrinol 2014; 221: T31-T41
    CrossrefPubMedGoogle Scholar
  • 58 McClean PL, Parthsarathy V, Faivre E. et al. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J Neurosci Off J Soc Neurosci 2011; 31: 6587-6594
    CrossrefPubMedGoogle Scholar
  • 59 Hunter K, Holscher C. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci 2012; 13: 33
    CrossrefPubMedGoogle Scholar
  • 60 Gengler S, McClean PL, McCurtin R. et al. Val(8)GLP-1 rescues synaptic plasticity and reduces dense core plaques in APP/ps1 mice. Neurobiol Aging 2012; 33: 265-276
    CrossrefPubMedGoogle Scholar
  • 61 Li Y, Duffy KB, Ottinger MA. et al. GLP-1 receptor stimulation reduces amyloid-beta peptide accumulation and cytotoxicity in cellular and animal models of Alzheimer’s disease. J Alzheimer’s Dis 2010; 19: 1205-1219
    CrossrefPubMedGoogle Scholar
  • 62 Aviles-Olmos I, Dickson J, Kefalopoulou Z. et al. Exenatide and the treatment of patients with Parkinson’s disease. J Clin Investig 2013; 123: 2730-2736
    CrossrefPubMedGoogle Scholar
  • 63 Muskiet MH, Smits MM, Morsink LM. et al. The gut-renal axis: do incretin-based agents confer renoprotection in diabetes?. Nat Rev Nephrol 2014; 10: 88-103
    CrossrefPubMedGoogle Scholar
  • 64 Campos RV, Lee YC, Drucker DJ. Divergent tissue-specific and developmental expression of receptors for glucagon and glucagon-like peptide-1 in the mouse. Endocrinology 1994; 134: 2156-2164
    CrossrefPubMedGoogle Scholar
  • 65 Crajoinas RO, Oricchio FT, Pessoa TD. et al. Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1. Am J Physiol Renal Physiol 2011; 301: F355-F363
    CrossrefPubMedGoogle Scholar
  • 66 Schlatter P, Beglinger C, Drewe J. et al. Glucagon-like peptide 1 receptor expression in primary porcine proximal tubular cells. Regulat Pept 2007; 141: 120-128
    CrossrefPubMedGoogle Scholar
  • 67 Pezeshki A, Muench GP, Chelikani PK. Short communication: expression of peptide YY, proglucagon, neuropeptide Y receptor y2, and glucagon-like peptide-1 receptor in bovine peripheral tissues. J Dairy Sci 2012; 95: 5089-5094
    CrossrefPubMedGoogle Scholar
  • 68 Yu M, Moreno C, Hoagland KM. et al. Antihypertensive effect of glucagon-like peptide 1 in Dahl salt-sensitive rats. J Hypertens 2003; 21: 1125-1135
    CrossrefPubMedGoogle Scholar
  • 69 Gutzwiller JP, Tschopp S, Bock A. et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab 2004; 89: 3055-3061
    CrossrefPubMedGoogle Scholar
  • 70 Rieg T, Gerasimova M, Murray F. et al. Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice. Am J Physiol Renal Physiol 2012; 303: F963-F971
    CrossrefPubMedGoogle Scholar
  • 71 Skov J. Effects of GLP-1 in the kidney. Rev Endocr Metab Disord 2014; 15: 197-207
    CrossrefPubMedGoogle Scholar
  • 72 Hall ME, do Carmo JM, da Silva AA. et al. Obesity, hypertension, and chronic kidney disease. Int J Nephrol Renovasc Dis 2014; 7: 75-88
    CrossrefPubMedGoogle Scholar
  • 73 Van Buren PN, Toto R. Hypertension in diabetic nephropathy: epidemiology, mechanisms, and management. Adv Chronic Kidney Dis 2011; 18: 28-41
    CrossrefPubMedGoogle Scholar
  • 74 Hendarto H, Inoguchi T, Maeda Y. et al. GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases. Metab Clin Exp 2012; 61: 1422-1434
    CrossrefPubMedGoogle Scholar
  • 75 Kodera R, Shikata K, Kataoka HU. et al. Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes. Diabetologia 2011; 54: 965-978
    CrossrefPubMedGoogle Scholar
  • 76 Park CW, Kim HW, Ko SH. et al. Long-term treatment of glucagon-like peptide-1 analog exendin-4 ameliorates diabetic nephropathy through improving metabolic anomalies in db/db mice. J Am Soc Nephrol 2007; 18: 1227-1238
    CrossrefPubMedGoogle Scholar
  • 77 Mima A, Hiraoka-Yamomoto J, Li Q. et al. Protective effects of GLP-1 on glomerular endothelium and its inhibition by PKCbeta activation in diabetes. Diabetes 2012; 61: 2967-2979
    CrossrefPubMedGoogle Scholar
  • 78 Chaudhuri A, Ghanim H, Vora M. et al. Exenatide exerts a potent antiinflammatory effect. J Clin Endocrinol Metab 2012; 97: 198-207
    CrossrefPubMedGoogle Scholar
  • 79 Malm-Erjefalt M, Bjornsdottir I, Vanggaard J. et al. Metabolism and excretion of the once-daily human glucagon-like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase. Drug Metab Disposit Biol Fate Chem 2010; 38: 1944-1953
    CrossrefPubMedGoogle Scholar
  • 80 Summary of Product Characteristics Victoza Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001026/WC500050017.pdf ). October, 17, 2022
    PubMed
  • 81 Summary of Product Characteristics Eperzan 2015. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002735/WC500165117.pdf. Accessed: October 16, 2022
    PubMed
  • 82 Highlights of US prescribing information TANZEUM 2015. Available at: https://www.gsksource.com/gskprm/htdocs/documents/TANZEUM-PI-MG-IFU-COMBINED.PDF ). Accessed: October 16, 2022
    PubMed
  • 83 Summary of Product Characteristics Lyxumia 2015. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002445/WC500140401.pdf. Accessed: October 15, 2022
    PubMed
  • 84 Samson SL, Bajaj M. Potential of incretin-based therapies for non-alcoholic fatty liver disease. J Diabet Compl 2013; 27: 401-406
    CrossrefPubMedGoogle Scholar
  • 85 Armstrong MJ, Barton D, Gaunt P. et al. Liraglutide efficacy and action in non-alcoholic steatohepatitis (LEAN): study protocol for a phase II multicentre, double-blinded, randomised, controlled trial. BMJ Open 2013; 3: e003995
    CrossrefPubMedGoogle Scholar
  • 86 Eguchi Y, Kitajima Y, Hyogo H. et al. Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN-J). Hepatol Res Off J Jpn Soc Hepatol Res 2015; 45: 269-278
    CrossrefPubMedGoogle Scholar
  • 87 Gupta NA, Kolachala VL, Jiang R. et al. The glucagon-like peptide-1 receptor agonist exendin 4 has a protective role in ischemic injury of lean and steatotic liver by inhibiting cell death and stimulating lipolysis. Am J Pathol 2012; 181: 1693-1701
    CrossrefPubMedGoogle Scholar
  • 88 Matthew JL. Empagliflozin for type 2 diabetes mellitus: an overview of phase 3 clinical trials. Curr Diabetes Rev 2017; 13: 405-423
    PubMedGoogle Scholar
  • 89 Pieber TR, Famulla S, Eilbracht J. Empagliflozin as adjunct to insulin in patients with type 1 diabetes: a 4-week, randomized, placebo-controlled trial (EASE-1). Diabetes Obes Metab 2015; 17: 928-935
    CrossrefPubMedGoogle Scholar
  • 90 Howes LG. Cardiovascular effects of drugs used to treat Alzheimer’s disease. Drug Saf 2014; 37: 391-395
    CrossrefPubMedGoogle Scholar
  • 91 Sato K, Urbano R, Yu C. et al. The effect of donepezil treatment on cardiovascular mortality. Clin Pharmacol Ther 2010; 88: 335-338
    CrossrefPubMedGoogle Scholar
  • 92 Kubo T, Sato T, Noguchi T. et al. Influences of donepezil on cardiovascular system–possible therapeutic benefits for heart failure – donepezil cardiac test registry (DOCTER) study. J Cardiovasc Pharmacol 2012; 310-314
    CrossrefPubMedGoogle Scholar
  • 93 Nordström P, Religa D, Wimo A. et al. The use of cholinesterase inhibitors and the risk of myocardial infarction and death: a nationwide cohort study in subjects with Alzheimer’s disease. Eur Heart J 2013; 34: 2585-2591
    CrossrefPubMedGoogle Scholar
  • 94 Monacelli F, Odetti P, Sartini M. et al. Cardioprotection and anticholinesterases in patients with Alzheimer’s disease: time for reappraisal. Dement Geriatr Cognit Dis Extra 2014; 4: 45-50
    CrossrefPubMedGoogle Scholar
  • 95 Mease PJ, McInnes IB, Kirkham B. et al. FUTURE 1 study group, secukinumab inhibition of interleukin-17A in patients with psoriatic arthritis. N Engl J Med 2015; 373: 1329-1339
    CrossrefPubMedGoogle Scholar
  • 96 Baeten D, Sieper J, Braun J. et al. MEASURE 1 Study Group, MEASURE 2 Study Group, Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis. N Engl J Med 2015; 373: 2534-2548
    CrossrefPubMedGoogle Scholar
  • 97 Makavos G, Ikonomidis I, Andreadou I. et al. Effects of interleukin 17A inhibition on myocardial deformation and vascular function in psoriasis. Can J Cardiol 2019; 36: 100-111
    CrossrefPubMedGoogle Scholar
  • 98 von Stebut E, Reich K, Thaçi D. et al. Impact of secukinumab on endothelial dysfunction and other cardiovascular disease parameters in psoriasis patients over 52 weeks. J Invest Dermatol 2019; 139: 1054-1062
    CrossrefPubMedGoogle Scholar
  • 99 Marovt M, Marko PB, Pirnat M. et al. Effect of biologics targeting IL-23/IL17 axis on subclinical atherosclerosis: results of a pilot study. Clin Exp Dermatol 2020; 45: 560-564
    CrossrefPubMedGoogle Scholar
  • 100 Gualtierotti R, Ingegnoli F, Boscolo M. et al. tocilizumab effects on coagulation factor XIII in patients with rheumatoid arthritis. Adv Ther 2019; 36: 3494-3502
    CrossrefPubMedGoogle Scholar
  • 101 Ruiz-Limón P, Ortega R, de la Rosa IA. et al. Tocilizumab improves the proatherothrombotic profile of rheumatoid arthritis patients modulating endothelial dysfunction, NETosis, and inflammation. Transl Res 2017; 183: 87-103
    CrossrefPubMedGoogle Scholar
  • 102 Williams K, Stern MP, Freeman GL. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum 2001; 44: 2737-2745
    CrossrefPubMedGoogle Scholar
  • 103 Aldridge MA, Ito MK. Colesevelam hydrochloride: a novel bile acid-binding resin. Ann Pharmacother 2001; 35: 898-907
    CrossrefPubMedGoogle Scholar
  • 104 Fonseca VA, Handelsman Y, Staels B. Colesevelam lowers glucose and lipid levels in type 2 diabetes: the clinical evidence. Diabetes Obes Metab 2010; 12: 384-392
    CrossrefPubMedGoogle Scholar
  • 105 Fonseca VA, Rosenstock J, Wang AC. et al. Colesevelam HCl improves glycemic control and reduces LDL cholesterol in patients with inadequately controlled type 2 diabetes on sulfonylurea-based therapy. Diabetes care 2008; 31: 1479-1484
    CrossrefPubMedGoogle Scholar
  • 106 Quianzon CC, Cheikh IE. History of current non-insulin medications for diabetes mellitus. J Community Hosp Intern Med Perspect 2012; 2 DOI: 10.3402/jchimp.v2i3.19081.
    CrossrefPubMedGoogle Scholar
  • 107 Younk LM, Davis SN. Evaluation of colesevelam hydrochloride for the treatment of type 2 diabetes. Expert Opin Drug Metab Toxicol 2012; 8: 515-525
    CrossrefPubMedGoogle Scholar
  • 108 Medicines in development diabetes presented by america’s biopharmaceutical research companies www.phrma.org; Accessed July 22, 2022
    PubMed
  • 109 Gaynor P, McCarberg B, Zheng W. Weight change with long-term duloxetine use in chronic painful conditions: an analysis of 16 clinical studies. Int J Clin Pract 2011; 65: 341-349
    CrossrefPubMedGoogle Scholar
  • 110 Li T, Providencia R, Jiang W. Association of metformin with the mortality and incidence of cardiovascular events in patients with pre-existing cardiovascular diseases. Drugs 2022; 82: 311-322
    CrossrefPubMedGoogle Scholar
  • 111 Yan L, Lei L, Bin W. Metformin in non-alcoholic fatty liver disease: A systematic review and meta-analysis. Biomed Rep 2013; 1: 57-64
    CrossrefPubMedGoogle Scholar
  • 112 Yijing T, Yonglan L, Yanxian Z. Repurposing a cardiovascular disease drug of cloridarol as hIAPP inhibitor. ACS chem. Neurosci 2021; 12: 1419-1427
    CrossrefPubMedGoogle Scholar
  • 113 Donnelly KL, Smith CI, Schwarzenberg SJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005; 115: 1343-1351
    CrossrefPubMedGoogle Scholar
  • 114 Choi JH, Banks AS, Estall JL. Anti-diabetic drugs inhibit obesity -linked phosphorylation of PPARgamma by Cdk5. Nature 2010; 466: 451-456
    CrossrefPubMedGoogle Scholar
  • 115 Choi JH, Banks AS, Kamenecka TM. Antidiabetic actions of a non -agonist PPARgamma ligand blocking Cdk5 -mediated phosphorylation. Nature 2011; 477: 477-481
    CrossrefPubMedGoogle Scholar
  • 116 Jain MR, Giri SR, Bhoi B. Dual PPARalpha/gamma agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models. Liver Int 2017; 38: 1084-1094
    CrossrefPubMedGoogle Scholar
  • 117 Joshi SR. Saroglitazar for the treatment of dyslipidemia in diabetic patients. Expert Opin Pharmacother 2015; 16: 597-606
    CrossrefPubMedGoogle Scholar
  • 118 Skat-Rørdam J, Ipsen DH, Lykkesfeldt J. A role of peroxisome proliferator-activated receptor – in non-alcoholic fatty liver disease. Basic Clin Pharmacol Toxicol 2018; 124: 528-537
    CrossrefPubMedGoogle Scholar
  • 119 Bagchia RA, Kate L. Histone deacetylases in cardiovascular and metabolic diseases. J Mol Cell Cardiol 2019; 130: 151-159
    CrossrefPubMedGoogle Scholar
  • 120 Soni D, Moises DS, Fabio DL. Emerging role of monoamine oxidase as a therapeutic target for cardiovascular disease. Curr Opin Pharmacol 2017; 33: 64-69
    CrossrefPubMedGoogle Scholar
  • 121 Global Health Observatory (GHO) data (2016) http://www.who.int/gho/ncd/risk_factors/blood_pressure_prevalence_ text/en/; Accessed September 19, 2022
    PubMed
  • 122 Fregoneze JB, Oliveira EF, Ribeiro VF. Multiple opioid receptors mediate the hypotensive response induced by central 5-HT 3 receptor stimulation. Neuropeptides 2011; 45: 219-227
    CrossrefPubMedGoogle Scholar
  • 123 Cozzolino D. Acute pressor and hormonal effects of betaendorphin at high doses in healthy and hypertensive subjects: role of opioid receptor agonism. J Clin Endocrinol Metab 2005; 90: 5167-5174
    CrossrefPubMedGoogle Scholar
  • 124 Gaddis RR, Dixon WR. Modulation of peripheral adrenergic neurotransmission by methionine-enkephalin. J Pharmacol Exp Ther 1982; 221: 282-287
    PubMedGoogle Scholar
  • 125 Arendt RM, Schmoeckel M, Wilbert U. Bidirectional effects of endogenous opioid peptides on endothelin release in porcine aortic endothelial cell culture: mediation by opioid receptor and opioid receptor antagonistinsensitive mechanisms. J Pharmacol Exp Ther 1995; 272: 1-7
    PubMedGoogle Scholar
  • 126 Kienbaum P, Heuter T, Michel MC. et al. Chronic delta-opioid receptor stimulation in humans decreases muscle sympathetic nerve activity. Circulation 2001; 103: 850-855
    CrossrefPubMedGoogle Scholar
  • 127 Fuenmayor N, Cubeddu L. Cardiovascular and endocrine effects of naloxone compared in normotensive and hypertensive patients. Eur J Pharmacol 1986; 126: 189-197
    CrossrefPubMedGoogle Scholar
  • 128 Published on Euractive Infographics, 2015 https://www.euractiv. com/section/health-consumers/infographic/infographic–the-high est-prevalence-of-high-cholesterol-in-the-world/; Accessed September 18, 2022
    PubMed
  • 129 Tian F, Zheng XY, Li J. et al. k-opioid receptor stimulation improves endothelial function via akt-stimulated no production in hyperlipidemic rats. Sci Rep 2016; 6: 26807
    CrossrefPubMedGoogle Scholar
  • 130 Orlistat (marketed as Alli and Xenical) Information https://www.fda.gov/drugs/postmarket-drugsafety-information-patients-and-providers/orlistat-marketed-alli-and-xenical-information
    PubMed
  • 131 Heck AM, Yanovski JA, Calis KA. Orlistat, a new lipase inhibitor for the management of obesity. Pharmacotherapy 2000; 20: 270-279
    CrossrefPubMedGoogle Scholar
  • 132 Bessesen DH, Van Gaal LF. Progress and challenges in anti-obesity pharmacotherapy. Lancet Diabetes Endocrinol 2018; 6: 237-248
    CrossrefPubMedGoogle Scholar
  • 133 Sahebkar A, Simental-Mendia LE, Reiner Z. et al. Effect of orlistat on plasma lipids and body weight: a systematic review and meta-analysis of 33 randomized controlled trials. Pharmacol Res 2017; 122: 53-65
    CrossrefPubMedGoogle Scholar
  • 134 Khera R, Pandey A, Chandar AK. et al. Effects of weight-loss medications on cardiometabolic risk profiles: a systematic review and network meta-analysis. Gastroenterology 2018; 154: 1309-1319 e1307
    CrossrefPubMedGoogle Scholar
  • 135 Gorgojo-Martinez JJ, Basagoiti-Carreno B, Sanz-Velasco A. et al. Effectiveness and tolerability of orlistat and liraglutide in patients with obesity in a real-world setting: the XENSOR Study. Int J Clin Pract 2019; 73: e13399
    CrossrefPubMedGoogle Scholar
  • 136 Grabarczyk TR. Observational comparative effectiveness of pharmaceutical treatments for obesity within the Veterans Health Administration. Pharmacotherapy 2018; 38: 19-28
    CrossrefPubMedGoogle Scholar
  • 137 Medicines in development heart disease and stroke: a report on cardiovascular disease www.phrma.org; Accessed September 15, 2022
    PubMed
  • 138 Novac N. Challenges and opportunities of drug repositioning. Trends Pharmacol Sci 2013; 34: 267-272
    PubMedGoogle Scholar
  • 139 Biomedicine KJ. NIH’s second-hand shop for tried-and-tested drugs. Science 2011; 332: 1492
    CrossrefPubMedGoogle Scholar
  • 140 Tartaglia LA. Complementary new approaches enable repositioning of failed drug candidates. Expert Opin Investig Drugs 2006; 15: 1295-1298
    CrossrefPubMedGoogle Scholar
  • 141 Cha Y, Erez T, Reynolds IJ. et al. Drug repurposing from the perspective of pharmaceutical companies: drug repurposing in pharmaceutical companies. Br J Pharmacol 2018; 175: 168-180
    CrossrefPubMedGoogle Scholar
  • 142 A collection of 68 deprioritized pharmaceutical compounds is being made available to academic researchers. Thepharmaletter.com, 2014. Available from: https://www.thepharmaletter.com/article/world-s-large st-collection-of-deprioritized-pharma-compounds-opens-to-resea rchers; Accessed: September 22, 2022
    PubMed
  • 143 Polamreddy P, Gattu N. The drug repurposing landscape from 2012 to 2017: evolution, challenges, and possible solutions. Drug Discov Today 2019; 24: 789-795
    CrossrefPubMedGoogle Scholar
  • 144 Feemster R. Gene Logic: Rescue squad [Internet]. Pharmaceutical Executive. 2006. Available from: https://www.pharm exec.com/view/gene-logic-rescue-squad; Accessed: September 20, 2022
    PubMed
  • 145 Mullard A. Drug repurposing programmes get lift of. Nat Rev Drug Discov 2012; 11: 505-506
    CrossrefPubMedGoogle Scholar
  • 146 Mullard A. Bank tests drug development waters. Nat Rev Drug Discov 2014; 13: 643-644
    CrossrefPubMedGoogle Scholar
  • 147 Nosengo N. Can you teach old drugs new tricks?. Nature 2016; 534: 314-316
    CrossrefPubMedGoogle Scholar
  • 148 Frail DE, Brady M, Escott KJ. et al. Pioneering government-sponsored drug repositioning collaborations: progress and learning. Nat Rev Drug Discov 2015; 14: 833-841
    CrossrefPubMedGoogle Scholar
  • 149 Hayes AG, Nutt DJ. Compound asset sharing initiatives between pharmaceutical companies, funding bodies, and academia: learnings and successes. Pharmacol Res Perspect 2019; 7: e00510
    CrossrefPubMedGoogle Scholar
  • 150 Novac N. Challenges and opportunities of drug repositioning. Trends Pharmacol Sci 2013; 34: 267-272
    CrossrefPubMedGoogle Scholar
  • 151 Mandrioli R, Mercolini L. Discontinued anxiolytic drugs (2009–2014). Expert Opin Investig Drugs 2015; 24: 557-573
    CrossrefPubMedGoogle Scholar
  • 152 Rogawski MA, Federof HJ. Disclosure of clinical trial results when product development is abandoned. Sci Transl Med 2011; 3: 102cm29
    CrossrefPubMedGoogle Scholar
  • 153 Chesbrough H, Chen EL. Recovering abandoned compounds through expanded external IP licensing. Calif Manage Rev 2013; 55: 83-101
    CrossrefPubMedGoogle Scholar
  • 154 Marusina K, Welsch DJ, Rose L. et al. The CTSA Pharmaceutical Assets Portal – a public-private partnership model for drug repositioning. Drug Discov Today Ther Strateg Winter 2011; 8: 77-83
    CrossrefPubMedGoogle Scholar
  • 155 Pushpakom S, Iorio F, Eyers PA. et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov 2019; 18: 41-58
    CrossrefPubMedGoogle Scholar
  • 156 Loging W, Rodriguez-Esteban R, Hill J. et al. Cheminformatic/bioinformatic analysis of large corporate databases: application to drug repurposing. Drug Discov Today Ther Strateg 2011; 8: 109-116
    CrossrefPubMedGoogle Scholar
  • 157 New indications and a sense of (re)purpose EBioMedicine 2015; 2: 1257-1258
    CrossrefPubMed
  • 158 Wadman M. New cures sought from old drugs. Nature 2012; 490: 15
    CrossrefPubMedGoogle Scholar
  • 159 Würth R, Thellung S, Bajetto A, Mazzanti M, Florio T, Barbieri F. Drugrepositioning opportunities for cancer therapy: novel molecular targets for known compounds. Drug Discov Today 2016; 21: 190-199
    CrossrefPubMedGoogle Scholar
  • 160 Oft PA. Why are pharmaceutical companies gradually abandoning vaccines?. Health Af (Millwood) 2005; 24: 622-630
    CrossrefPubMedGoogle Scholar
  • 161 Doan TL, Pollastri M, Walters MA. et al. The future of drug repositioning: old drugs, new opportunities. Annu Rep Med Chem 2011; 46: 385-401
    PubMedGoogle Scholar
  • 162 Campbell CM, Kipnes MS, Stouch BC. et al. Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy. PAIN 2012; 153: 1815-1823
    CrossrefPubMedGoogle Scholar