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11β-HSD1 Inhibitors for the Treatment of Type 2 Diabetes and Cardiovascular Disease

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Abstract

Inhibition of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been proposed as a novel therapeutic target for the treatment of type 2 diabetes mellitus. Over 170 new compounds targeting 11β-HSD1 have been developed. This article reviews the current published literature on compounds that have reached phase II clinical trials in patients with type 2 diabetes, and summarises the preclinical evidence that such agents may be useful for associated conditions, including peripheral vascular disease, coronary artery disease and cognitive decline. In clinical trials, 11β-HSD1 inhibitors have been well tolerated and have improved glycaemic control, lipid profile and blood pressure, and induced modest weight loss. The magnitude of the effects are small relative to other agents, so that further development of 11β-HSD1 inhibitors for the primary therapeutic indication of type 2 diabetes has stalled. Ongoing programmes are focused on additional benefits for cognitive function and other cardiovascular risk factors.

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References

  1. Wei L, MacDonald TM, Walker BR. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med. 2004;141:764–70.

    Article  PubMed  Google Scholar 

  2. Stewart PM, Krozowski ZS. 11 Beta-hydroxysteroid dehydrogenase. Vitam Horm. 1999;57:249–324.

    Article  PubMed  CAS  Google Scholar 

  3. Seckl JR, Walker BR. Minireview: 11beta-hydroxysteroid dehydrogenase type 1—a tissue-specific amplifier of glucocorticoid action. Endocrinology. 2001;142:1371–6.

    Article  PubMed  CAS  Google Scholar 

  4. Tomlinson JW, Walker EA, Bujalska IJ, et al. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev. 2004;25:831–66.

    Article  PubMed  CAS  Google Scholar 

  5. Andrew R, Westerbacka J, Wahren J, Yki-Jarvinen H, Walker BR. The contribution of visceral adipose tissue to splanchnic cortisol production in healthy humans. Diabetes. 2005;54:1364–70.

    Article  PubMed  CAS  Google Scholar 

  6. Stimson RH, Andersson J, Andrew R, et al. Cortisol release from adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 in humans. Diabetes. 2009;58:46–53.

    Article  PubMed  CAS  Google Scholar 

  7. Basu R, Singh RJ, Basu A, et al. Splanchnic cortisol production occurs in humans: evidence for conversion of cortisone to cortisol via the 11-beta hydroxysteroid dehydrogenase (11 beta-HSD) type 1 pathway. Diabetes. 2004;53:2051–9.

    Article  PubMed  CAS  Google Scholar 

  8. Walker BR. Glucocorticoids and cardiovascular disease. Eur J Endocrinol. 2007;157:545–59.

    Article  PubMed  CAS  Google Scholar 

  9. Masuzaki H, Paterson J, Shinyama H, et al. A transgenic model of visceral obesity and the metabolic syndrome. Science. 2001;294:2166–70.

    Article  PubMed  CAS  Google Scholar 

  10. Masuzaki H, Yamamoto H, Kenyon CJ, et al. Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice. J Clin Invest. 2003;112:83–90.

    PubMed  CAS  Google Scholar 

  11. Paterson JM, Morton NM, Fievet C, et al. Metabolic syndrome without obesity: hepatic overexpression of 11beta-hydroxysteroid dehydrogenase type 1 in transgenic mice. Proc Natl Acad Sci USA. 2004;101:7088–93.

    Article  PubMed  CAS  Google Scholar 

  12. Rask E, Olsson T, Soderberg S, et al. Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab. 2001;86:1418–21.

    Article  PubMed  CAS  Google Scholar 

  13. Rask E, Walker BR, Soderberg S, et al. Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity. J Clin Endocrinol Metab. 2002;87:3330–6.

    Article  PubMed  CAS  Google Scholar 

  14. Stewart PM, Boulton A, Kumar S, Clark PM, Shackleton CH. Cortisol metabolism in human obesity: impaired cortisone→cortisol conversion in subjects with central adiposity. J Clin Endocrinol Metab. 1999;84:1022–7.

    Article  PubMed  CAS  Google Scholar 

  15. Livingstone DE, Jones GC, Smith K, et al. Understanding the role of glucocorticoids in obesity: tissue-specific alterations of corticosterone metabolism in obese Zucker rats. Endocrinology. 2000;141:560–3.

    Article  PubMed  CAS  Google Scholar 

  16. Jamieson PM, Chapman KE, Edwards CR, Seckl JR. 11 beta-hydroxysteroid dehydrogenase is an exclusive 11 beta-reductase in primary cultures of rat hepatocytes: effect of physicochemical and hormonal manipulations. Endocrinology. 1995;136:4754–61.

    Article  PubMed  CAS  Google Scholar 

  17. Stimson RH, Andrew R, McAvoy NC, Tripathi D, Hayes PC, Walker BR. Increased whole-body and sustained liver cortisol regeneration by 11 beta-hydroxysteroid dehydrogenase type 1 in obese men with type 2 diabetes provides a target for enzyme inhibition. Diabetes. 2011;60:720–5.

    Article  PubMed  CAS  Google Scholar 

  18. Kotelevtsev Y, Holmes MC, Burchell A, et al. 11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. Proc Natl Acad Sci USA. 1997;94:14924–9.

    Article  PubMed  CAS  Google Scholar 

  19. Basu R, Basu A, Grudzien M, et al. Liver is the site of splanchnic cortisol production in obese nondiabetic humans. Diabetes 2009;58:39-45

    Google Scholar 

  20. Lavery GG, Zielinska AE, Gathercole LL, et al. Lack of significant metabolic abnormalities in mice with liver-specific disruption of 11 beta-hydroxysteroid dehydrogenase type 1. Endocrinology. 2012;153:3236–48.

    Article  PubMed  CAS  Google Scholar 

  21. Webster SP, Pallin TD. 11 beta-hydroxysteroid dehydrogenase type 1 inhibitors as therapeutic agents. Expert Opin Ther Patents. 2007;17:1407–22.

    Article  CAS  Google Scholar 

  22. Li RS, Nakagawa Y, Nakanishi T, Fujisawa Y, Ohzeki T. Different responsiveness in body weight and hepatic 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 mrna to 11beta-HSD inhibition by glycyrrhetinic acid treatment in obese and lean zucker rats. Metabolism. 2004;53:600–6.

    Article  PubMed  CAS  Google Scholar 

  23. Andrews RC, Rooyackers O, Walker BR. Effects of the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2 diabetes. J Clin Endocrinol Metab. 2003;88:285–91.

    Article  PubMed  CAS  Google Scholar 

  24. Walker BR, Connacher AA, Lindsay RM, Webb DJ, Edwards CR. Carbenoxolone increases hepatic insulin sensitivity in man: a novel role for 11-oxosteroid reductase in enhancing glucocorticoid receptor activation. J Clin Endocrinol Metab. 1995;80:3155–9.

    Article  PubMed  CAS  Google Scholar 

  25. Sandeep TC, Yau JLW, MacLullich AMJ, et al. 11Beta-hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics. Proc Natl Acad Sci USA. 2004;101:6734–9.

    Article  PubMed  CAS  Google Scholar 

  26. Sandeep TC, Andrew R, Homer NZM, Andrews RC, Smith K, Walker BR. Increased in vivo regeneration of cortisol in adipose tissue in human obesity and effects of the 11 beta-hydroxysteroid dehydrogenase type 1 inhibitor carbenoxolone. Diabetes. 2005;54:872–9.

    Article  PubMed  CAS  Google Scholar 

  27. Bujalska IJ, Kumar S, Stewart PM. Does central obesity reflect “Cushing’s disease of the omentum”? Lancet. 1997;349:1210–3.

    Article  PubMed  CAS  Google Scholar 

  28. Alberts P, Engblom L, Edling N, et al. Selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice. Diabetologia. 2002;45:1528–32.

    Article  PubMed  CAS  Google Scholar 

  29. Jones RM, Thurston DE, Rotella D, Guccione S, Martinez A. New therapeutic strategies for type 2 diabetes: small molecule approaches. Royal Society of Chemistry Publishing; 2012.

  30. St. Jean DJ, Yuan C, Bercot EA, et al. 2-(S)-Phenethylaminothiazolones as potent, orally efficacious inhibitors of 11β-hydroxysteriod dehydrogenase type 1. J Med Chem. 2007;50:429–32.

    Article  CAS  Google Scholar 

  31. Sundbom M, Kaiser C, Bjorkstrand E, et al. Inhibition of 11betaHSD1 with the S-phenylethylaminothiazolone BVT116429 increases adiponectin concentrations and improves glucose homeostasis in diabetic KKAy mice. BMC Pharmacol. 2008;8:3.

    Article  PubMed  Google Scholar 

  32. Courtney R, Stewart PM, Toh M, Ndongo MN, Calle RA, Hirshberg B. Modulation of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) activity biomarkers and pharmacokinetics of PF-00915275, a selective 11 beta HSD1 inhibitor. J Clin Endocrinol Metab. 2008;93:550–6.

    Article  PubMed  CAS  Google Scholar 

  33. Andrew R, Smith K, Jones GC, Walker BR. Distinguishing the activities of 11 beta-hydroxysteroid dehydrogenases in vivo using isotopically labeled cortisol. J Clin Endocrinol Metab. 2002;87:277–85.

    Article  PubMed  CAS  Google Scholar 

  34. A study to evaluate PF-00915275 in subjects with type 2 diabetes mellitus for 4-weeks [ClinicalTrials.gov identifier NCT00427401]. US National Institutes of Health, ClinicalTrials.gov [online]. http://www.clinicaltrials.gov (Accessed 7 Feb 2013).

  35. Hawkins M, Hunter D, Kishore P, et al. INCB013739, a selective inhibitor of 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta HSD1), improves insulin sensitivity and lowers plasma cholesterol over 28 days in patients with type 2 diabetes mellitus. Diabetes. 2008;57:A99–100.

    Google Scholar 

  36. Rosenstock J, Banarer S, Fonseca VA, et al. The 11-beta-hydroxysteroid dehydrogenase type 1 inhibitor INCB13739 improves hyperglycemia in patients with type 2 diabetes inadequately controlled by metformin monotherapy. Diabetes Care. 2010;33:1516–22.

    Article  PubMed  CAS  Google Scholar 

  37. Feig PU, Shah S, Hermanowski-Vosatka A, et al. Effects of an 11 beta-hydroxysteroid dehydrogenase type 1 inhibitor, MK-0916, in patients with type 2 diabetes mellitus and metabolic syndrome. Diabetes Obes Metab. 2011;13:498–504.

    Article  PubMed  CAS  Google Scholar 

  38. Morton NM, Holmes MC, Fievet C, et al. Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11 beta-hydroxysteroid dehydrogenase type 1 null mice. J Biol Chem. 2001;276:41293–300.

    Article  PubMed  CAS  Google Scholar 

  39. Berthiaume M, Laplante M, Festuccia WT, et al. 11beta-HSD1 inhibition improves triglyceridemia through reduced liver VLDL secretion and partitions lipids toward oxidative tissues. Am J Physiol Endocrinol Metab. 2007;293:E1045–52.

    Article  PubMed  CAS  Google Scholar 

  40. Hermanowski-Vosatka A, Balkovec JM, Cheng K, et al. 11 beta-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J Exp Med. 2005;202:517–27.

    Article  PubMed  CAS  Google Scholar 

  41. Schwartz SL, Rendell M, Ahmann AJ, Thomas A, Arauz-Pacheco CJ, Welles BR. Safety profile and metabolic effects of 14 days of treatment with DIO-902: results of a phase IIa multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in patients with type 2 diabetes mellitus. Clin Ther. 2008;30:1081–8.

    Article  PubMed  CAS  Google Scholar 

  42. Macfarlane DP, Forbes S, Walker BR. Glucocorticoids and fatty acid metabolism in humans: fuelling fat redistribution in the metabolic syndrome. J Endocrinol. 2008;197:189–204.

    Article  PubMed  CAS  Google Scholar 

  43. Bruce CR, Anderson MJ, Carey AL, et al. Muscle oxidative capacity is a better predictor of insulin sensitivity than lipid status. J Clin Endocrinol Metab. 2003;88:5444–51.

    Article  PubMed  CAS  Google Scholar 

  44. Shah S, Hermanowski-Vosatka A, Gibson K, et al. Efficacy and safety of the selective 11beta-HSD-1 inhibitors MK-0736 and MK-0916 in overweight and obese patients with hypertension. J Am Soc Hypertens. 2011;5:166–76.

    Article  PubMed  CAS  Google Scholar 

  45. Morton NM, Paterson JM, Masuzaki H, et al. Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 beta-hydroxysteroid dehydrogenase type 1-deficient mice. Diabetes. 2004;53:931–8.

    Article  PubMed  CAS  Google Scholar 

  46. Wang L, Liu J, Zhang A, et al. BVT.2733, a selective 11beta-hydroxysteroid dehydrogenase type 1 inhibitor, attenuates obesity and inflammation in diet-induced obese mice. PLoS One. 2012;7:e40056.

    Article  PubMed  CAS  Google Scholar 

  47. Alberts P, Nilsson C, Selen G, et al. Selective inhibition of 11 beta-hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains. Endocrinology. 2003;144:4755–62.

    Article  PubMed  CAS  Google Scholar 

  48. Iqbal J, Macdonald LJ, Low L, et al. Contribution of endogenous glucocorticoids and their intravascular metabolism by 11β-HSDs to postangioplasty neointimal proliferation in mice. Endocrinology. 2012;153:5896–905.

    Article  PubMed  CAS  Google Scholar 

  49. Merck. Dose-ranging study to evaluate the effectiveness and tolerability of MK0736 in patients with type 2 diabetes mellitus (T2DM) and hypertension [ClinicalTrials.gov identifier NCT00806585]. US National Institutes of Health, ClinicalTrials.gov [online]. http://www.clinicaltrials.gov (Accessed 7 Feb 2013).

  50. Hadoke PW, Iqbal J, Walker BR. Therapeutic manipulation of glucocorticoid metabolism in cardiovascular disease. Br J Pharmacol. 2009;156:689–712.

    Article  PubMed  CAS  Google Scholar 

  51. Thieringer R, Le Grand CB, Carbin L, et al. 11 beta-hydroxysteroid dehydrogenase type 1 is induced in human monocytes upon differentiation to macrophages. J Immunol. 2001;167:30–5.

    PubMed  CAS  Google Scholar 

  52. Walker BR, Yau JL, Brett LP, et al. 11 beta-hydroxysteroid dehydrogenase in vascular smooth muscle and heart: implications for cardiovascular responses to glucocorticoids. Endocrinology. 1991;129:3305–12.

    Article  PubMed  CAS  Google Scholar 

  53. Nuotio-Antar AM, Hachey DL, Hasty AH. Carbenoxolone treatment attenuates symptoms of metabolic syndrome and atherogenesis in obese, hyperlipidemic mice. Am J Physiol Endocrinol Metab. 2007;293:18.

    Article  Google Scholar 

  54. Lloyd DJ, Helmering J, Cordover D, et al. Antidiabetic effects of 11beta-HSD1 inhibition in a mouse model of combined diabetes, dyslipidaemia and atherosclerosis. Diabetes Obes Metab. 2009;11:688–99.

    Article  PubMed  CAS  Google Scholar 

  55. Garcia RA, Search DJ, Lupisella JA, et al. 11beta-hydroxysteroid dehydrogenase type 1 gene knockout attenuates atherosclerosis and in vivo foam cell formation in hyperlipidemic apoE(−)/(−) mice. PLoS One. 2013;8:e53192.

    Article  PubMed  CAS  Google Scholar 

  56. Kipari T, Hadoke PW, Iqbal J, et al. 11beta-hydroxysteroid dehydrogenase type 1 deficiency in bone marrow-derived cells reduces atherosclerosis. FASEB J. 2013;27:1519–31.

    Article  PubMed  CAS  Google Scholar 

  57. Atalar F, Vural B, Ciftci C, et al. 11beta-hydroxysteroid dehydrogenase type 1 gene expression is increased in ascending aorta tissue of metabolic syndrome patients with coronary artery disease. Genet Mol Res. 2012;11:3122–32.

    Article  PubMed  CAS  Google Scholar 

  58. Small GR, Hadoke PWF, Sharif I, et al. Preventing local regeneration of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 enhances angiogenesis. Proc Natl Acad Sci USA. 2005;102:12165–70.

    Article  PubMed  CAS  Google Scholar 

  59. McSweeney SJ, Hadoke PWF, Kozak AM, et al. Improved heart function follows enhanced inflammatory cell recruitment and angiogenesis in 11βHSD1-deficient mice post-MI. Cardiovasc Res. 2010;88:159–67.

    Article  PubMed  CAS  Google Scholar 

  60. Labrie F, Bélanger A, Cusan L, Gomez J-L, Candas B. Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab. 1997;82:2396–402.

    Article  PubMed  CAS  Google Scholar 

  61. Harno E, White A. Will treating diabetes with 11β-HSD1 inhibitors affect the HPA axis? Trends Endocrinol Metab. 2010;21:619–27.

    Article  PubMed  CAS  Google Scholar 

  62. Carter RN, Paterson JM, Tworowska U, et al. Hypothalamic-pituitary-adrenal axis abnormalities in response to deletion of 11 beta-HSD1 is strain-dependent. J Neuroendocrinol. 2009;21:879–87.

    Article  PubMed  CAS  Google Scholar 

  63. Coutinho AE, Brown JK, Yang F, et al. Mast cells express 11β-hydroxysteroid dehydrogenase type 1: a role in restraining mast cell degranulation. PLoS ONE. 2013;8:e54640.

    Article  PubMed  CAS  Google Scholar 

  64. Coutinho AE, Gray M, Brownstein DG, et al. 11Beta-hydroxysteroid dehydrogenase type 1, but not type 2, deficiency worsens acute inflammation and experimental arthritis in mice. Endocrinology. 2012;153:234–40.

    Article  PubMed  CAS  Google Scholar 

  65. Chapman KE, Coutinho A, Gray M, Gilmour JS, Savill JS, Seckl JR. Local amplification of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1 and its role in the inflammatory response. Ann N Y Acad Sci. 2006;1088:265–73.

    Article  PubMed  CAS  Google Scholar 

  66. Yau JLW, Noble J, Kenyon CJ, et al. Lack of tissue glucocorticoid reactivation in 11β-hydroxysteroid dehydrogenase type 1 knockout mice ameliorates age-related learning impairments. Proc Natl Acad Sci USA. 2001;98:4716–21.

    Article  PubMed  CAS  Google Scholar 

  67. Sooy K, Webster SP, Noble J, et al. Partial deficiency or short-term inhibition of 11 beta-hydroxysteroid dehydrogenase type 1 improves cognitive function in aging mice. J Neurosci. 2010;30:13867–72.

    Article  PubMed  CAS  Google Scholar 

  68. A study of R05093151 in patients with non-alcoholic fatty liver disease [ClinicalTrials.gov identifier NCT01277094]. US National Institutes of Health, ClinicalTrials.gov [online]. http://www.clinicaltrials.gov (Accessed 7 Feb 2013).

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Acknowledgments

Brian Walker is an inventor on relevant patents owned by the University of Edinburgh and has received consultancy fees and honoraria from several companies developing selective 11β-HSD1 inhibitors. Anna Anderson has no conflicts of interest that are relevant to the content of this review.

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  1. University/BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK

    Anna Anderson & Brian R. Walker

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Correspondence to Brian R. Walker.

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Anderson, A., Walker, B.R. 11β-HSD1 Inhibitors for the Treatment of Type 2 Diabetes and Cardiovascular Disease. Drugs 73, 1385–1393 (2013). https://doi.org/10.1007/s40265-013-0112-5

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