Therapeutics


SIRT1: This NAD+-dependent deacetylase has been identified as one of the principal downstream mediators of the beneficial effects of caloric restric- tion on lifespan and metabolic parameters. Potent small molecule activators of SIRT1 have recently been identified, and were shown to improve insulin sensitivity, lower plasma glucose and increase mitochondrial capacity in murine obesity models, and to improve whole-body glucose homeostasis and insulin sensitivity in the Zucker rat T2DM model16. In addition to their beneficial effects on diabetes parameters, SIRT1 activators are expected to have pleiotropic cardioprotective effects. For example, SIRT1 over-expression has shown protec- tion against atherosclerosis in a murine model, likely via anti-apoptotic effects in endothelial cells17. Furthermore, recent studies have demon- strated protective effects of SIRT1 over-expression on ischemia/reperfusion (I/R) injury in the heart18, and on neointima formation following vascular injury in mice19. It will therefore be of great inter- est to determine the effect of SIRT1 activators on cardiovascular risk in clinical studies.


SGLT2: Via the transporter SGLT2, the kidney plays a key role in the regulation of glucose home- ostasis, by mediating glucose reabsorption into the plasma. The development of SGLT2 inhibitors therefore holds promise for glycemic control in T2DM, since the inhibition of renal glucose reab- sorption results in increased glucose excretion in the urine. A number of SGLT2 inhibitors (includ- ing dapagliflozin, BI-10773, and LX4211) have been developed, and are in the advanced stages of Phase II/III clinical trials, where they have shown efficacy on glycated haemoglobin (HbA1c) levels, fasting plasma glucose, glucose tolerance, weight loss and blood pressure lowering20,21. Moreover, SGLT inhibition may show additional cardiopro- tective effects, since a recent study showed that treatment with a SGLT inhibitor led to a reduction in infarct size and edema in a murine stroke model22. Thus, the results of Phase III clinical tri- als of SGLT2 inhibitors are awaited to determine their effects on CVD.


GPR40: Similar to GPR119, this free fatty acid (FFA)-activated GPCR is expressed in both pan- creatic -cells and in the endocrine cells of the gastrointestinal tract, where it mediates FFA- induced incretin secretion23. GPR40 over- expression in pancreatic -cells has been shown to increase glucose-stimulated insulin secretion and improve glucose tolerance in normal and diabetic mice24, and small-molecule GPR40 ago-


Drug Discovery World Summer 2011


nists improved glucose tolerance in mice with high-fat diet-induced obesity25. However, a recent study showed that the treatment of Zucker diabetic rats with a small-molecule GPR40 antagonist improved insulin tolerance, while having no effect on glucose tolerance26. Thus, the specific role of GPR40 in T2DM remains open to debate, and should be thor- oughly addressed before proceeding with the clinical development of GPR40 modulators.


PPAR agonists


In addition to the new generation of potential anti-diabetic drug targets described above, opin- ion is evolving concerning the targeting of mem- bers of the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptor tran- scription factors. The PPAR agonist pioglitazone has shown ben- eficial effects on several clinical outcomes in predi- abetic and diabetic patients, including reducing the overall risk of cardiovascular events (ProActive Study27), renal complications28, and NASH/ NAFLD29. Moreover, Roche is developing alegli- tazar, a balanced mixed PPAR/ agonist, for sec- ondary cardiovascular prevention after myocardial infarction, with the promise of greater preventive effects due to reduction of multiple risk factors, as compared to current glitazone medications30. A Phase III clinical trial with aleglitazar is currently ongoing in patients with T2DM who have recently experienced a cardiac event. Interestingly, the pri- mary endpoint of this study is not glycemic con- trol, but cardiovascular events. Thus, future progress is likely to be focused on the development of PPAR agonists with specific profiles that enable them to address not only T2DM, but also its asso- ciated pathologies.


An emerging target in T2DM management is


PPAR, due to the positive effects of this PPAR sub-type on multiple features of the metabolic syndrome. Indeed, in pre-clinical studies, PPAR activation increased lipid catabolism in multiple tissues and improved the serum lipid profile, glu- cose homeostasis, and insulin sensitivity, while reducing inflammation and weight gain31. Finally, the FIELD32 and ACCORD33 studies showed that the PPAR agonist fenofibrate could lower the risk of retinopathy and diabetic nephropathy, as well as reducing CVD events in dyslipidemic patients, thus illustrating the inter- est of developing mixed PPAR/ or mixed PPAR/ agonists.


GFT505, a potent agonist of the PPAR and PPAR receptors, shows a unique therapeutic


Continued from page 12


18 Hsu, CP et al. Silent information regulator 1 protects the heart from ischemia/reperfusion. Circulation, 2010. 122(21): p. 2170-82. 19 Li, L et al. SIRT1 Acts as a Modulator of Neointima Formation Following Vascular Injury in Mice. Circ Res, 2011. 108(10): p. 1180-9. 20 Komoroski, B et al. Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus. Clin Pharmacol Ther, 2009. 85(5): p. 513-9. 21 Aires, I and Calado, J. BI- 10773, a sodium-glucose cotransporter 2 inhibitor for the potential oral treatment of type 2 diabetes mellitus. Curr Opin Investig Drugs, 2010. 11(10): p. 1182-90. 22Vemula, S et al. A functional role for sodium-dependent glucose transport across the blood-brain barrier during oxygen glucose deprivation. J Pharmacol Exp Ther, 2009. 328(2): p. 487-95. 23 Edfalk, S, Steneberg, P and Edlund, H. Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes, 2008. 57(9): p. 2280-7. 24 Nagasumi, K et al. Overexpression of GPR40 in pancreatic beta-cells augments glucose-stimulated insulin secretion and improves glucose tolerance in normal and diabetic mice. Diabetes, 2009. 58(5): p. 1067-76. 25Tan, CP et al. Selective small- molecule agonists of G protein- coupled receptor 40 promote glucose-dependent insulin secretion and reduce blood glucose in mice. Diabetes, 2008. 57(8): p. 2211-9. 26 Zhang, X et al. DC260126, a small-molecule antagonist of GPR40, improves insulin tolerance but not glucose tolerance in obese Zucker rats. Biomed Pharmacother, 2010. 64(9): p. 647-51.


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