Therapeutics
References 1 Grundy, SM. Drug therapy of the metabolic syndrome: minimizing the emerging crisis in polypharmacy. Nat Rev Drug Discov, 2006. 5(4): p. 295-309. 2 Haffner, SM et al., Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med, 1998. 339(4): p. 229-34. 3 Meier, M and Hummel, M. Cardiovascular disease and intensive glucose control in type 2 diabetes mellitus: moving practice toward evidence-based strategies. Vasc Health Risk Manag, 2009. 5: p. 859-71. 4 Best, JH 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. Diabetes Care, 2011. 34(1): p. 90-5. 5 Hermanowski-Vosatka, A et al. 11beta-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J Exp Med, 2005. 202(4): p. 517-27. 6 Rosenstock, J 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(7): p. 1516-22. 7 Feig, PU et al. Effects of an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor, MK-0916, in patients with type 2 diabetes mellitus and metabolic syndrome. Diabetes Obes Metab, 2011. 13(6): p. 498-504. 8 Chu, ZL et al. A role for beta-cell-expressed G protein- coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release. Endocrinology, 2007. 148(6): p. 2601-9.
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Figure 1: The pathophysiology of pre-diabetes and diabetes. T2DM may be visualised as an evolving pathophysiological process in which multiple risk factors accumulate to induce the pre-diabetic state of insulin resistance and moderate fasting hyperglycemia. The decreased insulin sensitivity of organs such as the liver, skeletal muscle and adipose tissue results in increased glucose output and reduced glucose uptake, leading to compensatory insulin over-secretion from the pancreas. The progressive development of pancreatic beta cell dysfunction and loss of beta cell mass ultimately lead to impaired insulin secretion and a chronic hyperglycemic state, the definition of overt T2DM. Chronic hyperglycemia and inflammation contribute to the development of associated micro- and macro-vascular disorders, including the liver disorders Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steato-Hepatitis (NASH)
and the risk of micro- and macrovascular compli- cations, including fatal CVD events. However, the recent ACCORD and ADVANCE trials in patients with longstanding T2DM have shown that aggres- sive glucose control in such patients has no clear benefits, or may even increase CVD events3. Therefore, other independent risk factors may exist that contribute significantly to CVD risk in these patients. Alternatively, such findings may simply reflect the limitations of current anti-diabetic ther- apies, due to off-target effects that counter the potential benefits of glucose lowering. New therapeutics must therefore address the multi-factorial nature of T2DM, and aim to treat diabetic patients at an earlier stage of the disease, if pharmacological interventions hope to halt the epidemic.
Current and future therapeutic approaches
Current widespread treatments for T2DM include metformin (suppressor of hepatic glucose produc- tion), sulfonylureas (insulin secretagogues), and the thiazolidinedione pioglitazone (PPAR agonist). More recent incretin-based treatment strategies include glucagon-like peptide-1 (GLP-1) mimetics and inhibitors of the enzyme that degrades GLP-1, dipeptidyl peptidase-4 (DPP-4). GLP-1 is an intestinally-derived peptide that stimulates insulin secretion in response to food intake, as well as
reducing the rate of gastric emptying, thus pro- moting satiety and weight loss. Despite a certain number of gastrointestinal side-effects, the GLP-1 mimetic exenatide was approved by the FDA in 2005, and its indication was extended in 2009 to standalone therapy for T2DM. A retrospective analysis of almost 40,000 patients treated with exenatide showed a reduced incidence of cardio- vascular events4, although these results should be confirmed by prospective studies.
New therapeutic approaches in the T2DM drug discovery pipeline are specifically designed to take into account the multi-factorial nature of T2DM by targeting multiple diabetes-related indications, and not simply focusing on glucose-lowering. Moreover, due to the elevated CVD risk in T2DM patients, current FDA recommendations require that all new anti-diabetic drugs show exemplary cardiovascular safety profiles. Thus, drugs that tar- get molecular pathways potentially implicated in both diabetes and CVD are especially desirable. Such approaches include the targeting of 11- hydroxysteroid dehydrogenase type 1 (11- HSD1), GPR119, TGR5, sirtuin 1 (SIRT1), the sodium-glucose co-transporter 2 (SGLT2), and GPR40, for each of which the rationale is briefly described below (Table 1).
11-HSD1: This enzyme mediates the generation of the glucocorticoid cortisol from its inactive precursor
Drug Discovery World Summer 2011
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