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Novel treatments for type 2

THE NEED FOR NOVEL are administered subcutaneously. to rodents, and to date there is no THERAPIES is associated with a sustained evidence of a causal relationship between mellitus is a major threat 3-year HbA1c reduction of 1%, and 46% and human C-cell medullary to health with a prevalence increasing in of patients achieve a target HbA1c <7%. thyroid cancer. Phase I trials of an oral epidemic proportions. The World Health In comparative studies with , agent of liraglutide are due to start this Organization estimates that by 2030, type sulphonylureas, and glargine, year. 2 diabetes will affect over 360 million exenatide has demonstrated superior Other GLP-1 analogues in people worldwide. Inevitably, diabetes HbA1c reductions. 2 phase include longer acting compounds, and its complications will strain public In comparative studies, liraglutide has which offer the advantage of once-weekly health resources. demonstrated superior HbA1c reductions administration. These include: Despite the availability of many anti- compared to , metformin, , and , diabetic agents, approximately 60% of , and . In a also known as AVE0010, and a once- patients do not achieve the target head-to-head comparative study against weekly preparation of exenatide. (HbA1C) level of exenatide, liraglutide was associated with superior HbA1c reductions of 0.3%. 3 AGONISTS ≤7%. Reasons for this include: non- compliance; side-effects of treatments; The popularity of GLP-1 agonists is Amylin agonists have all the incretin fear of hypoglycaemia; weight-gain; further enhanced by clinical data, which actions except stimulation of insulin problems with dose titration of anti- demonstrate disease modifying effects on secretion. is the only licensed diabetic agents; and more stringent the adverse cardiovascular profile amylin analogue and is associated with HbA1C targets set by healthcare associated with type 2 diabetes. HbA1C reductions of 0.5 –1.0%. Adverse organisations which tend to change. Exenatide is associated with ~5kg weight effects are mainly nausea, which Clearly, additional therapeutic options are reduction; 12% reduction in serum improves with continuing treatment. 7 needed that will overcome these clinical triglycerides; 5% reduction in serum total shortcomings. ; 6% reduction in serum low- DIPEPTIDYL PEPTIDASE IV density lipoprotein cholesterol; 24% INHIBITORS INCRETIN THERAPEUTICS increase in cardio-protective serum high- The therapeutic potential of endogenous Incretin therapeutics, which are based on density lipoprotein cholesterol; and GLP-1 is limited by its short physiologic mimicking the endogenous effects of improvement in the hepatic steatosis half-life, owing to its rapid inactivation by glucagon-like peptide 1 (GLP-1), have biomarkers (alanine aminotransferase) of dipeptidyl peptidase IV (DPP-IV). Several revolutionised the management of type 2 41%. 4 Liraglutide has demonstrated selective inhibitors of DPP-IV have been diabetes since they came into clinical use similar findings in addition to achieving a developed and those that are licensed in 2006. 4% reduction in systolic blood pressure. 3 include: , and, more GLP-1 mimetics have proved popular The most common side-effects recently, . They achieve a with both physicians and patients as they associated with exenatide include 0.4 –0.7% HbA1c reduction over offer an additional therapeutic strategy nausea, vomiting, and diarrhoea, which 12 months, and as monotherapy are not that overcomes many of the pitfalls are dose-dependent but subside over associated with hypoglycaemia. 8 Adverse associated with current therapies: they time. Cases of acute pancreatitis have effects include nasopharyngitis and avoid hypoglycaemia by acting in a been reported but estimates indicate an urinary tract infections. To date, 88 cases glucose-dependent manner; they incidence of 0.33 –0.44 per 1000 adults of pancreatitis associated with sitagliptin facilitate weight loss by slowing gastric per year. 5 Recently the Food and Drug therapy have been reported to the FDA. emptying and reducing satiety; and they Administration (FDA) issued a safety Other DPP-IV inhibitors, which are inhibit glucagon release. GLP-1 mimetics warning on exenatide associating it with currently in phase III clinical trials, include have proved valuable in bridging the gap the development of ischaemic renal , dutogliptin, , and between patients with poor diabetic failure. 6 . control (HbA1c >8%) who have failed oral In general, liraglutide appears well hypoglycaemic therapy but are reluctant tolerated with a lower incidence of nausea CENTRAL NEUROTRANSMITTER to start insulin due to the undesirable compared to exenatide. Liraglutide has MODULATORS effects of weight gain and fear of been associated with thyroid hyperplasia Body fat stores and insulin action are hypoglycaemia. 1 and medullary thyroid carcinoma, which controlled by the temporal interaction of The two licensed GLP-1 analogues are has led to a ‘black-box’ warning. circadian neuroendocrine oscillations. exenatide and liraglutide, both of which However, this association seems confined modulates neurotransmitter

British Journal of General Practice, January 2011 5 action in the brain. Studies using associated with HbA1c reductions of 2. Pratley RE, Gilbert M. Targeting incretins in type 2 diabetes: role of GLP-1 receptor agonists and DPP-4 bromocriptine in type 2 diabetes have 0.36 –1.35% as well as improving adverse inhibitors. Rev Diabet Stud 2008; 5(2): 73 –94. shown improvements in glycaemic control high-risk lipid profiles. It is now being 3. Hansen KB, Vilsbøll T, Knop FK. Incretin mimetics: a and glucose tolerance with HbA1c advanced into phase III clinical studies. novel therapeutic option for patients with type 2 diabetes — a review. Diabetes Metab Syndr Obes 2010; 9 reductions of ~0.56%. Despite receiving However, there are concerns about PPAR 3: 155 –163. FDA approval, bromocriptine is not part of α/γ ligands. Two such agents, 4. Klonoff DC, Buse JB, Nielsen LL, et al . Exenatide effects the type 2 diabetes management and , were on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes guidelines from the National Institute for withdrawn after concerns about their treated for at least 3 years. Curr Med Res Opin 2008; Health and Clinical Excellence. association with major cardiovascular 24(1): 275 –286. 5. Bain SC, Stephens JW. Exenatide and pancreatitis: an events. update. Expert Opin Drug Saf 2008; 7(6): 643 –644. EXPERIMENTAL AGENTS 6. Weise WJ, Sivanandy MS, Block CA, Comi RJ. The Glimins MBX-2982 Exenatide-associated ischemic renal failure. Diabetes Care 2009; 32(2): e22 –33. Imeglimin, an oxidative phosphorylation G-protein coupled receptor 119 (GPR119) 7. Schmitz O, Brock B, Rungby J. Amylin agonists: a novel inhibitor, is a first in a new class of oral is a receptor in the gut and pancreas that approach in the treatment of diabetes. Diabetes 2004; anti-diabetic drugs known as ‘the Glimins’, interacts with bioactive lipids to stimulate 53 (Suppl 3): S233 –S238. which target the three key defects of type glucose-dependent incretin and insulin 8. Mikhail N. Incretin mimetics and dipeptidyl peptidase 4 inhibitors in clinical trials for the treatment of type 2 2 diabetes : insufficient insulin production; secretion. MBX-2982, a GPR119 agonist, diabetes. Expert Opin Investig Drugs 2008; 17(6): excessive hepatic gluconeogenesis; and which has completed three phase I 845 –853. 9. Gaziano JM, Cincotta AH, O’Connor CM, et al . impaired glucose uptake by skeletal clinical studies, has consistently shown Randomized clinical trial of quick-release muscles. Its efficacy is currently being clinically meaningful glucose reductions. bromocriptine among patients with type 2 diabetes on 10 14 overall safety and cardiovascular outcomes. Diabetes examined in phase IIa clinical trials. It has now entered phase II clinical trials. Care 2010; 33(7): 1503 –1508. 10. Poxel. Imeglimin. http://www.poxel.com/product- Renal sodium-dependent glucose THE ROLE OF THE COMMUNITY pipeline/imeglimin (accessed 24 Nov 2010). co-transporter-2 inhibitors DIABETES TEAM 11. Chao EC, Henry RR. SGLT2 inhibition — a novel strategy for diabetes treatment. Nat Rev Drug Discov The glucose reabsorption system in the With the management of diabetes making 2010; 9(7): 551 –559. kidney is mediated by renal sodium- the transition from secondary into primary 12. Van Poelje PD, Potter SC, Chandramouli VC, et al . Inhibition of fructose 1,6-bisphosphatase reduces dependent glucose co-transporter 2 care, coupled with imposing pressures of excessive endogenous glucose production and (SGLT2) receptors. Most filtered glucose guidelines to tighten glycaemic control, attenuates hyperglycemia in Zucker diabetic fatty rats. is reabsorbed by the low affinity, high GPs will soon be leading the way in Diabetes 2006; 55(6): 1747 –1754. 13. Henry RR, Lincoff AM, Mudaliar S, et al . Effect of the capacity SGLT2 receptors located in the optimising therapeutic strategies for dual peroxisome proliferator-activated receptor- proximal renal tubule. SGLT2 inhibitors patients with type 2 diabetes. The next alpha/gamma agonist on risk of cardiovascular disease in patients with type 2 diabetes enhance urinary glucose excretion, which decade is likely to be exciting with the (SYNCHRONY): a phase II, randomised, dose-ranging lowers blood glucose levels independent explosive pace at which new, safer, and study. Lancet 2009; 374(9684): 126 –135. of insulin with HbA1c reductions of more effective anti-diabetic treatments 14. Metabolex. Pipeline MBX-2982. Potential oral incretin/islet therapy . Hayward, CA: Metabolex. 0.55 –0.9%; 11 examples include: are rolling off the clinical phase belt. The http://www.metabolex.com/MBX-2982.html (accessed remogliflozin, etabonate, sergliflozin, and role of the community diabetes team in 24 Nov 2010). . instituting these novel treatments will be DOI: 10.3399/bjgp11X548884 essential in improving diabetes care. Fructose 1,6-bisphosphatase inhibitors Jason Seewoodhary, Excessive gluconeogenesis is central to Specialist Registrar in Diabetes Mellitus & the pathophysiology of type 2 diabetes. Endocrinology and General Internal Medicine, Swansea School of Medicine, University of Recently, the use of selective fructose Wales, Swansea. 1,6-bisphosphatase inhibitors, a rate- controlling enzyme of gluconeogenesis, Stephen C Bain, has been explored. 12 Current data, which Professor and Consultant in Diabetes Mellitus & illustrate glucose-lowering effects, are Endocrinology and General Internal Medicine, limited to rodent studies. Swansea School of Medicine, University of Wales, Swansea. ADDRESS FOR CORRESPONDENCE

Peroxisome proliferator-activated Provenance Jason Seewoodhary receptor / ligands Commissioned, not externally peer reviewed. α γ Department of Diabetes and Endocrinology, The promise for peroxisome proliferator- Swansea School of Medicine, University of activated receptor (PPAR) agonists to REFERENCES Wales, Swansea, The Grove Building, reduce cardiovascular risk type 2 diabetes 1. Saydah SH, Fradkin J, Cowie CC. Poor control of risk Swansea, SA2 8PP. factors for vascular disease among adults with is of continued interest. In the previously diagnosed diabetes. JAMA 2004; 291(3): E-mail: [email protected] SYNCHRONY trial, 13 aleglitazar was 335 –342.

6 British Journal of General Practice, January 2011