Editorials Novel treatments for type 2 diabetes THE NEED FOR NOVEL are administered subcutaneously. to rodents, and to date there is no THERAPIES Exenatide is associated with a sustained evidence of a causal relationship between Type 2 diabetes mellitus is a major threat 3-year HbA1c reduction of 1%, and 46% liraglutide 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 metformin, agent of liraglutide are due to start this Organization estimates that by 2030, type sulphonylureas, and insulin glargine, year. 2 diabetes will affect over 360 million exenatide has demonstrated superior Other GLP-1 analogues in clinical trial 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 glimepiride, metformin, taspoglutide, albiglutide and lixisenatide, diabetic agents, approximately 60% of rosiglitazone, and insulin glargine. 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. glycated hemoglobin (HbA1C) level of exenatide, liraglutide was associated with superior HbA1c reductions of 0.3%. 3 AMYLIN 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. Pramlintide 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. cholesterol; 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: sitagliptin, vildagliptin and, more GLP-1 mimetics have proved popular The most common side-effects recently, saxagliptin. 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 linagliptin, dutogliptin, gemigliptin, and between patients with poor diabetic failure. 6 alogliptin. 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 Bromocriptine 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 muraglitazar and tesaglitazar, 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 aleglitazar on risk of