sign in sign up
<<
Home , Aleglitazar, Muraglitazar, Phenformin, Remogliflozin etabonate, Sergliflozin etabonate, Tesaglitazar

The Internet Journal of Pharmacology ISPUB.COM Volume 8 Number 2

Drugs In Pipeline For Type-2 R Mahajan, K Gupta

Citation R Mahajan, K Gupta. Drugs In Pipeline For Type-2 Diabetes. The Internet Journal of Pharmacology. 2009 Volume 8 Number 2.

Abstract Hyperglycemia, obesity, resistance, dyslipidemia and hypertension are interrelated cardiometabolic risk factors for the development of type-2 diabetes and metabolic syndrome. Prevalence of type-2 diabetes is growing at an alarming rate. Treatment target for type-2 diabetes is to keep daily glucose profile as close as possible to that of a non-diabetic person. , , , and inhibitors are already being used in controlling glucose levels in type-2 diabetes. This review discusses the new drugs with novel mechanism of actions; which are in pipeline and were marketed recently or will be in market in near future.

INTRODUCTION ); biguanides (, ); Type-2 diabetes is the most common metabolic disorder thiazolidinediones ( , ) meglitinides worldwide, and its prevalence is growing at an alarming rate (, ); alpha-glucosidase inhibitors in both developed and developing countries. This growth has (acarbose, , ) and miscellaneous ones been related to the increased prevalence of obesity. A cluster (aspartame, chromium picolinate, guargum, glucomannan), [4] of interrelated cardiometabolic risk factors is closely related available either singly or as combinations. With all these to the development of type-2 diabetes and cardiovascular available options, still, sometimes glucose control is not disease. Obesity, hyperglycemia and insulin resistance, maintained; and many patients ultimately have to put on dyslipidemia, inflammation, and hypertension represent insulin therapy. To fill the vacant space and to satisfy the interrelated therapeutic targets in the battle against the ever growing human-urge of research, new compounds have increasing prevalence of type-2 diabetes. [1] The evidence, surfaced which may stake its claim in the market in near that obesity and diabetes is associated with risk of carcinoma future. has made the picture murkier. The most common type of NEW ANTIDIABETIC DRUGS IN THE PIPELINE diabetes mellitus, type-2, seems to be associated with liver Many new antidiabetic drugs with novel mechanism of and pancreas cancer and probably with colorectal cancer. actions are in the pipeline; they have either been introduced The health consequences and economic costs of the recently or are undergoing late phase 3 trials or an NDA has overweight, obesity and type-2 diabetes epidemics are [5-11] [2] been applied for. These drugs with their classes are: enormous. Dopamine-2 (D ) receptor agonist: mesylate Treatment targets for type-2 diabetes include restoring blood 2 glucose to normal levels so as to abolish diabetic symptoms; Glucagon-like Peptide-1 (GLP-1) analogues: , and the risk of acute and chronic metabolic complications. In , a large scale study, a 1% reduction in HbAIC resulted in 21% reduction in diabetic related deaths, 37% reduction in Dipeptidyl Peptidase-4 (DPP-4) inhibitors: , microvascular disease, 14% reduction in myocardial , , , infarction and 21% reduction in all diabetes related end Dual Peroxisome Proliferator-Activated Receptor (PPAR) points. [3] agonists: , , Oral antidiabetic agents for type-2 diabetes already available Sodium-Glucose Transport Proteins-2 (SGLT-2) inhibitors: in market include sulfonylureas (, , Remogliflozin, Sergliflozin , , , ,

1 of 5 Drugs In Pipeline For Type-2 Diabetes

DOPAMINE-2 RECEPTOR AGONIST: dependent insulin secretion by the pancreatic beta-cell, BROMOCRIPTINE MESYLATE suppresses inappropriately elevated glucagon secretion, and (14) Idea of use of Bromocriptine in (used slows gastric emptying. otherwise in parkinsonism disease) originated by studying The medicine is available in two doses: 5 mcg and 10 mcg. the metabolism of migrating birds; that they develop Treatment often begins with the 5 mcg dosage, which is seasonal insulin resistance, and this insulin resistance if increased if adverse effects are not significant. The main side occurred in humans lead to type 2 diabetes, and dopamine is effects of exenatide use are gastrointestinal in nature, responsible for it. [12] On May 5th, 2009, FDA approved including acid or sour stomach, belching, diarrhoea, bromocriptine mesylate (cycloset) 0.8-mg quick-release heartburn, indigestion, nausea, and vomiting; exenatide is tablets for use alone or with other antidiabetic agents in the therefore not meant for people with severe gastrointestinal management of type 2 diabetes. The recommended starting disease. Other side effects include dizziness, headache, and dose is 0.8 mg taken once daily within 2 hours of waking feeling jittery. Few cases of pancreatitis were reported, so and is titrated in increments of 0.8 mg/week to a target dose FDA has issued a statuary warning. (14) ranging from 1.6 to 4.8 mg. Bromocriptine, a centrally- acting dopamine D2 receptor agonist, when administered as a In an open label randomized controlled trial of 551 patients, single timed morning dose, is thought to act on circadian exenatide treatment for 26 weeks was associated with 2.3 kg neuronal activities within the hypothalamus to reset weight loss; however, gastrointestinal symptoms were more abnormally elevated hypothalamic drive for increased common in the exenatide group, including nausea (57.1%), plasma glucose, triglyceride, and free fatty acid levels in vomiting (17.4%) and diarrhea (8.5%). For most patients, the [5] fasting and postprandial states in insulin-resistant patients. nausea is mild to moderate and goes away entirely after a st This is the 1 chronotherapeutic based treatment for type 2 few days or weeks. (15) diabetes. It is evident that one obvious advantage with exenatide is Adverse events most commonly reported in clinical trials of weight loss during treatment, which is seen only with other bromocriptine included nausea, fatigue, vomiting, headache, two antidiabetic drugs i.e. metformin and acarbose, but one and dizziness. These events lasted a median of 14 days and obvious disadvantage is that it has to be injected. were more likely to occur during initial titration of the drug. None of the reports of nausea or vomiting were described as Liraglutide is long acting GLP-1 analogue that awaits FDA serious. The FDA warns that bromocriptine can cause and EMEA (European Medical Agency) approval to be used (16) orthostatic hypotension and syncope, particularly on in type 2 diabetes as once daily subcutaneous injection, initiation of therapy and dose escalation. [5] but as on April 2, 2009 FDA advisory panel has expressed serious concern that the drug causes thyroid tumors. GLP-1 ANALOGUES Otherwise in a randomized study, in subjects with type 2 GLP-1 analogues have been developed by observing that diabetes, once-daily liraglutide induced similar glycemic glucose-dependent insulinotropic polypeptide (GIP) and control, reduced body weight, and lowered the occurrence of glucagon-like peptide-1 (GLP-1); also known as incretins, hypoglycemia compared with glimepiride, when both had (17) are released from upper and lower bowel that augments background therapy of metformin. glucose-dependent insulin secretion. This action is seen Albiglutide, another GLP-1 analogue is a novel dipeptidyl more with GLP-1. GLP-1 also reduces glucagon secretion, peptidase-4-resistant (Dipeptidyl peptidase-4 causes slows gastric emptying and decreases appetite; so ultimately metabolism of GLP-1 and its analogues) glucagon-like reduces postprandial glucose rise and weight loss. (13) peptide-1 dimer fused to human albumin designed to have Exenatide is a 39-amino acid peptide, a GLP-1 analogue and sustained efficacy in type 2 diabetics. It is still under insulin secretagogue with glucoregulatory effects. Exenatide investigation. Its half life ranges from 6-7 days, so weekly (7) is indicated for type 2 diabetic patients whose diabetes is not injections can be given. well-controlled by other oral . Exenatide is DPP IV INHIBITORS administered as a subcutaneous injection (under the skin) of the abdomen, thigh, or arm, 30 to 60 minutes before the first Dipeptidyl peptidase IV (DPP IV) is the major enzyme and last meal of the day. Exenatide enhances glucose- responsible for degrading the incretins in vivo. So the

2 of 5 Drugs In Pipeline For Type-2 Diabetes blockade of incretin degradation increases their PPAR alpha and PPAR gamma ligands in preventing the physiological actions, including the stimulation of insulin cardiovascular risks. The PPAR alpha/gamma dual agonists secretion and inhibition of gastric emptying. Incretins (GIP are developed to increase insulin sensitivity and & GLP-1) have powerful effects on beta-cell differentation, simultaneously prevent diabetic cardiovascular mitogenesis and survival. By potentiating these pleiotropic complications. Such compounds are under clinical trials and actions of the incretins, DPP IV inhibition can therefore proposed for treatment of Type-2 diabetes with secondary preserve beta-cell mass and improve secretory function in cardiovascular complications. (10) diabetics. (18) However, PPAR alpha/gamma dual agonists such as The first agent of this class, sitagliptin, (marketed under muraglitazar, tesaglitazar and ragaglitazar have been noted trade name Januvia) was approved by the FDA in October to produce several cardiovascular risks and carcinogenicity, 2006, for use in addition to diet and exercise to improve which raised number of questions about the clinical blood sugar levels in patients with type 2 diabetes, alone or applications of dual agonists in diabetes and its associated in combination with two other commonly prescribed oral complications. Further studies are on the track to develop diabetes medications, metformin or a PPAR-agonist, when PPAR alpha/delta and PPAR gamma/delta dual agonists and either of these drugs alone, along with diet and exercise, PPAR alpha/gamma/delta pan agonists for the treatment of don't provide adequate blood sugar control. Januvia was diabetic cardiovascular complications. (10) examined in a total of 2,719 patients with type 2 diabetes. These studies demonstrated improved blood sugar control SODIUM-GLUCOSE TRANSPORT PROTEINS-2 (SGLT-2) INHIBITORS when Januvia was used alone or in patients not satisfactorily managed with metformin or a PPAR agonist. The most Sodium-dependent glucose co-transporters are a family of common side effects in clinical studies were upper glucose transporters found in the intestinal mucosa of the respiratory tract infection, sore throat, and diarrhea. (19) small intestine (SGLT1) and the proximal tubules of the nephrons (SGLT2 and SGLT1). They contribute to renal Vildagliptin (trade name Galvus) is another oral antidiabetic glucose reabsorption. SGLT1 is responsible for only 2% drug which is a DPP-IV inhibitor. The Food and Drug renal glucose reabsorption, while SGLT2 is responsible for Administration had demanded additional clinical data before 98% of renal glucose reabsorption. (24) it could approve vildagliptin. While the drug is still not approved for use in the US, it has been approved by EMEA SGLT2 has a 1:1 ratio of sodium-glucose transport. SGLT1 for use within the EU. (20) works similarly but has a 2:1 ratio of sodium-glucose transport. SGLT2 inhibitors are being developed as potential Other drugs in this class are saxagliptin, linagliptin and antidiabetic agents because of their ability to specifically alogliptin, which are under development. Takeda has reduce transcellular epithelial glucose reabsorption. (25) submitted a New Drug Application (NDA) for alogliptin to the FDA, after positive results from Phase III clinical Dapagliflozin, the most advanced compound in this novel studies. (21) Similarly, AstraZeneca has submitted NDA for class of oral antidiabetic agents, is currently in phase III saxagliptin under trade name Onglyza to FDA and EMEA clinical testing for the treatment of type 2 diabetes. The drug for approval. (22) was discovered by Bristol-Myers Squibb and has been licensed to AstraZeneca for development and DUAL PPAR AGONISTS commercialization. Two trials are currently recruiting , the PPAR alpha agonists, first used in the 1970s, participants: one in diabetic subjects not adequately lower plasma triglycerides and VLDL particles and increase controlled on metformin alone and the other in those not HDL ; effects that are associated with adequately controlled with diet and exercise alone. (25) cardiovascular benefit. PPAR gamma agonists like Another drug of this class, Remogliflozin is a thiazolidinediones, influence free fatty acid flux and thus prodrug based on benzylpyrazole glucoside and is reduce insulin resistance and blood glucose levels. PPAR metabolized to its active form, remogliflozin, in the body. It gamma agonists are therefore used to treat type-2 diabetes. is a potent and highly selective SGLT2. Orally administered PPAR alpha and gamma agonists also affect inflammation, increased urinary glucose excretion vascular function, and vascular remodeling. (23) Several basic in a dose-dependent manner in both mice and rats. (26) This and clinical studies have exemplified the beneficial effects of

3 of 5 Drugs In Pipeline For Type-2 Diabetes drug is being developed by GlaxoSmithKline. 268-76 12. Hennessy T. Old Parkinson's drug tweaked into diabetes is a benzylphenol glucoside based treatment. The Associated Press, 2009 May 7. 13. Davis SN. Insulin, oral hypoglycemic agents, and the prodrug, which is again a potent SGLT2 inhibitor and is pharmacology of the endocrine pancreas. In: Brunton LL, currently under investigational phase. (27) Lazo JS, Parker KL. editors. Goodman and Gilman's The pharmacological basis of therapeutics. 11 th ed. McGraw- Hill: New York; 2006. p. 1641 CURRENT POSITION 14. Pharmaceuticals, Inc. Byetta: Exenatide Many of these drugs have been approved like bromocriptine injection. Last Updated Dec. 2007, (cited 2009 June 26) Available from: mesylate, exenatide, sitagliptin, vildagliptin (only in EU); http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/0 while questions have been raised on the safety issue 21773s012lbl.pdf 15. Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, regarding many new compounds being developed to counter Brodows RG. Exenatide versus in patients type 2 diabetes and FDA has asked for additional clinical with suboptimally controlled type 2 diabetes: a randomized trial data. Never the less, these agents provide novel trial. Ann Intern Med 2005; 143: 559-69 16. Medical New Today: Diabetes. Clinical Study Shows therapeutic mechanisms for controlling type 2 diabetes. So, Liraglutide Reduced Blood Sugar, Weight, And Blood let’s keep our fingers crossed!! Pressure In Patients With Type 2 Diabetes. Last Updated 2008 June 08 (cited 2009 June 26). Available from: References http://www.medicalnewstoday.com/articles/110349.php 17. Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, 1. Iqbal N. The burden of type 2 diabetes: strategies to Mitha IH, et al. Efficacy and safety comparison of prevent or delay onset. Vasc Health Risk Manag 2007; 3: liraglutide, glimepiride and placebo, all in combination with 511-20 metformin, in type 2 diabetes: The LEAD-2 study. Diabetes 2. Hjartaker A, Langseth H, Weiderpass E. Obesity and Care 2009; 32: 84-90 diabetes epidemics: cancer repercussions. Adv Exp Med 18. McIntosh CH, Demuth HU, Pospisilik JA, Pederson R. Biol 2008; 630: 72-93 Dipeptidyl peptidase IV inhibitors: how do they work as new 3. United Kingdom Prospective Diabetes Study Group. antidiabetic agents? Regul Pept 2005; 128: 159-65 Association of glycemia with macrovascular and 19. Alvey L. FDA approves new treatment for diabetes: First microvascular complications of type 2 diabetes. BMJ 2000; in a new class of diabetes drugs. News release, 2006 Oct 17 321: 412-19 (cited 2009 June 27). Available from: 4. Mishra L, editor. Drug Today: Ready reckoner of current http://www.fda.gov/NewsEvents/Newsroom/PressAnnounce medical formulations. 16th Vol. Delhi: Lorina Publications ments/2006/ucm108770.htm Inc; 2009. p 928-43 20. Egenter S. Update 2- EU approves Novartis disbetes 5. Waknine Y. FDA approvals: Fanapt and Cycloset. drug Galvus. Reuters 2008 Feb 1. (cited 2009 June 27) MedscapeCME [serial online] 2009 May 14 [cited 2009 May Available from: 27]. Available from: http://www.reuters.com/article/companyNews/idUSL011638 http://cme.medscape.com/viewarticle/702793. 7320080201 6. Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautman 21. Takeda Pharmaceutical Company. Takeda submits new M, Zhuanq D, et al. Exenatide once weekly versus twice drug application for alogliptin in the U.S. Press release. 2008 daily for the treatment of type 2 diabetes: a randomized, Jan 4. (cited 2009 June 27). Available from: open-label, non-inferiority study. Lancet 2008; 372: 1240-50 http://www.takeda.com/press/article_28864.html 7. Matthews JE, Stewart MW, De Boever EH, Dobbins RL, 22. The 10 most promising new drugs. Drug One, June Hodqe RJ, Walker SE, et al. Pharmacodynamics, 2009; 4: 19 pharmacokinetics, safety, and tolerability of albiglutide, a 23. Staels B, Fruchart JC. Therapeutic roles of peroxisome long-acting glucagon-like peptide-1 mimetic, in patients proliferator-activated receptor agonists. Diabetes 2005; 54: with type 2 diabetes. J Clin Endocrinol Metab 2008; 93: 2460-70 4810-7 24. Wright EM, Hirayama BA, Loo DF. Active sugar 8. Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch CL. transport in health and disease. J Intern Med 2007; 261: Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes 32–43 mellitus. Cochrane Database of Systematic Reviews 2008, 2. 25. Prous Science. Molecule of the month: Dapagliflozin. (cited 2009 June 22) Available from: 2007 Nov. (cited 2009 June 27). Available from: http://www.cochrane.org/reviews/en/ab006739.html http://www.prous.com/molecules/default.asp?ID=165 9. Bristol-Myers Squibb. Saxagliptin Treatment in Subjects 26. Fujimori Y, Katsuno K, Nakashima I, Ishikawa- with Type 2 Diabetes Who Are Not Controlled With Diet Takemura Y, Fujikura H, Isaji M. Remogliflozin etabonate, and Exercise. FDA Clinical trials Government. (cited 2009 in a novel category of selective low-affinity sodium glucose June 22) Available from: cotransporter (SGLT2) Inhibitors, exhibits antidiabetic http://clinicaltrials.gov/ct2/show/NCT00121641 efficacy in rodent models. J. Pharmacol Exp Ther 2008; 327: 10. Balakumar P, Rose M, Ganti SS, Krishan P, Singh M. 268-76 PPAR dual agonists: are they opening Pandora’s box. 27. Katsuno K, Fujimori Y, Takemura Y, Hiratochi M, Itoh Pharmacol Res 2007; 56: 91-8 F, Komatsu Y, et al. Sergliflozin a novel selective inhibitor 11. Fujimori Y, Katsuno K, Nakashima I, Ishikawa- of low-affinity sodium glucose cotransporter (SGLT2), Takemura Y, Fujikura H, Isaji M. Remogliflozin etabonate, validates the critical role of SGLT2 in renal glucose in a novel category of selective low-affinity sodium glucose reabsorption and modulates plasma glucose level. J cotransporter [SGLT2] inhibitors, exhibits antidiabetic Pharmacol Exp Ther 2007; 320: 323-30 efficacy in rodent models. J Pharmacol Exp Ther 2008; 327:

4 of 5 Drugs In Pipeline For Type-2 Diabetes

Author Information Rajiv Mahajan, M. D. Assistant Professor, Department of Pharmacology, Adesh Institute of Medical Sciences & Research

Kapil Gupta, Ph. D Assistant Professor, Department of Biochemistry, Adesh Institute of Medical Sciences & Research

5 of 5