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Newer Anti-Hyperglycemic Agents in Type 2 Diabetes Mellitus - Expanding the Horizon
 

Newer Anti-Hyperglycemic Agents in Type 2 Diabetes Mellitus - Expanding the Horizon

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Diabetes mellitus is a common, chronic and progressive disease resulting in micro and macrovascular complications. Many classes of drugs are available for treatment but still the search for newer ...

Diabetes mellitus is a common, chronic and progressive disease resulting in micro and macrovascular complications. Many classes of drugs are available for treatment but still the search for newer anti-hyperglycemic agents continues to combat significant adverse effect profile, loss of efficacy, progressive nature of disease and improve patient compliance. New emerging therapies in pipeline include drugs targeting various patho-physiologic mechanisms like incretin based therapies, sodium glucose co-transporter inhibitors, glucokinase inhibitors, 11b hydroxy steroid dehydrogenase inhibitors, drugs modulating fatty acid metabolism, selective PPARg receptor modulators and anti inflammatory agents. Aim of this review is to describe the emerging therapies for diabetes
mellitus.

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    Newer Anti-Hyperglycemic Agents in Type 2 Diabetes Mellitus - Expanding the Horizon Newer Anti-Hyperglycemic Agents in Type 2 Diabetes Mellitus - Expanding the Horizon Document Transcript

    • Newer Anti-Hyperglycemic Agents in Type 2 Diabetes Mellitus - Expanding the Horizon
    • a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 0 8 e1 1 2 Available online at www.sciencedirect.com journal homepage: www.elsevier.com/locate/apme Review Article Newer anti-hyperglycemic agents in type 2 diabetes mellitus e Expanding the horizon Savita Jain a,*, Nitin Gupta a, Radhika Jindal a, Tuhin Dubey a, Niti Agarwal b, Asim Siddiqui b, S.K. Wangnoo c a DNB Fellow, Department of Endocrinology, Indraprastha Apollo Hospital, Sarita Vihar, New Delhi, India Associate Consultant, Department of Endocrinology, Indraprastha Apollo Hospital, Sarita Vihar, New Delhi, India c Senior Consultant, Department of Endocrinology, Indraprastha Apollo Hospital, Sarita Vihar, New Delhi, India b article info abstract Article history: Diabetes mellitus is a common, chronic and progressive disease resulting in micro and Received 5 May 2013 macrovascular complications. Many classes of drugs are available for treatment but still Accepted 16 May 2013 the search for newer anti-hyperglycemic agents continues to combat significant adverse Available online 6 June 2013 effect profile, loss of efficacy, progressive nature of disease and improve patient compliance. New emerging therapies in pipeline include drugs targeting various patho- Keywords: physiologic mechanisms like incretin based therapies, sodium glucose co-transporter Type 2 diabetes mellitus inhibitors, glucokinase inhibitors, 11b hydroxy steroid dehydrogenase inhibitors, drugs Newer therapy modulating fatty acid metabolism, selective PPARg receptor modulators and anti in- Pathophysiology flammatory agents. Aim of this review is to describe the emerging therapies for diabetes mellitus. Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved. 1. Introduction Diabetes mellitus is a chronic disease reaching epidemic levels in both developed and developing countries. According to WHO by 2030, there will be 366 million diabetic patients worldwide and 80 million diabetics only in India. Significant morbidity, mortality and cost are associated with this disease due to progressive nature resulting in many micro and macrovascular complications. It requires continuous medical care and self-management by the patient to prevent both acute and chronic complications related to uncontrolled glycemic status. Many classes of drugs are available for treatment of diabetes mellitus like metformin, sulfonylureas, a-glucosidase inhibitors, glitazones, glinides and insulin. Newer drugs like DPP4 inhibitors, GLP1 agonists, SGLT2 inhibitors, insulin analogs have been added to this list during last few years.1 With these, clinical management of diabetes mellitus has undergone a significant change. Despite availability of numerous classes of drugs addressing different pathophysiologic mechanisms, search for new drugs continues to combat adverse drug effects associated with available drugs (weight gain, hypoglycemia, fluid retention, cardiovascular risk), efficacy, poor adherence due to need of injection or frequent administration, cost or other factors and most importantly to combat progressive decline in b cell function. In this review, we discuss new emerging therapies for treatment of type 2 diabetes and other potential targets for development of new drugs. * Corresponding author. E-mail addresses: dr.jain.savita@gmail.com, savitajain@yahoo.com (S. Jain). 0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved. http://dx.doi.org/10.1016/j.apme.2013.05.013
    • a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 0 8 e1 1 2 2. Pathogenesis b cells are the seat of pathophysiology of diabetes. b cell dysfunction is an important pathophysiologic mechanism underlying development of diabetes mellitus. There are nonmodifiable factors influencing b cell health like age and genetic predisposition. Also there are modifiable factors like insulin resistance, lipotoxicity, glucotoxicity, incretin defect and increase in islet amyloid polypeptide (IAPP). Along with b cell dysfunction, insulin resistance in liver, muscle and adipose tissue accounts for development of impaired glucose tolerance. There is increased gluconeogenesis from liver due to hyperglucagonemia with increased sensitivity to glucagon, lipotoxicity and glucotoxicity. Muscle is another major site for insulin resistance characterized by multiple intramyocellular defects like impaired glucose transport, phosphorylation, glycogenesis and glucose oxidation. Diabetic patients have increased lipolysis in adipose tissue thus causing release of excessive free fatty acids into the circulation. These free fatty acids are responsible for lipotoxicity in b cells, stimulate gluconeogenesis from liver and cause insulin resistance. Also there is increase in release of pro-inflammatory cytokines like leptin and decrease in anti-inflammatory cytokines like adiponectin thus further exacerbating insulin resistance.2 Central adiposity with visceral fat deposition confers a higher risk of developing diabetes mellitus. Drugs used earlier for diabetes targeted mainly these mechanisms for control of hyperglycemia. Other less important but established pathophysiologic mechanisms include a cell dysfunction causing increased glucagon release, enteroendocrine axis causing reduced glucagon like peptide 1 (GLP1) secretion, kidney dysfunction causing increased reabsorption of filtered glucose and dysfunctional hypothalamic centers for appetite regulation in brain. Newer drugs like DPP4 inhibitors, GLP1 agonists, bromocriptine & SGLT2 inhibitors target these pathophysiologic mechanisms for anti-hyperglycemic effect. All these features together form ominous octet responsible for the development of diabetes mellitus. Recently some other factors have been implicated and concept of dirty dozen was proposed. Other four factors include increased dopamine in brain, vitamin D deficiency, testosterone deficiency and dysfunction of local renin angiotensin system in b cells. Two other factors that have been proposed are increased iron stores causing insulin resistance and b cell damage and gut derived serotonin that activates hormone sensitive lipase and thus increases lipolysis in adipose tissue.2 Many new drugs are under development targeting these mechanisms. 3. Drugs 3.1. Incretins 3.1.1. DPP4 inhibitors DPP4 inhibitors are a class of orally active drugs that enhance incretin system activity by blocking GLP1 degradation. GLP1 is 109 a major incretin hormone responsible for glucose dependent increase in insulin secretion after meals, but its duration of action is shortened by DPP4 (Dipeptidyl peptidase 4) enzyme. Increased activity of DPP4 has been seen in diabetic patients. Thus DPP4 inhibitors are an attractive target as antihyperglycemic drug. AnNumber of DPP4 inhibitors have become available in last decade like sitagliptin, linagliptin, alogliptin, vildagliptin and saxagliptin. Others that are in various phases of trial include dutogliptin and gemigliptin. As a class, DPP4 inhibitors have been shown to reduce HbA1C by 0.75%. Benefits over older drugs include very low risk of hypoglycemia, weight neutrality, oral administration, cardiovascular safety and most importantly improving b cell health. Short-term studies have shown good tolerability. Adverse effects reported in different studies are minor and include pruritus, diarrhea, nausea, dizziness and diaphoresis. 3.1.2. GLP1 agonists GLP1 agonists increase insulin secretion in response to oral glucose ingestion, induce satiety by slowing gastric emptying, suppresses appetite, inhibit glucagon secretion and also have been proposed to cause b cell neogenesis and protection from cytokine and free fatty acid induced injury. Endogenous GLP1 released from intestinal L cells has a short half-life of 4e11 min. To overcome this, GLP1 analogs resistant to degradation by DPP4 have been devised. Various drugs available are exanatide and liraglutide. Drugs under development are albiglutide (awaiting FDA approval), lixisenatide and semaglutide. Potential benefits of these agents include control of postprandial hyperglycemia, less hypoglycaemia, satiety induction and thus promoting weight loss and most importantly disease modifying effect by causing b cell neogenesis. Major disadvantage is the need of injecting these drugs once or twice a day. To overcome this, exanatide extended release has recently been available. It is administered as once a week dose at any time of the day without regard to meal. Other minor adverse effects associated with the use of GLP1 agonists are nausea, fullness, bloating and vomiting (to overcome these, slow escalation of dose is done), nasopharyngitis, headache and extremity pain. Rarely pancreatitis and hypersensitivity reactions have been reported. 3.1.3. GPR40 agonists G-protein coupled receptor is present on b cells and are responsible for increased glucose dependent insulin secretion. It normally gets activated by fatty acids. GPR40 activation has been shown to be potential therapeutic target to improve insulin secretion and glucose tolerance.3 A novel GPR40 agonist TAK-875 has recently been shown to produce clinical and statistically significant improvement in glycemic control in type 2 diabetic subjects who were not controlled on diet and exercise alone.4 Efficacy in HbA1C has been shown to be equivalent to glimepride at higher doses, with lower propensity to cause hypoglycaemia and overall good tolerability. Doses tested range from 6.25 mg to 200 mg, >50 mg produce reduction in HbA1C equivalent to 1 mg glimepride. Adverse effect attributable to drug was nasopharyngitis, mild hypoglycaemic episodes and weight gain (lesser than glimepride).
    • 110 a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 0 8 e1 1 2 Another agent JTT-851 is under trial for safety, tolerability and efficacy.5 3.1.4. GPR119 agonist GPR119 is a lipid-sensing G protein coupled receptor (GPCR) present on enteroendocrine cells in the gut that regulate incretin secretion & have direct effects on insulin secretion in pancreatic b cells. GPR-119 agonists currently under development include SAR-260093/MBX-2982 (Metabolex) in phase 2 trial, GSK-1292263 in phase 2 trial and PSN-821 in phase 2 trials.6 They have been shown to be weight negative and have less risk of hypoglycemic episodes. Another important advantage is oral availability. It has been proposed that coadministration of GPR119 and DPP4 inhibitors (mechanism to protect secreted GLP-1) may offer dual benefit of providing improved glycemic control with weight loss (as observed with GLP-1 mimetics). 3.2. SGLT2 inhibitors Sodium glucose co-transporters (SGLT) are located in the proximal tubules of the kidney and are responsible for renal glucose reabsorption from proximal tubules. SGLT2 accounts for 90% of this reabsorption. SGLT2 inhibitors are another novel class of drugs with potential of improving hyperglycemia. These drugs lower glycemia by causing glucosuria and thus do not require functioning b cells. As a class they have modest efficacy in lowering HbA1C, do not cause hypoglycemia and have a potential use in type 1 diabetes also. Along with glycemic control these drugs are weight negative (due to calorie loss in urine), mild reduction in blood pressure due to chronic osmotic dieresis and associated with lower risk of hypoglycemia. Various drugs in this category include Dapagliflozin, Canagliflozin, Remogliflozin, Empagliflozin, Ipragliflozin, Luseogliflozin and Topogliflozin. Canagliflozin has recently been approved for clinical use (though cardiovascular safety profile still pending). Adverse effects include urinary tract infections (due to glucosuria providing a good medium for bacterial growth), nausea, constipation, diarrhea, concern for potential renal toxicity (short term studies have not shown any renal toxicity) and small risk of bladder and breast cancer.5,7 These agents do not have any effect on lipid profile, but long term cardiovascular safety data is still not available. 3.3. Glucokinase activators Glucokinase is an enzyme present in b and a cells of pancreas and plays an important role in glucose homeostasis. Glucokinase activation acts as glucose sensor and affects coupling factors ATP and ADP thus depolarizing the cell, resulting in calcium influx and stimulated insulin release. It also activates the GABA shunt, producing gamma-hydroxybutyrate that functions as an important paracrine inhibitor of glucagon secretion. Further insulin itself along with GABA may inhibit glucose-mediated alpha cell suppression. Glucokinase activator drugs thus have the potential as an anti-diabetic drugs.8 Glucokinase activation acts as a prominent regulator of hepatic intermediary and energy metabolic pathways like glycogen synthesis, amino acid (alanine, aspartate, glutamate, glycine and serine), lactate and urea production. Potential detrimental effects include enhanced lipogenesis and associated hepatosteatosis and hyperlipidemia. Also this class has propensity to cause hypoglycemia and glucolipotoxicity on b cell survival and function.5 Trials for two drugs MK0941 (Merck) and piragliatin (Roche) were terminated prematurely. To avoid hypoglycemia, hepatospecific compound TTP399 has been devised by modification by introducing charged side chains changing permeability characteristics. Preclinical trials have proven efficacy and apparently no hepatotoxicity and mild hypoglycemic effect, but this drug has not been extensively tested.5 3.4. Combined a and g PPAR agonists (the glitazars) PPARg receptors are nuclear receptors directly affecting peripheral insulin resistance and PPAR-a receptors- modulate lipids especially triglycerides. So compounds having combined PPAR-a &g agonist activity (glitazars) were developed to incorporate both insulin sensitizing and lipid lowering activity. These drugs are classified as thiazolidinedione variants that include DRF-2189 & KRP-297 and nonthiazolidinedione variants including JTT-501, BMS-298585 (muraglitazar), AZ242 (tesaglitazar) and NN-622 (ragaglitazar).1 These drugs had favorable side effect profile in relation to cardiac hypertrophy, less weight gain and beneficial for triglyceride levels and visceral adiposity. Other advantages found in animal models were antiproliferative properties, angiotensin 2 antagonism, antioxidant effects, reduction of blood pressure, correction of endothelial dysfunction and amelioration of cardiac fibrosis associated with HT & MI. But clinical trials revealed development of excessive peripheral edema, volume overload and heart failure. Other detrimental effects were bone marrow hematopoietic changes, soft tissue neoplasms in rodents (Ragaglitazar) and hepatotoxicity. 3.5. SPPARM’s PPARg agonists with partial agonistic activity (SPPARM), also known as selective PPARg receptor modulators. SPPARM’s bind to PPARg in a different manner from full agonists and recruit different coactivators, thus retaining insulin sensitizing effect with little side effects. Compounds under development in this class include INT-131, PN2034 (Wellstat) and mitoglitazone.1 3.6. 11b hydroxy steroid dehydrogenase 1 inhibitors 11b hydroxy steroid dehydrogenase (11b HSD1) catalyses activation of cortisone to cortisol in liver, adipose tissue, pancreas and brain. Cortisol acts as an insulin antagonist, promotes gluconeogenesis and reduces glycogenesis. Compounds in this novel class include INCB-13739, JTT-654, AZD4017, DIO902 and RG4929.5,9 These agents are undergoing phase 2 or 1 clinical trials. Preliminary data has shown good tolerability, HbA1c reduction similar to DPP4 inhibitors, modest weight loss, reduction in blood pressure & improvement in cholesterol profile without causing hypoglycemia.
    • a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 0 8 e1 1 2 3.7. Protein tyrosine phosphatase 1B inhibitors 3.11. 111 Anti-inflammatory therapies Protein tyrosine phosphatase (PTP) is a negative regulator of insulin signaling via dephosphorylation of insulin receptor and insulin receptor substrate-1 and leptin signaling by dephosphorylation of JAK and STAT3 in hypothalamic neuron. Thus protein tyrosine phosphatase 1B inhibition is another potential target for anti-hyperglycemic action.10 These agents have dual benefit of control of hyperglycemia and weight loss. But lack of selectivity over other similar PTPs and cell permeability are obstacles in development of these agents. Presently studies are underway for this class of drugs. Diabetes is a state of chronic low-grade inflammation. Inflammatory markers like interleukin-1b (IL-1b), Nuclear factor kB and chemokines have been implicated in the pathogenesis of type 2 diabetes. Monoclonal antibodies against IL-1b, anakinra and canakinubab are in clinical phase 2 studies. Recombinant IL-1 receptor antagonist Xoma052 is also under study. Two compounds Triolex and VGX-1027 modulating NFkB are in clinical phase 1 studies. Chemokine receptor (CCR2) antagonists BMS-741672 and CCX-140 are also in clinical phase 2 studies.5 3.8. 4. Regulators of fatty acid metabolism Fatty acid metabolism is an important pathophysiologic link in development of insulin resistance and glucose intolerance. Drugs targeting fatty acid metabolic pathways are an attractive target for development of anti-hyperglycemic drugs. Steroyl Co-A desaturase (SCD) and diacylglycerol acyltransferase (DGAT) are potential targets for drugs under development. SCD catalyses the rate limiting step in synthesis of monounsaturated fatty acids. Isoform SCD1 inhibition (found in liver and adipose tissue) decreases lipogenesis and increases fatty acid oxidation thus improving multiple metabolic parameters. But SCD1 inhibition is associated with reduced production of triglycerides, cholesterol and wax esters required for normal function of eyelid and skin also. To overcome this, liver-targeted approach has been employed by including acetic or carboxylic acid group in the inhibitors. DGAT catalyses the final step in triglyceride synthesis. DGAT1 inhibition has been shown in preliminary studies to benefit diabetes, obesity, dyslipidemia and metabolic syndrome. Potential adverse effect associated is alopecia due to retinoid toxicity. DGAT1 inhibitors being evaluated are AZD7687, PF4620110 and LCQ908. AZD7687 has been found to reduce postprandial triglyceride increase. Adverse effects reported in preliminary study are nausea, vomiting and diarrhea.11 3.9. Fibroblast growth factor 21 agonist Fibroblast growth factor 21 is a hormonal regulator with the potential to treat a variety of metabolic abnormalities like diabetes mellitus, obesity and cardiovascular disease. It activates glucose uptake on adipocytes and reduces triglyceride also. Currently a drug LP10152 is undergoing trial as antihyperglycemic drug. 3.10. Glycogen phosphorylase inhibitor Glycogen phosphorylase catalyses the breakdown of glycogen to glucose 1 phosphate in liver. Inhibits breakdown of glycogen and thus decrease hepatic glucose output. Glycogen phosphorylase inhibitors thus serve as a promising treatment strategy for hyperglycemia.12 An agent GSK1362885 is undergoing phase 1 trial presently.5 Conclusion Better understanding of pathophysiologic mechanisms underlying diabetes, has opened gateway for development of many new drugs for treating hyperglycemia. Many such drugs are in pipeline, proven to be efficacious in preliminary studies and may be available in coming few years. It is expected that availability of new drugs will provide choices for treating these patients better with lesser adverse effects. Conflicts of interest All authors have none to declare. references 1. Uwaifo Gabriel I, Ratner Robert E. Novel pharmacologic agents for type 2 diabetes. Endocrinol Metab Clin N Am. 2005;34:155e197. 2. Kalra S. Recent advances in pathophysiology of diabetes: beyond the dirty dozen. J Pakistan Med Assoc. February 2013;63(2):277e280. 3. Nagasumi Kae, Esaki Ritsuko, Iwachidow Kimihiko, et al. Overexpression of GPR40 in pancreatic b-cells augments glucose-stimulated insulin secretion and improves glucose tolerance in normal and diabetic mice. Diabetes. May 2009;58:1067e1076. 4. Kaku K, Araki T, Yoshinaka R. Randomized double- blind, dose ranging study of TAK-875, a novel GPR40 agonist in Japanese patients with inadequately controlled type 2 diabetes. Diabetes Care. 2013 Feb;36(2):245e250. 5. Cheon Hyae Gyeong. Latest research and development trends in non-insulin anti-diabetics. Arch Pharm Res. 2013;36:145e153. 6. Xiaoyun Zhu, Wenglong Huang and Hai Qian. GPR119 agonists: a novel strategy for type 2 diabetes treatment. Diabetes mellitus e insights and perspectives. Chapter 4. 7. Edward C, Chao, Henry Robert R. SGLT2 inhibition e a novel strategy for diabetes treatment. Nat Rev Drug Discov AOP, published online 28 May 2010. 8. Matschinsky Franz M. GKA’s for diabetes therapy: why no clinically useful drug after two decades of trying? Trends Pharmacol Sci. February 2013;34(2):90e99. 9. Ge R, Huyang Y, Liang G, Li X. 11b hydroxysteroid dehydrogenase type 1 inhibitors as promising therapeutic
    • 112 a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 0 8 e1 1 2 drugs for diabetes: status and development. Curr Med Chem. 2010;17(5):412e422. 10. Popoy D. Novel protein tyrosine phosphatase 1B inhibitors: interaction requirements for improved intracellular efficacy in type 2 diabetes mellitus and obesity control. Biochem Biophys Res Commun. 2011 Jul 8;410(3):377e378. 11. Denison H, Nilsson C, Kujacic M, et al. Proof of mechanism for the DGAT1 inhibitor AZD7687: results from a first-time-in-human single-dose study. Diabetes Obes Metab. Feb 2013;15(2):136e143. 12. Baker David J, Timmons James A, Greenhaff Paul L. Glycogen phosphorylase inhibition in type 2 diabetes therapy. Diabetes. August 2005;54:2453e2459.
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