DIPEPTIDYL PEPTIDASE-4 INHIBITORS: POTENTIAL FOR TREATMENT OF METABOLIC SYNDROME AND DEVELOPED FORMULATION APPROACHES


Rakesh Kumar Mishra, Shashikant Dhole

Abstract


 

 This review article deals with the pre-clinical and clinical findings reviewed or investigated by the researchers on dipeptidyl peptidase-4 (DPP4) inhibitors as a potential in the treatment of metabolic syndrome. Most of the researchers reported the activity of DPP4 inhibitors in the management of obesity, hyperlipidemia, hypertension, atherosclerosis, and in cardiometabolic risk which are summarized in the article. This article also focuses on the formulation approaches in which the formulators have reported and used in the designing or development of DPP4 inhibitors as dosage form. The formulation approaches which are commonly employed on DPP4 inhibitors are immediate release, sustain release, and combination therapy.  


Keywords


Dipeptidyl peptidase 4, Metabolic syndrome, Obesity, Hyperlipidemia, Hypertension, Atherosclerosis, Immediate release, Sustain release

| PDF |

References


VanWormer JJ, Boucher JL, Sidebottom AC, Sillah A, Knickelbine T. Lifestyle changes and prevention of metabolic syndrome in the heart of New Ulm Project. Prev Med Rep 2017;6:242-5.

Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: An American Heart Association/National Heart, Lung, and Blood Institute scientific statement: Executive Summary. Crit Pathw Cardiol 2005;4(17):198-203.

Hu G, Qiao Q, Tuomilehto J, Balkau B, Borch-Johnsen K, Pyorala K; DECODE Study Group. Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women. Arch Intern Med 2004;164(10):1066-76.

Sattigeri JA, Sethi S, Davis JA, Ahmed S, Rayasam GV, Jadhav BG, et al. Approaches towards the development of chimeric DPP4/ACE inhibitors for treating metabolic syndrome. Bioorg Med Chem Lett 2017;27:2313-8.

Gong Q, Rajagopalan S, Zhong J. Dpp4 inhibition as a therapeutic strategy in cardiometabolic disease: Incretin-dependent and-independent function. Int J Cardiol 2015;197:170-9.

Edwards KL, Stapleton M, Weis J, Irons BK. An update in incretin-based therapy: A focus on glucagon-like peptide-1 receptor agonists. Diabetes Technol Ther 2012;14(10):951-67.

Stonehouse AH, Darsow T, Maggs DG. Incretin-based therapies. J Diabetes 2012;4(1):55-67.

Bhavya K, Madhusudan N. Dipeptidyl peptidase-IV: A brief review. Res Rev J Chem 2013;2(3):1-6.

Zhi-Xu H, Tianxin Y, Shu-Feng Z. Dipeptidyl peptidase 4 inhibitors for the treatment of Type 2 diabetes mellitus: Focus on efficacy, disposition and safety. Austin J Pharmacol Ther 2013;1(1):1-3.

Hainer V, Toplak H, Mitrakou A. Treatment modalities of obesity: What fits whom? Diabetes Care 2008;31 Suppl 2:S269-77.

Aronne LJ, Thornton-Jones ZD. New targets for obesity pharmacotherapy. Clin Pharmacol Ther 2007;81(5):748-52.

Field BC, Wren AM, Cooke D, Bloom SR. Gut hormones as potential new targets for appetite regulation and the treatment of obesity. Drugs 2008;68(2):147-63.

Mentlein R, Dahms P, Grandt D, Krüger R. Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV. Regul Pept 1993;49(2):133-44.

Mentlein R, Gallwitz B, Schmidt WE. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36) amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem 1993;214(3):829-35.

Stephan M, Radicke A, Leutloff S, Schmiedl A, Pabst R, von Hörsten S, et al. Dipeptidyl peptidase IV (DPP4)-deficiency attenuates diet-induced obesity in rats: Possible implications for the hypothalamic neuropeptidergic system. Behav Brain Res 2011;216(2):712-8.

Blüher M. Adipokines - Removing road blocks to obesity and diabetes therapy. Mol Metab 2014;3(3):230-40.

Röhrborn D, Eckel J, Sell H. Shedding of dipeptidyl peptidase 4 is mediated by metalloproteases and up-regulated by hypoxia in human adipocytes and smooth muscle cells. FEBS Lett 2014;588(21):3870-7.

Röhrborn D, Brückner J, Sell H, Eckel J. Reduced DPP4 activity improves insulin signaling in primary human adipocytes. Biochem Biophys Res Commun 2016;471(3):348-54.

Stoffers DA, Kieffer TJ, Hussain MA, Drucker DJ, Bonner-Weir S, Habener JF, et al. Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. Diabetes 2000;49(5):741-8.

Perfetti R, Zhou J, Doyle ME, Egan JM. Glucagon-like peptide-1 induces cell proliferation and pancreatic-duodenum homeobox-1 expression and increases endocrine cell mass in the pancreas of old, glucose-intolerant rats. Endocrinology 2000;141(12):4600-5.

Pannacciulli N, Ducson NT, Salbe AD, Kewei C, Eric MR, Pietro AT, et al. Postprandial glucagon-like peptide-1 (GLP-1) response is positively associated with changes in neuronal activity of brain areas implicated in satiety and food intake regulation in humans. Neuroimage 2007;35(2):511-7.

Yu JH, Kim MS. Molecular mechanisms of appetite regulation. Diabetes Metab J 2012;36(6):391-8. 23. Ben-Shlomo S, Zvibel I, Shnell M, Shlomai A, Chepurko E, Halpern Z, et al. Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase. J Hepatol 2011;54(7):1214-23.

Lee EY, Kim YW, Oh H, Choi CS, Ahn JH, Lee BW, et al. Anti-obesity effects of KR-66195, a synthetic DPP-IV inhibitor, in diet-induced obese mice and obese-diabetic ob/ob mice. Metabolism 2014;63(6):793-9.

Fukuda-Tsuru S, Kakimoto T, Utsumi H, Kiuchi S, Ishii S. The novel dipeptidyl peptidase-4 inhibitor teneligliptin prevents high-fat diet-induced obesity accompanied with increased energy expenditure in mice. Eur J Pharmacol 2014;723:207-15.

Leenen R, van der Kooy K, Seidell JC, Deurenberg P, Koppeschaar HP. Visceral fat accumulation in relation to sex hormones in obese men and women undergoing weight loss therapy. J Clin Endocrinol Metab 1994;78(6):1515-20.

Sameshima A, Wada T, Ito T, Kashimura A, Sawakawa K, Yonezawa R, et al. Teneligliptin improves metabolic abnormalities in a mouse model of postmenopausal obesity. J Endocrinol 2015;227(1):25-36.

Monami M, Lamanna C, Desideri CM, Mannucci E. DPP-4 inhibitors and lipids: Systematic review and meta-analysis. Adv Ther 2012;29(1):14-25.

Monami M, Vitale V, Ambrosio M, Bartoli N, Toffanello G, Ragghianti B, et al. Effects on lipid profile of dipeptidyl peptidase 4 inhibitors, pioglitazone, acarbose, and sulfonylureas: Meta-analysis of placebo controlled trials. Adv Ther 2012;29(9):736-46.

Aoki K, Ijima T, Kamiyama H, Kamiko K, Terauchi Y. Anagliptin decreases serum lathosterol level in patients with Type 2 diabetes: A pilot study. Expert Opin Pharmacother 2015;16(12):1749-54.

Yano W, Inoue N, Ito S, Itou T, Yasumura M, Yoshinaka Y, et al. Mechanism of lipid-lowering action of the dipeptidyl peptidase-4 inhibitor, anagliptin, in low-density lipoprotein receptor-deficient mice. J Diabetes Investig 2017;8(2):155-60.

Matsubara J, Sugiyama S, Sugamura K, Nakamura T, Fujiwara Y, Akiyama E, et al. A dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin, improves endothelial function and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice. J Am Coll Cardiol 2012;59(3):265-76.

Nakagami H, Pang Z, Shimosato T, Moritani T, Kurinami H, Koriyama H, et al. The dipeptidyl peptidase-4 inhibitor teneligliptin improved endothelial dysfunction and insulin resistance in the SHR/NDmcr-cp rat model of metabolic syndrome. Hypertens Res 2014;37(7):629-35.

Jixin Z, Xiaoquan R, Rajagopalan S. An emerging role of dipeptidyl peptidase 4 (DPP4) beyond glucose control: Potential implications in cardiovascular disease. Atherosclerosis 2012;1:1-10.

Singh TP, Vangaveti VN, Malabu UH. Dipeptidyl peptidase-4 inhibitors and their potential role in the management of atherosclerosis - A review. Diabetes Metab Syndr 2015;9(4):223-9.

Okuda Y, Omoto S, Taniura T, Shouzu A, Nomura S. Effects of teneligliptin on PDMPs and PAI-1 in patients with diabetes on hemodialysis. Int J Gen Med 2016;9:65-71.

Hirano T, Yamashita S, Takahashi M, Hashimoto H, Mori Y, Goto M. Anagliptin, a dipeptidyl peptidase-4 inhibitor, decreases macrophage infiltration and suppresses atherosclerosis in aortic and coronary arteries in cholesterol-fed rabbits. Metabolism 2016;65(6):893-903.

Tschöpe D, Hanefeld M, Meier JJ, Gitt AK, Halle M, Bramlage P, et al. The role of co-morbidity in the selection of antidiabetic pharmacotherapy in Type-2 diabetes. Cardiovasc Diabetol 2013;12:62.

FDA. Guidance for Industry: Diabetes Mellitus - Evaluating Cardiovascular Risk in New Anti-Diabetic Therapies to Treat Type 2 Diabetes; 2008. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. [Last accessed on 2017 Mar 19].

Fisman EZ, Tenenbaum A. Antidiabetic treatment with gliptins: focus on cardiovascular effects and outcomes. Cardiovasc Diabetol 2015;14:129.

Tahara N, Yamagishi SI, Bekki M, Kodama N, Nakamura T, Sugiyama Y, et al. Anagliptin, a dipeptidyl peptidase-4 inhibitor ameliorates arterial stiffness in association with reduction of remnant-like particle cholesterol and alanine transaminase levels in Type 2 diabetic patients. Curr Vasc Pharmacol 2016;14(6):552-62.

Nyol S, Gupta M. Immediate drug release dosage form: A review. J Drug Deliv Ther 2013;3(2):155-61.

Deshmukh H, Chandrashekhara N, Murade A, Usgaunkar S. Superdisintegrants: A recent investigation and current approach. Asian J Pharm Technol Innov 2012;2:19-25.

Rina A, Effionora A, Retnosari A, Hanafi M. Formulation of orodispersible tablet of Luffa acutangula (l) Roxb using novel co-processed via spray dried excipients. Int J Pharm Pharm Sci 2015;7(1):124-9.

Iswariya V, Rao P, Babu V, Rao A. Formulation and evaluation of oro dispersive tablets of saxagliptin. Int J Pharm Sci Rev Res 2015;30(2):230-4.

Debnath M, Kumar A, Dharmaraju M. Formulation, development and in-vitro release kinetics of linagliptin tablet using different super disintegrating agents. J Pharm Sci 2015;4(3):12-25.

Shakya S. Formulation and optimization of immediate release tablet of sitagliptin phosphate using response surface methodology. Int J Pharm Bio Med Sci 2015;4:7-12.

Wale K, Salunkhe K, Sayyed SF, Chaudhari SR, Bhujbal SS. Formulation, development and in vitro evaluation of immediate release tablet of sitagliptin phosphate monohydrate. World J Pharm Res 2014;3(3):4945-57.

Jung E, Kim J, Kim SH, Kim S, Cho MH. Gemigliptin, a novel dipeptidyl peptidase-4 inhibitor, exhibits potent anti-glycation properties in vitro and in vivo. Eur J Pharmacol 2014;744:98-102.

Dash T, Verma P. Matrix tablets: An approach towards oral extended release drug delivery. Int J Pharm Res Rev 2013;2(2):12-24.

Nelson K, Varadarajan P, Chikkanna N, Prakasam K. Development and evaluation of oral controlled release matrix tablets of lamivudine: Optimization and in vitro-in vivo studies. Int J Pharm Pharm Sci 2015;7(1):95-101.

Kolli S, Dharavatu P, Sravani R, Reddy S, Kumar V. Formulation and evaluation of vildagliptin sustained release matrix tablets. Int J Curr Pharm Res 2014;6(4):69-75.

Kumar GY, Sreekanth J, Satyavati D. Formulation development and evaluation of sustained release matrix tablets of vildagliptin - Synthetic and natural polymers. Asian J Pharm 2015;9(4):26-33.

Martha S, Sagarika CH, Nandini K, Seshavardhan V, Kranthi M. Development and in-vitro characterisation of oral sustained release matrix tablets of gemigliptin. Int J Pharm Sci Res 2016;7(9):3770-80.

Gutierrez-Rocca J, Omidian H, Shan K. Progresses in gastroretentive drug delivery systems. Drug Deliv Oral 2003;23:152-6.

Garg S, Sharma S. Gastroretentive drug delivery sytems. Drug Deliv Oral 2003;20:160-6.

Vadaliya SK, Vadaliya KR, Desai HT, Patel JK. Formulation and in-vitro evaluation of floating microspheres of anti-diabetic drug prepared by solvent evaporation method. Int J Pharm Chem Sci 2013;2(1):397-403.

Gunjal T, Rangari N, Chaudhari S, Bhuktar D. Formulation development and evaluation of sitagliptin floating tablets containing natural polymer. Int J Pharm Pharm Res 2015;3(2):131-41.

Gulzar AM, Sanjana A, Vangapandu R. Design and optimization of gastroretentive drug delivery system of sitagliptin. Int J Pharm Sci Res 2016;7(5):2187-93.

Kumari S, Kumar R, Yamunappa A, Shetty P, Suvarna P, Swamy VB. Formulation and evaluation of gastro retentive matrix tablets of sitagliptin. Asian J Res Pharm Sci 2016;6(1):1-4.

Sam MT, Gayathri DS, Prasanth V, Vinod B. NSAIDs as microspheres. Int J Pharmacol 2008;6:1.

Devrim B, Canefe K. Preparation and evaluation of modified release ibuprofen microspheres with acrylic polymers (Eudragit) by quasi-emulsion solvent diffusion method: Effect of variables. Acta Pol Pharm 2006;63(6):521-34.

Khan S. Microspheres: A review. World J Pharm Pharm Sci 2012;1(1):125-45.

Alagusundaram M, Chetty CM, Umashankari K, Attulari B, Lavanya C, Ramakanth S. Microspheres as a novel drug delivery system - A review. Int J ChemTech Res 2009;1(3):526-34.

Naresh NS, Pratyusha A. Formulation design and evaluation of saxagliptin sustained release microspheres. Indo Am J Pharm Sci 2016;3(6):627-36.

Navaneetha K, Ramakrishna CH, Chinnala K, Reddy B. Formulation development and in-vitro characterization of sitagliptin microspheres. World J Pharm Res 2016;5(9):1756-67.

Pathak N, Kumar A, Methkar V, Pant P, Rao RT. Formulation and optimization of immediate release tablet of an anti-alcoholic drug by dry granulation method. Int J Compr Pharm 2011;2(3):1-4.

Shilpa SK, Kumar AM, Garigeyi P. Formulation and optimization of clopidogrel bisulfate immediate release tablet. Int J Pharm Chem Bio Sci 2012;2(1):38-51.

Deepak G, Rahul R, Senthil A, Uday S. Formulation and evaluation of irbesartan immediate release tablets. Int Res J Pharm 2012;3(4):410-5.

Ramadan WH, Kabbara WK. Sitagliptin/Simvastatin: A first combination tablet to treat Type 2 diabetes and hypercholesterolemia - aAreview of its characteristics. Vasc Health Risk Manag 2015;11:125-32. 71. Srinivas P, Chaitanya N. Formulation and evaluation of sitagliptin phosphate and metformin hydrochloride trilayered tablets. Int J Drug Deliv 2013;5(1):15-27.

Patel M, Sockan GN, Kavitha K, Mani T. Challenges in the formulation of bilayered tablets. Int J Pharm Res Dev 2010;2(2):23-35.

Margret CR, Palanisamy P, Jaykar B, Venkateswarlu BS, Pasupathi A. Formulation and evaluation of saxagliptin immediate release and metformin hydrochloride sustained release tablet. Int J Health Sci 2013;1(1):36-52.

Prasanthi S, Prasad A, Kumar G, Babu R, Sudhir M, Babu P. Formulation and evaluation of sitagliptin phosphate and simvastatin bilayered tablets. Indo Am J Pharm Res 2015;5(8):3654-66.

Vidyadhari K, Sharma JV, Ramteja YV, Ramesh CH, Pasha M, Kumar M, et al. Formulation and evaluation of linagliptin and metformin bilayer tablets. Int J Adv Pharm Sci 2016;7(2):3072-8.

Reddy S, Das P, Das H. MUPS (multiple unit pellet system) tablets - A brief review. J Pharm Biomed Sci 2011;12(2):1-5.

Agrawal S, Joshi K, Gaud R. Formulation development of multi unit particulate system (MUPS) for anti-diabetic drugs. Asian J Pharm Sci 2015;11(1):77-8.




About this article

Title

DIPEPTIDYL PEPTIDASE-4 INHIBITORS: POTENTIAL FOR TREATMENT OF METABOLIC SYNDROME AND DEVELOPED FORMULATION APPROACHES

Keywords

Dipeptidyl peptidase 4, Metabolic syndrome, Obesity, Hyperlipidemia, Hypertension, Atherosclerosis, Immediate release, Sustain release

DOI

10.22159/ajpcr.2017.v10i11.20342

Date

01-11-2017

Additional Links

Manuscript Submission

Journal

Asian Journal of Pharmaceutical and Clinical Research
Vol 10 Issue 11 November 2017 Page: 20-26

Print ISSN

0974-2441

Online ISSN

2455-3891

Statistics

21 Views | 57 Downloads

Authors & Affiliations

Rakesh Kumar Mishra
Department of Pharmaceutics, Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune - 411 018, Maharashtra, India.
India

Shashikant Dhole
Department of Pharmaceutics, Modern College of Pharmacy, Moshi, Pune - 412 105, Maharashtra, India.
India


Article Tools


Email this article (Login required)
Email the author (Login required)

Refbacks

  • There are currently no refbacks.