A review of the Mechanisms of Action and Side Effects of Anti-diabetic Agents

Document Type : Review Article

Authors

1 Department of Biochemistry, Modibbo Adama University, Yola, Nigeria.

2 Department of Science Laboratory Technology, Adamawa State Polytechnic Yola. Nigeria.

Abstract

Diabetes mellitus is a lifelong disease which occurs as a result of decreased insulin activity and/or insulin secretion associated with pathological changes such as nephropathy, retinopathy, and cardiovascular complications which occur as the disease progress. This disease has a global negative impact on both an individual and healthcare systems. Though glycemic control is considered the first step in management of diabetes, improving the general health and decreasing the impact of the chronic complications also remains a target. Single drug therapy such as insulin and insulin secretagogues, biguanides, insulin sensitizers, alpha glucosidase inhibitors, incretin mimetics, amylin antagonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors are mostly employed in the management of diabetes mellitus; however, dual drug therapies are recommended especially in type 2 diabetes where patients can’t achieve therapeutic goals with the single drug therapy. The mode of actions of these drugs are also key factors considered in the administration of these drugs due to their diverse side effects. So, the need for proper investigation prior to prescription of anti-diabetic agents to diabetic patients with attention for side effects that may arise. This review was aimed to outline anti-diabetic drugs taking account of their mechanism of action and associated side effects as they are applied in the management of diabetes.
Keywords: Anti-diabetic, Drugs, Side effects, Review.
Please cite this article as: Dahiru, Muhammad Mubarak, Nadro, Margret Samuel. A review of the mechanisms of action and side effects of anti-diabetic agents. Trends in Pharmaceutical Sciences. 2022;8(3):195-210. doi: 10.30476/TIPS.2022.95931.1153

Keywords


1.    World Health Organisation. Classification of diabetes mellitus. World Health Organization, Department for Management of Non-communica‌ble Diseases, Disability, Violence and Injury Pre‌vention, Switzerland.2019 [cited 2022 May 2]. 40 p. available from: https://apps.who.int/iris/handle/10665/325182.  
2.    American Diabetes Association Professional Practice Committee. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022 Jan 1;45(Suppl 1):S17-S38. doi: 10.2337/dc22-S002. 
3.    Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022 Jan;183:109119. doi: 10.1016/j.diabres.2021.109119. 
4.    American Diabetes Association. 3. Prevention or Delay of Type 2 Diabetes: Standards of Medical Care in Diabetes-2021. Diabetes Care. 2021 Jan;44(Suppl 1):S34-S39. doi: 10.2337/dc21-S003. PMID: 33298414.
5.    American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020 Jan;43(Suppl 1):S98-S110. doi: 10.2337/dc20-S009. Erratum in: Diabetes Care. 2020 Aug;43(8):1979. PMID: 31862752.
6.    Edelman SV, Polonsky WH. Type 2 Diabetes in the Real World: The Elusive Nature of Glycemic Control. Diabetes Care. 2017 Nov;40(11):1425-1432. doi: 10.2337/dc16-1974. 
7.    Satyanarayana U, Chakrapani U. 
Biochemistry; Fifth edition. India: Books and Allied (P) Ltd; 2019. 773p.
8.    Denise R. Lippincott’s Illustrated Reviews: Biochemistry Fifth Edition. Hong Kong: Wolters Kluwer Health; 2017. 531 p.
9.    Rodwell VW, Bender DA, Botham KM, Kennelly PJ, Weil PA. Harper's illustrated biochemistry Thirty-First edition. New York: New York: McGraw-Hill Education/Medical Publishing Division; 2018. 643 p.
10.    Dimitriadis G, Mitrou P, Lambadiari V, Maratou E, Raptis SA. Insulin effects in muscle and adipose tissue. Diabetes Res Clin Pract. 2011 Aug;93 Suppl 1:S52-9. doi: 10.1016/S0168-8227(11)70014-6. PMID: 21864752.
11.    Ahmad K. Insulin sources and types: a review of insulin in terms of its mode on diabetes mellitus. J Tradit Chin Med. 2014 Apr;34(2):234-7. doi: 10.1016/s0254-6272(14)60084-4. 
12.    Mohan V, Kalra S, Kesavadev J, Singh AK, Kumar A, Unnikrishnan AG, Chawla R, Mukherjee JJ, Sahay RK, Kumar JS, Bhoraskar A, Asirvatham AJ, Panda JK, Zargar AH, Das AK. Consensus on Initiation and Intensification of Premix Insulin in Type 2 Diabetes Management. J Assoc Physicians India. 2017 Apr;65(4):59-73. 
13.    Kalra S, Czupryniak L, Kilov G, Lamptey R, Kumar A, Unnikrishnan AG, et al. Expert Opinion: Patient Selection for Premixed Insulin Formulations in Diabetes Care. Diabetes Ther. 2018 Dec;9(6):2185-2199. doi: 10.1007/s13300-018-0521-2. 
14.    Belhekar MN, Pai S, Tayade P, Dalwadi P, Munshi R, Varthakavi P. A case of hypersensitivity to soluble and isophane insulins but not to insulin glargine. Indian J Pharmacol. 2015 Mar-Apr;47(2):227-9. doi: 10.4103/0253-7613.153438. 
15.    Saleem F, Sharma A. NPH Insulin. [Updated 2022 Jun 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549860/
16.    Fournier M, Germe M, Theobald K, Scholz GH, Lehmacher W. Indirect comparison of lixisenatide versus neutral protamine Hagedorn insulin as add-on to metformin and sulphonylurea in patients with type 2 diabetes mellitus. Ger Med Sci. 2014 Oct 16;12:Doc14. doi: 10.3205/000199. 
17.    Vargas-Uricoechea H, Aschner P. Comparative efficacy and safety of basal insulins: A review. Diabetes Metab Syndr. 2021 Nov-Dec;15(6):102318. doi: 10.1016/j.dsx.2021.102318. 
18.    Cunningham AM, Freeman AM. Glargine Insulin. 2022 Apr 21. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 32491688.
19.    Lispro. Prescribing Information. Eli Lilly and Company; 2018. [cited 2022 May 1]. 14 p. available from https://pi.lilly.com/us/insulin-lispro-uspi.pdf
20.    Center for drug evaluation and research. NovoLog (insulin aspart [rDNA origin] injection) package insert. Food and Drug Administration Silver Spring MD 20993. USA: Department of Health and Human Services: 2013. 245 p. available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/020986Orig1s061.pdf
21.    Helms KL, Kelley KW. Insulin glulisine: an evaluation of its pharmacodynamic properties and clinical application. Ann Pharmacother. 2009 Apr;43(4):658-68. doi: 10.1345/aph.1E662. 
22.    Levy P. Insulin analogs or premixed insulin analogs in combination with oral agents for treatment of type 2 diabetes. MedGenMed. 2007 Apr 16;9(2):12. 
23.    Schmid H. New options in insulin therapy. J Pediatr (Rio J). 2007 Nov;83(5 Suppl):S146-55. doi: 10.2223/JPED.1712. PMID: 18038020.
24.    Sanofi-aventis U.S. LLC. Lantus S-AU: (insulin glargine [rDNA origin] injection)[prescribing information]. Bridgewater, NJ: Sanofi-Aventis. 2010. 56 p.
25.    Plank J, Bodenlenz M, Sinner F, Magnes C, Görzer E, Regittnig W, et al. A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir. Diabetes Care. 2005 May;28(5):1107-12. doi: 10.2337/diacare.28.5.1107. PMID: 15855574.
26.    Potocka E, Amin N, Cassidy J, Schwartz SL, Gray M, Richardson PC, et al. Insulin pharmacokinetics following dosing with Technosphere insulin in subjects with chronic obstructive pulmonary disease. Curr Med Res Opin. 2010 Oct;26(10):2347-53. doi: 10.1185/03007995.2010.511971. 
27.    Rave K, Potocka E, Heinemann L, Heise T, Boss AH, Marino M, et al. Pharmacokinetics and linear exposure of AFRESA compared with the subcutaneous injection of regular human insulin. Diabetes Obes Metab. 2009 Jul;11(7):715-20. doi: 10.1111/j.1463-1326.2009.01039.x. Epub 2009 May 19. Erratum in: Diabetes Obes Metab. 2009 Dec;11(12):1175. Heinemann, L [added]; Heise, T [added]. PMID: 19476477.
28.    Tahrani AA, Barnett AH, Bailey CJ. Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Nat Rev Endocrinol. 2016 Oct;12(10):566-92. doi: 10.1038/nrendo.2016.86. 
29.    Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012 Mar;122(6):253-70. doi: 10.1042/CS20110386. 
30.    Andrzejewski S, Gravel SP, Pollak M, St-Pierre J. Metformin directly acts on mitochondria to alter cellular bioenergetics. Cancer Metab. 2014 Aug 28;2:12. doi: 10.1186/2049-3002-2-12. 
31.    Coughlan KA, Valentine RJ, Ruderman NB, Saha AK. AMPK activation: a therapeutic target for type 2 diabetes? Diabetes Metab Syndr Obes. 2014 Jun 24;7:241-53. doi: 10.2147/DMSO.S43731. 
32.    Maida A, Lamont BJ, Cao X, Drucker DJ. Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-α in mice. Diabetologia. 2011 Feb;54(2):339-49. doi: 10.1007/s00125-010-1937-z. Epub 2010 Oct 23. PMID: 20972533.
33.    Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015 Jan;38(1):140-9. doi: 10.2337/dc14-2441. PMID: 25538310.
34.    Jabade V, Hucche B, Bawage S. Metformin Drug. Int J Res Pub Rev. 2022;3:1.
35.    Corcoran C, Jacobs TF. Metformin. 2022 May 2. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. 
36.    Hsu WH, Hsiao PJ, Lin PC, Chen SC, Lee MY, Shin SJ. Effect of metformin on kidney function in patients with type 2 diabetes mellitus and moderate chronic kidney disease. Oncotarget. 2017 Dec 17;9(4):5416-5423. doi: 10.18632/oncotarget.23387. 
37.    Bailey CJ. The Current Drug Treatment Landscape for Diabetes and Perspectives for the Future. Clin Pharmacol Ther. 2015 Aug;98(2):170-84. doi: 10.1002/cpt.144.
38.    Mohammed S, Yaqub A, Sanda K, Nicholas A, Arastus W, Muhammad M, et al. Review on diabetes, synthetic drugs and glycemic effects of medicinal plants. J Med Plants Res. 2013;7(36):2628-37.
39.    Ferrannini E, DeFronzo RA. Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur Heart J. 2015 Sep 7;36(34):2288-96. doi: 10.1093/eurheartj/ehv239. 
40.    Vasudevan DM, Sreekumari S, Vaidyanathan K. Textbook of biochemistry for medical students: Jaypee brothers medical publishers; 2019. 672 p.
41.    Derosa G, Maffioli P. α-Glucosidase inhibitors and their use in clinical practice. Arch Med Sci. 2012 Nov 9;8(5):899-906. doi: 10.5114/aoms.2012.31621. 
42.    Kumar S, Narwal S, Kumar V, Prakash O. α-glucosidase inhibitors from plants: A natural approach to treat diabetes. Pharmacogn Rev. 2011 Jan;5(9):19-29. doi: 10.4103/0973-7847.79096. 
43.    White JR, Campbell RK. ADA/PDR Medications for the Treatment of Diabetes: American Diabetes Association; 2008. 15 p. 
44.    Grant JS, Graven LJ. Progressing From Metformin to Sulfonylureas or Meglitinides. Workplace Health Saf. 2016 Sep;64(9):433-9. 
45.    Nordisk N. Prandin®(repaglinide) tablets. July; 2018.
46.    Ferrannini G, Hach T, Crowe S, Sanghvi A, Hall KD, Ferrannini E. Energy Balance After Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care. 2015 Sep;38(9):1730-5. 
47.    Winkler K, Weltzien P, Friedrich I, Schmitz H, Nickell HH, Hauck P, et al. Qualitative effect of fenofibrate and quantitative effect of atorvastatin on LDL profile in combined hyperlipidemia with dense LDL. Exp Clin Endocrinol Diabetes. 2004 May;112(5):241-7. 
48.    Yau H, Rivera K, Lomonaco R, Cusi K. The future of thiazolidinedione therapy in the management of type 2 diabetes mellitus. Curr Diab Rep. 2013 Jun;13(3):329-41. 
49.    Yamanouchi T. Concomitant therapy with pioglitazone and insulin for the treatment of type 2 diabetes. Vasc Health Risk Manag. 2010 Apr 15;6:189-97. doi: 10.2147/vhrm.s5838. 
50.    LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–. PMID: 31643176.
51.    Juurlink DN, Gomes T, Lipscombe LL, Austin PC, Hux JE, Mamdani MM. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. BMJ. 2009 Aug 18;339:b2942. doi: 10.1136/bmj.b2942. 
52.    Scheen AJ. Hepatotoxicity with thiazolidinediones: is it a class effect? Drug Saf. 2001;24(12):873-88. 
53.    Dormandy J, Bhattacharya M, van Troostenburg de Bruyn AR; PROactive investigators. Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PROactive. Drug Saf. 2009;32(3):187-202. doi: 10.2165/00002018-200932030-00002. 
54.    Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011 Apr;91(2):733-94. 
55.    van Bommel EJ, Muskiet MH, Tonneijck L, Kramer MH, Nieuwdorp M, van Raalte DH. SGLT2 Inhibition in the Diabetic Kidney-From Mechanisms to Clinical Outcome. Clin J Am Soc Nephrol. 2017 Apr 3;12(4):700-710. 
56.    Thomas MC, Cherney DZI. The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure. Diabetologia. 2018 Oct;61(10):2098-2107. 
57.    Lupsa BC, Inzucchi SE. Use of SGLT2 inhibitors in type 2 diabetes: weighing the risks and benefits. Diabetologia. 2018 Oct;61(10):2118-2125. doi: 10.1007/s00125-018-4663-6. 
58.    Szalat A, Perlman A, Muszkat M, Khamaisi M, Abassi Z, Heyman SN. Can SGLT2 Inhibitors Cause Acute Renal Failure? Plausible Role for Altered Glomerular Hemodynamics and Medullary Hypoxia. Drug Saf. 2018 Mar;41(3):239-252. 
59.    Taylor SI, Blau JE, Rother KI. SGLT2 Inhibitors May Predispose to Ketoacidosis. J Clin Endocrinol Metab. 2015 Aug;100(8):2849-52. 
60.    Ogawa W, Sakaguchi K. Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors. J Diabetes Investig. 2016 Mar;7(2):135-8. 
61.    Monami M, Nreu B, Zannoni S, Lualdi C, Mannucci E. Effects of SGLT-2 inhibitors on diabetic ketoacidosis: A meta-analysis of randomised controlled trials. Diabetes Res Clin Pract. 2017 Aug;130:53-60. 
62.    Chaplin S. SGLT2 inhibitors and risk of genitourinary infections. Prescriber. 2016;27(12):26-30.
63.    Liu J, Li L, Li S, Jia P, Deng K, Chen W,et al. Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: a systematic review and meta-analysis. Sci Rep. 2017 Jun 6;7(1):2824. doi: 10.1038/s41598-017-02733-w. 
64.    Watts NB, Bilezikian JP, Usiskin K, Edwards R, Desai M, Law G, et al. Effects of Canagliflozin on Fracture Risk in Patients With Type 2 Diabetes Mellitus. J Clin Endocrinol Metab. 2016 Jan;101(1):157-66. doi: 10.1210/jc.2015-3167. 
65.    Pittampalli S, Upadyayula S, Mekala HM, Lippmann S. Risks vs Benefits for SGLT2 Inhibitor Medications. Fed Pract. 2018 Jul;35(7):45-48. 
66.    Nauck MA, Meier JJ. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol. 2016 Jun;4(6):525-36. 
67.    Nauck MA, Meier JJ. Incretin hormones: Their role in health and disease. Diabetes Obes Metab. 2018 Feb;20 Suppl 1:5-21. 
68.    Park H, Park C, Kim Y, Rascati KL. Efficacy and safety of dipeptidyl peptidase-4 inhibitors in type 2 diabetes: meta-analysis. Ann Pharmacother. 2012 Nov;46(11):1453-69. doi: 10.1345/aph.1R041. Epub 2012 Nov 7. PMID: 23136353.
69.    Shyangdan DS, Royle P, Clar C, Sharma P, Waugh N, Snaith A. Glucagon-like peptide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2011 Oct 5;2011(10):CD006423. doi: 10.1002/14651858.CD006423.pub2. 
70.    Fineman M, Flanagan S, Taylor K, Aisporna M, Shen LZ, Mace KF, Walsh B, Diamant M, Cirincione B, Kothare P, Li WI, MacConell L. Pharmacokinetics and pharmacodynamics of exenatide extended-release after single and multiple dosing. Clin Pharmacokinet. 2011 Jan;50(1):65-74. 
71.    Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009 Jul 4;374(9683):39-47. 
72.    Jensen TM, Saha K, Steinberg WM. Is there a link between liraglutide and pancreatitis? A post hoc review of pooled and patient-level data from completed liraglutide type 2 diabetes clinical trials. Diabetes Care. 2015 Jun;38(6):1058-66.  
73.    Noel RA, Braun DK, Patterson RE, Bloomgren GL. Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes: a retrospective cohort study. Diabetes Care. 2009 May;32(5):834-8. 
74.    Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011 Jul;141(1):150-6. doi: 10.1053/j.gastro.2011.02.018. 
75.    Bjerre Knudsen L, Madsen LW, Andersen S, Almholt K, de Boer AS, Drucker DJ, et al. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology. 2010 Apr;151(4):1473-86. doi: 10.1210/en.2009-1272. Epub 2010 Mar 4. Erratum in: Endocrinology. 2012 Feb;153(2):1000. Moerch, Ulrik [added]. 
76.    Reid T. Choosing GLP-1 receptor agonists or DPP-4 inhibitors: weighing the clinical trial evidence. Clin Diabetes. 2012;30(1):3-12.
77.    Gautier JF, Choukem SP, Girard J. Physiology of incretins (GIP and GLP-1) and abnormalities in type 2 diabetes. Diabetes Metab. 2008 Feb;34 Suppl 2:S65-72. 
78.    Salvo F, Moore N, Arnaud M, Robinson P, Raschi E, De Ponti F, et al. Addition of dipeptidyl peptidase-4 inhibitors to sulphonylureas and risk of hypoglycaemia: systematic review and meta-analysis. BMJ. 2016 May 3;353:i2231. 
79.    Pathak R, Bridgeman MB. Dipeptidyl Peptidase-4 (DPP-4) Inhibitors In the Management of Diabetes. P T. 2010 Sep;35(9):509-13. 
80.    Karagiannis T, Boura P, Tsapas A. Safety of dipeptidyl peptidase 4 inhibitors: a perspective review. Ther Adv Drug Saf. 2014 Jun;5(3):138-46. 
81.    Lamos EM, Levitt DL, Munir KM. A review of dopamine agonist therapy in type 2 diabetes and effects on cardio-metabolic parameters. Prim Care Diabetes. 2016 Feb;10(1):60-5.
82.    Raskin P, Cincotta AH. Bromocriptine-QR therapy for the management of type 2 diabetes mellitus: developmental basis and therapeutic profile summary. Expert Rev Endocrinol Metab. 2016 Mar;11(2):113-148. doi: 10.1586/17446651.2016.1131119. 
83.    Abrahami D, Douros A, Yin H, Yu OHY, Renoux C, Bitton A, et al. Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: population based cohort study. BMJ. 2018 Mar 21;360:k872. doi: 10.1136/bmj.k872.
84.    Sando KR, Taylor J. Bromocriptine: its place in type 2 diabetes Tx. J Fam Pract. 2011 Nov;60(11):E1-5. PMID: 22049355.
85.    Younk LM, Mikeladze M, Davis SN. Pramlintide and the treatment of diabetes: a review of the data since its introduction. Expert Opin Pharmacother. 2011 Jun;12(9):1439-51. doi: 10.1517/14656566.2011.581663. 
86.    Rosenstock J, Hanefeld M, Shamanna P, Min KW, Boka G, Miossec P, et al. Beneficial effects of once-daily lixisenatide on overall and postprandial glycemic levels without significant excess of hypoglycemia in type 2 diabetes inadequately controlled on a sulfonylurea with or without metformin (GetGoal-S). J Diabetes Complications. 2014 May-Jun;28(3):386-92. doi: 10.1016/j.jdiacomp.2014.01.012. 
87.    Feingold KR. Cholesterol Lowering Drugs. 2021 Mar 30. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, et al. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–. PMID: 27809434.
88.    Zema MJ. Colesevelam hydrochloride: evidence for its use in the treatment of hypercholesterolemia and type 2 diabetes mellitus with insights into mechanism of action. Core Evid. 2012;7:61-75. doi: 10.2147/CE.S26725. 
89.    Singh-Franco D, Perez A, Harrington C. The effect of pramlintide acetate on glycemic control and weight in patients with type 2 diabetes mellitus and in obese patients without diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2011 Feb;13(2):169-80. doi: 10.1111/j.1463-1326.2010.01337.x. 
90.    Qiao YC, Ling W, Pan YH, Chen YL, Zhou D, Huang YM, et al. Efficacy and safety of pramlintide injection adjunct to insulin therapy in patients with type 1 diabetes mellitus: a systematic review and meta-analysis. Oncotarget. 2017 Mar 8;8(39):66504-66515. doi: 10.18632/oncotarget.16008. 
91.    Ryan G, Briscoe TA, Jobe L. Review of pramlintide as adjunctive therapy in treatment of type 1 and type 2 diabetes. Drug Des Devel Ther. 2009 Feb 6;2:203-14. doi: 10.2147/dddt.s3225. 
92.    Hinnen D, Strong J. iGlarLixi: A New Once-Daily Fixed-Ratio Combination of Basal Insulin Glargine and Lixisenatide for the Management of Type 2 Diabetes. Diabetes Spectr. 2018 May;31(2):145-154. doi: 10.2337/ds17-0014. 
93.    Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. N Engl J Med. 2021 Jan 14;384(2):117-128. doi: 10.1056/NEJMoa2030183. 
94.    Bays HE, Kozlovski P, Shao Q, Proot P, Keefe D. Licogliflozin, a Novel SGLT1 and 2 Inhibitor: Body Weight Effects in a Randomized Trial in Adults with Overweight or Obesity. Obesity (Silver Spring). 2020 May;28(5):870-881. doi: 10.1002/oby.22764. 
95.    Ambery P, Parker VE, Stumvoll M, Posch MG, Heise T, Plum-Moerschel L, et al. MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study. Lancet. 2018 Jun 30;391(10140):2607-2618. doi: 10.1016/S0140-6736(18)30726-8. 
96.    She M, Hu X, Su Z, Zhang C, Yang S, Ding L, et al. Piromelatine, a novel melatonin receptor agonist, stabilizes metabolic profiles and ameliorates insulin resistance in chronic sleep restricted rats. Eur J Pharmacol. 2014 Mar 15;727:60-5. doi: 10.1016/j.ejphar.2014.01.037. 
97.    Shah N, Abdalla MA, Deshmukh H, Sathyapalan T. Therapeutics for type-2 diabetes mellitus: a glance at the recent inclusions and novel agents under development for use in clinical practice. Ther Adv Endocrinol Metab. 2021 Sep 23;12:20420188211042145. doi: 10.1177/20420188211042145. 
98.    Ge X, Wang Y, Lam KSL, Xu A. Metabolic actions of FGF21: molecular mechanisms and therapeutic implications. Acta Pharmaceutica Sinica B. 2012;2(4):350-7.
99.    Charles ED, Neuschwander-Tetri BA, Pablo Frias J, Kundu S, Luo Y, Tirucherai GS, et al. Pegbelfermin (BMS-986036), PEGylated FGF21, in Patients with Obesity and Type 2 Diabetes: Results from a Randomized Phase 2 Study. Obesity (Silver Spring). 2019 Jan;27(1):41-49. 
100.    Tsumura Y, Tsushima Y, Tamura A, Hasebe M, Kanou M, Kato H, et al. TMG-123, a novel glucokinase activator, exerts durable effects on hyperglycemia without increasing triglyceride in diabetic animal models. PLoS One. 2017 Feb 16;12(2):e0172252. 
101.    Eldor ROY, Fleming A, Neutel J, Homer K, Kidron M, Rosenstock J. Evening oral insulin (ORMD-0801): glycemic effects in uncon-trolled T2DM patients. European association for the study of diabetes; 2020. Available from: https://www.easd.org/virtualmeeting/home.html#!resources/evening-oral-insulin-ormd-0801-glycaemic-effects-in-uncontrolled-type-2-diabetes-patients-791ded58-c63a-448d-848a-65b019ce927a.
102.    Banerjee A, Lee J, Mitragotri S. Intestinal mucoadhesive devices for oral delivery of insulin. Bioeng Transl Med. 2016 Aug 19;1(3):338-346. doi: 10.1002/btm2.10015.