A Review of the Novel Antidiabetic Medications: Efficacy, Safety and
Innovation

Sepideh   Parchami   Ghazaee; Viktor      Tumanov; Natalia      Voloshyna; Kateryna      Marchenko-Tolsta; Murtaza      Hameed

doi:10.2174/04666230130095723

Abstract

Introduction: Type 2 diabetes is a chronic health condition affecting hundreds of millions of people. Type 2 diabetes has traditionally been combated with a combination of lifestyle modification, insulin therapy and pharmacological agents, including sulfonylureas, biguanides, thiazolidinediones and alpha-glucosidase inhibitors. Type 2 diabetes is associated with an increased risk of cardiovascular disease and the development of diabetic kidney disease. Although sulfonylureas are low-cost drugs and widely prescribed, they have been shown in recent cardiovascular outcome trials to present a high risk of hypoglycemia, which in turn increases the risk of negative cardiovascular outcomes. Metformin, a biguanide that is the most commonly-prescribed antidiabetic agent worldwide, is contraindicated in patients with risk factors for lactic acidosis, including heart failure and chronic kidney disease.

Objectives: The last decade has seen significant advances in the development of novel antidiabetic agents shown to possess both reno- and cardioprotective qualities. This article aims to review the available literature and recent studies demonstrating the efficacy and safety of these agents individually, as well as exploring areas of future development in the field.

Methods: The reporting of this review is based on the 2020 PRISMA statement. A literature search for all papers related to antidiabetic medication was conducted using reliable sources such PubMed and Google Scholar Databases, including a recent meta-analysis of renal and cardiovascular outcome trials.

Conclusion: A critical analysis of clinical trials on type 2 diabetes and the two most severe comorbidities in cardiovascular and chronic kidney diseases may help cardiologists, urologists and diabetes specialists to adapt their therapeutic approaches to individual patients. Data related to antidiabetic effects of agents of natural origin accompanied by their Cardioprotective and renoprotective capacity testify benefits of these compounds as novel therapeutic agents.

[1]
Tinajero MG, Malik VS. An update on the epidemiology of type 2 diabetes: A global perspective. Endocrinol Metab Clin North Am  2021; 50(3): 337-55.
 [http://dx.doi.org/10.1016/j.ecl.2021.05.013] [PMID: 34399949]

[2]
Khan MAB, Hashim MJ, King JK, Govender RD, Mustafa H, Al Kaabi J. Epidemiology of type 2 diabetes - global burden of disease and forecasted trends. J Epidemiol Glob Health  2019; 10(1): 107-11.
 [http://dx.doi.org/10.2991/jegh.k.191028.001] [PMID: 32175717]

[3]
Koufakis T, Dimitriadis G, Kotsa K. A lion in the room: Has the CAROLINA trial definitely resolved the issue of the cardiovascular safety of sulfonylureas? J Diabetes  2020; 12(7): 499-502.
 [http://dx.doi.org/10.1111/1753-0407.13035] [PMID: 32202061]

[4]
Flory J, Lipska K. Metformin in 2019. JAMA  2019; 321(19): 1926-7.
 [http://dx.doi.org/10.1001/jama.2019.3805] [PMID: 31009043]

[5]
Maqbool M, Cooper ME, Jandeleit-Dahm KAM. Cardiovascular disease and diabetic kidney disease. Semin Nephrol  2018; 38(3): 217-32.
 [http://dx.doi.org/10.1016/j.semnephrol.2018.02.003] [PMID: 29753399]

[6]
Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ  2021; 372(71): n71.
 [http://dx.doi.org/10.1136/bmj.n71] [PMID: 33782057]

[7]
Zhuang X, He X, Yang D, et al. Comparative cardiovascular outcomes in the era of novel anti-diabetic agents: a comprehensive network meta-analysis of 166,371 participants from 170 randomized controlled trials. Cardiovasc Diabetol  2018; 17(1): 79.
 [http://dx.doi.org/10.1186/s12933-018-0722-z] [PMID: 29871636]

[8]
Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol  2021; 9(10): 653-62.
 [http://dx.doi.org/10.1016/S2213-8587(21)00203-5] [PMID: 34425083]

[9]
Giugliano D, Scappaticcio L, Longo M, et al. GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes: an updated meta-analysis of eight CVOTs. Cardiovasc Diabetol  2021; 20(1): 189.
 [http://dx.doi.org/10.1186/s12933-021-01366-8] [PMID: 34526024]

[10]
Chadda KR, Cheng TS, Ong KK. GLP-1 agonists for obesity and type 2 diabetes in children: Systematic review and meta-analysis. Obes Rev  2021; 22(6): e13177.
 [http://dx.doi.org/10.1111/obr.13177] [PMID: 33354917]

[11]
Rosenstock J, Wysham C, Frías JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet  2021; 398(10295): 143-55.
 [http://dx.doi.org/10.1016/S0140-6736(21)01324-6] [PMID: 34186022]

[12]
Mucalo I, Jovanovski E, Rahelić D, Božikov V, Romić Ž, Vuksan V. Effect of American ginseng (Panax quinquefolius L.) on arterial stiffness in subjects with type-2 diabetes and concomitant hypertension. J Ethnopharmacol  2013; 150(1): 148-53.
 [http://dx.doi.org/10.1016/j.jep.2013.08.015] [PMID: 23973636]

[13]
Jovanovski E, Bateman EA, Bhardwaj J, Fairgrieve C, Mucalo I, Jenkins A, et al. Effect of Rg3-enriched Korean red ginseng (Panax ginseng) on arterial stiffness and blood pressure in healthy individuals: a randomized controlled trial. J Am Soc Hypertens  2014; 8(8): 537-41.
 [http://dx.doi.org/10.1016/j.jash.2014.04.004]

[14]
Park SH, Oh MR, Choi EK, et al. An 8-wk, randomized, double-blind, placebo-controlled clinical trial for the antidiabetic effects of hydrolyzed ginseng extract. J Ginseng Res  2014; 38(4): 239-43.
 [http://dx.doi.org/10.1016/j.jgr.2014.05.006] [PMID: 25379002]

[15]
Filippas-Ntekouan S, Filippatos TD, Elisaf MS. SGLT2 inhibitors: are they safe? Postgrad Med  2018; 130(1): 72-82.
 [http://dx.doi.org/10.1080/00325481.2018.1394152] [PMID: 29039237]

[16]
Vallon V, Verma S. Effects of SGLT2 inhibitors on kidney and cardiovascular Function. Annu Rev Physiol  2021; 83(1): 503-28.
 [http://dx.doi.org/10.1146/annurev-physiol-031620-095920] [PMID: 33197224]

[17]
Bhattacharya S, Rathore A, Parwani D, et al. An exhaustive perspective on structural insights of SGLT2 inhibitors: A novel class of antidiabetic agent. Eur J Med Chem  2020; 204: 112523.
 [http://dx.doi.org/10.1016/j.ejmech.2020.112523] [PMID: 32717480]

[18]
Nauck MA, Meier JJ. MANAGEMENT OF ENDOCRINE DISEASE: Are all GLP-1 agonists equal in the treatment of type 2 diabetes? Eur J Endocrinol  2019; 181(6): R211-34.
 [http://dx.doi.org/10.1530/EJE-19-0566] [PMID: 31600725]

[19]
Bosco E, Hsueh L, McConeghy KW, Gravenstein S, Saade E. Major adverse cardiovascular event definitions used in observational analysis of administrative databases: a systematic review. BMC Med Res Methodol  2021; 21(1): 241.
 [http://dx.doi.org/10.1186/s12874-021-01440-5] [PMID: 34742250]

[20]
Deacon CF. Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol  2020; 16(11): 642-53.
 [http://dx.doi.org/10.1038/s41574-020-0399-8] [PMID: 32929230]

[21]
Sesti G, Avogaro A, Belcastro S, et al. Ten years of experience with DPP-4 inhibitors for the treatment of type 2 diabetes mellitus. Acta Diabetol  2019; 56(6): 605-17.
 [http://dx.doi.org/10.1007/s00592-018-1271-3] [PMID: 30603867]

[22]
Makrilakis K. The Role of DPP-4 Inhibitors in the Treatment Algorithm of Type 2 Diabetes Mellitus: When to Select, What to Expect. Int J Environ Res Public Health  2019; 16(15): 2720.
 [http://dx.doi.org/10.3390/ijerph16152720] [PMID: 31366085]

[23]
Chen W, Balan P, Popovich DG. Review of ginseng anti-Diabetic studies. Molecules  2019; 24(24): 4501.
 [http://dx.doi.org/10.3390/molecules24244501] [PMID: 31835292]

[24]
Yoon JW, Kang SM, Vassy JL, et al. Efficacy and safety of ginsam, a vinegar extract from Panax ginseng, in type 2 diabetic patients: Results of a double-blind, placebo-controlled study. J Diabetes Investig  2012; 3(3): 309-17.
 [http://dx.doi.org/10.1111/j.2040-1124.2011.00185.x] [PMID: 24843582]

[25]
Tian W, Chen L, Zhang L, et al. Effects of ginsenoside Rg1 on glucose metabolism and liver injury in streptozotocin-induced type 2 diabetic rats. Genet Mol Res  2017; 16(1)
 [http://dx.doi.org/10.4238/gmr16019463] [PMID: 28362999]

[26]
Shaito A, Thuan DTB, Phu HT, et al. Herbal Medicine for Cardiovascular Diseases: Efficacy, Mechanisms, and Safety. Front Pharmacol  2020; 11: 422.
 [http://dx.doi.org/10.3389/fphar.2020.00422] [PMID: 32317975]

[27]
Aday AW, Ridker PM. Antiinflammatory Therapy in Clinical Care: The CANTOS Trial and Beyond. Front Cardiovasc Med  2018; 5: 62.
 [http://dx.doi.org/10.3389/fcvm.2018.00062] [PMID: 29922680]

[28]
Ragab TIM, Ali NA, El Gendy ANG, et al. Renoprotective and therapeutic effects of newly water, ethanol, and butanol ginseng fractions in hypertensive and chronic kidney disease with L-NAME. Biomed Pharmacother  2021; 142: 111978.
 [http://dx.doi.org/10.1016/j.biopha.2021.111978] [PMID: 34411920]

[29]
Sun C, Zhao C, Guven EC, et al. Dietary polyphenols as antidiabetic agents: Advances and opportunities. Food Front  2020; 1(1): 18-44. [DOI:10.1002/fft2.15 Corpus ID: 216323656].
 [http://dx.doi.org/10.1002/fft2.15]

[30]
Alkhalidy H, Moore W, Wang Y, et al. The Flavonoid Kaempferol Ameliorates Streptozotocin-Induced Diabetes by Suppressing Hepatic Glucose Production. Molecules  2018; 23(9): 2338.
 [http://dx.doi.org/10.3390/molecules23092338] [PMID: 30216981]

[31]
Sangeetha R. Luteolin in the management of type 2 diabetes mellitus. Curr Res Nutr Food Sci  2019; 7(2): 393-8. [DOI: http://dx.doi.org/10.12944/CRNFSJ.7.2.09].
 [http://dx.doi.org/10.12944/CRNFSJ.7.2.09]

[32]
Ciumărnean L, Milaciu MV, Runcan O, et al. The Effects of Flavonoids in Cardiovascular Diseases. Molecules  2020; 25(18): 4320.
 [http://dx.doi.org/10.3390/molecules25184320] [PMID: 32967119]

[33]
Vargas F, Romecín P, García-Guillén AI, et al. Flavonoids in Kidney Health and Disease. Front Physiol  2018; 9: 394.
 [http://dx.doi.org/10.3389/fphys.2018.00394] [PMID: 29740333]

[34]
Leite KM, Long AM, Ostroff ML, Borges L, Braden G. A review of the renoprotective effects of novel antidiabetic agents. J Pharm Pract  2021; 34(1): 141-8.
 [http://dx.doi.org/10.1177/0897190020902344] [PMID: 32067559]

[35]
Brown E, Heerspink HJL, Cuthbertson DJ, Wilding JPH. SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications. Lancet  2021; 398(10296): 262-76.
 [http://dx.doi.org/10.1016/S0140-6736(21)00536-5] [PMID: 34216571]

[36]
Kotsis V, Jordan J, Stabouli S, et al. Cardiovascular, renal and liver protection with novel antidiabetic agents beyond blood glucose lowering in type 2 diabetes: consensus article from the European Society of Hypertension Working Group on Obesity, Diabetes and the High-risk Patient. J Hypertens  2020; 38(3): 377-86.
 [http://dx.doi.org/10.1097/HJH.0000000000002279] [PMID: 31764586]

[37]
Zhu L, Rossi M, Doliba NM, Wess J. Beta-cell M3 muscarinic acetylcholine receptors as potential targets for novel antidiabetic drugs. Int Immunopharmacol  2020; 81: 106267.
 [http://dx.doi.org/10.1016/j.intimp.2020.106267] [PMID: 32044662]

[38]
Zhu L, Rossi M, Cohen A, et al. Allosteric modulation of β-cell M 3 muscarinic acetylcholine receptors greatly improves glucose homeostasis in lean and obese mice. Proc Natl Acad Sci USA  2019; 116(37): 18684-90.
 [http://dx.doi.org/10.1073/pnas.1904943116] [PMID: 31451647]

[39]
Hussain H, Nazir M, Saleem M, Al-Harrasi A, Elizbit , Green IR. Fruitful decade of fungal metabolites as anti-diabetic agents from 2010 to 2019: emphasis on α-glucosidase inhibitors. Phytochem Rev  2021; 20(1): 145-79. [DOI: 10.1007/s11101-020-09733-1].
 [http://dx.doi.org/10.1007/s11101-020-09733-1]

[40]
Cao H, Ou J, Chen L, et al. Dietary polyphenols and type 2 diabetes: Human Study and Clinical Trial. Crit Rev Food Sci Nutr  2019; 59(20): 3371-9.
 [http://dx.doi.org/10.1080/10408398.2018.1492900] [PMID: 29993262]

[41]
Da Porto A, Cavarape A, Colussi G, Casarsa V, Catena C, Sechi LA. Polyphenols Rich Diets and Risk of Type 2 Diabetes. Nutrients  2021; 13(5): 1445.
 [http://dx.doi.org/10.3390/nu13051445] [PMID: 33923263]

[42]
Schernthaner G, Shehadeh N, Ametov AS, et al. Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes. Cardiovasc Diabetol  2020; 19(1): 185.
 [http://dx.doi.org/10.1186/s12933-020-01154-w] [PMID: 33097060]

[43]
Rangaswami J, Bhalla V, de Boer IH, et al. Cardiorenal protection with the newer antidiabetic agents in patients with diabetes and chronic kidney disease: a scientific statement from the American heart association. Circulation  2020; 142(17): e265-86.
 [http://dx.doi.org/10.1161/CIR.0000000000000920] [PMID: 32981345]