Novel Approaches to the Management of Diabetes Mellitus in Patients with
Coronary Artery Disease

Evangelos      Oikonomou; Maria      Xenou; George   E.   Zakynthinos; Paraskevas      Tsaplaris; Stamatios      Lampsas; Evanthia      Bletsa; Ioannis      Gialamas; Konstantinos      Kalogeras; Athina      Goliopoulou; Maria   I.   Gounaridi; Theodoros      Pesiridis; Aikaterini      Tsatsaragkou; Manolis      Vavouranakis; Gerasimos      Siasos; Dimitris      Tousoulis
doi:10.2174/1381612829666230703161058
Abstract

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in individuals with diabetes mellitus (DM). Although benefit has been attributed to the strict control of hyperglycemia with traditional antidiabetic treatments, novel antidiabetic medications have demonstrated cardiovascular (CV) safety and benefits by reducing major adverse cardiac events, improving heart failure (HF), and decreasing CVD-related mortality. Emerging data underline the interrelation between diabetes, as a metabolic disorder, and inflammation, endothelial dysfunction, and oxidative stress in the pathogenesis of microvascular and macrovascular complications. Conventional glucose-lowering medications demonstrate controversial CV effects. Dipeptidyl peptidase- 4 inhibitors have not only failed to prove to be beneficial in patients with coronary artery disease, but also their safety is questionable for the treatment of patients with CVD. However, metformin, as the first-line option for type 2 DM (T2DM), shows CVD protective properties for DM-induced atherosclerotic and macrovascular complications. Thiazolidinedione and sulfonylureas have questionable effects, as evidence from large studies shows a reduction in the risk of CV events and deaths, but with an increased rate of hospitalization for HF. Moreover, several studies have revealed that insulin monotherapy for T2DM treatment increases the risk of major CV events and deaths from HF, when compared to metformin, although it may reduce the risk of myocardial infarction. Finally, this review aimed to summarize the mechanisms of action of novel antidiabetic drugs acting as glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors that show favorable effects on blood pressure, lipid levels, and inflammation, leading to reduced CVD risk in T2DM patients.
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[1]
Rawshani A, Rawshani A, Franzén S, et al. Mortality and cardiovascular disease in type 1 and type 2 diabetes. N Engl J Med  2017; 376(15): 1407-18.
 [http://dx.doi.org/10.1056/NEJMoa1608664] [PMID: 28402770]

[2]
 International Diabetes Federation. IDF Diabetes Atlas, 10th edn. Brussels, Belgium: 2021. Available at: https://www.diabetesatlas.org

[3]
Raghavan S, Vassy JL, Ho YL, et al. Diabetes mellitus–related all-cause and cardiovascular mortality in a national cohort of adults. J Am Heart Assoc  2019; 8(4)e011295
 [http://dx.doi.org/10.1161/JAHA.118.011295] [PMID: 30776949]

[4]
Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: A collaborative meta-analysis of 102 prospective studies. Lancet  2010; 375(9733): 2215-22.
 [http://dx.doi.org/10.1016/S0140-6736(10)60484-9] [PMID: 20609967]

[5]
Rawshani A, Sattar N, Franzén S, et al. Excess mortality and cardiovascular disease in young adults with type 1 diabetes in relation to age at onset: A nationwide, register-based cohort study. Lancet  2018; 392(10146): 477-86.
 [http://dx.doi.org/10.1016/S0140-6736(18)31506-X] [PMID: 30129464]

[6]
Tancredi M, Rosengren A, Svensson AM, et al. Excess mortality among persons with type 2 diabetes. N Engl J Med  2015; 373(18): 1720-32.
 [http://dx.doi.org/10.1056/NEJMoa1504347] [PMID: 26510021]

[7]
Antonopoulos AS, Siasos G, Oikonomou E, et al. Arterial stiffness and microvascular disease in type 2 diabetes. Eur J Clin Invest  2021; 51(2)e13380
 [http://dx.doi.org/10.1111/eci.13380] [PMID: 33368197]

[8]
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet  1998; 352(9131): 837-53.
 [http://dx.doi.org/10.1016/S0140-6736(98)07019-6] [PMID: 9742976]

[9]
Tsalamandris S, Antonopoulos AS, Oikonomou E, et al. The role of inflammation in diabetes: Current concepts and future perspectives. Eur Cardiol  2019; 14(1): 50-9.
 [http://dx.doi.org/10.15420/ecr.2018.33.1] [PMID: 31131037]

[10]
Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet  2014; 383(9911): 69-82.
 [http://dx.doi.org/10.1016/S0140-6736(13)60591-7] [PMID: 23890997]

[11]
Miller BJ, Appel MC, O’Neil JJ, Wicker LS. Both the Lyt-2+ and L3T4+ T cell subsets are required for the transfer of diabetes in nonobese diabetic mice. J Immunol  1988; 140(1): 52-8.
 [http://dx.doi.org/10.4049/jimmunol.140.1.52] [PMID: 3275717]

[12]
Feuerer M, Shen Y, Littman DR, Benoist C, Mathis D. How punctual ablation of regulatory T cells unleashes an autoimmune lesion within the pancreatic islets. Immunity  2009; 31(4): 654-64.
 [http://dx.doi.org/10.1016/j.immuni.2009.08.023] [PMID: 19818653]

[13]
Oikonomou E, Tsaplaris P, Anastasiou A, et al. Interleukin-1 in coronary artery disease. Curr Top Med Chem  2022; 22(28): 2368-89.
 [http://dx.doi.org/10.2174/1568026623666221017144734] [PMID: 36263481]

[14]
Sumpter KM, Adhikari S, Grishman EK, White PC. Preliminary studies related to anti-interleukin-1β therapy in children with newly diagnosed type 1 diabetes. Pediatr Diabetes  2011; 12(7): 656-67.
 [http://dx.doi.org/10.1111/j.1399-5448.2011.00761.x] [PMID: 21518168]

[15]
Moran A, Bundy B, Becker DJ, et al. Interleukin-1 antagonism in type 1 diabetes of recent onset: Two multicentre, randomised, double-blind, placebo-controlled trials. Lancet  2013; 381(9881): 1905-15.
 [http://dx.doi.org/10.1016/S0140-6736(13)60023-9] [PMID: 23562090]

[16]
Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology  2007; 132(6): 2169-80.
 [http://dx.doi.org/10.1053/j.gastro.2007.03.059] [PMID: 17498510]

[17]
Kanda H, Tateya S, Tamori Y, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest  2006; 116(6): 1494-505.
 [http://dx.doi.org/10.1172/JCI26498] [PMID: 16691291]

[18]
Antonopoulos AS, Margaritis M, Coutinho P, et al. Adiponectin as a link between type 2 diabetes and vascular NADPH oxidase activity in the human arterial wall: The regulatory role of perivascular adipose tissue. Diabetes  2015; 64(6): 2207-19.
 [http://dx.doi.org/10.2337/db14-1011] [PMID: 25552596]

[19]
Antoniades C, Antonopoulos AS, Tousoulis D, Stefanadis C. Adiponectin: From obesity to cardiovascular disease. Obes Rev  2009; 10(3): 269-79.
 [http://dx.doi.org/10.1111/j.1467-789X.2009.00571.x] [PMID: 19389061]

[20]
Nikolajczyk BS, Jagannathan-Bogdan M, Shin H, Gyurko R. State of the union between metabolism and the immune system in type 2 diabetes. Genes Immun  2011; 12(4): 239-50.
 [http://dx.doi.org/10.1038/gene.2011.14] [PMID: 21390053]

[21]
Eguchi K, Manabe I, Oishi-Tanaka Y, et al. Saturated fatty acid and TLR signaling link β cell dysfunction and islet inflammation. Cell Metab  2012; 15(4): 518-33.
 [http://dx.doi.org/10.1016/j.cmet.2012.01.023] [PMID: 22465073]

[22]
Jourdan T, Godlewski G, Cinar R, et al. Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Nat Med  2013; 19(9): 1132-40.
 [http://dx.doi.org/10.1038/nm.3265] [PMID: 23955712]

[23]
Westwell-Roper CY, Ehses JA, Verchere CB. Resident macrophages mediate islet amyloid polypeptide-induced islet IL-1β production and β-cell dysfunction. Diabetes  2014; 63(5): 1698-711.
 [http://dx.doi.org/10.2337/db13-0863] [PMID: 24222351]

[24]
Maedler K, Oberholzer J, Bucher P, Spinas GA, Donath MY. Monounsaturated fatty acids prevent the deleterious effects of palmitate and high glucose on human pancreatic beta-cell turnover and function. Diabetes  2003; 52(3): 726-33.
 [http://dx.doi.org/10.2337/diabetes.52.3.726] [PMID: 12606514]

[25]
Theofilis P, Sagris M, Oikonomou E, et al. Inflammatory mechanisms contributing to endothelial dysfunction. Biomedicines  2021; 9(7): 781.
 [http://dx.doi.org/10.3390/biomedicines9070781] [PMID: 34356845]

[26]
Tsalamandris S, Oikonomou E, Papageorgiou N, et al. The role of interleukin-6 genetic variant on inflammation and endothelial function in patients with unstable angina. Hellenic J Cardiol  2022; 63: 79-81.
 [http://dx.doi.org/10.1016/j.hjc.2021.03.011] [PMID: 33839283]

[27]
Oikonomou E, Theofilis P, Lampsas S, et al. Current concepts and future applications of non-invasive functional and anatomical evaluation of coronary artery disease. Life  2022; 12(11): 1803.
 [http://dx.doi.org/10.3390/life12111803] [PMID: 36362957]

[28]
Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med  2017; 377(12): 1119-31.
 [http://dx.doi.org/10.1056/NEJMoa1707914] [PMID: 28845751]

[29]
Alexander Y, Osto E, Schmidt-Trucksäss A, et al. Endothelial function in cardiovascular medicine: A consensus paper of the european society of cardiology working groups on atherosclerosis and vascular biology, aorta and peripheral vascular diseases, coronary pathophysiology and microcirculation, and thrombosis. Cardiovasc Res  2021; 117(1): 29-42.
 [http://dx.doi.org/10.1093/cvr/cvaa085] [PMID: 32282914]

[30]
Tousoulis D, Antoniades C, Stefanadis C. Evaluating endothelial function in humans: A guide to invasive and non-invasive techniques. Heart  2005; 91(4): 553-8.
 [http://dx.doi.org/10.1136/hrt.2003.032847] [PMID: 15772232]

[31]
Oikonomou E, Lampsas S, Pantelidis P, et al. Lipoprotein (a) levels and abdominal aortic aneurysm. A systematic review and meta-analysis. Curr Pharm Des  2022; 28(43): 3492-9.
 [http://dx.doi.org/10.2174/1381612829666221124110920] [PMID: 36424795]

[32]
Siasos G, Sara JD, Zaromytidou M, et al. Local low shear stress and endothelial dysfunction in patients with nonobstructive coronary atherosclerosis. J Am Coll Cardiol  2018; 71(19): 2092-102.
 [http://dx.doi.org/10.1016/j.jacc.2018.02.073] [PMID: 29747829]

[33]
Tousoulis D, Papageorgiou N, Androulakis E, et al. Diabetes mellitus-associated vascular impairment: novel circulating biomarkers and therapeutic approaches. J Am Coll Cardiol  2013; 62(8): 667-76.
 [http://dx.doi.org/10.1016/j.jacc.2013.03.089] [PMID: 23948511]

[34]
Oikonomou E, Souvaliotis N, Lampsas S, et al. The role of cardiometabolic risk factors and endothelial dysfunction in serum albumin levels of patients with COVID-19. Cardiol J  2022; 29(6): 1037-9.
 [http://dx.doi.org/10.5603/CJ.a2022.0088] [PMID: 36117293]

[35]
Rabbani N, Godfrey L, Xue M, et al. Glycation of LDL by methylglyoxal increases arterial atherogenicity: A possible contributor to increased risk of cardiovascular disease in diabetes. Diabetes  2011; 60(7): 1973-80.
 [http://dx.doi.org/10.2337/db11-0085] [PMID: 21617182]

[36]
Lampsas S, Xenou M, Oikonomou E, et al. Lipoprotein(a) in atherosclerotic diseases: From pathophysiology to diagnosis and treatment. Molecules  2023; 28(3): 969.
 [http://dx.doi.org/10.3390/molecules28030969] [PMID: 36770634]

[37]
Yuan T, Yang T, Chen H, et al. New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis. Redox Biol  2019; 20: 247-60.
 [http://dx.doi.org/10.1016/j.redox.2018.09.025] [PMID: 30384259]

[38]
Tsigkou V, Oikonomou E, Anastasiou A, et al. Molecular mechanisms and therapeutic implications of endothelial dysfunction in patients with heart failure. Int J Mol Sci  2023; 24(5): 4321.
 [http://dx.doi.org/10.3390/ijms24054321] [PMID: 36901752]

[39]
Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev  2013; 93(1): 137-88.
 [http://dx.doi.org/10.1152/physrev.00045.2011] [PMID: 23303908]

[40]
Chen J, Jing J, Yu S, et al. Advanced glycation endproducts induce apoptosis of endothelial progenitor cells by activating receptor RAGE and NADPH oxidase/JNK signaling axis. Am J Transl Res  2016; 8(5): 2169-78.
 [PMID: 27347324]

[41]
Menini S, Iacobini C, Ricci C, Fantauzzi CB, Pugliese G. Protection from diabetes-induced atherosclerosis and renal disease by d- carnosine-octylester: Effects of early vs. late inhibition of advanced glycation end-products in Apoe-null mice. Diabetologia  2015; 58(4): 845-53.
 [http://dx.doi.org/10.1007/s00125-014-3467-6] [PMID: 25471794]

[42]
Shen C, Li Q, Zhang YC, et al. Advanced glycation endproducts increase EPC apoptosis and decrease nitric oxide release via MAPK pathways. Biomed Pharmacother  2010; 64(1): 35-43.
 [http://dx.doi.org/10.1016/j.biopha.2009.03.002] [PMID: 19766439]

[43]
Tang WH, Martin KA, Hwa J. Aldose reductase, oxidative stress, and diabetic mellitus. Front Pharmacol  2012; 3: 87.
 [http://dx.doi.org/10.3389/fphar.2012.00087] [PMID: 22582044]

[44]
Kong L, Shen X, Lin L, et al. PKCβ promotes vascular inflammation and acceleration of atherosclerosis in diabetic ApoE null mice. Arterioscler Thromb Vasc Biol  2013; 33(8): 1779-87.
 [http://dx.doi.org/10.1161/ATVBAHA.112.301113] [PMID: 23766264]

[45]
Xie F, Chan JCN, Ma RCW. Precision medicine in diabetes prevention, classification and management. J Diabetes Investig  2018; 9(5): 998-1015.
 [http://dx.doi.org/10.1111/jdi.12830] [PMID: 29499103]

[46]
Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia  2009; 52(11): 2288-98.
 [http://dx.doi.org/10.1007/s00125-009-1470-0] [PMID: 19655124]

[47]
Doucet J, Verny C, Balkau B, Scheen AJ, Bauduceau B. Haemoglobin A1c and 5-year all-cause mortality in French type 2 diabetic patients aged 70 years and older: The GERODIAB observational cohort. Diabetes Metab  2018; 44(6): 465-72.
 [http://dx.doi.org/10.1016/j.diabet.2018.05.003] [PMID: 29859993]

[48]
Danne T, Nimri R, Battelino T, et al. International consensus on use of continuous glucose monitoring. Diabetes Care  2017; 40(12): 1631-40.
 [http://dx.doi.org/10.2337/dc17-1600] [PMID: 29162583]

[49]
Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J  2020; 41(2): 255-323.
 [http://dx.doi.org/10.1093/eurheartj/ehz486] [PMID: 31497854]

[50]
Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med  2013; 369(14): 1317-26.
 [http://dx.doi.org/10.1056/NEJMoa1307684] [PMID: 23992601]

[51]
Koyani CN, Kolesnik E, Wölkart G, et al. Dipeptidyl peptidase-4 independent cardiac dysfunction links saxagliptin to heart failure. Biochem Pharmacol  2017; 145: 64-80.
 [http://dx.doi.org/10.1016/j.bcp.2017.08.021] [PMID: 28859968]

[52]
Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med  2015; 373(3): 232-42.
 [http://dx.doi.org/10.1056/NEJMoa1501352] [PMID: 26052984]

[53]
Rosenstock J, Perkovic V, Johansen OE, et al. Effect of linagliptin vs. placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk. JAMA  2019; 321(1): 69-79.
 [http://dx.doi.org/10.1001/jama.2018.18269] [PMID: 30418475]

[54]
White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med  2013; 369(14): 1327-35.
 [http://dx.doi.org/10.1056/NEJMoa1305889] [PMID: 23992602]

[55]
Rosenstock J, Kahn SE, Johansen OE, et al. Effect of linagliptin vs. glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes. JAMA  2019; 322(12): 1155-66.
 [http://dx.doi.org/10.1001/jama.2019.13772] [PMID: 31536101]

[56]
Kato S, Fukui K, Kirigaya H, et al. Inhibition of DPP-4 by alogliptin improves coronary flow reserve and left ventricular systolic function evaluated by phase contrast cine magnetic resonance imaging in patients with type 2 diabetes and coronary artery disease. Int J Cardiol  2016; 223: 770-5.
 [http://dx.doi.org/10.1016/j.ijcard.2016.08.306] [PMID: 27573605]

[57]
Morgan ES, Tai LJ, Pham NC, et al. Antisense inhibition of glucagon receptor by IONIS-GCGRRx improves type 2 diabetes without increase in hepatic glycogen content in patients with type 2 diabetes on stable metformin therapy. Diabetes Care  2019; 42(4): 585-93.
 [http://dx.doi.org/10.2337/dc18-1343] [PMID: 30765435]

[58]
Yang TY, Liaw YP, Huang JY, Chang HR, Chang KW, Ueng KC. Association of sitagliptin with cardiovascular outcome in diabetic patients: A nationwide cohort study. Acta Diabetol  2016; 53(3): 461-8.
 [http://dx.doi.org/10.1007/s00592-015-0817-x] [PMID: 26687195]

[59]
Li L, Li S, Deng K, et al. Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies. BMJ  2016; 352: i610.
 [http://dx.doi.org/10.1136/bmj.i610] [PMID: 26888822]

[60]
Natali A, Ferrannini E. Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: A systematic review. Diabetologia  2006; 49(3): 434-41.
 [http://dx.doi.org/10.1007/s00125-006-0141-7] [PMID: 16477438]

[61]
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet  1998; 352(9131): 854-65.
 [http://dx.doi.org/10.1016/S0140-6736(98)07037-8] [PMID: 9742977]

[62]
Margolis DJ, Hoffstad O, Strom BL. Association between serious ischemic cardiac outcomes and medications used to treat diabetes. Pharmacoepidemiol Drug Saf  2008; 17(8): 753-9.
 [http://dx.doi.org/10.1002/pds.1630] [PMID: 18613215]

[63]
Hong J, Zhang Y, Lai S, et al. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care  2013; 36(5): 1304-11.
 [http://dx.doi.org/10.2337/dc12-0719] [PMID: 23230096]

[64]
Jong CB, Chen KY, Hsieh MY, et al. Metformin was associated with lower all-cause mortality in type 2 diabetes with acute coronary syndrome: A Nationwide registry with propensity score- matched analysis. Int J Cardiol  2019; 291: 152-7.
 [http://dx.doi.org/10.1016/j.ijcard.2019.03.021] [PMID: 30905518]

[65]
Lexis CPH, Wieringa WG, Hiemstra B, et al. Chronic metformin treatment is associated with reduced myocardial infarct size in diabetic patients with ST-segment elevation myocardial infarction. Cardiovasc Drugs Ther  2014; 28(2): 163-71.
 [http://dx.doi.org/10.1007/s10557-013-6504-7] [PMID: 24292206]

[66]
Varjabedian L, Bourji M, Pourafkari L, Nader ND. Cardioprotection by metformin: Beneficial effects beyond glucose reduction. Am J Cardiovasc Drugs  2018; 18(3): 181-93.
 [http://dx.doi.org/10.1007/s40256-018-0266-3] [PMID: 29478240]

[67]
Dolasık I, Sener SY, Celebı K, Aydın ZM, Korkmaz U, Canturk Z. The effect of metformin on mean platelet volume in dıabetıc patients. Platelets  2013; 24(2): 118-21.
 [http://dx.doi.org/10.3109/09537104.2012.674165] [PMID: 22494325]

[68]
Kataoka Y, Nicholls SJ, Andrews J, et al. Plaque microstructures during metformin therapy in type 2 diabetic subjects with coronary artery disease: Optical coherence tomography analysis. Cardiovasc Diagn Ther  2022; 12(1): 77-87.
 [http://dx.doi.org/10.21037/cdt-21-346] [PMID: 35282660]

[69]
Mohan M, Al-Talabany S, McKinnie A, et al. A randomized controlled trial of metformin on left ventricular hypertrophy in patients with coronary artery disease without diabetes: The MET-REMODEL trial. Eur Heart J  2019; 40(41): 3409-17.
 [http://dx.doi.org/10.1093/eurheartj/ehz203] [PMID: 30993313]

[70]
Markowicz-Piasecka M, Sadkowska A, Huttunen KM, Podsiedlik M, Mikiciuk-Olasik E, Sikora J. An investigation into the pleiotropic activity of metformin. A glimpse of haemostasis. Eur J Pharmacol  2020; 872: 172984.
 [http://dx.doi.org/10.1016/j.ejphar.2020.172984] [PMID: 32017937]

[71]
Mamputu JC, Wiernsperger NF, Renier G. Antiatherogenic properties of metformin: The experimental evidence. Diabetes Metab  2003; 29: 6S71-6.
 [http://dx.doi.org/10.1016/S1262-3636(03)72790-6]

[72]
De Caterina R, Marchetti P, Bernini W, Giannarelli R, Giannessi D, Navalesi R. The direct effects of metformin on platelet function in vitro. Eur J Clin Pharmacol  1989; 37(2): 211-3.
 [http://dx.doi.org/10.1007/BF00558236] [PMID: 2792178]

[73]
Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): A multicentre, randomised, open-label trial. Lancet  2009; 373(9681): 2125-35.
 [http://dx.doi.org/10.1016/S0140-6736(09)60953-3] [PMID: 19501900]

[74]
Dormandy JA, Charbonnel B, Eckland DJA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): A randomised controlled trial. Lancet  2005; 366(9493): 1279-89.
 [http://dx.doi.org/10.1016/S0140-6736(05)67528-9] [PMID: 16214598]

[75]
Erdmann E, Dormandy JA, Charbonnel B, Massi-Benedetti M, Moules IK, Skene AM. The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) study. J Am Coll Cardiol  2007; 49(17): 1772-80.
 [http://dx.doi.org/10.1016/j.jacc.2006.12.048] [PMID: 17466227]

[76]
Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med  2016; 374(14): 1321-31.
 [http://dx.doi.org/10.1056/NEJMoa1506930] [PMID: 26886418]

[77]
Young LH, Viscoli CM, Curtis JP, et al. Cardiac outcomes after ischemic stroke or transient ischemic attack. Circulation  2017; 135(20): 1882-93.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.116.024863] [PMID: 28246237]

[78]
Vaccaro O, Masulli M, Nicolucci A, et al. Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): A randomised, multicentre trial. Lancet Diabetes Endocrinol  2017; 5(11): 887-97.
 [http://dx.doi.org/10.1016/S2213-8587(17)30317-0] [PMID: 28917544]

[79]
Xiao CC, Ren A, Yang J, et al. Effects of pioglitazone and glipizide on platelet function in patients with type 2 diabetes. Eur Rev Med Pharmacol Sci  2015; 19(6): 963-70.
 [PMID: 25855920]

[80]
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med  2007; 356(24): 2457-71.
 [http://dx.doi.org/10.1056/NEJMoa072761] [PMID: 17517853]

[81]
Erdmann E, Charbonnel B, Wilcox RG, et al. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: Data from the PROactive study (PROactive 08). Diabetes Care  2007; 30(11): 2773-8.
 [http://dx.doi.org/10.2337/dc07-0717] [PMID: 17666462]

[82]
Inzucchi SE, Masoudi FA, Wang Y, et al. Insulin-sensitizing antihyperglycemic drugs and mortality after acute myocardial infarction: Insights from the national heart care project. Diabetes Care  2005; 28(7): 1680-9.
 [http://dx.doi.org/10.2337/diacare.28.7.1680] [PMID: 15983320]

[83]
Bain S, Druyts E, Balijepalli C, et al. Cardiovascular events and all-cause mortality associated with sulphonylureas compared with other antihyperglycaemic drugs: A Bayesian meta-analysis of survival data. Diabetes Obes Metab  2017; 19(3): 329-35.
 [http://dx.doi.org/10.1111/dom.12821] [PMID: 27862902]

[84]
Holman RR, Haffner SM, McMurray JJ, et al. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med  2010; 362(16): 1463-76.
 [http://dx.doi.org/10.1056/NEJMoa1001122] [PMID: 20228402]

[85]
Malmberg K. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ  1997; 314(7093): 1512-5.
 [http://dx.doi.org/10.1136/bmj.314.7093.1512] [PMID: 9169397]

[86]
Gamble JM, Simpson SH, Eurich DT, Majumdar SR, Johnson JA. Insulin use and increased risk of mortality in type 2 diabetes: A cohort study. Diabetes Obes Metab  2010; 12(1): 47-53.
 [http://dx.doi.org/10.1111/j.1463-1326.2009.01125.x] [PMID: 19788429]

[87]
Colayco DC, Niu F, McCombs JS, Cheetham TC. A1C and cardiovascular outcomes in type 2 diabetes: A nested case-control study. Diabetes Care  2011; 34(1): 77-83.
 [http://dx.doi.org/10.2337/dc10-1318] [PMID: 20937686]

[88]
Holden SE, Jenkins-Jones S, Morgan CL, Schernthaner G, Currie CJ. Glucose-lowering with exogenous insulin monotherapy in type 2 diabetes: Dose association with all-cause mortality, cardiovascular events and cancer. Diabetes Obes Metab  2015; 17(4): 350-62.
 [http://dx.doi.org/10.1111/dom.12412] [PMID: 25399739]

[89]
Smooke S, Horwich TB, Fonarow GC. Insulin-treated diabetes is associated with a marked increase in mortality in patients with advanced heart failure. Am Heart J  2005; 149(1): 168-74.
 [http://dx.doi.org/10.1016/j.ahj.2004.07.005] [PMID: 15660049]

[90]
Currie CJ, Poole CD, Evans M, Peters JR, Morgan CL. Mortality and other important diabetes-related outcomes with insulin vs. other antihyperglycemic therapies in type 2 diabetes. J Clin Endocrinol Metab  2013; 98(2): 668-77.
 [http://dx.doi.org/10.1210/jc.2012-3042] [PMID: 23372169]

[91]
Mellbin LG, Malmberg K, Norhammar A, Wedel H, Rydén L. Prognostic implications of glucose-lowering treatment in patients with acute myocardial infarction and diabetes: Experiences from an extended follow-up of the Diabetes Mellitus Insulin–Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 Study. Diabetologia  2011; 54(6): 1308-17.
 [http://dx.doi.org/10.1007/s00125-011-2084-x] [PMID: 21359582]

[92]
Anyanwagu U, Mamza J, Donnelly R, Idris I. Comparison of cardiovascular and metabolic outcomes in people with type 2 diabetes on insulin versus non-insulin glucose-lowering therapies (GLTs): A systematic review and meta-analysis of clinical trials. Diabetes Res Clin Pract  2016; 121: 69-85.
 [http://dx.doi.org/10.1016/j.diabres.2016.09.002] [PMID: 27662041]

[93]
Gerstein HC, Bosch J, Dagenais GR, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med  2012; 367(4): 319-28.
 [http://dx.doi.org/10.1056/NEJMoa1203858] [PMID: 22686416]

[94]
Holden SE, Jenkins-Jones S, Currie CJ. Association between insulin monotherapy versus insulin plus metformin and the risk of all-cause mortality and other serious outcomes: A retrospective cohort study. PLoS One  2016; 11(5)e0153594
 [http://dx.doi.org/10.1371/journal.pone.0153594] [PMID: 27152598]

[95]
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med  2008; 359(15): 1577-89.
 [http://dx.doi.org/10.1056/NEJMoa0806470] [PMID: 18784090]

[96]
Wing RR, Bolin P, Brancati FL, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med  2013; 369(2): 145-54.
 [http://dx.doi.org/10.1056/NEJMoa1212914] [PMID: 23796131]

[97]
Lean MEJ, Leslie WS, Barnes AC, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): An open-label, cluster-randomised trial. Lancet  2018; 391(10120): 541-51.
 [http://dx.doi.org/10.1016/S0140-6736(17)33102-1] [PMID: 29221645]

[98]
Stewart RAH. Primary prevention of cardiovascular disease with a mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl J Med  2018; 379(14): 1388.
 [PMID: 30285333]

[99]
Umpierre D, Ribeiro PA, Kramer CK, et al. Physical activity advice only or structured exercise training and association with HbA1c levels in type 2 diabetes: A systematic review and meta-analysis. JAMA  2011; 305(17): 1790-9.
 [http://dx.doi.org/10.1001/jama.2011.576] [PMID: 21540423]

[100]
Schwaab B, Windmöller M, König IR, Schütt M. Evaluation of aerobic exercise intensity in patients with coronary artery disease and type 2 diabetes mellitus. J Clin Med  2020; 9(9): 2773.
 [http://dx.doi.org/10.3390/jcm9092773] [PMID: 32867079]

[101]
Chi Y, Wang X, Jia J, Huang T. Smoking status and type 2 diabetes, and cardiovascular disease: A comprehensive analysis of shared genetic etiology and causal relationship. Front Endocrinol  2022; 13: 809445.
 [http://dx.doi.org/10.3389/fendo.2022.809445] [PMID: 35250867]

[102]
Shalaeva EV, Saner H, Janabaev BB, Shalaeva AV. Tenfold risk increase of major cardiovascular events after high limb amputation with non-compliance for secondary prevention measures. Eur J Prev Cardiol  2017; 24(7): 708-16.
 [http://dx.doi.org/10.1177/2047487316687103] [PMID: 28071959]

[103]
Pyke C, Heller RS, Kirk RK, et al. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology  2014; 155(4): 1280-90.
 [http://dx.doi.org/10.1210/en.2013-1934] [PMID: 24467746]

[104]
McLean BA, Wong CK, Campbell JE, Hodson DJ, Trapp S, Drucker DJ. Revisiting the complexity of glp-1 action from sites of synthesis to receptor activation. Endocr Rev  2021; 42(2): 101-32.
 [http://dx.doi.org/10.1210/endrev/bnaa032] [PMID: 33320179]

[105]
Wei Y, Mojsov S. Tissue-specific expression of the human receptor for glucagon-like peptide-I: brain, heart and pancreatic forms have the same deduced amino acid sequences. FEBS Lett  1995; 358(3): 219-24.
 [http://dx.doi.org/10.1016/0014-5793(94)01430-9] [PMID: 7843404]

[106]
Thorens B. Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci  1992; 89(18): 8641-5.
 [http://dx.doi.org/10.1073/pnas.89.18.8641] [PMID: 1326760]

[107]
Drucker DJ, Philippe J, Mojsov S, Chick WL, Habener JF. Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc Natl Acad Sci  1987; 84(10): 3434-8.
 [http://dx.doi.org/10.1073/pnas.84.10.3434] [PMID: 3033647]

[108]
Donnelly D. The structure and function of the glucagon-like peptide-1 receptor and its ligands. Br J Pharmacol  2012; 166(1): 27-41.
 [http://dx.doi.org/10.1111/j.1476-5381.2011.01687.x] [PMID: 21950636]

[109]
Kinzig KP, D’Alessio DA, Seeley RJ. The diverse roles of specific GLP-1 receptors in the control of food intake and the response to visceral illness. J Neurosci  2002; 22(23): 10470-6.
 [http://dx.doi.org/10.1523/JNEUROSCI.22-23-10470.2002] [PMID: 12451146]

[110]
Cornu M, Thorens B. GLP-1 protects β-cells against apoptosis by enhancing the activity of an IGF-2/IGF1-receptor autocrine loop. Islets  2009; 1(3): 280-2.
 [http://dx.doi.org/10.4161/isl.1.3.9932] [PMID: 21099285]

[111]
Kreymann B, Ghatei MA, Williams G, Bloom SR. Glucagon-like peptide-1 7-36: A physiological incretin in man. Lancet  1987; 330(8571): 1300-4.
 [http://dx.doi.org/10.1016/S0140-6736(87)91194-9] [PMID: 2890903]

[112]
Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol  1997; 273(5): E981-8.
 [PMID: 9374685]

[113]
Egan JM, Meneilly GS, Habener JF, Elahi D. Glucagon-like peptide-1 augments insulin-mediated glucose uptake in the obese state. J Clin Endocrinol Metab  2002; 87(8): 3768-73.
 [http://dx.doi.org/10.1210/jcem.87.8.8743] [PMID: 12161508]

[114]
Hinnen D. Glucagon-like peptide 1 receptor agonists for type 2 diabetes. Diabetes Spectr  2017; 30(3): 202-10.
 [http://dx.doi.org/10.2337/ds16-0026] [PMID: 28848315]

[115]
Shaefer CF Jr, Kushner P, Aguilar R. User’s guide to mechanism of action and clinical use of GLP-1 receptor agonists. Postgrad Med  2015; 127(8): 818-26.
 [http://dx.doi.org/10.1080/00325481.2015.1090295] [PMID: 26371721]

[116]
Elrick H, Stimmler L, Hlad CJ Jr, Arai Y. Plasma insulin response to oral and intravenous glucose administration1. J Clin Endocrinol Metab  1964; 24(10): 1076-82.
 [http://dx.doi.org/10.1210/jcem-24-10-1076] [PMID: 14228531]

[117]
Holst JJ, Knop FK, Vilsbøll T, Krarup T, Madsbad S. Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes. Diabetes Care  2011; 34(S2): S251-7.
 [http://dx.doi.org/10.2337/dc11-s227] [PMID: 21525464]

[118]
Brunzell JD, Robertson RP, Lerner RL, et al. Relationships between fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests. J Clin Endocrinol Metab  1976; 42(2): 222-9.
 [http://dx.doi.org/10.1210/jcem-42-2-222] [PMID: 1262429]

[119]
Shah M, Vella A. Effects of GLP-1 on appetite and weight. Rev Endocr Metab Disord  2014; 15(3): 181-7.
 [http://dx.doi.org/10.1007/s11154-014-9289-5] [PMID: 24811133]

[120]
Dailey MJ, Moran TH. Glucagon-like peptide 1 and appetite. Trends Endocrinol Metab  2013; 24(2): 85-91.
 [http://dx.doi.org/10.1016/j.tem.2012.11.008] [PMID: 23332584]

[121]
Drucker DJ, Buse JB, Taylor K, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: A randomised, open-label, non-inferiority study. Lancet  2008; 372(9645): 1240-50.
 [http://dx.doi.org/10.1016/S0140-6736(08)61206-4] [PMID: 18782641]

[122]
Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol Metab  2021; 46: 101102.
 [http://dx.doi.org/10.1016/j.molmet.2020.101102] [PMID: 33068776]

[123]
Rosenstock J, Raccah D, Korányi L, et al. Efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin: A 24-week, randomized, open-label, active-controlled study (GetGoal-X). Diabetes Care  2013; 36(10): 2945-51.
 [http://dx.doi.org/10.2337/dc12-2709] [PMID: 23698396]

[124]
Buse JB, Rosenstock J, Sesti G, 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; 374(9683): 39-47.
 [http://dx.doi.org/10.1016/S0140-6736(09)60659-0] [PMID: 19515413]

[125]
Nauck M, Rizzo M, Johnson A, Bosch-Traberg H, Madsen J, Cariou B. Once-daily liraglutide versus lixisenatide as add-on to metformin in type 2 diabetes: A 26-week randomized controlled clinical trial. Diabetes Care  2016; 39(9): 1501-9.
 [http://dx.doi.org/10.2337/dc15-2479] [PMID: 27311491]

[126]
Cornell S. A review of GLP-1 receptor agonists in type 2 diabetes: A focus on the mechanism of action of once-weekly agents. J Clin Pharm Ther  2020; 45(S1): 17-27.
 [http://dx.doi.org/10.1111/jcpt.13230] [PMID: 32910490]

[127]
Monami M, Marchionni N, Mannucci E. Glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized clinical trials. Eur J Endocrinol  2009; 160(6): 909-17.
 [http://dx.doi.org/10.1530/EJE-09-0101] [PMID: 19318378]

[128]
Zheng SL, Roddick AJ, Aghar-Jaffar R, et al. Association between use of sodium-glucose cotransporter 2 inhibitors, glucagon- like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes. JAMA  2018; 319(15): 1580-91.
 [http://dx.doi.org/10.1001/jama.2018.3024] [PMID: 29677303]

[129]
Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): A double-blind, randomised placebo-controlled trial. Lancet  2019; 394(10193): 121-30.
 [http://dx.doi.org/10.1016/S0140-6736(19)31149-3] [PMID: 31189511]

[130]
Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): A double-blind, randomised placebo-controlled trial. Lancet  2018; 392(10157): 1519-29.
 [http://dx.doi.org/10.1016/S0140-6736(18)32261-X] [PMID: 30291013]

[131]
Wysham CH, MacConell LA, Maggs DG, Zhou M, Griffin PS, Trautmann ME. Five-year efficacy and safety data of exenatide once weekly: long-term results from the DURATION-1 randomized clinical trial. Mayo Clin Proc  2015; 90(3): 356-65.
 [http://dx.doi.org/10.1016/j.mayocp.2015.01.008] [PMID: 25744115]

[132]
Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med  2016; 375(4): 311-22.
 [http://dx.doi.org/10.1056/NEJMoa1603827] [PMID: 27295427]

[133]
Zelniker TA, Wiviott SD, Raz I, et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation  2019; 139(17): 2022-31.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.118.038868] [PMID: 30786725]

[134]
Palmer SC, Tendal B, Mustafa RA, et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: Systematic review and network meta-analysis of randomised controlled trials. BMJ  2021; 372: m4573.
 [http://dx.doi.org/10.1136/bmj.m4573] [PMID: 33441402]

[135]
Gerstein HC, Sattar N, Rosenstock J, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med  2021; 385(10): 896-907.
 [http://dx.doi.org/10.1056/NEJMoa2108269] [PMID: 34215025]

[136]
Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med  2015; 373(23): 2247-57.
 [http://dx.doi.org/10.1056/NEJMoa1509225] [PMID: 26630143]

[137]
Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med  2017; 377(13): 1228-39.
 [http://dx.doi.org/10.1056/NEJMoa1612917] [PMID: 28910237]

[138]
Maloney A, Rosenstock J, Fonseca V. A model-based meta-analysis of 24 antihyperglycemic drugs for type 2 diabetes: Comparison of treatment effects at therapeutic doses. Clin Pharmacol Ther  2019; 105(5): 1213-23.
 [http://dx.doi.org/10.1002/cpt.1307] [PMID: 30457671]

[139]
Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med  2011; 154(9): 602-13.
 [http://dx.doi.org/10.7326/0003-4819-154-9-201105030-00336] [PMID: 21403054]

[140]
Draznin B, Aroda VR, Bakris G, et al. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care  2022; 45(S1): S125-43.
 [http://dx.doi.org/10.2337/dc22-S009]

[141]
Abdul-Ghani MA, Norton L, DeFronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev  2011; 32(4): 515-31.
 [http://dx.doi.org/10.1210/er.2010-0029] [PMID: 21606218]

[142]
Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med  2015; 373(22): 2117-28.
 [http://dx.doi.org/10.1056/NEJMoa1504720] [PMID: 26378978]

[143]
Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: Results of the EMPA-REG OUTCOME ® trial. Eur Heart J  2016; 37(19): 1526-34.
 [http://dx.doi.org/10.1093/eurheartj/ehv728] [PMID: 26819227]

[144]
Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med  2016; 375(4): 323-34.
 [http://dx.doi.org/10.1056/NEJMoa1515920] [PMID: 27299675]

[145]
Roden M, Weng J, Eilbracht J, et al. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol  2013; 1(3): 208-19.
 [http://dx.doi.org/10.1016/S2213-8587(13)70084-6] [PMID: 24622369]

[146]
Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med  2020; 383(15): 1413-24.
 [http://dx.doi.org/10.1056/NEJMoa2022190] [PMID: 32865377]

[147]
Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med  2021; 385(16): 1451-61.
 [http://dx.doi.org/10.1056/NEJMoa2107038] [PMID: 34449189]

[148]
Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med  2019; 380(4): 347-57.
 [http://dx.doi.org/10.1056/NEJMoa1812389] [PMID: 30415602]

[149]
Cahn A, Raz I, Leiter LA, et al. Cardiovascular, renal, and metabolic outcomes of dapagliflozin versus placebo in a primary cardiovascular prevention cohort: Analyses from DECLARE-TIMI 58. Diabetes Care  2021; 44(5): 1159-67.
 [http://dx.doi.org/10.2337/dc20-2492] [PMID: 33653824]

[150]
Leiter LA, Cefalu WT, de Bruin TWA, Gause-Nilsson I, Sugg J, Parikh SJ. Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease: A 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. J Am Geriatr Soc  2014; 62(7): 1252-62.
 [http://dx.doi.org/10.1111/jgs.12881] [PMID: 24890683]

[151]
Furtado RHM, Bonaca MP, Raz I, et al. Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes mellitus and previous myocardial infarction. Circulation  2019; 139(22): 2516-27.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.119.039996] [PMID: 30882239]

[152]
McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med  2019; 381(21): 1995-2008.
 [http://dx.doi.org/10.1056/NEJMoa1911303] [PMID: 31535829]

[153]
Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med  2022; 387(12): 1089-98.
 [http://dx.doi.org/10.1056/NEJMoa2206286] [PMID: 36027570]

[154]
Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med  2020; 383(15): 1436-46.
 [http://dx.doi.org/10.1056/NEJMoa2024816] [PMID: 32970396]

[155]
Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med  2017; 377(7): 644-57.
 [http://dx.doi.org/10.1056/NEJMoa1611925] [PMID: 28605608]

[156]
Neal B, Perkovic V, Matthews DR, et al. Rationale, design and baseline characteristics of the canagliflozin cardiovascular assessment study-renal (CANVAS-R): A randomized, placebo-controlled trial. Diabetes Obes Metab  2017; 19(3): 387-93.
 [http://dx.doi.org/10.1111/dom.12829] [PMID: 28120497]

[157]
Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol  2018; 6(9): 691-704.
 [http://dx.doi.org/10.1016/S2213-8587(18)30141-4] [PMID: 29937267]

[158]
Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med  2019; 380(24): 2295-306.
 [http://dx.doi.org/10.1056/NEJMoa1811744] [PMID: 30990260]

[159]
Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med  2021; 384(2): 129-39.
 [http://dx.doi.org/10.1056/NEJMoa2030186] [PMID: 33200891]

[160]
Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med  2021; 384(2): 117-28.
 [http://dx.doi.org/10.1056/NEJMoa2030183] [PMID: 33200892]

[161]
Kosiborod M, Cavender MA, Fu AZ, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs. Circulation  2017; 136(3): 249-59.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.117.029190] [PMID: 28522450]

[162]
Kosiborod M, Lam CSP, Kohsaka S, et al. Cardiovascular events associated with sglt-2 inhibitors versus other glucose-lowering drugs. J Am Coll Cardiol  2018; 71(23): 2628-39.
 [http://dx.doi.org/10.1016/j.jacc.2018.03.009] [PMID: 29540325]

[163]
Bischoff H. Pharmacology of alpha-glucosidase inhibition. Eur J Clin Invest  1994; 24(S3): 3-10.
 [PMID: 8001624]

[164]
Dirir AM, Daou M, Yousef AF, Yousef LF. A review of alpha-glucosidase inhibitors from plants as potential candidates for the treatment of type-2 diabetes. Phytochem Rev  2022; 21(4): 1049-79.
 [http://dx.doi.org/10.1007/s11101-021-09773-1] [PMID: 34421444]

[165]
McIver LA, Preuss CV, Tripp J. Acarbose. Treasure Island (FL): StatPearls 2023.

[166]
Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose for prevention of type 2 diabetes mellitus: The STOP-NIDDM randomised trial. Lancet  2002; 359(9323): 2072-7.
 [http://dx.doi.org/10.1016/S0140-6736(02)08905-5] [PMID: 12086760]

[167]
Chiasson JL, Gomis R, Hanefeld M, Josse RG, Karasik A, Laakso M. The STOP-NIDDM Trial: An international study on the efficacy of an α-glucosidase inhibitor to prevent type 2 diabetes in a population with impaired glucose tolerance: rationale, design, and preliminary screening data. Diabetes Care  1998; 21(10): 1720-5.
 [http://dx.doi.org/10.2337/diacare.21.10.1720] [PMID: 9773737]

[168]
Johnson AB, Taylor R. Does suppression of postprandial blood glucose excursions by the alpha-glucosidase inhibitor miglitol improve insulin sensitivity in diet-treated type II diabetic patients? Diabetes Care  1996; 19(6): 559-63.
 [http://dx.doi.org/10.2337/diacare.19.6.559] [PMID: 8725851]

[169]
Zheng H, Sigal RJ, Coyle D, et al. Comparative efficacy and safety of antihyperglycemic drug classes for patients with type 2 diabetes following failure with metformin monotherapy: A systematic review and network meta-analysis of randomized controlled trials. Diabetes Metab Res Rev  2022; 38(4)e3515
 [http://dx.doi.org/10.1002/dmrr.3515] [PMID: 34951928]

[170]
Holman RR, Cull CA, Turner RC. A randomized double-blind trial of acarbose in type 2 diabetes shows improved glycemic control over 3 years (U.K. Prospective Diabetes Study 44). Diabetes Care  1999; 22(6): 960-4.
 [http://dx.doi.org/10.2337/diacare.22.6.960] [PMID: 10372249]

[171]
Mannucci E, Gallo M, Pintaudi B, et al. All-cause mortality and cardiovascular events in patients with type 2 diabetes treated with alpha-glucosidase inhibitors: A meta-analysis of randomized controlled trials. Nutr Metab Cardiovasc Dis  2022; 32(2): 511-4.
 [http://dx.doi.org/10.1016/j.numecd.2021.10.010] [PMID: 34893404]

[172]
Holman RR, Coleman RL, Chan JCN, et al. Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol  2017; 5(11): 877-86.
 [http://dx.doi.org/10.1016/S2213-8587(17)30309-1] [PMID: 28917545]

[173]
Asakura M, Kim J, Asanuma H, et al. Does treatment of impaired glucose tolerance improve cardiovascular outcomes in patients with previous myocardial infarction? Cardiovasc Drugs Ther  2017; 31(4): 401-11.
 [http://dx.doi.org/10.1007/s10557-017-6740-3] [PMID: 28779371]

[174]
Coleman RL, Scott CAB, Lang Z, Bethel MA, Tuomilehto J, Holman RR. Meta-analysis of the impact of alpha-glucosidase inhibitors on incident diabetes and cardiovascular outcomes. Cardiovasc Diabetol  2019; 18(1): 135.
 [http://dx.doi.org/10.1186/s12933-019-0933-y] [PMID: 31623625]

[175]
Derosa G, Mereu R, D’Angelo A, et al. ORIGINAL ARTICLE: Effect of pioglitazone and acarbose on endothelial inflammation biomarkers during oral glucose tolerance test in diabetic patients treated with sulphonylureas and metformin. J Clin Pharm Ther  2010; 35(5): 565-79.
 [http://dx.doi.org/10.1111/j.1365-2710.2009.01132.x] [PMID: 20831680]

[176]
Zhang YS, Zheng YD, Yuan Y, Chen SC, Xie BC. Effects of anti- diabetic drugs on fracture risk: a systematic review and network meta-analysis. Front Endocrinol  2021; 12735824
 [http://dx.doi.org/10.3389/fendo.2021.735824] [PMID: 34721294]

[177]
Frias JP, Nauck MA, Van J, et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: A randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet  2018; 392(10160): 2180-93.
 [http://dx.doi.org/10.1016/S0140-6736(18)32260-8] [PMID: 30293770]

[178]
Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med  2021; 385(6): 503-15.
 [http://dx.doi.org/10.1056/NEJMoa2107519] [PMID: 34170647]

[179]
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]

[180]
Ludvik B, Giorgino F, Jódar E, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): A randomised, open-label, parallel-group, phase 3 trial. Lancet  2021; 398(10300): 583-98.
 [http://dx.doi.org/10.1016/S0140-6736(21)01443-4] [PMID: 34370970]

[181]
Del Prato S, Kahn SE, Pavo I, et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): A randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet  2021; 398(10313): 1811-24.
 [http://dx.doi.org/10.1016/S0140-6736(21)02188-7] [PMID: 34672967]

[182]
Dahl D, Onishi Y, Norwood P, et al. Effect of subcutaneous tirzepatide vs. placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes. JAMA  2022; 327(6): 534-45.
 [http://dx.doi.org/10.1001/jama.2022.0078] [PMID: 35133415]

[183]
Nauck MA, D’Alessio DA. Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction. Cardiovasc Diabetol  2022; 21(1): 169.
 [http://dx.doi.org/10.1186/s12933-022-01604-7] [PMID: 36050763]

[184]
Pirro V, Roth KD, Lin Y, et al. Effects of tirzepatide, a dual GIP and GLP-1 RA, on lipid and metabolite profiles in subjects with type 2 diabetes. J Clin Endocrinol Metab  2022; 107(2): 363-78.
 [http://dx.doi.org/10.1210/clinem/dgab722] [PMID: 34608929]

[185]
Sattar N, McGuire DK, Pavo I, et al. Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis. Nat Med  2022; 28(3): 591-8.
 [http://dx.doi.org/10.1038/s41591-022-01707-4] [PMID: 35210595]

[186]
Min T, Bain SC. The role of tirzepatide, dual gip and glp-1 receptor agonist, in the management of type 2 diabetes: The SURPASS clinical trials. Diabetes Ther  2021; 12(1): 143-57.
 [http://dx.doi.org/10.1007/s13300-020-00981-0] [PMID: 33325008]

[187]
Inagaki N, Takeuchi M, Oura T, Imaoka T, Seino Y. Efficacy and safety of tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono): A double-blind, multicentre, randomised, phase 3 trial. Lancet Diabetes Endocrinol  2022; 10(9): 623-33.
 [http://dx.doi.org/10.1016/S2213-8587(22)00188-7] [PMID: 35914543]

[188]
Kadowaki T, Chin R, Ozeki A, Imaoka T, Ogawa Y. Safety and efficacy of tirzepatide as an add-on to single oral antihyperglycaemic medication in patients with type 2 diabetes in Japan (SURPASS J-combo): a multicentre, randomised, open-label, parallel-group, phase 3 trial. Lancet Diabetes Endocrinol  2022; 10(9): 634-44.
 [http://dx.doi.org/10.1016/S2213-8587(22)00187-5] [PMID: 35914542]

[189]
Tillner J, Posch MG, Wagner F, et al. A novel dual glucagon-like peptide and glucagon receptor agonist SAR425899: Results of randomized, placebo-controlled first-in-human and first-in-patient trials. Diabetes Obes Metab  2019; 21(1): 120-8.
 [http://dx.doi.org/10.1111/dom.13494] [PMID: 30091218]

[190]
Ambery P, Parker VE, Stumvoll M, 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; 391(10140): 2607-18.
 [http://dx.doi.org/10.1016/S0140-6736(18)30726-8] [PMID: 29945727]

[191]
Matschinsky FM, Wilson DF. The central role of glucokinase in glucose homeostasis: A perspective 50 years after demonstrating the presence of the enzyme in islets of langerhans. Front Physiol  2019; 10: 148.
 [http://dx.doi.org/10.3389/fphys.2019.00148] [PMID: 30949058]

[192]
Matschinsky FM. Assessing the potential of glucokinase activators in diabetes therapy. Nat Rev Drug Discov  2009; 8(5): 399-416.
 [http://dx.doi.org/10.1038/nrd2850] [PMID: 19373249]

[193]
Zhu XX, Zhu DL, Li XY, et al. Dorzagliatin (HMS5552), a novel dual-acting glucokinase activator, improves glycaemic control and pancreatic β-cell function in patients with type 2 diabetes: A 28- day treatment study using biomarker-guided patient selection. Diabetes Obes Metab  2018; 20(9): 2113-20.
 [http://dx.doi.org/10.1111/dom.13338] [PMID: 29707866]

[194]
Wilding JPH, Leonsson-Zachrisson M, Wessman C, Johnsson E. Dose-ranging study with the glucokinase activator AZD1656 in patients with type 2 diabetes mellitus on metformin. Diabetes Obes Metab  2013; 15(8): 750-9.
 [http://dx.doi.org/10.1111/dom.12088] [PMID: 23464532]

[195]
Morrow LA, Leonsson-Zachrisson M, Ericsson H, et al. Safety, pharmacokinetics and pharmacodynamics of multiple-ascending doses of the novel glucokinase activator AZD1656 in patients with type 2 diabetes mellitus. Diabetes Obes Metab  2012; 14(12): 1114-22.
 [http://dx.doi.org/10.1111/j.1463-1326.2012.01661.x] [PMID: 22775976]

[196]
Bonadonna RC, Heise T, Arbet-Engels C, et al. Piragliatin (RO4389620), a novel glucokinase activator, lowers plasma glucose both in the postabsorptive state and after a glucose challenge in patients with type 2 diabetes mellitus: A mechanistic study. J Clin Endocrinol Metab  2010; 95(11): 5028-36.
 [http://dx.doi.org/10.1210/jc.2010-1041] [PMID: 20739378]

[197]
Zhi J, Zhai S. Effects of piragliatin, a glucokinase activator, on fasting and postprandial plasma glucose in patients with type 2 diabetes mellitus. J Clin Pharmacol  2016; 56(2): 231-8.
 [http://dx.doi.org/10.1002/jcph.589] [PMID: 26183686]

[198]
Katz L, Manamley N, Snyder WJ, et al. AMG 151 (ARRY-403), a novel glucokinase activator, decreases fasting and postprandial glycaemia in patients with type 2 diabetes. Diabetes Obes Metab  2016; 18(2): 191-5.
 [http://dx.doi.org/10.1111/dom.12586] [PMID: 26434934]

[199]
Chepurny OG, Bertinetti D, Diskar M, et al. Stimulation of proglucagon gene expression by human GPR119 in enteroendocrine L-cell line GLUTag. Mol Endocrinol  2013; 27(8): 1267-82.
 [http://dx.doi.org/10.1210/me.2013-1029] [PMID: 23798572]

[200]
Gao J, Tian L, Weng G, et al. Stimulating beta cell replication and improving islet graft function by GPR119 agonists. Transpl Int  2011; 24(11): 1124-34.
 [http://dx.doi.org/10.1111/j.1432-2277.2011.01332.x] [PMID: 21902730]

[201]
Yamada Y, Terauchi Y, Watada H, et al. Efficacy and safety of GPR119 agonist DS-8500a in Japanese patients with type 2 diabetes: A randomized, double-blind, placebo-controlled, 12-week study. Adv Ther  2018; 35(3): 367-81.
 [http://dx.doi.org/10.1007/s12325-018-0668-2] [PMID: 29488152]

[202]
Katz LB, Gambale JJ, Rothenberg PL, et al. Effects of JNJ-38431055, a novel GPR119 receptor agonist, in randomized, double-blind, placebo-controlled studies in subjects with type 2 diabetes. Diabetes Obes Metab  2012; 14(8): 709-16.
 [http://dx.doi.org/10.1111/j.1463-1326.2012.01587.x] [PMID: 22340428]

[203]
Nunez DJ, Bush MA, Collins DA, et al. Gut hormone pharmacology of a novel GPR119 agonist (GSK1292263), metformin, and sitagliptin in type 2 diabetes mellitus: Results from two randomized studies. PLoS One  2014; 9(4): e92494.
 [http://dx.doi.org/10.1371/journal.pone.0092494] [PMID: 24699248]

[204]
Vajda EG, Logan D, Lasseter K, et al. Pharmacokinetics and pharmacodynamics of single and multiple doses of the glucagon receptor antagonist LGD-6972 in healthy subjects and subjects with type 2 diabetes mellitus. Diabetes Obes Metab  2017; 19(1): 24-32.
 [http://dx.doi.org/10.1111/dom.12752] [PMID: 27501510]

[205]
Guzman CB, Zhang XM, Liu R, et al. Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes. Diabetes Obes Metab  2017; 19(11): 1521-8.
 [http://dx.doi.org/10.1111/dom.12958] [PMID: 28371155]

[206]
Kelly RP, Garhyan P, Raddad E, et al. Short-term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes. Diabetes Obes Metab  2015; 17(4): 414-22.
 [http://dx.doi.org/10.1111/dom.12446] [PMID: 25656305]

[207]
Bennett CF, Swayze EE. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol  2010; 50(1): 259-93.
 [http://dx.doi.org/10.1146/annurev.pharmtox.010909.105654] [PMID: 20055705]

[208]
Johnson TO, Ermolieff J, Jirousek MR. Protein tyrosine phosphatase 1B inhibitors for diabetes. Nat Rev Drug Discov  2002; 1(9): 696-709.
 [http://dx.doi.org/10.1038/nrd895] [PMID: 12209150]

[209]
Digenio A, Pham NC, Watts LM, et al. Antisense inhibition of protein tyrosine phosphatase 1b with IONIS-PTP-1BRx improves insulin sensitivity and reduces weight in overweight patients with type 2 diabetes. Diabetes Care  2018; 41(4): 807-14.
 [http://dx.doi.org/10.2337/dc17-2132] [PMID: 29439147]

[210]
Kharitonenkov A, Shiyanova TL, Koester A, et al. FGF-21 as a novel metabolic regulator. J Clin Invest  2005; 115(6): 1627-35.
 [http://dx.doi.org/10.1172/JCI23606] [PMID: 15902306]

[211]
Coskun T, Bina HA, Schneider MA, et al. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology  2008; 149(12): 6018-27.
 [http://dx.doi.org/10.1210/en.2008-0816] [PMID: 18687777]

[212]
Xu J, Lloyd DJ, Hale C, et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes  2009; 58(1): 250-9.
 [http://dx.doi.org/10.2337/db08-0392] [PMID: 18840786]

[213]
Berglund ED, Li CY, Bina HA, et al. Fibroblast growth factor 21 controls glycemia via regulation of hepatic glucose flux and insulin sensitivity. Endocrinology  2009; 150(9): 4084-93.
 [http://dx.doi.org/10.1210/en.2009-0221] [PMID: 19470704]

[214]
Kharitonenkov A, Wroblewski VJ, Koester A, et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology  2007; 148(2): 774-81.
 [http://dx.doi.org/10.1210/en.2006-1168] [PMID: 17068132]

[215]
Lundåsen T, Hunt MC, Nilsson LM, et al. PPARα is a key regulator of hepatic FGF21. Biochem Biophys Res Commun  2007; 360(2): 437-40.
 [http://dx.doi.org/10.1016/j.bbrc.2007.06.068] [PMID: 17601491]

[216]
Lampsas S, Tsaplaris P, Pantelidis P, et al. The role of endothelial related circulating biomarkers in COVID-19. A systematic review and meta-analysis. Curr Med Chem  2022; 29(21): 3790-805.
 [http://dx.doi.org/10.2174/1875533XMTE44NTYf0] [PMID: 34702152]

[217]
Charles ED, Neuschwander-Tetri BA, Pablo Frias J, 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; 27(1): 41-9.
 [http://dx.doi.org/10.1002/oby.22344] [PMID: 30520566]

[218]
Cheng X, Zhu B, Jiang F, Fan H. Serum FGF-21 levels in type 2 diabetic patients. Endocr Res  2011; 36(4): 142-8.
 [http://dx.doi.org/10.3109/07435800.2011.558550] [PMID: 21973233]

[219]
Gaich G, Chien JY, Fu H, et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab  2013; 18(3): 333-40.
 [http://dx.doi.org/10.1016/j.cmet.2013.08.005] [PMID: 24011069]

[220]
Holt RIG, Simpson HL, Sönksen PH. The role of the growth hormone-insulin-like growth factor axis in glucose homeostasis. Diabet Med  2003; 20(1): 3-15.
 [http://dx.doi.org/10.1046/j.1464-5491.2003.00827.x] [PMID: 12519314]

[221]
Clemmons DR, Miller S, Mamputu JC. Safety and metabolic effects of tesamorelin, a growth hormone-releasing factor analogue, in patients with type 2 diabetes: A randomized, placebo-controlled trial. PLoS One  2017; 12(6)e0179538
 [http://dx.doi.org/10.1371/journal.pone.0179538] [PMID: 28617838]

[222]
Corpas E, Harman SM, Piñeyro MA, Roberson R, Blackman MR. Growth hormone (GH)-releasing hormone-(1-29) twice daily reverses the decreased GH and insulin-like growth factor-I levels in old men. J Clin Endocrinol Metab  1992; 75(2): 530-5.
 [PMID: 1379256]

[223]
Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature  1999; 402(6762): 656-60.
 [http://dx.doi.org/10.1038/45230] [PMID: 10604470]

[224]
Benso A, St-Pierre DH, Prodam F, et al. Metabolic effects of overnight continuous infusion of unacylated ghrelin in humans. Eur J Endocrinol  2012; 166(5): 911-6.
 [http://dx.doi.org/10.1530/EJE-11-0982] [PMID: 22379116]

[225]
Özcan B, Neggers SJCMM, Miller AR, et al. Does des-acyl ghrelin improve glycemic control in obese diabetic subjects by decreasing acylated ghrelin levels? Eur J Endocrinol  2014; 170(6): 799-807.
 [http://dx.doi.org/10.1530/EJE-13-0347] [PMID: 23864339]

[226]
Allas S, Delale T, Ngo N, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of AZP-531, a first-in-class analogue of unacylated ghrelin, in healthy and overweight/obese subjects and subjects with type 2 diabetes. Diabetes Obes Metab  2016; 18(9): 868-74.
 [http://dx.doi.org/10.1111/dom.12675] [PMID: 27063928]

[227]
Nass R, Pezzoli SS, Oliveri MC, et al. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: A randomized trial. Ann Intern Med  2008; 149(9): 601-11.
 [http://dx.doi.org/10.7326/0003-4819-149-9-200811040-00003] [PMID: 18981485]

[228]
Tong J, Prigeon RL, Davis HW, et al. Ghrelin suppresses glucose-stimulated insulin secretion and deteriorates glucose tolerance in healthy humans. Diabetes  2010; 59(9): 2145-51.
 [http://dx.doi.org/10.2337/db10-0504] [PMID: 20584998]

[229]
Rooks DS, Laurent D, Praestgaard J, Rasmussen S, Bartlett M, Tankó LB. Effect of bimagrumab on thigh muscle volume and composition in men with casting-induced atrophy. J Cachexia Sarcopenia Muscle  2017; 8(5): 727-34.
 [http://dx.doi.org/10.1002/jcsm.12205] [PMID: 28905498]

[230]
Garito T, Roubenoff R, Hompesch M, et al. Bimagrumab improves body composition and insulin sensitivity in insulin-resistant individuals. Diabetes Obes Metab  2018; 20(1): 94-102.
 [http://dx.doi.org/10.1111/dom.13042] [PMID: 28643356]

[231]
Fournier B, Murray B, Gutzwiller S, et al. Blockade of the activin receptor IIb activates functional brown adipogenesis and thermogenesis by inducing mitochondrial oxidative metabolism. Mol Cell Biol  2012; 32(14): 2871-9.
 [http://dx.doi.org/10.1128/MCB.06575-11] [PMID: 22586266]

[232]
Heymsfield SB, Coleman LA, Miller R, et al. Effect of bimagrumab vs. placebo on body fat mass among adults with type 2 diabetes and obesity. JAMA Netw Open  2021; 4(1): e2033457.
 [http://dx.doi.org/10.1001/jamanetworkopen.2020.33457] [PMID: 33439265]

[233]
Gross B, Pawlak M, Lefebvre P, Staels B. PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD. Nat Rev Endocrinol  2017; 13(1): 36-49.
 [http://dx.doi.org/10.1038/nrendo.2016.135] [PMID: 27636730]

[234]
Ji L, Song W, Fang H, et al. Efficacy and safety of chiglitazar, a novel peroxisome proliferator-activated receptor pan-agonist, in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled, phase 3 trial (CMAP). Sci Bull  2021; 66(15): 1571-80.
 [http://dx.doi.org/10.1016/j.scib.2021.03.019] [PMID: 36654286]

[235]
Lincoff AM, Tardif JC, Schwartz GG, et al. Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial. JAMA  2014; 311(15): 1515-25.
 [http://dx.doi.org/10.1001/jama.2014.3321] [PMID: 24682069]

[236]
Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA  2005; 294(20): 2581-6.
 [http://dx.doi.org/10.1001/jama.294.20.joc50147] [PMID: 16239637]

[237]
Ratner RE, Parikh S, Tou C, Group GS. Efficacy, safety and tolerability of tesaglitazar when added to the therapeutic regimen of poorly controlled insulin-treated patients with type 2 diabetes. Diab Vasc Dis Res  2007; 4(3): 214-21.
 [http://dx.doi.org/10.3132/dvdr.2007.042] [PMID: 17907111]

[238]
Pirags V, Lebovitz H, Fouqueray P. Imeglimin, a novel glimin oral antidiabetic, exhibits a good efficacy and safety profile in type 2 diabetic patients. Diabetes Obes Metab  2012; 14(9): 852-8.
 [http://dx.doi.org/10.1111/j.1463-1326.2012.01611.x] [PMID: 22519919]

[239]
Fouqueray P, Pirags V, Diamant M, et al. The efficacy and safety of imeglimin as add-on therapy in patients with type 2 diabetes inadequately controlled with sitagliptin monotherapy. Diabetes Care  2014; 37(7): 1924-30.
 [http://dx.doi.org/10.2337/dc13-2349] [PMID: 24722500]

[240]
Fouqueray P, Pirags V, Inzucchi SE, et al. The efficacy and safety of imeglimin as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Diabetes Care  2013; 36(3): 565-8.
 [http://dx.doi.org/10.2337/dc12-0453] [PMID: 23160726]

[241]
Warder SE, Tucker LA, McLoughlin SM, et al. Discovery, identification, and characterization of candidate pharmacodynamic markers of methionine aminopeptidase-2 inhibition. J Proteome Res  2008; 7(11): 4807-20.
 [http://dx.doi.org/10.1021/pr800388p] [PMID: 18828628]

[242]
Griffith EC, Su Z, Turk BE, et al. Methionine aminopeptidase (type 2) is the common target for angiogenesis inhibitors AGM-1470 and ovalicin. Chem Biol  1997; 4(6): 461-71.
 [http://dx.doi.org/10.1016/S1074-5521(97)90198-8] [PMID: 9224570]

[243]
Ingber D, Fujita T, Kishimoto S, et al. Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature  1990; 348(6301): 555-7.
 [http://dx.doi.org/10.1038/348555a0] [PMID: 1701033]

[244]
Bråkenhielm E, Cao R, Gao B, et al. Angiogenesis inhibitor, TNP-470, prevents diet-induced and genetic obesity in mice. Circ Res  2004; 94(12): 1579-88.
 [http://dx.doi.org/10.1161/01.RES.0000132745.76882.70] [PMID: 15155527]

[245]
Siddik MAB, Das BC, Weiss L, Dhurandhar NV, Hegde V. A MetAP2 inhibitor blocks adipogenesis, yet improves glucose uptake in cells. Adipocyte  2019; 8(1): 240-53.
 [http://dx.doi.org/10.1080/21623945.2019.1636627] [PMID: 31264515]

[246]
Proietto J, Malloy J, Zhuang D, et al. Efficacy and safety of methionine aminopeptidase 2 inhibition in type 2 diabetes: a randomised, placebo-controlled clinical trial. Diabetologia  2018; 61(9): 1918-22.
 [http://dx.doi.org/10.1007/s00125-018-4677-0] [PMID: 29992370]

[247]
McCandless SE, Yanovski JA, Miller J, et al. Effects of METAP2 inhibition on hyperphagia and body weight in Prader–Willi syndrome: A randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab  2017; 19(12): 1751-61.
 [http://dx.doi.org/10.1111/dom.13021] [PMID: 28556449]

[248]
Burkey BF, Hoglen NC, Inskeep P, Wyman M, Hughes TE, Vath JE. Preclinical efficacy and safety of the novel antidiabetic, antiobesity MetAP2 Inhibitor ZGN-1061. J Pharmacol Exp Ther  2018; 365(2): 301-13.
 [http://dx.doi.org/10.1124/jpet.117.246272] [PMID: 29491038]

[249]
Wentworth JM, Colman PG. The methionine aminopeptidase 2 inhibitor ZGN-1061 improves glucose control and weight in overweight and obese individuals with type 2 diabetes: A randomized, placebo-controlled trial. Diabetes Obes Metab  2020; 22(7): 1215-9.
 [http://dx.doi.org/10.1111/dom.14009] [PMID: 32077231]

[250]
Kersten S. Physiological regulation of lipoprotein lipase. Biochim Biophys Acta Mol Cell Biol Lipids  2014; 1841(7): 919-33.
 [http://dx.doi.org/10.1016/j.bbalip.2014.03.013] [PMID: 24721265]

[251]
Hatsuda S, Shoji T, Shinohara K, et al. Association between plasma angiopoietin-like protein 3 and arterial wall thickness in healthy subjects. J Vasc Res  2007; 44(1): 61-6.
 [http://dx.doi.org/10.1159/000098153] [PMID: 17191020]

[252]
Christopoulou E, Elisaf M, Filippatos T. Effects of angiopoietin- like 3 on triglyceride regulation, glucose homeostasis, and diabetes. Dis Markers  2019; 2019: 1-8.
 [http://dx.doi.org/10.1155/2019/6578327] [PMID: 30944669]

[253]
Graham MJ, Lee RG, Brandt TA, et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N Engl J Med  2017; 377(3): 222-32.
 [http://dx.doi.org/10.1056/NEJMoa1701329] [PMID: 28538111]

[254]
Jiang S, Qiu GH, Zhu N, Hu ZY, Liao DF, Qin L. ANGPTL3: a novel biomarker and promising therapeutic target. J Drug Target  2019; 27(8): 876-84.
 [http://dx.doi.org/10.1080/1061186X.2019.1566342] [PMID: 30615486]
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DOI https://dx.doi.org/10.2174/1381612829666230703161058	Print ISSN 1381-6128
Publisher Name Bentham Science Publisher	Online ISSN 1873-4286
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