{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T19:01:55Z","timestamp":1793041315852,"version":"4.5.0"},"reference-count":112,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T00:00:00Z","timestamp":1701734400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The treatment of type 2 diabetes (T2D) necessitates a multifaceted approach that combines behavioral and pharmacological interventions to mitigate complications and sustain a high quality of life. Treatment encompasses the management of glucose levels, weight, cardiovascular risk factors, comorbidities, and associated complications through medication and lifestyle adjustments. Metformin, a standard in diabetes management, continues to serve as the primary, first-line oral treatment across all age groups due to its efficacy, versatility in combination therapy, and cost-effectiveness. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) offer notable benefits for HbA1c and weight reduction, with significant cardiovascular benefits. Sodium-glucose cotransporter inhibitors (SGLT-2i) lower glucose levels independently of insulin while conferring notable benefits for cardiovascular, renal, and heart-failure outcomes. Combined therapies emphasizing early and sustained glycemic control are promising options for diabetes management. As insulin therapy remains pivotal, metformin and non-insulin agents such as GLP-1 RA and SGLT-2i offer compelling options. Notably, exciting novel treatments like the dual GLP-1\/ glucose-dependent insulinotropic polypeptide (GIP) agonist show promise for substantially reducing glycated hemoglobin and body weight. This comprehensive review highlights the evolving landscape of pharmacotherapy in diabetes, the drugs currently available for treating diabetes, their effectiveness and efficacy, the impact on target organs, and side effects. This work also provides insights that can support the customization of treatment strategies.<\/jats:p>","DOI":"10.3390\/ijms242417147","type":"journal-article","created":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T08:09:17Z","timestamp":1701763757000},"page":"17147","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":116,"title":["Drug Therapies for Diabetes"],"prefix":"10.3390","volume":"24","author":[{"given":"Roni","family":"Weinberg Sibony","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Ben-Gurion University, Beer Sheva 8443944, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6661-8698","authenticated-orcid":false,"given":"Omri","family":"Segev","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saar","family":"Dor","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Ben-Gurion University, Beer Sheva 8443944, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itamar","family":"Raz","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112001, Israel"},{"name":"Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem 91240, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1056\/NEJMoa2024816","article-title":"Dapagliflozin in Patients with Chronic Kidney Disease","volume":"383","author":"Heerspink","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1056\/NEJMoa2206038","article-title":"Tirzepatide Once Weekly for the Treatment of Obesity","volume":"387","author":"Jastreboff","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1056\/NEJMoa2306963","article-title":"Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity","volume":"389","author":"Kosiborod","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"416","DOI":"10.2337\/dc17-1144","article-title":"The Legacy Effect in Type 2 Diabetes: Impact of Early Glycemic Control on Future Complications (The Diabetes & Aging Study)","volume":"42","author":"Laiteerapong","year":"2019","journal-title":"Diabetes Care"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1056\/NEJMoa2022190","article-title":"Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure","volume":"383","author":"Packer","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_6","first-page":"433","article-title":"Durability of Triple Combination Therapy Versus Stepwise Addition Therapy in Patients With New-Onset T2DM: 3-Year Follow-up of EDICT","volume":"44","author":"Puckett","year":"2020","journal-title":"Diabetes Care"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s40265-017-0694-4","article-title":"Early Combination Therapy with Oral Glucose-Lowering Agents in Type 2 Diabetes","volume":"77","author":"Bianchi","year":"2017","journal-title":"Drugs"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/S2213-8587(20)30230-8","article-title":"Diabetes in ageing: Pathways for developing the evidence base for clinical guidance","volume":"8","author":"Munshi","year":"2020","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"647","DOI":"10.2337\/dc20-1964","article-title":"Metformin Benefits: Another Example for Alternative Energy Substrate Mechanism?","volume":"44","author":"Giaccari","year":"2021","journal-title":"Diabetes Care"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6","DOI":"10.3389\/fendo.2017.00006","article-title":"Clinical Review of Antidiabetic Drugs: Implications for Type 2 Diabetes Mellitus Management","volume":"8","author":"Chaudhury","year":"2017","journal-title":"Front. Endocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"191","DOI":"10.3389\/fendo.2020.00191","article-title":"Metformin and Its Benefits for Various Diseases","volume":"11","author":"Lv","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1038\/s41574-023-00833-4","article-title":"Metformin: Update on mechanisms of action and repurposing potential","volume":"19","author":"Foretz","year":"2023","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.resuscitation.2022.03.017","article-title":"Metformin protects against cardiac and renal damage in diabetic cardiac arrest patients","volume":"174","author":"Rutledge","year":"2022","journal-title":"Resuscitation"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.3233\/JAD-180263","article-title":"Metformin Use Associated with Reduced Risk of Dementia in Patients with Diabetes: A Systematic Review and Meta-Analysis","volume":"65","author":"Campbell","year":"2018","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.canep.2012.12.009","article-title":"Association of metformin use with cancer incidence and mortality: A meta-analysis","volume":"37","author":"Zhang","year":"2013","journal-title":"Cancer Epidemiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1741-7015-9-33","article-title":"Understanding the benefit of metformin use in cancer treatment","volume":"9","author":"Dowling","year":"2011","journal-title":"BMC Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1007\/s00125-017-4372-6","article-title":"Repurposing metformin for the prevention of cancer and cancer recurrence","volume":"60","author":"DeCensi","year":"2017","journal-title":"Diabetologia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1007\/s00125-017-4337-9","article-title":"Impact of metformin on cardiovascular disease: A meta-analysis of randomised trials among people with type 2 diabetes","volume":"60","author":"Griffin","year":"2017","journal-title":"Diabetologia"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"UK Prospective Diabetes Study (UKPDS) Group (1998). Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet, 352, 854\u2013865.","DOI":"10.1016\/S0140-6736(98)07037-8"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1016\/S1473-3099(23)00299-2","article-title":"Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): A multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial","volume":"23","author":"Bramante","year":"2023","journal-title":"Lancet Infect. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2753","DOI":"10.2337\/dci22-0034","article-title":"Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)","volume":"45","author":"Davies","year":"2022","journal-title":"Diabetes Care"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1002\/cmdc.202100177","article-title":"Thiazolidinediones: An In\u2013Depth Study of Their Synthesis and Application to Medicinal Chemistry in the Treatment of Diabetes Mellitus","volume":"16","author":"Long","year":"2021","journal-title":"ChemMedChem"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1056\/NEJMoa1506930","article-title":"Pioglitazone after Ischemic Stroke or Transient Ischemic Attack","volume":"374","author":"Kernan","year":"2016","journal-title":"New Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.2337\/diacare.27.7.1647","article-title":"The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive)","volume":"27","author":"Charbonnel","year":"2004","journal-title":"Diabetes Care"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.numecd.2021.12.006","article-title":"Effects of pioglitazone on cardiovascular events and all-cause mortality in patients with type 2 diabetes: A meta-analysis of randomized controlled trials","volume":"32","author":"Mannucci","year":"2021","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1007\/s00535-017-1415-1","article-title":"Current and future pharmacological therapies for NAFLD\/NASH","volume":"53","author":"Sumida","year":"2017","journal-title":"J. Gastroenterol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1056\/NEJMoa060326","article-title":"A Placebo-Controlled Trial of Pioglitazone in Subjects with Nonalcoholic Steatohepatitis","volume":"355","author":"Belfort","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"615409","DOI":"10.3389\/fendo.2021.615409","article-title":"Pioglitazone for NAFLD Patients With Prediabetes or Type 2 Diabetes Mellitus: A Meta-Analysis","volume":"12","author":"Lian","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1002\/hep.25762","article-title":"The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association","volume":"55","author":"Chalasani","year":"2012","journal-title":"Hepatology"},{"key":"ref_30","first-page":"45","article-title":"DPP-4 inhibitors and GLP-1RAs: Cardiovascular safety and benefits","volume":"9","author":"Razavi","year":"2022","journal-title":"Mil. Med. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1056\/NEJMoa1501352","article-title":"Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes","volume":"373","author":"Green","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1056\/NEJMoa1307684","article-title":"Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus","volume":"369","author":"Scirica","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1056\/NEJMoa1305889","article-title":"Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes","volume":"369","author":"White","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Layman, S.N., Elliott, W.V., Neu, D.W., Howard, T.G., and Hamby, A. (2022). Alogliptin and Heart Failure Outcomes in Patients With Type 2 Diabetes. J. Pharm. Pract., 8971900221135656.","DOI":"10.1177\/08971900221135656"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"69","DOI":"10.2337\/dc16-0621","article-title":"Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial","volume":"40","author":"Mosenzon","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"107981","DOI":"10.1016\/j.diabres.2019.107981","article-title":"Pancreatitis and pancreatic cancer in patientes treated with Dipeptidyl Peptidase-4 inhibitors: An extensive and updated meta-analysis of randomized controlled trials","volume":"159","author":"Dicembrini","year":"2019","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"UK Prospective Diabetes Study (UKPDS) Group (1998). 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, 352, 837\u2013853.","DOI":"10.1016\/S0140-6736(98)07019-6"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1111\/dme.12232","article-title":"Sulphonylureas and risk of cardiovascular disease: Systematic review and meta-analysis","volume":"30","author":"Phung","year":"2013","journal-title":"Diabet. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1900","DOI":"10.1093\/eurheartj\/ehr077","article-title":"Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: A nationwide study","volume":"32","author":"Schramm","year":"2011","journal-title":"Eur. Heart J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1111\/dom.14102","article-title":"Positioning sulphonylureas in a modern treatment algorithm for patients with type 2 diabetes: Expert opinion from a European consensus panel","volume":"22","author":"Consoli","year":"2020","journal-title":"Diabetes Obes. Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"37","DOI":"10.2174\/1568026620666191224141617","article-title":"Mechanisms and Characteristics of Sulfonylureas and Glinides","volume":"20","author":"Lv","year":"2020","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"463","DOI":"10.2337\/diacare.22.3.463","article-title":"A 1-year multicenter randomized double-blind comparison of repaglinide and glyburide for the treatment of type 2 diabetes. Dutch and German Repaglinide Study Group","volume":"22","author":"Wolffenbuttel","year":"1999","journal-title":"Diabetes Care"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1185\/030079907X178766","article-title":"Oral antidiabetic agents in type 2 diabetes","volume":"23","author":"Levetan","year":"2007","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"886","DOI":"10.2337\/diacare.26.3.886","article-title":"Safety and Efficacy of Repaglinide in Type 2 Diabetic Patients With and Without Impaired Renal Function","volume":"26","author":"Hasslacher","year":"2003","journal-title":"Diabetes Care"},{"key":"ref_45","first-page":"1","article-title":"Meglitinide analogues for type 2 diabetes mellitus","volume":"2","author":"Black","year":"2007","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e10","DOI":"10.1016\/j.diabres.2014.06.009","article-title":"Comparison of repaglinide and metformin versus metformin alone for type 2 diabetes: A meta-analysis of randomized controlled trials","volume":"105","author":"Yin","year":"2014","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_47","first-page":"936","article-title":"The role of nateglinide and repaglinide, derivatives of meglitinide, in the treatment of type 2 diabetes mellitus","volume":"9","author":"Prioletta","year":"2013","journal-title":"Arch. Med. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/S2213-8587(19)30422-X","article-title":"Association of glucose-lowering medications with cardiovascular outcomes: An umbrella review and evidence map","volume":"8","author":"Zhu","year":"2020","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/S0149-2918(97)80069-0","article-title":"Acarbose: A review of US clinical experience","volume":"19","author":"Coniff","year":"1997","journal-title":"Clin. Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"817","DOI":"10.2337\/diacare.18.6.817","article-title":"Reduction of Glycosylated Hemoglobin and Postprandial Hyperglycemia by Acarbose in Patients With NIDDM: A placebo-controlled dose-comparison study","volume":"18","author":"Coniff","year":"1995","journal-title":"Diabetes Care"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1177\/2042018814559725","article-title":"GLP-1 receptor agonists: A review of head-to-head clinical studies","volume":"6","author":"Trujillo","year":"2014","journal-title":"Ther. Adv. Endocrinol. Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e12439","DOI":"10.1111\/cob.12439","article-title":"Glucagon-likepeptide-1 receptor agonists in the era of COVID-19: Friend or foe?","volume":"11","year":"2021","journal-title":"Clin. Obes."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1056\/NEJMoa2032183","article-title":"Once-Weekly Semaglutide in Adults with Overweight or Obesity","volume":"384","author":"Wilding","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/S0140-6736(21)00213-0","article-title":"Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): A randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial","volume":"397","author":"Davies","year":"2021","journal-title":"Lancet"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1001\/jama.2021.1831","article-title":"Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial","volume":"325","author":"Wadden","year":"2021","journal-title":"JAMA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1001\/jama.2021.3224","article-title":"Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity","volume":"325","author":"Abrahamsson","year":"2021","journal-title":"JAMA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"E722","DOI":"10.1161\/CIR.0000000000001040","article-title":"Comprehensive Management of Cardiovascular Risk Factors for Adults with Type 2 Diabetes: A Scientific Statement From the American Heart Association","volume":"145","author":"Joseph","year":"2022","journal-title":"Circulation"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s40256-020-00423-z","article-title":"Blood Pressure-Lowering Effect of Newer Antihyperglycemic Agents (SGLT-2 Inhibitors, GLP-1 Receptor Agonists, and DPP-4 Inhibitors)","volume":"21","author":"Liakos","year":"2020","journal-title":"Am. J. Cardiovasc. Drugs"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"384","DOI":"10.2337\/dc22-1148","article-title":"GLP-1 Receptor Agonists and the Risk of Thyroid Cancer","volume":"46","author":"Bezin","year":"2022","journal-title":"Diabetes Care"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Caruso, I., Cignarelli, A., Sorice, G.P., Natalicchio, A., Perrini, S., Laviola, L., and Giorgino, F. (2022). Cardiovascular and Renal Effectiveness of GLP-1 Receptor Agonists vs. Other Glucose-Lowering Drugs in Type 2 Diabetes: A Systematic Review and Meta-Analysis of Real-World Studies. Metabolites, 12.","DOI":"10.3390\/metabo12020183"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2749","DOI":"10.1161\/STROKEAHA.121.037775","article-title":"Effects of Semaglutide on Stroke Subtypes in Type 2 Diabetes: Post Hoc Analysis of the Randomized SUSTAIN 6 and PIONEER 6","volume":"53","author":"Strain","year":"2022","journal-title":"Stroke"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e006758","DOI":"10.1161\/CIRCHEARTFAILURE.119.006758","article-title":"Effects of Liraglutide on Worsening Renal Function Among Patients With Heart Failure With Reduced Ejection Fraction","volume":"13","author":"Redouane","year":"2020","journal-title":"Circ. Heart Fail."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1056\/NEJMoa1603827","article-title":"Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes","volume":"375","author":"Verma","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_64","unstructured":"EMA (2023, June 01). EMA Statement on Ongoing Review of GLP-1 Receptor Agonists. European Medicines Agency. Available online: https:\/\/www.ema.europa.eu\/en\/news\/ema-statement-ongoing-review-glp-1-receptor-agonists."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1056\/NEJMoa1411892","article-title":"A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management","volume":"373","author":"Astrup","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1001\/jama.2017.14752","article-title":"Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients with Type 2 Diabetes","volume":"318","author":"Davies","year":"2017","journal-title":"JAMA"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1056\/NEJMoa1901118","article-title":"Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes","volume":"381","author":"Husain","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1056\/NEJMoa2302392","article-title":"Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity","volume":"389","author":"Wharton","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1056\/NEJMoa2107519","article-title":"Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes","volume":"385","author":"Patoulias","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/S0140-6736(23)01163-7","article-title":"Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): A double-blind, randomised, multicentre, placebo-controlled, phase 3 trial","volume":"402","author":"Frias","year":"2023","journal-title":"Lancet"},{"key":"ref_71","unstructured":"FDA (2023, June 01). FDA Approves New Medication for Chronic Weight Management, Available online: https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-approves-new-medication-chronic-weight-management."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1056\/NEJMoa2301972","article-title":"Triple\u2013Hormone-Receptor Agonist Retatrutide for Obesity\u2014A Phase 2 Trial","volume":"389","author":"Jastreboff","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"251","DOI":"10.3390\/diabetology4030022","article-title":"Sodium-Glucose Co-Transporter 2 Inhibitors as a Powerful Cardioprotective and Renoprotective Tool: Overview of Clinical Trials and Mechanisms","volume":"4","year":"2023","journal-title":"Diabetology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1007\/s00592-021-01830-7","article-title":"Sodium-glucose cotransporter protein-2 inhibitors and glucagon-like peptide-1 receptor agonists versus thiazolidinediones for non-alcoholic fatty liver disease: A network meta-analysis","volume":"59","author":"Ding","year":"2022","journal-title":"Acta Diabetol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1056\/NEJMoa1911303","article-title":"Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction","volume":"381","author":"McMurray","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1056\/NEJMoa2107038","article-title":"Empagliflozin in Heart Failure with a Preserved Ejection Fraction","volume":"385","author":"Anker","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1038\/s41591-021-01536-x","article-title":"The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: A multicenter randomized trial","volume":"27","author":"Nassif","year":"2021","journal-title":"Nat. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0140-6736(18)32590-X","article-title":"SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: A systematic review and meta-analysis of cardiovascular outcome trials","volume":"393","author":"Zelniker","year":"2019","journal-title":"Lancet"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1001\/jamacardio.2020.6827","article-title":"Associations of empagliflozin with left ventricular volumes, mass, and function in patients with heart failure and reduced ejection fraction: A substudy of the empire HF randomized clinical trial","volume":"6","author":"Omar","year":"2021","journal-title":"JAMA Cardiol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Xanthopoulos, A., Katsiadas, N., Skoularigkis, S., Magouliotis, D.E., Skopeliti, N., Patsilinakos, S., Briasoulis, A., Triposkiadis, F., and Skoularigis, J. (2023). Association between Dapagliflozin, Cardiac Biomarkers and Cardiac Remodeling in Patients with Diabetes Mellitus and Heart Failure. Life, 13.","DOI":"10.3390\/life13081778"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e074068","DOI":"10.1136\/bmj-2022-074068","article-title":"Benefits and harms of drug treatment for type 2 diabetes: Systematic review and network meta-analysis of randomised controlled trials","volume":"381","author":"Shi","year":"2023","journal-title":"BMJ"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"927","DOI":"10.4103\/jfmpc.jfmpc_644_21","article-title":"Euglycemic diabetic ketoacidosis associated with SGLT2 inhibitors: A systematic review and quantitative analysis","volume":"11","author":"Dutta","year":"2022","journal-title":"J. Fam. Med. Prim. Care"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1056\/NEJMoa1611925","article-title":"Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes","volume":"377","author":"Neal","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1177\/1534734619878090","article-title":"Canagliflozin and Amputation Risk: Evidence So Far","volume":"19","author":"Papadokostaki","year":"2019","journal-title":"Int. J. Low. Extremity Wounds"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.diabres.2019.05.028","article-title":"Peripheral artery disease and amputations with Sodium-Glucose co-Transporter-2 (SGLT-2) inhibitors: A meta-analysis of randomized controlled trials","volume":"153","author":"Dicembrini","year":"2019","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e3170","DOI":"10.1002\/dmrr.3170","article-title":"Effects of SGLT2 inhibitors on fractures and bone mineral density in type 2 diabetes: An updated meta-analysis","volume":"35","author":"Li","year":"2019","journal-title":"Diabetes\/Metab. Res. Rev."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.diabet.2019.01.010","article-title":"Risk of bone fracture associated with sodium\u2013glucose cotransporter-2 inhibitor treatment: A meta-analysis of randomized controlled trials","volume":"45","author":"Cheng","year":"2019","journal-title":"Diabetes Metab."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2734","DOI":"10.1016\/j.mayocp.2020.02.019","article-title":"A Review of the Pathophysiology and Management of Diabetes in Pregnancy","volume":"95","author":"Egan","year":"2020","journal-title":"Mayo Clin. Proc."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1038\/s41574-019-0197-3","article-title":"Improving pregnancy outcomes in women with diabetes mellitus: Modern management","volume":"15","author":"Ringholm","year":"2019","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"S254","DOI":"10.2337\/dc23-S015","article-title":"15. Management of Diabetes in Pregnancy: Standards of Care in Diabetes\u20142023","volume":"46","author":"ElSayed","year":"2022","journal-title":"Diabetes Care"},{"key":"ref_91","unstructured":"(2023, June 01). Pregnancy With Type 1 or Type 2 Diabetes. Available online: www.acog.org."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"810","DOI":"10.2337\/dc18-2212","article-title":"Suboptimal nocturnal glucose control is associated with large for gestational age in treated gestational diabetes mellitus","volume":"42","author":"Law","year":"2019","journal-title":"Diabetes Care"},{"key":"ref_93","unstructured":"(2023, June 01). Pregestational (Preexisting) Diabetes Mellitus: Antenatal Glycemic Control. UpToDate. Available online: https:\/\/www.uptodate.com\/contents\/pregestational-preexisting-diabetes-mellitus-antenatal-glycemic-control."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e14700","DOI":"10.1111\/dme.14700","article-title":"Metformin for pregnancy and beyond: The pros and cons","volume":"39","author":"Newman","year":"2021","journal-title":"Diabet. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/S2213-8587(20)30310-7","article-title":"Metformin in women with type 2 diabetes in pregnancy (MiTy): A multicentre, international, randomised, placebo-controlled trial","volume":"8","author":"Feig","year":"2020","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1093\/humupd\/dmu022","article-title":"First-trimester exposure to metformin and risk of birth defects: A systematic review and meta-analysis","volume":"20","author":"Cassina","year":"2014","journal-title":"Hum. Reprod. Updat."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"325851","DOI":"10.1155\/2015\/325851","article-title":"Metformin Treatment in Type 2 Diabetes in Pregnancy: An Active Controlled, Parallel-Group, Randomized, Open Label Study in Patients with Type 2 Diabetes in Pregnancy","volume":"2015","author":"Ainuddin","year":"2015","journal-title":"J. Diabetes Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e000456","DOI":"10.1136\/bmjdrc-2017-000456","article-title":"Metformin in gestational diabetes: The offspring follow-up (MiG TOFU): Body composition and metabolic outcomes at 7\u20139 years of age","volume":"6","author":"Rowan","year":"2018","journal-title":"BMJ Open Diabetes Res. Care"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/S2213-8587(23)00004-9","article-title":"Outcomes in children of women with type 2 diabetes exposed to metformin versus placebo during pregnancy (MiTy Kids): A 24-month follow-up of the MiTy randomised controlled trial","volume":"11","author":"Feig","year":"2023","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"eRW6155","DOI":"10.31744\/einstein_journal\/2022RW6155","article-title":"Metformin versus glyburide in treatment and control of gestational diabetes mellitus: A systematic review with meta-analysis","volume":"20","author":"Andrade","year":"2022","journal-title":"Einstein"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"9804708","DOI":"10.1155\/2019\/9804708","article-title":"Comparative Efficacy and Safety of Metformin, Glyburide, and Insulin in Treating Gestational Diabetes Mellitus: A Meta-Analysis","volume":"2019","author":"Guo","year":"2019","journal-title":"J. Diabetes Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1159\/000515893","article-title":"Comparison of Insulin, Metformin, and Glyburide on Perinatal Complications of Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis","volume":"86","author":"Wang","year":"2021","journal-title":"Gynecol. Obstet. Investig."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"h102","DOI":"10.1136\/bmj.h102","article-title":"Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: A systematic review and meta-analysis","volume":"350","author":"Balsells","year":"2015","journal-title":"BMJ"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"110020","DOI":"10.1016\/j.diabres.2022.110020","article-title":"Safety and efficacy of insulin detemir versus NPH in the treatment of diabetes during pregnancy: Systematic review and meta-analysis of randomized controlled trials","volume":"190","author":"Athanasiadou","year":"2022","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.2337\/dc21-0472","article-title":"Risk of Major Congenital Malformations or Perinatal or Neonatal Death With Insulin Detemir Versus Other Basal Insulins in Pregnant Women With Preexisting Diabetes: The Real-World EVOLVE Study","volume":"44","author":"Mathiesen","year":"2021","journal-title":"Diabetes Care"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/S2213-8587(22)00307-2","article-title":"Insulin degludec versus insulin detemir, both in combination with insulin aspart, in the treatment of pregnant women with type 1 diabetes (EXPECT): An open-label, multinational, randomised, controlled, non-inferiority trial","volume":"11","author":"Mathiesen","year":"2023","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"771","DOI":"10.2337\/dc06-1887","article-title":"Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: A randomized trial of insulin aspart versus human insulin in 322 pregnant women","volume":"30","author":"Mathiesen","year":"2007","journal-title":"Diabetes Care"},{"key":"ref_108","first-page":"CD005542","article-title":"Continuous subcutaneous insulin infusion versus multiple daily injections of insulin for pregnant women with diabetes","volume":"2016","author":"Farrar","year":"2016","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1007\/s40011-019-01157-y","article-title":"Insulin Signalling: Essential Role of a 222 Da Molecular Mediator, Co-Insulin (Co-Ins)","volume":"90","author":"Thampan","year":"2019","journal-title":"Proc. Natl. Acad. Sci. India Sect. B Biol. Sci."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1007\/s13142-016-0447-z","article-title":"The healthy living partnerships to prevent diabetes and the diabetes prevention program: A comparison of year 1 and 2 intervention results","volume":"7","author":"Vitolins","year":"2017","journal-title":"Transl. Behav. Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1186\/s12933-021-01281-y","article-title":"From glucose lowering agents to disease\/diabetes modifying drugs: A \u201cSIMPLE\u201d approach for the treatment of type 2 diabetes","volume":"20","author":"Mosenzon","year":"2021","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/S2213-8587(18)30129-3","article-title":"Novel diabetes subgroups","volume":"6","author":"Dutta","year":"2018","journal-title":"Lancet Diabetes Endocrinol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/24\/17147\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:33:36Z","timestamp":1760132016000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/24\/17147"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,5]]},"references-count":112,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["ijms242417147"],"URL":"https:\/\/doi.org\/10.3390\/ijms242417147","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,5]]}}}