The increasing global incidence of obesity and type 2 diabetes mellitus (T2D) underscores the urgency of addressing these interconnected health challenges. Obesity enhances genetic and environmental influences on T2D, being not only a primary risk factor but also exacerbating its severity. The complex mechanisms linking obesity and T2D involve adiposity-driven changes in β-cell function, adipose tissue functioning, and multi-organ insulin resistance (IR). Early detection and tailored treatment of T2D and obesity are crucial to mitigate future complications. Moreover, personalized and early intensified therapy considering the presence of comorbidities can delay disease progression and diminish the risk of cardiorenal complications. Employing combination therapies and embracing a disease-modifying strategy are paramount. Clinical trials provide evidence confirming the efficacy and safety of glucagon-like peptide 1 receptor agonists (GLP-1 RAs). Their use is associated with substantial and durable body weight reduction, exceeding 15%, and improved glucose control which further translate into T2D prevention, possible disease remission, and improvement of cardiometabolic risk factors and associated complications. Therefore, on the basis of clinical experience and current evidence, the Eastern and Southern Europe Diabetes and Obesity Expert Group recommends a personalized, polymodal approach (comprising GLP-1 RAs) tailored to individual patient's disease phenotype to optimize diabetes and obesity therapy. We also expect that the increasing availability of dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists will significantly contribute to the modern management of the cardiometabolic continuum.

Catholic University of Croatia School of Medicine Zagreb Croatia

Clinic of Diabetes Nutrition and Metabolic Diseases Carol Davila University of Medicine and Pharmacy Bucharest Romania

Department of Diabetology and Internal Medicine Medical University of Warsaw Warszawa Poland

Department of Endocrinology Diabetes and Metabolic Diseases University Medical Center Ljubljana Ljubljana Slovenia

Department of Endocrinology Diabetes and Metabolism Unidade Local de Saúde São José Lisbon Portugal

Department of Endocrinology Faculty of Medicine Medical University Sofia Bulgaria

Department of Health Promotion Mother and Child Care Internal Medicine and Medical Specialties School of Medicine University of Palermo Palermo Italy

Department of Internal Medicine Endocrinology Section Clinical Centre of Montenegro Faculty of Medicine University of Montenegro Podgorica Montenegro

Department of Medicine and Oncology Semmelweis University Budapest Hungary

Department of Treatment of Obesity Metabolic Disorders and Clinical Dietetics University of Medical Sciences Poznan Poland

Diabetes Centre 2nd Department of Internal Medicine Democritus University of Thrace Alexandroupolis Greece

Diabetes Centre Institute for Clinical and Experimental Medicine Vídeňská 1958 9 140 21 Prague 4 Czech Republic

Diabetes Nutrition and Metabolic Diseases Department Carol Davila University of Medicine and Pharmacy Bucharest Romania

Division of Endocrinology Metabolism and Diabetes Istanbul University Cerrahpaşa Cerrahpaşa Medical Faculty Istanbul Turkey

Faculty of Medicine Clinic for Endocrinology Diabetes and Metabolic Diseases Clinical Center of Serbia University of Belgrade Belgrade Serbia

Faculty of Medicine in Pilsen Department of Public Health and Preventive Medicine and Faculty Hospital in Pilsen 1st Internal Clinic Charles University Pilsen Czech Republic

Josip Juraj Strossmayer University of Osijek School of Medicine Osijek Croatia

MetabolKLINIK sro Department for Diabetes and Metabolic Disorders Lipid Clinic MED PED Centre Biomedical Research Centre of Slovak Academy of Sciences Slovak Health University Bratislava Slovak Republic

NOVA Medical School New University of Lisbon Lisbon Portugal

Preventive Cardiology Unit Division of Medicine University Medical Centre Ljubljana and Chair of Internal Medicine Medical Faculty University of Ljubljana Ljubljana Slovenia

Vuk Vrhovac University Clinic for Diabetes Endocrinology and Metabolic Diseases Merkur University Hospital Zagreb Croatia

See more in PubMed

Naidoo V, Naidoo M, Ghai M. Cell-and tissue-specific epigenetic changes associated with chronic inflammation in insulin resistance and type 2 diabetes mellitus. Scand J Immunol. 2018;88(6): e12723. 10.1111/sji.12723 PubMed DOI

Ramos-Lopez O, Milagro FI, Riezu-Boj JI, Martinez JA. Epigenetic signatures underlying inflammation: an interplay of nutrition, physical activity, metabolic diseases, and environmental factors for personalized nutrition. Inflamm Res. 2021;70:29–49. 10.1007/s00011-020-01425-y PubMed DOI PMC

Suárez R, Chapela SP, Álvarez-Córdova L, et al. Epigenetics in obesity and diabetes mellitus: new insights. Nutrients. 2023;15(4):811. 10.3390/nu15040811 PubMed DOI PMC

Arpón A, Milagro FI, Santos JL, García-Granero M, Riezu-Boj J-I, Martínez JA. Interaction among sex, aging, and epigenetic processes concerning visceral fat, insulin resistance, and dyslipidaemia. Front Endocrinol. 2019;10:496.10.3389/fendo.2019.00496 PubMed DOI PMC

Chambers JC, Loh M, Lehne B, et al. Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study. Lancet Diabetes Endocrinol. 2015;3(7):526–34. 10.1016/S2213-8587(15)00127-8 PubMed DOI PMC

Muzurović E, Dragnic S, Medenica S, Smolovic B, Bulajic P, Mikhailidis DP. Weight-centric pharmacological management of type 2 diabetes mellitus - an essential component of cardiovascular disease prevention. J Diabetes Complications. 2020;34(8): 107619. 10.1016/j.jdiacomp.2020.107619 PubMed DOI

Sarma S, Sockalingam S, Dash S. Obesity as a multisystem disease: trends in obesity rates and obesity-related complications. Diabetes Obes Metab. 2021;23(Suppl 1):3–16. 10.1111/dom.14290 PubMed DOI

Czech MP. Mechanisms of insulin resistance related to white, beige, and brown adipocytes. Mol Metab. 2020;34:27–42. 10.1016/j.molmet.2019.12.014 PubMed DOI PMC

Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Invest. 2011;121(6):2094–101. 10.1172/JCI45887 PubMed DOI PMC

Kusminski CM, Scherer PE. Mitochondrial dysfunction in white adipose tissue. Trends Endocrinol Metab. 2012;23(9):435–43. 10.1016/j.tem.2012.06.004 PubMed DOI PMC

Tchkonia T, Thomou T, Zhu Y, et al. Mechanisms and metabolic implications of regional differences among fat depots. Cell Metab. 2013;17(5):644–56. 10.1016/j.cmet.2013.03.008 PubMed DOI PMC

Blüher M. Obesity: global epidemiology and pathogenesis. Nat Rev Endocrinol. 2019;15(5):288–98. 10.1038/s41574-019-0176-8 PubMed DOI

Bray GA, Jablonski KA, Fujimoto WY, et al. Relation of central adiposity and body mass index to the development of diabetes in the diabetes prevention program. Am J Clin Nutr. 2008;87(5):1212–8. 10.1093/ajcn/87.5.1212 PubMed DOI PMC

Ford ES, Williamson DF, Liu S. Weight change and diabetes incidence: findings from a national cohort of US adults. Am J Epidemiol. 1997;146(3):214–22. 10.1093/oxfordjournals.aje.a009256 PubMed DOI

Wensveen FM, Valentić S, Šestan M, Turk Wensveen T, Polić B. The, “Big Bang” in obese fat: events initiating obesity-induced adipose tissue inflammation. Eur J Immunol. 2015;45(9):2446–56. 10.1002/eji.201545502 PubMed DOI

Klein S, Wadden T, Sugerman HJ. AGA technical review on obesity. Gastroenterology. 2002;123(3):882–932. 10.1053/gast.2002.35514 PubMed DOI

Kopelman PG. Obesity as a medical problem. Nature. 2000;404(6778):635–43. 10.1038/35007508 PubMed DOI

Haffner SM. Abdominal obesity, insulin resistance, and cardiovascular risk in pre-diabetes and type 2 diabetes. Eur Heart J Suppl. 2006;8(suppl_B):B20–5.10.1093/eurheartj/sul004 DOI

Muzurović E, Peng CC-H, Belanger MJ, Sanoudou D, Mikhailidis DP, Mantzoros CS. Nonalcoholic fatty liver disease and cardiovascular disease: a review of shared cardiometabolic risk factors. Hypertension. 2022;79(7):1319–26. 10.1161/HYPERTENSIONAHA.122.17982 PubMed DOI

Ng ACT, Delgado V, Borlaug BA, Bax JJ. Diabesity: the combined burden of obesity and diabetes on heart disease and the role of imaging. Nat Rev Cardiol. 2021;18(4):291–304. 10.1038/s41569-020-00465-5 PubMed DOI

Blüher M, Ceriello A, Davies M, et al. Managing weight and glycaemic targets in people with type 2 diabetes—How far have we come? Endocrinology. Diabetes Metab. 2022;5(3):e00330. PubMed PMC

Yaribeygi H, Maleki M, Sathyapalan T, Jamialahmadi T, Sahebkar A. Anti-inflammatory potentials of incretin-based therapies used in the management of diabetes. Life Sci. 2020;241:117152. 10.1016/j.lfs.2019.117152 PubMed DOI

Wittwer JA, Golden SH, Joseph JJ. Diabetes and CVD risk: special considerations in African Americans related to care. Curr Cardiovasc Risk Rep. 2020;14:1–14.10.1007/s12170-020-00648-2 DOI

Musunuru K. Atherogenic dyslipidemia: cardiovascular risk and dietary intervention. Lipids. 2010;45(10):907–14. 10.1007/s11745-010-3408-1 PubMed DOI PMC

Blokhin IO, Lentz SR. Mechanisms of thrombosis in obesity. Curr Opin Hematol. 2013;20(5):437. 10.1097/MOH.0b013e3283634443 PubMed DOI PMC

Stratton IM, Adler AI, Neil HAW, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405–12. 10.1136/bmj.321.7258.405 PubMed DOI PMC

Palta P, Huang ES, Kalyani RR, Golden SH, Yeh HC. Hemoglobin A(1c) and mortality in older adults with and without diabetes: results from the National Health and Nutrition Examination Surveys (1988–2011). Diabetes Care. 2017;40(4):453–60. 10.2337/dci16-0042 PubMed DOI PMC

Seidu S, Cos X, Brunton S, et al. 2022 update to the position statement by primary care diabetes Europe: a disease state approach to the pharmacological management of type 2 diabetes in primary care. Prim Care Diabetes. 2022;16(2):223–44. 10.1016/j.pcd.2022.02.002 PubMed DOI

Khunti K, Seidu S. Therapeutic inertia and the legacy of dysglycemia on the microvascular and macrovascular complications of diabetes. Diabetes Care. 2019;42(3):349–51. 10.2337/dci18-0030 PubMed DOI

Weerakiet S, Srisombut C, Bunnag P, Sangtong S, Chuangsoongnoen N, Rojanasakul A. Prevalence of type 2 diabetes mellitus and impaired glucose tolerance in Asian women with polycystic ovary syndrome. Int J Gynecol Obstet. 2001;75(2):177–84.10.1016/S0020-7292(01)00477-5 PubMed DOI

Papamargaritis D, le Roux CW, Holst JJ, Davies MJ. New therapies for obesity. Cardiovasc Res. 2022;119(18):2825–42.10.1093/cvr/cvac176 PubMed DOI PMC

American Diabetes Association. 8. Obesity management for the treatment of type 2 diabetes: standards of medical care in diabetes-2021. Diabetes Care. 2021;44(1):100–10. PubMed

le Roux CW, Astrup A, Fujioka K, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet. 2017;389(10077):1399–409. 10.1016/S0140-6736(17)30069-7 PubMed DOI

Garvey WT, Ryan DH, Henry R, et al. Prevention of type 2 diabetes in subjects with prediabetes and metabolic syndrome treated with phentermine and topiramate extended release. Diabetes Care. 2014;37(4):912–21. 10.2337/dc13-1518 PubMed DOI PMC

Haase CL, Lopes S, Olsen AH, Satylganova A, Schnecke V, McEwan P. Weight loss and risk reduction of obesity-related outcomes in 0.5 million people: evidence from a UK primary care database. Int J Obes (Lond). 2021;45(6):1249–58. 10.1038/s41366-021-00788-4 PubMed DOI PMC

Lingvay I, Sumithran P, Cohen RV, le Roux CW. Obesity management as a primary treatment goal for type 2 diabetes: time to reframe the conversation. Lancet. 2022;399(10322):394–405. 10.1016/S0140-6736(21)01919-X PubMed DOI

Lean ME, 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. 10.1016/S0140-6736(17)33102-1 PubMed DOI

Lean MEJ, Leslie WS, Barnes AC, et al. Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial. Lancet Diabetes Endocrinol. 2019;7(5):344–55. 10.1016/S2213-8587(19)30068-3 PubMed DOI

Taheri S, Zaghloul H, Chagoury O, et al. Effect of intensive lifestyle intervention on bodyweight and glycaemia in early type 2 diabetes (DIADEM-I): an open-label, parallel-group, randomised controlled trial. Lancet Diabetes Endocrinol. 2020;8(6):477–89. 10.1016/S2213-8587(20)30117-0 PubMed DOI

Group LAR. Association of the magnitude of weight loss and changes in physical fitness with long-term cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: a post-hoc analysis of the Look AHEAD randomised clinical trial. Lancet Diabetes Endocrinol. 2016;4(11):913–21. 10.1016/S2213-8587(16)30162-0 PubMed DOI PMC

Group DPPR. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403. 10.1056/NEJMoa012512 PubMed DOI PMC

Garvey WT, Ryan DH, Henry R, et al. Prevention of type 2 diabetes in subjects with prediabetes and metabolic syndrome treated with phentermine and topiramate extended release. Diabetes Care. 2014;37(4):912–21. 10.2337/dc13-1518 PubMed DOI PMC

Rothberg AE, McEwen LN, Kraftson AT, Fowler CE, Herman WH. Very-low-energy diet for type 2 diabetes: an underutilized therapy? J Diabetes Complicat. 2014;28(4):506–10.10.1016/j.jdiacomp.2014.03.014 PubMed DOI PMC

Jackness C, Karmally W, Febres G, et al. Very low-calorie diet mimics the early beneficial effect of Roux-en-Y gastric bypass on insulin sensitivity and β-cell function in type 2 diabetic patients. Diabetes. 2013;62(9):3027–32. 10.2337/db12-1762 PubMed DOI PMC

Pastors JG, Warshaw H, Daly A, Franz M, Kulkarni K. The evidence for the effectiveness of medical nutrition therapy in diabetes management. Diabetes Care. 2002;25(3):608. 10.2337/diacare.25.3.608 PubMed DOI

Group U. UK Prospective Diabetes Study 7: response of fasting plasma glucose to diet therapy in newly presenting type II diabetic patients. Metabolism. 1990;39(9):905–912. PubMed

Monami M, Dicembrini I, Nardini C, Fiordelli I, Mannucci E. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2014;16(1):38–47. 10.1111/dom.12175 PubMed DOI

Burgmaier M, Heinrich C, Marx N. Cardiovascular effects of GLP-1 and GLP-1-based therapies: implications for the cardiovascular continuum in diabetes? Diabet Med. 2013;30(3):289–99. 10.1111/j.1464-5491.2012.03746.x PubMed DOI

Aoki K, Kamiyama H, Takihata M, et al. Effect of liraglutide on lipids in patients with type 2 diabetes: a pilot study. Endocr J. 2020;67(9):957–62. 10.1507/endocrj.EJ19-0464 PubMed DOI

Koska J, Schwartz EA, Mullin MP, Schwenke DC, Reaven PD. Improvement of postprandial endothelial function after a single dose of exenatide in individuals with impaired glucose tolerance and recent-onset type 2 diabetes. Diabetes Care. 2010;33(5):1028–30. 10.2337/dc09-1961 PubMed DOI PMC

Sun F, Wu S, Wang J, et al. Effect of glucagon-like peptide-1 receptor agonists on lipid profiles among type 2 diabetes: a systematic review and network meta-analysis. Clin Ther. 2015;37(1):225-241.e228. 10.1016/j.clinthera.2014.11.008 PubMed DOI

Hermansen K, Bækdal TA, Düring M, et al. Liraglutide suppresses postprandial triglyceride and apolipoprotein B48 elevations after a fat-rich meal in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, cross-over trial. Diabetes Obes Metab. 2013;15(11):1040–8. 10.1111/dom.12133 PubMed DOI

Xiao C, Dash S, Morgantini C, Adeli K, Lewis GF. Gut peptides are novel regulators of intestinal lipoprotein secretion: experimental and pharmacological manipulation of lipoprotein metabolism. Diabetes. 2015;64(7):2310–8. 10.2337/db14-1706 PubMed DOI

Berra CC, Rossi MC, Mirani M, et al. Real world effectiveness of subcutaneous semaglutide in type 2 diabetes: a retrospective, cohort study (Sema-MiDiab01). Front Endocrinol (Lausanne). 2022;13:1099451. 10.3389/fendo.2022.1099451 PubMed DOI PMC

Tuttolomondo A, Cirrincione A, Casuccio A, et al. Efficacy of dulaglutide on vascular health indexes in subjects with type 2 diabetes: a randomized trial. Cardiovasc Diabetol. 2021;20(1):1. 10.1186/s12933-020-01183-5 PubMed DOI PMC

Magkos F, Fraterrigo G, Yoshino J, et al. Effects of moderate and subsequent progressive weight loss on metabolic function and adipose tissue biology in humans with obesity. Cell Metab. 2016;23(4):591–601. 10.1016/j.cmet.2016.02.005 PubMed DOI PMC

Zhao L, Zhu C, Lu M, et al. The key role of a glucagon-like peptide-1 receptor agonist in body fat redistribution. J Endocrinol. 2019;240(2):271–86. 10.1530/JOE-18-0374 PubMed DOI

Wang B, Zhong J, Lin H, et al. Blood pressure-lowering effects of GLP-1 receptor agonists exenatide and liraglutide: a meta-analysis of clinical trials. Diabetes Obes Metab. 2013;15(8):737–49. 10.1111/dom.12085 PubMed DOI

Sivertsen J, Rosenmeier J, Holst JJ, Vilsbøll T. The effect of glucagon-like peptide 1 on cardiovascular risk. Nat Rev Cardiol. 2012;9(4):209–22. 10.1038/nrcardio.2011.211 PubMed DOI

Nyström T, Gonon AT, Sjöholm Å, Pernow J. Glucagon-like peptide-1 relaxes rat conduit arteries via an endothelium-independent mechanism. Regul Pept. 2005;125(1–3):173–7. 10.1016/j.regpep.2004.08.024 PubMed DOI

Filippatos TD, Elisaf MS. Effects of glucagon-like peptide-1 receptor agonists on renal function. World J Diabetes. 2013;4(5):190. 10.4239/wjd.v4.i5.190 PubMed DOI PMC

Robinson LE, Holt TA, Rees K, Randeva HS, O’Hare JP. Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: systematic review and meta-analysis. BMJ Open. 2013;3(1):e001986. 10.1136/bmjopen-2012-001986 PubMed DOI PMC

Ferdinand KC, Dunn J, Nicolay C, Sam F, Blue EK, Wang H. Weight-dependent and weight-independent effects of dulaglutide on blood pressure in patients with type 2 diabetes. Cardiovasc Diabetol. 2023;22(1):49. 10.1186/s12933-023-01775-x PubMed DOI PMC

Ruseva A, Michalak W, Zhao Z, Fabricatore A, Hartaigh B, Umashanker D. Semaglutide 2.4 mg clinical outcomes in patients with obesity or overweight in a real-world setting: a 6-month retrospective study in the United States (SCOPE). Obes Sci Pract. 2024;10(1):e737. 10.1002/osp4.737 PubMed DOI PMC

Wu W, Tong HM, Li YS, Cui J. The effect of semaglutide on blood pressure in patients with type-2 diabetes: a systematic review and meta-analysis. Endocrine. 2023. 10.1007/s12020-023-03636-9. 10.1007/s12020-023-03636-9 PubMed DOI PMC

Lee YS, Jun HS. Anti-inflammatory effects of GLP-1-based therapies beyond glucose control. Mediators Inflamm. 2016;2016:3094642. 10.1155/2016/3094642 PubMed DOI PMC

Chaudhuri A, Ghanim H, Vora M, et al. Exenatide exerts a potent antiinflammatory effect. J Clin Endocrinol Metab. 2012;97(1):198–207. 10.1210/jc.2011-1508 PubMed DOI PMC

Hendarto H, Inoguchi T, Maeda Y, et al. GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases. Metabolism. 2012;61(10):1422–34. 10.1016/j.metabol.2012.03.002 PubMed DOI

Kodera R, Shikata K, Kataoka HU, et al. Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes. Diabetologia. 2011;54(4):965–78. 10.1007/s00125-010-2028-x PubMed DOI

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. 10.15420/ecr.2018.33.1 PubMed DOI PMC

Bendotti G, Montefusco L, Lunati ME, et al. The anti-inflammatory and immunological properties of GLP-1 receptor agonists. Pharmacol Res. 2022;182:106320. 10.1016/j.phrs.2022.106320 PubMed DOI

Rakipovski G, Rolin B, Nøhr J, et al. The GLP-1 analogs liraglutide and semaglutide reduce atherosclerosis in ApoE−/− and LDLr−/− mice by a mechanism that includes inflammatory pathways. JACC Basic Transl Sci. 2018;3(6):844–57. 10.1016/j.jacbts.2018.09.004 PubMed DOI PMC

Zhang Y, Lin Y, Li G, et al. Glucagon-like peptide-1 receptor agonists decrease hyperinsulinemia and hyperandrogenemia in dehydroepiandrosterone-induced polycystic ovary syndrome mice and are associated with mitigating inflammation and inducing browning of white adipose tissue†. Biol Reprod. 2023;108(6):945–59. 10.1093/biolre/ioad032 PubMed DOI PMC

Guarnotta V, Bianco MJ, Vigneri E, et al. Effects of GLP-1 receptor agonists on myokine levels and pro-inflammatory cytokines in patients with type 2 diabetes mellitus. Nutr Metab Cardiovasc Dis. 2021;31(11):3193–201. 10.1016/j.numecd.2021.07.015 PubMed DOI

Varanasi A, Patel P, Makdissi A, Dhindsa S, Chaudhuri A, Dandona P. Clinical use of liraglutide in type 2 diabetes and its effects on cardiovascular risk factors. Endocr Pract. 2012;18(2):140–5. 10.4158/EP11169.OR PubMed DOI

Mosenzon O, Capehorn MS, De Remigis A, Rasmussen S, Weimers P, Rosenstock J. Impact of semaglutide on high-sensitivity C-reactive protein: exploratory patient-level analyses of SUSTAIN and PIONEER randomized clinical trials. Cardiovasc Diabetol. 2022;21(1):172. 10.1186/s12933-022-01585-7 PubMed DOI PMC

Gupta NA, Kolachala VL, Jiang R, et al. The glucagon-like peptide-1 receptor agonist exendin 4 has a protective role in ischemic injury of lean and steatotic liver by inhibiting cell death and stimulating lipolysis. Am J Pathol. 2012;181(5):1693–701. 10.1016/j.ajpath.2012.07.015 PubMed DOI PMC

Gaspari T, Welungoda I, Widdop RE, Simpson RW, Dear AE. The GLP-1 receptor agonist liraglutide inhibits progression of vascular disease via effects on atherogenesis, plaque stability and endothelial function in an ApoE−/− mouse model. Diab Vasc Dis Res. 2013;10(4):353–60. 10.1177/1479164113481817 PubMed DOI

Arakawa M, Mita T, Azuma K, et al. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes. 2010;59(4):1030–7. 10.2337/db09-1694 PubMed DOI PMC

Petrovic A, Igrec D, Rozac K, et al. The role of GLP1-RAs in direct modulation of lipid metabolism in hepatic tissue as determined using in vitro models of NAFLD. Curr Issues Mol Biol. 2023;45(6):4544–56. 10.3390/cimb45060288 PubMed DOI PMC

Samson SL, Bajaj M. Potential of incretin-based therapies for non-alcoholic fatty liver disease. J Diabetes Complicat. 2013;27(4):401–6.10.1016/j.jdiacomp.2012.12.005 PubMed DOI

Kokkorakis M, Muzurovic E, Volcansek S, et al. Steatotic liver disease: pathophysiology and emerging pharmacotherapies. Pharmacol Rev. 2024;76(3):454–99. 10.1124/pharmrev.123.001087 PubMed DOI

Li Z, Feng P-P, Zhao Z-B, Zhu W, Gong J-P, Du H-M. Liraglutide protects against inflammatory stress in non-alcoholic fatty liver by modulating Kupffer cells M2 polarization via cAMP-PKA-STAT3 signaling pathway. Biochem Biophys Res Commun. 2019;510(1):20–6. 10.1016/j.bbrc.2018.12.149 PubMed DOI

Stern JH, Rutkowski JM, Scherer PE. Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk. Cell Metab. 2016;23(5):770–84. 10.1016/j.cmet.2016.04.011 PubMed DOI PMC

Ma X, Liu Z, Ilyas I, et al. GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential. Int J Biol Sci. 2021;17(8):2050–68. 10.7150/ijbs.59965 PubMed DOI PMC

Ajabnoor GMA, Hashim KT, Alzahrani MM, et al. The possible effect of the long-term use of glucagon-like peptide-1 receptor agonists (GLP-1RA) on HbA1c and lipid profile in type 2 diabetes mellitus: a retrospective study in KAUH, Jeddah, Saudi Arabia. Diseases. 2023;11(1):50. 10.3390/diseases11010050 PubMed DOI PMC

Eguchi Y, Kitajima Y, Hyogo H, et al. Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN-J). Hepatol Res. 2015;45(3):269–78. 10.1111/hepr.12351 PubMed DOI

Ohki T, Isogawa A, Iwamoto M, et al. The effectiveness of liraglutide in nonalcoholic fatty liver disease patients with type 2 diabetes mellitus compared to sitagliptin and pioglitazone. Sci World J. 2012;2012: 496453.10.1100/2012/496453 PubMed DOI PMC

Bandyopadhyay S, Das S, Samajdar SS, Joshi SR. Role of semaglutide in the treatment of nonalcoholic fatty liver disease or non-alcoholic steatohepatitis: a systematic review and meta-analysis. Diabetes Metab Syndr. 2023;17(10):102849. 10.1016/j.dsx.2023.102849 PubMed DOI

Newsome P, Francque S, Harrison S, et al. Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity. Aliment Pharmacol Ther. 2019;50(2):193–203. 10.1111/apt.15316 PubMed DOI PMC

Zheng S, Huang H, Chen H, Liu Y. Glp-1 receptor agonists regulate the progression of diabetes mellitus complicated with fatty liver by down-regulating the expression of genes related to lipid metabolism. Appl Biochem Biotechnol. 2023;195(8):5238–51. 10.1007/s12010-023-04505-x PubMed DOI

Hartman ML, Sanyal AJ, Loomba R, et al. Effects of novel dual GIP and GLP-1 receptor agonist tirzepatide on biomarkers of nonalcoholic steatohepatitis in patients with type 2 diabetes. Diabetes Care. 2020;43(6):1352–5. 10.2337/dc19-1892 PubMed DOI PMC

Liu F, Yang Q, Zhang H, et al. The effects of glucagon-like peptide-1 receptor agonists on adipose tissues in patients with type 2 diabetes: a meta-analysis of randomised controlled trials. PLoS ONE. 2022;17(7):e0270899. 10.1371/journal.pone.0270899 PubMed DOI PMC

Kammerlander AA, Lyass A, Mahoney TF, et al. Sex differences in the associations of visceral adipose tissue and cardiometabolic and cardiovascular disease risk: the Framingham heart study. J Am Heart Assoc. 2021;10(11):e019968. 10.1161/JAHA.120.019968 PubMed DOI PMC

Abbasi SA, Hundley WG, Bluemke DA, et al. Visceral adiposity and left ventricular remodeling: the multi-ethnic study of atherosclerosis. Nutr Metab Cardiovasc Dis. 2015;25(7):667–76. 10.1016/j.numecd.2015.03.016 PubMed DOI PMC

Djoussé L, Bartz TM, Ix JH, et al. Adiposity and incident heart failure in older adults: the cardiovascular health study. Obesity (Silver Spring). 2012;20(9):1936–41. 10.1038/oby.2011.320 PubMed DOI PMC

Nicklas BJ, Cesari M, Penninx BW, et al. Abdominal obesity is an independent risk factor for chronic heart failure in older people. J Am Geriatr Soc. 2006;54(3):413–20. 10.1111/j.1532-5415.2005.00624.x PubMed DOI

Fukuda T, Bouchi R, Takeuchi T, et al. Ratio of visceral-to-subcutaneous fat area predicts cardiovascular events in patients with type 2 diabetes. J Diabetes Investig. 2018;9(2):396–402. 10.1111/jdi.12713 PubMed DOI PMC

Bouchi R, Takeuchi T, Akihisa M, et al. High visceral fat with low subcutaneous fat accumulation as a determinant of atherosclerosis in patients with type 2 diabetes. Cardiovasc Diabetol. 2015;14:136. 10.1186/s12933-015-0302-4 PubMed DOI PMC

Kim M, Platt MJ, Shibasaki T, et al. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med. 2013;19(5):567–75. 10.1038/nm.3128 PubMed DOI

Rieg T, Gerasimova M, Murray F, et al. Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice. Am J Physiol Renal Physiol. 2012;303(7):F963-971. 10.1152/ajprenal.00259.2012 PubMed DOI PMC

Muskiet MH, Smits MM, Morsink LM, Diamant M. The gut-renal axis: do incretin-based agents confer renoprotection in diabetes? Nat Rev Nephrol. 2014;10(2):88–103. 10.1038/nrneph.2013.272 PubMed DOI

Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–44. 10.1056/NEJMoa1607141 PubMed DOI

Tuttle KR, Bosch-Traberg H, Cherney DZI, et al. Post hoc analysis of SUSTAIN 6 and PIONEER 6 trials suggests that people with type 2 diabetes at high cardiovascular risk treated with semaglutide experience more stable kidney function compared with placebo. Kidney Int. 2023;103(4):772–81. 10.1016/j.kint.2022.12.028 PubMed DOI

FDA. Highlights of Prescribing Information: BYDUREON (exenatide). http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022200s000lbl.pdf). Accessed 29 Aug 2023.

EMA. Summary of Product Characteristics Victoza®. https://www.ema.europa.eu/en/medicines/human/EPAR/victoza. Accessed 29 Aug 2023.

Ryan D, Acosta A. GLP-1 receptor agonists: nonglycemic clinical effects in weight loss and beyond. Obesity (Silver Spring). 2015;23(6):1119–29. 10.1002/oby.21107 PubMed DOI PMC

Łuniewski M, Matyjaszek-Matuszek B, Lenart-Lipińska M. Diagnosis and non-invasive treatment of obesity in adults with type 2 diabetes mellitus: a review of guidelines. J Clin Med. 2023;12(13):4431. 10.3390/jcm12134431 PubMed DOI PMC

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. 10.1016/S0140-6736(19)31149-3 PubMed DOI

Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–44. 10.1056/NEJMoa1607141 PubMed DOI

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. 10.1056/NEJMoa1603827 PubMed DOI PMC

Janić M, Rizzo M, Cosentino F, et al. Effect of oral semaglutide on cardiovascular parameters and their mechanisms in patients with type 2 diabetes: rationale and design of the Semaglutide Anti-Atherosclerotic Mechanisms of Action Study (SAMAS). Diabetes Ther. 2022;13(4):795–810. 10.1007/s13300-022-01226-y PubMed DOI PMC

Michos ED, Lopez-Jimenez F, Gulati M. Role of glucagon-like peptide-1 receptor agonists in achieving weight loss and improving cardiovascular outcomes in people with overweight and obesity. J Am Heart Assoc. 2023;12(11): e029282. 10.1161/JAHA.122.029282 PubMed DOI PMC

Sattar N, Lee MM, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 2021;9(10):653–62. 10.1016/S2213-8587(21)00203-5 PubMed DOI

Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, Hardt-Lindberg S, Hovingh GK, Kahn SE, Kushner RF, Lingvay I, Oral TK, Michelsen MM, Plutzky J, Tornøe CW, Ryan DH; SELECT Trial Investigators. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221–32. 10.1056/NEJMoa2307563. PubMed

Muzurović E, Yumuk V, Rizzo M. GLP-1 and dual GIP/GLP-1 receptor agonists in overweight/obese patients for atherosclerotic cardiovascular disease prevention: where are we now? J Diabetes Complicat. 2023;37:108647.10.1016/j.jdiacomp.2023.108647 PubMed DOI

Patti AM, Giglio RV, Allotta A, et al. Effect of semaglutide on subclinical atherosclerosis and cardiometabolic compensation: a real-world study in patients with type 2 diabetes. Biomedicines. 2023;11(5):1362. 10.3390/biomedicines11051362 PubMed DOI PMC

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. 10.1056/NEJMoa1612917 PubMed DOI PMC

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. 10.1056/NEJMoa1509225 PubMed DOI

Kim BK, Seo KW. Changes of guidelines in the management of obese patients with diabetes in the metabolic surgery perspective. J Metab Bariatr Surg. 2022;11(2):13–9. 10.17476/jmbs.2022.11.2.13 PubMed DOI PMC

American Diabetes Association Professional Practice Committee. 8. Obesity and weight management for the prevention and treatment of type 2 diabetes: standards of medical care in diabetes-2022. Diabetes Care. 2022;45(1):113–124. PubMed

Yumuk V, Tsigos C, Fried M, et al. European guidelines for obesity management in adults. Obes Facts. 2015;8(6):402–24. 10.1159/000442721 PubMed DOI PMC

Yang W, Lu J, Weng J, et al. Prevalence of diabetes among men and women in China. N Engl J Med. 2010;362(12):1090–101. 10.1056/NEJMoa0908292 PubMed DOI

Lahti-Koski M, Männistö S, Pietinen P, Vartiainen E. Prevalence of weight cycling and its relation to health indicators in Finland. Obes Res. 2005;13(2):333–41. 10.1038/oby.2005.45 PubMed DOI

Ceriello A, Lucisano G, Prattichizzo F, et al. Variability in body weight and the risk of cardiovascular complications in type 2 diabetes: results from the Swedish National Diabetes Register. Cardiovasc Diabetol. 2021;20(1):173. 10.1186/s12933-021-01360-0 PubMed DOI PMC

Garvey WT, Mechanick JI, Brett EM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesityexecutive summary. Complete guidelines available at https://www.aace.com/publications/guidelines. Endocr Pract. 2016;22(7):842–84. Accessed 28 Aug 2023. PubMed

Kahan S, Fujioka K. Obesity pharmacotherapy in patients with type 2 diabetes. Diabetes Spectr. 2017;30(4):250. 10.2337/ds17-0044 PubMed DOI PMC

National Institute of Diabetes and Digestive and Kidney Health. Prescription medications to treat overweight and obesity. https://www.niddk.nih.gov/health-information/weight-management/prescription-medications-treat-overweight-obesity#available. Accessed Dec 13, 2021.

ElSayed NA, Aleppo G, Aroda VR, et al. 9 Pharmacologic approaches to glycemic treatment: standards of care in diabetes-2023. Diabetes Care. 2023;46(Suppl 1):S140–57. 10.2337/dc23-S009 PubMed DOI PMC

Professional Practice Committee. Addressing obesity in diabetes. Association of Diabetes Care and Education Specialists. 2018, p. 1. https://www.diabeteseducator.org/docs/def. Accessed 24 Aug 2023.

Pedersen SD, Manjoo P, Wharton S. Canadian adult obesity clinical practice guidelines: pharmacotherapy in obesity management. Available from: https://obesitycanada.ca/guidelines/pharmacotherapy. Accessed 01 Mar 2024.

Telci Caklili O, Cesur M, Mikhailidis DP, Rizzo M. Novel anti-obesity therapies and their different effects and safety profiles: a critical overview. Diabetes Metab Syndr Obes. 2023;16:1767–74. 10.2147/DMSO.S392684 PubMed DOI PMC

Committee ADAPP. Obesity and weight management for the prevention and treatment of type 2 diabetes: standards of care in diabetes–2024. Diabetes Care. 2023;47(Suppl_1):S145–S157. PubMed PMC

Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373(1):11–22. 10.1056/NEJMoa1411892 PubMed DOI

Herzlinger S, Horton ES. Extraglycemic effects of glp-1-based therapeutics: addressing metabolic and cardiovascular risks associated with type 2 diabetes. Diabetes Res Clin Pract. 2013;100(1):1–10. 10.1016/j.diabres.2012.11.009 PubMed DOI

Van Genugten R, Möller-Goede D, Van Raalte D, Diamant M. Extra-pancreatic effects of incretin-based therapies: potential benefit for cardiovascular-risk management in type 2 diabetes. Diabetes Obes Metab. 2013;15(7):593–606. 10.1111/dom.12050 PubMed DOI

Rosenstock J, Allison D, Birkenfeld AL, et al. Effect of additional oral semaglutide vs sitagliptin on glycated hemoglobin in adults with type 2 diabetes uncontrolled with metformin alone or with sulfonylurea: the PIONEER 3 randomized clinical trial. JAMA. 2019;321(15):1466–80. 10.1001/jama.2019.2942 PubMed DOI PMC

Davies M, Pieber TR, Hartoft-Nielsen ML, Hansen OKH, Jabbour S, Rosenstock J. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA. 2017;318(15):1460–70. 10.1001/jama.2017.14752 PubMed DOI PMC

EMA. Assessment report (Wegovy). 2021. https://www.ema.europa.eu/en/documents/assessment-report/wegovy-epar-public-assessment-report_en.pdf. Accessed 24 Aug 2023.

Patoulias D, Popovic DS, Stoian AP, Janez A, Sahebkar A, Rizzo M. Effect of semaglutide versus other glucagon-like peptide-1 receptor agonists on cardio-metabolic risk factors in patients with type 2 diabetes: a systematic review and meta-analysis of head-to-head, phase 3, randomized controlled trials. J Diabetes Complicat. 2023;37(8):108529.10.1016/j.jdiacomp.2023.108529 PubMed DOI

ElSayed NA, Aleppo G, Aroda VR, et al. Obesity and weight management for the prevention and treatment of type 2 diabetes: standards of care in diabetes-2023. Diabetes Care. 2023;46(Suppl 1):S128–S139. 10.2337/dc23-S008 PubMed DOI PMC

ESC. ESC guidelines on diabetes, pre-diabetes and cardiovascular diseases in collaboration with EASD. Eur Heart J. 2019. 10.1093/eurheartj/ehz486. Accessed 12 Sept 2023.10.1093/eurheartj/ehz486 DOI

Latif W, Lambrinos KJ, Rodriguez R. Compare and contrast the glucagon-like peptide-1 receptor agonists (GLP1RAs). Treasure Island: StatPearls; 2023. PubMed

Pratley RE, Aroda VR, Lingvay I, et al. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol. 2018;6(4):275–86. 10.1016/S2213-8587(18)30024-X PubMed DOI

Htike ZZ, Zaccardi F, Papamargaritis D, Webb DR, Khunti K, Davies MJ. Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a systematic review and mixed-treatment comparison analysis. Diabetes Obes Metab. 2017;19(4):524–36. 10.1111/dom.12849 PubMed DOI

Frias JP, Wynne AG, Matyjaszek-Matuszek B, et al. Efficacy and safety of an expanded dulaglutide dose range: a phase 2, placebo-controlled trial in patients with type 2 diabetes using metformin. Diabetes Obes Metab. 2019;21(9):2048–57. 10.1111/dom.13764 PubMed DOI

European Medicines Agency. Ozempic summary of product characteristics. 2019. https://www.ema.europa.eu/en/documents/product-information/ozempic-epar-product-information_en.pdf. Accessed 26 Aug 2023.

Food and Drug Administration. Ozempic prescribing information. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl.pdf. Accessed 26 Aug 2023.

Aroda VR, Ahmann A, Cariou B, et al. Comparative efficacy, safety, and cardiovascular outcomes with once-weekly subcutaneous semaglutide in the treatment of type 2 diabetes: Insights from the SUSTAIN 1–7 trials. Diabetes Metab. 2019;45(5):409–18. 10.1016/j.diabet.2018.12.001 PubMed DOI

Thethi TK, Pratley R, Meier JJ. Efficacy, safety and cardiovascular outcomes of once-daily oral semaglutide in patients with type 2 diabetes: the PIONEER programme. Diabetes Obes Metab. 2020;22(8):1263–77. 10.1111/dom.14054 PubMed DOI PMC

Rodbard HW, Rosenstock J, Canani LH, et al. Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial. Diabetes Care. 2019;42(12):2272–81. 10.2337/dc19-0883 PubMed DOI

Pratley R, Amod A, Hoff ST, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet. 2019;394(10192):39–50. 10.1016/S0140-6736(19)31271-1 PubMed DOI

Giorgino F, Benroubi M, Sun J-H, Zimmermann AG, Pechtner V. Efficacy and safety of once-weekly dulaglutide versus insulin glargine in patients with type 2 diabetes on metformin and glimepiride (AWARD-2). Diabetes Care. 2015;38(12):2241–9. 10.2337/dc14-1625 PubMed DOI

Wysham C, Blevins T, Arakaki R, et al. Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care. 2014;37(8):2159–67. 10.2337/dc13-2760 PubMed DOI

Salmen T, Serbanoiu L-I, Bica I-C, et al. A critical view over the newest antidiabetic molecules in light of efficacy: a systematic review and meta-analysis. Int J Mol Sci. 2023;24(11):9760. 10.3390/ijms24119760 PubMed DOI PMC

Van Gaal L, Scheen A. Weight management in type 2 diabetes: current and emerging approaches to treatment. Diabetes Care. 2015;38(6):1161–72. 10.2337/dc14-1630 PubMed DOI

Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669–701. 10.2337/dci18-0033 PubMed DOI PMC

American Diabetes Association. 9 Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2020. Diabetes Care. 2020;43(Suppl 1):S98–110. 10.2337/dc20-S009 PubMed DOI

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. 10.1056/NEJMoa1509225 PubMed DOI

Lipscombe L, Butalia S, Dasgupta K, et al. Pharmacologic glycemic management of type 2 diabetes in adults: 2020 update. Can J Diabetes. 2020;44(7):575–91. 10.1016/j.jcjd.2020.08.001 PubMed DOI

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. 10.1056/NEJMoa1504720 PubMed DOI

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. 10.1056/NEJMoa1611925 PubMed DOI

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. 10.1056/NEJMoa1812389 PubMed DOI

Aroda VR, Rosenstock J, Wysham C, et al. Efficacy and safety of lixilan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide in type 2 diabetes inadequately controlled on basal insulin and metformin: the LixiLan-L randomized trial. Diabetes Care. 2016;39(11):1972–80. 10.2337/dc16-1495 PubMed DOI

Billings LK, Doshi A, Gouet D, et al. Efficacy and safety of ideglira versus basal-bolus insulin therapy in patients with type 2 diabetes uncontrolled on metformin and basal insulin: the DUAL VII randomized clinical trial. Diabetes Care. 2018;41(5):1009–16. 10.2337/dc17-1114 PubMed DOI

Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205–16. 10.1056/NEJMoa2206038 PubMed DOI

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. 10.1016/S0140-6736(21)01443-4 PubMed DOI

Patoulias D, Caprio M, Stoian AP, Rizzo M. Tirzepatide and glucagon-like peptide-1 receptor agonists: safety always comes first! Expert Opin Drug Saf. 2023;22(9):763–5. 10.1080/14740338.2023.2247984 PubMed DOI

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. 10.1016/S0140-6736(21)01324-6 PubMed DOI

Frias JP, Bastyr EJ, Vignati L, et al. The sustained effects of a dual GIP/GLP-1 receptor agonist, NNC0090–2746, in patients with type 2 diabetes. Cell Metab. 2017;26(2):343–352.e2. 10.1016/j.cmet.2017.07.011 PubMed DOI

Rizvi AA, Rizzo M. The emerging role of dual GLP-1 and GIP receptor agonists in glycemic management and cardiovascular risk reduction. Diabetes Metab Syndr Obes. 2022;15:1023–30. 10.2147/DMSO.S351982 PubMed DOI PMC

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. 10.1001/jama.2011.576 PubMed DOI

Boniol M, Dragomir M, Autier P, Boyle P. Physical activity and change in fasting glucose and HbA1c: a quantitative meta-analysis of randomized trials. Acta Diabetol. 2017;54:983–91. 10.1007/s00592-017-1037-3 PubMed DOI

Colberg SR, Sigal RJ, Yardley JE, et al. Physical activity/exercise and diabetes: a position statement of the American Diabetes Association. Diabetes Care. 2016;39(11):2065. 10.2337/dc16-1728 PubMed DOI PMC

Rubino DM, Greenway FL, Khalid U, et al. Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight in adults with overweight or obesity without diabetes: the STEP 8 randomized clinical trial. JAMA. 2022;327(2):138–50. 10.1001/jama.2021.23619 PubMed DOI PMC

Singh S, Chang HY, Richards TM, Weiner JP, Clark JM, Segal JB. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med. 2013;173(7):534–9. 10.1001/jamainternmed.2013.2720 PubMed DOI

Gudin B, Ladhari C, Robin P, et al. Incretin-based drugs and intestinal obstruction: a pharmacovigilance study. Therapie. 2020;75(6):641–7. 10.1016/j.therap.2020.02.024 PubMed DOI

Sodhi M, Rezaeianzadeh R, Kezouh A, Etminan M. Risk of gastrointestinal adverse events associated with glucagon-like peptide-1 receptor agonists for weight loss. JAMA. 2023;330(18):1795–7. 10.1001/jama.2023.19574 PubMed DOI PMC

Kalas MA, Galura GM, McCallum RW. Medication-induced gastroparesis: a case report. J Investig Med High Impact Case Rep. 2021;9:23247096211051920. PubMed PMC

Ard J, Cannon A, Lewis C, et al. Efficacy and safety of liraglutide 3.0 mg for weight management are similar across races: subgroup analysis across the SCALE and phase II randomized trials. Diabetes Obesity Metab. 2016;18(4):430–5.10.1111/dom.12632 PubMed DOI PMC

Aroda VR, Bauer R, Christiansen E, et al. Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme. Diabetes Obes Metab. 2022;24(7):1338–50. 10.1111/dom.14710 PubMed DOI PMC

Aroda VR, Ahmann A, Cariou B, et al. Comparative efficacy, safety, and cardiovascular outcomes with once-weekly subcutaneous semaglutide in the treatment of type 2 diabetes: insights from the SUSTAIN 1–7 trials. Diabetes Metab. 2019;45(5):409–18. 10.1016/j.diabet.2018.12.001 PubMed DOI

Faillie JL, Yin H, Yu OHY, et al. Incretin-based drugs and risk of intestinal obstruction among patients with type 2 diabetes. Clin Pharmacol Ther. 2022;111(1):272–82. 10.1002/cpt.2430 PubMed DOI

Stokes CS, Lammert F. Excess body weight and gallstone disease. Visc Med. 2021;37(4):254–60. 10.1159/000516418 PubMed DOI PMC

Faillie J-L, Oriana HY, Yin H, Hillaire-Buys D, Barkun A, Azoulay L. Association of bile duct and gallbladder diseases with the use of incretin-based drugs in patients with type 2 diabetes mellitus. JAMA Intern Med. 2016;176(10):1474–81. 10.1001/jamainternmed.2016.1531 PubMed DOI

Nauck MA, Muus Ghorbani ML, Kreiner E, Saevereid HA, Buse JB. Investigators LPCobotLT. Effects of liraglutide compared with placebo on events of acute gallbladder or biliary disease in patients with type 2 diabetes at high risk for cardiovascular events in the LEADER randomized trial. Diabetes Care. 2019;42(10):1912–20. 10.2337/dc19-0415 PubMed DOI PMC

Wang T, Wang F, Gou Z, et al. Using real-world data to evaluate the association of incretin-based therapies with risk of acute pancreatitis: a meta-analysis of 1 324 515 patients from observational studies. Diabetes Obes Metab. 2015;17(1):32–41. 10.1111/dom.12386 PubMed DOI

Ozempic® Prescribing Information. Plainsboro NNNI. Available from: https://www.novo-pi.com/ozempic.pdf. Accessed 01 Mar 2024.

Data on File at Novo Nordisk Inc. P, NJ. NN9535–4216 (SUSTAIN 7), Nov 2017. Data on File at Novo Nordisk Inc., Plainsboro, NJ. NN9535–4269 (SUSTAIN 9), Feb 2019; Data on File at Novo Nordisk Inc., Plainsboro, NJ. NN9535–4339 (SUSTAIN 10), Dec 2018; Data on File at Novo Nordisk Inc., Plainsboro, NJ. NN9535–4506 (SUSTAIN FORTE), Jul 2021.

Ycaza A, Brito J, McCoy R, Shao H, Ospina N. GLP-1 receptor agonists and thyroid cancer: a narrative review. Thyroid. 2024;34:403–18. PubMed PMC

Pasternak B, Wintzell V, Hviid A, et al. Glucagon-like peptide 1 receptor agonist use and risk of thyroid cancer: Scandinavian cohort study. BMJ. 2024;385:e078225. 10.1136/bmj-2023-078225 PubMed DOI PMC

Cao C, Yang S, Zhou Z. GLP-1 receptor agonists and risk of cancer in type 2 diabetes: an updated meta-analysis of randomized controlled trials. Endocrine. 2019;66:157–65. 10.1007/s12020-019-02055-z PubMed DOI

Hu W, Song R, Cheng R, et al. Use of GLP-1 receptor agonists and occurrence of thyroid disorders: a meta-analysis of randomized controlled trials. Front Endocrinol. 2022;13:927859.10.3389/fendo.2022.927859 PubMed DOI PMC

Bezin J, Gouverneur A, Pénichon M, et al. GLP-1 receptor agonists and the risk of thyroid cancer. Diabetes Care. 2022;46(2):384–90.10.2337/dc22-1148 PubMed DOI

Yang Z, Lv Y, Yu M, et al. GLP-1 receptor agonist-associated tumor adverse events: a real-world study from 2004 to 2021 based on FAERS. Front Pharmacol. 2022;13:925377. 10.3389/fphar.2022.925377 PubMed DOI PMC

Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011;141(1):150–6. 10.1053/j.gastro.2011.02.018 PubMed DOI PMC

Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–44. 10.1056/NEJMoa1607141 PubMed DOI

Bain SC. At a glance factsheet: GLP-1 receptor agonists and diabetic retinopathy. Diabetes Primary Care. 2021;23:103–4.

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. 10.1056/NEJMoa1603827 PubMed DOI PMC

Vilsbøll T, Bain SC, Leiter LA, et al. Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy. Diabetes Obes Metab. 2018;20(4):889–97. 10.1111/dom.13172 PubMed DOI PMC

Vlacho B, Mata-Cases M, Fernandez-Camins B, Romera Liébana L, Barrot de la Puente J, Franch-Nadal J. Adherence to the therapeutic guidelines recommendations among the people with type 2 diabetes mellitus and obesity, frailty, or recent diagnosis, attended in primary health care centers in Spain: a cross-sectional study. Front Med (Lausanne). 2023;10:1138956. 10.3389/fmed.2023.1138956 PubMed DOI PMC

Mosenzon O, Alguwaihes A, Leon JLA, et al. CAPTURE: a multinational, cross-sectional study of cardiovascular disease prevalence in adults with type 2 diabetes across 13 countries. Cardiovasc Diabetol. 2021;20(1):154. 10.1186/s12933-021-01344-0 PubMed DOI PMC

Andreozzi F, Candido R, Corrao S, et al. Clinical inertia is the enemy of therapeutic success in the management of diabetes and its complications: a narrative literature review. Diabetol Metab Syndr. 2020;12:52. 10.1186/s13098-020-00559-7 PubMed DOI PMC

Fralick M, Jenkins AJ, Khunti K, Mbanya JC, Mohan V, Schmidt MI. Global accessibility of therapeutics for diabetes mellitus. Nat Rev Endocrinol. 2022;18(4):199–204. 10.1038/s41574-021-00621-y PubMed DOI PMC

Michos ED, Bakris GL, Rodbard HW, Tuttle KR. Glucagon-like peptide-1 receptor agonists in diabetic kidney disease: a review of their kidney and heart protection. Am J Prev Cardiol. 2023;14:100502. 10.1016/j.ajpc.2023.100502 PubMed DOI PMC

Reach G, Pechtner V, Gentilella R, Corcos A, Ceriello A. Clinical inertia and its impact on treatment intensification in people with type 2 diabetes mellitus. Diabetes Metab. 2017;43(6):501–11. 10.1016/j.diabet.2017.06.003 PubMed DOI

Khunti S, Khunti K, Seidu S. Therapeutic inertia in type 2 diabetes: prevalence, causes, consequences and methods to overcome inertia. Ther Adv Endocrinol Metab. 2019;10:2042018819844694. 10.1177/2042018819844694 PubMed DOI PMC

Mata-Cases M, Franch-Nadal J, Real J. Therapeutic inertia in patients treated with two or more antidiabetics in primary care: factors predicting intensification of treatment. Diabetes Obes Metab. 2018;20(1):103–12. 10.1111/dom.13045 PubMed DOI

Khunti K, Damci T, Meneghini L, Pan C, Yale JF, Group SS. Study of Once Daily Levemir (SOLVE™): insights into the timing of insulin initiation in people with poorly controlled type 2 diabetes in routine clinical practice. Diabetes Obes Metab. 2012;14(7):654–61. 10.1111/j.1463-1326.2012.01602.x PubMed DOI

De Pablos-Velasco P, Parhofer K, Eschwegee BC, et al. Current level of glycaemic control and its associated factors in patients with type 2 diabetes across europe: data from the PANoRAMA study. Clin Endocrinol (Oxf). 2014;80:47–56. 10.1111/cen.12119 PubMed DOI

Stone MA, Charpentier G, Doggen K, et al. Quality of care of people with type 2 diabetes in eight European countries: findings from the Guideline Adherence to Enhance Care (GUIDANCE) study. Diabetes Care. 2013;36(9):2628–38. 10.2337/dc12-1759 PubMed DOI PMC

Khunti K, Wolden ML, Thorsted BL, Andersen M, Davies MJ. Clinical inertia in people with type 2 diabetes: a retrospective cohort study of more than 80,000 people. Diabetes Care. 2013;36(11):3411–7. 10.2337/dc13-0331 PubMed DOI PMC

Polonsky WH, Henry RR. Poor medication adherence in type 2 diabetes: recognizing the scope of the problem and its key contributors. Patient Prefer Adherence. 2016;10:1299–1307. PubMed PMC

Laursen DH, Christensen KB, Christensen U, Frølich A. Assessment of short and long-term outcomes of diabetes patient education using the health education impact questionnaire (HeiQ). BMC Res Notes. 2017;10(1):1–9. 10.1186/s13104-017-2536-6 PubMed DOI PMC

Greenwood DA, Blozis SA, Young HM, Nesbitt TS, Quinn CC. Overcoming clinical inertia: a randomized clinical trial of a telehealth remote monitoring intervention using paired glucose testing in adults with type 2 diabetes. J Med Internet Res. 2015;17(7):e4112.10.2196/jmir.4112 PubMed DOI PMC