Therapy of Type 2 Diabetes

The Clinical Practice Guidelines of the German Diabetes Society/Deutsche Diabetes Gesellschaft (DDG) together with the German Society for Internal Medicine/Deutschen Gesellschaft für Innere Medizin (DGIM) are based on the contents of the National Treatment Guideline (Nationale Versorgungsleitlinie (NVL)) “Type 2 Diabetes” [1]. The modifications in therapy and their justifications made in the present Clinical Practice Guidelines were updated on the basis of new randomized controlled trials (RCTs) and meta-analyses.

In order to improve the work with the extensive practice guideline in practice, the authors have decided to move the individual glucose-lowering pharmaceuticals and some algorithms in the current practice guideline to a detailed appendix. The corresponding bibliography can also be found in the appendix.

Publication History

Article published online:
15 July 2022

• References

• 1 Nationale VersorgungsLeitlinien. NVL-2-Diabetes – Teilpublikation, 2. Auflage: www.leitlinien.de/themen/diabetes
• 2 Alberti KGMM, Eckel RH, Grundy SM. et al. Harmonizing the Metabolic Syndrome. Circulation 2009; 120: 1640-1645
• 3 Elwyn G, Vermunt NPCA. Goal-based shared decision-making: developing an integrated model. J Patient Exp 2019; 1-9
• 4 Wang R, Song Y, Yan Y. et al. Elevated serum uric acid and risk of cardiovascular or all-cause mortality in people with suspected or definite coronary artery disease: A meta-analysis. Atherosclerosis 2016; 254: 193-199
• 5 Parhofer KG, Birkenfeld AL, Krone W. et al. Lipidtherapie bei Patienten mit Diabetes mellitus. Diabetologie 2020; 15: S160-S165
• 6 Mach F, Baigent C, Catapano AL. et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020; 41: 111-188
• 7 The Task Force for the management of arterial hypertension of the European Society of cardiology (ESC) and the European Society of Hypertension (ESH). 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J 2018; 39: 3021-3104
• 8 Heinemann L, Kaiser P, Freckmann G. et al. HbA1c-Messung in Deutschland: Ist die Qualität ausreichend für Verlaufskontrolle und Diagnose?. Diabetologie 2018; 13: 46-53
• 9 Landgraf R, Nauck M, Freckmann G. et al. Fallstricke bei der Diabetesdiagnostik: Wird zu lax mit Laborwerten umgegangen?. Dtsch Med Wochenschr 2018; 143: 1549-1555
• 10 Nauck M, Gerdes C, Petersmann A. et al. Definition, Klassifikation und Diagnostik des Diabetes mellitus. Update 2020. Diabetologie 2020; 15: S9-S17
• 11 Landgraf R. HbA1c in der Diabetesdiagnostik. Der Goldstandard?. Diabetes aktuell 2021; 19: 22-29
• 12 Ahlqvist E, Storm P, Käräjämäki A. et al. Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol 2018; 6: 361-369
• 13 Zaharia OP, Strassburger K, Strom A. et al. Risk of diabetes-associated diseases in subgroups of patients with recent-onset diabetes: a 5-year follow-up study. Lancet Diabetes Endocrinol 2019; 7: 684-694
• 14 Dennis JM, Shields BM, Henley WE. et al. Disease progression and treatment response in data-driven subgroups of type 2 diabetes compared with models based on simple clinical features: an analysis using clinical trial data. Lancet Diabetes Endocrinol 2019; 7: 442-451
• 15 Zhang Y, Pan XF, Chen J. et al. Combined lifestyle factors and risk of incident type 2 diabetes and prognosis among individuals with type 2 diabetes: a systematic review and meta-analysis of prospective cohort studies. Diabetologia 2020; 63: 21-3316
• 16 Nationale VersorgungsLeitlinie (NVL) Diabetes – Strukturierte Schulungsprogramme 2018 www.leitlinien.de/nvl/diabetes/schulungsprogramme
• 17 Forouhi NG, Misra A, Mohan V. et al. Dietary and nutritional approaches for prevention and management of type 2 diabetes. BMJ 2018; 361: k2234
• 18 Serra-Majem L, Román-Viñas B, Sanchez-Villegas A. et al. Benefits of the Mediterranean diet: Epidemiological and molecular aspects. Mol Aspects Med 2019; 67: 1-55
• 19 Taylor R, Al-Mrabeh A, Sattar N. Understanding the mechanisms of reversal of type 2 diabetes. Lancet Diabetes Endocrinol 2019; 7: 726-736
• 20 Evert AB, Dennison M, Gardner CD. et al. Nutrition therapy for adults with Diabetes or prediabetes: a consensus report. Diabetes Care 2019; 42: 731-754
• 21 Hauner H. Evidenz in der Ernährungstherapie des Diabetes mellitus. Der Diabetologe 2021; 17: 687-696
• 22 Chester B, Babu JR, Greene MW. et al. The effects of popular diets on type 2 diabetes management. Diabetes Metab Res Rev 2019; 35: e3188
• 23 Kempf K, Altpeter B, Berger J. et al. Efficacy of the telemedical lifestyle intervention program TeLiPro in advanced stages of type 2 diabetes: A randomized controlled trial. Diabetes Care 2017; 40: 863-871
• 24 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-randomized trial. Lancet Diabetes Endocrinol 2019; 7: 344-355
• 25 Adipositas – Prävention und Therapie. AWMF-Register Nr. 050-001.
• 26 Aberle J, Lautenbach A, Meyhöfer S. et al. Adipositas und Diabetes. Diabetologe 2021; 16: S290-S298
• 27 Yang D, Yang Y, Li Y. et al. Physical exercise as therapy for type 2 diabetes mellitus: from mechanism to orientation. Ann Nutr Metab 2019; 74: 313-321
• 28 Tarp J, Støle AP, Blond K. et al. Cardiorespiratory fitness, muscular strength and risk of type 2 diabetes: a systematic review and metaanalysis. Diabetologia 2019; 62: 1129-1142
• 29 Liu Y, Ye W, Chen Q. et al. Resistance exercise intensity is correlated with attenuation of HbA1c and insulin in patients with type 2 diabetes: A systematic review and meta-analysis. Int J Environ Res Public Health 2019; 16: 140
• 30 Esefeld K, Kress S, Behrens M. et al. Diabetes, Sport und Bewegung. Diabetologe 2021; 16: S299-S307
• 31 Piercy KL, Richard P, Troiano RP. et al. The physical activity guidelines for Americans. JAMA 2018; 320: 2020-2028
• 32 Jabardo-Camprubí G, Donat-Roca R, Sitjà-Rabert M. et al. Drop-out ratio between moderate to high-intensity physical exercise treatment by patients with, or at risk of, type 2 diabetes mellitus: A systematic review and meta-analysis. Physiol Behav 2020; 215: 112786
• 33 Kar D, Gillies C, Nath M. et al. Association of smoking and cardiometabolic parameters with albuminuria in people with type 2 diabetes mellitus: a systematic review and meta-analysis. Acta Diabetologica 2019; 56: 839-850
• 34 Rauchen und Tabakabhängigkeit: Screening, Diagnostik und Behandlung. S3-Leitlinie Langversion AWMF-Register Nr. 076-006
• 35 Tabakatlas Deutschland 2020 www.dkfz.de/de/tabakkontrolle/download/Publikationen/sonstVeroeffentlichungen/Tabakatlas-Deutschland- 2020_dp.pdf Seiten 38–39 und 110–111
• 36 Fleming GA, Petrie JR, Bergenstal RM. et al. Diabetes Digital App Technology: Benefits, Challenges, and Recommendations. A Consensus Report by the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) Diabetes Technology Working Group. Diabetes Care 2020; 43: 250-260
• 37 Khunti K, Gomes MB, Pocock S. et al. Therapeutic inertia in the treatment of hyperglycaemia in patients with type 2 diabetes: A systematic review. Diabetes Obes Metab 2018; 20: 427-437
• 38 Matthews DR, Paldánius PM, Proot P. VERIFY study group et al. Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5-year, multicentre, randomised, double-blind trial. Lancet 2019; 394: 1519-1529
• 39 Gough SC, Bode B, Woo V. et al. Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes. Lancet Diabet Endocrinol 2014; 2: 885-893
• 40 Diamant M, Nauck MA, Shaginian R. et al. Glucagon-like peptide 1 receptor agonist or bolus insulin with optimized basal insulin in type 2 diabetes. Diabetes Care 2014; 37: 2763-2773
• 41 Ahmann A, Rodbard HW, Rosenstock J. et al. Efficacy and safety of liraglutide versus placebo added to basal insulin analogues (with or without metformin) in patients with type 2 diabetes: a randomized, placebo controlled trial. Diabetes Obes Metab 2015; 17: 1056-1064
• 42 Montvida O, Klein K, Kumar S. et al. Addition of or switch to insulin therapy in people treated with glucagon-like peptide-1 receptor agonists: A real-world study in 66 583 patients. Diabetes Obes Metab 2017; 19: 108-117
• 43 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: 1009-1016
• 44 Parhofer KG. Lipidtherapie. Diabetologe 2021; 16: S312-S317
• 45 Mengden T, Weisser B. Therapieüberwachung bei arterieller Hypertonie. Dtsch Ärztebl 2021; 118: 473-478
• 46 Nationale VersorgungsLeitlinie Nierenerkrankungen bei Diabetes im Erwachsenenalter 2018 www.leitlinien.de/nvl/diabetes/nierenerkrankungen
• 47 ESC/ESH Guidelines 2018. Management der arteriellen Hypertonie www.dgk.de
• 48 American Diabetes Association. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes – 2021. Diabetes Care 2021; 44: S125-S150
• 49 The SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015; 373: 2103-2116
• 50 Banegas JR, Ruilope LM, de la Sierra A. et al. Relationship between clinic and ambulatory blood-pressure measurements and mortality. N Engl JMed 2018; 378: 1509-1520
• 51 Lawall H, Huppert P, Rümenapf G. et al. Periphere arterielle Verschlusskrankheit (PAVK), Diagnostik, Therapie und Nachsorge. AWMF-Register Nr. 065–003 2015
• 52 Nationale VersorgungsLeitlinie Neuropathie bei Diabetes im Erwachsenenalter. 2016 www.leitlinien.de/mdb/downloads/nvl/ diabetesmellitus/dm-neuropathie
• 53 Nationale VersorgungsLeitlinie Prävention und Therapie von Netzhautkomplikationen bei Diabetes. 2016 www.leitlinien.de/nvl/ html/netz.hautkomplikationen
• 54 Nationale VersorgungsLeitlinie (NVL) Typ-2-Diabetes Präventions-und Behandlungsstrategien für Fußkomplikationen. 2018 www.leitlinien. de/nvl/diabetes/fusskomplikationen
• 55 Roeb E, Steffen HM, Bantel H. et al. S2k-Leitlinie: Nicht-alkoholische Fettlebererkrankungen. AWMF-Register Nr. 021–025 2015
• 56 Wang R, Song Y, Yan Y. et al. Elevated serum uric acid and risk of cardiovascular or all-cause mortality in people with suspected or definite coronary artery disease: A meta-analysis. Atherosclerosis 2016; 254: 193-199
• 57 Nationale VersorgungsLeitlinie Chronische Herzinsuffizienz. 2020 https://www.leitlinien.de/nvl/html/nvl-chronische-herzinsuffizienz
• 58 Nationale VersorgungsLeitlinie Chronische Koronare Herzerkrankung (KHK). 2019 https://www.leitlinien.de/mdb/downloads/nvl/khk/, www.leitlinien.de/nvl/html/nvl-chronische-khk
• 59 Nationale VersorgungsLeitlinie Nierenerkrankungen bei Diabetes im Erwachsenenalter. 2018 www.leitlinien.de/nvl/diabetes/ nierenerkrankungen
• 60 The Look AHEAD Research Group. Cardiovascular effects ofintensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013; 369: 145-154
• 61 Unick JL, Gaussoin SA, Hill JO. et al. Objectively assessed physical activity and weight loss maintenance among individuals enrolled in a lifestyle intervention. Obesity (Silver Spring) 2017; 25: 1903-1909
• 62 The Look AHEAD Research Group. Association of the magnitude of weight loss and changes in physical fitness with longterm cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: a post-hoc analysis of the Look AHEAD randomized clinical trial. Lancet Diabetes Endocrinol 2016; 4: 913-921
• 63 Gregg EW, Lin J, Bardenheier B. et al. Impact of Intensive Lifestyle Intervention on Disability-Free Life Expectancy: The Look AHEADStudy. Diabetes Care 2018; 41: 1040-1048
• 64 Chao AM, Wadden TA, Berkowitz RI. Look AHEAD Research Group et al. Weight change 2 years after termination of the intensive lifestyle intervention in the Look AHEAD Study. Obesity 2020; 28: 893-890
• 65 Yang D, Yang Y, Li Y. et al. Physical exercise as therapy for type 2 diabetes mellitus: from mechanism to orientation. Ann Nutr Metab 2019; 74: 313-321
• 66 Tarp J, Støle AP, Blond K. et al. Cardiorespiratory fitness, muscular strength and risk of type 2 diabetes: a systematic review and metaanalysis. Diabetologia 2019; 62: 1129-1142
• 67 Liu Y, Ye W, Chen Q. et al. Resistance exercise intensity is correlated with attenuation of HbA1c and insulin in patients with type 2 diabetes: A systematic review and meta-analysis. Int J Environ Res Public Health 2019; 16: E140
• 68 www.bfarm.de/SharedDocs/Risikoinformationen/Pharmakovigilanz/ DE/RV_STP/m-r/metformin.html
• 69 Lazarus B, Wu A, Shin JI. et al. Association of metformin use with risk of lactic acidosis across the range of kidney function. A communitybased cohort study. JAMA Intern Med 2018; 178: 903-910
• 70 Griffin SJ, Leaver JK, Irving GJ. et al. Impact of metformin on cardiovascular disease: a meta-analysis of randomized trails among people with type 2 diabetes. Diabetologia 2017; 60: 1620-1629
• 71 Palmer SC, Mavridis D, Nicolucci A. et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes. A meta-analysis. JAMA 2016; 316: 313-324
• 72 Madsen KS, Kähler P, Kähler LKA. et al. Metformin and second- or third generation sulphonylurea combination therapy for adults with type 2 diabetes mellitus. Cochrane Database Syst Rev 2019; 4: CD012 368
• 73 Sattar N, McGuire DK. Prevention of CV outcomes in antihyperglycemic drug-naive patients with type 2 diabetes with, or at elevated risk of, ASCVD: to start or not to start with metformin. Eur Heart J 2021; 42: 2574-2576
• 74 Rena G, Mordi IR, Lang CC. Metformin: still the sweet spot for CV protection in diabetes?. Curr Opin Pharmacol 2020; 54: 202-208
• 75 Mallik R, Chowdhury TA. Metformin in cancer. Diabetes Res Clin Pract 2018; 143: 409-419
• 76 Thakur S, Daley B, Klubo-Gwiezdzinska J. The role of the antidiabetic drug metformin in the treatment of endocrine tumors. J Mol Endocrinol 2019; 63: R17-R35
• 77 De A, Kuppusamy G. Metformin in breast cancer: preclinical and clinical evidence. Curr Probl Cancer 2020; 44: 100488
• 78 Rahmani J, Manzari N, Thompson J. et al. The effect of metformin on biomarkers associated with breast cancer outcomes: a systematic review, meta-analysis, and dose-response of randomized clinical trials. Clin Transl Oncol 2020; 22: 37-49
• 79 Fong W, To KKW. Drug repurposing to overcome resistance to various therapies for colorectal cancer. Cell Mol Life Sci 2019; 76: 3383-3406
• 80 Aljofan M, Riethmacher D. Anticancer activity of metformin: a systematic review of the literature. Future Sci OA 2019; 5: FSO410
• 81 Feng Z, Zhou X, Liu N. et al. Metformin use and prostate cancer risk: A meta-analysis of cohort studies. Medicine (Baltimore) 2019; 98: e14 955
• 82 Park YMM, Bookwalter DB, O’Brien KM. et al. A prospective study of type 2 diabetes, metformin use, and risk of breast cancer. Ann Oncol 2021; 32: 351-359
• 83 Lv Z, Guo Y. Metformin and Its Benefits for Various Diseases. Front Endocrinol 2020; 11: 191
• 84 Khunti K, Knighton P, Zaccardi F. et al. Prescription of glucoselowering therapies and risk of COVID-19 mortality in people with type 2 diabetes: a nationwide observational study in England. Lancet Diabetes Endocrinol 2021; 9: 293-303
• 85 Wargny M, Potier L, Gourdy P. et al. Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study. Diabetologia 2021; 64: 778-794
• 86 Kow CS, Hasan SS. Mortality risk with preadmission metformin use in patients with COVID-19 and diabetes: A meta-analysis. J Med Virol 2021; 93: 695-697
• 87 Lim S, Bae JH, Kwon H-S, Nauck MA. COVID-19 and diabetes mellitus: from pathophysiology to clinical management. Nat Rev Endocrinol 2021; 17: 11-30
• 88 Bornstein SR, Rubino F, Khunti K. et al. Practical recommendations for the management of diabetes in patients with COVID-19. Lancet Diabetes Endocrinol 2020; 8: 546-50
• 89 Oshima M, Jun M, Ohkuma T. et al. The relationship between eGFR slope and subsequent risk of vascular outcomes and all-cause mortality in type 2 diabetes: the ADVANCE-ON study. Diabetologia 2019; 62: 1988-1997
• 90 The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358: 2560-2572
• 91 Rosenstock J, Kahn SE, Johansen OE. on behalf of the CAROLINA. Investigators et al. Effect of linagliptin vs. glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: The CAROLINA randomized clinical trial. JAMA 2019; 322: 1155-1166
• 92 Rados DV, Pinto LC, Remonti LR. et al. The association between sulfonylurea use and all-cause and cardiovascular mortality: A meta-analysis with trial sequential analysis of randomized clinical trials. PLoS Med 2016; 13: e1002 091
• 93 Azoulay L, Suissa S. Sulfonylureas and the risks of cardiovascular events and death: A methodological meta-regression analysis of the observational studies. Diabetes Care 2017; 40: 706-714
• 94 Bain S, Druyts E, Balijepalli C. et al. Cardiovascular events and all-cause mortality associated with sulphonylureas compared with other antihyperglycaemic drugs: A Bayesian meta-analysis of survival data. Diabetes Obes Metab 2017; 19: 329-335
• 95 Zhuang XD, He X, Yang DY. et al. Comparative cardiovascular outcomes in the era of novel anti-diabetic agents: a comprehensive network meta-analysis of 166 371 participants from170 randomized controlled trials. Cardiovasc Diabetol 2018; 17: 79
• 96 Powell WR, Christiansen CL, Miller DR. Meta-analysis of sulfonylurea therapy on long-term risk of mortality and cardiovascular events compared to other oral glucose-lowering treatments. Diabetes Ther 2018; 9: 1431-1440
• 97 Simpson SH, Lee J, Choi S. et al. Mortality risk among sulfonylureas: a systematic review and network meta-analysis. Lancet Diabetes Endocrinol 2015; 3: 43-51
• 98 Hemmingsen B, Schroll JB, Lund SS. et al. Sulphonylurea monotherapy for patients with type 2 diabetes mellitus. Cochrane Database Syst Rev 2013; 4: CD009 008
• 99 Hemmingsen B, Schroll JB, Jorn Wetterslev J. et al. Sulfonylurea versus metformin monotherapy in patients with type 2 diabetes: a Cochranesystematic review and meta-analysis of randomized clinical trials and trial sequential analysis. CMAJ Open 2014; 2: E162-E175
• 100 Vaccaro O, Masulli M, Nicolucci M. et al. Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomized, multicenter trial. Lancet Diabetes Endocrinol 2017; 5: 887-897
• 101 Ogundipe O, Mazidi M, Chin KL. et al. Real-world adherence, persistence, and in-class switching during use of dipeptidyl peptidase-4 inhibitors: a systematic review and meta-analysis involving 594,138 patients with type 2 diabetes. Acta Diabetologica 2021; 58: 39-46
• 102 Chen K, Kang D, Yu M. et al. Direct head-to-head comparison of glycaemic durability of dipeptidyl peptidase-4 inhibitors and sulphonylureas in patients with type 2 diabetes mellitus: A metaanalysis of long-term randomized controlled trials. Diabetes Obes Metab 2018; 20: 1029-1033
• 103 Patorno E, Schneeweiss S, Gopalakrishnan C. et al. Using realworld data to predict findings of an ongoing phase IV cardiovascular outcome trial: Cardiovascular safety of linagliptin versus glimepiride. Diabetes Care 2019; 42: 2204-2210
• 104 Scirica BM, Bhatt DL, Braunwald E. et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013; 369: 1317-1326
• 105 White WB, Cannon CP, Heller SR. et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013; 369: 1327-1335
• 106 Green JB, Bethel MA, Armstrong PW. et al. TECOS Study Group Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015; 373: 232-242
• 107 Rosenstock J, Perkovic V, Johansen OE. et al. Effect of linagliptin vs placebo on major cardiovasculareEvents in adults with type 2 diabetes and high cardiovascular and renal risk: The CARMELINA Randomized Clinical Trial. JAMA 2019; 321: 69-79
• 108 Perkovic V, Toto R, Cooper ME. et al. Effects of Linagliptin on Cardiovascular and Kidney Outcomes in People With Normal and Reduced Kidney Function: Secondary Analysis of the CARMELINA Randomized Trial. Diabetes Care 2020; 43: 1803-1812
• 109 Monami M, Ahrén B, Dicembrini I. et al. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: ameta-analysis of randomized clinical trials. Diabetes Obes Metab 2013; 15: 112-120
• 110 Xu S, Zhang X, Tang L. et al. Cardiovascular effects of dipeptidylpeptidase-4 inhibitor in diabetic patients with and without established cardiovascular disease: a meta-analysis and systematic review. Postgrad Med 2017; 129: 205-215
• 111 Zheng SL, Roddick AJ, Aghar-Jaffar R. et al. Association between use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes. A systematic review and meta-analysis. JAMA 2018; 319: 1580-1591
• 112 Ling J, Cheng P, Ge L. et al. The efficacy and safety of dipeptidyl peptidase- 4 inhibitors for type 2 diabetes: a Bayesian network meta-analysis of 58 randomized controlled trials. Acta Diabetologica 2019; 56: 249-272
• 113 Li L, Li S, Deng K. et al. Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomized and observational studies. BMJ 2016; 352: i610
• 114 GuoWQ Li L, Su Q. et al. Effect of dipeptidylpeptidase-4 inhibitors on heart failure: A network meta-analysis. Value Health 2017; 20: 1427-1430
• 115 Nauck MA, Meier JJ, Cavender MA. et al. Cardiovascular actions and clinical outcomes with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Circulation 2017; 136: 849-870
• 116 Yan Xie Y, Bowe B, Gibson AK. et al. Comparative Effectiveness of SGLT2 Inhibitors, GLP-1 Receptor Agonists, DPP-4 Inhibitors, and Sulfonylureas on Risk of Kidney Outcomes: Emulation of a Target Trial Using Health Care Databases. Diabetes Care 2020; 43: 2859-2869
• 117 Sinha B, Ghosal S. Meta-analyses of the effects of DPP-4 inhibitors, SGLT2 inhibitors and GLP1 receptor analogues on cardiovascular death, myocardial infarction, stroke and hospitalization for heart failure. Diabetes Res Clin Pract 2019; 150: 8-16
• 118 Dougherty J, Guirguis E, Thornby KA. et al. A Systematic Review of Newer Antidiabetic Agents in the Treatment of Nonalcoholic Fatty Liver Disease. Annals of Pharmacotherapy 2021; 55: 65-79
• 119 Koufakis T, Mustafa OG, Zebekakis P, Kotsa K. Oral antidiabetes agents for the management of inpatient hyperglycaemia: so far, yet so close T. Diabet Med 2020; 37: 1418-1426
• 120 Du H, Wang DW, Chen C. The potential effects of DPP-4 inhibitors on cardiovascular system in COVID-19 patients. J Cell Mol Med 2020; 24: 10 274-10 278
• 121 Bonora BM, Avogaro A, Fadini GP. Disentangling conflicting evidence on DPP-4 inhibitors and outcomes of COVID-19: narrative review and meta-analysis. J Endocrinol Invest 2021; 44: 1379-1386
• 122 Tkáč I, Raz I. Combined analysis of three large interventional trials with gliptins indicates increased incidence of acute pancreatitis in patients with type 2 diabetes. Diabetes Care 2017; 40: 284-286
• 123 Pinto LC, Rados DV, Barkann SS. et al. Dipeptidyl peptidase-4 inhibitors, pancreatic cancer and acute pancreatitis: A meta-analysis with trial sequential analysis. Sci Rep 2018; 8: 782
• 124 Tasanen K, Varpuluoma O, Nishie W. Dipeptidyl Peptidase-4 Inhibitor-Associated Bullous Pemphigoid. Front Immunol 2019; 10: 1238
• 125 Overbeek JA, Bakker M, van der Heijden AAWA. et al. Risk of dipeptidyl peptidase-4 (DPP-4) inhibitors on site-specific cancer: A systematic review and meta-analysis. Diabetes Metab Res Rev 2018; 34: e3004
• 126 Abrahami D, Douros A, Yin H. et al. Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: population based cohort study. BMJ 2018; 360: k872
• 127 Li G, Crowley MJ, Tang H. et al. Dipeptidyl peptidase 4 inhibitors and risk of inflammatory bowel disease among patients with type 2 diabetes: A meta-analysis of randomized controlled trials. Diabetes Care 2019; 42: e119-e121
• 128 Storgaard H, Gluud LL, Bennett C. et al. Benefits and harms of sodium-glucose co-transporter 2 inhibitors in patients with type 2 diabetes: A systematic review and meta-analysis. PLoS One 2016; 11: e0166 125
• 129 Monami M, Liistro F, Scatena A. et al. Short andmedium-term efficacy of sodium glucose co-transporter-2 (SGLT-2) inhibitors: A metaanalysis of randomized clinical trials. Diabetes Obes Metab 2018; 20: 1213-1222
• 130 Usman MS, Siddiqi TJ, Memon MM. et al. Sodium-glucose cotransporter 2 inhibitors and cardiovascular outcomes: A systematic review and meta-analysis. Eur J Prev Cardiol 2018; 25: 495-502
• 131 Mishriky BM, Tanenberg RJ, Sewell KA. et al. Comparing SGLT-2 inhibitors to DPP-4 inhibitors as an add-on therapy to metformin in patients with type 2 diabetes: A systematic review and meta-analysis. Diabetes Metab 2018; 44: 112-120
• 132 Seidu S, Kunutsor SK, Cos X. et al. SGLT2 inhibitors and renal outcomes in type 2 diabetes with or without renal impairment: A systematic review and meta-analysis. Prim Care Diabetes 2018; 12: 265-283
• 133 Rådholm K, Wu JH, Wong MG. et al. Effects of sodium-glucose cotransporter- 2 inhibitors on cardiovascular disease, death and safety outcomes in type 2 diabetes – A systematic review. Diabetes Res Clin Pract 2018; 140: 118-128
• 134 Sinha B, Ghosal S. Meta-analyses of the effects of DPP-4 inhibitors, SGLT2 inhibitors and GLP1 receptor analogues on cardiovascular death, myocardial infarction, stroke and hospitalization for heart failure. Diabetes Res Clin Pract 2019; 150: 8-16
• 135 Zheng SL, Roddick AJ, Aghar-Jaffar R. et al. Association between use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes: A Systematic Review and Meta-analysis. JAMA 2018; 319: 1580-1591
• 136 Aronson R, Frias J, Goldman A. et al. Long-term efficacy and safety of ertugliflozin monotherapy in patients with inadequately controlled T2DMdespite diet and exercise: VERTIS MONO extension study. Diabetes Obes Metab 2018; 20: 1453-1460
• 137 Hollander P, Hill J, Johnson J. et al. Results of VERTIS SU extension study: safety and efficacy of ertugliflozin treatment over 104 weeks compared to glimepiride in patients with type 2 diabetes mellitus inadequately controlled on Metformin. Curr Med Res Opin 2019; 35: 1335-1343
• 138 Zelniker TA, Wiviott SD, Raz I. et al. 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. Lancet 201; 393: 31–39
• 139 Puckrin R, Saltiel MP, Reynier P. et al. SGLT-2 inhibitors and the risk of infections: a systematic review and meta-analysis of randomized controlled trials. Acta Diabetol 2018; 55: 503-514
• 140 Lega IC, Bronskill SE, Campitelli MA. et al. Sodium glucose cotransporter 2 inhibitors and risk of genital mycotic and urinary tract infection: A population-based study of older women and men with diabetes. Diabetes Obes Metab 2019; 21: 2394-2404
• 141 Dave CV, Schneeweiss S, Patorno E. Comparative risk of genital infections associated with sodium glucose co-transporter-2 inhibitors. Diabetes Obes Metab 2019; 21: 434-438
• 142 Lega IC, Bronskill SE, Campitelli MA. et al. Sodium glucose cotransporter 2 inhibitors and risk of genital mycotic and urinary tract infection: A population-based study of older women and men with diabetes. Diabetes Obes Metab 2019; 21: 2394-2404
• 143 McGovern AP, Hogg M, Shields BM. et al. Risk factors for genital infections in people initiating SGLT2 inhibitors and their impact on discontinuation. BMJ Open Diab Res Care 2020; 8: e001238
• 144 Yang JY, Wang T, Pate V. et al. Real-world evidence on sodium-glucose cotransporter-2 inhibitor use and risk of Fournier’s gangrene. BMJ Open Diab Res Care 2020; 8: e000985
• 145 Silverii GA, Dicembrini I, Monami M. et al. Fournier’s gangrene and sodium-glucose co-transporter-2 inhibitors: A meta-analysis of randomized controlled trials. Diabetes Obes Metab 2020; 22: 272-275
• 146 www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/SGLT2_inhibitors_(previously_Canagliflozin)/human_referral_prac_000059.jsp&mid=WC0b01ac05805c5
• 147 Neal B, Perkovic V, Mahaffey KW. et al. CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017; 377: 644-657
• 148 Scheen AJ. Does lower limb amputation concern all SGLT2 inhibitors?. Nat Rev Endocrinol 2018; 14: 326-328
• 149 Fioretto P, Del Prato S, Buse JB. et al. Efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment (CKD Stage 3 A): The DERIVE Study). Diabetes Obes Metab 2018; 20: 2532-2540
• 150 Inzucchi SE, Iliev H, Pfarr E. et al. Empagliflozin and assessment of lower limb amputations in the EMPA-REG OUTCOME trial. Diabetes Care 2018; 41: e4-e5
• 151 Perkovic V, Jardine MJ, Neal B. et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med 2019; 380: 2295-2306
• 152 Huang CY, Lee JK. Sodium-glucose co-transporter-2 inhibitors and major adverse limb events: A trial-level meta-analysis including 51 713 Individuals. Diabetes Obes Metab 2020; 22: 2348-2355
• 153 Zhou Z, Jardine M, Perkovic V. et al. Canagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program. Diabetologia 2019; 62: 1854-1867
• 154 Perkovic V, Jardine MJ, Neal N. et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380: 2295-2306
• 155 Mahaffey KW, Jardine MJ, Bompoint S. et al. Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups. Circulation 2019; 140: 739-750
• 156 Kohler S, Kaspers S, Salsali A. et al. Analysis of fractures in patients with type 2 diabetes treated with empagliflozin in pooled data from placebo-controlled trials and a head-to-head study versus glimepiride. Diabetes Care 2018; 41: 1809-1816
• 157 Ruanpeng D, Ungprasert P, Sangtian J. et al. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and fracture risk in patients with type 2 diabetes mellitus: A meta-analysis. Diabetes Metab Res Rev 2017; 33: e2903
• 158 Tang HL, Li DD, Zhang JJ. et al. Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab 2016; 18: 1199-1206
• 159 Li X, Li T, Cheng Y. et al. Effects of SGLT2 inhibitors on fractures and bone mineral density in type 2 diabetes: An updated meta-analysis. Diabetes Metab Res Rev 2019; 35: e3170
• 160 Hidayat K, Du X, Shi BM. Risk of fracture with dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, or sodiumglucose cotransporter-2 inhibitors in real-world use: systematic review and meta-analysis of observational studies. Osteoporos Int 2019; 30: 1923-1940
• 161 Fralick M, Schneeweiss S, Patorno E. Risk of diabetic ketoacidosis after initiation of an SGLT2 inhibitor. N Engl J Med 2017; 376: 2300-2303
• 162 Monami M, Nreu B, Zannoni S. et al. Effects of SGLT2 inhibitors on diabetic ketoacidosis: A meta-analysis of randomised controlled trials. Diabetes Res Clin Pract 2017; 130: 53-60
• 163 Fadini GP, Bonora BM, Avogaro A. SGLT2 inhibitors and diabetic ketoacidosis: data from the FDA Adverse Event Reporting System. Diabetologia 2017; 60: 1385-1389
• 164 Liu J, Li L, Li S. et al. Sodium-glucose co-transporter-2 inhibitors and the risk of diabetic ketoacidosis in patients with type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials. Diabetes Obes Metab 2020; 22: 1619-1627
• 165 Thiruvenkatarajan V, Meyer EJ, Nanjappa N. et al. Perioperative diabetic ketoacidosis associated with sodium-glucose cotransporter-2 inhibitors: a systematic review. Br J Anaesth 2019; 123: 27-36
• 166 Milder DA, Milder TY, Kam PCA. Sodium-glucose co-transporter type-2 inhibitors: pharmacology and perioperative considerations. Anaesthesia 2018; 73: 1008-1018
• 167 Donnan K, Segar L. SGLT2 inhibitors and metformin: Dual antihyperglycemic therapy and the risk of metabolic acidosis in type 2 diabetes. Eur J Pharmacol 2019; 846: 23-29
• 118 Wiviott SD, Raz I, Bonaca MP. et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019; 380: 347-357
• 169 Mosenzon O, Wiviott SD, Cahn A. et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. Lancet Diabetes Endocrinol 2019; 7: 606-617
• 170 Furtado RHM, Bonaca MP, Raz I. Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes mellitus and Previous Myocardial Infarction. Circulation 2019; 139: 2516-2527
• 171 Kato ET, Silverman MG, Mosenzon O. et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation 2019; 139: 2528-2536
• 172 McMurray JJV, Solomon SD, Inzucchi SE. et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019; 381: 1995-2008
• 173 Wheeler DC, Stefánsson BV, Jongs N. et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol 2021; 9: 22-31
• 174 Neuen BL, Young T, Heerspink HJL. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2019; 7: 845-854
• 175 Karagiannis T, Tsapas A, Athanasiadou E. et al. GLP-1 receptor agonists and SGLT2 inhibitors for older people with type 2 diabetes: A systematic review and meta-analysis. Diabetes Res Clin Pract 2021; 174: 108737
• 176 Bae JH, Park EG, Kim S. et al. Comparative Renal Effects of Dipeptidyl Peptidase-4 Inhibitors and Sodium-Glucose Cotransporter 2 Inhibitors on Individual Outcomes in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis. Endocrinol Metab (Seoul) 2021; 36: 388-400
• 177 Palmer SC, Tendal B, Mustafa RA. et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ 2021; 372: m4573
• 178 Zinman B, Wanner C, Lachin JM. et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117-2128
• 179 Inzucchi SE, Khunti K, Fitchett DH. et al. Cardiovascular Benefit of Empagliflozin Across the Spectrum of Cardiovascular Risk Factor Control in the EMPA-REG OUTCOME Trial. J Clin Endocrinol Metab 2020; 105: 3025-3035
• 180 McGuire DK, Zinman B, Inzucchi SE. et al. Effects of empagliflozin on first and recurrent clinical events in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a secondary [99] Inzucchi SE, Iliev H, Pfarr E et al. Empagliflozin and assessment of lower limb amputations in the EMPA-REG OUTCOME trial. Diabetes Care 2018; 41: e4-e5
• 181 Wanner C, Inzucchi SE, Zinman B. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016; 375: 323-334
• 182 Cherney DZI, Zinman B, Inzucchi SE. et al. Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebocontrolled trial. Lancet Diabetes Endocrinol 2017; 5: 610-621
• 183 Verma S, Mazer CD, Fitchett D. et al. Empagliflozin reduces cardiovascular events, mortality and renal events in participants with type 2 diabetes after coronary artery bypass graft surgery: sub-analysis of the EMPA-REG OUTCOME® randomized trial. Diabetologia 2018; 61: 1712-1723
• 184 Packer M, Anker SD, Butler J. et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med 2020; 383: 1413-24
• 185 Zou CY, Liu XK, Sang YQ. et al. Effects of SGLT2 inhibitors on cardiovascular outcomes and mortality in type 2 diabetes. A meta-analysis. Medicine (Baltimore) 2019; 98: e18245
• 186 Salah HM, Al’Aref SJ, Khan MS. et al. Effects of sodium-glucose cotransporter 1 and 2 inhibitors on cardiovascular and kidney outcomes in type 2 diabetes: A meta-analysis update. Am Heart J 2021; 233: 86-91
• 187 Qiu M, Ding L, Zhou H. Effects of SGLT2 inhibitors on cardiovascular and renal outcomes in type 2 diabetes: A meta-analysis with trial sequential analysis. Medicine 2021; 100: e25121
• 188 Palmer SC, Tendal B, Mustafa RA. et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ 2021; 372: m4573
• 189 Sattar N, McLaren J, Kristensen SL. et al. SGLT2 Inhibition and cardiovascular events: why did EMPA-REG Outcomes surprise and what were the likely mechanisms?. Diabetologia 2016; 59: 1333-1339
• 190 Ferrannini E, Mark M, Mayoux E. et al. CV Protection in the EMPA-REG OUTCOME Trial: A „thrifty substrate“ hypothesis. Diabetes Care 2016; 39: 1108-1114
• 191 Dutka M, Bobiński R, Ulman-Włodarz I. et al. Sodium glucose cotransporter 2 inhibitors: mechanisms of action in heart failure. Heart Failure Reviews 2021; 26: 603-622
• 192 Thomas MC, Cherney DZI. The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure. Diabetologia 2018; 61: 2098-2107
• 193 Yurista SR, Chong CR, Badimon JJ. et al. Therapeutic Potenzial of Ketone Bodies for Patients With Cardiovascular Disease: JACC State-of-the-Art Review. J Am Coll Cardiol 2021; 77: 1660-1669
• 194 https://www.gba.de/downloads/40–268–4342/2017–04–20_DMPARL_Aenderung-Anlage-1_DMP-Diabetes-mellitus_TrG.pdf
• 195 Cannon CP, McGuire DK, Pratley R. et al. VERTIS-CV Investigators. Design and baseline characteristics of the evaluation of ertugliflozin efficacy and Safety CardioVascular outcomes trial (VERTIS-CV). Am Heart J 2018; 206: 11-23
• 196 Cannon CP, Pratley R, Dagogo-Jack S. et al. Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes. N Engl J Med 2020; 383: 1425-1435
• 197 Rosenstock J, Frias J, Páll D. et al. Effect of ertugliflozin on glucose control, body weight, blood pressure and bone density in type 2 diabetes mellitus inadequately controlled on metformin monotherapy (VERTIS MET). Diabetes Obes Metab 2018; 20: 520-529
• 198 Hollander P, Liu J, Hill J. et al. Ertugliflozin Compared with Glimepiride in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin: The VERTIS SU Randomized Study. Diabetes Ther 2018; 9: 193-207
• 199 Cherney DZI, Heerspink HJL, Frederich R. et al. Effects of ertugliflozin on renal function over 104 weeks of treatment: a post hoc analysis of two randomised controlled trials. Diabetologia 2020; 63 1 128-1140
• 200 Cherney DZI, Charbonnel B, Cosentino F. Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: an analysis from the randomised VERTIS CV trial; VERTIS CV Investigators. Diabetologia 2021; 64: 1256-1267
• 201 Marrs JC, Anderson SL. Ertugliflozin in the treatment of type 2 diabetes mellitus. Drugs in Context. 2020 9. 2020–7–4
• 202 Yu J, Li J, Leaver PJ. et al. Effects of canagliflozin on myocardial infarction: a post hoc analysis of the CANVAS Program and CREDENCE trial. Cardiovasc Res 2021; 118: 1103-1114
• 203 Bhatt DL, Szarek M, Steg PG. et al. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. N Engl J Med 2021; 384: 117-128
• 204 Bhatt DL, Szarek M, Pitt B. et al. Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. N Engl J Med 2021; 384: 129-139
• 205 Levin PA, Nguyen H, Wittbrodt ET. et al. Glucagon-like peptide-1 receptor agonists: a systematic review of comparative effectiveness research. Diabetes Metab Syndr Obes 2017; 10: 123-139
• 206 Mac Isaac RJ. Dulaglutide and Insulin: How can the AWARD studies help guide clinical practice?. Diabetes Ther 2020; 11: 1627-1638
• 207 Gerstein HC, Colhoun HM, Dagenais GR. et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a doubleblind, randomised placebo-controlled trial. Lancet 2019; 394: 121-130
• 208 Gerstein HC, Colhoun HM, Dagenais GR. et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomized, placebo-controlled trial. Lancet 2019; 394: 131-138
• 209 Dagenais GR, Rydén L, Leiter LA. et al. Total cardiovascular or fatal events in people with type 2 diabetes and cardiovascular risk factors treated with dulaglutide in the REWIND trail: a post hoc analysis. Cardiovasc Diabetol 2020; 19: 199
• 210 Lundgren JR, Janus C, Jensen SBK. et al. Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined. N Engl J Med 2021; 384: 1719-1730
• 211 Marso SP, Daniels GH, Brown-Frandsen K. et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375: 311-322
• 212 Verma S, Bhatt DL, Bain SC. et al. Effect of liraglutide on cardiovascular events in patients with type 2 diabetes mellitus and polyvascular disease. Circulation 2018; 137: 2179-2183
• 213 Marso SP, Nauck MA, Monk Fries T. et al. Myocardial infarction subtypes in patients with type 2 diabetes mellitus and the effect of liraglutide therapy (from the LEADER Trial). Am J Cardiol 2018; 121: 1467-1470
• 214 Duan CM, Wan TF, Wang Y. et al. Cardiovascular outcomes of liraglutide in patients with type 2 diabetes. A systematic review and meta-analysis. Medicine (Baltimore) 2019; 98: 46 e17860
• 215 Mann JFE, Ørsted DD, Buse JB. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med 2017; 377: 839-848
• 216 Kristensen SL, Rørth R, Jhund PS. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019; 7: 776-785
• 217 Liu J, Li L, Deng K. et al. Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis. BMJ 2017; 357: j2499
• 218 Pasternak B, Wintzell V, Eliasson B. et al. Use of glucagon like peptide 1 receptor agonists and risk of serious renal events: Scandinavian cohort study. Diabetes Care 2020; 43: 1326-1335
• 219 Mishriky BM, Cummings DM, Powell JR. et al. Comparing once-weekly semaglutide to incretin-based therapies in patients with type 2 diabetes: a systematic review and meta-analysis. Diabetes Metab 2019; 45: 102-109
• 220 Wilding JPH, Batterham RL, Calanna S. et al. STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med 2021; 384: 989
• 221 Wadden TA, Bailey TS, Billings LK. et al. STEP 3 Investigators Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on BodyWeight in AdultsWith Overweight or Original Article Obesity: The STEP 3 Randomized Clinical Trial. JAMA 2021; 325: 1403-1413
• 222 Rubino D, Abrahamsson N, Davies M. et al. STEP 4 Investigators. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA 2021; 325: 1414-1425
• 223 Marso SP, Bain SC, Consoli A. et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016; 375: 1834-1844
• 224 Leiter LA, Bain SC, Hramiak I. et al. Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial. Cardiovasc Diabetol 2019; 18: 73
• 225 Husain M, Birkenfeld AL, Donsmark M. PIONEER 6 Investigators et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2019; 381: 841-851
• 226 Avgerinos I, Michailidis T, Liakos A. et al. Oral semaglutide for type 2 diabetes: A systematic review andmeta-analysis. Diabetes Obes Metab 2020; 22: 335-345
• 227 Husain M, Bain SC, Holst AG, Mark T, Rasmussen S, Lingvay I. Effects of semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: combined post hoc analysis of the SUSTAIN and PIONEER trials. Cardiovasc Diabetol 2020; 19: 156
• 228 Nauck MA, Quast DR. Cardiovascular Safety and Benefits of Semaglutide in Patients With Type 2 Diabetes: Findings From SUSTAIN 6 and PIONEER 6. Front Endocrinol (Lausanne) 2021; 12: 645 566
• 229 Zheng SL, Roddick AJ, Aghar-Jaffar R. et al. Association between use of sodium-glucose cotransporter 2 inhibitors, glucagonlike peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes. A systematic review and meta-analysis. JAMA 2018; 319: 1580-1591
• 180 Dicembrini I, Nreu B, Scatena A. et al. Microvascular effects of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized controlled trials. Acta Diabetol 2017; 54: 933-941
• 231 Mann JFE, Hansen T, Idorn T. et al. Effects of once-weekly subcutaneous semaglutide on kidney function and safety in patients with type 2 diabetes: a post-hoc analysis of the SUSTAIN 1–7 randomised controlled trials. Lancet Diabetes Endocrinol 2020; 8: 880-893
• 232 Home PD, Ahrén B, Reusch JEB. et al. Three-year data from 5 HARMONY phase 3 clinical trials of albiglutide in type 2 diabetes mellitus: Longterm efficacy with or without rescue therapy. Diabetes Res Clin Pract 2017; 131: 49-60
• 233 Ahrén B, Carr MC, Murphy K. et al. Albiglutide for the treatment of type 2 diabetes mellitus: An integrated safety analysis of the HARMONY phase 3 trials. Diabetes Res Clin Pract 2017; 126: 230-239
• 234 Hernandez AF, Green JB, Janmohamed S. et al. Harmony outcomes committees and investigators. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomized placebocontrolled trial. Lancet 2018; 392: 1519-1529
• 235 Rosenstock J, Nino A, Soffer J. et al. Impact of a Weekly Glucagon-Like Peptide 1 Receptor Agonist, Albiglutide, on Glycemic Control and on Reducing Prandial Insulin Use in Type 2 Diabetes Inadequately Controlled on Multiple Insulin Therapy: A Randomized Trial. Diabetes Care 2020; 43: 2509-2518
• 236 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: 1228-1239
• 237 Fudim M, White J, Pagidipati NJ. et al. Effect of Once-weekly exenatide in patients with type 2 diabetes mellitus with and without heart failure and heart failure–related outcomes. Insights from the EXSCEL trial. Circulation 2019; 140: 1613-1622
• 238 Bonora BM, Avogaro A, Fadini GP. Effects of exenatide longacting release on cardiovascular events and mortality in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Acta Diabetol 2019; 56: 1051-1060
• 239 Jabbour SA, Frías JP, Ahmed A. et al. Efficacy and Safety Over 2 Years of Exenatide Plus Dapagliflozin in the DURATION-8 Study: A Multicenter, Double-Blind, Phase 3, Randomized Controlled Trial. Diabetes Care 2020; 43: 2528-2536
• 240 Bethel MA, Patel RA, Merrill P. et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol 2018; 6: 105-113
• 241 van der Aart - van der Beek AB, van Raalte DH, Guja C et al. Exenatide once weekly decreases urinary albumin excretion in patients with type 2 diabetes and elevated albuminuria: Pooled analysis of randomized active controlled clinical trials. Diabetes Obes Metab 2020; 22: 1556–1566
• 242 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: 2247-57
• 243 Home P, Blonde L, Kalra S. et al. Insulin glargine/lixisenatide fixed-ratio combination (iGlarLixi) compared with premix or addition of meal-time insulin to basal insulin in people with type 2 diabetes: A systematic review and Bayesian network meta-analysis. Diabetes Obes Metab 2020; 22: 2179-2188
• 244 Gerstein HC, Sattar N, Rosenstock J. et al. Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes. N Engl J Med 2021; 385: 896-907
• 245 Frias JP, Nauck MA, Van J, DO J. et al. Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: A 12-week, randomized, double-blind, placebo-controlled study to evaluate different dose-escalation regimens. Diabetes Obes Metab 2020; 22: 938-946
• 246 Nauck MA, Wefers J, Meier JJ. Treatment of type 2 diabetes: challenges, hopes, and anticipated successes. Lancet Diabetes Endocrinol 2021; 9: 525-544
• 247 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, randomized, phase 3 trial. Lancet 2021; 398: 143-155
• 248 Frías JP, Davies MJ, Rosenstock J. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes; SURPASS-2 Investigators. N Engl J Med 2021; 385: 503-515
• 249 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 PatientsWith Type 2 Diabetes. Diabetes Care 2020; 43: 1352-1355
• 250 Wilson JM, Nikooienejad A, Robins DA. et al. The dual glucosedependent insulinotropic peptide andglucagon-like peptide-1 receptor agonist, tirzepatide, improves lipoprotein biomarkers associated with insulin resistance and cardiovascular risk in patients with type 2 diabetes. Diabetes Obes Metab 2020; 22: 2451-2459
• 251 Min T, Bain SC. The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials. Diabetes Ther 2021; 12: 143-157
• 252 Vilsbøll T, Bain SC, Leiter LA. et al. Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy. Diabetes Obes Metab 2018; 20: 889-897
• 253 Monami M, Nreu B, Scatena A. et al. Safety issues with glucagon-like peptide-1 receptor agonists (pancreatitis, pancreatic cancer and cholelithiasis): Data from randomized controlled trials. Diabetes Obes Metab 2017; 19: 1233-1241
• 254 Abd El Aziz M, Cahyadi O, Meier JJ. et al. Incretin-based glucoselowering medications and the risk of acute pancreatitis and malignancies: a meta-analysis based on cardiovascular outcomes trials. Diabetes Obes Metab 2020; 22: 699-704
• 255 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: 157-165
• 256 Azoulay L, Filion KB, Platt RW. et al. Association between incretinbased drugs and the risk of acute pancreatitis. JAMA Intern Med 2016; 176: 1464-1473
• 257 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 1324 515 patients from observational studies. Diabetes Obes Metab 2015; 17: 32-41
• 258 Ueda P, Wintzell V, Melbye M. et al. Use of incretin-based drugs and risk of cholangiocarcinoma: Scandinavian cohort study. Diabetologia 2021; 64: 2204-2214
• 259 Piccoli GF, Mesquita LA, Stein C. et al. Do GLP-1 Receptor Agonists Increase the Risk of Breast Cancer? A Systematic Review and Meta-analysis. J Clin Endocrinol Metab 2021; 106: 912-921
• 260 Newsome PN, Buchholtz K, Cusi K. et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med 2021; 384: 1113-1124
• 261 Mantsiou C, Karagiannis T, Kakotrichi P. et al. Glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors as combination therapy for type 2 diabetes: A systematic review and meta-analysis. Diabetes Obes Metab 2020; 22: 1857-1868
• 262 Russell-Jones D, Pouwer F, Khunti K. Identification of barriers to insulin therapy and approaches to overcoming them. Diabetes Obes Metab 2018; 20: 488-496
• 263 Landgraf R, Aberle J. Hundert Jahre – Insulin bleibt aktuell und notwendig. Diabetologie 2021; 16: 1-13
• 264 Marso SP, McGuire DK, Zinman B. et al. Efficacy and safety of degludec versus glargine in type 2 diabetes. New Engl J Med 2017; 377: 723-732
• 265 Pieber TR, Marso SP, McGuire DK. et al. DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality. Diabetologia 2018; 61: 58-65
• 266 Lau IT, Lee KF, So WY. et al. Insulin glargine 300 U/mL for basal insulin therapy in type 1 and type 2 diabetes mellitus. Diabetes Metab Syndr Obes 2017; 10: 273-284
• 267 Ritzel R, Roussel R, Giaccari A. et al. Better glycaemic control and less hypoglycaemia with insulin glargine 300 U/mL vs glargine 100 U/mL: 1-year patient-level meta-analysis of the EDITION clinical studies in people with type 2 diabetes. Diabetes Obes Metab 2018; 20: 541-548
• 268 Bonadonna RC, Renard E, Cheng A. et al. Switching to insulin glargine 300 U/mL: Is duration of prior basal insulin therapy important?. Diabetes Res Clin Pract 2018; 142: 19-25
• 269 Linnebjerg H, Lam EC, Seger ME. et al. Comparison of the pharmacokinetics and pharmacodynamics of LY2963 016 insulin glargine and EU and US-approved versions of lantus insulin glargi ne in healthy subjects: Three randomized euglycemic clamp studies. Diabetes Care 2015; 38: 2226-2233
• 270 Rosenstock J, Hollander P, Bhargava A. et al. Similar efficacy and safety of LY2963 016 insulin glargine and insulin glargine (Lantus®) in patients with type 2 diabetes who were insulin-naïve or previously treated with insulin glargine: a randomized, doubleblind controlled trial (ELEMENT 2 study). Diabetes Obes Metabol 2015; 17: 734-741
• 271 Yamada T, Kamata R, Ishinohachi K. et al. Biosimilar vs originator insulins: Systematic review and meta-analysis. Diabetes Obes Metab 2018; 20: 1787-1792
• 272 But A, De Bruin ML, Bazelier MT. et al. Cancer risk among insulin users: comparing analogues with human insulin in the CARING five-country cohort study. Diabetologia 2017; 60: 1691–1703 [222] Maiorino MI, Chiodini P, Bellastella G et al. Insulin and glucagon-like peptide1 receptor agonist combination therapy in type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials. Diabetes Care 2017; 40: 614-624
• 273 Guja C, Frías JP, Somogyi A. et al. Effect of exenatide QW or placebo, both added to titrated insulin glargine, in uncontrolled type 2 diabetes: The DURATION-7 randomized study. Diabetes Obes Metab 2018; 20: 1602-1161
• 274 Rodbard HW, Lingvay I, Reed J. et al. Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): A randomized, controlled trial. J Clin Endocrinol Metab 2018; 103: 2291-2301
• 275 Huthmacher JA, Meier JJ, Nauck MA. Efficacy and Safety of Short- and Long-Acting Glucagon-Like Peptide 1 Receptor Agonists on a Background of Basal Insulin in Type 2 Diabetes: A Metaanalysis. Diabetes Care 2020; 43: 2303-2312
• 276 Gentile S, Fusco A, Colarusso S. et al. A randomized, openlabel, comparative, crossover trial on preference, efficacy, and safety profiles of lispro insulin U-100 versus concentrated lispro insulin U-200 in patients with type 2 diabetes mellitus: a possible contribution to greater treatment adherence. Expert Opin Drug Saf 2018; 17: 445-450
• 277 Heise T, Hövelmann U, Brøndsted L. et al. Faster-acting insulin aspart: earlier onset of appearance and greater early pharmacokinetic and pharmacodynamic effects than insulin aspart. Diabetes Obes Metab 2015; 17: 682-688
• 278 Bowering K, Case C, Harvey J. et al. Faster aspart versus insulin aspart as part of a basal-bolus regimen in inadequately controlled type 2 diabetes: The ONSET 2 trial. Diabetes Care 2017; 40: 951-957
• 279 Leohr J, Dellva MA, Coutant DE. et al. Pharmacokinetics and glucodynamics of ultra rapid lispro (URLi) versus Humalog (lispro) in patients with type 2 diabetes mellitus: A phase I randomized, crossover study. Clin Pharmacokinet 2020; 59: 1601-1610
• 280 Preshaw PM, Alba AL, Herrera D. et al. Periodontitis and diabetes: a two-way relationship. Diabetologia 2012; 55: 21-31
• 281 Bundesärztekammer (BÄK), Kassenärztliche Bundesvereinigung (KBV), Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF). Nationale VersorgungsLeitlinie Therapie des Typ-2-Diabetes – Langfassung, 1. Auflage. Version 4. 2013, zuletzt geändert: November 2014: www.dm-therapieversorgungsleitlinien.de S206