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Physiopathology and clinical alterations of diabetes mellitus 2
Type 2 diabetes mellitus is a debilitating, degenerative and multifaceted clinical condition with a high prevalence worldwide. Given the complexity of its pathophysiology and the various therapeutic options that exist, this disease presents a challenge for the general practitioner, it is imperative to understand this pathology to improve its resolution in primary care. After an exhaustive bibliographic search of 103 studies published up to 2010, the most important aspects of both the physiology, pathophysiology, complications, and therapeutics of this pathology were identified. Insulin resistance (IR) is a central metabolic condition in the etiopathogenesis of this pathology. Classically it is possible to recognize both the loss of the peripheral action of insulin by the different tissues as well as defects in the secretion of insulin that leads to constant hyperglycemic states associated with both acute and chronic complications characterized by causing dysfunction and failure in different organs. It is generally known that an important part of the results in the management of this pathology are achieved with changes in lifestyle that range from modifications in diet to changes in the pattern of physical activity with loss of body weight. However, there also is a wide range of pharmacological therapies aimed at controlling hyperglycemic states in the event of the failure of non-pharmacological therapy. Within this same context, there are several therapeutic targets and objectives in the treatment of type 2 diabetics, however, they all converge in the metabolic control of hyperglycemic states and the prevention of their complications.
Galicia-García U, Benito-Vicente A, Jebari S, et al. Pathophysiology of type 2 diabetes mellitus. Int J Mol Sci. 2020;21(17):1-34. doi:10.3390/ijms21176275
International diabetes federation. International diabetes federation. International diabetes federation.
Petersen M, Vatner D. Regulation of hepatic glucose metabolism in health and disease. HHS Public Access. 2018;13(10):572-587. doi:10.1038/nrendo.2017.80.Regulation
Dashty M. A quick look at biochemistry: Carbohydrate metabolism. Clin Biochem. 2013;46(15):1339-1352. doi:10.1016/j.clinbiochem.2013.04.027
Keane K, Newsholme P. Metabolic Regulation of Insulin Secretion. Vol 95. 1st ed. Elsevier Inc.; 2014. doi:10.1016/B978-0-12-800174-5.00001-6
Tokarz VL, MacDonald PE, Klip A. The cell biology of systemic insulin function. J Cell Biol. 2018;217(7):2273-2289. doi:10.1083/jcb.201802095
de Jesús Sandoval-Muñiz R, Vargas-Guerrero B, FloresAlvarado LJ, Gurrola-Díaz CM. Glucotransportadores (GLUT): Aspectos clínicos, moleculares y genéticos. Gac Med Mex. 2016;152(4):547-557.
Holst JJ. The incretin system in healthy humans: The role of GIP and GLP-1. Metabolism. 2019;96:46-55. doi:10.1016/j.metabol.2019.04.014
Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab.2013;17(6):819-837. doi:10.1016/j.cmet.2013.04.008
Nauck MA, Meier JJ. The incretin effect in healthy individuals and those with type 2 diabetes: Physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol. 2016;4(6):525-536. doi:10.1016/S2213-8587(15)00482-9
DeFronzo RA, Davidson JA, del Prato S. The role of the kidneys in glucose homeostasis: A new path towards normalizing glycaemia. Diabetes, Obes Metab. 2012;14(1):5-14. doi:10.1111/j.1463- 1326.2011.01511.x
Pereira-Moreira R, Muscelli E. Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review. J Diabetes Res. 2020;2020.doi:10.1155/2020/8492467
Gutiérrez-Rodelo C, Roura-Guiberna A, OlivaresReyes JA. Mecanismos moleculares de la resistenciaa la insulina: Una actualización. Gac Med Mex.2017;153(2):214-228.
Díaz S. Papel de las isoformas del receptor de insulina en la regulación de la homeostasia glucídica y lipídica en un modelo de diabetes experimental. Published online 2017:1.106. https://eprints.ucm.es/43693/1/T39014.pdf
Samuel VT, Shulman GI. The pathogenesis of insulin resistance: Integrating signaling pathways and substrate flux. J Clin Invest. 2016;126(1):12-22. doi:10.1172/ JCI77812
Visser M, Mcquillan GM, Wener MH, Harris TB. Elevated C-Reactive Protein Levels. Published online 2015.
Ros Pérez M, Medina-Gómez G. Obesidad, adipogénesis y resistencia a la insulina. Endocrinol y Nutr. 2011;58(7):360-369. doi:10.1016/j.endonu.2011.05.008
Conesa González AI, González Calero TM. Aspectos más recientes en relación con la diabetes mellitus tipo MODY. Rev Cuba Endocrinol. 2012;23(2):186-194.
Ozougwu O. The pathogenesis and pathophysiology of type 1 and type 2 diabetes mellitus. J Physiol Pathophysiol. 2013;4(4):46-57. doi:10.5897/ jpap2013.0001
Kluth O, Mirhashemi F, Scherneck S, et al. Dissociation of lipotoxicity and glucotoxicity in a mouse model of obesity associated diabetes: Role of forkhead box O1 (FOXO1) in glucose-induced beta cell failure. Diabetologia. 2011;54(3):605-616. doi:10.1007/s00125- 010-1973-8
Cano R, Villalobos M, Aguirre M, et al. Tisular Y No Una Enfermedad From Obesity To Diabetes: InsulinResistance. Published online 2017.
Alam F, Kamal MA, Islam MA, Banu S. Current Genetic and Epigenetic Insights into Type 2 Diabetes Mellitus. Endocrine, Metab Immune Disord - Drug Targets. 2019;19(6):717-718. doi:10.2174/1871530319061907 24104004
Suárez-Carmona W, Sánchez-Oliver AJ, González-Jurado JA. Fisiopatología de la obesidad: Perspectiva actual. Rev Chil Nutr. 2017;44(3):226-233. doi:10.4067/s0717- 75182017000300226
Laforest S, Labrecque J, Michaud A, Cianflone K, Tchernof A. Adipocyte size as a determinant of metabolic disease and adipose tissue dysfunction. Crit Rev Clin Lab Sci. 2015;52(6):301-313. doi:10.3109/10408363.2015.1041582
Kolodziejczyk AA, Zheng D, Elinav E. Diet–microbiota interactions and personalized nutrition. Nat Rev Microbiol. 2019;17(12):742-753. doi:10.1038/s41579- 019-0256-8
Devaraj S, Hemarajata P, Versalovic J. La microbiota intestinal humana y el metabolismo corporal: Implicaciones con la obesidad y la diabetes. Acta Bioquim Clin Latinoam. 2013;47(2):421-434.
Palau-Rodriguez M, Tulipani S, Queipo-Ortuño MI, Urpi-Sarda M, Tinahones FJ, Andres-Lacueva C. Metabolomic insights into the intricate gut microbialhost interaction in the development of obesity and type 2 diabetes. Front Microbiol. 2015;6(OCT):1-12. doi:10.3389/fmicb.2015.01151
Tilg H, Moschen AR. Microbiota and diabetes: An evolving relationship. Gut. 2014;63(9):1513-1521. doi:10.1136/gutjnl-2014-306928
Larsen N, Vogensen FK, Van Den Berg FWJ, et al. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS One. 2010;5(2). doi:10.1371/journal.pone.0009085
Caesar R, Tremaroli V, Kovatcheva-Datchary P, Cani PD, Bäckhed F. Crosstalk between gut microbiota and dietary lipids aggravates WAT inflammation through TLR signaling. Cell Metab. 2015;22(4):658-668. doi:10.1016/j.cmet.2015.07.026
Sliwinska-Mosson M, Milnerowicz H. The impact of smoking on the development of diabetes and its complications. Diabetes Vasc Dis Res. 2017;14(4):265- 276. doi:10.1177/1479164117701876
López Zubizarreta M, Hernández Mezquita MÁ, Miralles García JM, Barrueco Ferrero M. Tobacco and diabetes: clinical relevance and approach to smoking cessation in diabetic smokers. Endocrinol Diabetes y Nutr. 2017;64(4):221-231. doi:10.1016/j.endinu.2017.02.010
Besingi W, Johansson Å. Smoke-related DNA methylation changes in the etiology of human disease. Hum Mol Genet. 2014;23(9):2290-2297. doi:10.1093/ hmg/ddt621
Chatterjee S, Khunti K, Davies MJ. Type 2 diabetes. Lancet. 2017;389(10085):2239-2251. doi:10.1016/ S0140-6736(17)30058-2
Risk NCD, Collaboration F. Worldwide trends in diabetes since 1980: a pooled analysis of 751 populationbased studies with 4.4 million participants. Lancet (London, England). 2016;387(10027):1513-1530.doi:10.1016/S0140-6736(16)00618-8
Fu Z, R. Gilbert E, Liu D. Regulation of InsulinSynthesis and Secretion and Pancreatic BetaCell Dysfunction in Diabetes. Curr Diabetes Rev. 2012;9(1):25-53. doi:10.2174/15733998130104
Nolan CJ, Damm P, Prentki M. Type 2 diabetes across generations: From pathophysiology to prevention and management. Lancet. 2011;378(9786):169-181. doi:10.1016/S0140-6736(11)60614-4
Corkey BE. Banting lecture 2011: Hyperinsulinemia: Cause or consequence? Diabetes. 2012;61(1):4-13. doi:10.2337/db11-1483
Jeffrey KD, Alejandro EU, Luciani DS, et al. Carboxypeptidase E mediates palmitate-induced β-cell ER stress and apoptosis. Proc Natl Acad Sci U S A. 2008;105(24):8452-8457. doi:10.1073/ pnas.0711232105
Staaf J, Ubhayasekera SJKA, Sargsyan E, et al. Initial hyperinsulinemia and subsequent β-cell dysfunction is associated with elevated palmitate levels. Pediatr Res. 2016;80(2):267-274. doi:10.1038/pr.2016.80
Vincent Poitout, Julie Amyot, Meriem Semache, Bader Zarrouki, Derek Hagman GF. Glucoliotoxicity of pancreatic beta cells. Biochim Biophys Acta. 2010;1801(3):289–298. doi:10.1016/j. bbalip.2009.08.006.Glucolipotoxicity
Mccormack SE, Shaham O, Mccarthy MA, et al. Circulating branched-chain amino acid concentrations are associated with obesity and future insulin resistance in children and adolescents. Pediatr Obes. 2013;8(1):52- 61. doi:10.1111/j.2047-6310.2012.00087.x
Thomas J. Wang, Martin G. Larson, Ramachandran S. Vasan, Susan Cheng, Eugene P. Rhee, Elizabeth McCabe, Gregory D. Lewis, Caroline S. Fox, Paul F. Jacques, Céline Fernandez, Christopher J. O’Donnell, Stephen A. Carr, Vamsi K. Mootha, Jose C. Florez, Amand CB, Clish and REG. Metabolite profiles and diabetes. Nat Med. 2011;17(4):448-453. doi:10.1038/nm.2307. Metabolite
Giri B, Dey S, Das T, Sarkar M, Banerjee J, Dash SK. Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: An update on glucose toxicity. Biomed Pharmacother. 2018;107(April):306-328. doi:10.1016/j. biopha.2018.07.157
Maletkovic J, Drexler A. Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State. Endocrinol Metab Clin North Am. 2013;42(4):677-695. doi:10.1016/j. ecl.2013.07.001
Cepas V, Collino M, Mayo JC, Sainz RM. Redox signaling and advanced glycation endproducts (AGEs) in diet-related diseases. Antioxidants. 2020;9(2):1-20. doi:10.3390/antiox9020142
Perrone A, Giovino A, Benny J, Martinelli F. Advanced Glycation End Products (AGEs): Biochemistry, Signaling, Analytical Methods, and Epigenetic Effects. Oxid Med Cell Longev. 2020;2020(Cml). doi:10.1155/2020/3818196
Mosquera JA. Papel del receptor para compuestos de glicosilación avanzada (RAGE) en la inflamación. Invest Clin. 2010;51(2):257-268.
L. Díaz-Casasola DL-P. Productos finales de glicación avanzada. Med e Investig. 2016;4(1):52-57.
Teissier T, Boulanger É. The receptor for advanced glycation end-products (RAGE) is an important pattern recognition receptor (PRR) for inflammaging. Biogerontology. 2019;20(3):279-301. doi:10.1007/ s10522-019-09808-3
Olmos PR, Niklitschek S, Olmos RI, et al. Bases fisiopatológicas para una clasificación de la neuropatía diabética A new physiopathological classification of diabetic neuropathy. artículo revisión rev Med chile. 2012;140:1593-1605.
Hammes HP. Diabetic retinopathy: hyperglycaemia, oxidative stress and beyond. Diabetologia. 2018;61(1):29-38. doi:10.1007/s00125-017-4435-8
Umanath K, Lewis JB. Update on Diabetic Nephropathy: Core Curriculum 2018. Am J Kidney Dis.2018;71(6):884-895. doi:10.1053/j.ajkd.2017.10.026
Meza Letelier CE, San Martín Ojeda CA, Ruiz Provoste JJ, Frugone Zaror CJ. Pathophysiology of diabetic nephropathy: a literature review. Medwave. 2017;17(1):e6839. doi:10.5867/medwave.2017.01.6839
Matoba K, Takeda Y, Nagai Y, Kawanami D, Utsunomiya K, Nishimura R. Unraveling the role of inflammation in the pathogenesis of diabetic kidney disease. Int J Mol Sci. 2019;20(14). doi:10.3390/ijms20143393
Shraim BA, Moursi MO, Benter IF, Habib AM, Akhtar S. The Role of Epidermal Growth Factor Receptor Family of Receptor Tyrosine Kinases in Mediating Diabetes-Induced Cardiovascular Complications. Front Pharmacol. 2021;12(August):1-23. doi:10.3389/ fphar.2021.701390
Tervaert TWC, Mooyaart AL, Amann K, et al. Pathologic classification of diabetic nephropathy. J Am Soc Nephrol. 2010;21(4):556-563. doi:10.1681/ASN.2010010010
Botas Velasco M, Cervell Rodríguez D, Rodríguez Montalbán AI, Vicente Jiménez S, Fernández de Valderrama Martínez I. An update on the diagnosis, treatment and prevention of diabetic peripheral neuropathy. Angiologia. 2017;69(3):174-181. doi:10.1016/j.angio.2016.06.005
Vinik AI, Nevoret ML, Casellini C, Parson H. Diabetic Neuropathy. Endocrinol Metab Clin North Am. 2013;42(4):747-787. doi:10.1016/j.ecl.2013.06.001
Yu Y, Zhou Z, Sun K, et al. Association between coronary artery atherosclerosis and plasma glucose levels assessed by dual-source computed tomography. J Thorac Dis. 2018;10(11):6050-6059. doi:10.21037/ jtd.2018.10.62
Barrett TJ. Macrophages in Atherosclerosis Regression. Arterioscler Thromb Vasc Biol. 2020;40(1):20-33. doi:10.1161/ATVBAHA.119.312802
Moore KJ, Tabas I. The Cellular Biology of Macrophages in Atherosclerosis. Cell. 2011;145(3):341-355. doi:10.1016/j.cell.2011.04.005.The
Martín-Timón I. Type 2 diabetes and cardiovascular disease: Have all risk factors the same strength? World JDiabetes. 2014;5(4):444. doi:10.4239/wjd.v5.i4.444
Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107(9):1058-1070. doi:10.1161/CIRCRESAHA.110.223545
Geraldes P, King GL. Emission security- Tempest Attacks. Circ Res. 2010;106(8):1319-1331. doi:10.1161/ CIRCRESAHA.110.217117.Activation
Cruz Hernández J, no Licea Puig ME, ar Hernández García P, is Yanes Quesada M. Aldosa reductasa y proteína quinasa C en las complicaciones crónicas de la diabetes mellitus. Rev Latinoam Patol Clínica y Med Lab. 2011;58(2):102-107.
Mu EG, Ang M, Escorza Q. Estrés oxidativo y diabetes mellitus. REB Rev Educ bioquímica. 2013;32(2):53-66.
Carvajal Carvajal C. Productos finales de glicación (AGES) y la nefropatía diabética. Med Leg Costa Rica. 2015;32(1):154-160.
Muntoni S, Muntoni S. Insulin resistance: Pathophysiology and rationale for treatment. Ann Nutr Metab. 2011;58(1):25-36. doi:10.1159/000323395
Bornfeldt K, Tabas I. Insulin Resistance, Hyperglycemia, and Atherosclerosis. Bone. 2011;23(1):1-20.doi:10.1016/j.cmet.2011.07.015.Insulin
Basal Insulin and Cardiovascular and Other Outcomes in Dysglycemia. N Engl J Med. 2012;367(4):319-328. doi:10.1056/nejmoa1203858
Goldberg I, Schulze C. Lipid Metabolism and Toxicity in the Heart. Cell metab. 2012;23(1):1-16. doi:10.1016/j. cmet.2012.04.006.Lipid
Moghetti P, Tosi F, Bonin C, et al. Divergences in insulin resistance between the different phenotypes of the polycystic ovary syndrome. J Clin Endocrinol Metab. 2013;98(4):628-637. doi:10.1210/jc.2012-3908
Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: An update on mechanisms and implications. Endocr Rev.2012;33(6):981-1030. doi:10.1210/er.2011-1034
Hazlehurst JM, Woods C, Marjot T, Cobbold JF, Tomlinson JW. Non-alcoholic fatty liver diseaseand diabetes. Metabolism. 2016;65(8):1096-1108. doi:10.1016/j.metabol.2016.01.001
Ramos-Molina B, Macías-González M, TINAHONES F. Hígado graso no alcohólico y diabetes tipo 2: epidemiología, fenotipo y fisiopatología del paciente con diabetes e hígado graso no alcohólico. Endocrinol Diabetes y Nutr. 2017;1(Supl.2):16-20.
Hamdy O, Barakatun-Nisak MY. Nutrition in Diabetes. Endocrinol Metab Clin North Am. 2016;45(4):799-817. doi:10.1016/j.ecl.2016.06.010
Carvallo P, Carvallo E, Barbosa-Da-Silva S, MandarimDe-Lacerda CA, Hernández A, Del Sol M. Metabolic effects of excessive fructose consumption added. Int JMorphol. 2019;37(3):1058-1066. doi:10.4067/S0717- 95022019000301058
Huhmann MB, Yamamoto S, Neutel JM, Cohen SS, Ochoa Gautier JB. Very high-protein and lowcarbohydrate enteral nutrition formula and plasma glucose control in adults with type 2 diabetes mellitus: a randomized crossover trial. Nutr Diabetes. 2018;8(1). doi:10.1038/s41387-018-0053-x
Chiu THT, Pan WH, Lin MN, Lin CL. Vegetarian diet, change in dietary patterns, and diabetes risk: A prospective study. Nutr Diabetes. 2018;8(1). doi:10.1038/s41387-018-0022-4
Henry CJ, Kaur B, Quek RYC. Chrononutrition in the management of diabetes. Nutr Diabetes. 2020;10(1). doi:10.1038/s41387-020-0109-6
Vetrivel Venkatasamy V, Pericherla S, Manthuruthil S, Mishra S, Hanno R. Effect of physical activity on insulin resistance, inflammation and oxidative stress in diabetes mellitus. J Clin Diagnostic Res. 2013;7(8):1764-1766. doi:10.7860/JCDR/2013/6518.3306
Hernández J, Licea M. Role of physical exercise in persons presenting with diabetes mellitus. Rev Cuba Endocrinol. 2010;2(1):1-20. doi:10.1177/026988110101500107
Márquez J, Suárez R. El ejercicio en el tratamiento de la diabetes mellitus tipo 2. Rev Argent Endocrinol Metab. 2012;48(4):1-10. doi:10.1016/S0304-5412(12)70482-1
Strasser B. Physical activity in obesity and metabolic syndrome. Ann N Y Acad Sci. 2013;1281(1):141-159. doi:10.1111/j.1749-6632.2012.06785.x
Van Proeyen K, Szlufcik K, Nielens H, et al. Training in the fasted state improves glucose tolerance duringfat-rich diet. J Physiol. 2010;588(21):4289-4302. doi:10.1113/jphysiol.2010.196493
Cahn A, Miccoli R, Dardano A, Del Prato S. New forms of insulin and insulin therapies for the treatment of type 2 diabetes. Lancet Diabetes Endocrinol. 2015;3(8):638- 652. doi:10.1016/S2213-8587(15)00097-2
Sanchez-Rangel E, Inzucchi SE. Metformin: clinical use in type 2 diabetes. Diabetologia. 2017;60(9):1586-1593. doi:10.1007/s00125-017-4336-x
Hostalek U, Gwilt M, Hildemann S. Therapeutic Use of Metformin in Prediabetes and Diabetes Prevention. Drugs. 2015;75(10):1071-1094. doi:10.1007/s40265-015-0416-8
Pernicova I, Korbonits M. Metformin-Mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014;10(3):143-156. doi:10.1038/ nrendo.2013.256
Griffin SJ, Angelyn Bethel M, Holman RR, et al. Metformin in non-diabetic hyperglycaemia: The glint feasibility RCT. Health Technol Assess (Rockv). 2018;22(18). doi:10.3310/hta22180
Infante M, Leoni M, Caprio M, Fabbri A. Longterm metformin therapy and vitamin B12 deficiency: an association to bear in mind. World J Diabetes. 2021;12(7):916-931. doi:10.4239/wjd.v12.i7.916
Gilbert MP, Pratley RE. GLP-1 Analogs and DPP-4 Inhibitors in Type 2 Diabetes Therapy: Review of Headto-Head Clinical Trials. Front Endocrinol (Lausanne). 2020;11(April):1-13. doi:10.3389/fendo.2020.00178
Alfonso Figueredo E, Reyes Sanamé FA, Pérez Álvarez ML, Batista Acosta Y, Peña Garcell Y. Inhibidores de la dipeptidil peptidasa 4 y una nueva estrategia farmacológica en la diabetes mellitus tipo 2. Rev Cubana Med. 2016;55(3):239- 256.
Carmen DRA, Aylwin G. Nuevos Fármacos En Diabetes Mellitus New Drugs for Treatment of Diabetes Mellitus. Rev Clínica Las Condes. 2016;27(2):235-256.
Ministerio de Salud Chile. Guía Practica Clínica Tratamiento de la Diabetes Mellitus Tipo 2. Rev Panam Salud Pública. 2017;5(1):15-36. http://www.cenetec. salud.gob.mx/descargas/gpc/CatalogoMaestro/718_GPC_ Tratamiento_de_diabetes_mellitus_tipo_2_/718GER.pdf
Kalra S, Bahendeka S, Sahay R, et al. Consensus recommendations on sulfonylurea and sulfonylurea combinations in the management of Type 2 diabetes mellitus - International Task Force. Indian J Endocrinol Metab. 2018;22(1):132-157. doi:10.4103/ijem. IJEM_556_17
Colagiuri S, Matthews D, Leiter LA, Chan SP, Sesti G, Marre M. The place of gliclazide MR in the evolving type 2 diabetes landscape: A comparison with other sulfonylureas and newer oral antihyperglycemic agents. Diabetes Res Clin Pract. 2018;143:1-14. doi:10.1016/j.diabres.2018.05.028
Nair S, Wilding JPH. Sodium glucose cotransporter 2 inhibitors as a new treatment for diabetes mellitus. J Clin Endocrinol Metab. 2010;95(1):34-42. doi:10.1210/ jc.2009-0473
Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: Results of the EMPAREG OUTCOME® trial. Eur Heart J. 2016;37(19):1526- 1534. doi:10.1093/eurheartj/ehv728
Baartscheer A, Schumacher CA, Wüst RCI, et al. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia. 2017;60(3):568-573. doi:10.1007/s00125-016-4134-x
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):644-657. doi:10.1056/ nejmoa1611925
McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995- 2008. doi:10.1056/NEJMoa1911303
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