medigraphic.com
ISSN 0326-3428 (Print)
Órgano de difusión científica de la Asociación Nefrológica de Buenos Aires

2023, Number 3

<< Back

Rev Nefrol Dial Traspl 2023; 43 (3)

Cardiovascular, renal, and cerebral protection by SGLT2. Hemodynamic, tissular, and cellular mechanisms involved

Inserra Fl, Gustavo T, Castellaro C

Language: Spanish
References: 62
Page: 184-196
PDF size: 437.85 Kb.


ABSTRACT

After many years of looking for new mechanisms and strategies for cardiovascular and renal protection, sodium-glucose co-transport inhibitors or gliflozins appeared, demonstrating not only a notable and unexpected protective effect on various organ lesions: heart, arteries, kidneys, and brain but also an impressive event reduction. These effects were initially associated with better control of metabolic diseases such as diabetes. However, with time and the results, functional and structural improvements in said organs were verified in people without diabetes. These improvements went beyond the responses initially sought and extended to hemodynamic aspects and the benefits on cellular and subcellular structures and functions associated with protection in various tissues. These facts allow us to understand the notable reduction of the various events seen in the patients, including a reduction in mortality of around 30%. This review will show the existing evidence in renal, cardiovascular, and brain protection that translates into notable changes in clinical practice guidelines. We will also review cellular mechanistic knowledge, particularly improving mitochondrial function, which leads to less oxidative stress and inflammation. In summary, the review explains at least part of the reasons for these drugs nowadays to occupy the first line of treatment for cardiovascular and renal diseases. Finally, we will give reasons suggesting that gliflozins can be used in the future to prevent highly prevalent diseases.


REFERENCES

  1. La carga de las enfermedades cardiovasculares en laRegión de las Américas, 2000-2019. Portal de Datos deNMH. Organización Panamericana de la Salud; 2021.

  2. 4ta Encuesta Nacional de Factores de Riesgo. Ministeriode Salud. Presidencia de la Nación. Argentina 2019.https://bancos.salud.gob.ar/sites/default/files/2020-01/4ta-encuesta-nacional-factores-riesgo_2019_informedefinitivo.pdf

  3. WHO. Diabetes, 5 April 2023. https://www.who.int/es/news-room/fact-sheets/detail/diabetes

  4. Ronco C, Haapio M, House AA, Anavekar N, BellomoR. Cardiorenal syndrome. J Am Coll Cardiol. 2008; 52:1527–1539. doi: 10.1016/j.jacc.2008.07.051

  5. Jankowski J, Floege J, Fliser D, Böhm M, Marx N.Cardiovascular Disease in Chronic Kidney Disease:Pathophysiological Insights and Therapeutic Options.Circulation. 2021; 143:1157-1172. doi: 10.1161/CIRCULATIONAHA.120.050686.

  6. Nissen SE, Wolski K. Effect of rosiglitazone on the riskof myocardial infarction and death from cardiovascularcauses. N Engl J Med. 2007 Jun 14;356(24):2457-71.doi: 10.1056/NEJMoa072761

  7. Zinman B. et al. Empagliflozin, cardiovascularoutcome, and mortality in type 2 diabetes. N Engl JMed 2015; 373:2117-2128

  8. Neal B. et al. Canagliflozin, cardiovascular and renalevents in type 2 diabetes. N Engl J Med 2017; 377:644-657

  9. Wiviott S. et al. Dapagliflozin and cardiovascularoutcomes in type 2 diabetes. N Engl J Med 2019;380:347-357

  10. Zlniker T et al. SLGT2 inhibitors for primary andsecondary prevention of cardiovascular and renaloutcomes in type 2 diabetes: a systematic review andmeta-analysis of cardiovascular outcome trials. Lancet2019; 393: 31–39

  11. Cannon C. Cardiovascular outcomes with ertugliflozinin type 2 diabetes. N Engl J Med 2020; 383:1425-1435

  12. Packer M, Anker SD, Butler J, et al. Cardiovascularand renal outcomes with empagliflozin in heart failure.N Engl J Med 2020; 383:1413-1424

  13. McMurray J. et al. Dapagliflozin in patients withheart failure and reduced ejection fraction. N Engl JMed 2019; 381:1995-2008

  14. Anker S. et al. Empagliflozin in heart failure witha preserved ejection fraction. N Engl J Med 2021;385:1451-1461

  15. Solomon S. et al. Dapagliflozin in heart failure withmadly reduced or preserved ejection fraction. N Engl JMed 2022; 387:1089-1098

  16. Bhatt D. et al Sotagliflozin in patients with diabetesand recent worsening heart failure. N Engl J Med 2021;384:117-128

  17. GBD 2017 Disease and Injury Incidence andPrevalence Collaborators (2018) Global, regional,and national incidence, prevalence, and years livedwith disability for 354 diseases and injuries for 195countries and territories, 1990–2017: a systematicanalysis for the Global Burden of Disease Study 2017.Lancet 392:1789–1858

  18. De Nicola L, Cozzolino M, Genovesi S, et al. CanSGLT2 inhibitors answer unmet therapeutic needs inchronic kidney disease? J Nephrol (2022) 35:1605–1618

  19. Remuzzi G, Bertani T (1998) Pathophysiology ofprogressive nephropathies. N Engl J Med 339(20):1448–1456

  20. De Nicola L, Gabbai FB, Garofalo C, Conte G,Minutolo R (2020) Nephroprotection by SGLT2inhibition: back to the future? J Clin Med 9(7):2243.

  21. Packer M. Cardioprotective Effects of Sirtuin-1and Its Downstream Effectors: Potential Role inMediating the Heart Failure Benefits of SGLT2(Sodium-Glucose Cotransporter 2) Inhibitors. CircHeart Fail. 2020 Sep;13(9): e007197. doi: 10.1161/CIRCHEARTFAILURE.120.007197.

  22. Packer M. Autophagy stimulation and intracellularsodium reduction as mediators of the cardioprotectiveeffect of sodium–glucose cotransporter 2 inhibitors.European Journal of Heart Failure. Eur J Heart Fail.2020; 22:618-628.

  23. Zinman B, Wanner C, Lachin JM, Fitchett D, BluhmkiE, Hantel S, et al. Empagliflozin, cardiovascularoutcomes, and mortality in type 2 diabetes. N Engl JMed. 2015; 373:2117-28.

  24. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, vonEynatten M, Mattheus M, et al. Empagliflozin andprogression of kidney disease in type 2 diabetes. NEngl J Med. 2016; 375:323-34.

  25. Neal B, Perkovic V, Mahaffey KW, de ZeeuwD, Fulcher G, Erondu N, et al. Canagliflozin andcardiovascular and renal events in type 2 diabetes. NEngl J Med. 2017; 377:644-57.

  26. Perkovic V, de Zeeuw D, Mahaffey KW, FulcherG, Erondu N, Shaw W, et al. Canagliflozin andrenal outcomes in type 2 diabetes: results from theCANVAS Program randomised clinical trials. LancetDiabetes Endocrinol. 2018; 6:691-704.

  27. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, KatoET, Cahn A, et al. Dapagliflozin and cardiovascularoutcomes in type 2 diabetes. N Engl J Med. 2019;380:347-57.

  28. CREDENCE trial Investigators. Canagliflozin andRenal Outcomes in Type 2 Diabetes and Nephropathy.N Engl J Med. 2019; 380:2295-2306.

  29. Heerspink HJL, Stefánsson BV, Correa-Rotter R,Chertow G, et al. Dapagliflozin in patients withchronic kidney disease. N Engl J Med 2020; 383:1436-1446

  30. William G. Herrington, Natalie Staplin, ChristophWanner, Jennifer B. Green, and et al. The EMPAKIDNEYCollaborative Group. Empagliflozin inPatients with Chronic Kidney Disease. N Engl J Med2023; 388:117-127

  31. Packer M, Anker SD, Butler J, et al. Cardiovascularand renal outcomes with empagliflozin in heart failure.N Engl J Med 2020; 383:1413-1424

  32. Stefan D. Anker, M.D., Ph.D., Javed Butler, M.D.,Gerasimos Filippatos, M.D., Ph.D., João P. Ferreira,M.D., et al. mpagliflozin in Heart Failure with aPreserved Ejection Fraction. N Engl J Med 2021;385:1451-1461

  33. John J.V. McMurray, M.D., Scott D. Solomon,M.D., Silvio E. Inzucchi, M.D., Lars Køber, M.D.,et al. Dapagliflozin in Patients with Heart Failureand Reduced Ejection Fraction. N Engl J Med 2019;381:1995-2008

  34. Scott D. Solomon, M.D., John J.V. McMurray, M.D.,Brian Claggett, Ph.D., Rudolf A. de Boer, M.D., et al.Dapagliflozin in Heart Failure with Mildly Reducedor Preserved Ejection Fraction. N Engl J Med 2022;387:1089-1098

  35. Deepak L. Bhatt, M.D., M.P.H., Michael Szarek,Ph.D., P. Gabriel Steg, M.D., Christopher P. Cannon,M.D., et al. Sotagliflozin in Patients with Diabetes andRecent Worsening Heart Failure. N Engl J Med 2021;384:117-128

  36. Keidai Y, Yoshiji S, Hasebe M, Minamino H,Murakami T, Tanaka D, et al. Stabilization of kidneyfunction and reduction in heart failure events withsodium-glucose co-transporter 2 inhibitors: A metaanalysisand meta-regression analysis. Diabetes ObesMetab. 2023 May 22. doi: 10.1111/dom.15122.

  37. GBD 2015 Mortality and Causes of DeathCollaborators (2016) Global, regional, and nationallifeexpentancy, all-cause mrtality, and cause specificmortality for 249 causes of death, 1980-2015: asystematic análisis for th Global Burden of DiseaseStudy 2015. Lancet 2016; 388:1459-1544

  38. 2020 Alzheimer’s disease facts and figures. Alzheimer´sDement 2020; 16:391-460

  39. Alzheimer´s disease: from pathomechanism insightsto biomarker Discovery and therapy strategy. BiomarkRes 2020 8:42

  40. Braak H, Alafuzoff I, Arzberger T et al. Staging ofAlzheimer disease-associated neurofibrillary pathologyusing paraffin sections and immunocytochemistry.Acta Neuropathol 2006 112: 389-404.

  41. Kandimalla R, Thirumala V and Reddy PH. IsAlzheimer´s disease a Type 3 Diabetes? A criticalappraisal. Biochim. Byophys. Acta Mol. Basis Dis. 20171863, 1078-1089.

  42. Zhang J, Chen C, Huan S, et al. An updatedmeta-analysis of cohort studies: Diabetes and risk ofAlzheimer´s disease. Diabetes Res. Clin. Pract. 2017124: 41-47.

  43. Rizzo MR, Di Meo I, Politto R et al. Cognitiveimpairment and type 2 diabetes mellitus: focus ofiSGLT2 inhibitors treatment. Pharmacol Res 2022; 176

  44. Wium-Andersen IK, Osler M, Jørgensen MB et al.Antidiabetic medication and rik of dementiain patientswith type 2 diabetes: a nested case-control study. Eur JEndocrinol 2019; 181:499-507.

  45. Akimoto H, Negishi A, Oshima S et al Antidiabeticdrugs for the risk of Alzheimer diseasein patients withType 2 DM using FAERS. Am J Alzheimers Dis OtherDemen 2020; 35:1533317519899546.

  46. Bohlken J, Jacob L, KostevK. Association betweenthe use of antihyglycemic drugs and dementia risk: acase-control study. J Alzheimers Dis 2018; 66:725-732.

  47. Siao WZ, Lin TK, Huang JY et al. The associationbetween sodium-glucose cotransporter 2 inhibitorsand incident dementia: A nationwide populationbasedlongitudinal study (2022). Diab Vasc Dis Res.2022 May-Jun:19(3)

  48. Wu CY, Iskander C, Wang C, et al. Association ofSodium-Glucose Cotransporter 2 Inhibitors withtime to dementia: A population-based Cohort Study.Diabetes Care 2023; 46(2): 297-304.

  49. Mui JV, Zhou J, Lee S et al. Sodium-glucosecotransporter 2 inhibitors vs dipeptidyl peptidasa 4(DPP4) inhibitors for new-onset dementia: a propensityscore-matched population-based study with competingrisk análisis. Front Cardiovasc Med 2021; 8:747620

  50. Rizvi SM, Shakil S, Biswas D et al. Invokana(Canagliflozin) as a dual inhibitor of acetylcholinesteraseand sodium-glucose co-transporter 2: advancementin Alzheimer´s disease-diabetes type 2 linkage viaan enzoinformatics study. CNS Neurol Disord DrugTargets 2014 Apr: 13(3):447-51

  51. Pawlos A, Broncel M, Woźniak E, Gorzelak-PabiśP. Neuroprotective Effect of SGLT2 Inhibitors.Molecules. 2021 Nov 28;26(23):7213. doi: 10.3390/molecules26237213.

  52. Sa-Nguanmoo P, Tanajak P, Kerdphoo S. et al.SGLT2 inhibitors and DPP-4 Inhibitor improve brainfunction via attenuating mitochondrial dysfunction,insulin-resistance, inflammation, and apoptosis inHFD-induced obese rats. Toxicol. Appl. Pharmacol.2017; 333:43-50

  53. Murphy MP, Hartley RC. Mitochondria as atherapeutic target for common pathologies. Nat RevDrug Discov. 2018; 17:865–86.

  54. Choi J, Matoba N, Setoyama D, et al. The SGLT2inhibitor empagliflozin improves cardiac energy statusvia mitochondrial ATP production in diabetic mice.Commun Biol. 2023 Mar 17;6(1):278.

  55. Packer M. Role of Impaired Nutrient and OxygenDeprivation Signaling and Deficient AutophagicFlux in Diabetic CKD Development: Implicationsfor Understanding the Effects of Sodium-GlucoseCotransporter 2-Inhibitors. J Am Soc Nephrol. 2020May;31(5):907-919.

  56. Esterline R, Oscarsson J, Burns J. A role for sodiumglucose cotransporter 2 inhibitors (SGLT2is) in thetreatment of Alzheimer’s disease? Int Rev Neurobiol.2020; 155:113-140. doi: 10.1016/bs.irn.2020.03.018.

  57. Kumar AA, Kelly DP, Chirinos JA. Mitochondrialdysfunction in heart failure with preserved ejectionfraction. Circulation. 2019; 139:1435–50. https://doi.org/ 10.1161/CIRCULATIONAHA. 118.036259

  58. Sanz RL, Inserra F, García Menéndez S, Mazzei L,Ferder L, Manucha W. Metabolic Syndrome andCardiac Remodeling Due to Mitochondrial OxidativeStress Involving Gliflozins and Sirtuins. Curr HypertensRep. 2023 Jun;25(6):91-106. doi: 10.1007/s11906-023-01240-w.

  59. Packer M. Critical Reanalysis of the MechanismsUnderlying the Cardiorenal Benefits of SGLT2Inhibitors and Reaffirmation of the NutrientDeprivation Signaling/Autophagy Hypothesis.Circulation. 2022 Nov;146(18):1383-1405. doi:10.1161/CIRCULATIONAHA.122.061732.

  60. Packer M. Role of ketogenic starvation sensorsin mediating the renal protective effects ofSGLT2 inhibitors in type 2 diabetes. J DiabetesComplications. 2020 Sep;34(9):107647. doi: 10.1016/j.jdiacomp.2020.107647.

  61. Lee JY, Lee M, Lee JY, et al. Ipragliflozin, anSGLT2 Inhibitor, Ameliorates High-Fat Diet-Induced Metabolic Changes by Upregulating EnergyExpenditure through Activation of the AMPK/ SIRT1Pathway. Diabetes Metab J. 2021 Nov;45(6):921-932.doi: 10.4093/dmj.2020.0187

  62. Wang Z, Zhai J, Zhang T, et al. Canagliflozinameliorates epithelial-mesenchymal transition in highsaltdiet-induced hypertensive renal injury throughrestoration of sirtuin 3 expression and the reductionof oxidative stress. Biochem Biophys Res Commun. 2023Apr 23; 653:53-61. doi: 10.1016/j.bbrc.2023.01.084.




2020     |     www.medigraphic.com