Display options
Share it on

Cardiovasc Drugs Ther. 2021 Nov 09; doi: 10.1007/s10557-021-07291-y. Epub 2021 Nov 09.

The Role of Combined SGLT1/SGLT2 Inhibition in Reducing the Incidence of Stroke and Myocardial Infarction in Patients with Type 2 Diabetes Mellitus.

Cardiovascular drugs and therapy

Bertram Pitt, Gabriel Steg, Lawrence A Leiter, Deepak L Bhatt

Affiliations

  1. University of Michigan, Ann Arbor, MI, USA.
  2. Université de Paris, Hopital Bichat, Paris, France.
  3. Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.
  4. Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA. [email protected].

PMID: 34750713 DOI: 10.1007/s10557-021-07291-y

Abstract

PURPOSE: In patients with type 2 diabetes mellitus (T2DM), both sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide receptor agonists (GLP-1 RAs) have demonstrated significant improvements in cardiovascular and kidney outcomes independent of their glycemic benefits. This paper will briefly compare the effect of SGLT2is and GLP-1 RAs to that of the SGLT1/2 inhibitor sotagliflozin on the incidence of myocardial infarction (MI) and stroke in patients with T2DM and further postulate mechanisms to account for these findings.

METHODS AND RESULTS: Thus far, the results from SCORED and SOLOIST (trials studying the SGLT1/2 inhibitor sotagliflozin) suggest that an increase in SGLT1 inhibition when added to SGLT2 inhibition may contribute to reductions in MI and stroke in patients with T2DM. This benefit is beyond what SGLT2is alone can accomplish and at least similar to GLP-1 RAs but with the added benefit of a reduction in hospitalizations and urgent visits for HF. Larger and longer studies are required to confirm the effectiveness of SGLT1/SGLT2 inhibition in reducing MI and stroke in patients with T2DM and elucidate the mechanisms associated with this finding.

CONCLUSIONS: The role of SGLT1/2 inhibition as an addition to GLP-1 RAs in patients with and without T2DM at increased risk for MI and stroke requires further study. Regardless, the finding that a relative increase in SGLT1/2 inhibition reduces the risk of MI and stroke as well as hospitalizations and urgent visits for heart failure could improve quality of life and reduce the healthcare burden associated with T2DM.

© 2021. The Author(s).

Keywords: Cardiovascular risk; Quality of life; Sodium-glucose cotransporter 1/2 inhibitors; Type 2 diabetes

References

  1. Das SR, Everett BM, Birtcher KK, et al. 2020 Expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes. J Am Coll Cardiol. 2020;76:1117–45. - PubMed
  2. Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force for diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD). Eur Heart J. 2020;41(2):255–323. - PubMed
  3. McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol. 2021;6(2):148–58. - PubMed
  4. Marsico F, Paolillo S, Gargiulo P, et al. Effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events in patients with type 2 diabetes mellitus with or without established cardiovascular disease: a meta-analysis of randomized controlled trials. Eur Heart J. 2020;41(35):3346–58. - PubMed
  5. Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Eng J Med. 2021;384:129–39. - PubMed
  6. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and worsening heart failure. N Eng J Med. 2021;384:117–28. - PubMed
  7. Pitt B, Bhatt DL. Can SGLT1 inhibition add benefit to SGLT2 inhibition in type 2 diabetes mellitus? Circulation. 2021;144:4–6. - PubMed
  8. Gilbert RE, Connelly KA. Reduction in the incidence of myocardial infarction with sodium-glucose linked cotransporter-2 inhibitors: evident and plausible. Cardiovasc Diabetol. 2019;18:6–9. - PubMed
  9. Ali A, Bain S, Hicks D, et al. SGLT2 inhibitors: cardiovascular benefits beyond HbA1c-translating evidence into practice. Diabetes Ther. 2019;10(5):1595–622. - PubMed
  10. The blood pressure lowering treatment trialists’ collaboration. Lancet. 2021;397(10285):1625–36. - PubMed
  11. Sano M, Goto S. Possible mechanisms of hematocrit elevation by sodium glucose cotransporter 2 inhibitors and associated beneficial renal and cardiovascular effects. Circulation. 2019;139(17):1985–7. - PubMed
  12. Yang R, Wang A, Ma L, et al. Hematocrit and the incidence of stroke: a prospective, population-based cohort study. Ther Clin Risk Manag. 2018;14:2081–8. - PubMed
  13. Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomized, placebo-controlled trial. Lancet. 2018;392(10157):1519–29. - PubMed
  14. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Eng J Med. 2016;375(19):1834–44. - PubMed
  15. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Eng J Med. 2019;381:841–51. - PubMed
  16. Trevisan M, Fu EL, Szummer K, et al. Glucagon-like peptide-1 receptor agonists and the risk of cardiovascular events in diabetes patients surviving an acute myocardial infarction. Eur Heart J. 2021;7(2):104–11. - PubMed
  17. Dave CV, Kim SC, Goldfine AB, Glynn RJ, Tong A, Patorno E. Risk of cardiovascular outcomes in patients with type 2 diabetes after addition of SGLT2 inhibitors versus sulfonylureas to baseline GLP-1RA therapy. Circulation. 2021;143:770–9. - PubMed
  18. Sayour AA, Celeng C, Oláh A, Ruppert M, Merkely B, Radovits T. Sodium-glucose cotransporter 2 inhibitors reduce myocardial infarct size in preclinical animal models of myocardial ischaemia-reperfusion injury: a meta-analysis. Diabetologia. 2021;64(4):737–48. - PubMed
  19. Sternkopf M, Nagy M, Baaten CCFMJ, et al. Native intact glucagon-like peptide is a natural suppressor of thrombus growth under physiologic flow conditions. Arterioscler Thromb Vasc Biol. 2020; e65-e77. https://doi.org/10.1161/ATVBAHA.119.313645 . - PubMed
  20. Burgmaier M, Liberman A, Möllmann J, Kahles F, Reith S, Lebherz C, Marx N, Lehrke M. Glucagon-like peptide-1 (GLP-1) and its split products GLP-1(9–37) and GLP-1(28–37) stabilize atherosclerotic lesions in apoe-/-mice. Atherosclerosis. 2013;231(2):427–35. - PubMed
  21. Avogaro A, Bonora E, Consoli A, Del Prato S, Genovese S, Giorgino F. Glucose-lowering therapy and cardiovascular outcomes in patients with type 2 diabetes mellitus and acute coronary syndrome. Diab Vasc Dis Res. 2019;16(5):399–414. - PubMed
  22. Shah MS, Brownlee M. Molecular and cellular mechanisms of cardiovascular disorders in diabetes. Circ Res. 2016;118(11):1808–29. - PubMed
  23. Tun NN, Arunagirinathan G, Munshi SK, Pappachan JM. Diabetes mellitus and stroke: a clinical update. World J Diabetes. 2017;8(6):235–48. - PubMed
  24. Cui J, Liu Y, Li F, Xu F, Liu Y. Type 2 diabetes and myocardial infarction: recent clinical evidence and perspective. Front Cardiovas Med. 2021;8: 644189. - PubMed
  25. Kelly DM, Rothwell PM. Does chronic kidney disease predict stroke risk independent of blood pressure?: a systematic review and meta-regression. Stroke. 2019;50(11):3085–92. - PubMed
  26. Banerjee SK, McGaffin KR, Pastor-Soler NM, Ahmad F. SGLT1 is a novel cardiac glucose transporter that is perturbed in disease states. Cardiovasc Res. 2009;84(1):111–8. - PubMed
  27. Seidelmann SB, Feofanova E, Yu B, et al. Genetic variations in SGLT1, glucose tolerance, and cardiometabolic risk. J Am Coll Cardiol. 2018;72(15):1763–73. - PubMed
  28. Dyer J, Wood IS, Palejwala A, Ellis A, Shirazi-Beechey SP. Expression of monosaccharaide transporters in intestine of diabetic humans. J Physiol Gastrointest Liver Physiol. 2002;282(2):G241-248. - PubMed
  29. Goodwin NC, Ding ZM, Harrison BA, et al. Discovery of LX2761, a sodium-dependent glucose co-transporter 1 (SGLT1) inhibitor restricted to the intestinal lumen, for the treatment of diabetes. J Med Chem. 2017;60(2):710–21. - PubMed
  30. Dobbins RL, Greenway FL, Chen L, et al. Selective sodium-dependent glucose transporter 1 inhibitors block glucose absorption and impair glucose-dependent insulinotropic peptide release. Am J Physiol Gastrointest Liver Physiol. 2015;308(11):G946-954. - PubMed
  31. Oguma T, Nakayama K, Kuriyama C, et al. Intestinal sodium glucose cotransporter 1 inhibition enhances glucagon-like peptide-1 secretion in normal and diabetic rodents. J Pharmacol Exp Ther. 2015;354(3):279–89. - PubMed
  32. Gorboulev V, Schürmann A, Vallon V, et al. Na(+)-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretion secretion. Diabetes. 2012;61(1):187–96. - PubMed
  33. Rieg JAD, Rieg T. What does sodium-glucose co-transporter 1 inhibition add: prospects for dual inhibition. Diabetes Obes Metab. 2019;21(suppl 2):43–52. - PubMed
  34. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121–30. - PubMed
  35. Aw W, Fukuda S. Understanding the role of the gut ecosystem in diabetes mellitus. J Diabetes Investig. 2018;9(1):5–12. - PubMed
  36. Nagpal R, Mainali R, Ahmadi S, et al. Gut microbiome and aging: physiological and mechanistic insights. Nutr Healthy Aging. 2018;4(4):267–85. - PubMed
  37. Hasan RA, Koh AY, Zia A. The gut microbiome and thromboembolism. Thromb Res. 2020;189:77–87. - PubMed
  38. Zhu W, Gregory JC, Org E, et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell. 2016;165(1):111–24. - PubMed
  39. Schneider C, Okun JG, Schwarz KV, et al. Trimethylamine-N-oxide is elevated in the acute phase after ischaemic stroke and decreases within the first days. Eur J Neurol. 2020;27(8):1596–603. - PubMed
  40. Senthong V, Wang Z, Li XS, et al. Intestinal microbiota-generated metabolite trimethylamine-N-oxide and 5-year mortality risk in stable coronary artery disease: the contributory role of intestinal microbiota in a COURAGE-like patient cohort. J Am Heart Assoc. 2016;5(6): e002816. - PubMed
  41. Koepsell H. Glucose transporters in brain in health and disease. Pflugers Arch. 2020;472:1299–343. - PubMed
  42. Vemula S, Roder KE, Yang T, Bhat J, Thekkumkara TJ, Abbruscato TJ. A functional role for sodium-dependent glucose transport across the blood-brain barrier during oxygen glucose deprivation. J Pharmacol Exp Ther. 2009;328(2):487–95. - PubMed
  43. Yamazaki Y, Harada S, Tokuyama S. Post-ischemic hyperglycemia exacerbates the development of cerebral ischemic neuronal damage through the cerebral sodium-glucose transporter. Brain Res. 2012;1489:113–20. - PubMed
  44. Yamazaki Y, Ogihara S, Harada S, Tokuyama S. Activation of cerebral sodium-glucose transporter type 1 function mediated by post-ischemic hyperglycemia exacerbates the development of cerebral ischemia. Neuroscience. 2015;310:674–85. - PubMed
  45. Yamazaki Y, Harada S, Wada T, Yoshida S, Tokuyama S. Sodium transport through the cerebral sodium-glucose transporter exacerbates neuron damage during cerebral ischaemia. J Pharm Pharmacol. 2016;68(7):922–31. - PubMed
  46. Sawa Y, Saito M, Ishida N, et al. Pretreatment with KGA-2727, a selective SGLT1 inhibitor, is protective against myocardial infarction-induced ventricular remodeling and heart failure in mice. J Pharmacol Sci. 2020;142(1):16–25. - PubMed
  47. Li Z, Agrawal V, Ramratnam V, et al. Cardiac sodium-dependent glucose cotransporter 1 is a novel mediator of ischaemia/reperfusion injury. Cardiovasc Res. 2019;115(11):1646–58. - PubMed
  48. Kashiwagi Y, Nagoshi T, Yoshino T, et al. Expression of SGLT1 in human hearts and impairment of cardiac glucose uptake by phlorizin during ischemia-reperfusion injury in mice. PLoS ONE. 2015;10(6): e0130605. - PubMed
  49. Szarek M, Bhatt DL, Steg PG, et al. Effect of sotagliflozin on total hospitalizations in patients with type 2 diabetes and worsening heart failure: a randomized trial. Ann Intern Med. 2021 Jun 22. - PubMed

Publication Types