Skip to main content

Advertisement

SpringerLink
Log in

Sodium-Glucose Cotransporter Type 2 (SGLT-2) Inhibitors and Ketogenesis: the Good and the Bad

  • Pharmacologic Treatment of Type 2 Diabetes (HE Lebovitz and G Bahtiyar, Section Editors)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The micro/macrovascular complications of diabetes cause considerable morbidity and premature mortality. The SGLT2 inhibitors are the first diabetes medications with significant benefits on microvascular disease (nephropathy) and macrovascular cardiovascular disease. In this review, we evaluate one of the potential mechanisms for these cardiorenal benefits—the production of ketones, their benefits, and risks.

Recent Findings

In recent cardiovascular outcome trials (CVOTs), the SGLT2 inhibitors demonstrated significant cardiorenal benefits and they are now approved to reduce CV events/death, heart failure hospitalization, and progression to end-stage renal disease. Glucosuria induced by the SGLT2 inhibitors leads to increased ketone production. Ketones are an efficient fuel source and can improve myocardial and renal function. Further, the ketone body beta-hydroxybutyrate exhibits anti-inflammatory/anti-oxidative actions, which favorably impact myocardial and renal remodeling/fibrosis. Uncontrolled ketogenesis leads to ketoacidosis, especially during conditions of acute illness and excessive insulin dose reductions.

Summary

The SGLT2 inhibitors have demonstrated significant cardiorenal benefits in large CVOTs. Studies are in progress to elucidate whether SGLT2 inhibitor–induced low-grade hyperketonemia contributes to these benefits.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Lau DC. Are diabetes care providers too glucocentric? Can J Diabetes. 2016;40(6):479–81.

    Article  PubMed  Google Scholar 

  2. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.

    Article  PubMed Central  Google Scholar 

  3. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.

    Article  CAS  PubMed  Google Scholar 

  4. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–57.

    Article  CAS  PubMed  Google Scholar 

  5. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–57.

    Article  CAS  PubMed  Google Scholar 

  6. •• McMurray JJV, DAPA-HF Trial Committees and Investigators, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995–2008 First study to demonstrate that an SGLT2 inhibitor can reduce HF hospitalization/CV mortality in patients with HFrEF irrespective of diabetes status.

    Article  CAS  PubMed  Google Scholar 

  7. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295–306.

    Article  CAS  PubMed  Google Scholar 

  8. Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Erondu N, Shaw W, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS program randomized clinical trials. Lancet Diabetes Endocrinol. 2018;6:691–704.

    Article  CAS  PubMed  Google Scholar 

  9. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323–34.

    Article  CAS  PubMed  Google Scholar 

  10. Mosenzon O, Wiviott SD, Cahn A, Rozenberg A, Yanuv I, Goodrich EL, 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 randomized trial. Lancet Diabetes Endocrinol. 2019;7:606–17.

    Article  CAS  PubMed  Google Scholar 

  11. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care. 2016;39:1115–22.

    Article  CAS  PubMed  Google Scholar 

  12. Ferrannini E, et al. Shift to fatty substrate utilization in response to sodium–glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes. 2016;65:1190–5.

    Article  CAS  PubMed  Google Scholar 

  13. •• Cahill GF. Fuel metabolism in starvation. Annu Rev Nutr. 2006;26:1–22 Comprehensive review of fuel metabolism in starvation.

    Article  CAS  PubMed  Google Scholar 

  14. Cahill GF Jr, Veech RL. Ketoacids? Good medicine? Trans Am Clin Climatol Assoc. 2003;114:149–63.

    PubMed  PubMed Central  Google Scholar 

  15. Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev. 1999;15(6):412–26.

    Article  CAS  PubMed  Google Scholar 

  16. Felig P, Lynch V. Starvation in human pregnancy: hypoglycemia, hypoinsulinemia, and hyperketonemia. Science. 1970;170(3961):990–2.

    Article  CAS  PubMed  Google Scholar 

  17. Ferrannini E. Sodium-glucose cotransporters and their inhibition: clinical physiology. Cell Metab. 2017;26:27–38.

    Article  CAS  PubMed  Google Scholar 

  18. Polidori D, Iijima H, Goda M, Maruyama N, Inagaki N, Crawford PA. Intra- and inter-subject variability for increases in serum ketone bodies in patients with type 2 diabetes treated with the sodium glucose co-transporter 2 inhibitor canagliflozin. Diabetes Obes Metab. 2018;20(5):1321–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yabe D, Iwasaki M, Kuwata H, Haraguchi T, Hamamoto Y, Kurose T, et al. Sodium-glucose co-transporter-2 inhibitor use and dietary carbohydrate intake in Japanese individuals with type 2 diabetes: a randomized, open-label, 3-arm parallel comparative, exploratory study. Diabetes Obes Metab. 2017;19:739–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, et al. Sabatine MS.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. 2019;393(10166):31–9.

    Article  CAS  PubMed  Google Scholar 

  21. Hupfeld C, Mudaliar S. Navigating the “MACE” in cardiovascular outcomes trials and decoding the relevance of atherosclerotic cardiovascular disease benefits versus heart failure benefits. Diabetes Obes Metab. 2019;21(8):1780–9.

    Article  PubMed  Google Scholar 

  22. FDA approves new treatment for a type of heart failure. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-type-heart-failure. Accessed June 27, 2020.

  23. Qiangwei F, Colgan SP, Shelley CS. Hypoxia: the force that drives chronic kidney disease. Clin Med Res. 2016;14(1):15–39.

    Article  CAS  Google Scholar 

  24. Abe H, Semba H, Takeda N. The roles of hypoxia signaling in the pathogenesis of cardiovascular diseases. J Atheroscler Thromb. 2017;24(9):884–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cho YI, Mooney MP, Cho DJ. Hemorheological disorders in diabetes mellitus. J Diabetes Sci Technol. 2008;2:1130–8.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Pu LJ, Shen Y, Lu L, Zhang RY, Zhang Q, Shen WF. Increased blood glycohemoglobin A1c levels lead to overestimation of arterial oxygen saturation by pulse oximetry in patients with type 2 diabetes. Cardiovasc Diabetol. 2012;11:110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. De Jong KA, Lopaschuk GD. Complex energy metabolic changes in heart failure with preserved ejection fraction and heart failure with reduced ejection fraction. Can J Cardiol. 2017;33(7):860–71.

    Article  PubMed  Google Scholar 

  28. Karwi QG, Uddin GM, Ho KL, Lopaschuk GD. Loss of metabolic flexibility in the failing heart. Front Cardiovasc Med. 2018;5:68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Okar DA. Starvation amidst plenty: PDKs and diabetes mellitus. Trends Endocrinol Metab. 2002;13:142.

    Article  CAS  PubMed  Google Scholar 

  30. Abel ED, O'Shea KM, Ramasamy R. Insulin resistance: metabolic mechanisms and consequences in the heart. Arterioscler Thromb Vasc Biol. 2012;32(9):2068–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Levelt E, Rodgers CT, Clarke WT, Mahmod M, Ariga R, Francis JM, et al. Cardiac energetics, oxygenation, and perfusion during increased workload in patients with type 2 diabetes mellitus. Eur Heart J. 2016;37(46):3461–9.

    Article  PubMed  Google Scholar 

  32. Pascual F, Coleman RA. Fuel availability and fate in cardiac metabolism: a tale of two substrates. Biochim Biophys Acta. 2016;1861(10):1425–33.

    Article  CAS  PubMed  Google Scholar 

  33. Lahnwong S, Palee S, Apaijai N, Sriwichaiin S, Kerdphoo S, Jaiwongkam T, et al. Acute dapagliflozin administration exerts cardioprotective effects in rats with cardiac ischemia/reperfusion injury. Cardiovasc Diabetol. 2020;19(1):91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Moellmann J, Klinkhammer BM, Droste P, et al. Empagliflozin improves left ventricular diastolic function of db/db mice [published online ahead of print, 2020 Apr 28]. Biochim Biophys Acta Mol basis Dis. 1866;2020(8):165807.

    Article  CAS  Google Scholar 

  35. Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, Ishikawa K, Watanabe S, Picatoste B, et al. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. J Am Coll Cardiol. 2019;73(15):1931–44.

    Article  CAS  PubMed  Google Scholar 

  36. •• Nielsen R, Møller N, Gormsen LC, et al. Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients. Circulation. 2019;139(18):2129–41 First study in humans to show that BHOB infusion may potentially constitute a novel treatment principle in HFrEF patients.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Oldgren J, Laurila S, Akerblom A, et al. Effects of 6 weeks of treatment with dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, on myocardial function and metabolism in type 2 diabetes patients: a randomized placebo-controlled study. J Am Coll Cardiol. 2020;75(11):1610.

    Article  Google Scholar 

  38. EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved). https://clinicaltrials.gov/ct2/show/NCT03057951. Accessed 27 June 2020.

  39. Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure. (DELIVER). https://clinicaltrials.gov/ct2/show/NCT03619213. Accessed 27 June 2020.

  40. Hansell P, Welch WJ, Blantz RC, Palm F. Determinants of kidney oxygen consumption and their relationship to tissue oxygen tension in diabetes and hypertension. Clin Exp Pharmacol Physiol. 2013;40(2):123–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Fine LG, Orphanides C, Norman JT. Progressive renal disease: the chronic hypoxia hypothesis. Kidney Int Suppl. 1998;65:S74–8.

    CAS  PubMed  Google Scholar 

  42. Friederich-Persson, et al. Kidney hypoxia, attributable to increased oxygen consumption, induces nephropathy independently of hyperglycemia and oxidative stress. Hypertension. 2013;62:914–9.

    Article  CAS  PubMed  Google Scholar 

  43. Körner A, Eklöf AC, Celsi G, Aperia A. Increased renal metabolism in diabetes. Mechanism and functional implications. Diabetes. 1994;43:629–33.

    Article  PubMed  Google Scholar 

  44. Muller ME, Pruijm M, Bonny O, Burnier M, Zanchi A. Effects of the SGLT-2 inhibitor empagliflozin on renal tissue oxygenation in non-diabetic subjects: a randomized, double-blind, placebo-controlled study protocol. Adv Ther. 2018;35(6):875–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 2017;25:262–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease and therapeutics. Nat Med. 2015;21:677–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. McKellar GE, et al. Role for TNF in atherosclerosis? Lessons from autoimmune disease. Nat Rev Cardiol. 2009;6:410–7.

    Article  CAS  PubMed  Google Scholar 

  48. Chakraborty S, Galla S, Cheng X, Yeo JY, Mell B, Singh V, et al. Salt-responsive metabolite, beta-hydroxybuterate, attenuates hypertension. Cell Rep. 2018;25(3):677–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kim SR, Lee SG, Kim SH, Kim JH, Choi E, Cho W, et al. SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease. Nat Commun. 2020;11:2127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107(9):1058–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Seto E, Yoshida M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol. 2014;6(4):a018713.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Ooi JY, Tuano NK, Rafehi H, et al. HDAC inhibition attenuates cardiac hypertrophy by acetylation and deacetylation of target genes. Epigenetics. 2015;10(5):418–30.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Verma, EMPA-HEART CardioLink-6 Investigators, et al. Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes mellitus and coronary artery disease. Circulation. 2019;140:1693–702.

    Article  PubMed  Google Scholar 

  54. Bami K, Gandhi S, Leong-Poi H, Yan AT, Ho E, Zahrani M, et al. Effects of empagliflozin on left ventricular remodeling in patients with type 2 diabetes and coronary artery disease: echocardiographic substudy of the EMPA-HEART CardioLink-6 randomized clinical trial. J Am Soc Echocardiogr. 2020;33(5):644–6.

    Article  PubMed  Google Scholar 

  55. Wang X, Liu J, Zhen J, Zhang C, Wan Q, Liu G, et al. Histone deacetylase 4 selectively contributes to podocyte injury in diabetic nephropathy. Kidney Int. 2014;86:712–25.

    Article  CAS  PubMed  Google Scholar 

  56. Hadden MJ, Advani A. Histone deacetylase inhibitors and diabetic kidney disease. Int J Mol Sci. 2018;19:2630.

    Article  PubMed Central  CAS  Google Scholar 

  57. Umino H, Hasegawa K, Minakuchi H, Muraoka H, Kawaguchi T, Kanda T, et al. High basolateral glucose increases sodium-glucose cotransporter 2 and reduces sirtuin-1 in renal tubules through glucose transporter-2 detection. Sci Rep. 2018;8(1):6791.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Fayfman M, Pasquel FJ, Umpierrez GE. Management of hyperglycemic crises: diabetic ketoacidosis and hyperglycemic hyperosmolar state. Med Clin North Am. 2017;101(3):587–606.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Bonora BM, Avogaro A, Fadini GP. Euglycemic ketoacidosis. Curr Diab Rep. 2020;20:25.

    Article  CAS  PubMed  Google Scholar 

  60. Rosenstock J, Ferranini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015;38:1638–42.

    Article  CAS  PubMed  Google Scholar 

  61. Bonner C, Kerr-Conte J, Gmyr V, Queniat G, Moerman E, Thévenet J, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015;21(5):512–7.

    Article  CAS  PubMed  Google Scholar 

  62. Hodson DJ, Rorsman P. A variation on the theme: SGLT2 inhibition and glucagon secretion in human islets. Diabetes. 2020;69(5):864–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. First oral add-on treatment to insulin for treatment of certain patients with type 1 diabetes. https://www.ema.europa.eu/en/news/first-oral-add-treatment-insulin-treatment-certain-patients-type-1-diabetes. Accessed June 27,2020.

  64. 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 [published online ahead of print, 2020 May 4]. Diabetes Obes Metab. 2020. https://doi.org/10.1111/dom.14075.

  65. Wang L, Voss EA, Weaver J, Hester L, Yuan Z, DeFalco F, et al. Diabetic ketoacidosis in patients with type 2 diabetes treated with SGLT2- inhibitors versus other antihyperglycemic agents: an observational study of four US administrative claims databases. Pharmacoepidemiol Drug Saf. 2019;28(12):1620–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Veterans Affairs Medical Center, San Diego, CA, USA

    Preethika Ekanayake, Christopher Hupfeld & Sunder Mudaliar

  2. Department of Medicine, University of California at San Diego, San Diego School of Medicine, San Diego, USA

    Preethika Ekanayake, Christopher Hupfeld & Sunder Mudaliar

  3. Diabetes/Metabolism Section, VA San Diego HealthCare System, 3350 La Jolla Village Drive (Mail Code: 111G), San Diego, CA, 92161, USA

    Sunder Mudaliar

Authors
  1. Preethika Ekanayake
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher Hupfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sunder Mudaliar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sunder Mudaliar.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Pharmacologic Treatment of Type 2 Diabetes

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ekanayake, P., Hupfeld, C. & Mudaliar, S. Sodium-Glucose Cotransporter Type 2 (SGLT-2) Inhibitors and Ketogenesis: the Good and the Bad. Curr Diab Rep 20, 74 (2020). https://doi.org/10.1007/s11892-020-01359-z

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11892-020-01359-z

Keywords

Search

Navigation