1932

Abstract

Clinical studies evaluating the cardiovascular safety/impact of sodium–glucose cotransporter–2 (SGLT-2) inhibitors demonstrated a reduction in major adverse cardiovascular events driven primarily by a reduced cardiovascular mortality in individuals with type 2 diabetes and previous cardiovascular disease. These somewhat unexpected results are coupled with SGLT-2 inhibitors’ known acute effect of improvement in glycemia, reduction in blood pressure, and weight loss. In this review, we summarize the mechanism of action of SGLT-2 inhibitors, the metabolic effects of this class of medication, and the remarkable results of cardiovascular safety trials. In addition, we discuss adverse effects associated with these medications and the current recommendations for the use of these agents in the management of diabetes.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-042017-094221
2019-01-27
2024-10-06
Loading full text...

Full text loading...

/deliver/fulltext/med/70/1/annurev-med-042017-094221.html?itemId=/content/journals/10.1146/annurev-med-042017-094221&mimeType=html&fmt=ahah

Literature Cited

  1. 1.  Himsworth HP 1931. The relation of glycosuria to glycaemia and the determination of the renal threshold for glucose. Biochem. J. 25:1128–46
    [Google Scholar]
  2. 2.  Wells RG, Pajor AM, Kanai Y et al. 1992. Cloning of a human kidney cDNA with similarity to the sodium-glucose co-transporter. Am. J. Physiol. 263:F459–65
    [Google Scholar]
  3. 3.  Wright EM, Loo DD, Hirayama BA 2011. Biology of human sodium glucose transporters. Physiol. Rev. 91:733–94
    [Google Scholar]
  4. 4.  Hummel CS, Lu C, Loo DD et al. 2011. Glucose transport by human renal Na+/D-glucose cotransporters SGLT1 and SGLT2. Am. J. Physiol. Cell Physiol 300:C14–21
    [Google Scholar]
  5. 5.  Vallon V, Platt KA, Cunard R et al. 2011. SGLT2 mediates glucose reabsorption in the early proximal tubule. J. Am. Soc. Nephrol. 22:104–12
    [Google Scholar]
  6. 6.  Gallo LA, Wright EM, Vallon V 2015. Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences. Diabetes Vasc. Dis. Res. 12:78–89
    [Google Scholar]
  7. 7.  Ferrannini E 2017. Sodium-glucose co-transporters and their inhibition: clinical physiology. Cell Metab 26:27–38
    [Google Scholar]
  8. 8.  Ehrenkranz RRL, Lewis NG, Kahn CR et al. 2005. Phlorizin: a review. Diabetes Metab. Res. Rev. 21:31–38
    [Google Scholar]
  9. 9.  Brazy PC, Dennis VW 1978. Characteristics of glucose-phlorizin interactions in isolated proximal tubules. Am. J. Physiol. 234:F279–86
    [Google Scholar]
  10. 10.  Rossetti L, Smith D, Shulman GI et al. 1987. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J. Clin. Invest. 79:1510–15
    [Google Scholar]
  11. 11.  Dimitrakoudis D, Vranic M, Klip A 1992. Effects of hyperglycemia on glucose transporters of the muscle: use of the renal glucose reabsorption inhibitor phlorizin to control glycemia. J. Am. Soc. Nephrol. 3:1078–91
    [Google Scholar]
  12. 12.  Thorens B, Mueckler M 2010. Glucose transporters in the 21st century. Am. J. Physiol. Endocrinol. Metab. 298:E141–45
    [Google Scholar]
  13. 13.  Ferrannini E, Solini A 2012. SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nat. Rev. Endocrinol. 8:495–502
    [Google Scholar]
  14. 14.  Heerspink HJ, Perkins BA, Fitchett DH et al. 2016. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation 134:752–72
    [Google Scholar]
  15. 15.  Kramer CK, Zinman B 2016. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors in patients with type 2 diabetes mellitus: the road ahead. Eur. Heart J. 37:3201–2
    [Google Scholar]
  16. 16.  Liu JJ, Lee T, DeFronzo RA 2012. Why do SGLT2 inhibitors inhibit only 30–50% of renal glucose reabsorption in humans?. Diabetes 61:2199–204
    [Google Scholar]
  17. 17.  Komoroski B, Vachharajani N, Boulton D 2009. Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin. Pharmacol. Ther. 85:520–26
    [Google Scholar]
  18. 18.  Grempler R, Thomas L, Eckhardt M et al. 2012. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes. Metab. 14:83–90
    [Google Scholar]
  19. 19.  Mudaliar S, Polidori D, Zambrowicz B et al. 2015. Sodium-glucose cotransporter inhibitors: effects on renal and intestinal glucose transport: from bench to bedside. Diabetes Care 38:2344–53
    [Google Scholar]
  20. 20.  Clar C, Gill JA, Court R et al. 2012. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open 2:e001007
    [Google Scholar]
  21. 21.  Musso G, Gambino R, Cassader M et al. 2012. A novel approach to control hyperglycemia in type 2 diabetes: sodium glucose co-transport (SGLT) inhibitors: systematic review and meta-analysis of randomized trials. Ann. Med. 44:375–93
    [Google Scholar]
  22. 22.  Stenlöf K, Cefalu WT, Kim KA et al. 2013. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes. Metab. 5:372–82
    [Google Scholar]
  23. 23.  Rosenstock J, Jelaska A, Frappin G et al. 2014. Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes Care 37:1815–23
    [Google Scholar]
  24. 24.  Ridderstråle M, Andersen KR, Zeller C et al. 2014. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol 2:691–700
    [Google Scholar]
  25. 25.  Vasilakou D, Karagiannis T, Athanasiadou E et al. 2013. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann. Intern. Med. 159:262–74
    [Google Scholar]
  26. 26.  Barnett AH, Mithal A, Manassie J et al. 2014. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2:369–84
    [Google Scholar]
  27. 27.  Shyangdan DS, Uthman OA, Waugh N 2016. SGLT-2 receptor inhibitors for treating patients with type 2 diabetes mellitus: a systematic review and network meta-analysis. BMJ Open 6:e009417
    [Google Scholar]
  28. 28.  Zaccardi F, Webb DR, Htike ZZ et al. 2016. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes. Metab. 18:783–94
    [Google Scholar]
  29. 29.  Zhang L, Feng Y, List J et al. 2010. Dapagliflozin treatment in patients with different stages of type 2 diabetes mellitus: effects on glycaemic control and body weight. Diabetes Obes. Metab. 12:510–16
    [Google Scholar]
  30. 30.  Liu XY, Zhang N, Chen R et al. 2015. Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes: a meta-analysis of randomized controlled trials for 1 to 2 years. J. Diabetes Complicat. 29:1295–303
    [Google Scholar]
  31. 31.  Dagogo-Jack S, Liu J, Eldor R et al. 2018. Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: the VERTIS SITA2 placebo-controlled randomized study. Diabetes Obes. Metab. 20:530–40
    [Google Scholar]
  32. 32.  Rosenstock J, Frias J, Páll D et al. 2018. 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. 20:520–29
    [Google Scholar]
  33. 33.  Ferrannini G, Hach T, Crowe S et al. 2015. Energy balance after sodium-glucose cotransporter 2 inhibition. Diabetes Care 38:1730–35
    [Google Scholar]
  34. 34.  Mazidi M, Rezaie P, Gao HK et al. 2017. Effect of sodium-glucose cotransport-2 inhibitors on blood pressure in people with type 2 diabetes mellitus: a systematic review and meta-analysis of 43 randomized control trials with 22 528 patients. J. Am. Heart Assoc. 6:6e004007
    [Google Scholar]
  35. 35.  Baker WL, Buckley LF, Kelly MS et al. 2017. Effects of sodium-glucose cotransporter 2 inhibitors on 24-hour ambulatory blood pressure: a systematic review and meta-analysis. J. Am. Heart Assoc. 6:5e005686
    [Google Scholar]
  36. 36.  Zhao Y, Xu L, Tian D et al. 2018. Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid level: a meta-analysis of randomized controlled trials. Diabetes Obes. Metab. 20:458–62
    [Google Scholar]
  37. 37.  Kramer CK, von Mühlen D, Jassal SK et al. 2010. A prospective study of uric acid by glucose tolerance status and survival: the Rancho Bernardo Study. J. Intern. Med. 267:561–66
    [Google Scholar]
  38. 38.  Kramer CK, von Mühlen D, Jassal SK et al. 2009. Serum uric acid levels improve prediction of incident type 2 diabetes in individuals with impaired fasting glucose: the Rancho Bernardo Study. Diabetes Care 32:1272–73
    [Google Scholar]
  39. 39.  Ferrannini E, Muscelli E, Frascerra S et al. 2014. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J. Clin. Investig. 124:499–508
    [Google Scholar]
  40. 40.  Bonner C, Kerr-Conte J, Gmyr V et al. 2015. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat. Med. 21:512–17
    [Google Scholar]
  41. 41.  Polidori D, Sha S, Mudaliar S et al. 2013. Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion: results of a randomized, placebo-controlled study. Diabetes Care 36:2154–61
    [Google Scholar]
  42. 42.  Merovci A, Solis-Herrera C, Daniele G et al. 2014. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J. Clin. Investig. 124:509–14
    [Google Scholar]
  43. 43.  Cefalu WT, Leiter LA, Yoon KH et al. 2013. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 382:9896941–50
    [Google Scholar]
  44. 44.  Barnett AH, Mithal A, Manassie J et al. 2014. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2:5369–84
    [Google Scholar]
  45. 45.  Wanner C, Inzucchi SE, Lachin JM et al. 2016. Empagliflozin and progression of kidney disease in type 2 diabetes. N. Engl. J. Med. 375:4323–34
    [Google Scholar]
  46. 46.  Neal B, Perkovic V, Mahaffey KW et al. 2017. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N. Engl. J. Med. 377:644–57
    [Google Scholar]
  47. 47.  Jardine MJ, Mahaffey KW, Neal B et al. 2017. The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study rationale, design, and baseline characteristics. Am. J. Nephrol. 46:6462–72
    [Google Scholar]
  48. 48.  Gerstein HC, Miller ME, Byington RP et al. 2008. Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J. Med. 358:2545–59
    [Google Scholar]
  49. 49.  Patel A, MacMahon S, Chalmers J et al. 2008. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 358:2560–72
    [Google Scholar]
  50. 50.  US Food Drug Admin 2008. Guidance for industry: diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes Guid. Ind., Cent. Drug Eval. Res., US Food Drug Admin., US Dep Health Hum. Serv Silver Spring, MD: https://www.fda.gov/downloads/Drugs/Guidances/ucm071627.pdf
    [Google Scholar]
  51. 51. WHO (World Health Organ.). 2016. Global report on diabetes WHO, Geneva. http://www.who.int/diabetes/global-report/en/
    [Google Scholar]
  52. 52.  Zinman B, Wanner C, Lachin JM et al. 2015. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373:222117–28
    [Google Scholar]
  53. 53.  Inzucchi SE, Zinman B, Fitchett D et al. 2018. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care 41:356–63
    [Google Scholar]
  54. 54.  Kosiborod M, Cavender MA, Fu AZ et al. 2017. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation 136:249–59
    [Google Scholar]
  55. 55.  Birkeland KI, Jørgensen ME, Carstensen B et al. 2017. Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): a multinational observational analysis. Lancet Diabetes Endocrinol 5:709–17
    [Google Scholar]
  56. 56.  Peters AL, Buschur EO, Buse JB et al. 2015. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care 38:1687–93
    [Google Scholar]
  57. 57.  Hayami T, Kato Y, Kamiya H et al. 2015. Case of ketoacidosis by a sodium-glucose cotransporter 2 inhibitor in a diabetic patient with a low-carbohydrate diet. J. Diabetes Investig. 6:587–90
    [Google Scholar]
  58. 58.  Perkins BA, Cherney DZ, Partridge H et al. 2014. Sodium-glucose cotransporter 2 inhibition and glycemic control in type 1 diabetes: results of an 8-week open-label proof-of-concept trial. Diabetes Care 37:51480–83
    [Google Scholar]
  59. 59.  Henry RR, Rosenstock J, Edelman S et al. 2015. Exploring the potential of the SGLT2 inhibitor dapagliflozin in type 1 diabetes: a randomized, double-blind, placebo-controlled pilot study. Diabetes Care 38:3412–19
    [Google Scholar]
  60. 60.  Cherney DZ, Perkins BA, Soleymanlou N et al. 2014. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 129:5587–97
    [Google Scholar]
  61. 61.  Inzucchi SE, Iliev H, Pfarr E et al. 2018. Empagliflozin and assessment of lower-limb amputations in the EMPA-REG OUTCOME trial. Diabetes Care 41:1e4–5
    [Google Scholar]
  62. 62.  Taylor SI, Blau JE, Rother KI 2015. Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol 3:18–10
    [Google Scholar]
  63. 63.  Qaseem A, Barry MJ, Humphrey LL et al. 2017. Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline update from the American College of Physicians. Ann. Intern. Med. 166:4279–90
    [Google Scholar]
  64. 64. Am. Diabetes Assoc 2018. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2018. Diabetes Care 41:Suppl. 1S73–85
    [Google Scholar]
/content/journals/10.1146/annurev-med-042017-094221
Loading
/content/journals/10.1146/annurev-med-042017-094221
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error