EVIDENCE BASED

Cardiovascular Health In Chronic Kidney Disease: Improving outcomes using SGLT-2 Inhibitors

FIGURE 1  |  Renal and cardiac burden in CKD patients follow the same pathways with mutual aggravation

Stages of chronic kidney disease compared with the progression of cardio vascular disease

POTENTIAL DISRUPTION: SGLT-2 INHIBITORS

SGLT-2 inhibitors are a new class of medication initially developed to facilitate glycemic control in T2DM by inducing glucosuria.13 In less than a decade, they have become the first-in-class treatment for diabetes, with impressive results on glycemic and overall metabolic control and outcomes.14,15 SGLT-2 inhibitors are associated with unexpected protective results on cardiac outcomes in this highly vulnerable population.16 Recent studies have identified that SGLT-2 inhibitors are associated with positive clinical benefits in various chronic diseases, such as heart failure and CKD, even among individuals without T2DM.17,18

Gliflozins are specific glucoside-based inhibitors of sodium-glucose co-transporters (SGLT).19,20 Sodium-dependent glucose transporters are a member of the protein family consisting of SGLT-2 and SGLT-1 located in the proximal kidney tubule. SGLT-2 proteins are mainly located in the initial part of the proximal tubule involved in 90% of glucose reabsorption filtered back to the systemic circulation (Figure 2). Inhibition of SGLT-2 increases the urinary glucose excretion with significant glucosuria (50 to 80 g per day in normoglycemic conditions, and up to 100 or 120 g per day in hyperglycemic conditions), facilitating glycemic control and inducing caloric loss and starvation adaptation. SGLT-2 inhibition increases urinary flow through its osmotic action but also natriuresis by blocking glucose-sodium protein cotransporters.21 Increase of natriuresis delivery at the macula densa site results in a deactivation of the tubuloglomerular feedback mechanism mediated by vasoconstriction of the glomerular afferent arteriole. Therefore, glomerular hypertension and hyperfiltration decreases, contributing to reduced glomerular stress and proteinuria, a hallmark of kidney dysfunction in diabetes.

FIGURE 2  |  Tubular action of SGLT-2 inhibitors

Tubular action graphic of SGLT-2 inhibitors

As of August 2021, dapagliflozin, canagliflozin, empagliflozin, and ertugliflozin are approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of T2DM.

INNOVATION FOR T2DM PATIENTS WITH DIABETIC KIDNEY DISEASE

Four major randomized controlled trials revealed the clinical benefits of SGLT-2 inhibition in T2DM patients (Figure 3).22

In brief, dapagliflozin, empagliflozin, and canagliflozin have remarkable and consistent class effects on renal outcomes. Baseline renal filtration function and degree of proteinuria are the most significant indicators of risk for both renal and cardiovascular events.

FIGURE 3  |  Four major randomized controlled trials studied SGLT-2 inhibition in type 2 diabetes mellitus

 Major randomized controlled trials studied SGLT-2 inhibition in type 2 diabetes mellitus. The table has the Trial Name, Study Population, Outcomes and Risk Reduction.

BENEFITS FOR TREATING HEART FAILURE

Additional analysis of several SGLT-2 inhibitor trials shows a consistent benefit for treating patients with heart failure, in particular with reduced ejection fraction, and advanced kidney disease from DKD.23,24,25,26,27,28, 29,30,31 In these studies, recruited patients were receiving optimal treatment for T2DM and cardiac disease with SGLT-2 inhibitors considered an add-on treatment. In all studies, primary cardiac outcomes of cardiac death and hospitalization for heart failure were improved, with 15% risk reduction on average (range 3 to 25%) in patients receiving SGLT-2 inhibitors.

The ongoing Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) study is assessing the effects of dapagliflozin versus placebo in managing heart failure patients with preserved ejection fraction, using the same primary endpoint as the Dapagliflozin and Prevention of Adverse Outcomes (DAPA) in Heart Failure trial.32,33 This study will complement other cardiovascular outcome studies evaluating the benefits and risks of SGLT-2 inhibitors in various cardiac settings (e.g., acute decompensated heart failure, chronic reduced or preserved ejection fraction with and without T2DM). Findings of these studies may have enormous implications for future treatment approaches.34

TREATING NON-DIABETIC CHRONIC KIDNEY DISEASE

In the Multiple Daily Injections and Continuous Glucose Monitoring in Diabetes (DIAMOND) study, 58 CKD patients without diabetes (eGFR≥25 mL/min; m GFR 58 mL/min) with proteinuria (≥500-3500 mg/d, m 1110 mg/24h) receiving a renin-angiotensin system blockade agent were randomly assigned to receive dapagliflozin (10 mg/d) or a placebo.35 eGFR declined by –6.6 mL/min at week six in the dapagliflozin group, but this reduction was fully reversible within six weeks after dapagliflozin discontinuation. Body weight was reduced by 1.5 kg with dapagliflozin, while changes in blood pressure did not differ significantly between dapagliflozin and placebo treatment.

In the subanalysis of the DAPA in Chronic Kidney Disease (DAPA CKD) trial, of the 270 participants with IgA nephropathy (94% confirmed by previous biopsy), 137 were randomized to dapagliflozin and 133 to a placebo.36,37 In this IgA subgroup, mean eGFR was 43.8 mL/min and median urinary albumin-to-creatinine ratio was 900 mg/g. Composite renal outcomes consisted of sustained eGFR, proteinuria, ESKD, or renal death. Relative risk reduction in a 50% sustained decrease in eGFR, ESKD, or death from renal causes was 46%, 39% in death from cardiovascular causes, and 26% for proteinuria in patients receiving dapagliflozin.

In this perspective, the ongoing EMPA-KIDNEY study, exploring cardio-renal effects of empagliflozin in CKD patients irrespective of whether the individual has diabetes, will be of tremendous interest.38 Potential risks of temporary or sustained eGFR decline associated with SGLT-2 inhibitors use in CKD with or without proteinuria deserve further trials to precisely assess the safety and renal protective effects of these drugs.39

PLEIOTROPIC EFFECTS OF SGLT-2 INHIBITORS

Effects of SGLT-2 inhibitors are well documented and largely encompass their effects on glycemic homeostasis and DKD.40,41 SGLT-2 inhibitors facilitate glycemic control without stimulating insulin release, weight loss due to glucosuria and caloric loss, reduction of body fat facilitating insulin action, reductions of salt load and extracellular volume, lowering of systemic blood pressure, and reduction of glomerular pressure and filtration marked by a reduction of proteinuria.42 Interesting findings have been observed with proteinuric glomerular disease and CKD that require further confirmatory studies to defi ne new therapeutic options.

Beyond the scope of glycemic control and DKD, the use of SGLT-2 inhibitors is expanding with promising results in the treatment of other conditions such as heart failure and cardiorenal syndrome. Further studies are needed to validate safety of this approach in advanced kidney disease. SGLT-2 inhibitors are associated with sustained sodium removal facilitating restoration of the whole-body sodium homeostasis. Furthermore, SGLT-2 inhibitors induce profound metabolic changes including ketogenesis from liver and reprioritization of energetic oxidation metabolic pathways favoring cardiomyocytes activity and regenerative process. Interestingly, the common denominator and the main action point of SGLT-2 inhibitors seems to be a way of depleting total body salt excess, restoring sodium and water homeostasis that include sodium osmotically active (extracellular compartment) but also tissue sodium (third compartment of water-free sodium).43

SUMMARY

Despite significant progress in cardiovascular disease management for advanced CKD patients, cardiac health remains one of the main challenges in this highly vulnerable population. Therapeutic approaches to reduce cardiac burden and slow kidney disease progression have steadily improved over recent years by effectively addressing the deleterious mechanical effects of fluid excess and hypertension on cardiac and kidney end organ damage. In this context, RAAS blockade agents have slowed down this process, but they have not been sufficient to halt it. SGLT-2 inhibitors beyond glucosuria and throughout their pleiotropic actions, off er a new and complementary approach for improving cardiac health in CKD patients without T2DM.44 Ongoing studies focusing on low eGFR patients are exploring the benefits and risks of these medications.45

Meet The Experts

 

BERNARD CANAUD, MD, PhD
Senior Chief Scientist, Global Medical Office

ALLAN J. COLLINS, MD, FACP
Senior Chief Scientist, Global Medical Office

References

  1. Drawz PE, Rosenberg ME. Slowing progression of chronic kidney disease. Kidney Int Suppl (2011) 2013;3(4):372-6.
  2. Solomon R. New approach to slowing the progression of chronic kidney disease. Cardiorenal Med 2019;9(5):334-6.
  3. Kelly TN, Raj D, Rahman M, et al. The role of renin-angiotensin-aldosterone system genes in the progression of chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort (CRIC) study. Nephrol Dial Transplant 2015;30(10):1711-18.
  4. Remuzzi G, Perico N, Macia M, Ruggenenti P. The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease. Kidney Int Suppl 2005(99):S57-65. 
  5. MacIsaac RJ, Jerums G, Ekinci EI. Effects of glycaemic management on diabetic kidney disease. World J Diabetes 2017;8(5):172-86. 
  6. Ruospo M, Saglimbene VM, Palmer SC, et al. Glucose targets for preventing diabetic kidney disease and its progression. Cochrane Database Syst Rev 2017;6(6):Cd010137.
  7. Pugh D, Gallacher PJ, Dhaun N. Management of hypertension in chronic kidney disease. Drugs 2019;79(4):365-79.
  8. Hallan SI. Cardiovascular disease prevention in CKD. Am J Kidney Dis2014;64(3):326-8.
  9. Herzog CA, Asinger RW, Berger AK, et al. Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2011;80(6):572-86.
  10. Collins AJ. Cardiovascular mortality in end-stage renal disease. Am J Med Sci 2003;325(4):163-67.
  11. Sarnak MJ, Levey AS. Cardiovascular disease and chronic renal disease: a new paradigm. Am J Kidney Dis 2000;35(4 Suppl 1):S117-131.
  12. Jankowski J, Floege J, Fliser D, et al. Cardiovascular disease in chronic kidney disease: pathophysiological insights and therapeutic options. Circulation 2021;143(11):1157-72.
  13. Chao EC, Henry RR. SGLT2 inhibition—a novel strategy for diabetes treatment. Nat Rev Drug Discov 2010;9(7):551-9.
  14. Ferrannini E, Solini A. SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nat Rev Endocrinol 2012;8(8):495-502.
  15. Hsia DS, Grove O, Cefalu WT. An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes mellitus. Curr Opin Endocrinol Diabetes Obes 2017;24(1):73-9.
  16. Kluger AY, Tecson KM, Lee AY, et al. Class effects of SGLT2 inhibitors on cardiorenal outcomes. Cardiovasc Diabetol 2019;18(1):99.
  17. Fernandez-Fernandez B, Sarafidis P, Kanbay M, et al. SGLT2 inhibitors for non-diabetic kidney disease: drugs to treat CKD that also improve glycaemia. Clin Kidney J 2020;13(5):728-33.
  18. Miyata KN, Zhang S-L, Chan JSD. The rationale and evidence for SGLT2 inhibitors as a treatment for nondiabetic glomerular disease. Glomerular Diseases 2021;1(1):21-33.
  19. Chao, Henry. SGLT2 inhibition—a novel strategy.
  20. Kalra S. Sodium glucose co-transporter-2 (SGLT2) inhibitors: a review of their basic and clinical pharmacology. Diabetes Ther 2014;5(2):355-66.
  21. Chao, Henry. SGLT2 inhibition—a novel strategy.
  22. Information comes from: (DECLARE-TIMI 58) Mosenzon O, Wiviott SD, Cahn A, 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 randomised trial. Lancet Diabetes Endocrinol 2019;7(8):606-17. (EMPA-REG OUTCOME) Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375(4):323-(CANVAS-R) Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol 2018;6(9):691-704. (CREDENCE) Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380(24):2295-2306.
  23. Mosenzon O, Wiviott SD, Cahn A, 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 randomised trial. Lancet Diabetes Endocrinol 2019;7(8):606-17.
  24. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375(4):323-34.
  25. Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol 2018;6(9):691-704.
  26. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380(24):2295-2306.
  27. Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med 2020;383(15):1425-35.
  28. 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.
  29. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380(4):347-57.
  30. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2021;384(2):117-28.
  31. Anker SD, Butler J, Filippatos G, et al. Effect of empagliflozin on cardiovascular and renal outcomes in patients with heart failure by baseline diabetes status: results from the EMPEROR-Reduced trial. Circulation 2021;143(4):337-49.
  32. McMurray et al. Dapagliflozin in patients with heart failure.
  33. Williams DM, Evans M. Dapagliflozin for heart failure with preserved ejection fraction: will the DELIVER study deliver? Diabetes Ther 2020;11(10):2207-19.
  34. Joshi SS, Singh T, Newby DE, Singh J. Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure. Heart 2021;107(13):1032-38.
  35. Cherney DZI, Dekkers CCJ, Barbour SJ, et al. Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non-diabetic patients with chronic kidney disease (DIAMOND): a randomised, double-blind, crossover trial. Lancet Diabetes Endocrinol 2020;8(7):582-93.
  36. Heerspink HJL, Stefansson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383(15):1436-46.
  37. Wheeler DC, Toto RD, Stefansson BV, et al. A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int 2021;100(1):215-24.
  38. Herrington WG, Preiss D, Haynes R, et al. The potential for improving cardio-renal outcomes by sodium-glucose co-transporter-2 inhibition in people with chronic kidney disease: a rationale for the EMPA-KIDNEY study. Clin Kidney J 2018;11(6):749-61.
  39. Anders HJ, Peired AJ, Romagnani P. SGLT2 inhibition requires reconsideration of fundamental paradigms in chronic kidney disease, “diabetic nephropathy”, IgA nephropathy and podocytopathies with FSGS lesions. Nephrol Dial Transplant 2020;gfaa329.
  40. Kalra S. Sodium glucose co-transporter-2 (SGLT2) inhibitors.
  41. Lu H, Meyer P, Hullin R. Use of SGLT2 inhibitors in cardiovascular diseases: why, when and how? Swiss Med Wkly 2020;150:w20341.
  42. Kanduri SR, Kovvuru K, Hansrivijit P, et al. SGLT2 inhibitors and kidney outcomes in patients with chronic kidney disease. J Clin Med 2020;9(9):2723.
  43. Karg MV, Bosch A, Kannenkeril D, et al. SGLT-2-inhibition with dapagliflozin reduces tissue sodium content: a randomised controlled trial. Cardiovasc Diabetol 2018;17(1):5.
  44. Kanduri et al. SGLT2 inhibitors and kidney outcomes.
  45. Herrington. The potential for improving cardio-renal outcomes.