Diabetes mellitus (DM) is a highly prevalent disease, encompassing 34.2 million (10.5%) of the US population and an estimated 415 million people worldwide.^1,2 One of the most common complications of diabetes is chronic kidney disease (CKD), and diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) in the US, accounting for >45% of all cases.³ However, not only is DKD a major contributor to CKD and ESRD, it also portends worse outcomes with a five-year survival rate of <40% in ESRD patients.⁴ Furthermore, DKD has been shown to be a large contributor to the excess risk for all-cause and cardiovascular disease-related mortality amongst type 2 diabetic patients.⁵ With the worldwide prevalence of diabetes estimated to increase to 642 million in 2040 (and along with it, DKD)² despite the use of current anti-diabetic agents such as insulin and metformin, there clearly exists a great need for novel therapies to help target progression of this large and significant chronic disease entity.

One such novel therapy that has garnered considerable attention are the class of medications known as the sodium-glucose co-transporter 2 (SGLT2) inhibitors. By inhibiting this co-transporter located in the proximal convoluted tubule of the nephron, it is possible to inhibit the reabsorption of about 90% of the glucose filtered via the glomerulus every day. Furthermore, this class of medication also helps to decrease sodium reabsorption and decrease glomerular hyperfiltration.⁶

Three recent major trials investigating the SGLT2 inhibitors have shown considerable impact on cardiovascular outcomes in diabetic patients. The Empagliflozin Cardiovascular Outcomes and Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME)⁷ trial and the Canagliflozin Cardiovascular Assessment Study (CANVAS)⁸ trial both demonstrated statistically significant reductions in their primary composite outcome of cardiovascular-related death, nonfatal myocardial infarction, and nonfatal stroke. The EMPA-REG OUTCOME trial demonstrated a 14% reduction in the primary composite outcome (n = 7,020; HR 0.86 [95% CI] 0.74-0.99; p = 0.04 for superiority), as did the CANVAS trial (n = 10,142; HR 0.86 [95% CI] 0.75-0.97; p = 0.02 for superiority), for their respective SGLT2 inhibitor versus placebo.^7,8 The Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infraction 58 (DECLARE-TIMI 58)⁹ trial demonstrated non-inferiority of dapagliflozin versus placebo for their similar primary composite outcome of major adverse cardiovascular events (n = 17,160; HR 0.93 [CI 0.84-1.03]; p < 0.001 for noninferiority).⁹

In addition, these trials have also demonstrated improvement in renal outcomes in diabetic patients as well. Exploratory endpoints from the EMPA-REG OUTCOME and CANVAS trial showed decreased albuminuria, while the CANVAS and DECLARE-TIMI58 trial also showed decreased composite renal outcomes of 40% reduction in estimated glomerular filtration rate (eGFR), initiation of renal-replacement therapy, and CKD related death.^7-9 However, these trials were not designed to address the possible reno-protective effects of the SGLT2 inhibitors because the participants enrolled were at relatively low risk for progression to kidney failure. The EMPA-REG OUTCOME and DECLARE-TIMI58 trials reported that 74% and 93% of their patient populations, respectively, had baseline eGFR levels of ≥60 mL/min/1.73 m² (Stage I-II CKD).^7,9 Furthermore, in terms of albuminuric kidney disease, the EMPA-REG OUTCOME and CANVAS trials reported that 88.1% and 92.4%, respectively, had urinary albumin-to-creatinine ratio levels of ≤300 mg/g (normo-to-microalbuminuria).^7,8 As such, only a small number of trial patients reached end-stage kidney disease endpoints.

Given the promising findings of these prior studies, the Canagliflozin and Renal Events in Diabetes and Nephropathy Clinical Evaluation (CREDENCE)¹⁰ trial was specifically designed to more definitively determine whether SGLT2-inhibitors could improve renal outcomes in a more advanced, high-risk DKD population. This prospective, double-blinded, randomized, event-driven, placebo-controlled trial recruited 4401 patients that had type 2 diabetes with albuminuric kidney disease, specifically with HbA1c levels between 6.5 to 12.0%, eGFR's between 30 to < 90 mL/min/1.73 m² (Stage II-III CKD), and urinary albumin-to-creatinine ratios of >300 to 5000 mg/g (macroalbuminuria). While previous trials had only stipulated for a population with eGFR ≥30 mL/min/1.73 m², the CREDENCE trial included a prespecified plan to include approximately 60% of patients with eGFR's 30 to <60 mL/min/1.73 m² or in other words, a majority Stage III CKD population. Moreover, this study required all participants to already be on maximally tolerated angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker therapy, the only approved reno-protective medication for diabetic nephropathy. The primary outcome of the study was a composite of ESRD (defined as dialysis or eGFR <15 ml/min/1.73 m² for ≥30 days), doubling of baseline serum creatinine level, or death from renal or cardiovascular disease.

The CREDENCE trial was initially predicted to have a total study duration of 5 years. However, the trial was stopped early at around 2.5 years after an interim analysis showed clear benefit for the primary outcome. The group receiving canagliflozin showed a significantly lower event rate for the primary composite outcome compared to the placebo group, with a hazard ratio of 0.70 (95% CI 0.59-0.82; p = 0.00001). The beneficial effect of canagliflozin also held true for each individual renal components of the primary outcome. The CREDENCE trial also demonstrated benefit in the composite outcome for cardiovascular death, myocardial infarction, or stroke (HR 0.80 [CI 0.67-0.95]; p=0.01), as well as for heart failure hospitalization (HR 0.61 [95% CI] 0.47-90.8; p < 0.001), in accordance with the results of three major trials preceding it. Interestingly, these benefits were observed despite modest group differences in blood glucose and blood pressure, suggesting that the mechanism of SGLT2 inhibitor benefit may actually be independent of blood glucose and instead rely on decreases in glomerular hyperfiltration. The analysis found no significant differences in adverse effects between canagliflozin and placebo, including the increased risk for amputation observed in the CANVAS trial.⁸

The conclusions of the CREDENCE trial are certainly exciting for clinicians managing DKD. The trial strengthens the preliminary results of those before it,¹¹ confirming that canagliflozin does have significant benefits in both renal and cardiovascular outcomes even in individuals with more advanced DKD. The fact that this benefit is observed even on a background of maximal ACE-I/ARBs use is encouraging that we may soon expand our currently scarce selection of reno-protective agents in diabetes. Furthermore, the glycemic-independent effect suggests there may be potential for this agent to be used in non-diabetic kidney disease as well. Limitations of the study include early cessation limiting the power for its secondary outcomes; inability to extrapolate the benefits to all SGLT2 inhibitors; and exclusion of patients with eGFR <30 mL/min/1.73 m², non-to-micro-albuminuric disease, and types of kidney disease other than due to type 2 diabetes. Indeed, ongoing studies are exploring the benefits of SGLT2 inhibitors in more advanced DKD populations with eGFR thresholds beyond that of current dosing recommendations,¹² as well as non-diabetic chronic kidney disease patients. One such trial, the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, addresses the efficacy of dapagliflozin at reducing a similar primary composite outcome as the CREDENCE trial in patients with albuminuric, primarily stage III-IV CKD versus placebo, but with an enrollment plan to include at least 30% of patients without diabetes.¹³ We eagerly anticipate the published results of this trial after recent news that, like the CREDENCE trial before it, the DAPA-CKD trial has also been terminated early after showing overwhelming efficacy of its SGLT2 inhibitor in its CKD population.¹⁴ In addition, the Study of Heart and Kidney Protection with Empagliflozin (EMPA-KIDNEY) trial, which is actively enrolling participants, aims to provide further information on the efficacy and safety of empagliflozin in patients with and without diabetes and with established CKD, and will encompass participants with an even lower eGFR threshold (i.e., ≥20 mL/min/1.73 m²) than included in the aforementioned trials.¹⁵

References

1. National Diabetes Statistics Report (CDC website). 2020. Available at: https://www.cdc.gov/diabetes/data/statistics/statistics-report.html. Accessed 03/15/2020.
2. Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: challenges, progress, and possibilities. Clin J Am Soc Nephrol 2017;12:2032-45.
3. U.S. Renal Data System. 2019 USRDS Annual Data Report: Atlas of chronic kidney disease and end-stage renal disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2019.
4. U.S. Renal Data System. 2014 USRDS Annual Data Report: Atlas of chronic kidney disease and end-stage renal disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2014.
5. Rhee CM, Kovesdy CP, Ravel VA, et al. Association of glycemic status during progression of chronic kidney disease with early dialysis mortality in patients with diabetes. Diabetes Care 2017;40:1050-7.
6. Neumiller JJ, Alicic RZ, and Tuttle KR. Therapeutic considerations for antihyperglycemic agents in diabetic kidney disease. J Am Soc Nephrol 2017;28:2263-74.
7. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28.
8. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–57.
9. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347-57.
10. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295-2306.
11. Neumiller JJ, Rhee CM, Kalantar-Zadeh K. Will canagliflozin lend credence to the potential effects of sodium-glucose co-transporter 2 inhibitors on renal endpoints in diabetic nephropathy. Am J Nephrol 2017;46:459-61.
12. Rhee CM, Kovesdy CP, Ravel VA, et al. Glycemic status and mortality in chronic kidney disease according to transition versus nontransition to dialysis. J Ren Nutr 2019;29:82-90.
13. Heerspink HJL, Bergur SV, Chertow GM, et al. Rationale and protocol of the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) randomized controlled trial. Nephrol Dial Transpl 2020;35:274-82.
14. Kemp, A. Farxiga Phase III DAPA-CKD trial will be stopped early after overwhelming efficacy in patients with chronic kidney disease (AstraZeneca website). 2020. Available at: www.astrazeneca.com/media-centre/press-releases/2020/farxiga-phase-iii-dapa-ckd-trial-will-be-stopped-early-after-overwhelming-efficacy-in-patients-with-chronic-kidney-disease.html. Accessed 03/31/2020.
15. EMPA-Kidney (The Study of Heart and Kidney Protection with Empagliflozin). 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT03594110. Accessed 04/11/2020.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Lipid Metabolism

Keywords: Diabetes Mellitus, Metabolic Syndrome, Diabetic Nephropathies, Blood Glucose, Creatinine, Albuminuria, Diabetes Mellitus, Type 2, Hemoglobin A, Insulin, Sodium-Glucose Transporter 2, Metformin, Glomerular Filtration Rate

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