R3i Editorials

Residual vascular risk in chronic kidney disease: new options on the horizon
Prof. Michel Hermans, Prof. Pierre Amarenco

Chronic kidney disease (CKD) is increasingly recognized as a worldwide health concern. Whereas there has been a general decline in rates of death and disability-adjusted life years due to non-communicable diseases, such favourable trends do not exist for CKD 1. With the escalating pandemics of obesity and diabetes, as well as aging societies, CKD now affects about 11-15% of people globally 2,3. While type 2 diabetes mellitus (T2DM) is a major risk factor for CKD, non-diabetic patients are also at risk. Thus, CKD represents an important unmet clinical need warranting urgent action.

Positive news comes from the newer glucose-lowering agents which have shown favourable effects on both renal and cardiovascular outcomes. The sodium-glucose co-transporter-2 (SGLT-2) inhibitors – canagliflozin, dapagliflozin, empagliflozin –demonstrated benefit (either superior or non-inferior versus placebo) in terms of reductions in major adverse cardiovascular events, as well as hospitalization for heart failure (4-6), supporting updates to guideline recommendations for the management of T2DM patients. Added to this, there is also evidence of renal benefit from major outcomes studies. The CREDENCE (Canagliflozin and Renal Events in Diabetes and Established Nephropathy Clinical Evaluation) study in patients with T2DM was stopped early for efficacy, showing a 30% reduction in the primary composite outcome (a composite of end-stage kidney disease [ESKD], doubling of serum creatinine, or death from kidney or cardiovascular causes), as well as 34% reduction in the primary kidney disease-related composite endpoint (as defined above, excluding death from cardiovascular causes) with canagliflozin 7.

Two later large-scale trials with SGLT-2 inhibitors also included non-diabetic patients. The first of these, DAPA-CKD in 2,152 patients was also stopped early due to efficacy, demonstrating 42% reduction in the primary composite endpoint (sustained decline in estimated glomerular filtration [eGFR] of at least 50%, ESKD, or death from renal or cardiovascular causes) in patients with and without T2DM 8. Most recently, EMPA-KIDNEY, which differed from both CREDENCE and DAPA-CKD by including patients with and without T2DM with lower mean eGFR, was also stopped early due to efficacy 9. While full publication is awaited, the results of all three trials have important clinical implications for the management of residual vascular risk – including CKD progression – among high-risk patients with and without diabetes.

Beyond these novel glucose-lowering therapies, there is also potential offered by lipid-modifying therapies. Dysregulation of lipid metabolism in CKD results in a dyslipidemia characterized by low plasma levels of high-density lipoprotein cholesterol and elevated triglycerides, usually with normal levels of low-density lipoprotein cholesterol (10). This dyslipidemia is associated with progression of declining kidney function due to deposition of lipids in the kidney (10,11). While the combination of a statin and ezetimibe has shown cardiovascular benefit in dyslipidemic patients with CKD, a high residual risk persists 12. Findings from clinical trials with the novel selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) pemafibrate are promising. Concomitant CKD did not decrease the efficacy of pemafibrate on top of statin therapy 13. Pemafibrate was also well tolerated with no worsening of eGFR in patients with moderate or severe renal impairment 13. The PROMINENT trial will provide important insights as to whether pemafibrate reduces cardiovascular events in patients with CKD.

There is new hope on the horizon for the management of residual cardiorenal risk. The SGLT-2 inhibitors represent one option to address the unmet clinical needs among patients with CKD, irrespective of concomitant T2DM. Added to this, there are novel approaches such as non-steroidal mineralocorticoid receptor antagonist finerenone, as well as the SPPARMα pemafibrate, a first-in-a class agent to manage atherogenic dyslipidemia associated with CKD. Together, these treatments have important implications for reducing the substantial burden of morbidity and mortality associated with CKD.

References

  1. Jager KJ, Fraser SDS. The ascending rank of chronic kidney disease in the global burden of disease study. Nephrol Dial Transplant 2017;32(suppl_2):ii121-ii128.
    2. Hill NR, Fatoba ST, Oke JL, et al. Global prevalence of chronic kidney disease – a systematic review and meta-analysis. Plos One 2016;117:e0158765.
    3. Jha V, Garcia-Garcia G, Iseki K. et al. Chronic kidney disease: global dimension and perspectives. Lancet 2013; 382: 260–272.
    4. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–2128.
    5. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377: 644–657.
    6. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347–335.
    7. 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.
    8. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436-1446.
    9. EMPA-KIDNEY. https://www.empakidney.org/news/empa-kidney-trial-stops-early-due-to-evidence-of-efficacy.
    10. Hager MR, Narla AD, Tannock LR. Dyslipidemia in patients with chronic kidney disease. Rev Endocr Metab Disord. 2017;18:29-40.
    11. Moorhead JF, Chan MK, El-Nahas M, et al. Lipid nephrotoxicity in chronic progressive glomerular and tubulo-interstitial disease. Lancet 1982;2:1309–1311.
    12. Stanifer JW, Charytan DM, White J, Lokhnygina Y, Cannon CP, Roe MT, Blazing MA. Benefit of ezetimibe added to simvastatin in reduced kidney function. J Am Soc Nephrol. 2017;28:3034-3043.
    13. Yokote K, Yamashita S, Arai H, Araki E, Suganami H, Ishibashi S, Of The K-Study Group OB. Long-term efficacy and safety of pemafibrate, a novel Selective Peroxisome Proliferator-Activated Receptor-α Modulator (SPPARMα), in dyslipidemic patients with renal impairment. Int J Mol Sci 2019;203.