Antidiabetics charting new territory in renal preservation
Emerging evidence is showing that the two major new classes of antidiabetic drugs — SGLT2* inhibitors and GLP-1** receptor agonists (RAs) — not only confer cardiovascular (CV) benefits to patients with type 2 diabetes (T2D), they also delay the loss of kidney function among these patients, potentially providing nephrologists with an additional tool in their armamentarium for managing patients with chronic kidney disease (CKD) in the future.
“We recognize, as nephrologists, that the increased risk of CVD in our patients is not only driven by atherosclerotic but also nonatherosclerotic mechanism. What we need are drugs that reduce both the atherosclerotic and nonatherosclerotic endpoints in a CKD population,” said Dr David Wheeler of University College London in London, UK.
SGLT2i CVOTs: CV and renal outcomes
Two major CV outcome trials (CVOTs) of SGLT2 inhibitors — CANVAS and EMPA-REG, which included more than 2,000 T2D patients with CKD at baseline each — the CV benefits of the SGLT2 inhibitors studied were also seen in patients with CKD, consistent with the findings in the overall population, Wheeler pointed out.
Specifically, the CANVAS trial saw a 30 percent reduction in the risk of 3-point MACE*** of nonfatal MI, stroke, and CV death with canagliflozin in the CKD population; while there were risk reductions of 29 percent for CV death and 39 percent for hospitalization for heart failure (HHF) with empagliflozin in EMPA-REG. [Circulation 2018;138:1537-1550; Circulation 2018;137:119-129]
Although reduction of atherosclerotic complications has been the main focus of recent major trials, renal disease has remained a recalcitrant problem in diabetes and is still on the rise.
While Wheeler noted that the renal endpoints examined in the major SGLT2 inhibitors CVOTs were diverse, the signals in renal benefits are “fairly consistent” in terms of reduction in albuminuria, CKD progression (as indicated by eGFR#), and end-stage renal disease (ESRD) events.
The risk was reduced by 39 percent for incident or worsening nephropathy## with empagliflozin in EMPA-REG, by 40 percent for the composite endpoint of >40 percent reduction in eGFR, requirement for renal-replacement therapy (RRT) and death from renal cause with canagliflozin in CANVAS, and 24 percent reduction in renal-specific composite outcome### with dapagliflozin in DECLARE-TIMI 58. [N Engl J Med 2016;375:323-334; N Engl J Med 2017;377:644-657]
It was also revealed in the latest findings from DECLARE-TIMI 58, released in conjunction with the ADA 2019 Meeting, that the prespecified renal outcome of a sustained ≥40 percent decline in eGFR was 46 percent lower and the risk of ESRD or renal death was 59 percent lower with dapagliflozin vs placebo. [Lancet Diabetes Endocrinol 2019;doi:10.1016/S2213-8587(19)30180-9]
“There were consistent reductions in renal endpoints in these trials, with suggestion of attenuation of renoprotection at lower eGFR levels,” observed Wheeler.
Noting that the glycaemic benefit of SGLT inhibitors was also greater in those with more preserved eGFR (≥90 percent) as reported in a meta-analysis of the three major CVOTs above, [Lancet 2019;393:31-39] Wheeler said this suggests that the renoprotective effect of the drugs was independent of glycaemic benefit. “Renoprotection likely results from haemodynamic changes and may be independent from reductions in HbA1c.”
Similar findings with GLP-1 RAs
Consistent with the evidence from SGLT2 inhibitors, CVOTs with GLP-1 RAs also showed renal benefits with this drug class. The risk of composite renal outcomes+ was reduced by 22 percent (p=0.003) with liraglutide vs placebo in the LEADER trial, which was driven mainly by new-onset persistent macroalbuminuria (hazard ratio [HR], 0.74; p=0.004). [N Engl J Med 2017;377:839-848]
Similar findings were seen with semaglutide, whereby its renal benefits were mainly driven by reduction in persistent macroalbuminuria (HR, 0.54; p=0.001) in SUSTAIN 6; and with dulaglutide, whereby preservation of eGFR was most pronounce in patients with macroalbuminuria in the AWARD-7 study. [ADA 2019, abstract 233-OR]
“GLP-1 RAs are associated with reductions in nephropathy in T2D at high CV risk, with the major endpoint impacted being albuminuria-lowering,” summarized Dr Julie Lovshin from Sunnybrook Health Sciences Centre, Toronto, Canada.
However, she cautioned that the findings were not from dedicated renal outcome trials but from CV safety trials, in which renal outcomes are secondary endpoints. “Bear in mind that the population has largely preserved renal function, with preserved eGFR and minimal albuminuria,” she continued.
The same sentiment was echoed by Wheeler, who said, “Most trials exclude patients with advanced CKD, the very patients that nephrologists get referred.”
“Therefore, dedicated renal outcomes trials in T2D are warranted for these drugs,” said Lovshin.
Already, two trials of SGLT2 inhibitors — Dapa-CKD and EMPA-KIDNEY — are currently ongoing which involved patients with severe CKD with or without T2D, Wheeler pointed out. These studies will help shed light on the role of SGLT2 inhibitors in more severe CKD, including patients without diabetes.