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More than the RAAS Blockade: Emerging Therapeutic Approaches for DKD Management

More than the RAAS Blockade: Emerging Therapeutic Approaches for DKD Management

The scope of the problem
Diabetic kidney disease (DKD) is one of the most common complications of diabetes, affecting up to 50% of diabetics, and leading to increased morbidity and mortality. DKD is the leading cause of dialysis-dependent chronic kidney disease (CKD) and end-stage renal disease (ESRD) in the US and in most countries.1 The coexistence of diabetes and kidney disease increases the risk of premature mortality and cardiovascular disease (CVD).1 Furthermore, DKD patients have other comorbidities, such as hypertension, obesity, and dyslipidemia, which can also contribute to its incidence and severity.2 As a result, the healthcare costs of DKD are estimated to be $43 billion annually in US, and the overall impacts of the disease are projected to increase.3
Due to the multiple comorbidities in patients with DKD, clinicians have to consider simultaneous approaches to preserve kidney function, including glucose and hypertension control, as well as treatment of dyslipidemia, which complicates the clinical management. Another major challenge in DKD is slowing the progression of the disease, given the very low survival rates in patients with diabetes and advanced-stage kidney disease.4 A great concern remains that despite optimized glycemic and blood pressure control using antihyperglycemic agents and RAAS inhibitors, many DKD patients still progress to kidney failure.4
The multifactorial management of DKD
Decreasing the incidence of end-stage renal disease depends on preventing new-onset diabetic nephropathy as well as preventing the progression of established diabetic nephropathy. However, major challenges associated with DKD management currently exist, including early diagnosis of at-risk patients, and lack of specific treatment options.5 DKD is characterized not only by decreased glomerular filtration rate (GFR), but also persistent proteinuria and high blood pressure.
Increased intraglomerular capillary pressure has been characterized as one of the underlying pathophysiologies of chronic kidney disease and lowering this pressure has been the target of clinical trials with renin-angiotensin-aldosterone system (RAAS) inhibitors.6 Indeed, several trials have shown that RAAS inhibitors, particularly angiotensinconverting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), reduce kidney disease events in patients with stage 3 CKD who have concurrent diabetes and hypertension.6 As a result, the use of ACE inhibitors or ARBs is recommended to lower hypertension in DKD patients, and they have also been shown to slow DKD progression.7 However, the combination of ACE inhibitors and ARBs is generally contraindicated due to increased risk of renal failure.7 Patients with T2DM have a significantly increased risk of atherosclerotic cardiovascular disease, which should be adequately controlled. Early intensive management of dyslipidemia is warranted to prevent macrovascular disease, and treatment to lower levels of LDL cholesterol is indicated. Current guidelines recommend the use of statins in diabetic patients with non-dialysis dependent CKD, as statins have been shown to decrease albuminuria in these patients.6
Maintaining glycemic goals is crucial in controlling the progression of DKD.7 Due to the plethora of antihyperglycemic drugs, it can be challenging for clinicians to recommend a specific regimen in the context of CKD, since many of these drugs are renally cleared and may require dose adjustments. Additionally, clinical practice guidelines are not specific when it comes to antihyperglycemic medications in DKD patients. Recently, some agents, such as sodium-glucose co-transporter 2 (SGLT-2) inhibitors (empagliflozin and canagliflozin) and the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide, in addition to glycemic control, have been shown to improve risk of worsening nephropathy and albuminuria progression in DKD.7
The promise of SGLT-2 inhibitors and GLP-1 receptor agonists
Encouraging results stemming from secondary analyses of cardiovascular outcome trials (CVOTs) with SGLT-2 inhibitors empagliflozin and canagliflozin, and GLP-1 RA liraglutide suggest that these agents may have a role in the management of DKD. SGLT-2 is a glucose transporter located in the proximal tubule of the kidney that is responsible for 90% of glucose reabsorption. SGLT-2 inhibitors block the reabsorption of glucose in the kidney, thereby increasing glucose excretion. In an analysis of prespecified secondary endpoints of the EMPA-REG OUTCOME study, empagliflozin was associated with slower progression of kidney disease and lower rates of clinically relevant renal events than placebo when added to standard care.8 Incident or worsening nephropathy occurred in 525 of 4124 patients (12.7%) in the empagliflozin group and in 388 of 2061 patients (18.8%) in the placebo group (hazard ratio, 0.61; P ≤ 0.001). In addition, doubling of the serum creatinine level occurred in 70 of 4645 patients (1.5%) in the active treatment group, vs in 60 of 2323 (2.6%) in the placebo group (relative risk reduction of 44%). Renalreplacement therapy was initiated in 13 of 4687 patients (0.3%) in the empagliflozin group and in 14 of 2333 patients (0.6%) in the placebo group (55% lower relative risk).8 An additional sub-analysis of this trial showed that empagliflozin reduced risk of cardiovascular death, all-cause mortality, and HF hospitalizations in type 2 diabetics with advanced (GFR < 60 mL/min) kidney disease.9 Results from the CANVAS-R trial demonstrated that treatment with SGLT-2 inhibitor canagliflozin was associated with a lower risk of progression of albuminuria, decreased GFR, need for renal-replacement therapy, or renal-caused mortality.10 However, renal effects were not the primary endpoint in these trials or they may not have been sufficiently powered to draw definitive conclusions, emphasizing a need for additional studies with a greater proportion of DKD patients. Indeed, larger clinical trials to evaluate whether canagliflozin, empagliflozin, and another SGLT-2 inhibitor, dapagliflozin, confer renoprotective effects in T2DM patients with CKD are currently ongoing.
A prespecified secondary analysis of the LEADER trial showed that liraglutide significantly reduced the risk of adverse renal outcomes compared with placebo in patients with T2DM and high cardiovascular risk who were receiving usual care.11 These outcomes included a composite of new-onset persistent macroalbuminuria (urinary albumin excretion rate > 300 mg/day), persistent doubling of the serum creatinine level, ESRD, or death due to renal disease. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed. At a median follow-up of 3.84 years, 22% fewer patients of 4,668 assigned to liraglutide reached the composite endpoint compared with 4672 patients receiving placebo (5.7% vs 7.2%; hazard ratio, 0.78; P = 0.003). According to the authors, the lower risk of developing the composite renal outcome with liraglutide was mainly due to a lower rate of new-onset persistent macroalbuminuria, with 26% fewer patients in the liraglutide group developing this complication vs those in the placebo group (3.4% vs 4.6%; HR, 0.74, P = 0.004).11
New frontiers
Although ACE inhibitors and ARBs have proven effective in reducing progression to advanced albuminuria in DKD, they do not slow progression to ESRD (ADA Standards of Care 2018). This incomplete effectiveness may be due to lack of inhibition of aldosterone, which has known detrimental effects to kidney function.12 Currently, the therapies to manage DKD mainly include addressing metabolic comorbidities and hypertension, but do not sufficiently address the kidney dysfunction.4,5 Some of these treatments may increase the levels of aldosterone, which in turn can exacerbate proteinuria and kidney damage.12 The results with SGLT-2 inhibitors and GLP-1 RAs, although promising, need to be evaluated in trials where the kidney outcomes are the primary endpoint.4 Additionally, the specific mechanisms of action of the renal benefits of GLP-1 RAs have not been fully elucidated. Due to the insufficiency of current pharmacological treatments, many patients with DKD ultimately progress to kidney failure despite optimal blood pressure and glycemic control, suggesting the need for additional therapies and therapeutic targets to improve this prognosis.4
As a result, several new therapies that target additional pathways involved in ESRD progression are currently in clinical development. Among them, mineralocorticoid receptor antagonists (MRAs) are currently being investigated due to their ability to block aldosterone signaling. Aldosterone acts via the mineralocorticoid receptor to regulate sodium balance but can also cause kidney inflammation and fibrosis.12 Steroidal MRAs, such as spironolactone and eplerenone, have been shown to reduce proteinuria, but they increase hyperkalemia, which can worsen CKD progression.12 In turn, non-steroidal MRA finerenone has decreased risks of hyperkalemia and has been shown to improve kidney outcomes in diabetic patients. The phase IIb trial ARTS-DN (ARTS-Diabetic Nephrophathy) analyzed the safety and efficacy of finerenone in diabetic patients with high or very high albuminuria receiving an ACEi or ARB.13 Results from this trial showed that finerenone decreased albuminuria in a dose-dependent manner with fewer incidents of hyperkalemia compared to placebo.13 The potential of finerenone in the treatment of DKD is currently being investigated in a large phase III trial (FIDELIO-DKD), with the primary endpoint being the composite onset of kidney failure for a follow up period of 48 months.12 Two additional trials, the phase III FIGARODKD trial, and the planned FINESSE-HF, will evaluate the role of this agent on reducing the cardiovascular morbidity and mortality in T2DM patients with a DKD diagnosis, and in patients with chronic heart failure with reduced ejection fraction and T2DM with or without CKD, respectively.12 The results from these trials will provide key data about the utility of finerenone in treating DKD and its associated cardiovascular morbidity and mortality.
Blocking the endothelin receptor is another potential new target in DKD. The rationale is that endothelin-1, acting via the endothelin receptor, is a potent mediator of kidney injury in diabetes, and blocking endothelin signaling may improve DKD.14 Indeed, promising results have been shown with endothelin receptor antagonist, atrasentan. This agent reduced proteinuria in patients with T2DM and nephropathy already on optimized ACEi/ ARB therapy in a phase II study.14 In addition, atrasentan has benefits on blood pressure and lipid profile in T2DM patients, which are known risk factors for CKD progression.14 Currently, the effect of atrasentan in reducing the risk of CKD progression in patients with T2DM already on optimized background ACEi/ARB therapy is being evaluated in a phase III trial.15
Additionally, several other potential pathways that may play a role in the advancement of DKD, such as immune pathways and inflammation are being investigated in the early phase clinical trials. Immune activation and inflammation have been shown to lead to kidney fibrosis and ultimately kidney failure through a variety of potential pathways: increasing oxidative stress, activation of the JAK/STAT pathway, transcription factors, release of inflammatory cytokines, glycosylation and advanced glycosylation end products (AGE).16 As such, a new wave of agents that target several steps in the immunity and inflammation cascade, such as chemokine receptor antagonists, antioxidants, JAK/STAT inhibitors, glycation and AGE inhibitors, may show promise in DKD treatment. One particular agent, monocyte chemoattractant-1 (MCP-1) receptor antagonist CCX140 reduced albuminuria in T2DM patients on ACEi/ARB therapy, suggesting that this may be a viable treatment target.17 However, the results of these trials, and subsequent larger trials, will determine the utility of these additional targets in DKD treatment.
The prevalence of DKD has increased in the recent years and it remains a major health problem with significant financial impacts to the US economy. The complicated pathophysiology of the condition and the insufficiency of current treatments are major barriers that clinicians face in reducing DKD progression, morbidity and mortality. The management of hypertension and hyperglycemia, in addition to other cardiometabolic risk factors, play an important role in controlling the incidence or progression of kidney disease in type 2 diabetes. However, even with optimal glycemic and blood pressure control, many patients progress to kidney failure. Newer anti-hyperglycemic agents, such as SGLT-2 inhibitors and GLP-1 RAs have shown promising results in DKD patients. Additionally, mineralocorticoid receptor and endothelin receptor antagonists, as well as agents that target immune activation and inflammation are in clinical development and may provide additional options for the management of DKD in the near future.


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    October 2019 | Vol. 2 Q4