Progress in the treatment of diabetic kidney disease: Feast after famine?

Reference: Sep-Oct 2024 | Issue 5 | Volume 17 | Page 29

The origin of the term ‘diabetes’ is an ancient one. Between the 1st and 2nd Century BCE, Demetrius of Apaemia is generally credited with deploying the term, διαβαίνω (diabaino), derived from an Ionic word meaning ‘to pass through’, as fluid through a syphon.¹ While definitive sources regarding etymology are elusive, the disease has doggedly troubled humanity for millennia. Diabetes and its complications reach across almost all medical specialities, and the battle to prevent, protect, and restore end-organ damage has produced a variety of treatments with various levels of success over recent decades.

The microvascular complications of diabetes include retinopathy, neuropathy, and diabetic kidney disease (DKD). DKD is one of the most severe complications of diabetes mellitus and is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) worldwide. The progressive nature of DKD, coupled with the increasing prevalence of diabetes, underscores the urgent need for effective management strategies. This article delves into these advancements, highlighting novel therapeutic approaches and comprehensive management strategies.

Understanding DKD globally and locally

DKD, also known as diabetic nephropathy, is usually characterised by persistent albuminuria or overt proteinuria, a progressive decline in glomerular filtration rate (GFR), and an increased risk of cardiovascular events. It develops in approximately 40 per cent of patients with diabetes and is a significant contributor to morbidity and mortality. Globally, the prevalence of CKD is approximately 10 per cent with around 30 per cent of all disability adjusted life years in CKD attributable to DKD.²

Last year, 2023, saw the release of Chronic Kidney Disease in Community-Dwelling Adults Aged 50+ Years in Ireland: A Report from TILDA and the National Renal Office.³ This analysis offered the first large population-based data set in the Republic of Ireland and made for interesting, albeit concerning, reading. The prevalence of CKD in adults in the community in Ireland aged 50 years or older was 11.7 per cent in 2009-2011, but rose to 15.6 per cent in 2014-2015. The national prevalence of CKD stage 3 or greater in individuals with diabetes mellitus was 25.21 per cent.

The apparent excess in prevalent CKD in Ireland compared to global figures is difficult to parse given the heterogeneous nature of the data used to compile global figures and estimates. However, the demographic trends unique to Ireland may explain part of this excess, with the percentage of those 65 or older growing faster than all comparative EU neighbours.⁴

The pathogenesis of DKD involves a complex interplay of metabolic, haemodynamic, and inflammatory factors. Hyperglycaemia, hypertension, and dyslipidaemia are key contributors, leading to glomerular hyperfiltration, increased permeability of the glomerular basement membrane, and tubulointerstitial fibrosis. Chronic inflammation and oxidative stress further exacerbate kidney damage, culminating in progressive renal function decline. The recognition and deeper understanding of this complicated milieu has led to advances in the application of novel agents to treat DKD.

Advances in therapeutic approaches

While the utility of optimum glycaemic control is established in reducing the likelihood of onset of DKD, in established disease it is of little utility in preventing progression. The treatment of DKD has evolved in the last decade beyond just glycaemic control and blood pressure management with the introduction of new therapeutic agents. These novel agents include sodium-glucose co-transporter (SGLT2) inhibitors, glucagon-like-peptide (GLP)-1 receptor agonists, and non-steroidal mineralocorticoid receptor antagonists (nsMRAs), amongst others. While most of these agents have been used for a variety of indications, recent trials with kidney-specific endpoints in populations with CKD have been published and strengthened the current trends in the clinical management of DKD.

1. SGLT2 inhibitors
Although SGLT-2 inhibitors were introduced in clinical practice to regulate hyperglycaemia in diabetes, it is now common knowledge that the beneficial effects of these agents on the kidney and cardiovascular system are independent of glucose-lowering. They exert pleiotropic responses including regulating renal epithelial cell integrity and inflammation. These agents reduce glucose reabsorption in the proximal tubules, leading to increased glycosuria, and reduce glomerular hyperfiltration via tubuloglomerular feedback.

While the nephroprotective effects of SGLT2 inhibitors were first noted as secondary endpoints of cardiovascular outcome trials, specific evidence for renal outcomes came from dedicated kidney-focused trials: CREDENCE, DAPA-CKD, and finally EMPAKIDNEY.^5,6,7 This class is also especially appropriate for those with concurrent heart failure, regardless of the level of albuminuria.

SGLT2 inhibitors and renin-angiotensin system (RAS) inhibitors – angiotensin-converting-enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) – have both been shown to delay the progression of CKD and remain the mainstay of treatment for the disease at present.

2. GLP-1 receptor agonists
GLP-1 receptor agonists, another class of antidiabetic agents, have shown promise in the management of DKD, again independent of the effect on glycaemic control. First extracted from the venom of the Gila monster, these drugs improve glycaemic control, famously promote weight loss, and have well-demonstrated cardiovascular benefits. Mechanistically, GLP-1 receptor agonists counter hyperglycaemia by augmenting insulin secretion, impairing glucagon release, and delaying gastric emptying, as well as centrally promoting satiety via direct neurohormonal signalling.

Studies like LEADER and SUSTAIN-6 have demonstrated that GLP-1 receptor agonists such as liraglutide and semaglutide can reduce the risk of nephropathy as measured by reductions in proteinuria and possible slowing of decline in estimated GFR (eGFR).^8,9 Again, the paucity of data in CKD populations with dedicated primary renal outcomes had tempered the nephrology community’s widespread use of GLP-1s.

The FLOW trial demonstrated that once-weekly subcutaneous semaglutide significantly decreased the risk of progression of DKD without significant adverse effects or safety concerns.¹⁰ While this data is concordant with previous trials, more than 90 per cent of participants had albuminuria and almost 80 per cent had an eGFR <60ml/min/1.73m². While certain limitations (no type 1 diabetics, co-administration of SGLT2 inhibitors was not necessary) leave questions to be answered, semaglutide seems to have established its place in the armamentarium of pharmacotherapy for DKD.

3. MRAs
The overactivation of the mineralocorticoid receptor in patients with diabetes and CKD leads to kidney and cardiovascular damage through the induction of inflammatory and fibrotic pathways. Steroidal (sMRAs) such as spironolactone and eplerenone have been shown to reduce albuminuria. However, their impact on clinical renal outcomes is uncertain and their side-effect profile, including the risk of hyperkalaemia and acute kidney injury (AKI), limits their use in high-risk populations.

nsMRAs such as finerenone demonstrate superior selectivity for mineralocorticoid receptors with no dramatic increase in side-effects related to androgen and oestrogen activity. Two large phase 3 trials have now shown the cardiovascular and renal benefits of finerenone in patients with type two diabetes (T2DM) and DKD. Pre-clinical models have shown that finerenone had greater anti-inflammatory and anti-fibrotic effects than sMRAs, however, its effect on kidney disease progression had not been reported until these trials.

The FIDELIO-DKD trial demonstrated that the use of finerenone in the treatment of patients with T2DM and CKD already being treated with RAS blockade resulted in a lower risk of CKD progression and cardiovascular events than the placebo group.¹¹ CKD exacerbates the risk of adverse cardiovascular events associated with T2DM. The FIGARO-DKD trial concluded that finerenone reduced the risk of cardiovascular outcomes in participants with T2DM and CKD being treated with RAS inhibitors.¹² The rate of mortality due to cardiovascular causes, nonfatal myocardial infarctions and strokes, and heart failure-related hospitalisations were all decreased in the finerenone group.

The FIDELITY analysis is a pooled analysis that was then conducted of the FIDELIO-DKD and FIGARO-DKD trials to demonstrate the efficacy and safety of finerenone in a wide range of patients with CKD and T2DM.¹³ This analysis, involving 13,026 patients across the two trials, confirmed the reported evidence that finerenone had both renal and cardiovascular protective effects.

International guidelines now suggest the addition of finerenone to first-line therapy for patients with T2DM and a high risk of CKD progression and cardiovascular events based on the results from these trials. However, some potential concerns include the higher rate of hyperkalaemia seen in the finerenone group in comparison to the control. There is also a lack of definitive data describing the effect of combining nsMRAs and SGLT2 inhibitors, but this is currently being investigated in the CONFIDENCE study.¹⁴

4. ‘Aldosterone breakthrough’ and aldosterone synthase inhibitors
Mindful of the established role of the renin-angiotensin-aldosterone system (RAAS) in kidney disease generally, and DKD specifically, several different approaches to modify the pathway using novel mechanisms have been attempted. Direct renin inhibitors as well as combining ACE inhibitors and ARBs have been examined in previous studies, but have proven unsuccessful commercially and demonstrated unacceptable side-effect profiles respectively.¹⁵

Aldosterone breakthrough is a concept that has led to the re-examination of the RAAS. After being first described in the 1980s,¹⁶ and confirmed in studies since, it elaborates on the effect of chronic RAAS inhibition and the resultant increase in aldosterone synthesis. Rates of breakthrough are reported variously as between 10 and 50 per cent,¹⁷ thus the deleterious effects of elevated aldosterone may perpetuate kidney disease despite achieving the intended clinical goal. This effect is effectively bypassed with the use of aldosterone synthase inhibitors (ASIs).

Other benefits include sparing the (necessary) cortisol-mediated activation of the mineralocorticoid receptor as part of ‘fight or flight’ responses, preventing the non-genomic effects of aldosterone (which are not inhibited by MRAs) and definitively avoiding the off-target oestrogenic effects of MRAs.

Last year saw the first phase 2 trial of ASI.¹⁸ Encouragingly, in a patient population of established CKD, the majority of whom were diabetic, a significant decrease in proteinuria  was detected both with and without SGLT2 inhibitors. Limited instances of adrenal insufficiency, hyperkalaemia, and AKI were noted and further trials are ongoing examining the role of ASIs in proteinuric CKD and for the treatment of hypertension.

Combination therapy for DKD – searching for synergy

The hunt for a multiple-drug regime in treatment for patients with DKD is an attractive avenue of research. The ability to tailor a treatment regimen for DKD could offer benefit in slowing the progression of disease while avoiding the potential side-effects that any one class alone may cause. The current guideline-recommended drug therapies may not be of benefit to all patients, as DKD is a heterogeneous disease; however, it is difficult to determine which drugs will be of benefit to specific individuals.

RAS inhibitors and SGLT2 inhibitors both decrease glomerular hypertension and hyperfiltration. The RECOLAR trial showed encouraging results in patients with T2DM.¹⁹ The combination of empagliflozin and losartan in people with T2DM had a larger blood pressure-lowering effect versus placebo than either of the drugs alone. This data shows that a combination of a RAS inhibitor and an SGLT2 inhibitor has a positive additive effect on markers of systemic and glomerular haemodynamic function. However, there is a risk of AKI when administering drugs that reduce glomerular pressure as this could lead to hypoperfusion of the kidneys. Further investigation is required to delve deeper into the significance of this risk.

The DURA-TION-8 study of patients with T2DM showed that the combination of an SGLT2 inhibitor and a GLP-1 receptor agonist had a greater positive effect on glycaemic control, body weight, and blood pressure than monotherapy.²⁰ Similarly, in the DECADE study, patients with DKD given a combination of dapagliflozin and exenatide resulted in a greater decrease in albuminuria than monotherapy.²¹

The ROTATE-3 study demonstrated the additive effect of the sMRA eplerenone and SGLT2 inhibitor-dapagliflozin. The results showed that the combination of the drugs resulted in a greater reduction of albuminuria than monotherapy.²² Additionally, in this study it was seen that dapagliflozin partly attenuated the increased serum potassium levels that eplerenone can induce. The hypothesis of SGLT2 inhibitors increasing the renal protective effects of MRAs is currently being investigated in he phase 2 CONFIDENCE trial, as previously mentioned.¹⁴

Conclusion

The management of DKD has witnessed significant advancements in recent years, driven by a deeper understanding of disease mechanisms and the development of novel therapeutic agents. SGLT2 inhibitors, GLP-1 receptor agonists, nsMRAs, and ASIs represent major breakthroughs in the treatment of DKD, offering renal and cardiovascular protection beyond traditional therapies. The concept of ‘4 pillars of DKD’ management has now gained significant currency as the cornerstone of treatment (namely RAAS inhibition, SGLT2 inhibitors, GLP1 agonists, and nsMRAs.

As research continues to unravel the complexities of DKD, it is imperative to translate these advancements into clinical practice to improve the lives of patients with diabetes and prevent the progression to ESKD. The integration of novel therapies, personalised medicine approaches, and innovative technologies will be key to achieving this goal and addressing the rapidly growing burden of DKD in Ireland and worldwide, perhaps lessening even more the burden of a disease recognised since antiquity as a smouldering and pernicious affliction.

“…. because the fluid does not remain in the body, but uses the man’s body as a ladder, whereby to leave it… and many parts of the flesh pass out along with the urine.” The first description of diabetes by Aretaeus of Cappadocia