Combination pharmacotherapy in type 2 diabetes and chronic kidney disease: translating evidence into clinical practice

ABSTRACT

Development of chronic kidney disease (CKD) in type 2 diabetes mellitus (T2DM) is a dual threat, imposing not only increased risk for end-stage renal disease but also substantially increasing cardiovascular risk and premature mortality. Its prevalence is staggering, affecting approximately 30%–40% of all patients with T2DM. Fortunately, advances in pharmacotherapies over the past 25 years, including sodium–glucose cotransporter 2 inhibitors, non-steroidal mineralocorticoid receptor antagonists and glucagon-like peptide-1 receptor agonists, together with blockade of renin–angiotensin aldosterone system activation with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, have transformed the clinical management of T2DM and CKD. By providing parallel reductions in both renal and cardiovascular risk, patients with T2DM and CKD (especially those at higher risk) experience improved survival, fewer cardiovascular events and require less initiation of dialysis as a result of delayed progression to end-stage renal failure. Recent evidence from clinical trials in T2DM and CKD supports simultaneous use of combinatory pharmacotherapies targeting distinct mechanistic pathophysiological pathways.

INTRODUCTION

Type 2 diabetes mellitus (T2DM) remains a leading risk factor contributing to the onset and progression of chronic kidney disease (CKD) worldwide [1, 2], and is a major contributor to end-stage kidney disease requiring dialysis or transplantation [1]. Approximately one-third of adults with T2DM develop kidney disease, defined by persistent (3 months) albuminuria (>30 mg/g) or reduced estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m²) [2, 3]. The presence of CKD markedly increases cardiovascular risk, and cardiovascular disease remains the leading cause of premature mortality in adults with T2DM and CKD [4]. Contemporary clinical care guidelines emphasize a step-wise sequential treatment approach incorporating optimization of lifestyle factors, blood pressure control, glycemic management, lipid lowering and the use of agents with proven renal and cardiovascular benefit [3].

PATHOPHYSIOLOGICAL BASIS OF CKD IN THE SETTING OF T2DM

CKD in the setting of T2DM arises from the complex interactions of both metabolic and hemodynamic pathways secondary to chronic exposure of hyperglycemia—a primary driver of renal and vascular injury in T2DM [5]. Sustained hyperglycemia promotes the formation of advanced glycation end products, oxidative stress and endothelial dysfunction, leading to structural and functional damage within the glomerulus and tubulointerstitium [5]. Systemic and intra-renal hemodynamic changes play a central role, principally through activation of the neurohormonal cascade known as the renin–angiotensin–aldosterone system (RAAS), which increases intraglomerular pressure and promotes glomerular hyperfiltration [5]. These intra-renal hemodynamic changes are driven in part by altered tubuloglomerular feedback and increased proximal tubular sodium reabsorption, resulting in afferent arteriolar dilation and efferent arteriolar constriction [6]. Over time, these changes lead to progressive albuminuria, declining GFR and eventual kidney failure. Activation of systemic and local pro-inflammatory and pro-fibrotic pathways further amplifies disease progression [5]. Recruitment of inflammatory cells and activation of cytokine signaling promotes tissue injury, while transforming growth factor-β and related inflammatory mediators drive extracellular matrix accumulation and tubulointerstitial fibrosis leading to irreversible kidney functional decline [5]. Additional contributors include lipotoxicity, mitochondrial dysfunction and hypoxia [5]. Common clinical risk factors for CKD, including hypertension, obesity, dyslipidemia, smoking, aging and prior acute kidney injury, accelerate these mechanisms and contribute to inter-individual heterogeneity in risk for disease progression. Urinary albuminuria remains a key clinical biomarker, reflecting glomerular injury and predictor of both renal and cardiovascular risk [4].

CARDIO-RENAL PHARMACOTHERAPIES IN T2DM

RAAS inhibition has long been the cornerstone of pharmacotherapy in CKD. Over 25 years ago, the landmark clinical trials RENAAL and IDNT demonstrated that in proteinuric patients with T2DM, use of angiotensin II receptor blockers significantly reduced the progression of nephropathy and mortality [7, 8]. Unfortunately, despite these benefits, substantial residual renal and cardiovascular risk persists in CKD [1]. In 2015, identification of the cardioprotective effects of sodium–glucose cotransporter 2 (SGLT-2) inhibition with empagliflozin in adults with established cardiovascular disease and T2DM[9], and later demonstration of the renoprotective effects of this drug class in 2017[10], fundamentally transformed the therapeutic landscape of CKD. Mechanistically, through inhibiting glucose and sodium reabsorption in the renal proximal tubule, SGLT-2 inhibitors (SGLT-2i) restore tubuloglomerular feedback and reduce intraglomerular hypertension [6]. Large prospective randomized controlled trials (RCTs) of SGLT-2i in adults with T2DM and albuminuric CKD, including the CREDENCE [10]and DAPA-CKD [11]trials, demonstrated significant reductions in kidney disease progression and cardiovascular events [10, 11]. Mineralocorticoid receptor activation also contributes to inflammation and fibrosis in diabetic kidney disease. Finerenone, a selective non-steroidal mineralocorticoid receptor antagonist (nsMRA), has also demonstrated clinically meaningful renal benefits in patients with T2DM and CKD. In the FIDELIO-DKD trial (higher risk patients—lower baseline eGFR, higher albuminuria) use of finerenone compared with placebo significantly reduced the risk of kidney disease progression [12]. While in FIGARO-DKD (lower risk patients—higher baseline eGFR, lower albuminuria) use of finerenone compared with placebo demonstrated cardiovascular benefit, particularly in reducing hospitalization for heart failure, as well as reductions in albuminuria but not composite renal outcomes [[13]]. Finally, glucagon-like peptide-1 receptor agonists (GLP-1RAs)—potent glycemic and body-weight lowering agents—also exert protective cardio-metabolic effects, reducing major adverse cardiovascular outcomes in T2DM [14, 15]. Use of GLP-1RAs was also associated with improving secondary renal endpoints in these cardiovascular outcome trials principally by reducing albuminuria [14]. In the first dedicated renal outcomes trial with once-weekly subcutaneous semaglutide (1 mg), the FLOW trial, use of semaglutide substantially reduced the risk for major adverse renal events in T2DM and CKD [16]. While mechanisms linking GLP-1 receptor signaling to renal risk reduction remain unknown, an active area of investigation centers on GLP-1 receptor signaling suppressing pro-inflammatory pathways leading to reducing inflammation, fibrosis and kidney injury [16].

EARLY COMBINATION THERAPY

Given that SGLT-2i, nsMRA, GLP-1RA, RAAS inhibitors have renoprotective effects targeting unique pathophysiology in CKD as described above, there is a flurry of enthusiasm advocating for the combinatory use of these pharmacotherapies to achieve additive or even synergistic renal benefits [19]. A key limitation to the widespread implementation of this clinical approach, however, is that traditional therapeutic algorithums operate on a step-wise sequential escalation basis. In clinical practice however, clinical inertia, driven by patient, clinician and health-system level barriers, delays treatment intensification enabling kidney disease to progress [20]. Accordingly, the need for alternative clinical approaches to manage CKD is evident. Recently, evidence supporting early combination therapy has been bolstered by the CONFIDENCE (a randomized, double-blind, double-dummy, multicenter phase 2 study evaluating simultaneous initiation of finerenone and empagliflozin compared with either agent alone) trial findings [18]. Adults with T2DM + CKD randomized to combination therapy on a background of optimized renin–angiotensin system blockade resulted in greater reductions in albuminuria compared with monotherapy without additional safety signals, suggesting that the use of SGLT-2i and nsMRA in T2DM + CKD is safe and additive [18]. These findings, however, were only tested under short-term conditions (180 days) and observation under longer-term RCT settings are warranted [19]. Furthermore, the choice of primary endpoint (change in urinary albumin-to-creatinine ratio), although valid, represents only a “surrogate” marker of renal risk and disease progression [19]. While hyperkalemia is a known risk with nsMRA use, importantly, combinatory nsMRA + SGLT-2i use did not amplify this risk, and hemodynamic safety monitoring early within the trial at the time of co-initiation indicated no increased risk for acute hypotension when starting both drugs simultaneously [18]. Finally, it is important to highlight that the concept of simultaneous-initiation combination therapy is not unique to T2DM and CKD—it should also be studied and applicable in adults with CKD without diabetes, as the renoprotective mechanisms of these therapies are well established in patients without diabetes.

Implementation of combination therapy, however, will require clinical vigilance and careful patient selection, particularly around serum potassium levels prior to initiation, and early monitoring of hemodynamics, hyperkalemia and renal dysfunction shortly after initiating therapy beyond routine clinical care. Multidisciplinary care with nephrology and endocrinology may help to bridge clinical care gaps, together with the pharmacovigilance offered by pharmacists to help improve safety and adherence [17].

CONCLUSION

The management of CKD has evolved toward comprehensive multi-pillar cardiorenal protection. Evidence from multiple RCTs strongly substantiates the use of SGLT-2i, nsMRAs and GLP-1RAs in addition to standard of care with RAAS inhibitors as adjunctive cardio-renoprotective therapies [10–16]. Early combination therapy represents a promising strategy to address clinical shortfalls in addressing CKD early to reduce future renal and cardiovascular risk. Future research should focus on long-term outcomes associated with early combination therapy to substantiate whether reductions in albuminuria translate into sustained and additive improvements in kidney survival and cardiovascular outcomes [19]. Moreover, additional studies are needed to evaluate the role of goal-directed triple combinational approaches incorporating SGLT-2i, nsMRAs and GLP-1RAs in diverse patient populations. As our clinical armamentarium expands, equal effort should be directed into broadening and scaling access to these therapies, especially amongst underrepresented and vulnerable populations, to address disparities in kidney disease outcomes [20]. Similarly, to increase the generalizability of combinatory therapy, clinical trials designs in CKD in the future will need to be well aligned with real-world clinical settings, including eligibility, care-delivery and follow-up.

AUTHORS’ CONTRIBUTIONS

J.A.L. was responsible for the content and editing of the manuscript.

CONFLICT OF INTEREST STATEMENT

J.A.L. has received speaking honorariums and attended Advisory Boards for Boehringer Ingelheim, Eli Lilly and Novo Nordisk.

FUNDING

This virtual roundtable was financially supported by Bayer AG and the scientific content has not been influenced in any way by the sponsor.