Integrating Blood Pressure Control With Multi-Class Kidney Protective Agents in Diabetic Kidney Disease

Abstract

Diabetic kidney disease (DKD) remains a leading cause of chronic kidney disease progression and cardiovascular morbidity and mortality. Blood pressure (BP) control is a cornerstone of risk reduction in DKD, yet its management has become increasingly complex with the emergence of multi-class kidney-protective agents. Traditionally centered on renin-angiotensin-aldosterone system (RAAS) blockade with additional antihypertensive agents, contemporary treatment now incorporates sodium-glucose cotransporter-2 (SGLT2) inhibitors, non-steroidal mineralocorticoid receptor antagonists, and incretin-based therapies. Recent trials evaluating intensive systolic BP targets have demonstrated cardiovascular benefit in selected high-risk populations; however, the balance between benefit and kidney-related harm remains relevant in DKD. While RAAS blockade provides meaningful BP reduction and renoprotection, SGLT2 inhibitors, finerenone, and incretin-based therapies confer modest but clinically relevant BP lowering alongside substantial cardiorenal benefits through complementary mechanisms. Although these agents are not primarily used for antihypertensive intensification, their meaningful BP-lowering effects can influence overall BP control in routine practice. Although combination therapy appears biologically plausible and may enhance overall cardio-kidney-metabolic protection, definitive evidence supporting optimal sequencing, parallel initiation, or superiority in hard clinical outcomes remains limited. A pragmatic, individualized approach integrating disease-modifying therapies with conventional antihypertensive agents is therefore warranted. Future dedicated trials are needed to clarify optimal integration strategies to achieve safe BP control while maximizing long-term kidney and cardiovascular protection in DKD.

INTRODUCTION

Diabetic kidney disease (DKD) remains a leading cause of chronic kidney disease (CKD) progression and end-stage kidney disease and it is strongly associated with excess cardiovascular morbidity and mortality [1]. Among the various modifiable risk factors in DKD, control of blood pressure (BP) and glucose are consistently recognized as key factors to reduce albuminuria progression, decline in glomerular filtration rate, and adverse cardiovascular outcomes [2,3].

Over the past decade, the management of DKD has undergone a major paradigm shift. Traditionally, BP control has been achieved primarily through renin-angiotensin-aldosterone system (RAAS) blockade as the cornerstone of pharmacologic treatment with additional antihypertensive agents as needed, whereas glycemic control has relied on glucose-lowering agents as a separate domain. However, therapeutic landscape has rapidly expanded with the emergence of multi-class kidney-protective agents, including sodium-glucose cotransporter-2 (SGLT2) inhibitors, mineralocorticoid receptor antagonists (MRAs) such as finerenone, and incretin-based therapies such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) [4,5,6,7,8,9,10]. Beyond their primary indications (e.g., glycemic control and weight reduction), these agents commonly provide a modest but consistent BP-lowering effect. Consequently, BP management in DKD is no longer solely dependent on conventional antihypertensive agents, and clinicians now have an expanding range of therapeutic options that can simultaneously address BP, glucose, and other metabolic risk factors that lead to long-term cardiorenal protection. In other words, the clinical challenge has evolved from simply “adding more BP-lowering agents” to making individualized decisions based on patients’ characteristics and comorbidities. At the same time, their adverse-effect profiles and monitoring requirements differ substantially, particularly with regard to volume status changes, kidney function dynamics, gastrointestinal tolerability, and the risk of hyperkalemia [11,12,13]. Collectively, the key questions in real-world clinics to manage DKD is how clinicians can strategically select and combine multi-class kidney-protective therapies to achieve safe BP target while maximizing overall clinical benefit.

In contemporary clinical practice, multi-class kidney-protective agents are not primarily initiated for BP lowering. However, BP reduction effects of these agents may influence overall BP control and necessitate adjustment of concomitant antihypertensive medications. Therefore, understanding the magnitude and characteristics of BP-lowering effects of each therapeutic class has important implications for real-world treatment strategies. In this review, we aim to provide a practical framework for integrating these therapies by clarifying their relative contributions to BP reduction in DKD. We summarize contemporary BP targets in guidelines, review foundational background therapies, including RAAS blockade and SGLT2 inhibitors, and then focus on newer agents such as finerenone and incretin-based therapies, highlighting their distinct cardiorenal benefits, safety profiles, and monitoring needs.

BP TARGETS IN DKD

For the last decade, there has been a trend toward more intensive BP control for hypertensive patients, whereas the optimal BP target in DKD remains an area of active debate. The landmark SPRINT trial compared an intensive systolic blood pressure (SBP) target (< 120 mmHg) with a standard target (< 140 mmHg) in high-risk hypertensive adults and showed significant reductions in major cardiovascular events and all-cause mortality with intensive treatment [14]. However, this study excluded patients with diabetes. In contrast, the ACCORD-BP trial, which specifically enrolled patients with type 2 diabetes, did not show a significant reduction in the primary composite cardiovascular outcome with intensive SBP targeting < 120 mmHg compared with < 140 mmHg, although stroke risk was reduced at the expense of more adverse events [15]. However, more recent ESPRIT trial enrolled patients at high cardiovascular risk, with and without diabetes or prior stroke, and compared SBP targets of < 120 versus < 140 mmHg [16]. Likewise, the BPROAD trial focused on patients with type 2 diabetes and evaluated intensive SBP lowering toward < 120 mmHg [17]. Together, these trials have reinforced the concept that intensive SBP lowering can translate into cardiovascular benefit in selective patients with type 2 diabetes.

Nevertheless, in DKD, the clinical dilemma is not simply whether intensive BP lowering can improve cardiovascular outcomes, but whether pursuing SBP < 120 mmHg is always necessary when kidney-related harms are explicitly considered. This question is particularly relevant in DKD because patients often have heightened hemodynamic vulnerability due to reduced nephron reserve, frequent diuretic exposure, autonomic dysfunction. Consequently, very intensive BP lowering may be accompanied by kidney-related adverse effects even when long-term cardiovascular benefit is anticipated [18]. A recent meta-analysis pooled six pivotal intensive BP trials (ACCORD-BP, SPRINT, ESPRIT, BPROAD, STEP, and CRHCP) and quantified this benefit-harm trade-off, demonstrating that intensive BP control reduced major cardiovascular events while increasing adverse events of interest, including kidney-related outcomes (acute kidney injury, renal failure, kidney failure/dialysis, or substantial estimated glomerular filtration rate [eGFR] decline) [19]. Importantly, when outcomes were further analyzed by SBP target category (< 120 mmHg vs. < 130 mmHg), the absolute cardiovascular risk reduction with intensive treatment was numerically greater in the < 120 mmHg target (1.84%, 95% confidence interval [CI], 1.75–1.92) than in the < 130 mmHg target (1.65%, 1.54–1.76). However, when harms were incorporated using adjudicated benefit-to-harm weights, net benefit versus total adverse events of interest was 0.97 (0.87–1.06) for < 120 mmHg target and 1.27 (1.16–1.37) for < 130 mmHg target, while net benefit versus kidney-related adverse events was 0.77 (0.59–0.92) for < 120 mmHg target versus 1.43 (1.32–1.53) for < 130 mmHg target. These findings suggest that although more intensive SBP lowering toward < 120 mmHg may yield incremental cardiovascular risk reduction, a pragmatic SBP target < 130 mmHg may offer a more favorable benefit-harm balance, particularly when kidney-related harms are explicitly weighed, an issue of heightened relevance in DKD.

Current guidelines reflect both the momentum toward lower BP targets and the need for cautious implementation. The 2021 Kidney Disease: Improving Global Outcomes (KDIGO) BP guideline recommends treating adults with CKD and hypertension to SBP < 120 mmHg (when tolerated), but critically specifies that this target should be applied only with standardized office BP measurement, acknowledging the gap between trial-grade measurement and routine clinic BP values [20]. More recent 2022 Korean Society of Hypertension BP guideline also emphasizes the importance of office BP measurement with standardized method, but also recommends to use out-of-office BP measurements, such as ambulatory blood pressure monitoring (ABPM) or home blood pressure monitoring (HBPM) for diagnosis and monitoring of hypertension [21,22]. Additionally, the KSH guideline supports targeting < 130/80 mmHg in high-risk individuals, including patients with diabetes plus additional cardiovascular risk factors or those with CKD accompanied by albuminuria, to balance between clinical benefit and masked side effects during intensive BP control [23]. Most recently, the 2025 American College of Cardiology (ACC)/American Heart Association (AHA)/Multisociety BP guideline provides a broadly applicable target of < 130/80 mmHg for most adults, reinforcing the importance of early treatment and intensification in high-risk conditions such as diabetes and CKD [24]. However, the ACC/AHA guideline encourages to achieve lower SBP targets (approaching < 120 mmHg) selectively in case of well-tolerable patients with diabetes. Taken together, these recommendations support a pragmatic DKD strategy in which < 130/80 mmHg serves as a broadly implementable default target, while SBP < 120 mmHg is reserved for carefully selected individuals with very high cardiovascular risk, reliable standardized (and/or out-of-office) BP assessment, and good treatment tolerability.

BACKGROUND BP MANAGEMENT WITH CLASSICAL ANTIHYPERTENSIVE AGENTS IN DKD

RAAS blockade remains a foundational component of BP management in DKD, primarily because of its well-established renoprotective effect [25,26,27]. Accordingly, abovementioned BP guidelines consistently recommend to use of RAAS blockade as first-line therapy to treat hypertension in patients with DKD, especially when patients have albuminuria [20,23,24]. In terms of BP reduction per se, a large systematic review and meta-analysis, which pooled 484 randomized controlled trials (RCTs), demonstrated that standard-dose monotherapy reduced SBP by an average of 6.8 mmHg (95% CI, 5.9–7.7) for angiotensin-converting enzyme (ACE) inhibitors and 8.5 mmHg (7.8–9.3) for angiotensin II receptor blockers (ARBs) [28]. Moreover, doubling the dose of monotherapy resulted in only a modest additional SBP reduction of approximately 1–2 mmHg, supporting the notion that RAAS blockade monotherapy may not enough to achieve BP target in most patients. Meanwhile, evidence specific to CKD further refines this interpretation. In a systematic review and meta-analysis of 24 RCTs focusing on patients with concomitant hypertension and CKD, ARB monotherapy reduced SBP by approximately 12–15 mmHg and diastolic BP by 6–10 mmHg, with numerically greater reductions observed with longer treatment duration [29].

Additionally, both meta-analyses consistently demonstrate that combination therapy is substantially more effective than dose escalation of a single agent. Among the classical antihypertensive agents, calcium channel blockers (CCBs) and thiazide or thiazide-like diuretics are the most commonly selected second-line options. In the same large-scale meta-analysis of 484 RCTs, standard-dose CCB monotherapy was associated with a mean SBP reduction of approximately 8–11 mmHg, and thiazide-type diuretics achieved SBP reductions of approximately 9–12 mmHg from comparable baseline BP levels [28]. High-quality RCTs specifically designed to optimal second-line choice in DKD remain limited, but several influential studies provide important insights. In a large trial with hypertensive patients with a high-risk of cardiovascular disease (CVD), an ACE inhibitor combined with a dihydropyridine CCB was superior to the same ACE inhibitor combined with a thiazide diuretic in reducing cardiovascular events, despite similar achieved BP levels [30]. Subsequent analyses also suggested less progression of CKD in the CCB-based group, supporting the use of CCBs as a second-line agent when CVD risk reduction is a primary therapeutic goal [31]. Conversely, a recent CKD-focused observational study suggests that diuretics may offer advantages [32]. This study including moderate to advanced CKD patients have reported comparable cardiovascular outcomes but potentially more favorable kidney outcomes when diuretics were added to background RAAS blockade, compared with CCBs-based combinations. These findings are biologically plausible, given the increasing contribution of sodium retention and volume expansion to hypertension as kidney function declines. In contrast, previous trials have shown that combination of RAAS blockades increases the risk of hyperkalemia and acute kidney injury [33,34]. Therefore, combination of RAAS blockade is not recommend as a BP-lowering strategy.

POSITIONING SGLT2 INHIBITORS AS SECOND-LINE THERAPY AFTER RAAS BLOCKADE

Meanwhile, with the advent of SGLT2 inhibitors, the traditional paradigm of selecting CCBs or diuretics as second-line therapy after RAAS blockade for BP-lowering in DKD warrants reconsideration. Although SGLT2 inhibitors were initially developed as glucose-lowering agents, multiple large-scale outcome trials have consistently demonstrated substantial kidney and cardiovascular benefits in patients with DKD, most of whom were receiving background RAAS blockade [4,5,35]. In addition, a recent meta-analysis showed that protective effect of SGLT2 inhibitor for CKD progression was consistent across almost all range of eGFR and albuminuria categories [36]. Accordingly, current KDIGO guidelines commonly recommend the use of SGLT2 inhibitors in all CKD patients with eGFR greater than 20 mL/min/1.73 m² [3,37], positioning SGLT2 inhibitors as foundational therapy in contemporary DKD management.

From a BP-lowering perspective, SGLT2 inhibitors exert a modest but consistent antihypertensive effect, with meta-analyses reporting an average SBP reduction of approximately 3–5 mmHg compared with placebo [38,39]. However, accumulating evidence suggests that this effect is highly heterogeneous and strongly influenced by patient phenotype. Greater BP reductions have been observed in individuals with higher baseline BP, obesity, salt sensitivity, and features of volume expansion, as well as in those with uncontrolled nocturnal or masked hypertension despite background RAAS blockade [40]. Studies using ABPM or HBPM further indicate that SGLT2 inhibitors may preferentially lower 24-hour, nighttime, and early morning BP rather than office BP, thereby improving adverse circadian BP patterns that are common in patients with diabetes and CKD [41]. In selected populations, including elderly patients, East Asian cohorts, and those with resistant or nocturnal hypertension, SBP reductions exceeding 7–10 mmHg have been reported [42,43].

Taken together, these data support that the combination of RAAS blockade and an SGLT2 inhibitor may be sufficient to achieve guideline-recommended BP targets in a subset of patients with DKD. However, given the modest and variable magnitude of BP reduction associated with SGLT2 inhibitors, a substantial proportion of patients will require additional antihypertensive therapy to reach BP goals. At the same time, the use of SGLT2 inhibitors necessitates careful attention to safety and tolerability. Adverse effects such as volume depletion, genital infections, and diabetic ketoacidosis may limit their use in selected patients, particularly in those receiving concomitant diuretic therapy or in older patients with frailty and sarcopenia [11,44,45,46]. Accordingly, initiation of SGLT2 inhibitors should be accompanied by assessment of volume status, consideration of diuretic dose adjustment, and close clinical monitoring.

NON-STEROIDAL MRAS AND BP CONTROL IN DKD

Non-steroidal MRAs, represented by finerenone, have emerged as an important disease-modifying therapy in DKD. Previous two large clinical trials, FIGARO-DKD and FIDELIO-DKD, encompassing a broad spectrum of DKD patients with eGFR greater than 25 mL/min/1.73 m² with albuminuria have shown that finerenone significantly reduced the risks of CKD progression and cardiovascular events compared with placebo on a background of optimized RAAS blockade [6,7,47]. Reflecting this body of evidence, finerenone has been incorporated into contemporary 2022 KDIGO guideline for diabetes management in CKD as an add-on therapy for patients with type 2 diabetes and CKD who have persistent albuminuria despite optimized RAAS blockade [3].

However, from a BP perspective, finerenone produces a modest reduction in BP. In previous trials, finerenone lowered office SBP by approximately 2–4 mmHg compared with placebo [6,7], which is smaller than that observed with traditional steroidal MRAs. In comparative analyses involving patients with resistant hypertension and moderate-to-advanced CKD, finerenone was associated with a smaller reduction in SBP than spironolactone [48]. While spironolactone achieved greater BP reductions, this benefit was offset by markedly higher rates of potassium elevation and drug discontinuation, even when combined with potassium-binding agents. Mediation analyses further demonstrated that BP lowering accounted for only a small proportion of the observed kidney and cardiovascular benefits, indicating that finerenone’s therapeutic effects are largely mediated through non-hemodynamic mechanisms, including attenuation of mineralocorticoid receptor-driven inflammation and fibrosis [49]. Thus, in contrast to steroidal MRAs such as spironolactone, which are often used for resistant hypertension due to their substantial BP-lowering effects, the clinical value of finerenone in DKD lies predominantly in its disease-modifying effects, with BP reduction serving as an ancillary benefit. However, recent clinical trial provided randomized evidence regarding the BP lowering effect of combined use of finerenone and an SGLT2 inhibitor. In patients with DKD receiving background RAAS blockade, combination therapy with finerenone and empagliflozin resulted in a greater early reduction in albuminuria and a transiently larger reduction in SBP, approximately 7 mmHg within the first month, compared with either agent alone, without an excess risk of symptomatic hypotension or acute kidney injury [50].

When initiating finerenone, careful attention to adverse effects and monitoring is essential. Hyperkalemia remains the principal safety concern, although its incidence and severity are substantially lower than those observed with steroidal MRAs. Current clinical practice therefore requires routine monitoring of serum potassium and kidney function, particularly after treatment initiation or dose escalation and in patients with advanced CKD.

INCRETIN-BASED THERAPIES AND BP CONTROL IN DKD

Incretin-based therapies, most notably GLP-1 RAs and more recently dual incretin agonists such as tirzepatide, have become increasingly relevant in DKD. In patients with type 2 diabetes and CKD, the FLOW trial demonstrated that once-weekly semaglutide reduced clinically important kidney outcomes and cardiovascular death compared with placebo, supporting GLP-1 RAs as disease-modifying therapies in DKD [8]. In addition, recent evidence also showed that tirzepatide was associated with a sustained reduction in albuminuria without adverse effects on eGFR in participants with overweight or obesity with type 2 diabetes [51]. Importantly, incretin-based therapies have shown to reduce the risk of atherosclerotic CVD accompanied by improvements in body weight, glycemic control, and lipid profiles [52]. Collectively, these data position incretin-based therapies as adjunctive agents that can contribute cardiometabolic and renal benefits in patients with DKD, particularly those with overweight or obesity.

The FLOW trial showed a modest reduction in SBP (3.8 mmHg) with semaglutide which an achieved SBP difference of approximately 2 mmHg compared with placebo [8]. A recent meta-analysis of semaglutide trials reported that SBP lowering effect of semaglutide was 3–5 mmHg in hypertensive patients with obesity, and mediation analysis suggested that nearly 90% of SBP reduction was attributable to weight loss in this population [53]. Similarly, post-hoc analyses of five clinical trials of tirzepatide reported dose-dependent SBP and body weight reductions, and maximum dose of tirzepatide was associated with SBP reduction of up to 11 mmHg in patient with obesity, indicating that SBP reduction of tirzepatide was primarily mediated by weight loss [54]. These findings suggest that in patients with DKD, BP reduction with incretin-based therapies may be more clinically relevant in those with obesity, with BP reduction serving as a secondary and modest effect. Beyond weight loss, experimental studies suggest that incretin-based therapies may contribute to BP lowering through additional pathways, including attenuation of sympathetic nervous system activity, improvement in endothelial function, and promotion of natriuresis in the kidney [55]. However, careful attention to tolerability is required, as gastrointestinal adverse effects (nausea, vomiting, and diarrhea) may precipitate volume depletion and worsen kidney function, particularly in patients receiving concomitant diuretics or SGLT2 inhibitors. Additional safety considerations include the potential risk of gallbladder disease, and the need for caution in patients with a history of pancreatitis or advanced diabetic retinopathy during rapid glycemic improvement.

Meanwhile, because both SGLT2 inhibitors and incretin-based therapies provide substantial cardiorenal benefit, there has been growing interest in whether their combined use can further improve outcomes. Although recent observational study showed lower risks of CVD and renal events with this combination [56], definitive evidence from dedicated head-to-head RCTs remained limited, and it is still uncertain whether combined therapy provides incremental benefit beyond either class alone for hard clinical endpoints [57]. From BP perspective, a meta-analysis of seven RCTs showed that combination of GLP-1 RAs and SGLT2 inhibitors lowered SBP compared with GLP-1 RAs alone (−2.6 mmHg) or SGLT2 inhibitors alone (−1.5 mmHg) [58]. However, these trials were short-term, not specifically designed for DKD populations, and often included heterogeneous background antihypertensive regimens. Therefore, while dual therapy is biologically plausible and may offer modest incremental BP lowering through complementary mechanisms, natriuresis and plasma volume contraction (SGLT2 inhibitors) together with weight loss and neurovascular effects (GLP-1 RAs), the magnitude and durability of BP benefit in DKD remain uncertain. Collectively, with current evidence, although BP reduction alone should not be the primary rationale for combination therapy, combined use should be considered mainly to strengthen overall cardio-kidney-metabolic protection, with BP effects viewed as an ancillary benefit.

PRACTICAL INTEGRATION OF MULTI-CLASS KIDNEY-PROTECTIVE AND ANTIHYPERTENSIVE AGENTS FOR BP CONTROL IN DKD

BP management in DKD should be approached through a pragmatic framework that integrates multi-class kidney-protective therapies with conventional antihypertensive agents (Table 1). Therapies used in DKD can be broadly categorized into two groups: agents primarily used for antihypertensive intensification (RAAS blockades, CCBs, diuretics), and disease-modifying therapies that confer cardio-renal protection with modest or secondary BP-lowering effects (SGLT2 inhibitors, finerenone, incretin-based therapies). Optimized RAAS blockade remains foundational first-line therapy, particularly in albuminuric DKD. Following RAAS blockade, early initiation of an SGLT2 inhibitor is increasingly viewed as background therapy, given its robust cardiorenal benefits and modest SBP lowering. In patients with persistent albuminuria despite background therapy, add-on kidney-protective agents may be considered. Finerenone provides modest SBP reduction with predominantly non-hemodynamic cardiorenal benefits. Incretin-based therapies may be particularly useful in patients with obesity or high cardiovascular risk, offering modest and largely weight-mediated SBP reduction alongside substantial cardiometabolic benefit.

Table 1. Practical integration of multi-class kidney-protective agents for BP control in diabetic kidney disease.

Agent class		Typical position	Expected SBP reduction (approx.)	Key determinants of BP response	Safety monitoring/key cautions
Background agents
	RAAS blockade (ACEi or ARB)	First-line (foundational)	7–9 mmHg	Baseline BP, sodium intake	Serum creatinine/eGFR and potassium after initiation and dose escalation
Add-on kidney-protective agents
	SGLT2 inhibitors	Early second-line/background therapy	3–5 mmHg (up to 7–10 mmHg in selected patients)	Volume status, baseline BP, salt sensitivity, nocturnal/masked HTN	Genital infections, rare DKA, volume status
	Non-steroidal MRA (finerenone)	Add-on for persistent albuminuria	2–4 mmHg	Baseline BP, RAAS background therapy	Potassium and kidney function monitoring
	GLP-1 RAs/dual incretin agonists	Add-on for obesity and high risk of CVD	2–5 mmHg (up to 10–11 mmHg in obesity)	Body weight change, baseline BP, metabolic profile	GI intolerance, gallbladder disease, pancreatitis, rare retinopathy
Add-on antihypertensive agents
	Calcium channel blockers	Add-on when BP remains above target	8–11 mmHg	Vascular tone, baseline BP	Peripheral edema, headache
	Diuretics (thiazide/thiazide-like or loop)	Add-on when BP remains above target and volume expansion present	9–12 mmHg	Volume status, kidney function, sodium intake	Electrolyte imbalance, volume depletion, gout

The estimated SBP reductions presented in this table are derived from different clinical trials with heterogeneous populations, study designs, background therapies, and follow-up durations. Therefore, these values should be interpreted as approximate reference ranges rather than directly comparable estimates.

ARB, angiotensin II receptor blocker; ACEi, angiotensin-converting enzyme inhibitor; BP, blood pressure; CVD, cardiovascular disease; DKA, diabetic ketoacidosis; eGFR, estimated glomerular filtration rate; GI, gastrointestine; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HTN, hypertension; MRA, mineralocorticoid receptor antagonist; RAAS, renin-angiotensin-aldosterone system; SBP, systolic blood pressure; SGLT2, sodium-glucose cotransporter 2.

When BP remains above target, conventional antihypertensive agents, most commonly CCBs or diuretics, remain essential and should be selected according to clinical phenotype and volume status. Overall, this approach emphasizes early use of disease-modifying therapies and individualized antihypertensive intensification. However, it remains uncertain whether these agents should be introduced sequentially or in parallel, and which combinations are optimal. Moreover, there is still no definitive evidence that combination strategies improve hard clinical outcomes compared with single-class therapy.

CONCLUSIONS

BP control remains a central component of risk reduction in DKD, yet its management has become increasingly complex in the era of multi-class kidney-protective therapies. Although these agents are not primarily used for antihypertensive intensification, they exert modest but clinically meaningful BP-lowering effects that may influence overall BP control in routine practice. Despite the growing role of disease-modifying therapies, conventional antihypertensive agents such as CCBs and diuretics remain essential for achieving BP targets. Accordingly, clinicians should recognize that initiation of kidney-protective therapies may require adjustment of conventional antihypertensive medications to achieve optimal BP targets while minimizing adverse effects. A practical approach therefore requires careful integration of disease-modifying therapies with conventional antihypertensive agents based on individual patient characteristics. Although combination therapy of kidney-protective agents appears biologically plausible and may enhance overall risk reduction, definitive evidence supporting specific sequencing strategies or superiority in hard clinical outcomes remains limited. Future trials are needed to clarify optimal integration strategies to achieve individualized BP control while maximizing long-term kidney and cardiovascular protection.