Abstract
Background
Chronic kidney disease (CKD) is frequently complicated by hypertension, a dual contributor to disease progression and cardiovascular risk. Despite standard therapy with renin–angiotensin–aldosterone system inhibitors, residual risk remains high. Sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as a novel therapy with proven renal and cardiovascular benefits, but their effects in hypertensive CKD patients remain less well defined.
Methods
We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) that evaluated SGLT2 inhibitors in CKD patients with baseline systolic blood pressure ≥140 mmHg or renovascular disease. PubMed, Embase, and Cochrane Library were searched from inception to August 2024. Eligible RCTs compared an SGLT2 inhibitor versus placebo and reported outcomes in hypertensive subgroups. Primary outcome was a composite of kidney failure, sustained decline in estimated glomerular filtration rate (eGFR ≥40–50 %), or cardiovascular death. Secondary outcomes included kidney-specific endpoints, cardiovascular composite outcomes, and serious adverse events (SAEs). Pooled odds ratios (ORs) were calculated using random-effects models.
Results
Three RCTs were included: CREDENCE (canagliflozin), DAPA-CKD (dapagliflozin), and EMPA-KIDNEY (empagliflozin), encompassing 5436 hypertensive participants. For the primary outcome, SGLT2 inhibitors reduced risk compared with placebo (OR 0.76, 95 % CI 0.65–0.88). Kidney outcomes showed consistent benefit (OR 0.70, 95 % CI 0.58–0.85). Cardiovascular events were modestly reduced (OR 0.79, 95 % CI 0.64–0.97). SAEs were slightly lower with SGLT2 inhibitors (OR 0.85, 95 % CI 0.74–0.96). Overall certainty of evidence was graded as moderate.
Conclusions
Among hypertensive patients with CKD, SGLT2 inhibitors significantly reduce renal disease progression and cardiovascular events while maintaining favorable safety. These findings support their integration into standard therapy for this high-risk population.
Keywords: Chronic kidney disease, Hypertension, SGLT2 inhibitors, Cardiovascular outcomes, Renal outcomes
1. Introduction
Chronic kidney disease (CKD) is a progressive and irreversible condition defined by persistent structural or functional abnormalities of the kidney for more than 3 months [1]. Globally, CKD affects over 10 % of the adult population and contributes to approximately 1.2 million deaths annually, with 28 million years of life lost each year.[[2], [3]] The burden of CKD continues to rise, particularly in low- and middle-income countries, making it a major global health challenge [4] (see Table 4, Fig. 1, Fig. 2)
Table 4.
GRADE assesment.
| Outcome | No of participants (studies) | Study design | Risk of bias | Inconsistency | Indirectness | Imprecision | Publication bias | Overall certainty | Summary of findings |
|---|---|---|---|---|---|---|---|---|---|
| Primary composite outcome (Kidney failure/≥50 % eGFR decline/CV death) | 4352 (3 RCTs) | RCT | Not serious | Not serious | Not serious | Serious (CI crosses 1 in EMPA-KIDNEY) | Undetected | Moderate ●●●◯ | SGLT2i reduce risk of primary outcome (OR ∼0.78, 95 % CI 0.63–0.96) |
| Kidney outcomes (progression, kidney death) | 4352 (3 RCTs) | RCT | Not serious | Not serious | Not serious | Serious (wide CI in EMPA-KIDNEY kidney death subgroup) | Undetected | Moderate ●●●◯ | Consistent kidney benefit across trials (OR ∼0.72, 95 % CI 0.57–0.91) |
| Cardiovascular composite outcome (CV death, HF hospitalization, MACE) | 3463 (3 RCTs) | RCT | Not serious | Not serious | Not serious | Serious (CIs wide, esp. EMPA-KIDNEY) | Undetected | Moderate ●●●◯ | Reduction in CV events with SGLT2i (OR ∼0.77, 95 % CI 0.60–0.99) |
| Serious adverse events (SAEs) | 3977 (2 RCTs) | RCT | Not serious | Not serious | Not serious | Serious (CI includes no effect) | Undetected | Moderate ●●●◯ | SAEs slightly reduced, but effect not statistically significant (OR ∼0.86, 95 % CI 0.72–1.02) |
Fig. 1.
PRISMA flowchart.
Fig. 2.
Meta-analysis of Outcomes a) Primary Outcome, b) Kidney Outcome, c) Cardiovascular Outcome, d) Serious adverse effects.
Hypertension plays a dual role in the pathogenesis of CKD: it is both a major cause and a frequent complication of the disease [5]. Nearly one-quarter of kidney failure cases worldwide are attributed to hypertension, and almost 70–90 % of patients with advanced CKD present with uncontrolled blood pressure.5 6 The coexistence of hypertension not only accelerates CKD progression but also amplifies the risk of cardiovascular disease (CVD), which remains the leading cause of death in this population [7]. Therefore, comprehensive management of CKD requires strategies that both preserve kidney function and reduce cardiovascular risk.1 5
Renin–angiotensin–aldosterone system (RAAS) inhibitors have long been the cornerstone of therapy in CKD, but residual cardiorenal risk remains substantial [1]. Sodium–glucose cotransporter-2 (SGLT2) inhibitors, initially developed as glucose-lowering agents, have emerged as a novel therapeutic class with robust evidence of renal and cardiovascular benefits [8]. Landmark randomized controlled trials, CREDENCE, DAPA-CKD, and EMPA-KIDNEY demonstrated that SGLT2 inhibitors significantly reduced the risk of CKD progression, end-stage kidney disease (ESKD), and major cardiovascular events in patients with or without diabetes [[9], [10], [11]]. Meta-analyses further confirmed a consistent 30–40 % risk reduction in kidney disease progression and heart failure hospitalization across diverse populations [12].
Beyond their nephroprotective effect, SGLT2 inhibitors exert modest blood pressure-lowering properties, typically reducing systolic BP by 3–5 mmHg [13]. These antihypertensive benefits are clinically relevant for patients with CKD and concomitant hypertension, where control of both renal decline and cardiovascular burden is critical. However, the specific magnitude of benefit in this subgroup has not been comprehensively evaluated. Thus, we conducted a systematic review and meta-analysis to synthesize the available evidence on the cardiorenal effects of SGLT2 inhibitors in patients with CKD and hypertension.
2. Methods
2.1. Protocol and reporting
This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines.
2.2. Data sources and search strategy
We systematically searched PubMed/MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from database inception until August 2024, without language restrictions. The PubMed search strategy used the following Boolean string: ("Sodium-Glucose Transporter 2 Inhibitors"[Mesh] OR "SGLT2 inhibitor" OR canagliflozin OR dapagliflozin OR empagliflozin)∗ AND ("Chronic Kidney Disease"[Mesh] OR CKD OR "renal insufficiency" OR "kidney disease") AND (hypertension OR "high blood pressure"), with filters applied for randomized controlled trials and human studies. For Embase, equivalent Emtree terms were used, including sodium glucose cotransporter 2 inhibitor, chronic kidney disease, and hypertension, combined with Boolean operators and restricted using the Embase randomized controlled trial filter. The CENTRAL search employed similar keywords and controlled vocabulary without additional methodological filters, as CENTRAL exclusively indexes controlled trials. In addition, ClinicalTrials.gov was searched using the terms SGLT2 inhibitor, chronic kidney disease, and hypertension to identify completed or ongoing randomized trials. Reference lists of included studies and relevant systematic reviews were manually screened to ensure completeness.
2.3. Eligibility criteria
We included randomized controlled trials that enrolled adult patients with chronic kidney disease and compared an SGLT2 inhibitor against placebo on top of standard of care. Eligible trials were required to report outcomes specifically in patients with hypertension, defined as a baseline systolic blood pressure of at least 140 mmHg or documented renovascular disease. Studies that were non-randomized, lacked placebo comparators, did not stratify by hypertensive status, or duplicated data from earlier publications were excluded. Trials such as SCORED, FIGARO-DKD, EMPEROR-HF, and EMPEROR-Preserved were excluded because they did not report renal-specific primary outcomes in CKD populations or did not provide extractable hypertensive subgroup data aligned with our predefined renal composite endpoints. For EMPA-KIDNEY, hypertensive participants were identified based on trial-defined hypertension status or antihypertensive treatment at baseline, rather than mean SBP alone.
2.4. Outcomes
The primary outcome of interest was the composite of kidney failure, sustained decline in estimated glomerular filtration rate by at least 40–50 % depending on the trial definition, or cardiovascular death. Kidney-specific outcomes included kidney failure, kidney-related death, or a sustained decline in kidney function. Cardiovascular outcomes included cardiovascular death, hospitalization for heart failure, or major adverse cardiovascular events. Safety outcomes focused on serious adverse events, with additional assessment of acute kidney injury, volume depletion, and treatment discontinuations.
2.5. Study selection and data extraction
Two reviewers independently screened all titles, abstracts, and full-text articles for eligibility, and disagreements were resolved by consensus or discussion with a third reviewer. Data were extracted using a standardized electronic form and included study characteristics, participant demographics, baseline clinical data, and outcome event counts within the hypertensive subgroups. When event numbers were not directly reported in the main text, subgroup data were obtained from supplementary appendices or trial registries.
2.6. Risk of bias and certainty assessment
The risk of bias for each included trial was assessed using the Cochrane Risk of Bias 2 tool, which evaluates the domains of randomization, deviations from intended interventions, missing outcome data, outcome measurement, and selective reporting. Each domain was rated as low risk, some concerns, or high risk, and overall judgments were made accordingly. The certainty of evidence across outcomes was further evaluated using the GRADE framework, taking into account study design, risk of bias, inconsistency, indirectness, imprecision, and potential publication bias, and the overall certainty of evidence was categorized as high, moderate, low, or very low.
2.7. Statistical analysis
For each trial and outcome, event counts and total numbers were extracted for the hypertensive subgroup. Odds ratios with corresponding 95 % confidence intervals were calculated, and pooled estimates were generated using a random-effects model with the DerSimonian–Laird method to account for between-study heterogeneity. Statistical heterogeneity was quantified using the I2 statistic and Cochran's Q test, with I2 values of 25 %, 50 %, and 75 % representing low, moderate, and high heterogeneity. The possibility of publication bias was assessed through visual inspection of funnel plots and Egger's test where applicable. Sensitivity analyses were conducted using fixed-effects models and leave-one-out analyses. All statistical analyses were performed in R software (version 2023.09.1 + 494) with the “meta” package, and two-sided p-values below 0.05 were considered statistically significant. Hazard ratios were not consistently available for hypertensive subgroups across trials. Therefore, odds ratios were calculated using subgroup event counts to allow uniform pooling. Given the relatively low event rates, ORs were considered a reasonable approximation of relative effects.
3. Result
A total of 396 records were identified through database searches, including 312 from PubMed and 84 from ClinicalTrials.gov. Although 84 records were retrieved from ClinicalTrials.gov, none met the inclusion criteria for quantitative synthesis. These records either represented duplicate trial registrations, ongoing studies without published results, or registry-only entries lacking outcome data for hypertensive subgroups. After removing 40 duplicates, 356 records remained for title and abstract screening. Of these, 340 records were excluded. The remaining 16 full-text articles were assessed for eligibility. Among these, 13 articles were excluded. Ultimately, three randomized controlled trials met the inclusion criteria and were included in the qualitative and quantitative synthesis: CREDENCE (canagliflozin), DAPA-CKD (dapagliflozin), and EMPA-KIDNEY (empagliflozin) [[9], [10], [11]].
Baseline characteristics were broadly comparable across the three trials (Table 1), although important differences reflect their distinct inclusion criteria. Participants in CREDENCE (n = 2219) and DAPA-CKD (n = 1772) were younger than those in EMPA-KIDNEY (n = 1445), with mean ages of 63.8, 64.3, and 68.4 years, respectively. No statistical heterogeneity was observed (Cochran's Q = 1.02, p = 0.60; I2 = 0 %). Visual inspection of the funnel plot for the primary composite outcome did not suggest asymmetry (Supplementary Fig. S1). Egger's regression test did not indicate small-study effects (intercept −0.12, p = 0.23), suggesting a low likelihood of publication bias. Interpretation is limited by the small number of included trials. The proportion of women was consistently low, ranging from 29.8 % to 34.1 %. Diabetes prevalence distinguished the cohorts: all patients in CREDENCE had type 2 diabetes, compared with 75 % in DAPA-CKD and only 27.5 % in EMPA-KIDNEY. Kidney function was more impaired in DAPA-CKD (mean eGFR 42.7 mL/min/1.73 m2) and EMPA-KIDNEY (35.1 mL/min/1.73 m2) compared with CREDENCE (55.5 mL/min/1.73 m2). Median UACR exceeded 1000 mg/g in CREDENCE and DAPA-CKD, but was much lower in EMPA-KIDNEY (114 mg/g). Cardiovascular disease was present in about half of CREDENCE participants, compared with 41 % in DAPA-CKD and 36 % in EMPA-KIDNEY. Background use of renin–angiotensin system inhibitors was nearly universal in CREDENCE and DAPA-CKD, but lower in EMPA-KIDNEY.
Table 1.
Baseline characteristics of participants with hypertension.
| Characteristic | CREDENCE (n = 2219) | DAPA-CKD (n = 1772) | EMPA-KIDNEY (n = 1445) |
|---|---|---|---|
| Age, years (mean ± SD) | 63.8 ± 8.9 | 64.3 ± 10.7 | 68.4 ± 11.9 |
| Female, n (%) | 757 (34.1) | 574 (32.4) | 430 (29.8) |
| Male, n (%) | 1462 (65.9) | 1198 (67.6) | 1015 (70.2) |
| BMI, kg/m2 (mean ± SD) | 31.7 ± 6.2 | 30.4 ± 6.1 | 30.0 ± 6.3 |
| SBP, mmHg (mean ± SD) | 152.4 ± 9.3 | 153.1 ± 10.1 | 138.0 ± 18.4 |
| DBP, mmHg (mean ± SD) | 81.2 ± 9.0 | 81.4 ± 11.0 | 78.0 ± 12.2 |
| eGFR, mL/min/1.73m2 (mean ± SD) | 55.5 ± 17.7 | 42.7 ± 12.5 | 35.1 ± 11.6 |
| UACR, mg/g (median, IQR) | 1040 (566–2307) | 1200 (617–2516) | 114 (18–623) |
| Type 2 diabetes, n (%) | 2219 (100) | 1329 (75.0) | 397 (27.5) |
| HbA1c, % (mean ± SD) | 8.2–8.3 | 7.2 ± 1.6 | – (not reported) |
| History of CVD, n (%) | 1151 (51.9) | 733 (41.4) | 516 (35.7) |
| RAS inhibitor use, n (%) | 2218 (99.9) | 1733 (97.8) | 1188 (82.2) |
| Diuretic use, n (%) | 1153 (52.0) | 884 (49.8) | 533 (36.9) |
The overall risk of bias across the included trials was judged to be low (Table 2). All three studies employed robust randomization with proper allocation concealment, were double-blind and placebo-controlled, had minimal and balanced missing outcome data with intention-to-treat analysis, and relied on objective, adjudicated clinical endpoints. Furthermore, prespecified outcomes were reported according to published protocols or trial registries, ensuring transparency and reducing the likelihood of selective reporting (see Table 3).
Table 2.
Risk of bias analysis.
| Domain | CREDENCE (2019) | DAPA-CKD (2020) | EMPA-KIDNEY (2023) |
|---|---|---|---|
| Randomization process | Low risk – central randomization, allocation concealed | Low risk – computer-generated, stratified by region | Low risk – central web-based randomization |
| Deviations from intended interventions | Low risk – double-blind, placebo-controlled | Low risk – double-blind, placebo-controlled | Low risk – double-blind, placebo-controlled |
| Missing outcome data | Low risk – balanced dropout, ITT analysis | Low risk – minimal loss to follow-up, ITT | Low risk – minimal loss to follow-up, ITT |
| Measurement of outcomes | Low risk – objective endpoints (eGFR, dialysis, death) | Low risk – objective outcomes, blinded adjudication | Low risk – outcomes adjudicated, standardized |
| Selection of reported results | Low risk – protocol published, prespecified outcomes | Low risk – protocol registered, prespecified | Low risk – prespecified outcomes, registry available |
| Overall risk of bias | Low | Low | Low |
Table 3.
Study outcomes.
| Category | Trial (Drug) | SGLT2i Events/Total (%) | Placebo Events/Total (%) | OR (95 % CI) |
|---|---|---|---|---|
| Primary Outcome |
CREDENCE (Canagliflozin) | 142/1097 (12.9 %) | 192/1122 (17.1 %) | 0.73 (0.57–0.94) |
| DAPA-CKD (Dapagliflozin) | 104/870 (12.0 %) | 140/888 (15.8 %) | 0.74 (0.56–0.97) | |
| EMPA-KIDNEY (Empagliflozin) |
82/706 (11.6 %) |
96/739 (13.0 %) |
0.88 (0.64–1.21) |
|
| Kidney Outcomes |
CREDENCE (Canagliflozin) | 93/1097 (8.5 %) | 136/1122 (12.1 %) | 0.69 (0.53–0.89) |
| DAPA-CKD (Dapagliflozin) | 81/870 (9.3 %) | 112/888 (12.6 %) | 0.74 (0.55–0.99) | |
| EMPA-KIDNEY (Empagliflozin) |
25/706 (3.5 %) |
33/739 (4.5 %) |
0.73 (0.43–1.22) |
|
| Cardiovascular Composite |
CREDENCE (Canagliflozin) | 109/1097 (9.9 %) | 129/1122 (11.5 %) | 0.86 (0.66–1.13) |
| DAPA-CKD (Dapagliflozin) | 49/870 (5.6 %) | 67/888 (7.5 %) | 0.74 (0.50–1.08) | |
| EMPA-KIDNEY (Empagliflozin) |
25/706 (3.5 %) |
37/739 (5.0 %) |
0.71 (0.42–1.20) |
|
| Serious Adverse Events (SAEs) | CREDENCE (Canagliflozin) | 386/1097 (35.2 %) | 432/1122 (38.5 %) | 0.89 (0.73–1.08) |
| DAPA-CKD (Dapagliflozin) | 297/870 (34.1 %) | 343/888 (38.6 %) | 0.84 (0.68–1.04) | |
| EMPA-KIDNEY (Empagliflozin) | NA | NA | – |
A combined sample of over 5000 patients with chronic kidney disease and hypertension were analyzed. The pooled analysis consistently demonstrated that SGLT2 inhibitors were associated with a reduced risk of adverse renal and cardiovascular outcomes compared with placebo, with generally favorable safety profiles.
For the primary composite outcome of kidney disease progression or cardiovascular death, all three trials showed numerically lower event rates in the SGLT2 inhibitor groups compared with placebo. In CREDENCE, events occurred in 12.9 % of patients on canagliflozin versus 17.1 % in placebo, yielding an OR of 0.73 (95 % CI, 0.57–0.94). Similarly, DAPA-CKD reported events in 12.0 % versus 15.8 % (OR 0.74, 95 % CI 0.56–0.97), while EMPA-KIDNEY found 11.6 % versus 13.0 % (OR 0.88, 95 % CI 0.64–1.21). The pooled analysis demonstrated a significant 24 % risk reduction (OR 0.76, 95 % CI 0.65–0.88), with no evidence of heterogeneity (I2 = 0 %).
In terms of kidney-specific outcomes, including end-stage kidney disease, sustained decline in eGFR, or kidney death, results were similarly consistent. Canagliflozin in CREDENCE reduced events to 8.5 % versus 12.1 % in placebo (OR 0.69, 95 % CI 0.53–0.89), while dapagliflozin in DAPA-CKD reported 9.3 % versus 12.6 % (OR 0.74, 95 % CI 0.55–0.99). Empagliflozin in EMPA-KIDNEY showed 3.5 % versus 4.5 % (OR 0.73, 95 % CI 0.43–1.22). When pooled, SGLT2 inhibitors were associated with a 30 % relative risk reduction (OR 0.70, 95 % CI 0.58–0.85), again with low heterogeneity (I2 = 0 %).
For the cardiovascular composite outcome of cardiovascular death or hospitalization for heart failure, results were less consistent across trials. CREDENCE reported 9.9 % versus 11.5 % (OR 0.86, 95 % CI 0.66–1.13), while DAPA-CKD observed 5.6 % versus 7.5 % (OR 0.74, 95 % CI 0.50–1.08). EMPA-KIDNEY reported 3.5 % versus 5.0 % (OR 0.71, 95 % CI 0.42–1.20). The pooled effect demonstrated a modest but statistically significant reduction (OR 0.79, 95 % CI 0.64–0.97), suggesting cardiovascular protection in hypertensive CKD patients.
With respect to safety, serious adverse events (SAEs) were available from CREDENCE and DAPA-CKD. In CREDENCE, 35.2 % of patients in the canagliflozin group experienced SAEs compared with 38.5 % in placebo (OR 0.89, 95 % CI 0.73–1.08). In DAPA-CKD, the corresponding rates were 34.1 % versus 38.6 % (OR 0.84, 95 % CI 0.68–1.04). Data were not available for EMPA-KIDNEY. The pooled analysis nonetheless indicated a significant reduction in SAEs with SGLT2 inhibitors (OR 0.85, 95 % CI 0.74–0.96), without evidence of heterogeneity (I2 = 0 %).
Overall, these findings demonstrate that SGLT2 inhibitors significantly reduce the risk of primary composite renal and cardiovascular outcomes, kidney disease progression, and serious adverse events in patients with CKD and hypertension, supporting their use as an effective and safe therapeutic option in this high-risk population.
Using the GRADE approach, the certainty of evidence was judged moderate across all outcomes. For the primary composite outcome (kidney failure, ≥50 % eGFR decline, or CV death), SGLT2 inhibitors reduced risk (OR ∼0.78, 95 % CI 0.63–0.96), though downgraded for imprecision. Kidney outcomes consistently showed benefit (OR ∼0.72, 95 % CI 0.57–0.91), also downgraded for imprecision. The cardiovascular composite demonstrated reduced events (OR ∼0.77, 95 % CI 0.60–0.99), but with wide CIs. For serious adverse events, the effect was neutral to slightly protective (OR ∼0.86, 95 % CI 0.72–1.02). Overall, evidence supports renal and cardiovascular benefits of SGLT2 inhibitors in CKD with moderate certainty.
4. Discussion
4.1. Principal findings
In this systematic review and meta-analysis of randomized controlled trials, we demonstrate that sodium–glucose cotransporter-2 (SGLT2) inhibitors significantly reduce the risk of renal disease progression and cardiovascular events among patients with chronic kidney disease (CKD) and concomitant hypertension. Across three large, high-quality trials—CREDENCE, DAPA-CKD, and EMPA-KIDNEY—SGLT2 inhibitors consistently lowered the risk of the primary composite outcome, kidney-specific endpoints, and serious adverse events, with modest but meaningful cardiovascular benefit. These findings extend prior evidence by specifically focusing on a hypertensive CKD population, a subgroup at particularly high risk for adverse renal and cardiovascular outcomes [[8], [9], [10], [11], [12]].
4.2. Renal protective mechanisms in hypertensive CKD
The renal benefits observed in this analysis are biologically plausible and supported by several complementary mechanisms. SGLT2 inhibitors reduce proximal tubular sodium and glucose reabsorption, thereby restoring tubuloglomerular feedback and lowering intraglomerular pressure. This mechanism is particularly relevant in hypertensive CKD, where sustained elevations in systemic and intraglomerular pressure accelerate glomerulosclerosis and nephron loss [[6], [7], [8]].
In addition, SGLT2 inhibition improves renal oxygen handling by reducing tubular energy demand and mitigating cortical hypoxia, a recognized driver of CKD progression. Experimental and clinical data further suggest that these agents may attenuate renal inflammation and fibrosis, contributing to long-term structural preservation [[8], [9], [10], [11], [12]]. The consistent reduction in kidney failure and sustained eGFR decline across trials, despite differences in baseline kidney function and albuminuria, supports a class-wide nephroprotective effect that is largely independent of glycemic status [[9], [10], [11]].
Another emerging mechanism involves stimulation of erythropoietin production and modest increases in hematocrit, which may enhance tissue oxygen delivery and contribute to improved renal resilience [12]. These combined effects provide a mechanistic framework for the robust and consistent kidney outcomes observed in hypertensive CKD populations.
4.3. Blood pressure modulation and tubuloglomerular feedback
Although the blood pressure–lowering effect of SGLT2 inhibitors is modest—typically a 3–5 mmHg reduction in systolic blood pressure—it may have amplified clinical relevance in patients with CKD and uncontrolled hypertension [13]. Even small reductions in systolic blood pressure are associated with meaningful decreases in the risk of CKD progression and cardiovascular events [[5], [6], [7]].
Importantly, the renal benefits of SGLT2 inhibitors appear to exceed what would be expected from blood pressure reduction alone, suggesting that hemodynamic effects at the level of the glomerulus play a dominant role. Restoration of tubuloglomerular feedback leads to afferent arteriolar vasoconstriction and reduced intraglomerular pressure, a mechanism that complements renin–angiotensin system blockade and may explain the additive benefits observed when SGLT2 inhibitors are used on top of standard antihypertensive therapy [8,9].
4.4. Cardiovascular and vascular protection
Cardiovascular disease remains the leading cause of morbidity and mortality in patients with CKD and hypertension [7]. In this analysis, SGLT2 inhibitors were associated with a modest but statistically significant reduction in cardiovascular composite outcomes, driven largely by reductions in heart failure–related events. These findings are consistent with prior cardiovascular outcome trials and meta-analyses demonstrating a class effect on heart failure prevention [8,12].
Potential mechanisms underlying cardiovascular protection include osmotic diuresis with preferential interstitial fluid removal, improved ventricular loading conditions, reduced arterial stiffness, and favorable effects on myocardial energetics. In hypertensive CKD patients, who frequently exhibit volume overload and left ventricular hypertrophy, these mechanisms may be particularly beneficial. Although effects on atherosclerotic events appear more modest, the overall cardiovascular risk reduction supports the integration of SGLT2 inhibitors into comprehensive cardiorenal risk management strategies [8].
4.5. Safety considerations
Safety is a critical concern in patients with advanced CKD and multiple comorbidities. Across the included trials, SGLT2 inhibitors demonstrated a favorable safety profile, with no increase in serious adverse events and a trend toward overall risk reduction. Importantly, concerns regarding acute kidney injury were not substantiated; on the contrary, several trials reported lower rates of acute kidney injury with SGLT2 inhibition [[9], [10], [11]].
While volume depletion and genitourinary infections remain recognized adverse effects, these events were generally mild and manageable [13]. The absence of excess serious harm reinforces the suitability of SGLT2 inhibitors for use in hypertensive CKD populations when appropriately monitored.
4.6. Clinical implications
These findings have important clinical implications. Patients with CKD and hypertension represent a high-risk population in whom traditional therapies often fail to fully mitigate renal and cardiovascular risk [1,5]. The consistent benefits observed across diverse CKD phenotypes—including diabetic and non-diabetic disease—support the early incorporation of SGLT2 inhibitors as part of standard therapy in hypertensive CKD patients, in line with current international guideline recommendations [1].
5. Limitations
Although several cardiovascular outcome trials reported hypertension subgroup analyses, these studies primarily enrolled heart failure or cardiovascular populations rather than CKD-specific cohorts, limiting comparability and increasing indirectness. Use of odds ratios instead of hazard ratios may overestimate effect size; however, direction and consistency of effects remained robust across trials. Mean SBP values may obscure individual-level hypertension status; however, subgroup definitions were consistent with trial-specific classifications, minimizing misclassification bias.
6. Conclusion
SGLT2 inhibitors significantly reduce kidney disease progression and cardiovascular events in patients with chronic kidney disease and hypertension, with consistent benefits across major trials. These findings support their early use as part of standard therapy to improve long-term renal and cardiovascular outcomes.
CRediT authorship contribution statement
R. Mohamad Javier: Conceptualization. Iqbal Faizin: Data curation. Andiani: Methodology. Dian Samudra: Writing – original draft. Renny Anggraeni Puspitasari: Writing – review & editing. Ahmad Surya Dharma: Investigation. Brianka Yudha Nurpradika: Conceptualization. Fauqi Amalia: Writing – review & editing. Siska Suridanda Danny: Software. Brm Ario Suryo Kuncoro: Formal analysis. Yusra Pintaningrum: Writing – original draft. Muhammad Almy Firasghani: Project administration. Puput Fiohana: Writing – original draft. Yosua Darmadi Kosen: Writing – original draft. Kristian Kurniawan: Conceptualization, Data curation, Investigation, Formal analysis, Funding acquisition, Methodology, Visualization, Writing – original draft.
Funding
This study received financial support from the Faculty of Medicine, University of Indonesia (D50MD03391711B2).
Declaration of competing interest
The authors declare that none of the work presented in this study was influenced by any known conflicting financial interests or personal relationships.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.ijcrp.2026.200585.
Contributor Information
R. Mohamad Javier, Email: jjforwork98@gmail.com.
Kristian Kurniawan, Email: kristiank2802@gmail.com.
Appendix A. Supplementary data
The following is/are the supplementary data to this article.
References
- 1.KDIGO 2024 Clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2024;105(4S):S117–S314. doi: 10.1016/j.kint.2023.10.018. [DOI] [PubMed] [Google Scholar]
- 2.GBD Chronic Kidney Disease Collaboration Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis. Lancet. 2020;395(10225):709–733. doi: 10.1016/S0140-6736(20)30045-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Xie Y., Bowe B., Mokdad A.H., Xian H., Yan Y., Li T., et al. Analysis of the global burden of disease study highlights CKD trends. Kidney Int. 2018;94(3):567–581. doi: 10.1016/j.kint.2018.04.011. [DOI] [PubMed] [Google Scholar]
- 4.Foreman K.J., Marquez N., Dolgert A., Fukutaki K., Fullman N., McGaughey M., et al. Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: 2016–40. Lancet. 2018;392(10159):2052–2090. doi: 10.1016/S0140-6736(18)31694-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Sowers J.R., Epstein M., Frohlich E.D. Diabetes, hypertension, and cardiovascular disease: an update. Hypertension. 2001;37(4):1053–1059. doi: 10.1161/01.hyp.37.4.1053. [DOI] [PubMed] [Google Scholar]
- 6.Stevens L.A., Coresh J., Greene T., Levey A.S. Assessing kidney function — measured and estimated glomerular filtration rate. N. Engl. J. Med. 2006;354(23):2473–2483. doi: 10.1056/NEJMra054415. [DOI] [PubMed] [Google Scholar]
- 7.Go A.S., Chertow G.M., Fan D., McCulloch C.E., Hsu C.Y. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N. Engl. J. Med. 2004;351(13):1296–1305. doi: 10.1056/NEJMoa041031. [DOI] [PubMed] [Google Scholar]
- 8.Kalantar-Zadeh K., Jafar T.H., Nitsch D., Neuen B.L., Perkovic V. Chronic kidney disease. Lancet. 2021;398(10302):786–802. doi: 10.1016/S0140-6736(21)00519-5. [DOI] [PubMed] [Google Scholar]
- 9.Perkovic V., Jardine M.J., Neal B., Bompoint S., Heerspink H.J.L., Charytan D.M., et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy (CREDENCE) N. Engl. J. Med. 2019;380(24):2295–2306. doi: 10.1056/NEJMoa1811744. [DOI] [PubMed] [Google Scholar]
- 10.Heerspink H.J.L., Stefánsson B.V., Correa-Rotter R., Chertow G.M., Greene T., Hou F.F., et al. Dapagliflozin in patients with chronic kidney disease (DAPA-CKD) N. Engl. J. Med. 2020;383(15):1436–1446. doi: 10.1056/NEJMoa2024816. [DOI] [PubMed] [Google Scholar]
- 11.EMPA-KIDNEY Collaborative Group. Herrington W.G., Staplin N., Wanner C., Green J.B., Hauske S.J. Empagliflozin in patients with chronic kidney disease. N. Engl. J. Med. 2023;388(2):117–127. doi: 10.1056/NEJMoa2204233. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Nuffield Department of Population Health Renal Studies Group SGLT2 inhibitor meta-analysis cardio-renal trialists' consortium. Impact of diabetes on the effects of sodium–glucose cotransporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet. 2022;400(10365):1788–1801. doi: 10.1016/S0140-6736(22)02074-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Weber M.A., Mansfield T.A., Cain V.A., Iqbal N., Parikh S., Ptaszynska A. Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Diabetes Endocrinol. 2016;4(3):211–220. doi: 10.1016/S2213-8587(15)00417-9. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.