The potential of spironolactone to mitigate the risk of nonalcoholic fatty liver disease in hypertensive populations: evidence from a cohort study

Abstract

Objective

While the link between nonalcoholic fatty liver disease (NAFLD) and hypertension is well recognized, the potential protective effects of the widely used antihypertensive medication, spironolactone, on NAFLD risk remain unclear. This study aimed to evaluate the impact of spironolactone on the development of NAFLD in hypertensive patients, shedding light on its potential broader clinical benefits beyond blood pressure control.

Methods

A total of 7241 participants were included. Propensity score matching (1 : 4 ratio) was employed to minimize confounding factors, creating balanced groups of spironolactone users and nonusers. Multivariate Cox regression analysis and Kaplan–Meier survival analysis were used to evaluate the association between spironolactone use and NAFLD risk. Restricted cubic splines (RCS) were applied to assess the dose–response relationship, and subgroup and sensitivity analyses were performed to validate the robustness of the findings.

Results

After matching, the study included 4110 participants (822 spironolactone users and 3288 nonusers). Spironolactone use was associated with a significantly lower risk of NAFLD, with a 16.3% reduction in risk compared with nonusers (hazard ratio: 0.821; 95% confidence interval: 0.714–0.944). The RCS analysis revealed that a cumulative spironolactone dose exceeding 635 mg*months was associated with a significant reduction in NAFLD risk. Subgroup and sensitivity analyses confirmed the consistency of these findings across various patient characteristics and conditions.

Conclusion

This study demonstrates a significant association between spironolactone use and a reduced risk of NAFLD in hypertensive patients, suggesting that it may have potential dual benefits in managing hypertension and protecting liver health.

Introduction

Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition defined by excessive fat accumulation in the liver, excluding secondary causes such as alcohol consumption [1,2]. With the growing prevalence of obesity, diabetes, and other metabolic disorders, the incidence of NAFLD has been steadily rising year by year [3,4]. NAFLD not only leads to severe liver complications, such as cirrhosis, and hepatocellular carcinoma, but is also closely associated with cardiovascular diseases [5,6]. This dual impact significantly increases the risk of mortality, making it an urgent public health issue that demands immediate attention [7,8].

Hypertension, a highly prevalent chronic condition affecting roughly one-third of the global adult population, frequently coexists with NAFLD [9–11]. Emerging evidence indicates that managing hypertension may also help prevent or alleviate NAFLD-related complications [12]. In this context, antihypertensive agents, especially those targeting the renin–angiotensin–aldosterone system (RAAS), have drawn growing interest for their potential benefits beyond blood pressure regulation [13,14]. Among these, spironolactone – a mineralocorticoid receptor antagonist and RAAS inhibitor – has garnered attention because of its proven ability to reduce inflammation, fibrosis, and metabolic dysregulation, which are central to the pathophysiology of NAFLD [15].

Spironolactone is commonly prescribed for the treatment of hypertension and heart failure, as well as conditions associated with excessive aldosterone secretion [16]. However, the effects of spironolactone may extend far beyond this. Some studies have indicated that spironolactone not only improves hemodynamic characteristics but also alleviates tissue damage caused by oxidative stress and inflammation [17–19]. Recent research has demonstrated that, in preclinical models of liver disease, spironolactone can reduce hepatic fat accumulation and slow the progression of fibrosis [20]. Moreover, human studies have suggested that spironolactone may improve liver function markers and metabolic health [21]. These findings suggest spironolactone may play a potential role in reducing the risk of NAFLD development in patients with hypertension.

Currently, large-scale clinical studies investigating the impact of spironolactone on the progression of NAFLD, particularly in hypertensive populations, remain limited, and the relationship between the two is not yet fully understood. Exploring this relationship could offer valuable insights into the broader benefits of spironolactone and guide clinical strategies for managing patients at risk of both hypertension and liver disease. To address this issue, our study explored the relationship between spironolactone use and the risk of NAFLD in patients with hypertension. We adopted a retrospective cohort study design with propensity score matching to minimize potential confounding factors and ensure reliable results. By doing so, we aim to contribute meaningful evidence to the growing recognition of spironolactone’s cardiometabolic and hepatoprotective effects in clinical practice.

Materials and methods

Screening of the study population

Inclusion criteria

This study included hypertensive patients who attended the Xinjiang Hypertension Center between January 2012 and December 2024 and were evaluated during multiple follow-up visits.

Exclusion criteria

First, we excluded participants with missing basic information, those younger than 18 years old, those with follow-up periods shorter than 6 months, and those without information on antihypertensive medications. Subsequently, considering the impact of other factors, we further excluded participants who had NAFLD at enrollment, lacked abdominal ultrasound or computed tomography scans, had a history of acute or chronic liver disease, suffered from severe cardiovascular or cerebrovascular diseases, had severe renal insufficiency, or were diagnosed with malignant tumors. After applying these exclusion criteria, 7241 participants met the study requirements (Fig. 1).

Fig. 1.

Flowchart of the study. CT, computed tomography.

This study was approved by the Ethics Committee of the People’s Hospital of Xinjiang Uygur Autonomous Region (KY2022080905). All research procedures were conducted in accordance with the Helsinki Declaration, and informed consent was obtained from all participants. To protect patient privacy, participants were assigned random codes, with their identities kept confidential.

Data collection and definitions

Basic patient information, including clinical history, physical examination results, medication history, and laboratory test results were collected from the hospital’s electronic medical records and medical insurance data. Height, weight, waist circumference, blood pressure, and smoking status were measured by a professional nurse using standardized procedures, with further details provided in the Supplementary Materials S1, http://links.lww.com/EJGH/B157. Laboratory results included total bilirubin, direct bilirubin, indirect bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), serum potassium, fasting blood glucose, creatinine, blood urea nitrogen, and plasma aldosterone concentrations, plasma renin activity, aldosterone–renin ratio, total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). These were all measured using a fully automated biochemical analyzer under standardized procedures. Hormone measurements were performed according to current guidelines and prior studies conducted at our center, ensuring normative operability [22–26]. The definitions of various diseases, including hypertension, diabetes, coronary heart disease, and hyperlipidemia, are provided in detail in the Supplementary Materials S1, http://links.lww.com/EJGH/B157.

Definition of drug use and cumulative drug dose

Building on previous research at our center, we defined spironolactone use as participants having taken the drug for at least six consecutive months in the past. Those who met this criterion were classified as spironolactone users [27]. Similarly, cumulative drug doses were assessed based on both the daily dose and the duration of medication use. Cumulative doses (in mg*months) were calculated by multiplying the daily dose (in milligrams) by the number of months of use.

Study outcome and follow-up

The process started with a clinician conducting an initial assessment for NAFLD, which was followed by annual abdominal ultrasounds to monitor the condition [28,29]. The identification of endpoint events was primarily based on medical records, medical insurance data, and telephone interviews. Follow-up continued from the participant’s initial entry into the study until the occurrence of the first instance of NAFLD, death, or 31 December 2024, whichever came first. More details about the NAFLD assessment can be found in the Supplementary Materials S1, http://links.lww.com/EJGH/B157.

Propensity score matching

The purpose of this study was to investigate the effect of spironolactone use on NAFLD. To minimize potential confounding bias, we used propensity score matching to closely match spironolactone users with nonusers. Matching was performed using the method recommended by Lonjon et al. [30], which estimates the likelihood of each participant using spironolactone. We conducted strict 1 : 4 matching based on gender, age, BMI, hypertension duration, ALT, AST, GGT, TC, TG, HDL-C, and LDL-C within the propensity score matching model. The caliper width was limited to 0.2 SDs to ensure precise matching, and the matching process was nonreplacement. In addition, to assess the balance of variables between the groups before and after matching, we used the standardized mean difference (SMD), with an SMD value below 0.10 indicating a balanced distribution [27,30,31].

Statistical analysis

We evaluated multicollinearity via the variance inflation factor (VIF), omitting variables with VIF greater than or equal to 10 to ensure model reliability (Table S1, Supplemental Digital Content 1, http://links.lww.com/EJGH/B157). Participants were first divided into two groups based on their spironolactone use: the spironolactone use group and the nonuse group. To assess the effect of spironolactone on NAFLD, we performed multifactor Cox regression analysis before and after matching. In addition, Kaplan–Meier (KM) survival analysis was used to estimate the cumulative risk of MAFLD in both groups, and the log-rank test was applied for comparison. To evaluate the effect of spironolactone cumulative dose on NAFLD, we used restricted cubic splines (RCS) to assess the dose–response relationship. Furthermore, a two-stage comparative analysis was conducted based on the turning points identified in the RCS curve. To validate the robustness of our findings, we also performed subgroup and sensitivity analyses. Detailed information on the statistical methods can be found in the Supplementary Materials S1, http://links.lww.com/EJGH/B157.

All statistical analyses were conducted using R 4.2.2, with bilateral P values less than 0.05 considered statistically significant.

Results

Patient selection

Following strict 1 : 4 matching based on propensity scores, the study included a total of 4110 participants, with 822 users of spironolactone and 3288 nonusers. The participant selection process is illustrated in Fig. 1.

Baseline results before and after matching

Before matching, spironolactone users were more likely to be female, younger, and had lower systolic blood pressure and higher plasma aldosterone levels compared with nonusers. They also had a higher prevalence of current dyslipidemia (DLP) and diabetes mellitus (DM). In addition, those who used spironolactone long-term were more likely to take diuretics, calcium channel blockers, beta blockers, as well as more hypoglycemic and lipid-lowering medications. After strict matching, individual indicators achieved intergroup balance (SMD < 0.1). The balance of variables before and after matching is shown in Table 1 and Figure S1, Supplemental Digital Content 1, http://links.lww.com/EJGH/B157.

Table 1.

Baseline characteristics before propensity score matching

Characteristics	Before propensity score matching			After propensity score matching
	Nonuser	User	SMD	Nonuser	User	SMD
Sample size, n	6417	823		3288	822
Age (years)	53.5 ± 12.5	51.4 ± 11.3	0.171	51.2 ± 11.6	51.4 ± 11.3	0.018
Sex			0.045			0.018
Women	3247 (50.60%)	435 (52.86%)		1707 (51.92%)	434 (52.80%)
Men	3170 (49.40%)	388 (47.14%)		1581 (48.08%)	388 (47.20%)
BMI (kg/m2)	25.4 ± 3.1	25.5 ± 3.0	0.03	25.5 ± 3.0	25.5 ± 3.0	0.013
Waist circumference (cm)	93.1 ± 9.8	92.9 ± 9.7	0.028	93.0 ± 9.7	92.9 ± 9.7	0.011
Systolic blood pressure (mmHg)	145.6 ± 18.7	144.1 ± 18.6	0.081	145.5 ± 18.6	144.0 ± 18.6	0.077
Diastolic blood pressure (mmHg)	88.0 ± 13.5	88.1 ± 12.9	0.007	89.1 ± 13.5	88.1 ± 12.9	0.076
Current smoking (%)	1787 (27.85%)	254 (30.86%)	0.066	950 (28.89%)	253 (30.78%)	0.041
Duration of hypertension (%)			0.053			0.014
<5 years	4581 (71.39%)	607 (73.75%)		2404 (73.11%)	606 (73.72%)
≥5 years	1836 (28.61%)	216 (26.25%)		884 (26.89%)	216 (26.28%)
Biochemical indexes
TBIL (μmol/L)	12.7 ± 5.2	12.8 ± 5.3	0.016	12.6 ± 5.2	12.8 ± 5.3	0.038
DBIL (μmol/L)	4.4 ± 1.9	4.4 ± 1.9	0.006	4.4 ± 1.9	4.4 ± 1.9	0.038
IBIL (μmol/L)	8.4 ± 3.8	8.5 ± 4.0	0.032	8.3 ± 3.8	8.5 ± 4.0	0.045
AST (U/L)	18.5 ± 5.0	18.3 ± 4.7	0.038	18.2 ± 4.8	18.3 ± 4.7	0.026
ALT (U/L)	19.8 ± 9.3	20.0 ± 9.11	0.022	19.8 ± 9.3	20.0 ± 9.1	0.015
GGT (U/L	26.2 ± 15.4	26.6 ± 15.4	0.027	26.7 ± 15.5	26.6 ± 15.4	0.005
Serum potassium (mmol/L)	3.9 ± 0.4	3.9 ± 0.4	0.084	3.9 ± 0.4	3.9 ± 0.4	0.059
Fasing blood glucose (mmol/L)	4.9 ± 0.8	4.8 ± 0.8	0.055	4.8 ± 0.8	4.8 ± 0.8	0.013
Serum creatinine (µmol/L)	65.8 ± 15.1	65.6 ± 15.2	0.013	65.4 ± 15.2	65.6 ± 15.2	0.008
BUN (mmol/L)	5.1 ± 1.4	5.0 ± 1.3	0.045	5.0 ± 1.3	5.0 ± 1.3	0.01
UA (μmol/L)	317.1 ± 79.8	319.5 ± 80.2	0.03	316.2 ± 80.0	319.3 ± 80.1	0.04
PAC (ng/dl)	15.6 ± 6.3	17.4 ± 6.5	0.288	15.9 ± 6.5	17.4 ± 6.5	0.241
PRA (ng/ml/h)	1.7 ± 1.3	1.8 ± 1.4	0.033	1.7 ± 1.4	1.8 ± 1.4	0.026
ARR	20.1 ± 25.1	20.5 ± 24.5	0.015	20.5 ± 25.7	20.5 ± 24.5	0.003
Total cholesterol (mmol/L)	4.3 ± 0.9	4.3 ± 0.9	0.017	4.4 ± 0.9	4.3 ± 0.9	0.011
Triglyceride (mmol/L)	1.4 ± 0.7	1.5 ± 0.7	0.044	1.4 ± 0.7	1.5 ± 0.7	0.015
HDL-C (mmol/L)	1.1 ± 0.3	1.1 ± 0.3	0.008	1.1 ± 0.3	1.1 ± 0.3	0.005
LDL-C (mmol/L)	2.6 ± 0.8	2.6 ± 0.8	0.001	2.6 ± 0.8	2.6 ± 0.8	0.026
Comorbidities (%)
Dyslipidemia	765 (11.92%)	107 (13.00%)	0.033	384 (11.68%)	107 (13.02%)	0.041
Coronary heart disease	713 (11.11%)	68 (8.26%)	0.096	305 (9.28%)	68 (8.27%)	0.035
Diabetes mellitus	763 (11.89%)	115 (13.97%)	0.062	379 (11.53%)	115 (13.99%)	0.074
Medications use (%)
ACEIs/ARBs	2871 (44.74%)	351 (42.65%)	0.042	1478 (44.95%)	351 (42.70%)	0.045
Diuretic	708 (11.03%)	202 (24.54%)	0.359	371 (11.28%)	202 (24.57%)	0.352
Calcium channel blockers	3366 (52.45%)	476 (57.84%)	0.108	1653 (50.27%)	476 (57.91%)	0.154
β-Blockers	1265 (19.71%)	189 (22.96%)	0.079	661 (20.10%)	189 (22.99%)	0.07
Antidiabetic agents	429 (6.69%)	73 (8.87%)	0.082	201 (6.11%)	73 (8.88%)	0.105
Lipid-lowering drugs	807 (12.58%)	125 (15.19%)	0.076	366 (11.13%)	125 (15.21%)	0.121
Outcome	2321 (36.17%)	217 (26.37%)	0.213	1248 (37.96%)	217 (26.40%)	0.249

Data are presented as mean ± SD, median (interquartile range), or as numbers, and percentages.

ACEI, angiotensin-converting enzyme inhibitor; ALT, alanine aminotransferase; ARB, angiotensin receptor blocker; AST, aspartate aminotransferase; BUN, blood urea nitrogen; DBIL, direct bilirubin; GGT, gamma-glutamyl transferase; HbA1c, glycosylated hemoglobin; HDL-C, high-density lipoprotein cholesterol; IBIL, indirect bilirubin; LDL-C, low-density lipoprotein cholesterol; PAC, plasma aldosterone concentration; PRA, plasma renin activity; SMD, standardized mean difference; TBIL, total bilirubin; UA, uric acid.

Relationship between spironolactone use and nonalcoholic fatty liver disease (user vs. nonuser)

Before matching, multifactorial Cox regression analyses indicated that spironolactone use was strongly associated with a significantly lower risk of developing NAFLD. In the fully adjusted model 5, long-term spironolactone users had a 17.9% lower risk of NAFLD compared with nonusers (hazard ratio: 0.821, 95% confidence interval: 0.714–0.944) (Table 2). The KM curves also demonstrated consistent results (Fig. 2). After matching, the findings remained consistent. Specifically, long-term spironolactone users had a 16.3% lower risk of developing NAFLD compared with nonusers (Table 3). The KM curves further confirmed that drug users had a lower risk of developing the disease compared with nonusers (Fig. 3). These results suggest that spironolactone use may help reduce the future risk of NAFLD in patients with hypertension.

Table 2.

Effect of user versus nonuser on nonalcoholic fatty liver disease before matching

Exposure	Model 1 HR (95% CI)	Model 2 HR (95% CI)	Model 3 HR (95% CI)	Model 4 HR (95% CI)	Model 5 HR (95% CI)
Nonuser	Reference	Reference	Reference	Reference	Reference
User	0.802 (0.698–0.922)	0.797 (0.693–0.916)	0.800 (0.696–0.920)	0.800 (0.696–0.920)	0.821 (0.714–0.944)

Model 1: Unadjusted (univariate analysis).

Model 2: Adjusted for age, sex, smoking status, alcohol consumption, and duration of hypertension.

Model 3: Model 2 plus additional adjustments for systolic blood pressure, diastolic blood pressure, BMI, waist circumference, diabetes mellitus, dyslipidemia, and coronary heart disease.

Model 4: Model 3 plus further adjustments for GGT, serum creatinine, uric acid, triglyceride, HDL-C, fasting blood glucose, and HbA1c.

Model 5: Model 4 plus adjustments for the use of antidiabetic medications, lipid-lowering agents, and antihypertensive drugs.

CI, confidence interval; GGT, gamma-glutamyl transferase; HbA1c, glycosylated hemoglobin; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio.

Fig. 2.

Kaplan–Meier curves for NAFLD in the spironolactone user and nonuser groups (before propensity score matching). NAFLD, nonalcoholic fatty liver disease.

Table 3.

Effect of user versus nonuser on nonalcoholic fatty liver disease after matching

Exposure	Model 1 HR (95% CI)	Model 2 HR (95% CI)	Model 3 HR (95% CI)	Model 4 HR (95% CI)	Model 5 HR (95% CI)
Nonuser	Reference	Reference	Reference	Reference	Reference
User	0.780 (0.715–0.850)	0.804 (0.737–0.877)	0.803 (0.736–0.876)	0.810 (0.741–0.884)	0.837 (0.766–0.915)

Model 1: Unadjusted (univariate analysis).

Model 2: Adjusted for age, sex, smoking status, alcohol consumption, and duration of hypertension.

Model 3: Model 2 plus additional adjustments for systolic blood pressure, diastolic blood pressure, BMI, waist circumference, diabetes mellitus, dyslipidemia, and coronary heart disease.

Model 4: Model 3 plus further adjustments for GGT, serum creatinine, uric acid, triglyceride, HDL-C, fasting blood glucose, and HbA1c.

Model 5: Model 4 plus adjustments for the use of antidiabetic medications, lipid-lowering agents, and antihypertensive drugs.

CI, confidence interval; GGT, gamma-glutamyl transferase; HbA1c, glycosylated hemoglobin; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio.

Fig. 3.

Kaplan–Meier curves for NAFLD in the spironolactone user and nonuser groups (after propensity score matching). NAFLD, nonalcoholic fatty liver disease.

Relationship between spironolactone cumulative dose and nonalcoholic fatty liver disease

To further investigate the association between spironolactone use and NAFLD, we conducted a cumulative drug dose analysis for all participants using spironolactone. The results showed that in model 1, each 100 mg increase in spironolactone dose was associated with a 7.4% reduction in the risk of NAFLD. In the fully adjusted model 5, this effect remained consistent, with a 7.7% reduction in NAFLD risk (Table 4). To further assess the dose–response relationship, the RCS results indicated that when the cumulative dose of spironolactone exceeded 635 mg*months, the risk of NAFLD was significantly reduced (Fig. 4). Specifically, the two-stage comparative analysis showed that participants with a cumulative dose of 635 mg*months or greater had a 71.9% lower risk of NAFLD compared to those with a cumulative dose below 635 mg*months (Table 5). These findings further support a significant association between spironolactone and a reduced risk of NAFLD. Moreover, as the cumulative dose of spironolactone increased, the risk of NAFLD gradually increased, highlighting the potential benefit of spironolactone in reducing the future occurrence of NAFLD in hypertensive patients.

Table 4.

The relationship between cumulative drug dose and nonalcoholic fatty liver disease

Exposure	Model 1 HR (95% CI)	Model 2 HR (95% CI)	Model 3 HR (95% CI)	Model 4 HR (95% CI)	Model 5 HR (95% CI)
Cumulative dose (per 100 mg*months increase)	0.926 (0.918–0.934)	0.924 (0.916–0.932)	0.923 (0.915–0.931)	0.923 (0.915–0.931)	0.923 (0.915–0.931)

Model 1: Unadjusted (univariate analysis).

Model 2: Adjusted for age, sex, smoking status, alcohol consumption, and duration of hypertension.

Model 3: Model 2 plus additional adjustments for systolic blood pressure, diastolic blood pressure, BMI, waist circumference, diabetes mellitus, dyslipidemia, and coronary heart disease.

Model 4: Model 3 plus further adjustments for GGT, serum creatinine, uric acid, triglyceride, HDL-C, fasting blood glucose, and HbA1c.

Model 5: Model 4 plus adjustments for the use of antidiabetic medications, lipid-lowering agents, and antihypertensive drugs.

CI, confidence interval; GGT, gamma-glutamyl transferase; HbA1c, glycosylated hemoglobin; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio.

Fig. 4.

Dose–response relationship between cumulative drug dose and NAFLD. CI, confidence interval; HR, hazard ratio; NAFLD, nonalcoholic fatty liver disease.

Table 5.

The impact of cumulative dose before and after the restricted cubic splines turning point on nonalcoholic fatty liver disease

Exposure	Model 1 HR (95% CI)	Model 2 HR (95% CI)	Model 3 HR (95% CI)	Model 4 HR (95% CI)	Model 5 HR (95% CI)
Turning point (mg*months) 635
Cumulative dose < 635 mg*months	Reference	Reference	Reference	Reference	Reference
Cumulative dose ≥ 635 mg*months	0.301 (0.274–0.331)	0.289 (0.262–0.318)	0.280 (0.254–0.309)	0.281 (0.255–0.310)	0.281 (0.255–0.310)

Model 1: Unadjusted (univariate analysis).

Model 2: Adjusted for age, sex, smoking status, alcohol consumption, and duration of hypertension.

Model 3: Model 2 plus additional adjustments for systolic blood pressure, diastolic blood pressure, BMI, waist circumference, diabetes mellitus, dyslipidemia, and coronary heart disease.

Model 4: Model 3 plus further adjustments for GGT, serum creatinine, uric acid, triglyceride, HDL-C, fasting blood glucose, and HbA1c.

Model 5: Model 4 plus adjustments for the use of antidiabetic medications, lipid-lowering agents, and antihypertensive drugs.

CI, confidence interval; GGT, gamma-glutamyl transferase; HbA1c, glycosylated hemoglobin; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio.

Subgroup analysis and sensitivity analysis

To account for the potential influence of participants’ underlying conditions on the study results, we first stratified the participants by age, sex, BMI, SBP, DBP, current smoking status, hypertension duration, DLP, coronary heart disease (CHD), and DM. The results remained consistent with the overall findings, showing that spironolactone use was associated with a reduced risk of developing NAFLD across all subgroups (Fig. 5). Similarly, recognizing that hypertensive patients often use multiple antihypertensive medications, we restratified the participants based on their use of various medications (Figure S2, Supplemental Digital Content 1, http://links.lww.com/EJGH/B157). The results remained unchanged, indicating that the effect of spironolactone on reducing the risk of NAFLD was not affected by these factors. To further exclude potential interference from other variables, we conducted several sensitivity analyses. First, to address the effect of diabetes on NAFLD, we excluded all participants with diabetes, and the results remained consistent both before and after matching (Tables S2 and S3, Supplemental Digital Content 1, http://links.lww.com/EJGH/B157). Second, considering that obesity is a major risk factor for NAFLD, we excluded participants with a BMI greater than 30 kg/m², and again, the results did not change (Tables S4 and S5, Supplemental Digital Content 1, http://links.lww.com/EJGH/B157). Third, to account for the possibility of reverse causality, we excluded participants with less than 1 year of follow-up, and the results remained stable (Tables S6 and S7, Supplemental Digital Content 1, http://links.lww.com/EJGH/B157). Fourth, after excluding participants with hyperlipidemia, the results were unaffected (Tables S8 and S9, Supplemental Digital Content 1, http://links.lww.com/EJGH/B157). Finally, given that participants with primary aldosteronism are more likely to take spironolactone, we also excluded those with primary aldosteronism, and the results remained robust (Tables S10 and S11, Supplemental Digital Content 1, http://links.lww.com/EJGH/B157). These findings further suggest that spironolactone use may provide benefits for liver health in hypertensive patients, regardless of their underlying conditions, and may help reduce the future risk of NAFLD in this population. To evaluate the potential impact of unmeasured confounders, we performed an E value analysis. The results suggested that the influence of confounding factors was minimal, and the probability of our findings being overturned was low (Table S12, Supplemental Digital Content 1, http://links.lww.com/EJGH/B157).

Fig. 5.

Association between cumulative drug dose and osteoporosis in various subgroups. CHD, coronary heart disease; CI, confidence interval; DBP, diastolic blood pressure; DLP, dyslipidemia; DM, diabetes mellitus; HR, hazard ratio; SBP, systolic blood pressure.

Discussion

This study demonstrates a significant link between spironolactone use and a reduced risk of NAFLD in hypertensive patients. The data further show that higher cumulative doses of spironolactone are associated with a progressively lower risk of NAFLD, emphasizing its potential role in preventing the condition in this population. Beyond its primary use as a widely prescribed antihypertensive drug, spironolactone may also offer additional benefits, such as reducing liver fibrosis and potentially slowing NAFLD progression. These findings suggest it could have broader clinical applications in managing both hypertension- and liver-related metabolic disorders.

NAFLD is strongly linked to hypertension, metabolic imbalance, and systemic inflammation, all of which drive its progression [32–35]. Among these, hypertension stands out as an independent risk factor, as it fosters oxidative stress, impairs vascular function, and facilitates hepatic fat deposition [1,36,37]. Aldosterone, a pivotal hormone in maintaining fluid and electrolyte homeostasis, plays a significant role in regulating blood pressure and is a key factor in conditions like primary aldosteronism, a major cause of secondary and treatment-resistant hypertension [38,39]. Moreover, beyond its well-established involvement in hypertension, aldosterone, as an integral part of the RAAS, is increasingly recognized for its potential role in the onset and progression of NAFLD [40–42]. Elevated aldosterone levels have been linked to increased hepatic steatosis, inflammation, and fibrosis through mechanisms such as mitochondrial dysfunction and enhanced lipid peroxidation [43]. Over the years, several studies have explored spironolactone, a mineralocorticoid receptor antagonist that directly counteracts aldosterone, for its hepatoprotective effects [44–46]. Preclinical studies using rodent NAFLD models have demonstrated that spironolactone reduces hepatic fat accumulation, inflammation, and fibrosis, potentially through mechanisms involving the attenuation of oxidative stress, suppression of inflammatory cytokines, and improvement of mitochondrial function [47]. These findings suggest spironolactone may not only reduce liver damage but also slow the progression of NAFLD to more severe stages, such as nonalcoholic steatohepatitis (NASH) [16].

Although research on the effects of spironolactone on the liver is relatively limited, the available evidence still offers hope that it promotes liver health. A small randomized-controlled trial involving patients with cirrhosis found that spironolactone improved liver function parameters, reduced fibrosis markers, and alleviated portal hypertension – one of the complications of advanced liver disease [48]. Similarly, a study in patients with obesity and metabolic dysfunction showed that spironolactone decreased hepatic fat content and improved insulin sensitivity, underscoring its therapeutic potential for addressing both metabolic and liver-related aspects of NAFLD [15]. In addition, its effects on related conditions, such as lowering inflammation and oxidative stress in patients with metabolic syndrome or heart failure, further provide indirect evidence of its potential hepatoprotective role [49]. Although previous studies have highlighted spironolactone’s potential in reducing hepatic fat deposition, inflammation, and fibrosis, most of these investigations have been limited to preclinical studies or small clinical trials. Moreover, despite the large population of hypertensive patients, there is still a lack of data specifically addressing the effects of spironolactone on NAFLD in this group. To address this gap, our study, which is based on large-scale longitudinal data, demonstrates that spironolactone reduces the risk of NAFLD in hypertensive patients. In addition, our findings reveal that increasing cumulative spironolactone use further lowers the risk of developing NAFLD. These results suggest that spironolactone not only demonstrates excellent efficacy in treating cardiovascular disease but may also play an important role in the treatment of NAFLD, offering valuable evidence for future research.

The protective effects of spironolactone against NAFLD arise from its ability to target multiple interrelated pathways, positioning it as a promising therapeutic candidate [50]. Central to its mechanism is the suppression of aldosterone, a hormone that exacerbates hepatic steatosis by impairing insulin sensitivity, stimulating lipogenesis, and driving inflammation through oxidative stress [51]. As a mineralocorticoid receptor antagonist, spironolactone directly inhibits these harmful processes, thereby mitigating aldosterone’s pathological influence [47]. First and foremost, the most plausible mechanism may be that spironolactone competitively inhibits androgen receptors and potentially increases estrogen levels, leading to an imbalance in the estrogen/androgen ratio [52]. Estrogen, by activating estrogen receptors, regulates the expression of genes involved in lipid metabolism, thereby inhibiting hepatic lipogenesis and promoting fatty acid oxidation [53,54]. Furthermore, estrogen can elevate adiponectin levels, an adipokine known for its anti-inflammatory properties and ability to enhance insulin sensitivity, which in turn reduces hepatic fat accumulation [55,56]. In addition, spironolactone exhibits strong anti-inflammatory properties by lowering levels of proinflammatory cytokines and enhancing antioxidant capacity [57]. These effects not only attenuate systemic and liver-specific inflammation but also improve hepatic insulin sensitivity, further reducing the accumulation of fat in the liver [58]. Moreover, spironolactone contributes to better metabolic health by decreasing visceral fat, improving lipid regulation, and enhancing overall insulin responsiveness [59]. These combined actions significantly limit hepatic fat deposition and the progression of steatosis [40,60]. Beyond its metabolic benefits, spironolactone positively impacts cardiovascular and hemodynamic parameters. By lowering blood pressure and reducing vascular stiffness, it alleviates hepatic vascular hypertension and decreases the hepatic venous pressure gradient, processes that play a role in slowing NAFLD progression [61,62]. Furthermore, spironolactone’s ability to counteract oxidative stress, a major driver of mitochondrial dysfunction in the liver, supports more efficient lipid metabolism and reduces inflammation, thereby strengthening its hepatoprotective capacity [63]. Overall, the multifaceted mechanisms of spironolactone highlight its potential to not only address key drivers of NAFLD but also manage hypertension, making it an especially effective option for protecting liver health in hypertensive individuals.

This study has several strengths. It is the first to use large-scale longitudinal data to examine the significant impact of spironolactone on reducing the risk of NAFLD in a broad range of hypertensive patients. In addition, the application of propensity score matching to minimize potential confounders, along with extensive subgroup analyses and sensitivity tests, provides strong evidence for the robustness of the results. Moreover, these findings hold considerable clinical significance and may offer a new approach to treating NAFLD in hypertensive patients. Despite these strengths, several limitations should be acknowledged. First, as a retrospective cohort study, our ability to demonstrate causal effects is limited, and we cannot establish a definitive cause-and-effect relationship. Second, the lack of detailed data on factors such as dietary habits, physical activity, and alcohol consumption – key influences on NAFLD – represents another limitation. However, we addressed potential confounders by using propensity score matching. Third, reliance on electronic medical records restricts our ability to assess patient adherence to spironolactone therapy, which is an important limitation that future studies should address. Fourth, the absence of histological data in our study may hinder the accurate assessment of NAFLD progression, particularly with regard to hepatic fibrosis and NASH. Future research should explore these aspects in greater depth. Finally, since our study cohort consisted exclusively of Chinese hypertensive patients, the generalizability of our findings to other ethnic or demographic groups may be limited.

Conclusion

In conclusion, this study is the first to identify an association between spironolactone use and a reduced risk of NAFLD in hypertensive patients, with a further reduction in risk as cumulative drug doses increase. These findings are of significant clinical importance, as they suggest that spironolactone’s benefits extend beyond blood pressure reduction and may also play a crucial role in improving liver health.

Acknowledgements

This study was provided by the Major Science and Technology Projects of the Xinjiang Uygur Autonomous Region (2022A03012-4).

D.S. and S.S. both contributed equally to this project. The research was done by D.S., S.S., J.H., and X.C. Data analysis and interpretation were done by D.S., Q.Z., and Y.Z. The paper was written by D.S. and S.S., and it was critically corrected by X.C., R.M., P.Z., Z.Z., J.H., and N.L. N.L. directed the entire research process.

Conflicts of interest

There are no conflicts of interest.