Renin-angiotensin system-modifying antihypertensive drugs can reduce the risk of cardiovascular complications in lupus: a retrospective cohort study

Abstract

Background:

Patients with systemic lupus erythematosus have a higher incidence of cardiovascular disease than the general population. Antihypertensive drugs that modify the renin-angiotensin system (RAS) are used to protect renal function in lupus nephritis and may also have extrarenal effects that lower cardiovascular disease risk due to their anti-inflammatory properties. In this study, we compared the effects of RAS versus non-RAS antihypertensive drugs on cardiovascular disease incidence in patients with lupus.

Methods:

Using a medical insurance claims dataset, 220,168 patients with lupus were identified, of which 31,647 patients (4,018 patients prescribed RAS drugs, 27,629 patients prescribed non-RAS drugs) were eligible for the study. Patients had a mean age of 46.1 years, 93.0% female, and healthy (96.9% Charlson Comorbidity Index score 0–4). Patients in the two drug groups were propensity score matched using demographic data, risk factors, and comorbidities.

Results:

Use of RAS versus non-RAS drugs lowered the relative risk (RR) of diagnosis of cardiovascular disease (RR 0.80, 95% CI [0.74–0.87]), which was more pronounced after propensity score matching (RR 0.62, 95% CI [0.57–0.68]). The decreased risk in cardiovascular disease occurred regardless of lupus nephritis status (with lupus nephritis: RR 0.51, 95% CI [0.39–0.65]; without lupus nephritis: RR 0.65, 95% CI [0.59–0.72]). RAS-modifying therapies significantly increased cardiovascular disease-free survival probability over a 5-year period (86.0% versus 78.3% probability).

Conclusions:

RAS-modifying drugs reduced the risk of cardiovascular disease in patients with systemic lupus erythematosus in this dataset. These findings have the potential to impact clinical decision making with regards to hypertension management in patients with lupus.

Introduction

Systemic Lupus Erythematosus is an autoimmune disease characterized by multisystem involvement, inflammation, and tissue damage.¹ The etiology is multifactorial; genetic, hormonal, environmental, and immunologic factors likely play a role.² Many of the clinical manifestations are mediated directly or indirectly by the formation of autoantibodies to nuclear and cytoplasmic antigens and the creation of immune complexes.³ Immune complex deposition and complement activation in the kidney is responsible for tissue damage in lupus nephritis, and immune complexes have also been detected at the dermal-epidermal junction of the skin, the pericardium, and the pleural cavity of lupus patients.^3,4,5 Clinical manifestations range from mild to life-threatening; most patients present the classical symptoms of fever, joint pain, and rash, but many patients also experience more serious morbidities when major organs are affected, resulting most notably in renal, cardiovascular, hematologic, pulmonary, and central nervous system dysfunction.^1,6,7

Focus on the treatment of lupus nephritis has significantly reduced patient morbidity and mortality due to kidney failure. With this advance, cardiovascular disease is now a leading cause of death for patients with lupus.^8,9,10 Cardiac complications affect roughly half of patients with systemic lupus erythematosus and cause significant morbidity and mortality in spite of current therapeutic options.¹¹ This impact is magnified by the fact that cardiovascular disease occurs at a younger average age in patients with lupus and at a rate of 2 to 50 times the general population.^{12,13,14,15,16,17} The exact connection between lupus and cardiovascular disease is unknown, but inflammation appears to be involved.¹⁸ Cardiovascular disease has an immune component apart from lupus; a low level of chronic inflammation has been found to be associated with atherosclerotic plaque formation, including autoantibodies to LDL cholesterol.¹⁹ In addition, accelerated atherosclerosis and cardiovascular disease occur not just in lupus, but in other autoimmune diseases like rheumatoid arthritis and psoriasis.²⁰ Cardiovascular disease risk in lupus is affected not only by traditional risk factors (for example, hypertension, obesity, and diabetes), but also features specific to lupus (including chronic inflammation, antiphospholipid antibodies, lupus nephritis, and corticosteroid use), which may explain its accelerated presence in lupus.^18,21 One traditional risk factor in particular, hypertension, occurs in 33 to 74 percent of lupus patients, and it has been linked to atherosclerotic plaque development and artery stiffening in lupus, increasing cardiovascular disease risk by two to seven times.^{17,22,23,24,25,26,27}

The current therapeutic options for lupus are primarily focused on the use of immunosuppressive therapies.²⁸ However, the use of immunosuppressive therapy is associated with a risk of serious complications, including uncontrolled infections and the development of cancer, and may not address all the morbidities associated with lupus.^29,30 Decades of focusing on a single therapeutic strategy has resulted in a limited number of viable alternatives to immunosuppression for the foreseeable future. In addition, despite the additional risk factors in patients with lupus, optimized and standardized guidelines for lupus-specific treatment to prevent cardiovascular disease have not been developed.^22,31,32 Improving the current clinical guidelines is essential, as there has been little improvement in cardiovascular disease-caused mortality in recent years.³³

Given this, we sought to evaluate the effect that anti-hypertensive medications that modify the renin-angiotensin system (RAS) have on CVD outcomes. RAS is involved in blood pressure, sodium, and fluid regulation, ultimately affecting cardiovascular, circulatory, hemodynamic, and renal functions.^34,35,36 In more recent studies, RAS has also been found to be directly involved in inflammation, immune responses, and oxidative stress.^35,36 Specifically, use of RAS-modifying drugs (angiotensin-converting enzyme inhibitors [ACE-Is] and angiotensin II type 1 receptor blockers [ARBs]) effectively treat high blood pressure, slow the effects of lupus-associated kidney disease, and reduce elevated and dysregulated pro-inflammatory cytokines and chemokines in a number of disease states, including in lupus mouse models.^{37,38,39,40,41,42,43,44,45,46}

Herein, we use insurance claims data mining to compare the relative impact of treating hypertension with RAS-modifying drugs (ACE-Is and ARBs) versus non-RAS drugs (diuretics, calcium-channel blockers, and beta blockers) in the context of lupus patient progression to cardiovascular disease. We hypothesize that patients with systemic lupus erythematosus may have greater cardiovascular protection from RAS modulators relative to other non-RAS antihypertensive therapeutic options because RAS drugs affect the cardiovascular risk factors of inflammation and renal disease in addition to hypertension.

Methods

Data source

The PearlDiver Mariner database is a commercially accessible database containing insurance claims records from all payer types (including commercial, Medicare, Medicaid, and self-pay).⁴⁷ When the study was run, the database held 53 million patients from all U.S. states and territories with records from 2010 to April 2020. The claims are longitudinal, validated, harmonized, integrated, and de-identified, and consist of diagnosis codes (International Classification of Diseases, ICD-9 and ICD-10), national drug codes (NDC), and prescription groupings. Datamining was performed using the graphical user interface Bellwether. The study was conducted April 2021 to April 2022.

Study population and variables

Systemic lupus erythematosus diagnosis was defined as patients with two or more records with ICD-9/ICD-10 diagnosis codes for lupus (Figure 1; Supplemental Table 1). Patients with ICD-9/ICD-10 diagnosis codes for systemic sclerosis and/or dermatomyositis were removed.⁴⁸ The population was further filtered to exclude patients who had never taken RAS or non-RAS antihypertensive drugs, or patients who had taken both RAS and non-RAS drugs, based on NDC and prescription groupings (Supplemental Table 2). Patients who had an ICD-9/ICD-10 diagnosis code for cardiovascular disease outcomes predating the initial antihypertensive prescription date were removed. Finally, patients were included only if they met active insurance enrollment criteria of continual data for a minimum of 6 months before and 18 months after the initial antihypertensive prescription date (the index date). This was done to attempt to capture only new users of the antihypertensive drugs and only include patients who had sufficient data after the index date. Patients were followed from the index date until they left the database.

Figure 1:

Study design RAS = renin-angiotensin system; ACE-I = ACE inhibitors; ARBs = angiotensin receptor blockers; CCBs = calcium channel blockers

The demographic data, comorbidities, and risk factors used in propensity score matching (PSM) were: age, sex, Charlson Comorbidity Index, tobacco use, obesity, type 1 diabetes, type 2 diabetes, chronic kidney disease, glomerular diseases, asthma, pregnancy, family history of cardiovascular disease, proteinuria or albumin abnormality, hypertension, hyperlipidemia, elevated blood glucose, antiphospholipid antibody disorder, and corticosteroid use (Table 1; Supplemental Table 3). The cardiovascular disease outcome variables were coronary or cerebral atherosclerosis, heart failure, myocardial infarction, and stroke (hemorrhage or cerebral infarction) (Supplemental Table 1). The use of 1 diagnosis code to measure cardiovascular outcomes has been validated in other studies.^49,50 The database did not have mortality data, so death could not be included as an outcome.

Table 1:

Patient characteristics of unadjusted and propensity score-matched cohorts RAS = renin-angiotensin system; SD = standard deviation

		Unadjusted cohort			Propensity score-matched cohort
		RAS drugs (n = 4,018)	Non-RAS drugs (n = 27,629)	P-value	RAS drugs (n = 4,018)	Non-RAS drugs (n = 4,018)	P-value
Mean follow-up time (SD) in years		5.5 (2.3)	5.8 (2.4)	<0.0001	5.5 (2.3)	5.9 (2.4)	<0.0001
Sex	Female	3,414 (85.0%)	26,022 (94.2%)	< 0.0001	3,414 (85.0%)	3,463 (86.2%)	0.13
	Male	604 (15.0%)	1,607 (5.8%)		604 (15.0%)	555 (13.8%)
Age of first antihypertensive prescription	0 to 29	538 (13.4%)	3,814 (13.8%)		538 (13.4%)	401 (10.0%)
	30 to 39	584 (14.5%)	6,040 (21.9%)		584 (14.5%)	679 (16.9%)
	40 to 49	947 (23.6%)	6,799 (24.6%)		947 (23.6%)	976 (24.3%)
	50 to 59	1,048 (26.1%)	5,645 (20.4%)		1,048 (26.1%)	957 (23.8%)
	60 to 69	618 (15.4%)	3,474 (12.6%)		618 (15.4%)	627 (15.6%)
	70 to 84	283 (7.0%)	1,857 (6.7%)		283 (7.0%)	378 (9.4%)
	→ Average age (SD)	47.7 (15.0)	45.9 (14.5)	<0.0001	47.7 (15.0)	49.0 (14.5)	0.0001
Comorbidities	Tobacco use	1,210 (30.1%)	9,550 (34.6%)	<0.0001	1,210 (30.1%)	1,209 (30.1%)	>0.9999
	Obesity	1,382 (34.4%)	10,240 (37.1%)	0.001	1,382 (34.4%)	1,412 (35.1%)	0.50
	Type 1 diabetes	234 (5.8%)	541 (2.0%)	<0.0001	234 (5.8%)	210 (5.2%)	0.26
	Type 2 diabetes	1,218 (30.3%)	5,317 (19.2%)	<0.0001	1,218 (30.3%)	1,212 (30.2%)	0.90
	Chronic kidney disease	838 (20.9%)	3,345 (12.1%)	<0.0001	838 (20.9%)	809 (20.1%)	0.44
	Glomerular disease	864 (21.5%)	1,533 (5.5%)	<0.0001	864 (21.5%)	812 (20.2%)	0.16
	Asthma	965 (24.0%)	8,351 (30.2%)	<0.0001	965 (24.0%)	979 (24.4%)	0.73
	Pregnancy	311 (7.7%)	4,218 (15.3%)	<0.0001	311 (7.7%)	289 (7.2%)	0.37
	Family history of cardiovascular disease	275 (6.8%)	2,618 (9.5%)	< 0.0001	275 (6.8%)	253 (6.3%)	0.34
	Proteinuria / albumin abnormality	891 (22.2%)	2,009 (7.3%)	< 0.0001	891 (22.2%)	810 (20.2%)	0.029
	Hypertension	3,092 (77.0%)	15,279 (55.3%)	<0.0001	3,092 (77.0%)	3,267 (81.3%)	<0.0001
	Hyperlipidemia	2,169 (54.0%)	12,596 (45.6%)	<0.0001	2,169 (54.0%)	2,206 (54.9%)	0.42
	Elevated blood glucose	1,090 (27.1%)	5,637 (20.4%)	<0.0001	1,090 (27.1%)	1,077 (26.8%)	0.76
	Antiphospholipid antibody disorder	574 (14.3%)	4,559 (16.5%)	0.0003	574 (14.3%)	561 (14.0%)	0.70
	Corticosteroid use	3,461 (86.1%)	25,066 (90.7%)	<0.0001	3,461 (86.1%)	3,454 (86.0%)	0.85
Charlson Comorbidity Index	0–4	3,846 (95.7%)	26,813 (97.0%)		3,846 (95.7%)	3,819 (95.0%)
	5–9	156 (3.9%)	739 (2.7%)		156 (3.9%)	181 (4.5%)
	10+	16 (0.4%)	77 (0.3%)		16 (0.4%)	18 (0.4%)
	→ Average CCI (SD)	1.55 (1.65)	1.22 (1.45)	<0.0001	1.55 (1.65)	1.47 (1.68)	0.050

Propensity score estimation

A propensity score allowed statistical balancing of patient populations by quantifying the probability of a patient receiving a RAS versus non-RAS prescription based on relevant patient demographics and comorbidities.⁵¹ Variables used in the nearest neighbor PSM were found to significantly affect treatment assignment or affect cardiovascular disease outcomes in logistic regression analysis.

Outcome analyses

The occurrence of cardiovascular disease outcomes after the index date was compared between patients who had insurance codes for RAS versus non-RAS drugs prior to and after PSM using relative risk (with 95% confidence interval) and two-sided Fisher’s exact tests. Survival probability was analyzed with the Kaplan-Meier time-to-event model and log-rank test for 5 years post index date. Subgroup analyses were conducted in patients with and without lupus nephritis, and patients prescribed only ACE-Is and only ARBs. Patients with lupus nephritis were defined according to a previously validated algorithm; patients had at least 3 claims with lupus diagnosis codes, at least 3 claims with any combination of glomerular disease, chronic kidney disease, kidney failure, or proteinuria diagnosis codes, and at least 3 claims from a nephrologist (Supplemental Table 1).⁵² PSM was performed in these subgroups using variables significant in logistic regression. Statistical analyses were run in the Bellwether program (using integrated statistical tools implemented in R) or Prism 9.

Role of the funding sources

The funding sources, the National Institute on Aging and the National Institute of Neurological Disorders and Stroke, had no role in the study’s design, conduct, and reporting.

Results

Study population

220,168 patients were found to have at least 2 records with a diagnosis code for lupus. After applying the study inclusion and exclusion criteria, patients were divided into the treatment group (4,018 patients prescribed RAS drugs) and the control group (27,629 patients prescribed non-RAS drugs) (Figure 1). Patients who had been prescribed multiple RAS drug classes or multiple non-RAS drug classes were included, but patients who had been prescribed both RAS and non-RAS drugs were removed. The treatment and control populations after PSM consisted of 4,018 patients each.

Sample characteristics

Patient details before and after PSM are outlined in Table 1. PSM improved the similarity of patient characteristics and comorbidities between the treatment and control groups. Consistent with the demographics of lupus in general, the matched populations were primarily female (RAS 85.0%; non-RAS 86.2%). The average age of antihypertensive drug initiation in the RAS and non-RAS drug PSM cohorts were 47.7 and 49.0 years, respectively. In the RAS drug PSM cohort, 80.2% of patients had a prescription code for ACE-Is and 32.6% had a prescription code for ARBs. The most common RAS drugs prescribed were lisinopril (69.4%), losartan (25.7%), and enalapril (6.9%). In the non-RAS drug PSM cohort, 42.3% of patients had a prescription code for calcium channel blockers, 57.3% for diuretics, and 55.7% for beta blockers. The most common non-RAS drugs prescribed were furosemide (30.0%), metoprolol (28.9%), amlodipine (28.0%), and hydrochlorothiazide (27.0%). Patients were followed from initial prescription until they left the database, with mean (SD) follow-up times in the PSM populations of 5.5 (2.3) years for RAS users and 5.9 (2.4) years for non-RAS users.

Cardiovascular disease risk

In the unadjusted cohort, there was a significant decrease in incidence of any cardiovascular disease in patients receiving RAS antihypertensive drugs compared with patients receiving non-RAS antihypertensive drugs (15.4% versus 19.2%, relative risk [RR] 0.80, 95% CI [0.74–0.87]) (Figure 2A). This decline in incidence was strengthened after PSM (15.4% versus 24.9%, RR 0.63, 95% CI [0.57–0.68]) (Figure 2B). When evaluating each cardiovascular disease individually, the relative risk of atherosclerosis was significantly decreased for RAS users in the unadjusted and PSM cohorts (unadjusted cohort: 7.9% versus 9.9%, RR 0.80, 95% CI [0.71–0.89]; PSM cohort: 7.9% versus 13.0%, RR 0.60, 95% CI [0.53–0.69]) (Figures 2A, 2B). Heart failure had the lowest relative risk with RAS drug use in both cohorts (unadjusted cohort: 3.8% versus 7.6%, RR 0.51, 95% CI [0.43–0.60]; PSM cohort: 3.8% versus 10.4%, RR 0.37, 95% CI [0.31–0.44]) (Figures 2A, 2B). There was no significant difference in myocardial infarction and stroke incidence between RAS and non-RAS drugs in the unadjusted cohort, but after PSM, RAS drugs were shown to significantly decrease these outcomes (myocardial infarction PSM cohort: 1.7% versus 3.1%, RR 0.54, 95% CI [0.40–0.72]; stroke PSM cohort: 6.5% versus 7.8%, RR 0.83, 95% CI [0.71–0.98]) (Figures 2A, 2B).

Figure 2:

Relative risk of cardiovascular disease Relative risk of cardiovascular disease in patients prescribed RAS antihypertensive drugs versus non-RAS antihypertensive drugs. (A) Unadjusted cohort; (B) PSM cohort; (C) PSM cohort broken down by age of first antihypertensive prescription. RAS = renin-angiotensin system; PSM = propensity score match

Further, cardiovascular disease incidence in the PSM cohort was significantly lower with RAS drug use in male and female populations individually (male patients: 21.0% versus 31.0%, RR 0.68, 95% CI [0.56–0.83]; female patients: 14.4% versus 23.9%, RR 0.60, 95% CI [0.55–0.67]) (Supplemental Figure 1A). Breakdown of the PSM cohort by age of first antihypertensive drug prescription revealed that RAS drug use was protective against cardiovascular disease at all ages (Figure 2C). Patients prescribed RAS drugs also had reduced risk of having two or more distinct cardiovascular outcomes in the PSM cohort (3.6% versus 7.3%, RR 0.49, 95% CI [0.40–0.59]) (Supplemental Figure 1A).

Cardiovascular disease-free survival analysis

The Kaplan-Meier time-to-event model was used to analyze the probability of cardiovascular disease-free survival in the PSM data (Figure 3). Patients with lupus using a RAS drug had a significantly higher probability of cardiovascular disease-free survival over 5 years than patients using non-RAS drugs (86.0% versus 78.3%, p-value < 0.0001) (Figure 3A).

Figure 3:

Kaplan-Meier cardiovascular disease-free survival curves Kaplan-Meier cardiovascular disease-free survival curves (with 95% confidence intervals) for PSM cohort, followed for 5 years post index date. Survival distributions were compared using the log-rank test. (A) Any cardiovascular disease outcome; (B) atherosclerosis; (C) heart failure; (D) myocardial infarction; (E) stroke. RAS = renin-angiotensin system; PSM = propensity score match

Similar results were observed for atherosclerosis-free, heart failure-free, and myocardial infarction-free survival over the 5-year period (atherosclerosis: 93.0% versus 89.3%, p-value < 0.0001; heart failure: 96.2% versus 91.3%, p-value < 0.0001; myocardial infarction: 98.5% versus 97.4%, p-value 0.003) (Figures 3B, 3C, 3D). Despite RAS drugs having been found to be protective against stroke compared to non-RAS drugs, there was no significant difference in stroke-free survival probability between the two drug classes over 5 years (94.2% versus 93.5%, p-value 0.05) (Figure 3E).

Sensitivity analyses

Patients with lupus nephritis have an increased risk of cardiovascular disease.^{17, 18} Regardless of lupus nephritis diagnosis, RAS use was found to reduce overall cardiovascular disease incidence (without lupus nephritis: 15.5% versus 23.8%, RR 0.65, 95% CI [0.59–0.72]; with lupus nephritis: 14.8% versus 29.2%, RR 0.51, 95% CI [0.39–0.65]) (Figure 4A, 4B). However, RAS drugs were not protective against myocardial infarction in lupus nephritis patients (2.6% versus 2.8%, 0.93 [0.45–1.92]).

Figure 4:

Lupus nephritis sensitivity analyses Relative risk of cardiovascular disease in patients prescribed RAS antihypertensive drugs versus non-RAS antihypertensive drugs for (A) patients without lupus nephritis; (B) patients with lupus nephritis. RAS = renin-angiotensin system

ACE-Is and ARBs were independently evaluated, and cardiovascular disease risk was significantly reduced in each RAS drug class compared to non-RAS drugs (ACE-Is: 15.1% versus 23.4%, RR 0.65, 95% CI [0.58–0.72]; ARBs: 14.8% versus 24.5%, RR 0.61, 95% CI [0.49–0.74]) (Supplemental Figures 1B, 1C). Neither drug class was found to be significantly more protective than the other.

Discussion

RAS is well known for its effects on blood pressure, sodium retention, and fluid balance.^34,35,36 However, RAS drugs have additional benefits in that they reduce the actions of angiotensin II, which is inflammatory and fibrotic. Receptors and peptides associated with RAS are expressed throughout the body, including the kidneys, heart, and vasculature.^34,35 ACE-Is, one class of RAS drugs evaluated here, inhibit the formation of the vasoactive peptide angiotensin II through the inhibition of ACE. ARBs, the other RAS drug class assessed, antagonize the angiotensin II type 1 receptor (AT1R). Use of either drug effectively treats high blood pressure.^34,35,36 Chronic activation of RAS through AT1R leads to hypertension, kidney disease, and cardiovascular disease. In more recent studies, RAS has also been found to be directly involved in inflammation, immune responses, and oxidative stress.^35,36 This suggests that RAS-modifying therapies may provide a synergistic benefit in the context of lupus above that which would be expected by ‘mere’ symptom control by directly targeting pro-inflammatory cytokines that are elevated and dysregulated during lupus in addition to managing hypertension, thereby reducing cardiovascular disease as well as preserving kidney function.^37,42 This study found that RAS drugs reduced the risk of any cardiovascular disease, atherosclerosis, and heart failure in unadjusted and PSM cohort analyses, compared to non-RAS drugs. After PSM, RAS drugs also decreased the risk of myocardial infarction and stroke. RAS drugs also increased the probability of cardiovascular disease-free survival for at least 5 years after drug initiation. Similar findings were found upon evaluating patients with or without lupus nephritis and the individual effects of ACE-Is and ARBs.

Stringent guidelines were used to identify patients with lupus that have been treated with only RAS or non-RAS drugs. Approximately one third of the patients were removed from the study due to not taking any blood pressure medications (the majority of which did not have a hypertension diagnosis), and another third was excluded because they had been exposed to both RAS- and non-RAS-modifying antihypertensive drugs. Although the use of RAS modifiers is recommended by several organizations to reduce kidney disease progression in patients with lupus, only 13% of the patients taking an antihypertensive monotherapy were prescribed RAS drugs.^38,39,41 This may be in part due to the known teratogenic effects of the drugs or other side effects that limit use.

Prior to PSM, patients on RAS drugs were older and had more kidney disease, diabetes, and dyslipidemia. Even with these baseline disparities, the use of RAS drugs significantly reduced the risk for overall cardiovascular disease, and this reduction was more pronounced after PSM. Further, RAS drugs reduced the risk of multiple cardiovascular disease events in patients with lupus after PSM. PSM allowed statistical balancing of observational data to somewhat imitate a randomized controlled trial and reduce confounding systematic effects that differ between the groups being compared, even when non-random physician expertise was responsible for prescription choice.⁵¹ The drug groups here were matched based upon criteria shown to be significant with logistic regression.

Sensitivity analyses indicated that RAS drugs remained protective against cardiovascular disease in patients with lupus nephritis. Patients in this vulnerable population may find RAS drugs greatly beneficial due to both slowing kidney disease and decreasing the risk of cardiovascular disease. ACE-Is and ARBs each decreased overall cardiovascular disease, indicating that use of either drug is protective against cardiovascular disease.

Clinicians should be aware of risk factor reduction in the prevention and treatment of cardiovascular disease among those with systemic lupus erythematosus. Smoking cessation, regular exercise, achieving an ideal body mass index, and consuming heart-healthy meals should be recommended.⁵³ Statins have anti-inflammatory and antithrombotic effects that can reduce lipid levels in lupus patients, potentially reducing their risk for cardiovascular disease.⁵⁴ In a study of 4095 patients with systemic lupus erythematosus, use of high dose statins reduced the risk of coronary artery and cardiovascular disease.⁵⁵ Hydroxychloroquine use has been associated with increased survival in lupus, reduced risk of thrombosis, and lipid-lowering effects, and may have significant beneficial effects on minimizing cardiovascular risk in lupus.^56,57,58 Aggressive therapy to control hypertension is also necessary, but the optimal antihypertensive medication is unclear.⁵³ In hypertensive patients without lupus, the American College of Cardiology/American Heart Association recommend ACE-Is, ARBs, diuretics, and calcium channel blockers (used alone or in combination) for primary treatment.⁵⁹ When comparing these antihypertensive drugs to each other, several studies showed similar decreases in cardiovascular risk and cardiovascular mortality in patients of the general population regardless of drug class.^60,61,62,63

In this report, the use of RAS-modifying drugs in patients with systemic lupus erythematosus reduced the risk of cardiovascular disease, finding ACE-Is and ARBs to be beneficial beyond just kidney protection. Consideration of these additional benefits should be a part of the choice of therapeutic options to control hypertension in patients with lupus. Optimizing the current therapies available for patients with lupus will also decrease morbidity in the absence of new therapeutic interventions. In the long-run, this data can provide new hypotheses to test directly by intervention or low-throughput research. RAS-modification may be a novel target for potential non-immunosuppressive therapies for lupus-related morbidities.

Study strengths and limitations

The strengths of this study include a large number of patients with lupus, stringent study design guidelines, and the use of PSM to imitate a randomized controlled trial. However, the use of retrospective insurance claims datasets have several limitations. First, the patients evaluated may have obtained services outside of those paid for by their insurance company. Second, there could be factors, known and unknown, that are not adequately addressed even with PSM. Small differences in comorbidities that cannot be fully accounted for with the data available may affect the different disease states of exposed and unexposed. In this respect, this dataset does not include lab or genetic values which may affect the outcomes. Third, the differential effects of steroid-sparing agents were not evaluated. However, there is no robust evidence to suggest that such agents may affect the beneficial effects of antihypertensive RAS agents.

Conclusions

The data shown indicates that use of RAS-modifying drugs to treat hypertension in patients with systemic lupus erythematosus reduced the risk of cardiovascular disease in this dataset. Understanding and quantifying these data can have an immediate impact by augmenting existing clinical decision making and lead to lupus-specific hypertension management guidelines.

Clinical Significance.

• Among those with systemic lupus erythematosus, use of a medication that modifies the renin-angiotensin system (RAS, e.g., ACE-inhibitor) is associated with lower risk of cardiovascular disease.

• Specifically, use of a RAS-modifying medicine may lower the risk of having atherosclerosis, heart failure, and myocardial infarction among those with lupus.

• Upon choosing the most appropriate anti-hypertensive medication for those with lupus, the cardiovascular benefits of RAS-modifying medicines should be strongly considered.