Renin-Angiotensin System-Modifying Antihypertensive Drugs Can Reduce the Risk of Cardiovascular Complications in Lupus: A Retrospective Cohort Study

Published:December 07, 2022DOI:



      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 vs non-RAS antihypertensive drugs on cardiovascular disease incidence in patients with lupus.


      Using a medical insurance claims dataset, 220,168 patients with lupus were identified, of which 31,647 patients (4018 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, were 93.0% female, and healthy (96.9% Charlson Comorbidity Index score 0-4). Patients in the 2 drug groups were propensity score matched using demographic data, risk factors, and comorbidities.


      Use of RAS vs non-RAS drugs lowered the relative risk (RR) of diagnosis of cardiovascular disease (RR 0.80; 95% confidence interval [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% vs 78.3% probability).


      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.


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      1. Centers for Disease Control and Prevention (CDC)]. Systemic lupus erythematosus (SLE). 2018. Available at: Accessed January 6, 2022.

        • Maidhof W
        • Hilas O
        Lupus: an overview of the disease and management options.
        P T. 2012; 37: 240-246
        • Dema B
        • Charles N
        Autoantibodies in SLE: specificities, isotypes and receptors.
        Antibodies (Basel). 2016; 5: 2
      2. Dein E, Douglas H, Petri M, Law G, Timlin H. Pericarditis in lupus. Cureus. 2019;11(3):e4166.

        • Anevlavis S
        • Tzouvelekis A
        • Bouros D
        Mechanisms of pleural involvement in orphan diseases.
        Respiration. 2012; 83: 5-12
        • Cojocaru M
        • Cojocaru IM
        • Silosi I
        • Vrable CD
        Manifestations of systemic lupus erythematosus.
        Maedica (Bucur). 2011; 6: 330-336
        • D'Cruz DP
        • Khamashta MA
        • Hughes GRV
        Systemic lupus erythematosus.
        Lancet. 2007; 369: 587-596
        • Bernatsky S
        • Boivin J-F
        • Joseph L
        • et al.
        Mortality in systemic lupus erythematosus.
        Arthritis Rheum. 2006; 54: 2550-2557
      3. Lupus Foundation of America. The leading causes of death in lupus. July 18, 2013. Available at: Accessed November 6, 2022.

        • Nossent J
        • Cikes N
        • Marchesoni A
        • et al.
        Current causes of death in systemic lupus erythematosus in Europe, 2000-2004: relation to disease activity and damage accrual.
        Lupus. 2007; 16: 309-317
        • Jain D
        • Halushka MK
        Cardiac pathology of systemic lupus erythematosus.
        J Clin Pathol. 2009; 62: 584-592
        • McMahon M
        • Hahn BH
        • Skaggs BJ
        Systemic lupus erythematosus and cardiovascular disease: prediction and potential for therapeutic intervention.
        Expert Rev Clin Immunol. 2011; 7: 227-241
        • Kim CH
        • Al-Kindi SG
        • Jandali B
        • Askari AD
        • Zacharias M
        • Jandali B
        Incidence and risk of heart failure in systemic lupus erythematosus.
        Heart. 2017; 103: 227-233
        • Manzi S
        • Meilahn EN
        • Rairie JE
        • et al.
        Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study.
        Am J Epidemiol. 1997; 145: 408-415
        • Esdaile JM
        • Abrahamowicz M
        • Grodzicky T
        • et al.
        Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus.
        Arthritis Rheum. 2001; 44: 2331-2337
        • Schoenfeld SR
        • Kasturi S
        • Costenbader KH
        The epidemiology of atherosclerotic cardiovascular disease among patients with SLE: a systematic review.
        Semin Arthritis Rheum. 2013; 43: 77-95
        • Tektonidou MG
        • Kravvariti E
        • Konstantonis G
        • Tentolouris N
        • Sfikakis PP
        • Protogerou A
        Subclinical atherosclerosis in systemic lupus erythematosus: comparable risk with diabetes mellitus and rheumatoid arthritis.
        Autoimmun Rev. 2017; 16: 308-312
        • Zeller CB
        • Appenzeller S
        Cardiovascular disease in systemic lupus erythematosus: the role of traditional and lupus related risk factors.
        Curr Cardiol Rev. 2008; 4: 116-122
        • Wolf D
        • Ley K
        Immunity and inflammation in atherosclerosis.
        Circ Res. 2019;; 124: 315-327
      4. Whelton SP, Mody FV, McKevoy JW, Martin SS, Blumenthal RS. Cardiovascular risk assessment and allocation of lipid-lowering therapy in patients with chronic inflammatory diseases. June 29, 2017. Available at: Accessed November 5, 2022.

        • Sinicato NA
        • Cardosa PAS
        • Appenzeller S
        Risk factors in cardiovascular disease in systemic lupus erythematosus.
        Curr Cardiol Rev. 2013; 9: 15-19
        • Munguia-Realpozo P
        • Mendoza-Pinto C
        • Benito CS
        • et al.
        Systemic lupus erythematosus and hypertension.
        Autoimmun Rev. 2019; 18102371
        • Giannelou M
        • Mavragani CP
        Cardiovascular disease in systemic lupus erythematosus: a comprehensive update.
        J Autoimmun. 2017; 82: 1-12
        • Dhakal BP
        • Kim CH
        • Al-Kindi SG
        • Oliveira GH
        Heart failure in systemic lupus erythematosus.
        Trends Cardiovasc Med. 2018; 28: 187-197
        • Fernández-Nebro A
        • Rúa-Figueroa I
        • López-Longo FJ
        • et al.
        Cardiovascular events in systemic lupus erythematosus: a nationwide study in Spain from the RELESSER registry.
        Medicine (Baltimore). 2015; 94: e1183
        • Bengtsson C
        • Ohman M-L
        • Nived O
        • Rantapää Dahlqvist S
        Cardiovascular event in systemic lupus erythematosus in northern Sweden: incidence and predictors in a 7-year follow-up study.
        Lupus. 2012 Apr; 21: 452-459
        • McMahon M
        • Grossman J
        • Skaggs B
        • et al.
        Dysfunctional proinflammatory high-density lipoproteins confer increased risk of atherosclerosis in women with systemic lupus erythematosus.
        Arthritis Rheum. 2009; 60: 2428-2437
        • Felten R
        • Dervovic E
        • Chasset F
        • et al.
        The 2018 pipeline of targeted therapies under clinical development for systemic lupus erythematosus: a systematic review of trials.
        Autoimmun Rev. 2018; 17: 781-790
        • Feldman CH
        • Hiraki LT
        • Winkelmayer WC
        • et al.
        Serious infections among adult Medicaid beneficiaries with systemic lupus erythematosus and lupus nephritis.
        Arthritis Rheumatol. 2015; 67: 1577-1585
        • Hsu CY
        • Lin MS
        • Su YJ
        • et al.
        Cumulative immunosuppressant exposure is associated with diversified cancer risk among 14,832 patients with systemic lupus erythematosus: a nested case-control study.
        Rheumatology (Oxford). 2017; 56: 620-628
        • Skaggs BJ
        • Hahn BH
        • McMahon M
        Accelerated atherosclerosis in patients with SLE-mechanisms and management.
        Nat Rev Rheumatol. 2012; 8: 214-223
        • Tselios K
        • Kourmaras C
        • Urowitz MB
        • Gladman DD
        Do current arterial hypertension treatment guidelines apply to systemic lupus erythematosus patients? A critical appraisal.
        Semin Arthritis Rheum. 2014; 43: 521-525
        • Björnådal L
        • Yin L
        • Granath F
        • Klareskog L
        • Ekbom A
        Cardiovascular disease a hazard despite improved prognosis in patients with systemic lupus erythematosus: results from a Swedish population based study 1964-95.
        J Rheumatol. 2004; 31: 713-719
        • Lavoie JL
        • Sigmund CD
        Minireview: overview of the renin-angiotensin system—an endocrine and paracrine system.
        Endocrinology. 2003; 144: 2179-2183
        • Sparks MA
        • Crowley SD
        • Gurley SB
        • Mirotsou M
        • Coffman TM
        Classical renin-angiotensin system in kidney physiology.
        Compr Physiol. 2014; 4: 1201-1228
        • Jackson L
        • Eldahshan W
        • Fagan SC
        • Ergul A
        Within the brain: the renin angiotensin system.
        Int J Mol Sci. 2018; 19: 876
        • Ibrahim MM
        RAS inhibition in hypertension.
        J Hum Hypertens. 2006; 20: 101-108
        • Beck L
        • Bomback AS
        • Choi MJ
        • et al.
        KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis.
        Am J Kidney Dis. 2013; 62: 403-441
        • Fanouriakis A
        • Kostopoulou M
        • Cheema K
        • et al.
        2019 Update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis.
        Ann Rheum Dis. 2020; 79: 713-723
        • Durán-Barragán S
        • McGwin G
        • Vilá LM
        • Reveille JD
        • Alarcón GS
        • LUMINA (LIX): a multiethnic US cohort
        Angiotensin-converting enzyme inhibitors delay the occurrence of renal involvement and are associated with a decreased risk of disease activity in patients with systemic lupus erythematosus—results from LUMINA (LIX): a multiethnic US cohort.
        Rheumatology (Oxford). 2008; 47 (Jr): 1093-1096
        • Hahn BH
        • McMahon MA
        • Wilkinson A
        • et al.
        American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis.
        Arthritis Care Res (Hoboken). 2012; 64: 797-808
        • Ranjbar R
        • Shafiee M
        • Hesari A
        • Ferns GA
        • Ghasemi F
        • Avan A
        The potential therapeutic use of renin-angiotensin system inhibitors in the treatment of inflammatory diseases.
        J Cell Physiol. 2019; 234: 2277-2295
        • Nocito C
        • Lubinsky C
        • Hand M
        • et al.
        Centrally acting angiotensin-converting enzyme inhibitor suppresses type I interferon responses and decreases inflammation in the periphery and the CNS in lupus-prone mice.
        Front Immunol. 2020; 11573677
        • Pérez de Lema G
        • de Wit C
        • Cohen CD
        • et al.
        Angiotensin inhibition reduces glomerular damage and renal chemokine expression in MRL/lpr mice.
        J Pharmacol Exp Ther. 2003; 307: 275-281
        • Tarkowski A
        • Carlsten H
        • Herlitz H
        • Westberg G
        Differential effects of captopril and enalapril, two angiotensin converting enzyme inhibitors, on immune reactivity in experimental lupus disease.
        Agents Actions. 1990; 31: 96-101
        • Nestor J
        • Arinuma Y
        • Huerta TS
        • et al.
        Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors.
        J Exp Med. 2018; 215: 2554-2566
      5. PearlDiver. PearlDiver Mariner Patient Claims Database. Colorado Springs, CO: PearlDiver Technologies. Available at: Accessed April 19, 2021.

        • Chibnik LB
        • Massarotti E
        • Costenbader KH
        Identification and validation of lupus nephritis cases using administrative data.
        Lupus. 2010; 19: 741-743
        • Barnado A
        • Casey C
        • Carroll RJ
        • Wheless L
        • Denny JC
        • Crofford LJ
        Developing electronic heath record algorithms that accurately identify patients with systemic lupus erythematosus.
        Arthritis Care Res (Hoboken). 2017; 69: 687-693
        • Ono Y
        • Taneda Y
        • Takeshima T
        • Iwasaki K
        • Yasui A
        Validity of claims diagnosis codes for cardiovascular diseases in diabetes patients in Japanese administrative database.
        Clin Epidemiol. 2020; 12: 367-375
        • Cozzolino F
        • Montedori A
        • Abraha I
        • et al.
        A diagnostic accuracy study validating cardiovascular ICD-9-CM codes in healthcare administrative databases. The Umbra Data-Value Project.
        PLoS One. 2019; 14e0218919
        • Austin PC
        An introduction to propensity score methods for reducing the effects of confounding in observational studies.
        Multivariate Behav Res. 2011; 46: 399-424
        • Wajed J
        • Ahmad Y
        • Durrington PN
        • Bruce IN
        Prevention of cardiovascular disease in systemic lupus erythematosus–proposed guidelines for risk factor management.
        Rheumatology (Oxford). 2004; 43: 7-12
        • Costenbader KH
        • Liang MH
        • Chibnik LB
        • et al.
        A pravastatin dose-escalation study in systemic lupus erythematosus.
        Rheumatol Int. 2007; 27: 1071-1077
        • Yu HH
        • Chen PC
        • Yang YH
        • et al.
        Statin reduces mortality and morbidity in systemic lupus erythematosus patients with hyperlipidemia: A nationwide population-based study.
        Atherosclerosis. 2015; 243: 11-18
        • Alarcón GS
        • McGwin G
        • Bertoli AM
        • et al.
        Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (LUMINA L).
        Ann Rheum Dis. 2007; 66: 1168-1172
        • Jung H
        • Bobba R
        • Su J
        • et al.
        The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus.
        Arthritis Rheum. 2010; 62: 863-868
        • Rahman P
        • Gladman DD
        • Urowitz MB
        • Yuen K
        • Hallett D
        • Bruce IN
        The cholesterol lowering effect of antimalarial drugs is enhanced in patients with lupus taking corticosteroid drugs.
        J Rheumatol. 1999; 26: 325-330
        • Whelton PK
        • Carey RM
        • Aronow WS
        • et al.
        2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
        Hypertension. 2018; 71: 1269-1324
        • Thomopoulos C
        • Parati G
        • Zanchetti A
        Effects of blood pressure-lowering treatment on cardiovascular outcomes and mortality: 14 - effects of different classes of antihypertensive drugs in older and younger patients: overview and meta-analysis.
        J Hypertens. 2018; 36: 1637-1647
        • Ettehad D
        • Emdin CA
        • Kiran A
        • et al.
        Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis.
        Lancet. 2016; 387: 957-967
        • Chen YJ
        • Li LJ
        • Tang WL
        • et al.
        First-line drugs inhibiting the renin angiotensin system versus other first-line antihypertensive drug classes for hypertension.
        Cochrane Database Syst Rev. 2018; 11CD008170
        • Turnbull F
        • Neal B
        • et al.
        • Blood Pressure Lowering Treatment Trialists’ Collaboration
        Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomized trials.
        BMJ. 2008; 336: 1121-1123