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Basic studies suggest that statins as add-on therapy may benefit patients with COVID-19; however, real-world evidence of such a beneficial association is lacking.
We investigated differences in SARS-CoV-2 test positivity and clinical outcomes of COVID-19 (composite endpoint: admission to intensive care unit, invasive ventilation, or death) between statin users and nonusers.
Two independent population-based cohorts were analyzed, and we investigated the differences in SARS-CoV-2 test positivity and severe clinical outcomes of COVID-19, such as admission to the intensive care unit, invasive ventilation, or death, between statin users and nonusers. One group comprised an unmatched cohort of 214,207 patients who underwent SARS-CoV-2 testing from the Global Research Collaboration Project (GRCP)-COVID cohort, and the other group comprised an unmatched cohort of 74,866 patients who underwent SARS-CoV-2 testing from the National Health Insurance Service (NHIS)-COVID cohort.
The GRCP-COVID cohort with propensity score matching had 29,701 statin users and 29,701 matched nonusers. The SARS-CoV-2 test positivity rate was not associated with statin use (statin users, 2.82% [837/29,701]; nonusers, 2.65% [787/29,701]; adjusted relative risk [aRR] 0.97; 95% CI 0.88-1.07). Among patients with confirmed COVID-19 in the GRCP-COVID cohort, 804 were statin users and 1573 were matched nonusers. Statin users were associated with a decreased likelihood of severe clinical outcomes (statin users, 3.98% [32/804]; nonusers, 5.40% [85/1573]; aRR 0.62; 95% CI 0.41-0.91) and length of hospital stay (statin users, 23.8 days; nonusers, 26.3 days; adjusted mean difference –2.87; 95% CI –5.68 to –0.93) than nonusers. The results of the NHIS-COVID cohort were similar to the primary results of the GRCP-COVID cohort.
Our findings indicate that prior statin use is related to a decreased risk of worsening clinical outcomes of COVID-19 and length of hospital stay but not to that of SARS-CoV-2 infection.
COVID-19 is caused by SARS-CoV-2, and started in Wuhan, China. The World Health Organization (WHO) declared COVID-19 a pandemic on March 12, 2020 [
In this context, statins are inexpensive and easily available therapeutic agents, and their multiple pharmacologic mechanisms include anti-inflammation, antioxidation, inhibition of the angiotensin-converting enzyme 2 (ACE2) pathway, and lowering bodily lipid levels [
We hypothesized that prior statin use could either decrease the risks of COVID-19 or of severe clinical outcomes of COVID-19 (ie, death, admission to the intensive care unit, and invasive ventilation). Through 2 independent nationwide cohort studies on Korean patients, with propensity score matching, we investigated the potential association of previous statin use with the likelihood of a positive SARS-CoV-2 test result (viral infectivity) in all patients who underwent the test. Furthermore, we aimed to clarify the difference in clinical outcomes of patients with laboratory-confirmed SARS-CoV-2 infection who were and who were not administered statins.
Two independent cohorts were analyzed: the Global Research Collaboration Project on COVID-19 (GRCP-COVID) cohort [
During the COVID-19 pandemic, the Korean Government shared the first nationwide claims-based database consisting of all people who were tested for SARS-CoV-2 in South Korea. This high-quality, large-scale nationwide cohort included all people who tested through medical or Korea Centers for Disease Control referrals (excluding self-referral) in South Korea via services facilitated by the Health Insurance Review and Assessment Service of Korea, the Korea Centers for Disease Control and Prevention, and the Ministry of Health and Welfare, Republic of Korea [
We identified all patients older than 20 years who underwent tests for SARS-CoV-2 infection in South Korea between January 1, 2020, and May 15, 2020 (n=214,207). As the pathophysiology of COVID-19 differs between children and adults, we excluded pediatric patients from the analysis [
A history of diabetes mellitus, cardiovascular disease, cerebrovascular disease, chronic obstructive pulmonary disease (COPD), hypertension, or chronic kidney disease was identified in at least two claims of inpatients or outpatients, or both, within 1 year using the appropriate International Classification of Disease 10th revision (ICD-10) codes [
Data were from individuals aged 20 years or older who underwent a SARS-CoV-2 test through a medical or Korea Centers for Disease Control referral (excluding self-referral) between January 1, 2020, and May 31, 2020, or through a general health examination between January 1, 2019, and December 31, 2019, as registered by the National Health Insurance Service of Korea (n=74,866).
Baseline information was obtained for each individual at the time of the general health examination. A history of diabetes mellitus, stroke, or cardiovascular disease; previous use of medication for hypertension, diabetes mellitus, or cardiovascular disease; smoking habit; physical activity; and frequency of alcohol consumption were obtained via self-reported questionnaires [
We identified all lipophilic (atorvastatin, simvastatin, fluvastatin, lovastatin, and cerivastatin) and hydrophilic (rosuvastatin and pravastatin) statins, prescribed within 1 year before the index data [
The primary outcome was a laboratory-confirmed SARS-CoV-2 positivity, among all patients who were tested. The secondary outcomes were severe outcomes of COVID-19 [
In the GRCP-COVID cohort, we performed each propensity score matching twice to compare SARS-CoV-2 test positivity (primary outcome) with severe clinical outcomes of patients with COVID-19 (secondary outcome), to minimize potential confounding factors and balance the baseline covariates of the 2 groups. First, we assessed the predicted probability of statin users versus nonusers among patients who underwent the SARS-CoV-2 test (n=214,207) using a logistic regression model with adjustment for potential confounding factors by age; sex; region of residence (rural or urban); a history of diabetes mellitus, cardiovascular disease, cerebrovascular disease, COPD, hypertension, or chronic kidney disease; Charlson Comorbidity Index (0, 1, or ≥2); use of aspirin, metformin, or systemic glucocorticoids. Second, we assessed the predicted probability of statin users versus nonusers among patients who tested positive for SARS-CoV-2 (n=7566) with the aforementioned adjustments for potential confounding factors. We performed the matching in the 2 groups in a 1:1 or 1:2 ratio using a “greedy nearest-neighbor” algorithm among all individuals who underwent the SARS-CoV-2 test and among those who tested positive for SARS-CoV-2, respectively, using random selection without replacement within caliper widths of 0.01 SDs.
In the NHIS-COVID cohort, we performed each propensity score matching twice, using the same methods as those used for the GRCP-COVID cohort, with adjustment for potential confounding factors by age (20-59, 60-69, and ≥70 years); sex; region of residence; a history of diabetes mellitus, stroke, cardiovascular disease; Charlson Comorbidity Index; body mass index (<25, 25-30, and ≥30 kg/m2); systolic blood pressure (continuous); diastolic blood pressure (continuous); fasting blood glucose (continuous); serum total cholesterol (continuous); serum low-density lipoprotein-cholesterol (continuous); serum high-density lipoprotein-cholesterol (continuous); estimated glomerular filtration rate (normal, mildly decreased, and moderately to severely decreased); household income (low, middle, and high); smoking status (never smoker, ex-smoker, and current smoker); frequency of alcohol consumption (<1, 1-2, 3-4, 5-6, and 7 times per week); physical activity (0, 1-2, 3-4, 5-6, and 7 sessions per week); and medication for hypertension, diabetes mellitus, or cardiovascular disease.
Adequate propensity score matching was confirmed by comparing propensity score densities (
The “exposure” considered the current use of statin, and the “primary endpoint” was the positive test results for SARS-CoV-2 among all patients who were tested for SARS-CoV-2. The “secondary endpoint” was the severe clinical outcomes and the length of hospital stay among patients with laboratory-confirmed COVID-19. Data were analyzed using modified Poisson regression models, and adjusted relative risks (aRRs) with 95% CIs for the 2 groups in each propensity score–matched cohort were estimated after adjusting for potential covariates.
Among patients who underwent SARS-CoV-2 testing (n=214,207), we identified 178,897 nonusers and 35,310 statin users in the full unmatched cohort (
Baseline characteristics of all patients who were tested for SARS-CoV-2 infection and of those with laboratory-confirmed SARS-CoV-2 infection in the GRCPa-COVID cohort (South Korea; January 1 to May 15, 2020).
Characteristic | Patients tested for SARS-CoV-2 infection (n=214,207) | Patients with laboratory-confirmed SARS-CoV-2 infection (n=7566) | ||||||||
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Nonusers of statin | Users of statin | Nonusers of statin | Users of statin | ||||||
Total, n (%) | 178,897 (83.52) | 35,310 (16.48) | 6547 (86.53) | 1019 (13.47) | ||||||
Age in years, mean (SD) | 46.0 (19.0) | 67.6 (13.6) | 43.5 (17.8) | 65.5 (13.7) | ||||||
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Male | 84,477 (47.22) | 17,004 (48.16) | 2996 (45.76) | 490 (48.09) | |||||
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Female | 94,420 (52.78) | 18,306 (51.84) | 3551 (54.24) | 529 (51.91) | |||||
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Rural | 79,786 (44.60) | 14,216 (40.26) | 2492 (38.06) | 423 (41.51) | |||||
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Urban | 99,111 (55.40) | 21,094 (59.74) | 4055 (61.94) | 596 (58.49) | |||||
History of cardiovascular disease, n (%) | 15,969 (8.93) | 14,339 (40.61) | 448 (6.84) | 343 (33.66) | ||||||
History of cerebrovascular disease, n (%) | 10,745 (6.01) | 9582 (27.14) | 304 (4.64) | 250 (24.53) | ||||||
History of diabetes mellitus, n (%) | 17,949 (10.03) | 17,293 (48.97) | 559 (8.54) | 472 (46.32) | ||||||
History of chronic obstructive pulmonary disease, n (%) | 12,106 (6.77) | 5511 (15.61) | 368 (5.62) | 137 (13.44) | ||||||
History of hypertension, n (%) | 35,166 (19.66) | 26,694 (75.60) | 1083 (16.54) | 729 (71.54) | ||||||
History of chronic kidney disease, n (%) | 7856 (4.39) | 6190 (17.53) | 372 (5.68) | 172 (16.88) | ||||||
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0 | 116,359 (65.04) | 3915 (11.09) | 4557 (69.60) | 129 (12.66) | |||||
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1 | 20,728 (11.59) | 4418 (12.51) | 717 (10.95) | 157 (15.41) | |||||
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≥2 | 41,810 (23.37) | 26,977 (76.40) | 1273 (19.44) | 733 (71.93) | |||||
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Aspirin | 5502 (3.08) | 9066 (25.68) | 112 (1.71) | 243 (23.85) | |||||
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Metformin | 7090 (3.96) | 10,664 (30.20) | 210 (3.21) | 322 (31.60) | |||||
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Systemic glucocorticoids | 64,441 (36.02) | 14,149 (40.07) | 2085 (31.85) | 390 (38.27) |
aGRCP: Global Research Collaboration Project.
Graphical depiction of patient enrollment in the GRCP-COVID cohort (South Korea; January 1 to May 15, 2020). GRCP: Global Research Collaboration Project.
After propensity score matching among patients who underwent SARS-CoV-2 testing, we found there were no major imbalances in the baseline covariates between the 2 groups assessed by SMD (
Propensity score–matched baseline characteristics, positive SARS-CoV-2 infection test results, and statin use in all patients who were tested for SARS-CoV-2 infection in the GRCPa-COVID cohort (n=59,402; South Korea; January 1 to May 15, 2020).
Characteristic | Nonusers of statin (n=29,701) | Users of statin (n=29,701) | Standardized mean differenceb | ||||
Age, years (SD) | 67.5 (15.0) | 66.1 (13.8) | 0.094 | ||||
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0.030 | ||||
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Male | 14,966 (50.39) | 14,522 (48.89) |
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Female | 14,735 (49.61) | 15,179 (51.11) |
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0.005 | ||||
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Rural | 12,095 (40.72) | 12,031 (40.51) |
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Urban | 17,606 (59.28) | 17,670 (59.49) |
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History of cardiovascular disease, n (%) | 10,079 (33.93) | 10,660 (35.89) | 0.049 | ||||
History of cerebrovascular disease, n (%) | 6988 (23.53) | 7210 (24.28) | 0.021 | ||||
History of diabetes mellitus, n (%) | 12,176 (41.00) | 12,597 (42.41) | 0.034 | ||||
History of chronic obstructive pulmonary disease, n (%) | 4733 (15.94) | 4557 (15.34) | 0.019 | ||||
History of hypertension, n (%) | 22,250 (74.91) | 21,180 (71.31) | 0.087 | ||||
History of chronic kidney disease, n (%) | 4613 (15.53) | 4705 (15.84) | 0.010 | ||||
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0.015 | ||||
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0 | 4664 (15.70) | 3859 (12.99) |
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1 | 4526 (15.24) | 4322 (14.55) |
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≥2 | 20,511 (69.06) | 21,520 (72.46) |
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Aspirin | 4865 (16.38) | 5738 (19.32) | 0.076 | |||
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Metformin | 5835 (19.65) | 6938 (23.36) | 0.090 | |||
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Systemic glucocorticoids | 11,923 (40.14) | 11,923 (40.14) | <0.001 | |||
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787 (2.65) | 837 (2.82) |
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aGRCP: Global Research Collaboration Project.
bA standardized mean difference (SMD) below 0.1 indicates no major imbalance. All SMD values were less than 0.1 in the propensity score–matched cohort.
cMinimally adjusted relative risk (95% CI): 1.04 (0.94-1.14),
dFully adjusted relative risk (95% CI): 0.97 (0.88-1.07),
Propensity score-matched association of statin use with (1) positive SARS-CoV-2 test result among patients who underwent SARS-CoV-2 testing (primary outcome), and (2) severe clinical outcomes of COVID-19 among patients who tested positive for SARS-CoV-2 (secondary outcome) in the GPCR-COVID cohort and in the NHIS-COVID cohort (South Korea). Significant values are in bold. GRCP: Global Research Collaboration Project; NHIS: National Health Insurance Service.
After propensity score matching among patients who tested positive for SARS-CoV-2, we found there were no major imbalances in the baseline covariates between the 2 groups assessed by SMD (
Propensity score–matched baseline characteristics and the composite endpoint with statin use among patients with laboratory-confirmed SARS-CoV-2 infection in the GRCPa-COVID cohort (n=2377; South Korea; January 1 to May 15, 2020).
Characteristic | Nonusers of statin (n=1573) | Users of statin (n=804) | Standardized mean differenceb | |
Age, years (SD) | 63.6 (15.7) | 63.7 (13.9) | 0.003 | |
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0.009 | |
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Male | 745 (47.4) | 377 (46.9) |
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Female | 828 (52.6) | 427 (53.1) |
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0.006 | |
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Rural | 647 (41.1) | 333 (41.4) |
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Urban | 926 (58.9) | 471 (58.6) |
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History of cardiovascular disease, n (%) | 410 (26.1) | 229 (28.5) | 0.054 | |
History of cerebrovascular disease, n (%) | 259 (16.5) | 163 (20.3) | 0.098 | |
History of diabetes mellitus, n (%) | 501 (31.8) | 294 (36.6) | 0.100 | |
History of chronic obstructive pulmonary disease, n (%) | 198 (12.6) | 103 (12.8) | 0.008 | |
History of hypertension, n (%) | 957 (60.8) | 525 (65.3) | 0.093 | |
History of chronic kidney disease, n (%) | 263 (16.7) | 133 (16.5) | 0.006 | |
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0.099 | |
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0 | 489 (31.1) | 122 (15.2) |
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1 | 203 (12.9) | 142 (17.7) |
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≥2 | 881 (56.0) | 540 (67.2) |
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Aspirin | 105 (6.7) | 75 (9.3) | 0.099 |
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Metformin | 194 (12.3) | 123 (15.3) | 0.087 |
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Systemic glucocorticoids | 622 (39.5) | 305 (37.9) | 0.034 |
Severe outcomes of COVID-19c,d,e, n (%) | 85 (5.4)g | 32 (4.0)g |
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Length of stay for patients in hospital (days), mean (SD)f | 26.3 (15.7)g | 23.8 (14.2)g |
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aGRCP: Global Research Collaboration Project.
bA standardized mean difference (SMD) below 0.1 indicates no major imbalance. All SMD values were less than 0.1 in the propensity score–matched cohort.
cSevere outcomes of COVID-19 consisted of admission to the intensive care unit, invasive ventilation, or death.
dMinimally adjusted relative risk (95% CI): 0.64 (0.40 to 0.96),
eFully adjusted relative risk (95% CI): 0.62 (0.41 to 0.91),
fThe fully adjusted mean difference (95% CI) was –2.87 (–5.68 to –0.93). Risk factors were adjusted for age and sex.
gStatistically significant differences (
Among patients who underwent SARS-CoV-2 testing (n=74,866), we identified 57,416 nonusers and 17,450 statin users in the full unmatched cohort (
Baseline characteristics of all patients who were tested for SARS-CoV-2 infection and of those with laboratory-confirmed SARS-CoV-2 infection in the NHISa-COVID cohort (South Korea; January 1 to May 31, 2020).
Characteristics | Patients tested for SARS-CoV-2 infection (n=74,866) | Patients with laboratory-confirmed SARS-CoV-2 infection (n=2666) | |||||||
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Users of statin | Nonusers of statin | Users of statin | Nonusers of statin | |||||
Total, n (%) | 57,416 (76.69) | 17,450 (23.3) | 2105 (79.0) | 561 (21.0) | |||||
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20-59 | 38,120 (66.39) | 4443 (25.46) | 1401 (66.56) | 169 (30.12) | ||||
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60-69 | 7987 (13.91) | 4721 (27.05) | 422 (20.05) | 187 (33.33) | ||||
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≥70 | 11,309 (19.70) | 8286 (47.48) | 282 (13.40) | 205 (36.54) | ||||
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Male | 28,092 (48.93) | 8289 (47.50) | 770 (36.58) | 202 (36.01) | ||||
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Female | 29,324 (51.07) | 9161 (52.50) | 1335 (63.42) | 359 (63.99) | ||||
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Rural | 20,892 (36.39) | 6385 (36.59) | 216 (10.26) | 39 (6.95) | ||||
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Urban | 36,524 (63.61) | 11,065 (63.41) | 1889 (89.74) | 522 (93.05) | ||||
History of diabetes mellitus, n (%) | 3603 (6.28) | 5227 (29.95) | 103 (4.89) | 169 (30.12) | |||||
History of stroke, n (%) | 694 (1.21) | 881 (5.05) | 13 (0.62) | 22 (3.92) | |||||
History of cardiovascular disease, n (%) | 1215 (2.12) | 2531 (14.50) | 25 (1.19) | 52 (9.27) | |||||
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0 | 37,320 (65.00) | 1939 (11.11) | 1201 (57.05) | 56 (9.98) | ||||
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1 | 6660 (11.60) | 2181 (12.50) | 362 (17.20) | 100 (17.83) | ||||
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≥2 | 13,436 (23.40) | 13,330 (76.39) | 542 (25.75) | 405 (72.19) | ||||
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<25 | 38,976 (67.88) | 9467 (54.25) | 1427 (67.79) | 309 (55.08) | ||||
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25-30 | 15,524 (27.04) | 6652 (38.12) | 587 (27.89) | 223 (39.75) | ||||
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>30 | 2916 (5.08) | 1331 (7.63) | 91 (4.32) | 29 (5.17) | ||||
Systolic blood pressure (mmHg), mean (SD) | 121.4 (15.2) | 128.2 (15.5) | 120.4 (15.2) | 127.6 (15.4) | |||||
Diastolic blood pressure (mmHg), mean (SD) | 74.9 (10.1) | 76.8 (10.2) | 74.4 (10.1) | 77.0 (10.1) | |||||
Fasting blood glucose (mg/dL), mean (SD) | 98.6 (24.7) | 112.8 (37.4) | 98.5 (25.6) | 112.7 (33.5) | |||||
Serum total cholesterol (mg/dL), mean (SD) | 191.5 (37.1) | 182.4 (50.0) | 195.3 (35.7) | 188.3 (46.5) | |||||
Serum low-density lipoprotein cholesterol (mg/dL), mean (SD) | 110.8 (33.0) | 101.5 (45.5) | 115.3 (31.5) | 106.6 (42.0) | |||||
Serum high-density lipoprotein cholesterol (mg/dL), mean (SD) | 56.9 (18.8) | 53.5 (16.5) | 57.9 (27.3) | 56.5 (38.4) | |||||
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Normal (≥90) | 29,258 (51.96) | 5693 (32.62) | 1066 (50.64) | 216 (38.50) | ||||
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Mildly decreased (60-89) | 24,714 (43.04) | 8962 (51.36) | 958 (45.51) | 289 (51.52) | ||||
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Moderately to severely decreased (<59) | 3444 (6.00) | 2795 (16.02) | 81 (3.85) | 56 (9.98) | ||||
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Low (0th-39th percentile) | 15,480 (27.96) | 4771 (27.34) | 784 (37.24) | 185 (32.98) | ||||
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Middle (40th-79th percentile) | 21,313 (37.12) | 5227 (29.95) | 685 (32.54) | 178 (31.73) | ||||
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High (80th-100th percentile) | 20,623 (35.92) | 7452 (42.70) | 636 (30.21) | 198 (35.29) | ||||
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Never smoker | 37,145 (64.69) | 11,270 (64.58) | 1681 (79.86) | 419 (74.69) | ||||
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Ex-smoker | 9278 (16.16) | 3708 (21.25) | 280 (13.30) | 101 (18.00) | ||||
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Current smoker | 10,993 (19.15) | 2472 (14.17) | 144 (6.84) | 41 (7.31) | ||||
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<1 | 32,184 (56.05) | 12,667 (72.59) | 1472 (69.93) | 423 (75.40) | ||||
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1-2 | 18,048 (31.43) | 3152 (18.06) | 489 (23.23) | 94 (16.76) | ||||
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3-4 | 4981 (8.68) | 1021 (5.85) | 103 (4.89) | 32 (5.70) | ||||
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≥5 | 2203 (3.84) | 610 (3.50) | 41 (1.95) | 12 (2.14) | ||||
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0 | 29,958 (52.18) | 10,061 (57.66) | 1154 (54.82) | 331 (59.00) | ||||
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1-2 | 14,079 (24.52) | 2943 (16.87) | 469 (22.28) | 86 (15.33) | ||||
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3-4 | 7563 (13.17) | 2301 (13.19) | 286 (13.59) | 73 (13.01) | ||||
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5-6 | 3846 (6.70) | 1253 (7.18) | 141 (6.70) | 39 (6.95) | ||||
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7 | 1970 (3.43) | 892 (5.11) | 55 (2.61) | 32 (5.70) | ||||
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Medication for hypertension, n (%) | 9074 (15.80) | 8939 (51.23) | 266 (12.64) | 263 (46.88) | ||||
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Medication for diabetes mellitus, n (%) | 3328 (5.80) | 4989 (28.59) | 93 (4.42) | 159 (28.34) | ||||
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Medication for cardiovascular disease, n (%) | 1028 (1.79) | 2400 (13.75) | 18 (0.86) | 52 (9.27) |
aNHIS: National Health Insurance Service.
Graphical depiction of patient enrollment in the NHIS-COVID cohort (South Korea; January 1 to May 31, 2020). NHIS: National Health Insurance Service.
After propensity score matching among patients who underwent SARS-CoV-2 testing, we found there were no major imbalances in the baseline covariates between 2 groups assessed by SMD (
Propensity score–matched baseline characteristics, positive SARS-CoV-2 infection test results, and statin use in all patients who were tested for SARS-CoV-2 infection in the NHISa-COVID cohort (n=28,888; South Korea; January 1 to May 31, 2020).
Characteristic | Nonusers of statins | Users of statins | Standardized mean differenceb | |
Total, n | 14,444 | 14,444 |
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0.099 | |
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20-59 | 4524 (31.32) | 4479 (31.01) |
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60-69 | 2938 (20.34) | 3505 (24.27) |
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≥70 | 6982 (48.34) | 6460 (44.72) |
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0.019 | |
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Male | 7107 (49.20) | 6967 (48.23) |
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Female | 7337 (50.80) | 7477 (51.77) |
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0.009 | |
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Rural | 5341 (36.98) | 5277 (36.53) |
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Urban | 9103 (63.02) | 9167 (63.47) |
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History of diabetes mellitus, n (%) | 3002 (20.78) | 3434 (23.77) | 0.082 | |
History of stroke, n (%) | 537 (3.72) | 580 (4.02) | 0.017 | |
History of cardiovascular disease, n (%) | 1013 (7.01) | 1367 (9.46) | 0.089 | |
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0.049 | |
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0 | 2549 (17.65) | 1341 (9.28) |
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1 | 1524 (10.55) | 1879 (13.01) |
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≥2 | 10,371 (71.80) | 11,224 (77.71) |
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0.049 | |
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<25 | 7966 (55.15) | 8154 (56.45) |
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25-30 | 5167 (35.77) | 5331 (36.91) |
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>30 | 1311 (9.08) | 959 (6.64) |
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Systolic blood pressure (mmHg), mean (SD) | 128.5 (16.0) | 127.3 (15.3) | 0.082 | |
Diastolic blood pressure (mmHg), mean (SD) | 77.4 (10.4) | 76.6 (10.1) | 0.075 | |
Fasting blood glucose (mg/dL), mean (SD) | 109.5 (38.2) | 109.9 (34.2) | 0.013 | |
Serum total cholesterol (mg/dL), mean (SD) | 189.7 (38.9) | 186.0 (50.9) | 0.083 | |
Serum low-density lipoprotein cholesterol (mg/dL), mean (SD) | 108.4 (33.5) | 105.0 (46.7) | 0.088 | |
Serum high-density lipoprotein cholesterol (mg/dL), mean (SD) | 53.5 (15.5) | 54.0 (17.0) | 0.025 | |
|
|
|
0.018 | |
|
Normal (≥90) | 5214 (36.10) | 5018 (34.74) |
|
|
Mildly decreased (60-89) | 6976 (48.30) | 7468 (51.70) |
|
|
Moderately to severely decreased (<59) | 2254 (15.61) | 1958 (13.56) |
|
|
|
|
0.005 | |
|
Low (0th-39th percentile) | 3802 (26.32) | 4002 (27.71) |
|
|
Middle (40th-79th percentile) | 4688 (32.46) | 4368 (30.24) |
|
|
High (80th-100th percentile) | 5954 (41.22) | 6074 (42.05) |
|
|
|
|
0.007 | |
|
Never smoker | 9319 (64.52) | 9250 (64.04) |
|
|
Ex-smoker | 2845 (19.70) | 3058 (21.17) |
|
|
Current smoker | 2280 (15.79) | 2136 (14.79) |
|
|
|
|
0.002 | |
|
<1 | 10,174 (70.44) | 10,192 (70.56) |
|
|
1-2 | 2817 (19.50) | 2794 (19.34) |
|
|
3-4 | 909 (6.29) | 918 (6.36) |
|
|
≥5 | 544 (3.77) | 540 (3.74) |
|
|
|
|
0.007 | |
|
0 | 8268 (57.24) | 8241 (57.05) |
|
|
1-2 | 2555 (17.69) | 2541 (17.59) |
|
|
3-4 | 1781 (12.33) | 1917 (13.27) |
|
|
5-6 | 1066 (7.38) | 1063 (7.36) |
|
|
7 | 774 (5.36) | 682 (4.72) |
|
|
|
|
|
|
|
Medication for hypertension, n (%) | 6758 (46.79) | 6515 (45.11) | 0.038 |
|
Medication for diabetes mellitus, n (%) | 2797 (19.36) | 3246 (22.47) | 0.086 |
|
Medication for cardiovascular disease, n (%) | 904 (6.26) | 1280 (8.86) | 0.099 |
COVID-19, n (%)c,d | 483 (3.34) | 492 (3.41) |
|
aNHIS: National Health Insurance Service.
bA standardized mean difference (SMD) of less than 0.1 indicates no major imbalance. All SMD values were less than 0.1 in each propensity score–matched cohort.
cMinimally adjusted relative risk (95% CI): 1.00 (0.88-1.13),
dFully adjusted relative risk (95% CI): 1.01 (0.89-1.15),
After propensity score matching among patients who tested positive for SARS-CoV-2, we found there were no major imbalances in the baseline covariates between the 2 groups assessed by SMD (
Propensity score–matched baseline characteristics and the severe clinical outcomes with statin use among patients with laboratory-confirmed SARS-CoV-2 infection in the NHISa-COVID cohort (n=615; South Korea; January 1 to May 31, 2020).
Characteristic | Nonusers of statins (n=410) | Users of statins (n=205) | Standardized mean differenceb | |
|
|
|
0.011 | |
|
20-59 | 175 (42.7) | 88 (42.9) |
|
|
60-69 | 121 (29.5) | 61 (29.8) |
|
|
≥70 | 114 (27.8) | 56 (27.3) |
|
|
|
|
0.081 | |
|
Male | 132 (32.2) | 74 (36.1) |
|
|
Female | 278 (67.8) | 131 (63.9) |
|
|
|
|
0.043 | |
|
Rural | 39 (9.5) | 17 (8.3) |
|
|
Urban | 371 (90.5) | 188 (91.7) |
|
History of diabetes mellitus, n (%) | 40 (9.8) | 24 (11.7) | 0.063 | |
History of stroke, n (%) | 4 (1.0) | 3 (1.5) | 0.044 | |
History of cardiovascular disease, n (%) | 8 (2.0) | 7 (3.4) | 0.091 | |
|
|
|
0.077 | |
|
0 | 98 (23.9) | 42 (20.5) |
|
|
1 | 107 (26.1) | 59 (28.8) |
|
|
≥2 | 208 (50.7) | 104 (50.7) |
|
|
|
|
0.090 | |
|
<25 | 251 (61.2) | 128 (62.4) |
|
|
25-30 | 140 (34.1) | 71 (34.6) |
|
|
>30 | 19 (4.6) | 6 (2.9) |
|
Systolic blood pressure (mmHg), mean (SD) | 125.1 (15.6) | 123.7 (15.5) | 0.090 | |
Diastolic blood pressure (mmHg), mean (SD) | 77.2 (10.4) | 76.3 (10.4) | 0.086 | |
Fasting blood glucose (mg/dL), mean (SD) | 105.6 (29.4) | 102.8 (20.6) | 0.093 | |
Serum total cholesterol (mg/dL), mean (SD) | 201.0 (37.8) | 203.0 (49.5) | 0.050 | |
Serum low-density lipoprotein cholesterol (mg/dL), mean (SD) | 117.9 (33.3) | 121.5 (43.7) | 0.093 | |
Serum high-density lipoprotein cholesterol (mg/dL), mean (SD) | 58.2 (16.8) | 58.2 (52.1) | <0.001 | |
|
|
|
0.067 | |
|
Normal (≥90) | 171 (41.7) | 81 (39.5) |
|
|
Mildly decreased (60-89) | 207 (50.5) | 110 (53.7) |
|
|
Moderately to severely decreased (<59) | 32 (7.8) | 14 (6.8) |
|
|
|
|
0.096 | |
|
Low (0th-39th percentile) | 141 (34.4) | 68 (33.2) |
|
|
Middle (40th-79th percentile) | 141 (34.4) | 64 (31.2) |
|
|
High (80th-100th percentile) | 128 (31.2) | 73 (35.6) |
|
|
|
|
0.084 | |
|
Never smoker | 318 (77.6) | 155 (75.6) |
|
|
Ex-smoker | 66 (16.1) | 39 (19.0) |
|
|
Current smoker | 26 (6.3) | 11 (5.4) |
|
|
|
|
0.080 | |
|
<1 | 314 (76.6) | 153 (74.6) |
|
|
1-2 | 70 (17.1) | 39 (19.0) |
|
|
3-4 | 19 (4.6) | 8 (3.9) |
|
|
≥5 | 7 (1.7) | 5 (2.4) |
|
|
|
|
0.085 | |
|
0 | 233 (56.8) | 118 (57.6) |
|
|
1-2 | 85 (20.7) | 37 (18.0) |
|
|
3-4 | 59 (14.4) | 34 (16.6) |
|
|
5-6 | 22 (5.4) | 11 (5.4) |
|
|
7 | 11 (2.7) | 5 (2.4) |
|
|
|
|
|
|
|
Medication for hypertension, n (%) | 102 (24.9) | 46 (22.4) | 0.057 |
|
Medication for diabetes mellitus, n (%) | 36 (8.8) | 22 (10.7) | 0.066 |
|
Medication for cardiovascular disease, n (%) | 5 (1.2) | 6 (2.9) | 0.120 |
Severe clinical outcomes of COVID-19, n (%)c,d | 50 (12.2)e | 11 (5.4)e |
|
|
Length of stay for patients in hospital (days), mean (SD) | 26.3 (15.7)e | 23.9 (14.3)e |
|
aNHIS: National Health Insurance Service.
bA standardized mean difference (SMD) below 0.1 indicates no major imbalance. All SMD values were less than 0.1 in the propensity score–matched cohort, except medication for cardiovascular disease among nonusers versus statin users.
cMinimally adjusted relative risk (95% CI): 0.44 (0.22-0.87),
dFully adjusted relative risk (95% CI): –2.53 (–5.54 to –0.37);
eStatistically significant differences (
Among those in the GRCP-COVID cohort (n=214,207) and NHIS-COVID cohort (n=74,866) who underwent SARS-CoV-2 testing, 16.5% (35,310/214,207) and 23.3% (17,450/74,866) were currently taking statins, respectively. We examined the potential association between positive SARS-CoV-2 test results with the current use of statins in the propensity score–matched cohort (GRCP-COVID, n=59,402; NHIS-COVID, n=28,888) and clinical outcomes of patients with COVID-19 taking statins in the propensity score–matched cohort (GRCP-COVID, n=2377; NHIS-COVID, n=615). After controlling for various confounding variables using propensity matching and statistical adjustment, the use of statins was associated with improved clinical outcomes of COVID-19 and decreased length of hospital stay but not with the risk of susceptibility to SARS-CoV-2 infection.
This study demonstrated that statin use was associated with improved clinical outcomes and decreased length of hospital stay in patients with COVID-19. Many plausible pathophysiology could contribute to the association of statin use with COVID-19 outcomes.
The entry of SARS-CoV-2 is initiated by the binding of viral spike protein to the cellular receptor ACE2 [
Immune modulatory effects of statins may influence recovery from COVID-19. COVID-19 is accompanied by the activation of the immune system and the elevation of inflammatory cytokines, such as C-reactive protein, ferritin, and interleukin-6 (IL-6) [
Statins are a well-known class of drugs that protect the vascular endothelium from reactive oxygen species [
Numerous studies have reported the effects of statins on clinical improvements in viral infections, namely, Ebola (positive association) [
A recent previous study reported the beneficial association between in-hospital use of statin and mortality in patients with COVID-19 [
This study has some limitations. First, the GRCP-COVID cohort had a maximum follow-up duration less than 3 years, whereas the history of statin use can span decades. For rapid data acquisition and real-time analysis in this global crisis, the Korean Government provides relatively short-term histories (maximum 3 years) of patients with COVID-19. Second, in the GRCP-COVID cohort, the serum lipid profiles of patients were not accessible. However, the Korean National Health Insurance program has strict regulations regarding reimbursement for the treatment of hyperlipidemia that count the risk factors and consider the serum cholesterol levels. This makes the inclusion of the patients with dyslipidemia very robust. Third, important missing covariates included smoking status, blood pressure levels, biomarkers including basal sugar levels, and factors that could influence the outcomes of COVID-19. To overcome this issue, we adjusted the statistics by obtaining the histories of hypertension, diabetes, and COPD, a well-known smoking-associated disorder, verified by ICD codes. Fourth, our analysis lacked the evaluation of patient adherence to statins based on either the medical record or the questionnaire. Further meticulous review of data including the drug adherence is necessary to overcome this issue. Fifth, our analysis lacked personal information of the socioeconomic status (education level and household income) of the patients, which might affect the treatment compliance of patients with COVID-19. However, all COVID-19–related costs were provided complimentarily by the Korean Government; thus, the impact of the socioeconomic status of the patients on the clinical outcomes of COVID-19 may be minimal. Sixth, we were unable to obtain full information about all baseline variables on the index date in the NHIS-COVID cohort; therefore, the values of time-varying variables might differ from their values on the index date. To overcome this issue, we used the data measured on the date closest to the index date as the baseline data. Besides, we did not investigate whether statin medication was continued while the patients were hospitalized. A further study is warranted to clarify this issue. Seventh, as our study cohort involves patients tested for SARS-CoV-2, there was potential for ascertainment bias wherein those who have pre-existing health conditions (some necessitating statins) may have greater COVID-19 awareness, and be more likely to undergo screening, and be referred to care settings. However, the prevalence of patients with statin use (GRCP-COVID cohort, 16.48% [35,310/214,207]) is comparable to a nationally representative cohort of the general US population aged over 20 years (17.23%) [
Another limitation was that although the NHIS-COVID cohort had more key covariates than the GRCP cohort (ie, serum glucose, lipid profile, body mass index, household income, smoking status, physical activity status, and frequency of alcohol consumption), the total sample size (n=74,866) was less than that of the GRCP-COVID cohort (n=214,207). Finally, although 2 organizations (NHIS and Health Insurance Review and Assessment Service [HIRA]) independently constructed the cohorts, there is a possibility that patient data may have been duplicated.
Statins are inexpensive and readily available therapeutic agents. Despite the aforesaid limitations, our study highlights for the first time the potential protective effects of previous statin use on the clinical outcomes of patients with COVID-19. Two large cohort studies provided clinical evidence that previous and current statin use is associated with decreased risks of severe COVID-19 outcomes; one study used claims-based data (GRCP-COVID cohort) and the other used interview-based data (NHIS-COVID cohort), with propensity score matching. Furthermore, our study included a large number of patients and well-designed statistical techniques were implemented. Thus, our use of 2 independent cohorts increases the generalizability and reliability of our results, and this makes the results of this study robust and reliable.
Prior statin use was associated with a decreased likelihood of severe clinical outcomes of COVID-19 and a shorter length of hospital stay. Our well-designed observational study suggests that the use of statins may play a potential protective role for patients with COVID-19 and that randomized controlled trials of the therapeutic use of statins for COVID-19 are warranted.
Supplementary figures.
angiotensin-converting enzyme 2
adjusted relative risk
bacillus Calmette–Guérin
chronic obstructive pulmonary disease
Global Research Collaboration Project
Health Insurance Review and Assessment Service
International Classification of Disease 10th revision
interleukin
National Health Insurance Service
standardized mean difference
World Health Organization
The authors appreciate health care professionals dedicated to treating patients with COVID-19 in Korea, the Ministry of Health and Welfare, the Health Insurance Review & Assessment Service of Korea, and the National Health Insurance Service of Korea for sharing invaluable national cohorts in a prompt manner. This work was supported by an Institute of Information and Communications Technology Planning & Evaluation (IITP) grant funded by the Korean Government (Ministry of Science and ICT [MSIT]; No. 2020-0-01969; Development of HW/SW platform for interactive self-monitoring in real-time addressing the mental health problems based on brain-cognitive behavioral data). The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
DY, JY, and SL had full access to all of the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. All authors approved the final version before submission. DY was responsible for study concept and design. SL and SM performed acquisition, analysis, or interpretation of data. SK, JY, and DY drafted the manuscript. All authors provided critical revision of the manuscript for important intellectual content. SL, SM, and DY performed statistical analysis. DY, JY, and SL are corresponding authors (DY,
None declared.