Why carry out this study? |
We previously demonstrated that a premorbid prescription of either glucagon-like peptide-1 receptor agonists (GLP-1RA) or sodium-glucose cotransporter-2 inhibitors (SGLT-2i), compared to dipeptidyl peptidase 4 inhibitors (DPP-4i), is associated with reduced severity of COVID-19 through analyses of observational data from the National COVID Cohort Collaborative (N3C). |
With access to a sixfold larger N3C cohort gathered over approximately 3 years of the pandemic (1 January 2020–15 September 2022), we reassessed the association of GLP-1RA or SGLT-2i prescriptions alone and in combination with COVID-19 severity. |
What was learned from this study? |
Prescriptions for GLP-1RA and SGLT-2i continue to be associated with lower COVID-19 mortality compared to prescriptions for DPP-4i. |
When compared to the use of SGLT-2i alone, concomitant prescription of GLP-1RA/SGLT-2i is associated with lower odds of secondary outcomes, including emergency room visits, hospitalizations, and mechanical ventilation, suggesting that there may be additive, protective effects from the concomitant use of GLP-1RA/SGLT-2i in the context of COVID-19. |
Digital Features
Introduction
Methods
Study Design
Statistical Analysis
Ethics Compliance
Results
Demographics and clinical characteristics | Crude characteristics | Weighted characteristicsa | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
All (N = 78,806) | GLP-1RA users (N = 42,799) | SGLT-2i users (N = 25,421) | DPP-4i users (N = 20,200) | GLP-1RA users (N = 41,703) | DPP-4i users (N = 17,931) | SMD | SGLT-2i users (N = 24,752) | DPP-4i users (N = 19,633) | SMD | |
Ageb, years (N = 78,806) | 58.7 ± 13.3 | 55.6 ± 12.8 | 58.6 ± 12.0 | 64.4 ± 12.8 | 57.87 ± 12.93 | 60.11 ± 13.44 | 0.17 | 60.59 ± 11.93 | 61.45 ± 13.31 | 0.07 |
Sexb, Female (N = 78,804) | 43,618 (55.35) | 26,474 (61.86) | 11,492 (45.21) | 10,500 (51.98) | 24,534 (58.83) | 9943 (55.45) | 0.07 | 11,795 (47.66) | 9571 (48.75) | 0.02 |
Raceb, White (N = 69,668) | 51,352 (65.16) | 28,536 (66.67) | 17,341 (68.22) | 12,113 (59.97) | 31,871 (76.42) | 13,584 (75.76) | 0.02 | 19,143 (77.34) | 15,015 (76.48) | 0.02 |
Ethnicityb, Hispanic or Latino (N = 71,382) | 9689 (12.29) | 4705 (10.99) | 2971 (11.69) | 3087 (15.28) | 5059 (12.13) | 2402 (13.39) | 0.04 | 3252 (13.14) | 2710 (13.80) | 0.02 |
Current smokerb (N = 78,806) | 15,657 (19.87) | 8078 (18.87) | 5144 (20.24) | 4275 (21.16) | 8116 (19.46) | 3605 (20.11) | 0.02 | 5070 (20.48) | 4065 (20.71) | 0.01 |
BMIb, kg/m2 (N = 48,807) | 34.8 ± 8.6 | 36.7 ± 8.6 | 34.3 ± 8.2 | 31.8 ± 7.8 | 35.40 ± 6.94 | 34.04 ± 6.93 | 0.20 | 33.39 ± 6.43 | 32.96 ± 6.64 | 0.07 |
Body weight, kg (N = 49,851) | 104.2 ± 36.8 | 109.1 ± 36.9 | 103.5 ± 34.8 | 96.5 ± 37.5 | 105.86 ± 29.89 | 102.20 ± 31.39 | 0.12 | 100.35 ± 28.09 | 100.48 ± 31.34 | 0.00 |
Glycated hemoglobinb, % (N = 61,142) | 7.8 ± 2.0 | 7.8 ± 2.0 | 8.0 ± 1.8 | 7.8 ± 1.9 | 7.82 ± 1.79 | 7.90 ± 1.69 | 0.04 | 7.99 ± 1.61 | 7.96 ± 1.74 | 0.02 |
Heart rateb, bpm (N = 27,459) | 84.8 ± 15.7 | 86.0 ± 15.2 | 84.6 ± 15.7 | 83.2 ± 16.6 | 85.39 ± 9.46 | 84.78 ± 10.12 | 0.06 | 84.36 ± 9.85 | 84.19 ± 9.99 | 0.02 |
Systolic blood pressureb, mmHg (N = 44,132) | 131.3 ± 19.6 | 131.1 ± 18.7 | 129.6 ± 19.3 | 133.4 ± 21.0 | 131.78 ± 14.66 | 132.47 ± 14.89 | 0.05 | 131.03 ± 15.52 | 131.82 ± 14.97 | 0.05 |
Diastolic blood pressureb, mmHg (N = 43,590) | 76.0 ± 11.8 | 76.9 ± 11.4 | 75.6 ± 11.5 | 74.5 ± 12.3 | 76.28 ± 8.83 | 75.69 9.30 | 0.06 | 75.33 ± 9.11 | 75.18 ± 9.24 | 0.02 |
eGFRb, mL/min/1.73 m2 (N = 61,803) | 77.1 ± 29.0 | 81.3 ± 28.1 | 79.4 ± 26.3 | 67.5 ± 30.7 | 78.13 ± 26.50 | 74.64 ± 28.55 | 0.13 | 75.94 ± 24.66 | 74.13 ± 27.86 | 0.07 |
Creatinine, mg/dL (N = 70,055) | 1.2 ± 1.2 | 1.1 ± 1.1 | 1.1 ± 0.8 | 1.5 ± 1.6 | 1.17 ± 1.10 | 1.35 ± 1.43 | 0.15 | 1.13 ± 0.84 | 1.34 ± 1.37 | 0.19 |
Alanine aminotransferase, U/L (N = 64,967) | 30.7 ± 62.2 | 30.1 ± 38.9 | 31.7 ± 50.2 | 30.7 ± 94.5 | 29.92 ± 37.90 | 31.88 ± 79.27 | 0.03 | 31.00 ± 44.46 | 31.98 ± 81.54 | 0.01 |
Aspartate aminotransferase, U/L (N = 64,535) | 31.0 ± 98.4 | 29.0 ± 56.3 | 30.4 ± 62.7 | 34.6 ± 161.0 | 29.37 ± 57.19 | 34.02 ± 135.05 | 0.04 | 30.52 ± 55.41 | 34.18 ± 139.07 | 0.03 |
Medication | ||||||||||
Metforminb | 48,645 (61.73) | 25,501 (59.58) | 17,433 (68.58) | 12,843 (63.58) | 25,515 (61.18) | 11,422 (63.70) | 0.05 | 16,711 (67.52) | 13,123 (66.84) | 0.01 |
Sulfonylureab | 20,850 (26.46) | 9167 (21.42) | 7287 (28.67) | 7230 (35.79) | 10,639 (25.51) | 5328 (29.72) | 0.09 | 7819 (31.59) | 6441 (32.81) | 0.03 |
Insulina | 38,185 (48.45) | 21,835 (51.02) | 12,807 (50.38) | 9449 (46.78) | 21,025 (50.41) | 9067 (50.56) | 0.00 | 12,027 (48.59) | 9381 (47.78) | 0.02 |
Statinb | 53,377 (67.73) | 27,198 (63.55) | 18,823 (74.05) | 14,850 (73.51) | 27,779 (66.61) | 12,603 (70.29) | 0.08 | 18,211 (73.58) | 14,383 (73.26) | 0.01 |
ACEi/ARBb | 49,458 (62.76) | 25,572 (59.75) | 17,713 (69.68) | 13,084 (64.77) | 25,595 (61.37) | 11,415 (63.66) | 0.05 | 16,803 (67.89) | 13,113 (66.79) | 0.02 |
Remdesivir | 399 (0.51) | 182 (0.43) | 145 (0.57) | 111 (0.55) | 186 (0.45) | 96 (0.53) | 0.01 | 142 (0.57) | 106 (0.54) | 0.00 |
Medical history | ||||||||||
Myocardial infarctionb,c | 7337 (9.31) | 3152 (7.36) | 3083 (12.13) | 2035 (10.07) | 3408 (8.17) | 1616 (9.01) | 0.03 | 2774 (11.21) | 2092 (10.65) | 0.02 |
Congestive heart failureb,c | 13,943 (17.69) | 5993 (14.00) | 5463 (21.49) | 4051 (20.05) | 6518 (15.63) | 3091 (17.24) | 0.04 | 5087 (20.55) | 3905 (19.89) | 0.02 |
Cancer or metastatic cancerb,c | 7881 (10.00) | 3743 (8.75) | 2470 (9.72) | 2466 (12.21) | 4043 (9.70) | 1904 (10.62) | 0.03 | 2642 (10.68) | 2169 (11.05) | 0.01 |
Dementia or strokeb,c | 10,917 (13.85) | 4834 (11.29) | 3482 (13.70) | 3769 (18.66) | 5536 (13.27) | 2718 (15.16) | 0.05 | 3792 (15.32) | 3168 (16.13) | 0.02 |
Chronic kidney disease or end-stage renal diseaseb | 17,294 (21.95) | 8080 (18.88) | 5031 (19.79) | 5992 (29.66) | 9139 (21.91) | 4466 (24.91) | 0.07 | 5669 (22.90) | 4810 (24.50) | 0.04 |
Peripheral vascular diseasec | 17,775 (22.56) | 9063 (21.18) | 5766 (22.68) | 5048 (24.99) | 9514 (22.81) | 4063 (22.66) | 0.00 | 5915 (23.90) | 4589 (23.37) | 0.01 |
Mild liver diseasec | 11,332 (14.38) | 6625 (15.48) | 3860 (15.18) | 2457 (12.16) | 6307 (15.12) | 2372 (13.23) | 0.05 | 3649 (14.74) | 2492 (12.69) | 0.06 |
Severe liver diseasec | 1484 (1.88) | 669 (1.56) | 523 (2.06) | 451 (2.23) | 702 (1.68) | 392 (2.18) | 0.04 | 518 (2.09) | 412 (2.10) | 0.00 |
Pulmonary disease | 21,325 (27.06) | 11,991 (28.02) | 6609 (26.00) | 5309 (26.28) | 11,523 (27.63) | 4907 (27.36) | 0.01 | 6401 (25.86) | 5245 (26.72) | 0.02 |
Coronary artery disease | 16,531 (20.98) | 7493 (17.51) | 6455 (25.39) | 4742 (23.48) | 8230 (19.73) | 3638 (20.29) | 0.01 | 6331 (25.58) | 4434 (22.58) | 0.07 |
Heart failure | 13,232 (16.79) | 5617 (13.12) | 5201 (20.46) | 3876 (19.19) | 6107 (14.64) | 2956 (16.48) | 0.05 | 4870 (19.68) | 3697 (18.83) | 0.02 |
Hypertension | 57,543 (73.02) | 30,595 (71.49) | 19,365 (76.18) | 15,146 (74.98) | 30,644 (73.48) | 13,110 (73.11) | 0.01 | 18,953 (76.57) | 14,534 (74.03) | 0.06 |
Liver disease | 4694 (5.96) | 2418 (5.65) | 1627 (6.40) | 1242 (6.15) | 2428 (5.82) | 1105 (6.16) | 0.01 | 1595 (6.45) | 1179 (6.01) | 0.02 |
Characteristics, mean ± standard deviation or n (%) | Crude characteristics | Weighted characteristicsa | |||||||
---|---|---|---|---|---|---|---|---|---|
GLP-1RA mono (N = 36,942) | SGLT-2i mono (N = 20,656) | GLP-1RA/SGLT-2i (N = 11,594) | GLP-1RA mono users (N = 36,885) | GLP-1RA/SGLT-2i (N = 10,644) | SMD | SGLT-2i mono (N = 20,427) | GLP-1RA/SGLT-2i (N = 11,161) | SMD | |
Ageb, years (N = 69,192) | 55.6 ± 13.2 | 59.9 ± 12.2 | 57.0 ± 11.3 | 55.99 (13.08) | 56.79 (11.51) | 0.07 | 58.96 (12.27) | 58.29 ± 11.22 | 0.06 |
Sexb, female (N = 38,664) | 23,857 (64.58) | 8874 (42.96) | 5933 (51.17) | 22,659 (61.43) | 6075 (57.07) | 0.09 | 9326 (45.66) | 5283 (47.34) | 0.03 |
Raceb, White (N = 46,336) | 24,351 (65.92) | 13,968 (67.62) | 8017 (69.15) | 28,431 (77.08) | 8267 (77.67) | 0.01 | 16,209 (79.35) | 8877 (79.54) | 0,00 |
Ethnicityb, Hispanic or Latino (N = 8242) | 4163 (11.27) | 2718 (13.16) | 1361 (11.74) | 4206 (11.40) | 1241 (11.66) | 0.01 | 2601 (12.73) | 1399 (12.53) | 0.01 |
Current smokerb (N = 13,420) | 6968 (18.86) | 4228 (20.47) | 2224 (19.18) | 6984 (18.94) | 2035 (19.12) | 0.00 | 4121 (20.18) | 2242 (20.09) | 0.00 |
BMIb, kg/m2 (N = 42,681) | 36.8 ± 8.7 | 33.1 ± 7.8 | 35.7 ± 8.2 | 36.54 ± 6.96 | 36.13 ± 6.79 | 0.06 | 33.96 ± 6.79 | 34.58 ± 6.33 | 0.09 |
Body weight, kg (N = 44.037) | 109.3 ± 37.7 | 99.8 ± 33.4 | 107.5 ± 35.8 | 109.10 ±30.52 | 107.89 ±29.30 | 0.04 | 101.62 ± 28.09 | 105.32 ± 29.17 | 0.13 |
Glycated hemoglobinb, % (N = 54,300) | 7.7 ± 2.1 | 8.0 ± 1.8 | 8.3 ± 1.8 | 7.86 ± 1.89 | 8.12 ± 1.60 | 0.15 | 8.09 ± 1.68 | 8.16 ± 1.60 | 0.04 |
Heart rateb, bpm (N = 24,393) | 85.9 ± 15.2 | 83.4 ± 15.8 | 86.2 ± 15.0 | 85.91 ± 9.46 | 86.03 ± 9.24 | 0.01 | 84.55 ± 9.99 | 85.17 ± 9.20 | 0.06 |
Systolic blood pressureb, mmHg (N = 39,179) | 131.5 ± 18.8 | 129.6 ± 19.5 | 130.1 ± 18.7 | 131.28 ± 13.97 | 130.99 ± 14.67 | 0.02 | 129.71 ± 14.91 | 129.87 ± 14.33 | 0.01 |
Diastolic blood pressureb, mmHg (N = 38,721) | 77.1 ± 11.5 | 75.3 ± 11.6 | 76.0 ± 11.2 | 76.80 ± 8.70 | 76.44 ± 8.75 | 0.04 | 75.63 ± 9.08 | 75.77 ± 8.63 | 0.02 |
eGFRb, mL/min/1.73 m2 (N = 54,712) | 80.4 ± 28.9 | 77.8 ± 26.4 | 82.0 ± 25.7 | 81.19 ± 26.51 | 81.23 ± 24.61 | 0.00 | 79.55 ± 24.37 | 80.42 ± 23.58 | 0.04 |
Creatinine, mg/dL (N = 61,411) | 1.1 ± 1.1 | 1.1 ± 0.8 | 1.0 ± 0.8 | 1.12 ± 1.04 | 1.05 ± 0.79 | 0.08 | 1.08 ± 0.78 | 1.06 ± 0.78) | 0.02 |
Alanine aminotransferase, U/L (N = 56,871) | 30.2 ± 41.1 | 32.2 ± 62.1 | 30.8 ± 27.5 | 30.56 ± 37.16 | 30.35 ± 24.65 | 0.01 | 32.37 ± 55.79 | 30.84 ± 26.54 | 0.04 |
Aspartate aminotransferase, U/L (N = 56,465) | 29.4 ± 60.3 | 31.7 ± 87.4 | 28.3 ± 28.7 | 29.66 ± 55.05 | 28.20 ± 27.26 | 0.03 | 31.56 ± 77.54 | 28.40 ± 27.67 | 0.05 |
Medication | |||||||||
Metforminb | 21,148 (57.25) | 14,058 (68.06) | 8676 (74.83) | 22,676 (61.48) | 7247 (68.08) | 0.14 | 14,373 (70.36) | 8057 (72.19) | 0.04 |
Sulfonylureab | 7921 (21.44) | 6587 (31.89) | 3744 (32.29) | 8873 (24.06) | 2997 (28.16) | 0.09 | 6566 (32.14) | 3661 (32.80) | 0.01 |
Insulinb | 18,063 (48.90) | 8823 (42.71) | 6981 (60.21) | 19,084 (51.74) | 6117 (57.47) | 0.12 | 9918 (48.55) | 5747 (51.49) | 0.06 |
Statinb | 22,629 (61.26) | 15,193 (73.55) | 9131 (78.76) | 24,142 (65.45) | 7682 (72.18) | 0.15 | 15,371 (75.25) | 8514 (76.29) | 0.02 |
ACEi/ARBb | 21,287 (57.62) | 14,231 (68.90) | 8382 (72.30) | 22,538 (61.10) | 7086 (66.58) | 0.11 | 14,280 (69.91) | 7859 (70.41) | 0.01 |
Remdesivir | 161 (0.44) | 135 (0.65) | 43 (0.37) | 169 (0.46) | 38 (0.36) | 0.02 | 137 (0.67) | 42 (0.37) | 0.04 |
Medical history | |||||||||
Myocardial infarctionb,c | 2494 (6.75) | 2575 (12.47) | 1125 (9.70) | 2729 (7.40) | 895 (8.41) | 0.04 | 2364 (11.57) | 1205 (10.80) | 0.02 |
Congestive heart failureb,c | 4997 (13.53) | 4596 (22.25) | 1870 (16.13) | 5198 (14.09) | 1615 (15.18) | 0.03 | 4118 (20.16) | 2054 (18.40) | 0.04 |
Cancer or metastatic cancerb,c | 3353 (9.08) | 2168 (10.50) | 975 (8.41) | 3301 (8.95) | 957 (8.99) | 0.00 | 2006 (9.82) | 1044 (9.35) | 0.02 |
Dementia or strokeb,c | 4222 (11.43) | 2943 (14.25) | 1442 (12.44) | 4306 (11.67) | 1305 (12.26) | 0.02 | 2785 (13.63) | 1471 (13.18) | 0.01 |
Chronic kidney disease or end-stage renal diseaseb | 7232 (19.58) | 4122 (19.96) | 2179 (18.79) | 7162 (19.42) | 2099 (19.72) | 0.01 | 4009 (19.63) | 2151 (19.27) | 0.01 |
Peripheral vascular diseasec | 7763 (21.01) | 4641 (22.47) | 2543 (21.93) | 7832 (21.23) | 2310 (21.70) | 0.01 | 4496 (22.01) | 2546 (22.81) | 0.02 |
Mild liver diseasec | 5621 (15.22) | 2905 (14.06) | 1962 (16.92) | 5635 (15.28) | 1827 (17.16) | 0.05 | 2971 (14.54) | 1825 (16.35) | 0.05 |
Severe liver diseasec | 578 (1.56) | 436 (2.11) | 194 (1.67) | 580 (1.57) | 180 (1.69) | 0.01 | 422 (2.07) | 193 (1.73) | 0.02 |
Pulmonary diseasec | 10,480 (28.37) | 5139 (24.88) | 3132 (27.01) | 10,420 (28.25) | 2946 (27.68) | 0.01 | 5195 (25.43) | 2937 (26.32) | 0.02 |
Coronary artery disease | 6074 (16.44) | 5309 (25.70) | 2599 (22.42) | 6405 (17.37) | 2207 (20.74) | 0.09 | 4964 (24.30) | 2691 (24.11) | 0.00 |
Heart failure | 4698 (12.72) | 4392 (21.26) | 1747 (15.07) | 4877 (13.22) | 1,524 (14.31) | 0.03 | 3,952 (19.35) | 1,903 (17.05) | 0.06 |
Hypertension | 25,942 (70.22) | 15,440 (74.75) | 9105 (78.53) | 26,475 (71.78) | 8196 (77.00) | 0.12 | 15,345 (75.12) | 8709 (78.03) | 0.07 |
Liver disease | 2060 (5.58) | 1286 (6.23) | 713 (6.15) | 2061 (5.59) | 678 (6.37) | 0.03 | 1273 (6.23) | 687 (6.16) | 0.00 |