High-risk patients may benefit from additional LDL-C lowering beyond that achieved by statins alone. |
Evolocumab outperformed ezetimibe in lipid goal attainment in four patient populations analyzed (patients receiving each agent as monotherapy, patients on low-intensity statin or high-intensity statin, and with statin intolerance). |
Both evolocumab and ezetimibe showed good safety and tolerability profiles. |
These data may guide management of high-risk patients with inadequate response or intolerance to initial lipid-lowering therapies. |
Introduction
Methods
Study Selection
Study | Population | Ezetimibe QD | Evolocumab Q2W or QM |
---|---|---|---|
No. of patients | No. of patients | ||
MENDEL-2 | Monotherapy | 154 | 306 |
LAPLACE-2 | Combined with low-intensity statin | 111 | 220 |
LAPLACE-2 | Combined with high-intensity statin | 110 | 219 |
GAUSS-2 | Statin-intolerant | 102 | 205 |
Total | 477 | 950 |
Efficacy and Safety Evaluations
Statistical Analyses
Results
Baseline Characteristics
Monotherapy | With low-intensity statin | With high-intensity statin | Statin intolerance | |||||
---|---|---|---|---|---|---|---|---|
Ezetimibe (N = 154) | EvoMab (N = 306) | Ezetimibe (N = 111) | EvoMab (N = 220) | Ezetimibe (N = 110) | EvoMab (N = 219) | Ezetimibe (N = 102) | EvoMab (N = 205) | |
Demographics | ||||||||
Age, years, mean (SD) | 53.4 (12.0) | 52.7 (12.9) | 60.8 (9.1) | 59.0 (9.8) | 60.8 (9.6) | 59.9 (10.2) | 61.0 (9.4) | 61.7 (10.0) |
Sex, female, n (%) | 105 (68.2) | 205 (67.0) | 57 (51.4) | 100 (45.5) | 52 (47.3) | 91 (41.6) | 49 (48.0) | 92 (44.9) |
Race, Caucasian, n (%) | 123 (79.9) | 261 (85.3) | 105 (94.6) | 198 (90.0) | 99 (90.0) | 209 (95.4) | 95 (93.1) | 192 (93.7) |
Body mass index, kg/m2, mean (SD) | 29.2 (6.2) | 28.6 (6.3) | 29.0 (4.6) | 29.8 (5.8) | 29.4 (5.9) | 28.8 (4.8) | 28.4 (5.3) | 29.1 (4.7) |
Cardiovascular risk factors, n (%) | ||||||||
Current smoker | 26 (16.9) | 32 (10.5) | 17 (15.3) | 34 (15.5) | 20 (18.2) | 37 (16.9) | 9.0 (8.8) | 15 (7.3) |
Type 2 diabetes | 0 (0.0) | 0 (0.0) | 17 (15.3) | 38 (17.3) | 27 (24.5) | 34 (15.5) | 27 (26.5) | 35 (17.1) |
Hypertension | 42 (27.3) | 103 (33.7) | 58 (52.3) | 126 (57.3) | 66 (60.0) | 129 (58.9) | 68 (66.7) | 113 (55.1) |
Peripheral arterial disease | 0 (0.0) | 0 (0.0) | 3.0 (2.7) | 14 (6.4) | 4.0 (3.6) | 9.0 (4.1) | 7.0 (6.9) | 11 (5.4) |
Coronary artery disease | 1.0 (0.6) | 0 (0.0) | 19 (17.1) | 40 (18.2) | 19 (17.3) | 67 (30.6) | 28 (27.5) | 62 (30.2) |
Angina due to atherosclerotic coronary disease | 1.0 (0.6) | 0 (0.0) | 10 (9.0) | 15 (6.8) | 11 (10.0) | 40 (18.3) | 15 (14.7) | 28 (13.7) |
Myocardial infarction | 0 (0.0) | 0 (0.0) | 11 (9.9) | 21 (9.5) | 6.0 (5.5) | 32 (14.6) | 11 (10.8) | 34 (16.6) |
Transient ischemic attack | 0 (0.0) | 1.0 (0.3) | 2.0 (1.8) | 6.0 (2.7) | 2.0 (1.8) | 4 (1.8) | 4.0 (3.9) | 8.0 (3.9) |
Stroke | 0 (0.0) | 0 (0.0) | 2.0 (1.8) | 6.0 (2.7) | 2.0 (1.8) | 3.0 (1.4) | 6.0 (5.9) | 4.0 (2.0) |
Lipid parameters | ||||||||
LDL-C, mg/dL, mean (SD) | 143.4 (23.4) | 143.1 (22.8) | 123.1 (40.4) | 124.2 (45.3) | 95.6 (27.8) | 94.0 (33.5) | 195.0 (57.8) | 192.1 (59.0) |
Non–HDL-C, mg/dL, mean (SD) | 169.1 (28.0) | 168.4 (26.1) | 151.1 (45.7) | 153.3 (49.4) | 121.7 (31.0) | 118.7 (39.3) | 232.1 (61.4) | 225.0 (59.9) |
HDL-C, mg/dL, mean (SD) | 58.2 (17.7) | 58.4 (18.0) | 53.4 (15.5) | 56.0 (17.8) | 50.1 (13.9) | 49.7 (13.2) | 50.2 (15.2) | 52.5 (16.2) |
VLDL-C, mg/dL, median (Q1, Q3) | 23.5 (17.0, 32.0) | 23.0 (16.5, 32.0) | 25.0 (18.0, 32.0) | 25.5 (17.5, 35.0) | 24.0 (17.0, 32.0) | 21.0 (16.0, 30.0) | 33.5 (24.0, 48.0) | 30.0 (21.5, 40.0) |
Lp(a), nmol/L, median (Q1, Q3) | 28.0 (12.0, 104.0) | 25.0 (8.0, 76.0) | 36.0 (8.0, 178.0) | 39.0 (8.0, 148.0) | 31.0 (12.0, 167.0) | 26.5 (11.0, 129.0) | 32.5 (12.0, 188.0) | 31.8 (9.0, 97.0) |
ApoB, mg/dL, mean (SD) | 106.7 (18.7) | 106.4 (17.6) | 98.1 (26.6) | 98.5 (27.7) | 82.0 (20.4) | 78.9 (23.3) | 140.0 (34.0) | 136.7 (32.3) |
Triglycerides, mg/dL, median (Q1, Q3) | 116.0 (84.0, 159.0) | 114.5 (81.5, 160.0) | 123.0 (92.0, 159.0) | 128.5 (91.0, 176.5) | 120.0 (86.0, 158.0) | 106 (80.0, 150.0) | 168.0 (120.5, 239.5) | 149.0 (107.0, 200.5) |
PCSK9, ng/mL,a mean (SD) | 267.7 (93.7) | 272.8 (82.7) | 333.3 (101.4) | 331.0 (105.3) | 370.2 (120.3) | 358.8 (109.6) | 305.8 (111.9) | 276.0 (88.2) |
Effects of Ezetimibe and Evolocumab on LDL-C and Non–HDL-C
Monotherapy | With low-intensity statin | With high-intensity statin | Statin intolerance | |||||
---|---|---|---|---|---|---|---|---|
Ezetimibe (N = 154) | EvoMab (N = 306) | Ezetimibe (N = 111) | EvoMab (N = 220) | Ezetimibe (N = 110) | EvoMab (N = 219) | Ezetimibe (N = 102) | EvoMab (N = 205) | |
LDL-C | ||||||||
Absolute value at week 12, mg/dL, mean (SE) | 115.8 (2.0) | 61.2 (1.3) | 96.5 (3.5) | 49.4 (1.9) | 80.8 (5.4) | 36.1 (1.6) | 156.6 (5.2) | 88.3 (3.7) |
Absolute change from baseline to week 12, mg/dL, mean (SE) | −27.9 (1.6) | −81.8 (1.3) | −26.1 (3.0) | −79.8 (2.5) | −16.5 (4.1) | −59.9 (2.0) | −35.3 (3.2) | −104.2 (2.8) |
Percent change from baseline to week 12, %, mean (SE) | −19.0 (1.1) | −57.3 (0.7) | −19.8 (2.2) | −60.4 (1.2) | −17.8 (3.2) | −60.8 (1.5) | −17.9 (1.4) | −55.3 (1.1) |
Treatment difference, %, mean (95% CI) | −38.4 (−41.1, −35.7)a | −40.4 (−45.0, −35.83)a | −42.9 (−49.9, −35.9)a | −37.7 (−41.4, −34.1)a | ||||
Achievement of LDL-C < 70 mg/dL, n (%)b | 2.0 (1.4) | 186 (69.1) | 21 (20.8) | 173 (84.8) | 55 (53.9) | 186 (92.1) | 1.0 (1.1) | 85 (43.8) |
Treatment difference, %, mean (95% CI) | 67.7 (60.9, 73.0)a | 64.0 (53.5, 72.0)a | 38.2 (27.8, 48.2)a | 42.8 (34.5, 49.8)a | ||||
Achievement of LDL-C < 100 mg/dL, n (%)b | 38 (27.3) | 253 (94.1) | 68 (67.3) | 191 (93.6) | 82 (80.4) | 197 (97.5) | 5.0 (5.3) | 141 (72.7) |
Mean treatment difference, % (95% CI) | 66.7 (58.0, 73.8)a | 26.3 (16.9, 36.3)a | −17.1 (9.9, 26.0)a | 67.4 (58.0, 73.9)a | ||||
Non–HDL-C | ||||||||
Absolute value at week 12, mg/dL, mean (SE) | 140.6 (2.5) | 82.4 (1.4) | 123.6 (4.1) | 71.4 (2.2) | 103.3 (5.7) | 54.7 (1.9) | 191.2 (5.5) | 117.9 (3.9) |
Percent change from baseline to week 12, %, mean (SE) | −16.6 (1.0) | −50.9 (0.7) | −16.6 (2.0) | −53.3 (1.2) | −16.1 (2.9) | −52.9 (1.4) | −16.0 (1.2) | −48.3 (1.0) |
Treatment difference, %, mean (95% CI) | −34.2 (−36.6, −31.8)a | −36.5 (−40.8, −32.2)a | −36.5 (−42.7, −30.2)a | −32.5 (−35.8, −29.1)a | ||||
Achievement of non–HDL-C < 100 mg/dL, n (%)b | 8.0 (5.7) | 214 (79.6) | 34 (33.7) | 177 (86.8) | 64 (62.7) | 188 (93.1) | 0 (0) | 86 (44.1) |
Treatment difference, %, mean (95% CI) | 73.8 (66.5, 79.0)a | 53.1 (42.1, 62.5)a | 30.3 (20.5, 40.4)a | 44.1 (36.3, 51.1)a | ||||
Achievement of non–HDL-C < 130 mg/dL, n (%)b | 54 (38.6) | 261 (97.0) | 66 (65.3) | 192 (94.1) | 83 (81.4) | 196 (97.0) | 10 (10.6) | 140 (71.8) |
Treatment difference, %, mean (95% CI) | 58.5 (49.7, 66.2)a | 28.8 (19.3, 38.8)a | 15.7 (8.5, 24.4)a | 61.2 (50.8, 68.7)a | ||||
HDL-C | ||||||||
Absolute value at week 12, mg/dL, mean (SE) | 58.6 (1.5) | 61.8 (1.2) | 52.6 (1.5) | 60.1 (1.3) | 49.8 (1.3) | 53.5 (1.0) | 50.4 (1.5) | 55.1 (1.2) |
Percent change from baseline to week 12, %, mean (SE) | −0.2 (0.9) | 4.8 (0.7) | −1.2 (1.2) | 7.4 (1.0) | 0.4 (1.3) | 8.5 (1.1) | 2.2 (1.6) | 6.2 (1.0) |
Treatment difference, %, mean (95% CI) | 4.6 (2.2, 7.0)c | 8.6 (5.4, 11.8)a | 7.7 (4.4, 11.0)a | 4.3 (0.7, 7.8)d | ||||
Triglycerides | ||||||||
Absolute value at week 12, mg/dL, median (Q1, Q3) | 109.0 (79.0, 144.0) | 101.0 (74.0, 141.0) | 109.0 (83.0, 136.0) | 127.5 (86.5, 161.0) | 113.0 (80.0, 134.0) | 101.0 (79.5, 141.0) | 150.5 (109.0, 208.0) | 135.0 (99.0, 192.0) |
Percent change from baseline to week 12, %, mean (SE) | 0.5 (2.3) | −7.5 (1.9) | 3.3 (4.17) | −8.3 (2.3) | −4.9 (3.3) | −6.3 (2.4) | −1.6 (3.9) | −3.4 (2.1) |
Treatment difference, %, mean (95% CI) | −7.4 (−13.8, −0.9)d | −11.1 (−20.6, −1.6)d | −0.3 (−8.4, 7.8) | −1.4 (−9.15, 6.4) | ||||
Apolipoprotein B | ||||||||
Absolute value at week 12, mg/dL, mean (SE) | 91.4 (1.6) | 55.5 (0.8) | 83.5 (2.5) | 49.7 (1.3) | 72.2 (3.0) | 39.7 (1.2) | 120.8 (3.1) | 76.2 (2.1) |
Percent change from baseline to week 12, %, mean (SE) | −13.5 (1.1) | −47.3 (0.7) | −13.7 (1.7) | −49.4 (1.2) | −12.3 (2.3) | −48.8 (1.3) | −11.9 (1.5) | −44.6 (1.1) |
Treatment difference, %, mean (95% CI) | −33.3 (−35.9, −30.7)a | −35.6 (−39.5, −31.6)a | −35.8 (−41.3, −30.3)a | −33.0 (−37.0, −29.4)a | ||||
Lp(a) | ||||||||
Absolute value at week 12, nmol/L, median (Q1, Q3) | 27.0 (11.0, 82.0) | 15.0 (5.0, 53.5) | 43.0 (11.0, 189.0) | 22.5 (5.0, 108.0) | 40.0 (12.0, 160.0) | 15.5 (6.0, 99.0) | 34.0 (14.0, 179.0) | 17.0 (6.0, 73.0) |
Percent change from baseline to week 12, %, mean (SE) | 1.9 (2.4) | −21.5 (1.4) | 5.2 (2.4) | −23.6 (1.7) | 9.4 (2.9) | −24.4 (1.7) | 2.0 (3.8) | −24.3 (1.6) |
Treatment difference, %, mean (95% CI) | −23.3 (−28.4, −18.3)a | −28.4 (−34.0, −22.8)a | −33.9 (−39.7, −28.1)a | −26.4 (−33.2, −19.5)a | ||||
VLDL-C | ||||||||
Absolute value at week 12, mg/dL, median (Q1, Q3) | 21.5 (16.0, 28.0) | 20.0 (15.0, 28.0) | 23.5 (17.0, 29.0) | 21.0 (16.0, 29.0) | 21.0 (16.0, 27.0) | 19.0 (14.0, 27.0) | 29.0 (22.0, 41.0) | 27.0 (20.0, 37.0) |
Percent change from baseline to week 12, %, mean (SE) | −1.3 (2.1) | −7.2 (1.9) | −0.7 (3.2) | −9.2 (1.9) | −6.7 (3.0) | −6.0 (2.5) | −4.7 (3.3) | −4.4 (2.0) |
Treatment difference, %, mean (95% CI) | −5.8 (−12.1, 0.5) | −8.5 (−17.2, 0.1) | 1.7 (−6.3, 9.6) | 0.02 (−7.2, 7.2) | ||||
PCSK9 | ||||||||
Absolute value at week 12, ng/mL, mean (SE)e | 262.6 (6.8) | 123.9 (5.8) | 359.0 (10.7) | 174.4 (7.8) | 415.2 (12.8) | 218.1 (8.5) | 279.3 (9.4) | 129.4 (6.4) |
Percent change from baseline to week 12, %, mean (SE) | 15.7 (14.4) | −53.7 (2.1) | 12.9 (3.6) | −45.3 (2.4) | 17.3 (4.6) | −32.2 (4.7) | 0.9 (5.2) | −44.9 (8.8) |
Treatment difference, %, mean (95% CI) | −64.1 (−85.7, −42.2)a | −57.1 (−72.9, −41.3)a | −49.2 (−62.4, −36.0)a | −44.2 (−68.8, −19.5)c |
Changes in Other Lipids Following Treatment with Ezetimibe or Evolocumab
Safety and Tolerability
n (%) | Monotherapy | With low-intensity statin | With high-intensity statin | Statin intolerance | ||||
---|---|---|---|---|---|---|---|---|
Ezetimibe (N = 154) | EvoMab (N = 306) | Ezetimibe (N = 111) | EvoMab (N = 220) | Ezetimibe (N = 110) | EvoMab (N = 219) | Ezetimibe (N = 102) | EvoMab (N = 205) | |
Any AE | 70 (45.5) | 134 (43.8) | 47 (42.3) | 78 (35.5) | 42 (38.2) | 84 (38.4) | 74 (72.5) | 135 (65.9) |
Serious AEs | 1 (0.6) | 4 (1.3) | 0 (0.0) | 6 (2.7) | 2 (1.8) | 4 (1.8) | 4 (3.9) | 6 (2.9) |
Most common AEsa | ||||||||
Myalgia | 3 (1.9) | 3 (1.0) | 2 (1.8) | 1 (0.5) | 2 (1.8) | 3 (1.4) | 18 (17.6) | 16 (7.8) |
Fatigue | 3 (1.9) | 4 (1.3) | 1 (0.9) | 5 (2.3) | 1 (0.9) | 5 (2.3) | 10 (9.8) | 9 (4.4) |
Headache | 5 (3.2) | 10 (3.3) | 5 (4.5) | 1 (0.5) | 0 (0.0) | 4 (1.8) | 9 (8.8) | 16 (7.8) |
Diarrhea | 3 (1.9) | 9 (2.9) | 1 (0.9) | 2 (0.9) | 1 (0.9) | 6 (2.7) | 7 (6.9) | 5 (2.4) |
Nausea | 3 (1.9) | 8 (2.6) | 1 (0.9) | 2 (0.9) | 0 (0.0) | 4 (1.8) | 7 (6.9) | 9 (4.4) |
Pain in extremity | 1 (0.6) | 3 (1.0) | 2 (1.8) | 2 (0.9) | 1 (0.9) | 2 (0.9) | 1 (1.0) | 14 (6.8) |
Muscle spasms | 1 (0.6) | 2 (0.7) | 3 (2.7) | 7 (3.2) | 3 (2.7) | 3 (1.4) | 4 (3.9) | 13 (6.3) |
Back pain | 1 (0.6) | 5 (1.6) | 4 (3.6) | 3 (1.4) | 3 (2.7) | 3 (1.4) | 3 (2.9) | 9 (4.4) |
Arthralgia | 3 (1.9) | 4 (1.3) | 1 (0.9) | 3 (1.4) | 3 (2.7) | 8 (3.7) | 4 (3.9) | 8 (3.9) |
Nasopharyngitis | 6 (3.9) | 6 (2.0) | 3 (2.7) | 2 (0.9) | 1 (0.9) | 1 (0.5) | 3 (2.9) | 7 (3.4) |
Upper respiratory tract infection | 5 (3.2) | 5 (1.6) | 2 (1.8) | 2 (0.9) | 1 (0.9) | 4 (1.8) | 0 (0.0) | 3 (1.5) |
Abdominal distension | 2 (1.3) | 1 (0.3) | NR | NR | NR | NR | 1 (1.0) | 6 (2.9) |
Constipation | 1 (0.6) | 6 (2.0) | 0 (0.0) | 0 (0.0) | 1 (0.9) | 0 (0.0) | 0 (0.0) | 6 (2.9) |
Urinary tract infection | 3 (1.9) | 7 (2.3) | 1 (0.9) | 3 (1.4) | 1 (0.9) | 4 (1.8) | 2 (2.0) | 3 (1.5) |
Injection site erythema | 2 (1.3) | 5 (1.6) | NR | NR | NR | NR | 3 (2.9) | 4 (2.0) |
Injection site pain | 1 (0.6) | 5 (1.6) | NR | NR | NR | NR | 0 (0.0) | 3 (1.5) |
Edema peripheral | 1 (0.6) | 5 (1.6) | NR | NR | NR | NR | 3 (2.9) | 2 (1.0) |
Potential muscle events | 5 (3.2) | 8 (2.6) | 5 (4.5) | 2 (0.9) | 3 (2.7) | 4 (1.8) | 23 (22.5) | 25 (12.2) |
Discontinued blinded oral treatment | 12 (7.8) | 17 (5.6) | 7 (6.3) | 7 (3.2) | 7 (6.4) | 11 (5.0) | 14 (13.7) | 17 (8.3) |
Discontinued blinded SC treatment | 9 (5.8) | 15 (4.9) | 9 (8.1) | 9 (4.1) | 5 (4.5) | 11 (5.0) | 6 (5.9) | 8 (3.9) |
Discontinued statin | N/A | N/A | 6 (5.4) | 7 (3.2) | 4 (3.6) | 9 (4.1) | N/A | N/A |
Discontinued treatment due to muscle symptoms | 0 (0.0) | 2 (0.7) | 0 (0.0) | 1 (0.5) | 1 (0.9) | 1 (0.5) | 6 (5.9) | 5 (2.4) |
Discontinued oral treatment | 0 (0.0) | 2 (0.7) | 0 (0.0) | 1 (0.5) | 1 (0.9) | 1 (0.5) | 6 (5.9) | 5 (2.4) |
Discontinued SC treatment | 0 (0.0) | 2 (0.7) | 0 (0.0) | 1 (0.5) | 0 (0.0) | 0 (0.0) | 3 (2.9) | 1 (0.5) |