Table 1.
Alirocumab ODYSSEY and Evolocumab PROFICIO Phase 3 Studies Show Similar Reductions in Calculated LDL‐C Levels From Baseline to Primary End Point in Individuals With vs Without DM, Pre‐DM, and Metabolic Syndrome (ITT Analysis)
| % Change From Baseline (LDL‐C) to Primary End Point | Difference vs Control, LS Mean % Change From Baseline (SE or 95% CI If Published), Unless Otherwise Specified | Interaction P Value | |||||
|---|---|---|---|---|---|---|---|
| ALI or EVO | Control (PBO or EZE) | ||||||
| n | LS Mean (SE), Unless Otherwise Specified | n | LS Mean (SE), Unless Otherwise Specified | ||||
| ALIROCUMAB 150 mg Q2W vs PBO (with statin), 24 wks | |||||||
| LONG TERM, ALI 150 vs PBO62 | |||||||
| Overall | All (n=2310) | 1530 | −61.0 (0.7) | 780 | 0.8 (1.0) | −61.9 (1.3) | – |
| DM subanalysis | DM (n=818) | 545 | −60.0 (1.3) | 273 | −1.0 (1.8) | −59.0 | 0.0957 |
| Non‐DM (n=1492) | 985 | −61.6 (0.9) | 507 | 1.8 (1.3) | −63.4 | ||
| Pooled analysis of HIGH FH, LONG TERM, ALI 150 vs PBO | |||||||
| Overall59, 60 | All (n=2416) | 1601 | −60.4 (0.7) | 815 | 0.5 (1.0) | −60.9 (−63.3 to −58.5) | – |
| DM subanalysis69 | DM (n=833) | 554 | −59.7 (1.2) | 279 | −1.4 (1.7) | −58.3 (2.1) | 0.13 |
| Non‐DM (n=1583) | 1047 | −60.7 (0.9) | 536 | 1.5 (1.2) | −62.3 (1.5) | ||
| Pre‐DM subanalysis72 | Pre‐DM (n=876) | – | −61.8 (1.2) | – | 2.1 (1.6) | −63.9 | 0.1431 |
| NG (n=656) | – | −59.5 (1.4) | – | −0.1 (1.9) | −59.4 | ||
| DM+ASCVD subanalysis68 | DM+ASCVD (n=512) | 340 | −61.5 (1.6) | 172 | −1.0 (2.2) | −60.5 (−65.9 to −55.2) | – |
| ALIROCUMAB 75/150 mg Q2W vs PBO (with statins), 24 wks | |||||||
| Pool of FH I & II, ALI 75/150 vs PBO46 | |||||||
| Overall | All (n=732) | – | −48.8 (1.2) | – | 7.1 (1.7) | −55.9 | – |
| DM subanalysis | DM (n=66) | – | −51.4 (4.5) | – | 2.4 (5.5) | −53.8 | 0.7912 |
| Non‐DM (n=666) | – | −48.5 (1.3) | – | 7.6 (1.8) | −56.1 | ||
| COMBO I, ALI 75/150 vs PBO47 | |||||||
| Overall | All (n=311), estimated mean (95% CI) | 205 | −48.2 (−52.0 to −44.4) | 106 | −2.3 (−7.6 to 3.1) | −45.9 (−52.5 to −39.3) | – |
| DM subanalysis | DM (n=135), estimated mean (95% CI) | 94 | −42.2 (−47.8 to −36.6) | 41 | −2.6 (−11.1 to 5.8) | −39.6 | 0.0841 |
| Non‐DM (n=176), estimated mean (95% CI) | 111 | −53.2 (−58.4 to −48.1) | 65 | −2.0 (−8.8 to 4.8) | −51.2 | ||
| Pooled analysis of FH I & II, COMBO I, ALI 75/150 vs PBO | |||||||
| Overall59, 60 | All (n=1043) | 693 | −48.6 (1.0) | 350 | 4.2 (1.5) | −52.7 (−56.3 to −49.2) | – |
| DM subanalysis69 | DM (n=201) | 131 | −43.4 (2.6) | 70 | 0.3 (3.4) | −43.7 (4.1) | 0.02b |
| Non‐DM (n=842) | 562 | −49.8 (1.2) | 280 | 5.1 (1.6) | −54.8 (2.0) | ||
| Pre‐DM subanalysis72 | Pre‐DM (n=396) | – | −52.4 (1.7) | – | 3.3 (2.4) | −55.7 | 0.8451 |
| NG (n=422) | – | −46.1 (1.6) | – | 8.9 (2.3) | −55.0 | ||
| DM+ASCVD subanalysis68 | DM+ASCVD (n=137) | 92 | −46.4 (3.0) | 45 | 6.3 (4.5) | −52.7 (−63.5 to −41.9) | – |
| DM‐INSULIN75 | |||||||
| DM+insulin | T2DM (n=429) | 287 | −48.2 (1.6) | 142 | 0.8 (2.2) | −49.0 (2.7) | – |
| T1DM (n=74) | 49 | −51.8 (3.7) | 25 | −3.9 (5.3) | −47.8 (6.5) | – | |
| ALIROCUMAB 75/150 mg Q2W vs EZE, 24 wks | |||||||
| COMBO II DM subanalysis, ALI 75/150 vs EZE (with statin) | |||||||
| Overall45 | All (n=707) | 467 | −50.6 (1.4) | 240 | −20.7 (1.9) | −29.8 (2.3) | – |
| DM subanalysis67 | DM (n=225a) | 148b | −49.1 | 77b | −18.4 | −30.7 | 0.8025 |
| Non‐DM (n=495a) | 331b | −51.2 | 164b | −21.8 | −29.5 | ||
| Pooled analysis of COMBO II, OPTIONS I & II, ALI 75/150 vs EZE (with statin) | |||||||
| Overall59, 60 | All (n=1105) | 669 | −48.9 (1.4) | 436 | −19.3 (1.7) | −29.6 (−33.8 to −25.3) | – |
| Pre‐DM subanalysis72 | Pre‐DM (n=432) | – | −51.7 (2.2) | – | −16.1 (2.6) | −35.6 | 0.0428 |
| NG (n=244) | – | −45.8 (2.8) | – | −21.8 (3.6) | −24.0 | ||
| DM+ASCVD subanalysis68 | DM+ASCVD (n=283) | 173 | −48.7 (2.6) | 110 | −20.6 (3.3) | −28.1 (−36.6 to −19.6) | – |
| ALTERNATIVE, ALI 75/150 vs EZE (without statin) | |||||||
| Overall48 | All (n=168) | 90 | −54.8 (1.4) | 78 | −20.1 (2.4) | −34.7 | |
| DM+ASCVD subanalysis68 | DM+ASCVD (n=34) | 23 | −54.9 (6.0) | 11 | 4.0 (8.8) | −58.9 (−80.9 to −36.8) | – |
| Pooled analysis of ALTERNATIVE & MONO, ALI 75/150 vs EZE (without statin) | |||||||
| Overall59, 60 | All (n=351) | 178 | −45.6 (1.8) | 173 | −14.8 (1.8) | −30.9 (−35.9 to −25.9) | – |
| Pre‐DM subanalysis72 | Pre‐DM (n=135) | – | −44.0 (2.9) | – | −16.0 (2.7) | −28.0 | 0.4073 |
| NG (n=147) | – | −46.3 (2.7) | – | −13.7 (2.6) | −32.6 | ||
| DM‐DYSLIPIDEMIAd, 77 | |||||||
| T2DM+mixed dyslipidemiad | All (n=409)d | 273d | −43.3d | 136d | −0.3d | −43.0d | – |
| EVOLOCUMAB 140 mg Q2W or 420 mg QM vs PBO | |||||||
| Pool of LAPLACE‐2 & RUTHERFORD‐2, EVO 140 or 420 vs PBO, 12 wks66 | |||||||
| T2DM subanalysis | T2DM (n=304) | 210 | – | 94 | – | −60 (−69 to −51)c | 0.27 |
| Non‐T2DM (n=1700) | 1127 | – | 573 | – | −66 (−70 to −62)c | ||
| DESCARTES, EVO 420 vs PBO, 52 wks | |||||||
| Overall61 | All (n=901) | 599 | – | 302 | – | −57.0 (2.1) | – |
| Subanalysis by glycemic status and MetS73 | T2DM (n=120) | 77 | – | 43 | – | −50.8 (6.0) | – |
| IFG (n=293) | 194 | – | 99 | – | −59.4 (3.4) | – | |
| MetS (n=289) | 182 | – | 107 | – | −55.0 (3.5) | – | |
| No dysglycemia or MetS (n=393) | 274 | – | 119 | – | −58.1 (3.5) | – | |
| FOURIER, EVO 140 or 420 vs PBO, 48 wks | |||||||
| Overall63 | All (n=27 563) | 13 784 | – | 13 779 | – | −59 (58 to 60) | – |
| DM subanalysis71 | DM (n=11 031) | 5515 | – | 5516 | – | −57 (56 to 58) | – |
| Non‐DM (n=16 533) | 8269 | – | 8264 | – | −60 (60 to 61) | ||
| EVOLOCUMAB 140 mg Q2W or 420 mg QM vs EZE | |||||||
| Pool of LAPLACE‐2 (atorvastatin cohorts only) & GAUSS‐2, EVO 140 or 420 vs EZE, 12 wks66 | |||||||
| T2DM subanalysis | T2DM (n=187) | 114 | – | 73 | – | −39 (−47 to −32)c | 0.79 |
| Non‐T2DM (n=780) | 530 | – | 250 | – | −40 (−45 to −36)c | ||
LS means and SEs taken from mixed‐effect model with repeated measures analysis. All values shown are as published in the respective referenced articles; if the values for difference vs control were not published, values were estimated based on the respective percent changes with alirocumab/evolocumab and controls. ALI indicates alirocumab; ASCVD, atherosclerotic cardiovascular disease; CI, confidence interval; DM, diabetes mellitus; DESCARTES, Durable Effect of PCSK9 Antibody Compared with Placebo Study; EVO, evolocumab; EZE, ezetimibe; FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; GAUSS‐2, Goal Achievement after Utilizing an Anti‐PCSK9 Antibody in Statin Intolerant Subjects; HDL‐C, high‐density lipoprotein cholesterol; IFG, impaired fasting glucose; ITT, intention‐to‐treat; LAPLACE‐2, LDL‐C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy; LDL‐C, low‐density lipoprotein cholesterol; LS, least squares; MetS, metabolic syndrome; NG, normoglycemia; PBO, placebo; Q2W, every 2 weeks; QM, once monthly; RUTHERFORD‐2, Reduction of LDL‐C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder‐2; SE, standard error; T1, type 1; T2, type 2.
Randomized population.
Because of a higher proportion of participants without DM receiving an alirocumab dose increase at wk 12 (36.5% vs 25.6%).
Random‐effects treatment difference (95% CI) between evolocumab and control (placebo or ezetimibe), generated by use of the DerSimonian and Laird random‐effect estimator.
The comparator in the DM‐DYSLIPIDEMIA trial was usual care, which included the option to continue on maximally tolerated statin therapy without adding another lipid‐lowering therapy at randomization, or with the addition of one of the following at randomization: ezetimibe, fenofibrate, omega‐3 fatty acids, or nicotinic acid. Mixed dyslipidemia was defined as non‐HDL‐C ≥100 mg/dL (2.59 mmol/L), and triglycerides ≥150 mg/dL (1.70 mmol/L) and <500 mg/dL (5.65 mmol/L) at the screening visit. The primary efficacy end point in this trial was non‐HDL‐C: at week 24, mean non‐HDL‐C changes were superior with alirocumab (−37.3%) vs usual care (−4.7%). The LDL‐C reduction (secondary end point) values shown for DM‐DYSLIPIDEMIA in this table are measured LDL‐C values, not calculated LDL‐C.76, 77