Although statins have proven to be a valuable and efficacious low-density lipoprotein cholesterol (LDL-C)-lowering medication, they may not be sufficient or appropriate for every patient in need. |
Some patients may benefit from additional or alternative approaches for LDL-C lowering, particularly those with familial hypercholesterolaemia and other patients in whom LDL-C lowering is not sufficient or who are intolerant to statins. |
Alternative therapies should be considered for patients who do not reach their LDL-C target, for example, ezetimibe or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. |
1 Introduction
2 Treatment Aims and Low-Density Lipoprotein Cholesterol (LDL-C) Targets
3 Statin Non-Adherence and Intolerance
Study | AE | Comment |
---|---|---|
Silva et al. [51] (meta-analysis of RCTs) | All AEs | OR 1.44 (95 % CI 1.33–1.55; p < 0.001) intensive- vs. moderate-dose statin therapy |
Silva et al. [51] (meta-analysis of RCTs) | AEs leading to treatment discontinuation | OR 1.28 (95 % CI 1.18–1.39; p < 0.001) intensive- vs. moderate-dose statin therapy |
Dale et al. [52] (meta-analysis of RCTs) Silva et al. [51] (meta-analysis of RCTs) | CK elevation | OR 6.12 (95 % CI 1.36–27.5) higher- vs. lower- dose statin therapy (the odds appeared to be greater for lipophilic statins, which have more muscle penetration) OR 9.97 (95 % CI 1.3–77.9, p = 0.028) intensive- vs. moderate-dose statin therapy |
Dale et al. [52] (meta-analysis of RCTs) Silva et al. [51] (meta-analysis of RCTs) | LFT elevation | LFT (transaminase) elevation OR 2.7 (1.5–5.0) higher- vs. lower- dose statin therapy (the effect appeared to be greater for hydrophilic statins LFT elevation (alanine or aspartate aminotransferase ≥3 times the ULN) OR 4.5 (95 % CI 3.3–6.2) intensive- vs. moderate-dose statin therapy |
SEARCH Collaborative Group [53] (randomized trial of 12,064 pts who received simvastatin 20 or 80 mg daily) | Rhabdomyolysis | 49 cases of ‘definite myopathy’ in the simvastatin 80-mg group vs. 2 in the simvastatin 20-mg group. 49 cases of ‘incipient myopathy’ in the simvastatin 80-mg group vs. 6 in the simvastatin 20-mg group |
Golomb et al. [54] | Non-CK elevating muscle symptoms | Recurrence of statin AEs was significantly higher when pts were rechallenged with same or higher potency statins vs. rechallenge with a lower potency statins (~95 vs. 55 %, p < 0.01) |
4 Familial Hypercholesterolaemia
5 Prevention of Cardiovascular Events
6 Alternative Treatment Options After Statin Use
6.1 Ezetimibe
6.2 Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors
Study | Population | Primary endpoints | Efficacy | Safety |
---|---|---|---|---|
GAUSS-2 [79] (evolocumab vs. ezetimibe) | Pts with hyperlipidemia who cannot tolerate statin therapy; N = 307 | Percent change from BL in LDL-C level at the mean of weeks 10 and 12, and at week 12 | Evolocumab reduced LDL-C from BL by 53–56 %: tx differences vs. ezetimibe of 37–39 % (p < 0.001) | Muscle AEs: 12 % of evolocumab-treated pts vs. 23 % of ezetimibe-treated pts; TEAEs and laboratory abnormalities comparable across tx groups |
RUTHERFORD-2 [80] (evolocumab vs. PL) | Pts with HeFH, on stable lipid-lowering therapy; N = 329 | Percent change from BL in LDL-C level at the mean of weeks 10 and 12, and at week 12 | Evolocumab reduced mean LDL-C at week 12 (every-2-week dose: 59 % reduction, monthly dose: 61 % reduction; both p < 0.0001) and at the mean of week 10 and 12 (60 % reduction and 66 % reduction; both p < 0.0001) | Similar rates of AEs in both groups, except for nasopharyngitis (19 pts [9 %] in the evolocumab group vs. 5 [5 %] in the PL group) and muscle-related AEs (10 pts [5 %] in the evolocumab group vs. 1 [1 %] in the PL group) |
TESLA [81] (evolocumab vs. PL) | Pts with HoFH, on stable lipid-lowering therapy; N = 49 | Percentage change from BL in ultracentrifugation LDL-C level at week 12 | Evolocumab reduced ultracentrifugation LDL-C at 12 weeks by 31 % (p < 0.0001) | TEAEs occurred in 10 (63 %) of 16 pts in the PL group and 12 (36 %) of 33 in the evolocumab group |
DESCARTES [82] (evolocumab vs. PL) | Pts with hyperlipidemia and a wide range of CV risk, after a run-in period of background lipid-lowering therapy; N = 901 | Percent change from BL in ultracentrifugation LDL-C level at week 52 | Overall LSM (±SE) reduction in LDL-C 57 ± 2 % (taking into account reduction in PL group) (p < 0.001); mean reduction 56 ± 4 % in pts with diet alone as background therapy, 62 ± 3 % with atorvastatin 10 mg, 57 ± 5 % with atorvastatin 80 mg, and 49 ± 5 % with combination of atorvastatin 80 mg and ezetimibe 10 mg (p < 0.001 for all comparisons) | Overall incidence of AE occurring during tx was similar in the evolocumab and PL groups: 448 of 599 pts (75 %) vs. 224 of 302 pts (74 %); most common AEs in the evolocumab group: nasopharyngitis, URTI, influenza, and back pain |
LAPLACE-2 [83] (evolocumab vs. ezetimibe and PL) | Pts at risk for CVD receiving statin therapy; N = 1899 | Percent change from BL in LDL-C level at mean of weeks 10 and 12 and at week 12 | Evolocumab reduced LDL-C levels by 66–75 % (every 2 weeks) and by 63–75 % (monthly) vs. PL at mean of weeks 10 and 12 in the moderate- and high-intensity statin-treated groups; LDL-C reductions at week 12 were comparable | AEs reported in 36 %, 40 %, and 39 % of evolocumab-, ezetimibe-, and PL-treated pts, respectively; most common AEs in evolocumab-treated pts were back pain, arthralgia, headache, muscle spasms, and pain in extremity (all <2 %) |
TAUSSIG [84] (evolocumab long-term open-label; interim results; estimated completion, January 2020) | Pts with HoFH, receiving stable lipid-lowering therapy; N = 100 (non-apheresis, N = 66; apheresis, N = 34) | Percentage change from BL in LDL-C at week 12 | Evolocumab reduced LDL-C in the overall cohort by 21 % (p < 0.05); reduction maintained in the longer-term (up to 48 weeks); in a subset of non-apheresis pts, who uptitrated to 420 mg every 2 weeks (N = 28), LDL-C was reduced by a further 6 % (p = 0.01) | Evolocumab was well-tolerated |
Study | Population | Primary/co-primary endpoints | Efficacy | Safety |
---|---|---|---|---|
ODYSSEY LONG TERM [88] (alirocumab vs. PL) | Pts with LDL-C >1.8 mmol/l on maximum-tolerated dose of statins with or without other lipid-lowering therapy; N = 2341 | Percent change in calculated LDL-C level from BL to week 24 | Alirocumab reduced LDL-C by 62 % (p < 0.001) vs. PL by week 24 | Alirocumab vs. PL injection-site reactions (6 vs. 4 %), myalgia (5 vs. 3 %), neurocognitive events (1 vs. 0.5 %), and ophthalmologic events (3 vs. 2 %). In a post hoc analysis, the rate of major adverse CV events was lower with alirocumab than with PL (2 vs. 3 %; p = 0.02) |
ODYSSEY FH I and FH II [89] (alirocumab 75 mg every 2 weeks vs. PL) | Pts with HeFH and inadequate LDL-C control on maximally tolerated lipid-lowering therapy; N = 735 | Percent change in calculated LDL-C from BL to week 24 (both studies) | Alirocumab reduced LDL-C 58 % vs. PL at week 24 in FH I and by 51 % vs. PL in FH II. LDL-C 1.8 mmol/l (was achieved at week 24 by 60 % and 68 % of alirocumab-treated pts in FH I and FH II, respectively | AE-related tx discontinuation in 3 % of alirocumab-treated pts in FH I (vs. 6 % PL) and 4 % (vs. 1 %) in FH II. Injection-site reactions in alirocumab-treated pts 12 % in FH I and 11 % in FH II (vs. 11 % and 7 % with PL) |
ODYSSEY HIGH FH [90] (alirocumab 150 mg every 2 weeks vs. PL) | Pts with HeFH and inadequate LDL-C control on maximally tolerated lipid-lowering therapy; N = 107 | Percent change in LDL-C from BL to 24 weeks (ITT) | Alirocumab reduced LDL-C by 46 vs. 7 % with PL (p < 0.0001) | TEAEs were generally comparable between groups: 61 % of pts in the alirocumab group vs. 71 % of pts in the PL group |
ODYSSEY OPTIONS I [91] (atorvastatin plus alirocumab vs. atorvastatin plus ezetimibe; or double atorvastatin; or rosuvastatin) | Pts with very high CVD risk and LDL-C >70 mg/dl or high CVD risk and LDL-C of >100 mg/dl on BL atorvastatin 20 or 40 mg; N = 355 | Percent change in LDL-C from BL to 24 weeks (ITT) | In atorvastatin 20 and 40 mg regimens, respectively: Add-on alirocumab reduced LDL-C levels by 44 % and 54 % (p < 0.001 vs. all comparators) Add-on ezetimibe, 21 % and 23 % Double atorvastatin dose, 5 % in both cases Switching atorvastatin 40 mg to rosuvastatin 40 mg, 21 % | TEAEs occurred in 65 % of alirocumab pts vs. 64 % ezetimibe and 64 % double atorvastatin/switch to rosuvastatin (data were pooled) |
ODYSSEY OPTIONS II [92] (rosuvastatin plus alirocumab vs. rosuvastatin plus ezetimibe; or double-dose rosuvastatin) | Pts with very high CVD risk and LDL-C >70 mg/dl or high CVD risk and LDL-C of >100 on BL rosuvastatin 20 or 40 mg; N = 305 | Percent change in LDL-C from BL to 24 weeks (ITT) | In the BL rosuvastatin 10-mg group, add-on alirocumab reduced LDL-C by 51 % vs. ezetimibe (14 %) and double-dose rosuvastatin (16 %) (p < 0.0001 in both cases). In the BL rosuvastatin 20-mg group, add-on alirocumab reduced LDL-C by 36 % vs. ezetimibe (11 %) and double-dose rosuvastatin (16 %) (p = 0.0136 and p = 0.0453, respectively; pre-specified threshold for significance, p < 0.0125) | TEAEs occurred in 56 % of alirocumab pts vs. 54 % ezetimibe and 67 % double-dose rosuvastatin (data were pooled) |
ODYSSEY ALTERNATIVE [93] (alirocumab vs. ezetimibe) | Statin-intolerant pts with very high BL LDL-C levels; N = 314 | Percent reductions in LDL-C at week 24 | Significantly more pts achieved LDL-C goals with alirocumab than with ezetimibe (42 vs. 4 %, p < 0.0001) | Alirocumab was better tolerated than atorvastatin (HR 1.63, p = 0.042) with a significantly lower rate of skeletal muscle adverse events (p < 0.05) |
ODYSSEY COMBO I [94] (alirocumab vs. PL) | Pts with high CV risk with sub-optimally controlled hypercholesterolemia on maximum tolerated dose of statins with or without other lipid-lowering therapy; N = 316 | Percent change in LDL-C from BL to 24 weeks (ITT) | Alirocumab reduced LDL-C by 48 vs. 2 % with PL (p < 0.0001) | TEAEs (76 % of pts in both groups) and tx-emergent serious AEs (13 % of pts in both groups) were similar in the alirocumab and PL groups |
ODYSSEY COMBO II [95] (alirocumab vs. ezetimibe) | Pts with high CV risk with suboptimally-controlled hypercholesterolaemia on maximum tolerated dose of statins; N = 720 | Percent change in LDL-C from BL to 24 weeks (ITT) | Alirocumab reduced LDL-C by 51 vs. 21 % with ezetimibe (p < 0.0001) | Percentages of pts experiencing at least one tx-emergent AE or serious AEs were comparable between the two groups: 71 and 19 %, respectively (alirocumab) vs. 67 and 18 %, respectively (ezetimibe) |
ODYSSEY CHOICE I [96] (alirocumab 300 mg every 4 weeks vs. alirocumab 75 mg every 2 weeks [calibrator arm] vs. PL) | Pts with moderate very high CVD risk on maximum tolerated dose of statins; pts with moderate CV risk not receiving statins; pts with moderate to very high CVD risk and statin intolerance; N = 803 | Percentage LDL-C change from BL to week 24 and to averaged LDL-C for weeks 21–24 | Alirocumab 300 mg every 4 weeks mean differences vs. PL were −52 % (pts not receiving statin) and −59 % (pts receiving statins) (p < 0.0001); average reductions to weeks 21–24 were also greater in the alirocumab 300-mg group vs. PL in pts not receiving statins (55 %) and in pts receiving statins (65 %) (p < 0.0001) | TEAEs ranged from 61 to 75 % (PL) and 72 to 78 % with alirocumab 300 mg; higher rate of injection-site reactions with alirocumab 300 mg vs. PL |
ODYSSEY CHOICE II [97] (alirocumab 150 mg every 4 weeks, alirocumab 75 mg every 2 weeks [calibrator arm] or PL for 24 weeks) | Pts with moderate to very high CV risk and SAMS (inability to tolerate ≥2 statins due to muscle symptoms), or moderate CV risk without SAMS; N = 233 | Percentage change in LDL-C from BL to week 24 | Overall, 63.9 % of pts in the alirocumab 150 mg every 4 weeks arm achieved pre-defined LDL-C target levels at week 24 vs. 1.8 % of PL pts (ITT analysis) | TEAEs occurred in 63.8 and 77.6 % of PL- and alirocumab 150 mg every 4 wk-treated pts, respectively. Muscle symptoms were infrequent; the most common TEAEs were injection-site reactions, arthralgia, headache, and nasopharyngitis |
Study | Population | Comparison | Estimated completion |
---|---|---|---|
Pts with HeFH with high and very high CVD risk (with statin therapy) | Bococizumab vs. PL at 12 weeks | January 2016 | |
Pts with high and very high CVD risk (with statin therapy) | Bococizumab vs. PL at 12 weeks | January 2016 | |
Pts with high and very high CVD risk (with statin therapy) | Bococizumab vs. PL at 12 weeks | December 2015 | |
Pts with high and very high CVD risk (with lipid-lowering therapy) | Bococizumab vs. PL at 5 years (effects on major CV events) | August 2017 | |
Pts with high and very high CVD risk (with lipid-lowering therapy) | Bococizumab vs. PL at 5 years (effects on major CV events) | August 2017 |
PCSK9 inhibitor | Indications |
---|---|
Evolocumab [108] (evolocumab SmPC) | Adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, as an adjunct to diet in combination with a statin or statin with other lipid-lowering therapies in pts unable to reach LDL-C goals with the maximum tolerated dose of a statin or alone or in combination with other lipid-lowering therapies in pts who are statin intolerant or for whom a statin is contraindicated |
Adults and adolescents aged ≥12 years with homozygous FH in combination with other lipid-lowering therapies | |
Alirocumab [109] (alirocumab SmPC) | Adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidemia as an adjunct to diet: in combination with a statin or statin with other lipid-lowering therapies in pts unable to reach LDL-C goals with the maximum tolerated dose of a statin or alone or in combination with other lipid-lowering therapies in pts who are statin intolerant or for whom a statin is contraindicated |