Table 1.
Novel therapeutic approaches targeting HDL: evidence from randomized controlled studies.
| Study | Drug | Population | No (Intervention/ Control) | Intervention Group | Control Group | Follow/Up | Impact on Lipid Parameters | Impact on CV Outcomes | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Nissen et al. [124] |
Muraglitazar | Patients with type 2 diabetes | 3,725 (2,374/ 1,351) |
Muraglitazar +/- metformin or glyburide |
Pioglitazone or placebo +/- metformin or glyburide | 24-104 weeks | N/A | ↑ death, MI or nonfatal stroke (RR=2.23, P=0.03) and ↑composite risk of death, MI, nonfatal stroke, CHF or TIA (RR= 2.62, P=0.004) |
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| Rubin et al. [125] | Muraglitazar | Patients with type 2 diabetes | 1,805 | Muraglitazar 2.5 mg or 5 mg | Glimepiride 1 mg | 52 weeks | ↑HDL ↓TG (P<0.0001) |
↓HbA1c with both doses (P<0.0001) ; CV events were similar among the groups (2%); there was a trend towards ↑total mortality |
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| Lincoff et al. [70] | Aleglitazar | Patients with ACS and type 2 diabetes | 7,226 (3,613/3,613) |
Aleglitazar 150 μg | Placebo | 104 weeks | N/A | no effect on CV death, nonfatal MI or nonfatal stroke | ||||||
| Barter et al. [72] | Torcetrapib | Patients at high CV risk | 15,067 (7,533/7,534) |
Torcetrapib+ atorvastatin |
Atorvastatin monotherapy | 12 months | ↑HDL by 72.1% ↓LDL by 24.9% (p<0.001) | ↑risk of MACE (HR=1.25, P=0.001), ↑ death from any cause (HR=1.58, P=0.006) | ||||||
| Schwartz et al. [73] | Dalcetrapib | Patients with recent ACS | 15,871 | 600 mg dalcetrapib + best available evidence-based care | Placebo + best available evidence-based care | 31 months | ↑HDL by 31-40% compared to 4-11% in the placebo group | No effect on the risk of the primary end point; no significant effect on any component of the primary end point or total mortality |
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| Cannon et al. [77] |
Anacetrapib | Patients on statin that had reached LDL goal levels | 1,623 (811/812) |
100 mg anacetrapib | Placebo | 18 months | Intervention group: ↓LDL (from 81 mg/dl to 45 mg/dl); ↑HDL (from 41 mg/dl to 101 mg/dl); placebo group: ↓LDL (from 82 mg/dl to 77 mg/dl); ↑HDL (from 40 mg/dl to 46 mg/dl) (P<0.001) |
CV events occurred in 2% of patients on anacetrapib and 2.6% of patients on placebo (P=0.40) | ||||||
| Nissen et al. [80] | ETC-216 | Patients with ACS | 57 | ETC-216 (5 weekly infusions at 15 mg/kg or 45 mg/kg) |
Placebo | 5 weeks | N/A | ↓atheroma volume in the combined treatment groups by 4.2% (P<0.001) | ||||||
| Tardif et al. [81] | CSL-111 (reconstituted HDL) | Patients with CAD | 138 (123/60 |
CSL-111 (4 weekly infusions of 40 mg/kg or 80 mg/kg) | Placebo | 6 weeks | N/A | no significant effect on the atheroma volume; significant improvement in the plaque characterization index and coronary score on QCA | ||||||
| Study | Drug | Population | No (Intervention/ Control) | Intervention Group | Control Group | Follow/Up | Impact on Lipid Parameters | Impact on CV Outcomes | ||||||
| Tardif et al. [82] | CER-001 (reconstituted HDL) | Patients with ACS | 507 (352/118) |
CER-001 (6 weekly infusions of 3mg/kg, 6 mg/kg or 12 mg/kg) |
Placebo | 6 months | N/A | CER-001 infusions did not reduce coronary atherosclerosis on IVUS and QCA; any MACE occurred in 8,3%, 13,3%, 13,7% and 9,8% of the patients in the placebo, 3mg/kg, 6mg/kg and 12mg/kg group respectively |
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| Chenevard et al. [83] | Reconstituted HDL | Patients with ACS | 29 (19/10) |
Reconstituted HDL | Albumin | 4 hours | ↑plasma HDL (P<0.0001) and ↓plasma LDL (P<0.0001); | no effect on the response to endothelium dependent and in dependent vasodilators; no effect on oxidized LDL and hs CRP levels |
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| Waksman et al. [85] | Delipidated HDL | Patients with ACS | 28 (14/14) |
7 weekly delipidated HDL infusions | Control plasma apheresis/ reinfusions | 14 days | ↑prebeta-like HDL from 5.6% to 79.1%; ↓ alpha-HDL from 92.8% to 20.9% |
There was a trend towards regression in the total atheroma volume assessed by IVUS | ||||||
| Bloedon et al. [87] | Unformulated D-4F (HDL mimetic) | Patients with CHD | 40 (32/8) |
A single dose of 30, 100, 300 or 500 mg of unformulated D-4F |
Placebo | 4 hours | no effect | The HDL anti-inflammatory index significantly improved (P<0.05) | ||||||
| Nicholls et al. [92] | RVX-208 | Statin treated patients with CAD | 299 | RVX-208 at 50, 100 or 150 mg twice daily | Placebo | 12 weeks | ↑apoA-I levels dose-dependently up to 5.6% (P=0.035); ↑ HDL from 3.2% to 8.3% (P=0.02); ↑ large HDL from 11.1% to 21.1% (P=0.003) |
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Abbreviations: HDL: high-density lipoprotein, MI: myocardial infarction, RR: relative ratio, CHF: congestive heart failure, TIA: transient ischemic attack, N/A: not available, Hb1Ac: glycated hemoglobin; TG: triglycerides; ACS: acute coronary syndromes; CV: cardiovascular, MACE: major adverse cardiovascular events; CHD: coronary heart disease; SBP: systolic blood pressure; CRP: C-reactive protein; LDL; low-density lipoprotein; UA: unstable angina; IVUS: intravascular ultrasound; QCA: quantitative coronary angiography; CAD: coronary artery disease; +/-: plus/minus; ↑: increased; ↓:decreased; No: number.