BackgroundSome data suggest that low levels of low-density lipoprotein cholesterol (LDL-C) are associated with risk of cataracts. Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors... Show moreBackgroundSome data suggest that low levels of low-density lipoprotein cholesterol (LDL-C) are associated with risk of cataracts. Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors reduce LDL-C below levels achieved with statins alone. We determined whether the incidence of cataracts was influenced by treatment with the PCSK9 inhibitor alirocumab versus placebo, and whether that incidence was affected by achieved LDL-C levels.MethodsThe ODYSSEY OUTCOMES trial (NCT01663402) compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome receiving high-intensity or maximum-tolerated statin. Incident cataracts were pre-specified events of interest. In multivariable analysis using propensity score-matching on characteristics including cataract risk factors, incident cataracts were compared in the alirocumab and placebo groups according to LDL-C levels achieved with alirocumab.ResultsOver median follow-up of 2.8 years (interquartile range 2.3 − 3.4), the incidence of cataracts was similar with alirocumab (127/9462 [1.3%]) versus placebo (134/9462 [1.4%]); hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.74 − 1.20). In patients treated with alirocumab with ≥ 2 LDL-C values < 25 mg/dL (0.65 mmol/L), the incidence of cataracts was 71/4305 (1.6%), versus 60/4305 (1.4%) in propensity score-matched patients from the placebo group (HR 1.10, CI 95% 0.78 − 1.55). In patients treated with alirocumab with ≥ 2 LDL-C values < 15 mg/dL (0.39 mmol/L), the incidence of cataracts was 13/782 (1.7%), versus 36/2346 (1.5%) in matched patients from the placebo group (HR 1.03, CI 95% 0.54 − 1.94).ConclusionTreatment with alirocumab versus placebo, added to statin, did not influence the incidence of cataracts, even when achieved LDL-C levels on alirocumab were very low. Longer follow-up studies might be necessary to exclude the long-term effects on the incidence or progression of cataracts. Show less
Schwartz, G.G.; Szarek, M.; Bhatt, D.L.; Bittner, V.A.; Bujas-Bobanovic, M.; Diaz, R.; ... ; ODYSSEY OUTCOMES Investigators 2023
AimsLong-term, placebo-controlled cholesterol-lowering trials have demonstrated legacy effects (clinical benefits that persist or emerge after trial end). It is unknown whether legacy effects... Show moreAimsLong-term, placebo-controlled cholesterol-lowering trials have demonstrated legacy effects (clinical benefits that persist or emerge after trial end). It is unknown whether legacy effects follow a short period of very low low-density lipoprotein cholesterol (LDL-C) levels achieved with statin plus proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.Methods and resultsIn 18 924 patients with recent acute coronary syndrome, the ODYSSEY OUTCOMES trial compared the PCSK9 inhibitor alirocumab with placebo, each added to high-intensity or maximum-tolerated statin therapy. Patients with two consecutive LDL-C levels <0.39 mmol/L (15 mg/dL) on alirocumab had blinded placebo substitution for the remainder of the trial with continued statin treatment. In post hoc analyses, major adverse cardiovascular events (MACE) in these patients were compared to MACE in propensity score–matched patients from the placebo group with similar baseline characteristics and study medication adherence. In the alirocumab group, 730 patients had blinded placebo substitution at a median of 8.3 months from randomization, after a median of 6.0 months with LDL-C <0.39 mmol/L. They were matched to 1460 placebo patients. Both groups had lower baseline LDL-C and lipoprotein(a) and better study medication adherence than those of the overall cohort. Over a median follow-up of 2.8 years, MACE occurred in 47 (6.4%) alirocumab patients with limited-duration, very low achieved LDL-C vs. 122 (8.4%) matched placebo patients (treatment hazard ratio 0.72; 95% confidence interval 0.51, 0.997; P = 0.047).ConclusionA short period of LDL-C levels <0.39 mmol/L achieved with statin and alirocumab, followed by statin monotherapy, was associated with a lower risk of MACE than statin monotherapy throughout the observation period. Clinical benefit persisted for several years. Show less
BACKGROUND Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ... Show moreBACKGROUND Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains >= 70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk.OBJECTIVES In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels.METHODS ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was <70 mg/dL (median 69.4 mg/dL; interquartile range: 64.3-74.0 mg/dL); in 14,573 patients (77.0%), both determinations were >= 70 mg/dL (median 94.0 mg/dL; interquartile range: 83.2-111.0 mg/dL).RESULTS In the lower LDL-C subgroup, MACE rates were 4.2 and 3.1 per 100 patient-years among placebo-treated patients with baseline lipoprotein(a) greater than or less than or equal to the median (13.7 mg/dL). Corresponding adjusted treatment hazard ratios were 0.68 (95% confidence interval [CI]: 0.52-0.90) and 1.11 (95% CI: 0.83-1.49), with treatment-lipoprotein(a) interaction on MACE (P-interaction = 0.017). In the higher LDL-C subgroup, MACE rates were 4.7 and 3.8 per 100 patient-years among placebo-treated patients with lipoprotein(a) >13.7 mg/dL or <= 13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with P-interaction = 0.43.CONCLUSIONS In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402) (C) 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. Show less
The most important risk factor for atherosclerotic cardiovascular disease is increased levels of LDL-C. Statins have long been the most potent LDL-C lowering drugs on the market. However,... Show moreThe most important risk factor for atherosclerotic cardiovascular disease is increased levels of LDL-C. Statins have long been the most potent LDL-C lowering drugs on the market. However, statin treatment is complicated by the fact that a considerable number of patients is unable to tolerate full therapeutic doses, or can be classified as statin low or non-responders. In >25% of patients at (very) high risk for cardiovascular disease, statin efficacy is too limited to achieve current guideline-mandated LDL-C target goals, and aggressive statin therapy decreases relative risk for ASCD by only 30-35%, leaving an unacceptable residual relative risk of 65-70% for life-threatening events. It is clear that on-treatment LDL-C levels and on-treatment measures of systemic inflammation are of equal importance in this residual risk. Both for residual cholesterol risk and residual inflammatory risk, effective drug therapy has been lacking for decades. In this thesis, we describe the first clinical studies with novel compounds based on increased LDL-C levels and inflammation (including the required methodology), and present the methodology that may be useful to develop future compounds based on dysfunctional endothelial barrier function resulting in subendothelial cholesterol accumulation and subsequent atheroma formation. Show less
