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Dyslipidemia
Published in Jahangir Moini, Matthew Adams, Anthony LoGalbo, Complications of Diabetes Mellitus, 2022
Jahangir Moini, Matthew Adams, Anthony LoGalbo
PCSK9 monoclonal antibodies are formulated for subcutaneous injection, once to twice per month. They stop proprotein convertase subtilisin/kexin type 9 from attaching to LDL receptors, improving their function. The LDL is lowered by 40%–70%. Trials with alirocumab and evolocumab revealed less cardiovascular events when previous atherosclerotic cardiovascular disease was present. The cholesterol absorption inhibitors, including ezetimibe, inhibit absorption of cholesterol and phytosterol in the intestines. The LDL is usually lowered by ezetimibe by 15%–20%, with small increases in HDL and a slight decrease in total triglycerides. Ezetimibe can be used alone if the patient cannot tolerate statins, or it can be added to statins if the patient is on maximum statin dosage, with LDL remaining chronically elevated. Adverse effects of cholesterol absorption inhibitors are rare.
Familial hypercholesterolemia
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
All medications which lower lipids are contraindicated during pregnancy [107]. A prudent diet for these patients is one low in cholesterol and saturated fat. Oxidative stress contributes to lipid peroxidation and decreases nitric oxide (NO) bioavailability in atherosclerosis. Long-chain (n-3) polyunsaturated fatty acids (PUFA) are easily oxidized and improve endothelial function. In experimental animals, a fish oil-rich diet increased NO production and endothelial NO synthase expression. A fish oil-rich or supplemented diet appears prudent [108]. Double heterozygotes for mutations in LDLR and APOB tend to respond to treatment with statins [3]. Monoclonal antibodies to the PCSK9 convertase have emerged as treatment for even homozygous FH [109]. Two injectable human antibodies, Alirocumab and Evolucumab, have been approved by the FDA. They are capable of reducing LDL cholesterol by 50–70 percent.A cholesterylester transfer protein inhibitor Anacetrapib 100 mg daily added to statin therapy reduced LDL cholesterol by 30 percent [110]. Patients with APOB are responsive to statins [83].
Clinical Strategies for Managing Dyslipidemias
Published in James M. Rippe, Lifestyle Medicine, 2019
Ulf G. Bronas, Mary Hannan, Arthur S. Leon
The PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors are another newer class of medication that have shown benefit when added to a statin regimen. PCSK9 inhibitors are a human monoclonal antibody to PCSK9, which binds to PCSK9 and increases LDL receptors by increasing recycling of receptors to the cell surface, which should decrease LDL-C.18,20 Three trials have supported the use of PCSK9 inhibitors in decreasing CHD risk. The FOURIER trial, a placebo-controlled trial of over 27,000 patients, reported that the addition of evolocumab (PCSK9 inhibitor) to statin therapy lowered LDL by 59% and reduced the risk of cardiovascular events.21 The ODYSSEY trial, utilizing the PCSK9 inhibitor alirocumab on over 2,000 patients, reported that, at 2 4 weeks, the difference in LDL-C between the placebo and alirocumab group was 62%, and this effect remained at 78 weeks.22 The PCSK9 inhibitor, bococizumab was evaluated in the SPIRE-1 and SPIRE-2 trials, which found a 56% reduction in LDL-C, compared to the placebo group that had a 2.9% increase in patients with high cardiovascular risk at 14 weeks.23 Bococizumab further reduced risk of cardiovascular events in the high-risk patients (HR.79, p = 0.02) but not the low-risk group (HR .99, p = 0.94). The trial was, however, stopped prematurely due to the finding of high rates of antidrug antibodies.23
Achieving coronary plaque regression: a decades-long battle against coronary artery disease
Published in Expert Review of Cardiovascular Therapy, 2022
Venkat S. Manubolu, Matthew J. Budoff
Two additional studies have assessed the role of PCSK9 inhibitors specifically in patients with recent ACS events. The 2019 ODYSSEY J-IVUS trial evaluated the effect of alirocumab on coronary atheroma volume in 206 participants with LDL-C levels greater than or equal to 100 mg at the time of their ACS event, despite statin therapy [49]. Participants were randomized to receive alirocumab 5 mg every 2 weeks or standard of care (atorvastatin ≥10 mg/day or rosuvastatin ≥5 mg/day) for 36 weeks. The primary endpoint of the percent change in normalized TAV was reduced in the alirocumab group compared to the standard of care group (−3.1% vs −4.8% respectfully), however this change was not significant (p = 0.23). Absolute change in PAV was also not significant at 36 weeks (p = 0.79). Despite these non-significant findings in the atheroma volume, LDL-C levels were significantly reduced in the alirocumab group (p < 0.0001) compared to the standard of care group. Currently, the ongoing PACMAN-AMI trial is also assessing the impact of alirocumab on plaque burden after ACS [50]. In this study, 300 patients with recent ACS (within the preceding 24 hours) were randomized to receive biweekly injections of alirocumab (150 mg) versus placebo for 52 weeks. All participants also received rosuvastatin 20 mg daily. The results from this study will hopefully provide further insight into the role of PCSK9 inhibitors in addition to high-intensity statin therapy in the post-ACS period.
Efficacy and tolerability of alirocumab in Austrian clinical practice – results of the non-interventional PEARL-AT study
Published in Current Medical Research and Opinion, 2020
Deborah R. Leitner, Hermann Toplak, Ludmilla Kedenko, Thomas Steinmaurer, Verena Gräff, Thomas Metzner, Elisabeth M. Schwaiger, Rudolf Prager
Adult patients (≥18 years) on treatment with alirocumab for hypercholesterolemia according to the summary of product characteristics (SmPC) and without contraindications, who did not participate in the ODYSSEY APPRISE study12 could be enrolled in PEARL-AT. According to the SmPC, alirocumab is indicated for 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 patients 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 patients who are statin-intolerant, or for whom a statin is contraindicated. Alirocumab is also indicated for adults with established atherosclerotic cardiovascular disease to reduce cardiovascular risk by lowering LDL-C levels, in combination with the maximum tolerated dose of a statin with or without other lipid-lowering therapies or, alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated. Contraindications according to the SmPC include hypersensitivity to the active substance or to any of the excipients13.
PCSK9 inhibitors and cardiovascular outcomes
Published in Expert Opinion on Biological Therapy, 2020
Daniel Steffens, Peter Bramlage, Céline Scheeff, Mario Kasner, Adel Hassanein, Julian Friebel, Ursula Rauch-Kröhnert
The lipid-lowering efficacy of alirocumab has been reviewed in detail previously [15,23,31,32]. Alirocumab provides significant and durable LDL-C lowering when administered as monotherapy or in combination with statins (± ezetimibe), in patients with hypercholesterolemia, mixed dyslipidemia or HeFH, and in statin-intolerant patients. The LDL-C lowering effect of alirocumab added to maximally tolerated statins (± other lipid-lowering therapy) has been demonstrated in patients with different degrees of CV risk, and in patients with or without diabetes [33–44]. Alirocumab is generally well tolerated; in clinical trials adverse events reported at a higher rate with alirocumab than with placebo were injection site reactions, pruritus and upper respiratory tract infection [15,45]. A slightly higher rate of neurocognitive events was observed in one of the long-term studies with alirocumab [46]; however, meta-analysis of data from 14 phase 2 or 3 trials of up to 104 weeks’ duration found no significant difference in the incidence of neurocognitive treatment-emergent adverse events between alirocumab and control groups [47]. A placebo-controlled study formally evaluating neurocognitive events during 2 years of alirocumab treatment is underway (clinicaltrials.gov identifier: NCT02957682). Alirocumab did not increase the incidence of new-onset diabetes [48].