Gene-based therapy in lipid management: the winding road from promise to practice

Tromp, Tycho R.; Stroes, Erik S.G.; Hovingh, G. Kees

doi:10.1080/13543784.2020.1757070

Cited by 22 publications

(14 citation statements)

References 106 publications

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“…In large placebo-controlled trials that evaluated PCSK9 inhibitors, the risk of MACE among patients assigned to placebo was associated with lipoprotein(a) concentration (7)(8)(9)(10) and reduction in the risk of MACE with the PCSK9 inhibitor alirocumab was associated with the magnitude of lipoprotein(a) reduction (7,10). Pharmacologic agents under development that inhibit the synthesis of apolipoprotein(a) may reduce lipoprotein(a) concentration by .70% and are being evaluated for effects on MACE (11,12). An unexplained observation in cohort studies and clinical trials has been an association of lower lipoprotein(a) levels with greater prevalence of type 2 diabetes (13)(14)(15).…”

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confidence: 99%

Relation of Lipoprotein(a) Levels to Incident Type 2 Diabetes and Modification by Alirocumab Treatment

et al. 2021

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In observational data, lower levels of lipoprotein(a) have been associated with greater prevalence of type 2 diabetes. Whether pharmacologic lowering of lipoprotein(a) influences incident type 2 diabetes is unknown. We determined the relationship of lipoprotein(a) concentration with incident type 2 diabetes and effects of treatment with alirocumab, a PCSK9 inhibitor. RESEARCH DESIGN AND METHODSIn the ODYSSEY OUTCOMES trial alirocumab was compared with placebo in patients with acute coronary syndrome. Incident diabetes was determined from laboratory, medication, and adverse event data. RESULTSAmong 13,480 patients without diabetes at baseline, 1,324 developed type 2 diabetes over a median 2.7 years. Median baseline lipoprotein(a) was 21.9 mg/dL. With placebo, 10 mg/dL lower baseline lipoprotein(a) was associated with hazard ratio 1.04 (95% CI 1.0221.06, P < 0.001) for incident type 2 diabetes. Alirocumab reduced lipoprotein(a) by a median 23.2% with greater absolute reductions from higher baseline levels and no overall effect on incident type 2 diabetes (hazard ratio 0.95, 95% CI 0.85-1.05). At low baseline lipoprotein(a) levels, alirocumab tended to reduce incident type 2 diabetes, while at high baseline lipoprotein(a) alirocumab tended to increase incident type 2 diabetes compared with placebo (treatmentbaseline lipoprotein(a) interaction P 5 0.006). In the alirocumab group, a 10 mg/dL decrease in lipoprotein(a) from baseline was associated with hazard ratio 1.07 (95% CI 1.0321.12; P 5 0.0002) for incident type 2 diabetes. CONCLUSIONSIn patients with acute coronary syndrome, baseline lipoprotein(a) concentration associated inversely with incident type 2 diabetes. Alirocumab had neutral overall effect on incident type 2 diabetes. However, treatment-related reductions in lipoprotein(a), more pronounced from high baseline levels, were associated with increased risk of incident type 2 diabetes. Whether these findings pertain to other therapies that reduce lipoprotein(a) is undetermined.

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confidence: 99%

Relation of Lipoprotein(a) Levels to Incident Type 2 Diabetes and Modification by Alirocumab Treatment

et al. 2021

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“…Gemcabene is able to enhance the clearance of VLDLs in plasma and inhibition of production of cholesterol and TGs in liver through its liver-directed downregulation of hepatic apolipoprotein C-III (apoC-III) [20]. ARO-ANG3 also inhibits ANGPTL3 and is designed to reduce triglycerides and decrease LDL-C in patients with mixed dyslipidemia [21]. Bempedoic acid inhibits ATP-citrate lyase, which is a component of the cholesterol synthesis pathway [22].…”

Section: New Medications Since 2018mentioning

confidence: 99%

Current Management Guidelines on Hyperlipidemia: The Silent Killer

Mittal

Ramgobin

et al. 2021

Journal of Lipids

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Given the high incidence of cardiovascular events in the United States, strict control of modifiable risk factors is important. Pharmacotherapy is helpful in maintaining control of modifiable risk factors such as elevated lipids or hypercholesterolemia. Hypercholesterolemia can lead to atherosclerotic disease which may increase the risk of acute coronary events. Statin therapy has long been a mainstay in the treatment of hypercholesterolemia, but while highly regarded, statin therapy also has side effects that may lead to patient noncompliance. Therefore, various medicines are being developed to manage hypercholesterolemia. This paper will discuss the role that lipids play in the pathophysiology of atherosclerotic disease, review the current lipid management guidelines, and discuss new treatment options that are alternatives to statin therapy.

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“…Gene therapy is one of the most promising treatment strategies for CVD [ 30 , 31 , 32 , 33 , 34 ], inherited or acquired, through targeting the causative genes engaged in the induction and progression of the disease. It works through replacing defective genes, silencing overexpressed ones or providing functional copies of specific therapeutic genes, thanks to DNA, RNA (siRNA, microRNA, mRNA), and antisense oligonucleotides (ASO) [ 35 ].…”

Section: Conventional and Novel Therapies To Treat Cvdmentioning

confidence: 99%

“…One of the major accumulation sites of the drug in animals is mesenteric lymph nodes, assuming a considerable absorption by the lymphatics [ 149 ]. Kynamro has been withdrawn from the market in 2019 due to safety issues represented in liver toxicity, injection-site reaction, and flu-like symptoms [ 32 , 150 ].…”

Section: Treating Cvd Through Various Administration Routesmentioning

confidence: 99%

Focus on the Lymphatic Route to Optimize Drug Delivery in Cardiovascular Medicine

et al. 2021

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While oral agents have been the gold standard for cardiovascular disease therapy, the new generation of treatments is switching to other administration options that offer reduced dosing frequency and more efficacy. The lymphatic network is a unidirectional and low-pressure vascular system that is responsible for the absorption of interstitial fluids, molecules, and cells from the peripheral tissue, including the skin and the intestines. Targeting the lymphatic route for drug delivery employing traditional or new technologies and drug formulations is exponentially gaining attention in the quest to avoid the hepatic first-pass effect. The present review will give an overview of the current knowledge on the involvement of the lymphatic vessels in drug delivery in the context of cardiovascular disease.

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Gene-based therapy in lipid management: the winding road from promise to practice

Cited by 22 publications

References 106 publications

Relation of Lipoprotein(a) Levels to Incident Type 2 Diabetes and Modification by Alirocumab Treatment

Relation of Lipoprotein(a) Levels to Incident Type 2 Diabetes and Modification by Alirocumab Treatment

Current Management Guidelines on Hyperlipidemia: The Silent Killer

Focus on the Lymphatic Route to Optimize Drug Delivery in Cardiovascular Medicine

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