Effect of atorvastatin, cholesterol ester transfer protein inhibition, and diabetes mellitus on circulating proprotein subtilisin kexin type 9 and lipoprotein(a) levels in patients at high cardiovascular risk

Arsenault, Benoît J.; Petrides, Francine; Tabet, Fatiha; Bao, Weihang; Hovingh, G. Kees; Boekholdt, S. Matthijs; Ramin‐Mangata, Stéphane; Meilhac, Olivier; DeMicco, David A.; Rye, Kerry‐Anne; Waters, David D.; Kastelein, John J.P.; Barter, Philip J.; Lambert, Gilles

doi:10.1016/j.jacl.2017.10.001

Cited by 48 publications

(40 citation statements)

References 46 publications

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“…Similar reductions were observed with alirocumab therapy in the trials included in the ODYSSEY program . Interestingly, while statin therapy has been shown to increase plasma levels of both PCSK9 and Lp(a), PCSK9 inhibitors appear to lower Lp(a) levels by ∼25–30% …”

Section: Approved Therapeutic Agents With Documented Cardiovascular Bsupporting

confidence: 53%

Therapeutic Agents Targeting Cardiometabolic Risk for Preventing and Treating Atherosclerotic Cardiovascular Diseases

Arsenault

Perrot

Puri

2018

Clin Pharma and Therapeutics

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Targeting atherogenic lipoprotein levels with statins remains the current cornerstone of atherosclerotic cardiovascular disease (ACVD) management. In patients at high ACVD risk who cannot achieve the desired low-density lipoprotein (LDL) cholesterol target, the addition of compounds such as ezetimibe and proprotein subtilisin/kexin type-9 (PCSK9) inhibitors incrementally lowers cardiovascular risk. New glucose-lowering drugs such as glucacon-like peptide-1 receptor (GLP1R) agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors were also shown to improve cardiometabolic risk factors and provide cardiovascular benefits in patients with type 2 diabetes. Our objective is to review the role of these agents in the management of patients at high ACVD risk and introduce new and (re)-emerging drugs targeting atherogenic lipoproteins such as LDL (inclisiran, bempedoic acid, etc.), remnant-like particles (fibrates, volanesorsen, and angiopoietin-like protein-3 (ANGPTL3) inhibitors), and lipoprotein(a) (AKCEA-APO[A]L ). The potential role of drugs targeting inflammation (canakinumab, methotrexate, and colchicine) in ACVD risk prevention/management will also be discussed.

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Section: Approved Therapeutic Agents With Documented Cardiovascular Bsupporting

confidence: 53%

Therapeutic Agents Targeting Cardiometabolic Risk for Preventing and Treating Atherosclerotic Cardiovascular Diseases

Arsenault

Perrot

Puri

2018

Clin Pharma and Therapeutics

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“…Besides PCSK9's impact on LDL‐C metabolism, several observations suggest a relationship between PCSK9, diabetes and diabetic dyslipidaemia. Multiple studies—though not all—have found increased plasma PCSK9 levels in T1DM or T2DM patients, linking PCSK9 to glucose homeostasis . Indeed, in vitro studies, in vivo studies in mice and some human studies have proposed that insulin is a positive regulator of hepatic PCSK9 expression through the SREPB1c pathway .…”

Section: Pcsk9 and Diabetesmentioning

confidence: 99%

“…Multiple studies-though not all-have found increased plasma PCSK9 levels in T1DM or T2DM patients, linking PCSK9 to glucose homeostasis. [26][27][28][29][30][31][32] Indeed, in vitro studies, in vivo studies in mice and some human studies have proposed that insulin is a positive regulator of hepatic PCSK9 expression through the SREPB1c pathway. [33][34][35] Fasting-which lowers circulating insulin levelsstrongly reduces PCSK9 levels and mice with a liver-specific knockout of the insulin receptor have significantly reduced hepatic Pcsk9 mRNA and plasma PCSK9 levels.…”

Section: Pcsk9 and Diabetesmentioning

confidence: 99%

Efficacy and safety of proprotein convertase subtilisin/kexin 9 inhibitors in people with diabetes and dyslipidaemia

Dijk

Cariou

2019

Diabetes Obesity Metabolism

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Diabetic dyslipidaemia, characterized by quantitative, qualitative and kinetic changes in all major circulating lipids, contributes to the increased cardiovascular risk in patients with type 2 diabetes mellitus (T2DM). A promising therapeutic avenue is the inhibition of the proprotein convertase subtilisin kexin 9 (PCSK9) with human monoclonal antibodies (mAbs) that potently reduce plasma low‐density lipoprotein cholesterol (LDL‐C) levels on top of statin treatment. The aim of this review is to evaluate the efficacy of PCSK9 inhibitors to lower the residual cardiovascular risk of T2DM patients and to discuss the safety of PCSK9 inhibition in these patients. PCSK9 inhibitors potently lower plasma LDL‐C levels in T2DM patients and reduce risk for the development of cardiovascular disease. Anti‐PCSK9 mAbs are generally not more or less effective in T2DM patients compared to a general high‐risk population. Nevertheless, due to their higher cardiovascular risk, the absolute risk reduction of major cardiovascular events is more significant in T2DM patients. This suggests that treatment of T2DM patients with anti‐PCSK9 mAbs could be attractive from a cost‐effectiveness perspective. Treatment with anti‐PCSK9 mAbs did not result in significant treatment‐emergent adverse effects. While genetic studies suggest a potential link between PCSK9 inhibition and glucose homeostasis, anti‐PCSK9 mAbs did not worsen glycaemic control in T2DM patients, but their safety should be verified after a longer‐term follow‐up.

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“…In patients at high cardiovascular risk, PCSK9 positively and dose-dependently correlated with atorvastatin dosage, and this effect was magnified in diabetics. 76 Additionally, in diabetic patients with pathological albuminuria enrolled in the large DIABHYCAR study, plasma PCSK9 tertiles were associated with the incidence of cardiovascular events. 77 Although this was not replicated in the smaller SURDIAGENE cohort that enrolled patients with milder albuminuria, 77 Since the publication of our work where we presented a previously described variant in the PRKG1 gene as a cause of nonsyndromic familial aortic disease (NSAD), 81 no new work describing causal variants in this gene has been published.…”

Section: Pcsk9 In Diabetic Kidney Disease 7 5 (Beatriz Fernandez-fementioning

confidence: 99%

Research update for articles published in EJCI in 2016

Adlbrecht

Blanco-Verea

Bouzas-Mosquera

et al. 2018

Eur J Clin Investigation

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Effect of atorvastatin, cholesterol ester transfer protein inhibition, and diabetes mellitus on circulating proprotein subtilisin kexin type 9 and lipoprotein(a) levels in patients at high cardiovascular risk

Cited by 48 publications

References 46 publications

Therapeutic Agents Targeting Cardiometabolic Risk for Preventing and Treating Atherosclerotic Cardiovascular Diseases

Therapeutic Agents Targeting Cardiometabolic Risk for Preventing and Treating Atherosclerotic Cardiovascular Diseases

Efficacy and safety of proprotein convertase subtilisin/kexin 9 inhibitors in people with diabetes and dyslipidaemia

Research update for articles published in EJCI in 2016

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