PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: the role of the low-density lipoprotein receptor

Dalt, L. Da; Ruscica, Massimiliano; Bonacina, Fabrizia; Balzarotti, G.; Dhyani, A.; Cairano, E. Di; Baragetti, Andrea; Arnaboldi, Lorenzo; Metrio, S. De; Pellegatta, Fabio; Grigore, Liliana; Botta, Margherita; Macchi, Chiara; Uboldi, Patrizia; Perego, Carla; Catapano, Alberico L.; Norata, Giuseppe Danilo

doi:10.1093/eurheartj/ehy357

Cited by 137 publications

(137 citation statements)

References 38 publications

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“…Analogous circumstances have been examined for T2D, where evidence from human genetics suggests reduced PCSK9 activity leads to greater diabetes risk, but there is no clear evidence to show that this risk increase has borne out among RCT participants exposed to PCSK9 inhibitors . The disparities may be reconciled if localized PCSK9 function in pancreatic tissue were to affect glycemic control independently of any inhibition of PCSK9 in circulation, as has been suggested by data from tissue‐selective Pcsk9 knockout mice . If data from larger GWASs of circulating PCSK9 become available, improved MR analyses of circulating PCSK9 concentrations and AD risk (ie, using multiple genome‐wide SNPs to index differences in exposure) would help to evaluate the role of peripheral PCSK9 inhibition specifically.…”

Section: Discussionmentioning

confidence: 99%

“…31,48 The disparities may be reconciled if localized PCSK9 function in pancreatic tissue were to affect glycemic control independently of any inhibition of PCSK9 in circulation, as has been suggested by data from tissue-selective Pcsk9 knockout mice. 49 If data from larger GWASs of circulating PCSK9 become available, improved MR analyses of circulating PCSK9 concentrations and AD risk (ie, using multiple genome-wide SNPs to index differences in exposure) would help to evaluate the role of peripheral PCSK9 inhibition specifically. Third, given that genetic effects are often lifelong, we cannot distinguish critical periods of exposure to these targets in which disease risk might be specifically affected, such as neurodevelopment.…”

Section: Discussionmentioning

confidence: 99%

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Lipid lowering and Alzheimer disease risk: A mendelian randomization study

Williams

Finan

Schmidt

et al. 2019

Annals of Neurology

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Objective To examine whether genetic variation affecting the expression or function of lipid‐lowering drug targets is associated with Alzheimer disease (AD) risk, to evaluate the potential impact of long‐term exposure to corresponding therapeutics. Methods We conducted Mendelian randomization analyses using variants in genes that encode the protein targets of several approved lipid‐lowering drug classes: HMGCR (encoding the target for statins), PCSK9 (encoding the target for PCSK9 inhibitors, eg, evolocumab and alirocumab), NPC1L1 (encoding the target for ezetimibe), and APOB (encoding the target of mipomersen). Variants were weighted by associations with low‐density lipoprotein cholesterol (LDL‐C) using data from lipid genetics consortia (n up to 295,826). We meta‐analyzed Mendelian randomization estimates for regional variants weighted by LDL‐C on AD risk from 2 large samples (total n = 24,718 cases, 56,685 controls). Results Models for HMGCR, APOB, and NPC1L1 did not suggest that the use of related lipid‐lowering drug classes would affect AD risk. In contrast, genetically instrumented exposure to PCSK9 inhibitors was predicted to increase AD risk in both of the AD samples (combined odds ratio per standard deviation lower LDL‐C inducible by the drug target = 1.45, 95% confidence interval = 1.23–1.69). This risk increase was opposite to, although more modest than, the degree of protection from coronary artery disease predicted by these same methods for PCSK9 inhibition. Interpretation We did not identify genetic support for the repurposing of statins, ezetimibe, or mipomersen for AD prevention. Notwithstanding caveats to this genetic evidence, pharmacovigilance for AD risk among users of PCSK9 inhibitors may be warranted. ANN NEUROL 2020;87:30–39

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lipid lowering and Alzheimer disease risk: A mendelian randomization study

Williams

Finan

Schmidt

et al. 2019

Annals of Neurology

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“…Such a mechanism is supported by the impaired glucose tolerance and β‐cell function and impaired glucose tolerance observed in fully Pcsk9‐ deficient mice in some studies but not others . The loss‐of‐function PCSK9 variant R46L has equally been associated with a reduced β‐cell function, although this did not translate into a reduced insulin sensitivity . To what extent circulating PCSK9 and treatment with anti‐PCSK9 mAbs can modulate pancreatic β‐cell LDLR expression and function remains unclear, but the absence of hyperglycaemia in mice with a hepatocyte‐specific deletion of Pcsk9 suggests a local regulatory mechanism …”

Section: Safety Of Pcsk9 Inhibitors In T2dm Patientsmentioning

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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“…The reduction in PCSK9 within their model found increased LDL receptor expression with increased cholesterol in islets, subsequently reducing insulin excretion. Importantly, their studies found no change in insulin resistance with PCSK9 deficiency (Figure ) …”

Section: Translational Biologymentioning

confidence: 97%

“…13 (Figure 1). 14 17 Other outcomes found that adjudicated cases of new onset diabetes were 8.1% in the evolocumab arm (677/13 769) versus 7.7% (644/13 756) in the placebo arm. It should be noted that the total numbers of patients with diabetes were 8339 in the placebo arm and 8337 in the evolocumab arm because prevalent diabetes patients were excluded at the start of the trial.…”

mentioning

confidence: 99%