PCSK9 Inhibition and Risk of Diabetes: Should We Worry?

Carugo, Stefano; Sirtori, Cesare R.; Corsini, Alberto; Tokgözoğlu, Lâle; Ruscica, Massimiliano

doi:10.1007/s11883-022-01074-y

Cited by 24 publications

(15 citation statements)

References 74 publications

(104 reference statements)

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“…Although ezetimibe alone has no positive results in risk reduction MACE, when added to statin therapy, ezetimibe has shown remarkable ability to reduce the risk of serious vascular events. It is important to note that the magnitude of relative risk reduction in MACE is directly proportional to the absolute degree of LDL-C reduction, a relationship consistent with the observed effects of statins [29]. In the study IMPROVE-IT, which included a subgroup of patients diagnosed with T2DM, it was expected that this subgroup would have a higher rate of major vascular events than patients without DM.…”

Section: Ezetimibementioning

confidence: 59%

Importance of Dyslipidaemia Treatment in Patients with Type 2 Diabetes Mellitus

Strikić,

Vujević,

Perica

et al. 2023

Preprint

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Type 2 diabetes mellitus (T2DM) is a common metabolic disease characterised by insulin resistance and elevated blood glucose levels, affecting millions of people worldwide. T2DM patients with dyslipidaemia have an increased risk of cardiovascular disease (CVD). A complex interplay of risk factors such as hyperglycaemia, dyslipidaemia, hypertension, obesity, inflammation and oxidative stress favour the development of atherosclerosis, a central mechanism in the pathogenesis of cardiovascular disease. Dyslipidaemia, a hallmark of T2DM, is characterised by elevated triglycerides, decreased high-density lipoprotein (HDL) cholesterol and the presence of small, dense low-density lipoprotein (LDL) particles, all of which promote atherosclerosis. In this article, we have attempted to present various treatment strategies that include pharmacological interventions such as statins, ezetimibe, PCSK9 inhibitors, fibrates and omega-3 fatty acids. We have also tried to highlight the pivotal role of lifestyle modifications, including physical activity and dietary changes, in improving lipid profiles and overall cardiovascular health in T2DM patients. We have also tried to present the latest clinical guidelines for the management of dyslipidaemia in T2DM patients. In conclusion, the treatment of dyslipidaemia in T2DM patients is of great importance as it lowers lipid particle levels, slows the progression of atherosclerosis and ultimately reduces susceptibility to cardiovascular disease.

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Section: Ezetimibementioning

confidence: 59%

Importance of Dyslipidaemia Treatment in Patients with Type 2 Diabetes Mellitus

Strikić,

Vujević,

Perica

et al. 2023

Preprint

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“…In addition, six loci were linked to insulin resistance, type 2 diabetes, or reduction in HbA1c levels in type 2 diabetes ( APOB , HPR , TM6SF2 , KSR2 , JMJD1C , and SLCO1B1 ). This might contribute to the ongoing discussion of PCSK9 inhibitors increasing the risk of diabetes [ 72 ].…”

Section: Discussionmentioning

confidence: 99%

Sex and statin-related genetic associations at the PCSK9 gene locus: results of genome-wide association meta-analysis

Pott,

Kheirkhah,

Gadin

et al. 2024

Biol Sex Differ

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Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player of lipid metabolism with higher plasma levels in women throughout their life. Statin treatment affects PCSK9 levels also showing evidence of sex-differential effects. It remains unclear whether these differences can be explained by genetics. Methods We performed genome-wide association meta-analyses (GWAS) of PCSK9 levels stratified for sex and statin treatment in six independent studies of Europeans (8936 women/11,080 men respectively 14,825 statin-free/5191 statin-treated individuals). Loci associated in one of the strata were tested for statin- and sex-interactions considering all independent signals per locus. Independent variants at the PCSK9 gene locus were then used in a stratified Mendelian Randomization analysis (cis-MR) of PCSK9 effects on low-density lipoprotein cholesterol (LDL-C) levels to detect differences of causal effects between the subgroups. Results We identified 11 loci associated with PCSK9 in at least one stratified subgroup (p < 1.0 × 10–6), including the PCSK9 gene locus and five other lipid loci: APOB, TM6SF2, FADS1/FADS2, JMJD1C, and HP/HPR. The interaction analysis revealed eight loci with sex- and/or statin-interactions. At the PCSK9 gene locus, there were four independent signals, one with a significant sex-interaction showing stronger effects in men (rs693668). Regarding statin treatment, there were two significant interactions in PCSK9 missense mutations: rs11591147 had stronger effects in statin-free individuals, and rs11583680 had stronger effects in statin-treated individuals. Besides replicating known loci, we detected two novel genome-wide significant associations: one for statin-treated individuals at 6q11.1 (within KHDRBS2) and one for males at 12q24.22 (near KSR2/NOS1), both with significant interactions. In the MR of PCSK9 on LDL-C, we observed significant causal estimates within all subgroups, but significantly stronger causal effects in statin-free subjects compared to statin-treated individuals. Conclusions We performed the first double-stratified GWAS of PCSK9 levels and identified multiple biologically plausible loci with genetic interaction effects. Our results indicate that the observed sexual dimorphism of PCSK9 and its statin-related interactions have a genetic basis. Significant differences in the causal relationship between PCSK9 and LDL-C suggest sex-specific dosages of PCSK9 inhibitors.

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“…In addition, ANGPTL3 LOF mutations prevent CAD without serious adverse health consequences and are expressed predominantly in hepatocytes, several features that make nucleic acid therapy potentially more effective than monoclonal antibodies. In particular, inhibition of ANGPTL3 by siRNA may be a future panacea against hypertriglyceridemia in a variety of dyslipidemia conditions, 181 including residual LDL-C elevation in FH. 135,166,182 Similarly, ANGPTL3 is an attractive target for in vivo gene editing.…”

Section: Drug Development Of Angptl3mentioning

confidence: 99%

Drug development advances in human genetics‐based targets

Zhang,

Yu,

et al. 2024

MedComm

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Drug development is a long and costly process, with a high degree of uncertainty from the identification of a drug target to its market launch. Targeted drugs supported by human genetic evidence are expected to enter phase II/III clinical trials or be approved for marketing more quickly, speeding up the drug development process. Currently, genetic data and technologies such as genome‐wide association studies (GWAS), whole‐exome sequencing (WES), and whole‐genome sequencing (WGS) have identified and validated many potential molecular targets associated with diseases. This review describes the structure, molecular biology, and drug development of human genetics‐based validated beneficial loss‐of‐function (LOF) mutation targets (target mutations that reduce disease incidence) over the past decade. The feasibility of eight beneficial LOF mutation targets (PCSK9, ANGPTL3, ASGR1, HSD17B13, KHK, CIDEB, GPR75, and INHBE) as targets for drug discovery is mainly emphasized, and their research prospects and challenges are discussed. In conclusion, we expect that this review will inspire more researchers to use human genetics and genomics to support the discovery of novel therapeutic drugs and the direction of clinical development, which will contribute to the development of new drug discovery and drug repurposing.

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PCSK9 Inhibition and Risk of Diabetes: Should We Worry?

Cited by 24 publications

References 74 publications

Importance of Dyslipidaemia Treatment in Patients with Type 2 Diabetes Mellitus

Importance of Dyslipidaemia Treatment in Patients with Type 2 Diabetes Mellitus

Sex and statin-related genetic associations at the PCSK9 gene locus: results of genome-wide association meta-analysis

Drug development advances in human genetics‐based targets

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