We evaluated the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, alirocumab, among individuals with type 2 diabetes (T2DM), high LDL-C or non-HDL-C, and established ASCVD receiving maximally tolerated statin in ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) and DM-INSULIN (NCT02585778).
A number of vasoactive mediators including proprotein convertase subtilisin-kexin type 9 (PCSK9), endothelin-1, nitric oxide, and angiotensin II have fundamental roles in the pathophysiology of atherosclerotic events; moreover, their levels are affected by dyslipidemia and oxidative stress due to renal dysfunction.
The recent introduction of anti-PCSK9 monoclonal antibodies and other therapies targeted to the molecular mechanisms of lipid transport disrupted in NS holds promise for the future treatment of dyslipidemia in NS.
The relevance of the LDL-independent effects of PCSK9 inhibitors, such as lowering lipoprotein(a) or ameliorating dyslipidaemia in patients with nephrotic syndrome, has to be determined.
PCSK9 inhibitor prescribing increased over time for patients with coronary artery disease or coronary heart disease but not for those with dyslipidemia.
This article reviews the underlying aetiology and pathophysiology of this dyslipidaemia and atherosclerosis in those with diabetes, provides insights from epidemiological and genetic studies, and current cardiovascular risk reducing interventions including novel therapies such as PCSK-9 inhibitors.
Monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol levels and subsequently the risk of cardiovascular events in patients with dyslipidaemia.
Reduced lipoprotein lipase activity, increased very low-density lipoprotein production, increased proprotein convertase subtilisin kexin type 9 (PCSK9) expression and loss of hepatic heparan sulfate proteoglycans (HSPG) syndecan-1 have been associated with CKD-related dyslipidemia.
Statins remain the first-line lipid-lowering agents for the management of dyslipidemia in individuals with diabetes; however, the addition of non-statin therapies to lower LDL cholesterol, such as ezetimibe and PCSK-9 inhibitors, to maximally tolerated statin therapy is recommended in patients with atherosclerotic cardiovascular disease and baseline LDL cholesterol over 70 mg/dl.
Thyroid hormone administration possibly also sustains and enhances the efficacy of hypolipidemic drugs, such as statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9), in patients with dyslipidemia and hypothyroidism.
Elevated levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) have been reported to be related to dyslipidemia, including patients with kidney dysfunction.
Here we report the rationale and design of a phase 3, double-blind study specifically designed to evaluate the lipid-lowering efficacy of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab in patients with T2DM and hyperlipidemia or mixed dyslipidemia who are on background statin therapy.
We aimed to determine the correlation of PCSK9 levels with predictors of cardiovascular risk, such as central hemodynamics and carotid intima-media thickness (cIMT), in subjects with familial dyslipidemias.
While exposing the polygenic architecture of circulating lipids and the underpinnings of dyslipidaemia, these genome-wide association studies (GWAS) have provided further evidence of the critical role that lipids play in coronary heart disease (CHD) risk, as indicated by the 2.7-fold enrichment for macrophage gene expression in atherosclerotic plaques and the association of 25 loci (such as PCSK9, APOB, ABCG5-G8, KCNK5, LPL, HMGCR, NPC1L1, CETP, TRIB1, ABO, PMAIP1-MC4R, and LDLR) with CHD.
Rabbits fed a cholesterol-rich diet demonstrated dyslipidemia, increased inflammatory state, and elevated serum levels of PCSK9, compared to the NC group.
We conclude that the PCSK9rs374603772" genes_norm="255738">R496W (rs374603772) and rs137852912" genes_norm="255738">D374Y (rs137852912) GOF mutations may be significant risk factors in the development of primary dyslipidemia and may have significant impact on lipid parameters in general population.