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.
While gain-of-function mutations aggravate the degradation of LDLR as in familial hypercholesterolemia whereas loss of function mutations reduce the ability of PCSK9 to promote the degradation of LDLR and thus lower the plasma level of LDL-C and dyslipidemia.
Since it was recently reported that an antibody for proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces the risk of cardiovascular events in a clinical context, PCSK9 inhibition is thought to be an attractive therapy for dyslipidemia.
To compare alirocumab, a proprotein convertase subtilisin-kexin type 9 inhibitor, with usual care (UC) in individuals with type 2 diabetes (T2DM) and mixed dyslipidaemia not optimally managed by maximally tolerated statins in the ODYSSEY DM-DYSLIPIDEMIA trial (NCT02642159).
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.
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.
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.
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.
The recent discovery of mutations in PCSK9 protein associated with low plasma low-density lipoprotein in humans, the characterization of PCSK9-deficient mice hypersensitive to statins and the severely pathological phenotype of D374YPCSK9-mutated patients shed a new light on this gene: is it a promising therapeutic target for dyslipidemias?
Proprotein convertase subtilisin kexin type 9 (PCSK9) is a new component of lipid metabolism and correlated to the development of dyslipidemia and atherosclerosis.
Initial data from investigations of PCSK9 inhibition in humans are promising and indicate that PCSK9 inhibition may be a viable new therapeutic option for the treatment of dyslipidemia and associated cardiovascular diseases.
An Expert Panel convened by the National Lipid Association was charged with updating the recommendations on the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody therapy that were provided by the 2015 National Lipid Association Recommendations for the Patient-Centered Management of Dyslipidemia: Part 2.
Recently, biologic and genetic research proposed several approaches to inhibit or reduce PCSK9 to improve lipid profile and cardiovascular performance in patients with dyslipidemia, particularly hypercholesterolemia.
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.
In addition, mice with hepatic deletion of Pcsk9 were treated with NTS to determine the contribution of PCSK9 to the dyslipidemia of nephrotic syndrome.