Page 515 - fbkCardioDiabetes_2017

Cardio Diabetes Medicine 2017 491

New Lipid Lowering Therapies

Dr. Devaki Nair

Consultant Chemical Pathologist and Clinical lead for Clinical biochemistry,
Royal Free Hospital and North Middlesex University Hospital, United Kingtom.

Introduction tion of apolipoprotein B 100 containing lipoprotein-
Cardiovascular disease remains a major cause for Very low density lipoprotein(VLDL)(4).This drug is
mortality worldwide. Epidemiological studies as well administered as a subcutaneous injection once fort-
as clinical trials with various lipid lowering therapies nightly. The second agent Lomitapide administered
have shown the causal relationship of raised low orally inhibits the Microsomal triglyceride transfer
density lipoprotein cholesterol (LDL-C)(1). It is well protein and these results in reduction of synthesis
established that statin therapy is the corner stone of Apolipoprotein B containing VLDL and chylomi-
for prevention of cardiovascular disease, but there crons. Both the drugs have been approved for use
remains some residual risk and low High Density in homozygous FH. The side effects for both these
Lipoprotein cholesterol (HDL-C) has been implicated drugs include raised transaminases and fatty liver as
and there is much interest in drug targets to raise they interfere with secretion of VLDL. Skin reaction at
HDL-C (2). But there the progress has been very slow the injection site with mipomersen and GI side effects
from getting these experimental drugs from bench to with lomitapide are not uncommon(4).
bedside, however intervention strategies for raising Another class of drugs – a Pro-protein convertase
HDL –C and are still being investigated. There has subtilisin-like kexin type 9 inhibitor (PCSK9 inhib-
been some rapid progress in assessment and man- itor) has revolutionalised management of patients
agement of patients with high to very high Triglycer- with very high concentration of LDL-C such as those
ide (TG) concentration. Other pharmacological targets with inherited hyperlipidaemia. PCSK9 enzyme a pro-
such as inflammation in prevention of progression of tease is involved in the endocytosis and degradation
atherosclerosis are also being tested. of LDL receptor. Inhibition of this enzyme through
The challenges we face in relation to lipid lowering use of monoclonal antibodies has shown promise to
therapy include inadequate response to available lip- many of the challenges that we face with statin in
id lowering therapy (LLT), intolerance to LLT, adverse reducing LDL –C levels(5) Two of the PCSK9 inhibi-
interactions with concomitant medication and inad- tors have been approved and further outcome data
equate response both to raising HDL and lowering is expected in the very near future from their exten-
LDL-C and TG concentration in those with inherited sive clinical trial programme. However there have also
problems. In addition the short and long term side ef- been some setbacks as one of the drugs in this class
fects as perceived by the patients and the problems have also been withdrawn in early phase 3 trials, due
associated with adherence may also be a challenge to lack of effectiveness(6). They exhibit excellent side
that leads to development of newer therapies for ex- effect profile and are likely to become an alternate
ample with less frequent dosing schedule(3). option to statin once cardiovascular outcome trials
are published.
New LDL lowering therapies While the monoclonal antibodies to PCSK9 only
The two new therapies recently approved by FDA to blocks the extracellular component, another drug tar-
lower LDL levels include Mipomersen an antisense geting inhibition of PCSK9 works by inhibiting both
oligonucleotide that binds to apolipoprotein B100 extracellular and intracellular PCSK9 by inhibiting the
mRNA inducing degradation and reducing the secre- synthesis through a novel interfering RNA (RNAi) to

Cardio Diabetes Medicine