Lipid Lowering Agents: Hypocholesterolaemic Drugs Presentation

Lipid Lowering Agents Overview

LIPID LOWERING AGENTS (HYPOCHOLESTEROLAEMIC DRUGS) Statins Fibrates Cholesterol absorption inhibitors Bile acid-binding (anion exchange) resins Niacin Q-3 fatty acids PCSK9 inhibitors Bempedoic acid

There is a wide range of lipid lowering agents available, using a diverse array of mechanisms. These currently include statins, fibrates, the cholesterol absorption inhibitor ezetimibe, bile acid-binding (anion exchange) resins, niacin, omega-3 long chain polyunsaturated fatty acids (fish oils), PCSK9 inhibitors and most recently bempedoic acid. Therapeutic lipid-lowering mainly refers to the ability to lower non-HDL cholesterol and plasma triglycerides (TG), but these agents may also have desirable effects to increase HDL. Non-HDL cholesterol, including VLDL- and LDL-cholesterol, is of course causally linked with the development of atherosclerosis and ultimately the risk of ischaemic heart disease, stroke and peripheral arterial disease. The types of conditions lipid lowering agents may be used for include primary (familial and non- familial) hypercholesterolaemia, mixed hyperlipidaemia and severe hypertriglyceridaemia. Furthermore, statins have a particular role in managing cardiovascular risk in the prevention of cardiovascular disease. It's important to appreciate that the main general clinical interest with lipid lowering therapy is typically to reduce levels of non-HDL cholesterol (as sources of atherogenic cholesterol); and this is principally achieved by reducing LDL cholesterol.

Drugs Affecting Lipid Metabolism

Here we have a summary of the major lipid targets of lipid lowering agents. We see that reducing LDL cholesterol to some extent is the main business of the majority of these drugs; and with the drug class of choice here being statins. In contrast, fibrates and omega-3 fatty acids focus on TG reduction - with fibrates being the drug class of choice there. Niacin is the drug of choice for raising HDL.

Drugs Targeting LDL & Total Cholesterol

C Drugs that mainly target LDL & total cholesterol

• statins
• cholesterol absorption inhibitors
• bile acid-binding (anion exchange) resins
• PCSK9 inhibitors bempedoic acid

Drugs Targeting Triglycerides

O Drugs that mainly target triglycerides

• fibrates

. 2-3 fatty acids / fish oils

Drugs of Choice for Lipid Reduction

o Drugs of choice in reducing LDL

• statins

o Drugs of choice in reducing triglycerides

• fibrates

o Drug of choice in raising HDL

• niacin

Statins

O Eg. lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin 0 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors

• inhibit formation of mevalonate from HMG CoA

O Reduce hepatic cholesterol synthesis inhibit rate limiting step O Increase hepatic LDL-R expression, LDL clearance & reduce VLDL production O Raise HDL (modest) O Lower LDL, VLDL & triglycerides o Pleiotropic effects

• eg. improve endothelial function, reduce coagulation, reduce inflammation

o Drugs of choice in lowering LDL Indicated in e.g. hypercholesterolaemia and in reduction of cardiovascular risk O Associated with hepatotoxicity, myopathy, myositis, rhabdomyolysis, GI upset, abdominal pain, nausea, dizziness, blurred vision, headache O NB: increased risk of rhabdomyolysis if statin combined with eg. fibrate or niacin O NB: as an alternative to statins, bempedoic acid is a novel ATP citrate lyase inhibitor therapeutic that reduces hepatic cholesterol synthesis

o We start by considering statins such as lovastatin, simvastatin, atorvastatin and rosuvastatin. These last two are designated as high intensity statins in view of their ability to reduce LDL cholesterol by more than 40%. High dose simvastatin is also considered high intensity. Statins are inhibitors of the enzyme HMG CoA reductase, which is essential for cholesterol synthesis. Their main effect and site of action is to block the rate-limiting step represented by the formation of mevalonate from HMG CoA in the liver. Reduced hepatic synthesis of cholesterol leads to an intracellular cholesterol shortage which the liver attempts to make up for by importing more LDL cholesterol from the circulation (via the upregulated expression of hepatic LDL receptors). This leads to greater LDL clearance and subsequent (and marked) LDL lowering. This is a very effective mechanism to lower LDL cholesterol and statins are the drugs of choice here. Restricting the availability of hepatic cholesterol also limits VLDL production, which leads to lower VLDL as well as TG levels. Furthermore, HDL is modestly raised by statins. Statins enjoy a special role in managing cardiovascular risk (principally via LDL lowering but also possibly through pleiotropic effects such as anti- thrombotic and anti-inflammatory actions) both in established cardiovascular disease and in individuals at high cardiovascular risk re primary prevention. An alternative way of blocking hepatic cholesterol synthesis has recently been provided by the ATP citrate lyase inhibitor and LDL-lowering agent bempedoic acid.

Bile Acid-Binding Resins

Another way of starving the liver of cholesterol and forcing greater (compensatory) hepatic LDL receptor expression (to once again import more LDL cholesterol and increase LDL clearance from the blood), is to block the reabsorption of bile acids (synthesised from hepatic stores of cholesterol) with insoluble, cationic polymers such as colestipol that act as bile acid-binding (or anion exchange) resins. These prevent enterohepatic bile acid circulation and thereby limit (bile acid) cholesterol reabsorption by the liver and subsequently drain the hepatic store of cholesterol (as more hepatic cholesterol needs to be used in the replacement of the lost bile acids). The outcomes of letting bile acid cholesterol go to waste in this way include LDL lowering (as well as a modest rise in HDL), along with the activation of the enzyme responsible for hepatic bile acid synthesis. However, a compensatory stimulation of hepatic cholesterol synthesis can be expected to blunt the LDL lowering effect and there may also be a rise in VLDL and TG. Furthermore the absorption of fat soluble vitamins is impaired (along with some drugs), which can e.g. contribute to bleeding in respect of vitamin K deficiency.

O Eg. colestipol, cholestyramine, colesevelam O Insoluble, cationic polymers O Reduce bile acid reabsorption

• interrupts enterohepatic bile acid circulation
• reduces (bile acid) cholesterol reabsorption

O Increase bile acid synthesis

. activation of hepatic 7-a-hydroxylase

• more cholesterol needed for de novo bile acid synthesis
• reduces hepatic store of cholesterol

O Increase hepatic LDL-R expression & LDL clearance May raise HDL (modest) O Lower LDL Indicated in hypercholesterolaemia Associated with compensatory increase in hepatic cholesterol synthesis, increased hepatic VLDL production & modest rise in triglycerides, reduced absorption of fat soluble vitamins (A, D, E, K), susceptibility to bleeding (reduced vitamin K), bloating, dyspepsia, flatulence, GI upset [ Reduces absorption of digoxin, warfarin, thyroxine, cholorothiazide NB: anion exchange resins are unpalatable & several grams need to be taken; but novel agent colesevelam intended to improve tolerability

Specific Cholesterol Absorption Inhibitors

An alternative therapeutic approach to depleting hepatic cholesterol stores involves inhibiting the cholesterol uptake receptor/Niemann-Pick C1-like 1 (NPC1L1) transport protein found in the small intestine, with a specific cholesterol absorption inhibitor represented by ezetimibe. This prevents the absorption of both dietary and bile (free) cholesterol; but does not affect the absorption of e.g. dietary TG, fat soluble vitamins or bile acids. This leads to the now familiar hepatic compensatory response to upregulate LDL receptor expression in an attempt to get more LDL cholesterol from the blood to replace depleted cholesterol stores. This of course reduces LDL; and hepatic VLDL production is also curtailed. A compensatory increase in hepatic cholesterol synthesis can also be expected, but this is not sufficient to negate the effects of ezetimibe re LDL lowering.

0 Eg. ezetimibe

. also plant sterols & stanols Inhibit absorption of dietary & bile cholesterol Inhibit cholesterol uptake receptor

O

• NPC1L1 transporter in brush border of small intestinal mucosa

. no effect on absorption of triglycerides, fat soluble vitamins, bile acids O Reduce hepatic VLDL production O Increase hepatic LDL-R expression & LDL clearance O Reduce LDL Indicated in hypercholesterolaemia Ezetimibe associated with compensatory increase in hepatic cholesterol synthesis, myopathy, rhabdomyolysis, dyspepsia, diarrhoea, abdominal pain, arthralgia, myalgia, headache, elevated liver function tests, angioedema O Ezetimibe can enhance cyclosporine levels O NB: ezetimibe may be absorbed systemically & also undergoes enterohepatic recirculation

PCSK9 Inhibitors

Proprotein convertase subtilisin/kexin type 9 PCSK9 inhibitors

O Eg. alirocumab, evolocumab o Anti-PCSK9 monoclonal antibodies Inhibit action of liver-produced enzyme (serine protease) PCSK9, responsible for promoting metabolism and subsequent degradation of LDL-R on liver cells

. inhibit breakdown of LDL-R O Increase hepatic LDL-R expression and LDL clearance O Raise HDL (modest) O Lower LDL, VLDL & triglycerides O Indicated in primary hypercholesterolaemia or mixed dyslipidaemia not responding adequately to other appropriate measures O Administered by subcutaneous injection Associated with e.g. oropharyngeal pain, pruritus, rhinorrhoea, arthralgia, back pain, upper respiratory tract infection NB: as an alternative to these PCSK9 inhibitors, inclisiran is a novel small interfering RNA (siRNA) therapeutic that reduces hepatic PCSK9 production

Staying with the very successful pharmacotherapeutic theme of overexpressing hepatic LDL receptors in order to clear the blood of more LDL (and thereby lower circulating LDL cholesterol), we now look at a novel, alternative approach to inducing this situation - with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. PCSK9 is an enzyme that plays a role in preventing the recycling to the cell surface of LDL receptors that have been endocytosed as a result of binding with LDL. As anti-PCSK9 monoclonal antibodies, alirocumab and evolocumab therefore ensure more LDL receptors avoid lysosomal degradation after LDL cholesterol uptake and instead contribute to an overexpression of hepatic LDL receptors. As well as markedly lowering circulating LDL, these agents also lower VLDL and TG and furthermore raise HDL. An alternative way of reducing PCSK9 activity has recently been provided by the small interfering RNA (siRNA) and LDL- lowering agent inclisiran, which selectively silences PCSK9 gene expression.