Oral cholesterol-lowering therapies are the basis of cardiovascular disease prevention, and I will be talking about this. Here, you can see my disclosures.

Multiple lines of evidence confirm that LDL cholesterol is causal for atherosclerotic vascular disease. For this reason, LDL cholesterol is the primary target in the guidelines, and lower LDL cholesterol goals than ever are recommended in the most recent guidelines. Lifestyle and statins are the backbone of lipid-lowering therapy, but with the new stringent goals, they're not always adequate to get to goal. Combination therapy may be required in several patients, especially those at higher risk. Today, we have a wealth of oral and injectable combination therapies, and I will be talking about the oral combination therapies.

Statins have been around for a long time. They have stood the test of time. They are efficacious and safe. They work by blocking HMG-CoA reductase, increasing LDL receptors therefore increasing LDL cholesterol clearance. Although they do have pleiotropic effects like anti-inflammatory, anti-thrombotic, antioxidative, their main effect is regulated via lowering LDL cholesterol. Sophisticated imaging techniques have shown the impact of statins on atherosclerotic plaque. Especially at high doses, statins can regress the plaque. They can thicken the fibrous cap, decrease inflammation, and decrease the lipid-laden necrotic core of the plaque. More importantly, there is a linear relation between LDL reduction and cardiovascular disease. The CTT has shown us that, for each 1 millimole reduction in LDL cholesterol, statin reduces major cardiovascular events by around 20% The lower LDL cholesterol, the better. We know that high-intensity statins lower LDL cholesterol by about 50% Real life studies like the DA VINCI trial have shown underutilization of high-intensity statins with about 28% use. This is surprising because the cardiovascular benefits of statins far outweigh the risk of adverse events such as dysglycemia and muscle symptoms.

Muscle symptoms are one of the reasons of decreased adherence, and the prevalence of statin intolerance is thought to be around 9% Most of this intolerance is probably the nocebo or drucebo effect, but a meta-analysis of 19 randomized trials has shown us that 90% of all reports of muscle symptoms were not really due to the statin. Nevertheless, this is something we really have to deal with in the clinic and we have to make shared decision-making with the patient taking account into preferences, but we should really also get the patient to goal. For this reason, we can use lower doses of statins with combination therapy or switch to different statins.

Ezetimibe is another oral agent reducing absorption of cholesterol from the intestine and lowering LDL cholesterol by about 15% to 20%. It's the first choice in combination therapy so far because it's cheap and safe, and it was the first non-statin to improve cardiovascular outcomes as demonstrated in the IMPROVE-IT study. We know that adding Ezetimibe to a statin can lower LDL more than increasing the dose of the statin. This has been demonstrated over and over in several trials. The efficacy and safety of moderate-intensity statin combination with Ezetimibe versus high-intensity statin monotherapy has been compared in the RACING trial in about 3,700 patients with atherosclerotic vascular disease. At the end of three years, combination therapy was non-inferior to high-intensity statin monotherapy, and the higher proportion of patients on combination achieved LDL below 70 milligrams per deciliter. There was lower intolerance-related drug discontinuation or dose reduction. We also know that if we have a fixed dose statin Ezetimibe compared to a separate pill combination, it reduces LDL cholesterol more in a retrospective analysis of 300,000 patients. This is probably because patients adhere more to the medication.

Another group of agents we don't really use too much in clinical practice are the bile acid sequestrants. They disrupt the enterohepatic circulation of bile acids and lower LDL cholesterol by 12% to 20%. However, they do have gastrointestinal side effects and they decrease the absorption of fat-soluble vitamins. The advantage they have is that they're not absorbed systemically, so it's safe to use in children and in pregnant women.

A newer agent on the field is bempedoic acid. It inhibits ATP citrate lyase, an enzyme upstream of HMG-CoA reductase. It's a pro-drug and cannot be activated in the muscle, therefore, leads to less muscular side effects. It has a dual mechanism of action, also activating AMP-activated protein kinase. We think this leads to improved glucose tolerance and reduces high-sensitivity CRP. In a pooled analysis of phase 3 studies, bempedoic acid has shown to lower LDL cholesterol about 18% in patients on a statin and 25% in statin-intolerant patients. This year, the cardiovascular outcome study of bempedoic acid was published. The CLEAR OUTCOMES, the largest study in statin-intolerant patients. In 14,000 high and very high risk patients, unable or unwilling to take statins, bempedoic acid monotherapy was compared to placebo. LDL cholesterol was reduced by 22%. 4 point MACE reduced by 13% without any increase in diabetes. Gout and uric acid were increased. A secondary analysis of only primary prevention patients showed that 30% decrease in 4 point MACE. It's also possible to have bempedoic acid and ezetimibe fixed dose combination. In a phase 3 randomized trial, the fixed-dose combination added to stable background statins reduced LDL cholesterol by a further 36%

There is an upcoming new oral PCSK9 inhibitor. In the past, oral PCSK9 inhibitors were not feasible because of decreased bioavailability, but this new peptide is resistant to gastrointestinal degradation. Since it's poorly absorbed it requires a permeation enhancer. In the phase 2B trial, it showed a 60% reduction in LDL cholesterol and was well tolerated. Oral therapies can reduce LDL cholesterol significantly.

We have a large armamentarium of oral therapies to choose from. When we use a triple oral combination, LDL cholesterol can be reduced up to 70% thus helping us get to goal only with oral agents. In conclusion, lowering LDL cholesterol levels is the most important pharmacological intervention to mitigate atherosclerotic cardiovascular events. Of course, statins will always be the first choice if tolerated, and if the patient is getting to goal. With the new options, significant reductions in LDL cholesterol are now possible with combination oral therapies.

Thank you for your attention.

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