Payal Kohli, MD, FACC

Dr Taub, Dr Patel, and Dr Kohli look ahead to the future of the management of cardiovascular risk and hyperlipidemia

Looking Into the Future of Lipid Management

The experts envision increased use of targeted therapies like siRNA that allow less frequent dosing for hypercholesterolemia and other conditions. Exciting data on “one-and-done” gene editing may enable permanent PCSK9 inhibition in familial hypercholesterolemia. Such innovations promise elegant, well-tolerated long-term solutions.

However, while much progress is being made in developing novel therapies for cardiovascular prevention (“first mile” investigations), major global burden exists in implementation and uptake (“last mile”). Even long available treatments take about a decade to achieve 50-70% adoption. Thus, reducing health inequities and accelerating real-world access remains key.

Beyond scientific advances, addressing rising obesity rates holds great potential to impact cholesterol management and overall risk. With obesity now recognized as a disease, more aggressive multifactorial treatment may emerge, benefiting lipids as well. Lipoprotein(a) is also garnering increasing interest as a causal risk factor amendable to new targeted therapies that may soon demonstrate cardiovascular improvements.

In summary, the experts express excitement about the future scientific pipeline while emphasizing the immense implementation challenges ahead in equitable delivery of cardiovascular prevention. Realizing the full potential of powerful emerging therapies will require overcoming barriers in dissemination and uptake among diverse populations. Continued innovation in treatment must therefore be matched by innovation in health systems’ ability to connect the right interventions with the right patients.

This summary was AI-generated and edited for clarity and readability. 

Videos

Cardiologists discuss how to select the right treatment for your patient with hyperlipidemia

How to Select Between Available LDL-C Lowering Therapies

The experts discuss considerations around selecting non-statin therapies for high cholesterol, either as add-on options to maximally tolerated statins or alternatives for statin-intolerant patients. The choice depends on the degree of additional LDL lowering required to reach one's personalized LDL "end zone" or target.

If the LDL is not too far from goal, options like ezetimibe, which reduces LDL around 20%, may suffice. The new agent bempedoic acid lowers LDL 17-24% and has demonstrated cardiovascular event reduction in a large outcomes trial in statin-intolerant patients. For larger LDL reductions around 50-60%, injectable PCSK9 inhibitor immunotherapy like evolocumab and alirocumab may be utilized. The recently approved siRNA inclisiran, while highly effective at lowering LDL, lacks outcomes data thus far.

Contraindications are minimal with these newer agents apart from hypersensitivity reactions. However, small creatinine elevations are expected with bempedoic acid due to mild renal effects, while inclisiran and the PCSK9 monoclonal antibodies are not affected by kidney or liver dysfunction given their targeted mechanisms.

In summary, newer non-statin agents provide varying degrees of additive LDL lowering, allowing clinicians to appropriately intensify therapy depending on just how far a patient's LDL level stands from their recommended treatment target. Ongoing assessment of changing cardiovascular risk helps determine the appropriate LDL "end zone" to guide medication selection.

Expert cardiologists discuss the recent clinical trials results of the CLEAR-OUTCOMES trial and thee sub analysis on the inflammatory marker hcCRP.  

Clinical Trial Results on Novel Nonstatins Agents.

The experts discuss the CLEAR Outcomes trial results for the newer cholesterol-lowering agent bempedoic acid in statin-intolerant patients. This 14,000-patient trial included a mix of primary and secondary prevention patients and demonstrated a significant reduction in 3-point major adverse cardiovascular events (MACE). While LDL lowering was modest, the MACE reduction aligned with expectations based on the degree of LDL lowering. Bempedoic acid also reduced inflammation, measured by hsCRP, without increasing diabetes risk, unlike statins.

There was additional analysis showing more benefit in the 30% of trial subjects who were high-risk primary prevention patients. Notably, there was a reduction in all-cause mortality for bempedoic acid in these patients. This reinforces the concept of a continuum of residual risk, where apparently healthy people can still be at high latent cardiovascular risk in the absence of cholesterol lowering therapy.

Beyond LDL, the experts emphasize assessing residual inflammatory risk with hsCRP, residual thrombotic risk, residual cholesterol risk as measured by triglycerides for icosapent ethyl therapy, and emerging risk markers like Lp(a). They advocate a personalized approach to matching specific therapies to a patient's dominant driver of residual risk. This more holistic, multi-pathway framework for risk reduction stands to optimize outcomes compared to focusing on LDL alone.

Dr. Kohli gives an overview of the mechanisms of action of non-statin agents for the management of hyperlipidemia.

Mechanism of Action of Nonstatin Therapies

The experts discuss additional lipid-lowering options beyond statins for those unable to tolerate statins or reach LDL cholesterol targets on statins alone. Long-used options include ezetimibe, which reduces intestinal cholesterol absorption, typically lowering LDL around 20%. The newer agent bempedoic acid is a prodrug activated in the liver that, like statins, reduces cholesterol production and increases LDL receptor activity. It lowers LDL around 17% on top of statins and 24% in statin-intolerant patients.

The PCSK9 inhibitor monoclonal antibodies evolocumab and alirocumab powerfully reduce LDL through improved LDL receptor recycling and clearance. LDL drops approximately 60% on these injectable agents, reaching under 55 mg/dL in over 80% by 4 weeks when added to statins. These antibodies have demonstrated safety, efficacy, and a “legacy effect” with earlier initiation conferring later cardiovascular risk reduction advantages.

In summary, the experts review current and emerging non-statin agents for treating high cholesterol, including those add-on or alternative therapies for statin intolerance. The PCSK9 inhibitors stand out given their potency, rapid onset of action, favorable tolerability, and most importantly, evidence demonstrating lower cardiovascular event rates with their early and continued use over the long-term. Taken together, these newer agents provide tools to intensify lipid lowering therapy quickly to reach lower LDL targets.


This summary was AI-generated and edited for clarity and 

Dr Kohli gives an overview of the mechanisms of action of non-statin agents for the management of hyperlipidemia.

Payal Kohli, MD, FACC

Articles