Issue: October 2020
Source: Healio Interviews
Disclosures: Jones reports he was on the scientific advisory board for Amgen, Esperion and Sanofi/Regeneron. Toth reports he is a consultant for Amarin, Amgen and Kowa and a speaker for Amarin, Amgen, Esperion and Kowa. Hawkins, Isaacs and Subramanian report no relevant financial disclosures.
October 16, 2020
11 min read

Lipid management options expand with novel drugs, new targets

Issue: October 2020
Source: Healio Interviews
Disclosures: Jones reports he was on the scientific advisory board for Amgen, Esperion and Sanofi/Regeneron. Toth reports he is a consultant for Amarin, Amgen and Kowa and a speaker for Amarin, Amgen, Esperion and Kowa. Hawkins, Isaacs and Subramanian report no relevant financial disclosures.
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Management of lipids and residual cardiovascular risk has been a growing concern in endocrinology, and new data in this area are encouraging.

Much emphasis has been placed on the use of therapies such as PCSK9 inhibitors, statins and ezetimibe to achieve target LDL levels. However, controlling LDL does not always control CVD risk, and because some patients are not able to achieve LDL and other targets on existing therapies, new options are needed.

“In the last 5 years, there has been a lot of change in lipidology,” Savitha Subramanian, MD, associate professor in the division of metabolism, endocrinology and nutrition and medical director of the lipid clinic at the University of Washington School of Medicine, told Endocrine Today. “With the availability of PCSK9 inhibitors in 2015, the landscape changed. Since then we have seen a big, game-changing trial with icosapent ethyl in 2019. Now we have bempedoic acid. It is a very exciting time in lipidology, simply because there are so many new therapies coming out and so many more options for management than we used to have.”

For adults with very high CVD risk, very low LDL levels are safe no matter how they are reduced, according to Savitha Subramanian, MD.

Photo by Nikhil Gopalakrishnan. Printed with permission.

In recent years, studies have demonstrated the effectiveness of agents such as icosapent ethyl (Vascepa, Amarin) and bempedoic acid (Nexletol, Esperion Therapeutics) in addressing residual risk, which led to FDA approval and potential benefit to people who may not respond to maximally tolerated statin therapy. Agents in development such as inclisiran (Novartis) have shown similar promise in early studies. Other research has demonstrated success of PCSK9 inhibitors as adjuncts to statin therapy.

Progress continues on development of agents to target other lipids.

“It’s quite astounding to watch the ideas and the changes,” Peter H. Jones, MD, medical director of the Houston Methodist Weight Management Center, director of the Lipid Metabolism and Atherosclerosis Clinic and associate professor of medicine at Baylor College of Medicine, and past president of the National Lipid Association, told Endocrine Today. “We are now identifying patients who are at high risk but have achieved LDL control. We now know from Mendelian randomization studies that triglyceride-rich lipoproteins, particularly remnant cholesterol and lipoprotein(a), are directly causative of atherosclerotic vascular events. The focus now is to come up with more effective therapies for these patients to lower triglyceride-rich lipoproteins and, potentially, lipoprotein(a).”

Lessons learned

In recent years, knowledge of how to manage lipids and residual CV risk has expanded, such as the importance of lowering apolipoprotein B-containing lipoproteins, which reduces risk in a short period. These insights were gained from the FOURIER trial of evolocumab (Repatha, Amgen) and the ODYSSEY OUTCOMES trial of alirocumab (Praluent, Sanofi/Regeneron).

An analysis of the ODYSSEY OUTCOMES trial presented at the American College of Cardiology Scientific Session in March 2019 demonstrated that corrected LDL reduction was the main driver for event reduction, responsible for 96% of event reduction in patients at the 25th percentile of baseline lipoprotein(a), 89% of event reduction at the 50th percentile and 73% of event reduction at the 75th percentile.

“What we have learned is if you have a very high-risk patient, as low as you can go with LDL is safe,” Subramanian said. “With the PCSK9 inhibitor studies, especially in FOURIER, there were people with LDLs in the single digits or in the undetectable range — 0 mg/dL. The amplitude, the degree of LDL lowering appears to be what is important, and not how you get to it.”

The 2018 Guideline on the Management of Blood Cholesterol from the American Heart Association, American College of Cardiology and 10 other societies released in 2017 recommended a stepped approach, including statins, ezetimibe and PCSK9 inhibitors, for patients with prior CVD at very high risk for another event. This guideline also recommended an LDL target of less than 70 mg/dL for certain high-risk patients, including those with multiple major atherosclerotic CVD events or one major atherosclerotic CVD event and several high-risk conditions.

Meredith A. Hawkins

Although statins remain the first option for LDL lowering, several new drugs have been developed in recent years and are FDA approved to offer more options for patients.

“There is a much greater push toward combination therapy than there ever was before,” Scott D. Isaacs, MD, FACE, FACP, chair of the Lipids and Cardiovascular Health Disease State Network of the American Association of Clinical Endocrinologists, medical director of Atlanta Endocrine Associates and adjunct assistant professor of medicine at Emory University School of Medicine, told Endocrine Today. “It used to be you had a choice between a high-dose statin or a low-dose statin, and that was it. These nonstatin options have been especially good not just for achieving LDL goals, but for the many people who have statin intolerance. Whether that is real or perceived, it is a definite barrier to achieving LDL goals.”

In October, AACE and the American College of Endocrinology released a Management of Dyslipidemia and Prevention of Cardiovascular Disease algorithm and consensus statement, incorporating newer data that were not available when the 2017 AACE lipid guideline was drafted. AACE established LDL cholesterol goals ranging from less than 55 mg/dL to less than 130 mg/dL, according to individual atherosclerotic CVD risk, based on a large body of evidence of numerous outcomes trials with statins, ezetimibe and PCSK9 inhibitors.

In a meta-analysis of 26 prospective statin trials involving approximately 170,000 participants by the Cholesterol Treatment Trialists group highlighted in the consensus statement, each 38 mg/dL reduction in LDL led to a 29% decrease in major vascular events (nonfatal myocardial infarction or atherosclerotic CVD death) when baseline LDL cholesterol was less than 77 mg/dL and a 37% reduction when baseline was less than 70 mg/dL.

“The findings from these trials consistently demonstrate that atherosclerotic CVD risk decreases with LDL cholesterol along a continuum, supporting a ‘lower is better’ approach,” the algorithm states.

New and existing treatments

Addressing residual risk for high-risk patients can be more complicated than other forms of risk.

“The biggest thing that has changed in lipidology the last few years has been our understanding of residual risk,” Isaacs said. “We have always known that patients — even patients that take statin medications — are not protected from CVD, especially those who already had CV events. We’ve seen a lowering of LDL targets and we are now realizing that even with all the guidelines out there right now, our LDL targets may not be low enough.”

Lowering LDL is a major treatment goal, but the question of how low to go remains.

Scott D. Isaacs

“I would turn that question and ask, ‘Why is it taking us so long to figure that out?’” Meredith A. Hawkins, MD, professor of endocrinology, the Harold and Muriel Block Chair in Medicine and director of the Global Diabetes Institute at Albert Einstein College of Medicine, told Endocrine Today. “What I speculate is that we are only just coming to appreciate the incredible genetic heterogeneity that contributes to atherosclerosis — so many polymorphisms in so many genes. It may be possible at some point, when we understand things a little bit better, to give patients their own, individualized ideal goal.”

A substantial component of residual risk is inadequate LDL cholesterol lowering in the large majority of patients, according to Peter P. Toth, MD, PhD, FAHA, FESC, FACC, director of preventive cardiology at CGH Medical Center in Sperling, Illinois; professor of clinical family and community medicine at University of Illinois College of Medicine in Peoria; professor of medicine at Michigan State University College of Osteopathic Medicine in East Lansing; and president of the American Society for Preventive Cardiology.

Toth, who said “ultra-low” LDL levels are safe with no apparent downsides, noted that the rapid expansion of therapeutic options has been helpful, especially for people who are statin intolerant.

“This is crucial, as over 50% of risk for CVD is attributable to lipids, on average,” Toth told Endocrine Today. “There are significant tolerability issues with the statins, and some patients have intolerance to other lipid-lowering medications as well. Being able to draw on therapeutic alternatives is critical if these patients are to be appropriately treated.”

Several agents approved and studied in recent years focus on patients who may not achieve LDL targets despite maximally tolerated statin therapy. Icosapent ethyl was approved by the FDA in December as an adjunctive therapy to reduce risk for CV events among adults with elevated triglyceride levels, based on results from the REDUCE-IT trial. It is the first drug approved by the FDA to reduce CV risk in patients with elevated triglycerides when added to maximally tolerated statin therapy.

“Eicosapentaenoic acid (EPA) in the form of icosapent ethyl at a high dose given to high-risk individuals designed to primarily lower triglycerides did provide substantial reduction in cardiovascular risk, even with very modest lowering of triglycerides,” Jones said. “This raises the question: Did the result come from lowering triglycerides or are there other mechanisms that EPA has to reduce events in patients with well-controlled LDL levels?”

Inclisiran, an investigational cholesterol-lowering therapy in the small-interfering RNA class that stops, at the source, the production of PCSK9, a critical protein in the regulation of LDL, has been shown to provide sustained LDL reductions with twice-yearly dosing, and may prove beneficial in patients who are are intolerant of LDL-lowering medications. The ORION-9, ORION-10 and ORION-11 trials were published in The New England Journal of Medicine in March. ORION-9 focused on patients with familial hypercholesterolemia (FH) and the other two included patients with atherosclerotic CVD or atherosclerotic CVD risk equivalents on maximally tolerated doses of LDL-lowering therapies.

“Inclisiran provides an exciting new approach to PCSK9 inhibition, especially since it can be dosed according to a 6-month schedule,” Toth said.

Bempedoic acid is another option for patients who are statin-intolerant, which the FDA approved in February for reducing LDL as an adjunct to diet and maximally tolerated statin therapy in patients with heterozygous FH or established atherosclerotic CVD. Shortly thereafter, the agency approved a bempedoic acid/ezetimibe combination (Nexlizet, Esperion Therapeutics) to lower LDL as an adjunct to diet and maximally tolerated statin therapy in the same patient population.

Peter P. Toth

“There are more people who cannot take statins than actually identified, so I am prescribing bempedoic acid now that it is available,” Subramanian said. “It is a good option, even though we don’t have a CV outcomes trial for it. But if it lowers LDL, there is a good chance there may be some benefit from a CV standpoint.”

Research, drugs in development

Areas that require more focus remain. One example is more research on how to lower triglycerides in high-risk patients, including defining the role of inhibiting apolipoprotein C-III, angiopoietin-like protein 3 (ANGPTL3) and lipoprotein(a).

“While triglyceride-rich lipoproteins are causative of atherosclerosis, most of the trials that focused on treating high triglycerides have not utilized the newer or available therapies out there,” Jones said. “Older drugs like niacin and fibrates lowered triglycerides, but the trials with them didn’t show benefit in statin-treated patients. Now there is icosapent ethyl, which does lower triglycerides a little bit, but its outcome benefit seems to be beyond just triglyceride lowering.”

Another focus is targeted drugs to address lipoprotein(a) beyond PCSK9 inhibitors. Antisense oligonucleotide therapy is in development to reduce circulating lipoprotein(a) levels (AKCEA-APO(a)-LRx; TQJ230, Akcea/Ionis/Novartis), ApoC-III (AKCEA-APOCIII-LRx, Akcea/Ionis) and triglycerides (AKCEA-ANGPTL3-LRx, Akcea/Ionis).

The PROMINENT trial is assessing pemafibrate (Kowa) to determine whether the novel selective peroxisome proliferator-activated receptor (PPAR)-alpha modulator can improve CV outcomes by reducing triglycerides in patients with diabetes.

“The inhibition of angiopoietin-like protein 3 with a monoclonal antibody appears to be a promising approach for the management of hypertriglyceridemia,” Toth said.

Inclisiran is being studied in several trials, including ORION-8, a long-term extension study assessing the safety, efficacy and tolerability of long-term dosing of the drug in patients with atherosclerotic CVD, heterozygous or homozygous FH, elevated LDL despite maximally tolerated therapies and risk equivalents of atherosclerotic CVD such as diabetes. The ORION-4 trial was designed to assess inclisiran for reduction of CV outcomes in 15,000 participants with CVD; however, enrollment has been paused due to COVID-19.

One area of great potential is use of SGLT2 inhibitors, traditionally considered diabetes drugs, to reduce CVD risk in patients without diabetes. Notably, the DAPA-HF trial found that dapagliflozin (Farxiga, AstraZeneca) reduced risk for worsening HF and CV death in patients with HF with reduced ejection fraction regardless of whether they had diabetes; the FDA in May approved dapagliflozin for reduction of risk for CV death and HF hospitalization in patients with HF with reduced ejection fraction with or without diabetes.

In August, data from the EMPEROR-Reduced trial presented at the virtual European Society of Cardiology Congress showed that empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) improved CV and renal outcomes in patients with HFrEF regardless of diabetes status.

“SGLT2 inhibitors are now hitting the mainstream and have literally exploded in the last year, with all of the clinical trial data,” Subramanian said. “Yes, they have a role in people with diabetes; yes, they have a role in people without diabetes for CV risk reduction, especially from a heart failure standpoint, as the DAPA-HF study showed. SGLT2 inhibitors are not going away. They have become antihyperglycemic drugs that we are probably going to see used more from a CV and renal standpoint. Patient selection and counseling are important, because of the side effect profile.”

Evolving field

The field of lipidology has experienced a shift in focus from increasing HDL, which was not shown to impact patient outcomes, back to LDL and now expanding to lowering triglyceride-rich lipoproteins.

Peter H. Jones

“We used to talk about how we had HDL cholesterol as a target, and now we know that raising HDL does not lower risk,” Isaacs said. “Now there is a greater push to target triglycerides and lipoprotein(a), and statin medications do not much for either one of those two areas.”

Nonlipid factors for CVD — which likely make up about 50% of the risk — are also important to manage, Isaacs said.

“Apart from genetics, factors such as obesity, hypertension, diabetes and inflammation have helped the endocrinologist, the lipidologist and cardiologist have a more comprehensive approach to CVD and lowering risk, as opposed to just treating numbers,” Isaacs said.

Cross-specialty collaboration

Addressing lipids and residual risk in patients at high CVD risk requires cross-collaboration between several specialties, including lipidologists, cardiologists, endocrinologists and primary care providers.

“Let’s take a person with diabetes who has a lipid disorder,” Subramanian said. “Yes, they’re seeing a preventive cardiologist for their heart issues, but they want to start them on an SGLT2 inhibitor. If the person is taking insulin, or even if the patient is prescribed an oral agent like a sulfonylurea, you really must be cautious. You must educate the patient that they can develop hypoglycemia and make appropriate medication adjustments. Unless there is a special fellowship program that incorporates cardiology, diabetes and nephrology — which doesn’t exist so far — I don’t think every specialist has all the skill sets. You need a collaborative clinic set-up to treat people.”

Patients expect such collaboration, but getting it will be a challenge, Jones said.

“For example, since SGLT2 inhibitors could be used to modify residual risk, endocrinologists will need to collaborate with cardiologists about using these drugs to modify the risk for HF and death, and the same goes for lipidologists who take over diabetes management in these patients,” Jones said.