Novel drugs, new targets expand options for lipid management
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Management of lipids and residual CV risk has been a primary focus in cardiology for decades, and new data in this area are encouraging. Much emphasis has been placed on the use of therapies including PCSK9 inhibitors, statins and ezetimibe to achieve target LDL levels. But 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 recent years, studies have demonstrated the effectiveness of new 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 Cardiology 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 Lp(a), 89% of event reduction at the 50th percentile and 73% of event reduction at the 75th percentile.
“We’ve confirmed further LDL lowering is a good thing and that achieving low LDL is safe, which has been a concern in some practitioners’ minds about possible adverse effects,” Jones said.
The 2018 Guideline on the Management of Blood Cholesterol from the AHA, ACC and 10 other societies recommended a stepped approach including statins, ezetimibe and PCSK9 inhibitors in 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 ASCVD event and several high-risk conditions.
“In very high-risk patients, if the LDL cholesterol was over 70 mg/dL, you need to intensify statin therapy and consider adding a nonstatin to get LDL to a lower level. That provides benefits in regard to reducing cardiovascular events and slowing the progression of or enhancing the regression of coronary atherosclerosis,” Christie M. Ballantyne, MD, professor and chief of cardiology at Baylor College of Medicine in Houston, told Cardiology Today.
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.
“Statins are an ‘iconic’ drug class and have been the cornerstone of addressing dyslipidemia for the past 3 decades,” Pam R. Taub, MD, FACC, director of the Step Family Cardiac Wellness and Rehabilitation Center and associate professor of medicine at University California, San Diego, said in an interview. “New classes of drugs have been introduced, and have given the clinician more tools to address dyslipidemia.”
New and existing treatments
Addressing residual risk in high-risk patients can be more complicated than other forms of risk.
“We have learned that residual risk is very complex and that there are many facets to it,” Taub said.
Lowering LDL is a major treatment goal, but the question of how low to go remains.
“When it comes to LDL-C, lower is better, but lowest is best,” 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-elect of the American Society for Preventive Cardiology, said in an interview. “A significant component of residual risk is inadequate LDL-C lowering in the large majority of patients. Ultra-low LDL-C is safe with no apparent downside.”
Toth said the rapid expansion of therapeutic options (See Table below) 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,” he said. “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 mainly 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 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 ASCVD or ASCVD 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. “The ORION trial demonstrates significant efficacy for LDL-C reduction and safety. It will be exciting to see how inclisiran impacts CV outcomes when used in combination with a statin.”
Bempedoic acid is another option for patients who are statin-intolerant. The FDA approved it in February for reducing LDL as an adjunct to diet and maximally tolerated statin therapy in patients with heterozygous FH or established ASCVD. 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.
“Bempedoic acid monotherapy or used in combination with ezetimibe or a statin provides a much-needed additional member of our pharmacologic armamentarium, especially for statin-intolerant patients,” Toth said.
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 Lp(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 Lp(a) beyond PCSK9 inhibitors. Antisense oligonucleotide therapy is in development to reduce circulating Lp(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.
Volanesorsen (Waylivra, Akcea), an antisense oligonucleotide inhibitor of ApoC-III, lowered triglycerides by 77% at 3 months in patients with familial chylomicronemia syndrome in the APPROACH trial, but was not approved by the FDA. However, volanesorsen has been approved for use in the European Union. In the meantime, Akcea has an early access program to expand access to the drug for up to 100 patients with familial chylomicronemia syndrome.
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 ASCVD, heterozygous or homozygous FH, elevated LDL despite maximally tolerated therapies and risk equivalents of ASCVD such as diabetes. The ORION-4 trial, which is currently recruiting, will assess inclisiran for reduction of CV outcomes in patients with CVD.
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 HFrEF with or without diabetes. (Read more here.)
“SGLT2 inhibitors, and perhaps GLP-1receptor agonists, that reduce both CV and heart failure events along with weight loss, and that work in diabetic and nondiabetic patients are likely to be blockbusters,” Jennifer G. Robinson, MD, professor in the department of epidemiology and director of the Preventive Intervention Center at the University of Iowa College of Public Health, said in an interview. “They may be much bigger than any new novel lipid agents.”
“It’s a very dynamic area,” Ballantyne said. “There’s a lot happening, but I can assure you, the future will be equally exciting, if not more exciting.”
Evolving field of lipidology
Lipidology continues to evolve as a field with increasing recognition as a subspecialty.
“The therapies in development continue to leverage highly specific aspects of lipid and lipoprotein metabolism. Knowing when and how to use these new therapies requires additional expertise,” Toth said in an interview.
Another area of focus is FH identification and treatment.
“Familial hypercholesterolemia is the most common fatal genetic disorder in the world that is curable. This is such a no-brainer. It’s truly a call to action for people — not just lipidologists, but primary care doctors, cardiologists, endocrinologists, pediatricians — to screen for familial hypercholesterolemia,” Robinson told Cardiology Today.
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. “We’ve come back to triglycerides, which we thought were a risk 20 years ago; however, we got sidetracked on the HDL cholesterol story. Now we understand that cholesterol and triglyceride-rich lipoproteins are causative of atherosclerosis, and that newer treatments that focus on lowering triglycerides in higher-risk patients could be very beneficial,” Jones said.
‘Multidisciplinary approach is important’
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.
“Patients expect that collaboration, but getting it to occur is going to 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.
Many institutions and practices are already implementing this multidisciplinary approach.
“A multidisciplinary approach is important, given the increasing complexity of lipid management and its associated comorbidities,” Taub said. “At my institution and in many parts of the country, ‘cardiometabolic clinics’ are being formed to address this need.”
Cardiometabolic clinics typically include cardiologists, endocrinologists, pharmacists and dietitians that provide comprehensive care for patients with complex cardiometabolic disease; for example, a patient with CAD, hyperlipidemia and type 2 diabetes, Taub said.
Communication with all involved specialists is key.
“We need to communicate better who really needs these drugs the most,” Robinson said. “That goes back to which patients are most likely to have a large meaningful benefit from adding these drugs, and then really press the system to make sure those patients have access.”
- References:
- Bittner V, et al. Featured Clinical Research III. Presented at: American College of Cardiology Scientific Session; March 16-18, 2019; New Orleans.
- ClinicalTrials.gov. A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease (ORION-4). Available at: www.clinicaltrials.gov/ct2/show/NCT03705234. Accessed May 15, 2020.
- ClinicalTrials.gov. Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides In Patients With Diabetes. Available at: www.clinicaltrials.gov/ct2/show/NCT03071692. Accessed May 15, 2020.
- ClinicalTrials.gov. Trial to Assess the Effect of Long-Term Dosing of Inclisiran in Subjects with High CV Risk and Elevated LDL-C (ORION-8). Available at: www.clinicaltrials.gov/ct2/show/NCT03814187. Accessed May 15, 2020.
- ClinicalTrials.gov. Volanesorsen Early Access Program for Patients With Familial Chylomicronemia Syndrome. Available at: www.clinicaltrials.gov/ct2/show/NCT03544060. Accessed May 15, 2020.
- Grundy SM, et al. Circulation. 2018;doi:10.1161/CIR.0000000000000625.
- McMurray JJV, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1911303.
- Raal FJ, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa1913805.
- Ray KK, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa1912387.
- Sabatine MS, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615664.
- Schwartz GG, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1801174.
- Witzum JL, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1715944.
- For more information:
- Christie M. Ballantyne, MD, can be reached at cmb@bcm.edu; Twitter: @cballantynemd.
- Peter H. Jones, MD, can be reached at jones@bcm.edu.
- Jennifer G. Robinson, MD, can be reached at jennifer-g-robinson@uiowa.edu.
- Pam R. Taub, MD, FACC, can be reached at ptaub@ucsd.edu.
- Peter P. Toth, MD, PhD, FAHA, FESC, FACC, can be reached at peter.toth@cghmc.com.
Editor’s Note: This article was updated on June 22, 2020 to modify the description of inclisiran at the request of Novartis.
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