ENDO Online 2020: The Endocrine Society's Virtual Meeting:

Moving from High Risk to Low Risk Prevention of CVD Outcomes

with Robert P. Giugliano, MD, Daniel Soffer, MD, and Priyathama Vellanki, MD

The FOURIER Trial (Further Cardiovascular Outcomes Research of Evolocumab in subjects with Elevated Risk) was the first ''event" study to demonstrate that a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, evolocumab (Repatha), has the potential to induce a significant reduction in serum LDL-cholesterol that subsequently leads to lower cardiovascular morbidity and mortality.1 Evolocumab is being prescribed for patients with a higher residual cardiovascular risk who are already on statin therapy.1

Clinical trial initiated to assess potential for evolocumab (PCSK9) as primary prevention of CVD in diabetic patients. Treating to reduce cardiovascular disease outcomes in patients with type 2 diabetes advances from focus on high to low risk patients. Photo: Shidlovski @ iStock

New Trial to Evaluate Potential to Effect Low Risk CVD 

At the 17th annual World Congress on Insulin Resistance Diabetes and Cardiovascular Disease (WCIRDC), Robert P. Giugliano, MD, SM, FACC, FAHA, clinical cardiologist at Brigham & Women's Hospital and professor of medicine at Harvard Medical School, reviewed the evidence of secondary prevention of CV events with Repatha and then discussed primary prevention, detailing the goals and timeline for the newly-launched VESALIUS-CV  trial.

"We've been enrolling since June," Dr. Guigliono told attendees, and setting our sights on primary prevention as the outcomes goal is crucial.  We anticipate having at least 13,000 high risk patients with atherosclerosis or diabetes with no history of prior myocardial infarction (MI) or stroke randomized to receive either evolocumab or placebo for up to five years.

They all have a high low-density lipoprotein-cholesterol (LDL-c) or non-HDL-C levels despite intensive lipid-lowering therapy,1 he said , "but it's important that they [participants] have no prior history of primary cardiovascular events."   

Benefits of CVD 2o Prevention in Diabetes:  FOURIER  

For the sake of comparison, the trial design of FOURIER was to follow 27,564 patients with established cardiovascular disease (CVD) who were deemed stable but at high risk to receive evolocumab or a placebo for up to five years. They had to have had a prior MI, stroke, or symptomatic peripheral artery disease. All participants were receiving moderate or high intensity statin therapy for LDL-C at or above 70 mg/dL (1.8 mmol/L) or non-HDL-c at or above 100 mg/dL (2.6 mmol/L).2

Patients were randomized to evolocumab 140 mg every 2 weeks or 420 mg QM or placebo group, and the median follow-up was 2.2 years.

The findings of this PCSK9 inhibitor demonstrated that it is safe, well-tolerated, and achieved a significant decrease in LDL-c of 59%, down to a median of 30 md/dl (P < 0.00001). In comparing evolocumab to placebo, the treatment group benefited from a risk reduction in the primary end point (composite of cardiovascular death, MI, stroke, hospitalization for unstable angina or coronary revascularization) by 15% (HR, 0.85, CI, 0.79 to 0.92).3

Analysis of the 11,031 patients with diabetes and 16,533 without found that evolocumab reduced CV outcomes consistently with and without diabetes at baseline. For the primary composite endpoint, the HRs were 0.83 (P = 0.0008) for those with disease and 0.87 (P = 0.0052) for those without diabetes.4

Vesalius-CV Trial to Assess for Primary Prevention 

The Vesalius CV Trial, a multinational clinical outcomes study of 13,000 high risk patients with atherosclerosis or diabetes but no prior history of MI or stroke for the prevention of a first cardiovascular event.1 This cohort will be randomized to receive either evolocumab (140 mg, twice weekly) or placebo. The trial will be event-driven, Dr. Giugliano said, with a minimum of four or more years of follow-up.

The dual primary composite endpoints are—coronary heart disease death, MI or ischemic stroke and coronary heart disease death, MI, ischemic stroke or ischemia-driven revascularization.1

These are the key inclusion criteria, Dr. Giugliano said, of which all four parameters had to be met to participate:

  • Ages 50 to 79 for men, 55 to 79 for women
  • An LDL-C of 100 mg/dL or higher or non-HDL-c of 130 mg/dL or higher on optimized lipid-lowering therapy.
  • Evidence of 1 or more: CAD without prior MI, cerebrovascular disease without prior stroke, peripheral arterial disease, diabetes mellitus.
  • At least 1 high-risk feature.1

"The trial began enrolling patients in June 2019," Dr. Giugliano said"and the enrollment phase is projected to last for about 12-15 months. The minimum follow-up is four years for the last patient enrolled, so we foresee the trial extending out to the summer of 2024." "There is no plan to release interim data to anyone (myself included), except for the Data Safety Monitoring Board,'' he said.

Who is the ideal candidate for primary prevention? "Patients with advanced diabetes, an LDL more than 100 mg/DL and who have a higher risk for atherosclerotic events. For example, with a family history of premature CHD," Dr. Giugliano told EndocrineWeb.

The VESALIUS-CV  is part of Amgen's PROFICIO (Program to Reduce LDL-C and cardiovascular Outcomes Following Inhibition of PCSK9 In different pOpulations) program,initiated to investigate the impact of   evolocumab on CVD across multiple populations. To date, the program encompasses 36 trials of more than 38,000 patients globally.

Other Potential PSCK9 Inhibitors Are Available But Non Validated for CVD

Alirocumab (Praluent), a human monoclonal antibody given by injection, is on the market already. Another PCSK9 inhibitor, inclisiran, is in development; it inhibits this pathway by interfering with RNA synthesis, and is administered twice yearly by injection. "Neither of these two therapies have a cardiovascular outcomes study data in lower-risk patients or in primary prevention as in VESALIUS-CV," Dr. Giugliano said.

VESALIUS-CV—Reducing Diabetes/CVD Risk Sooner?

In commenting on his takeaway from this presentation, Daniel Soffer, MD, FNLA, a clinical associate professor of medicine at the Perelman School of Medicine, University of Pennsylvania, and a local investigator with the VESALIUS-CV Trial,challenged the position that this is a primary prevention outcomes study. 

"The medical community should stop using the terms primary prevention and secondary prevention," he said, when referring to the group being enrolled. While the participants were precluded if they had had an MI or stroke, they still had atherosclerosis, Dr. Soffer told EndocrineWeb, and if a patient has atherosclerosis, s/he is already at risk, and ''that is what we are treating them for—Our priority is to prevent the first event—to keep them from having an MI or stroke, and to slow progression of atherosclerosis so it stops building up over time."

That said, the review of the FOURIER findings was instructive because it points to the data (together with findings from the ODYSSEY study) that led to changes in clinical practice and updated cholesterol guideline,1,6 according to Dr. Soffer. "FOURIER laid the groundwork for adding PCSK9 inhibitors even in patients who are taking high intensity statins to achieve a reduced CVD risk profile for secondary prevention outcomes."

As such, the next logical step, he said, is to find out what this PCSK9 inhibitor might do for individuals who have not yet had a CV event. In so much as this new study is looking at a lower risk population, these patients still have established atherosclerosis, so it is not accurate to consider this as a “primary prevention” trial. Informative yes, but not truly offering full out disease inhibition.

Will the results change the course of practice? "Clinicians are already using PCSK9 inhibitors for anyone who has coronary artery disease," Dr. Soffer said. For that reason, it might be challenging to enroll people in a true primary prevention trial as patients who are already taking this monoclonal antibody would probably see little personal benefit from joining a clinical trial.

Another endocrine specialist, Priyathama Vellanki, MD, assistant professor of medicine at Emory University School of Medicine, agreed with Dr. Soffer. The patients eligible for enrollment in the VESALIUS-CV Trial, she said: ''are not really at low risk,'' so we should not view the findings as informing us of the potential for primary prevention.

What will be important from the data derived from this trial, she told EndocrineWeb, is our ability to evaluate the absolute risk reduction to see how it translates to real life outcomes.

Dr. Giugliano reports research grant support through Brigham and Women's Hospital from Amgen, Daiichi Sankyo and Merck, and CME program, scientific advisory boards and consulting for Akcea,  Amarin, Amgen, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, Merck and Pfizer. Dr. Soffer is on the advisory boards for Amgen, Medicure and The Medicines Company. He has clinical trial support from Amgen, Akcea Therapeuics Astra-Zeneca, Novartis, Regeneron, REgenXBio/NIH. Dr. Vellanki has no relevant financial disclosures.

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