Lipid Management, Statins, and New Therapies on the Horizon

June 15, 2015
Mary K. Caffrey

Evidence-Based Diabetes Management, Patient Centered Diabetes Care 2015, Volume 21, Issue SP9

Statins have been the mainstay of LDL cholesterol management for 20 years, but can the PCSK9 inhibitors do more for some patients?

To the degree that diabetes management involves balance, the same can be said of lipid management. At Patient-Centered Diabetes Care 2015, attendees heard from Om P. Ganda, MD, director of the Lipid Clinic at Joslin Diabetes Center, as he explained how elevated cholesterol levels cause cardiovascular (CV) disease, and the relationship between these conditions and diabetes.

In his April 17, 2015, presentation, “Finding the Balance in Lipid Management,” Ganda first explained how problems with low-density lipoprotein (LDL), or “bad,” cholesterol can start at an early age and build up over time, which is why clinicians who treat children are so worried about trends they see.

Too much LDL cholesterol can trigger atherogenesis—development of plaque in arterial walls. This is what creates a blockage and ultimately causes a heart attack or stroke.

“It begins very early on, so that depending upon how high your cholesterol is, it is a cumulative effect of the level of cholesterol and the duration of hypercholesterolemia,” Ganda said, referring to the condition of high levels of cholesterol in the blood.

For 20 years, statins have been the therapeutic workhorse in treating elevated LDL cholesterol, and there’s plenty of evidence that they work, Ganda said. “We have had many very good, long-term, very large statin trials, which have proved beyond any doubt that this is one class of drugs that actually saves lives and prevents cardiovascular disease,” he said. However, some patients with poor diet or poor medication adherence cannot get their cholesterol levels where they should be, “particularly patients with diabetes, who have a very high risk of cardiovascular disease.”

Lancet

1

Ganda cited a meta-analysis of 21 tri- als involving 170,000 patients published in , which found that for every 1 mmol/liter reduction in LDL cholesterol, there was a 20% to 25% reduction in major CV end points, including stroke.

Lancet

And, increasing the intensity of therapy offers benefits for patients who can tolerate it: the analysis found an additional reduction of 20% to 25% in CV end points when patients transitioned from less intensive to more intensive statin therapy.

Evidence-Based Diabetes Management,

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As Ganda explained, there was little debate about recommendations that patients with existing CV disease continue therapy, or that those older than 75 years with existing comorbidities take a moderate intensity statin.

Then, there’s the 3 primary prevention groups,” he said. Here there was debate, and Ganda explained the guidelines and their relationship with the CV risk calculator:

Those with LDL cholesterol ≥ 190 mg/ dL should be treated with high-intensity statins to get their LDL levels to 50% below the baseline.

Persons with type 1 or type 2 diabetes mellitus, aged between 40 and 75 years, should receive moderate statin therapy. However, those whose 10- year risk on the CV calculator is ≥7.5% should use high-intensity therapy.

Among persons without diabetes, those with a 10-year risk ≥7.5% should consider statin therapy of at least moderate intensity.How do you define statin therapy as intensive or non-intensive?” Ganda asked. He described doses of statins based on what was used in various clinical trials, but acknowledged there would be differences of opinion. Response to statin therapy is very different with each patient, depending on how well that person is doing with lifestyle changes and other

The accumulating evidence propelled new guidelines from the American College of Cardiology and the American Heart Association in late 2013, although they stirred controversy. As reported by there were complaints about a new CV risk calculator, designed to estimate a person’s 10-year risk of a CV event. Critics said it was too age-driven and, if followed precisely, would result in too many people taking statins.factors. In 1 study, Ganda said, there were 45 different variations in plasma concentrations of statins among the patients.

He addressed the controversy over the risk calculator and how many patients it captures. “Is there an overestimation of risk because it is so guided by age? That’s an important question to consider. Once again, individualizing therapy and looking at other risk factors becomes an important issue.”

3 The excitement now, he said, is with the PCSK9 inhibitors, an injectable drug taken once or twice a month that promises previously unseen levels of cholesterol reduction; more recently, the drug class recently has been shown to reduce CV risk as well. Ganda walked the attendees through how the drug works: PCSK9 is a very important enzyme, a protease really, that gets into the inside of the cell with the LDL particle through the LDL receptor. Basically, when the LDL gets into the cell, it not only degrades the LDL itself, but also the LDL receptor is degraded through the enzyme PCSK9.”

In the past year, the National Lipid Association has produced guidelines that put more emphasis on a lack of high-density lipoprotein (HDL), or “good” cholesterol. No matter which guideline is used, when treating individual patients, some will not be able to tolerate statins. Also, there is the concern that statins can cause diabetes. But Ganda put that in perspective. “If you treat 200 patients with statin therapy over 5 years, you might get 1 new case of diabetes over and above what was going to happen,” he said. “But at the same time, you will prevent 5 new [CV] events in these patients.” Ganda also reviewed the IMPROVE-IT trial results, which were reported in November 2014 at the annual meeting of the American Heart Association. This involved the drug ezetimibe, marketed as Zetia, a non-statin used to treat LDL cholesterol. Long-term results found that when added to simvastatin, ezetimibe brought LDL cholesterol down 15% to 20%, and there was a 6.4% reduction in CV events. “For the first time in this trial, they were able to show that there was a modest but significant reduction in cardiovascular end points”

The mechanism was discovered almost by accident, when patients who lacked expression of the PCSK9 enzyme were found to have very low cholesterol and much lower risk of CV events. The thinking was that if the enzyme could be blocked, a powerful cholesterol fighter would be created.

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Two such drugs are near the end of the FDA review process: evolocumab, from Amgen, and alirocumab, from Sanofi-Regeneron, face deadlines for approval this summer.Trials have shown the drugs lower LDL cholesterol in the range of 60%. In some trials with evolocumab, patients achieved LDL levels as low as 25 mg/dL, Ganda said.

“The question that I would like to propose at this point is, how low to go? Do we really need to go that low? Will the result be further reduction in the cardiovascular end point?” he asked.

And the other question: who should get this new therapy, given its anticipated five-figure cost? Patients who are extremely statin-intolerant “would be the number one choice,” Ganda said. “There will have to be certain guidelines set as to which patients should be allowed to have this treatment.”

References

Lancet.

1. Cholesterol Treatment Trials Collaboration. Ef- ficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. 2010; 376(9753):1670-1681.

2.

Smith A. Understanding the role of big data in the CV risk calculator controversy.

Am J Manag Care.

2014;20(SP1):SP22-SP23.

3.

O’Riordan M. IMPROVE-IT: “Modest” benefit when adding ezetimibe to statins in post-ACS patients. Medscape website. http://www.medscape.com/ viewarticle/835030. Published November 21, 2014. Accessed May 21, 2015.

4.

The American Journal of Managed Care

Caffrey MK. Review touts benefits of new choles- terol drugs, but editorial calls for cautious enthusi- asm. website. http://www.ajmc.com/focus-of-the-week/0415/ Review-Touts-Benefits-of-New-Cholesterol-Drugs- But-Editorial-Calls-for-Cautious-Enthusiasm. Pub- lished April 28, 2015. Accessed May 21, 2015.