LDL—How Low to Go In People With Diabetes?

Compelling data supports achieving a very low LDL-Cholesterol with combined statin-evolocumab therapy to reduce further risk of cardiovascular events, which presents important implications for people with diabetes.

With Robert Giugliano, MD, and Priyathama Vellanki, MD

Reducing LDL-cholesterol to less than 30 mg/dL with a combination of a statin and the PCSK9 inhibitor, evolocumab (Repatha), produced favorable clinical outcomes in patients at high risk for cardiovascular disease (CVD), including significant reductions in myocardial infarctions (MI) and stroke,1 according to findings presented at the American College of Cardiology annual scientific sessions, and simultaneously published in the New England Journal of Medicine.2

Among the more than 27,000 patients enrolled in the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial,2  LDL-C was lowered 59%, but more telling was a 15% reduction in the 5-point composite of MI, stroke, hospitalization for angina, revascularization, and mortality.

CVD Risk Points to Need for Very Low LDL-Cholesterol 

The study findings validated the lipid recommendation of the American Association of Clinical Endocrinologists (AACE),3 to treat patients who fell into the extreme risk category for CVD to achieve LDL levels of less than 55 mg/dl, published earlier this year in the AACE Lipids Guidelines Update.

Adding evolocumab to a statin will reduce future heart attacks by drastically lowing LDL cholesterol.

In the FOURIER trial, evolocumab was typically given in combination with a background statin, said Robert Giugliano, MD, a professor of medicine at Harvard Medical School who was on the executive committee for the study, and coauthor of the journal paper. "The drug compared to placebo reduced LDL to a very low level, an average of 30 mg/dL, and reduced the risk of future cardiovascular events," Dr. Giugliano told Endocrine Web.

''The primary endpoint was a five-way composite," Dr. Giugliano said. These included cardiovascular death, MI, stroke, hospitalization for unstable angina or coronary revascularization. The evolocumab compared to placebo significantly reduced the risk of the primary endpoint, 9.8% versus 11.3% (HR 0.85, 95% CI, 0.79 to 0.92, P<0.001).2

The key secondary efficacy endpoint was a composite of CV death, MI or stroke. ''The risk of MI was reduced 27%," Dr. Giugliano said, and ''the risk of stroke was reduced by 21%."  When evaluated individually, evolocumab had no observed effect on cardiovascular death. The follow-up was 2.2 years.

For these high-risk patients, ''we think the new target ought to be even lower than 55," Dr. Giugliano told Endocrine Web. And this was achieved safely and consistently regardless of statin, age, sex, type of CVD, or evolocumab-dosing.

Take-Away for Endocrinologists

These findings have important implications for endocrinologists, and others treating those with diabetes (DM), Dr. Giugliano said. More than a third of the patients (37%) in the FOURIER trial had DM, in equal proportions across both groups.

The researchers found no significant differences in adverse events between groups, including new-onset DM and neurocognitive events, with the exception of injection site reactions, in which there were more for those receiving evolocumab (2.1% versus 1.6%).2 The findings indicated no differences in new-onset diabetes should be reassuring, he said, as previous research has triggered some concerns about an association between statins and the development of diabetes.

The ongoing research has changed his thinking, Dr. Giugliano said.  He moved from 70 mg/dL as being acceptable to aiming for under 50 mg/dL, in line with AACE guideline for patients with recent coronary events, he said to EndocrineWeb. Now, he believes the new findings suggest that maybe below 30 mg/dL is necessary.

An Endocrinologist's Perspective

The findings offer promise of avoiding an increase in new-onset DM, which is reassuring, said Priyathama Vellanki, MD, assistant professor of medicine at Emory University.

Based on the outcomes achieved in the FOURIER trial, Dr. Vellanki told EndocrineWeb that her approach would be for ''patients with diabetes we should still start with a statin, as firstline, and further refine who would benefit from the addition of evolocumab. I would consider this drug for LDL lowering more if they are still having cardiovascular events on the maximum dose of statins."

A patient who is obese, but without diabetes or cardiovascular disease, or otherwise at high risk, would not have a need for the evolocumab, she said, rather "I would have them focus on weight control to avoid developing diabetes or CVD."

It's important to remember that the FOURIER trial is looking at secondary prevention, she said. The findings are likely to trigger a reevaluation of guidelines by the American Diabetes Association, the Endocrine Society, and other professional organizations, she said.

Features of the FOURIER Trial

The researchers randomized 27,564 patients who had diagnosed atherosclerosis and an LDL-C level of at least 70 mg/dL despite taking a statin to receive either evolocumab or placebo. Treated patients received either a 140 mg injection dose of evolocumab every 2 weeks, or a monthly dose of 420 mg.1,2 The placebo group received similarly timed subcutaneous injections.

The mean age of these patients was 63 years, and 81.1% had a history of MI, while 19.4% had a history of nonhemorrhagic stroke and 13.2% peripheral artery disease that was symptomatic. At baseline, 69.3% were on high-dose statins in line with American College of Cardiology and American Heart Association joint guidelines.2

Evolocumab, like other PCSK9 inhibitors, is known to dramatically reduce LDL-C levels, by attaching to the LDL receptors in the liver. The FOURIER researchers set out to evaluate was the effect of the drug on cardiovascular events, which had not been certain.

At the 48-week mark, the least-squares mean percentage reduction in LDL cholesterol with evolocumab went from a median baseline of 92 mg to 30 mg (P<0.001), to achieve the 59% reduction over placebo.

Funding for this trial was provided by Amgen, and Dr. Giugliano has  consulted with Amgen.

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