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Lowering LDL, regardless of method, can reduce CV risk in patients with diabetes
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PHILADELPHIA — LDL plays an important role in cardiometabolic conditions in patients with diabetes, according to a presentation at the Heart and Diabetes Medical Conference. 
Henry N. Ginsberg, MD, director emeritus of the Irving Institute, Herbert and Florence Irving Professor of Medicine and co-director of the Pilot and Collaborative Studies Resource at Columbia University Medical Center, discussed the benefits of lowering LDL, as shown in various studies.
Although the advantage of lowering LDL has been proven, there are still clinicians that deny its impact, especially in Europe, Ginsberg said.
Cholesterol-carrying lipoproteins are one of the main causes of atherosclerosis, according to the presentation.
“It’s an inflammatory disease once it’s initiated, but without increased levels of [apolipoprotein B]-containing lipoproteins, LDL being the most abundant, without them being transported through the endothelium in the coronary arteries or other vascular beds that are important to atherosclerosis, you don’t get atherosclerosis,” Ginsberg said.
Observational data from Japan more than 30 years ago showed the importance of LDL as the initiating factor for atherosclerosis. Ginsberg said these studies included patients who had LDL levels in the 60 mg/dL to 70 mg/dL range and although they smoked heavily, and had strokes from hypertension, they did not have coronary disease.
Measuring apoB may add to the more typical measurements of plasma lipids like LDL in the detection of risk for atherosclerosis before it begins, he said.
“These apoB lipoproteins are atherogenic, … and however you want to measure it will be helpful, but my choice is to have you measure apoB levels,” Ginsberg said. “Plasma apoB is a very well standardized measurement.”
Studies have shown that LDL is not only important, but also causal, according to the presentation. Prospective cohort studies linked elevated LDL levels and future CVD. Randomized controlled trials have demonstrated its causality by proving that reducing LDL with a statin reduced the risk for major atherosclerotic CVD events. Prospective cohort studies linked elevated LDL levels and future CVD.
Mendelian randomization studies showed the continuous association between absolute change in LDL level based on genetic variation and lifetime risk for CHD, according to the presentation. However, the genetic data suggest that lowering LDL early in life, even if it’s a smaller reduction, can have a greater effect on the lifelong burden of cholesterol compared with lowering LDL at an advanced age, he said.
A study in JAMA reviewed the benefits of any treatment for LDL reduction. Patients treated with statins or non-statin treatments including diet, ileal bypass surgery and bile acid sequestrants had the same slope with regards to relative risk.
Patients assigned evolocumab (Repatha, Amgen) in the GLAGOV trial lowered their LDL from 90 mg/dL to 35 mg/dL, according to the presentation. Most patients had baseline LDL above 70 mg/dL, and after reducing that level to 35 mg/dL on average for 18 months, plaque regression occurred in 65% of the treated patients, but only in 50% of those on placebo, as all patients were on statins. Patients with baseline LDL below 70 mg/dL whose LDL was lowered to about 25 mg/dL on average had regression in 85% of this group.
PCSK9 inhibitors are “one of the great scientific stories,” Ginsberg said. “In studies that we did at Columbia published in Circulation last winter, in which we used alirocumab (Praluent, Sanofi-Regeneron),we demonstrated that all of us have an LDL that, no matter what it is, is twice as high as what it could be if we did not have PCSK9. It’s because we have half the number of receptors on the surface of our livers than we could have if we didn’t have PSCK9; this is why when you are treated with an antibody to PCSK9, you double the efficiency of removal of LDL.”
In the FOURIER study, patients with stable coronary disease on statins were assigned evolocumab or placebo, and the evolocumab group had reduced risk for major adverse CV events at 2 years. Although the magnitude of benefit was less than expected by some investigators, it is what was expected for only 2 years of treatment.
“Very surprisingly they don’t show the diabetic subgroup,” Ginsberg said. “Thirty-six percent of these patients were diabetic. Diabetics always do at least as well if not better than non-diabetics.”
The bottom line, Ginsberg said, is “we shouldn’t lose sight of the fact that LDL cholesterol is the best demonstrated marker in clinical trials, and we need to lower that as much as possible before we then go on to attack other lipid abnormalities that are associated with residual risk.” – by Darlene Dobkowski
Reference:
Ginsberg HN. The Role of LDL-C in Diabetes & Cardiometabolic Conditions – Implication of the FOURIER Outcome trial. Presented at: Heart in Diabetes Medical Conference; July 14-16, 2017; Philadelphia.
Ference BA, et al. Eur Heart J. 2017;doi:10.1093/eurheartj/ehx144.
Nicholls SJ, et al. JAMA. 2016;doi:10.1001/jama.2016.16951.
Sabatine MS, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615664.
Silverman MG, et al. JAMA. 2016;doi:10.1001/jama.2016.13985.
Disclosure: Ginsberg reports serving as a chair of the Phase III Lipid Studies Steering Committee, receiving a research grant from and serving as an investigator for Sanofi-Regeneron, and consulting for Amgen and Regeneron.