New FIELD Study Assessment Links HDL Fractions to T2D Cardiovascular Risks

New analysis from the 14-year old FIELD study show about a dozen raised serum levels of lipoprotein subclasses and apolipoproteins in adults with type 2 diabetes (T2D) who suffered from cardiovascular events and death.

The findings show a wider range of biomarkers for clinicians seeking to treat for cardiovascular risk in patients with T2D, and complements results of fenofibrate’s benefit for such biomarkers.

The study, presented by author Steven R. Jones, MD, director of Inpatient Cardiology at Johns Hopkins Medicine, undertook a different understanding of the 9795-patient study originally published in 2005 with results showing fenofibrate (Tricor) reduced total cardiovascular events in older patients with type 2 diabetes mellitus (T2DM).

When presenting the new findings at a late-breaking session at the American Diabetes Association (ADA) 2019 Scientific Sessions in San Francisco, CA, Jones told MD Magazine® the analysis sought to look at predictors of macrovascular outcomes in what was then the largest trial to assess fenofibrate in patients with T2DM.

“It’s really looking in diabetes in general, by going beyond the standard lipids—total cholesterol, triglyceride, HDL—and doing ultracentrifugation, subfractionization of lipids,” Jones said.

Jones and colleagues conducted the ultracentrifugation via vertical auto profile (VAP) of patient plasma during 2 different time periods of the FIELD study: at baseline, and after 6 weeks of fenofibrate exposure. They adjusted for patient gender, and set values for each subclass and apolipoprotein with Cox proportional hazards and logistic regression analysis.

Total cardiovascular disease was defined as nonfatal myocardial infarction (MI), nonfatal stroke, coronary and carotid revascularization, and cardiovascular mortality.

Investigators found total cardiovascular disease correlated most negatively with HDL-C, HDL3-C, and APoA1 (HR .82 for all; 95% CI: .77 - .88). HDL3-C and ApoA2 also reported similarly negative correlations.

In cardiovascular disease-associated death, it was again ApoA1 (HR .66; 95% CI: .57 - .76) and HDL-C (HR .73; 95% CI: .63 - .85) with the most protective benefits, and associated measures of subfractions and apolipoproteins with similar correlations.

ApoB/ApoA1 and ApoB/ApoA2 each were associated with hazard ratios > 1.2 for both cardiovascular disease and associated deaths. Triglyceride/ApoC measures were also associated with a high hazard ratio for cardiovascular disease death (HR 1.21; 95% CI: 1.11 — 1.32; P< .001).

“If we look at just the great macrovascular outcome category, it’s very heavily driven by total non-HDL particle load—less so, interestingly, by fractioning out the triglyceride-lipoprotein fractions,” Jones said.

Jones added the HDL subfractions were notably protective, but “what took the day” were the ApoB/ApoA ratios—an association with cardiovascular risks already established in prior research.

“Of all the lipid outcomes, that’s probably the best one,” he said. “And the epidemiology has been shown.”

Across all the observed nonfatal cardiovascular outcomes, triglycerides and lipoproteins served as positive indicators—emitting signals as large as the more popular biomarker of raised LDL-C rates, Jones noted.

The established triglyceride association is a benefit for fenofibrate and the original findings from the FIELD trial, as the therapy most prominently benefits triglyceride rates in patients with T2D at risk for cardiovascular events.

Investigators concluded that a number of the identified lipoprotein and apoprotein associated with increased cardiovascular risks in patients with T2DM could be treated properly with fenofibrate. Jones added a follow-up analysis will look into the specifics of fenofibrate’s benefit in each fraction and subgroup.

Future studies may influence the usage rate and research into some of the drug classes recently established in diabetes care to reduce patient cardiovascular risks—SGLT-2 inhibitors, GLP-1 receptor agonists, and so forth.

“There’s no question whatsoever, beyond any pale or doubt, that LDL is absolutely something we need to minimize in order to reduce risks,” Jones said. “However, the part of this which has been a major debate for some time is whether taking this gross, aggregate measure is beneficial.”

He advised that his peers begin considering—and seeking out&mdash;new biologic agents designed to treat lipoprotein in patients with T2D.

The study, "Lipoprotein Subfractions Are Associated with Diabetic Cardiovascular Disease and Death among 9,795 Patients in the FIELD Trial," was presented at ADA 2019.