Novel Drug Lowers Cholesterol in Patients with Type 2 Diabetes and Hypercholesterolemia

A novel drug developed by Esperion Therapeutics lowered low-density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes mellitus (T2DM) and hypercholesterolemia, according to results from a phase 2 study published in Arteriosclerosis, Thrombosis, and Vascular Biology.

The compound, which lowered LDL-C levels by 43%, works by triggering adenosine monophosphate (AMP)-activated protein kinase and inhibiting adenosine triphosphate (ATP) citrate lyase.

For the trial, researchers observed 60 patients aged 18-70 years who halted their anti-diabetic and lipid-lowering medications at enrollment. The participants were randomized into 2 groups: one received once-daily ETC-1002 80 mg for 2 weeks followed by once-daily ETC-1002 120 mg for 2 weeks, while the other was assigned to placebo for 4 weeks.

After 29 days, patients in the ETC-1002 group had a mean 43% reduction in LDL-C levels, compared to 4% in the placebo group. The scientists noted the ETC-1002 group also showed significant LDL-C reduction after completing the first 2-week 80 mg dosage.

The researchers also found ETC-1002 patients had a mean 32% reduction in non-high-density lipoprotein (HDL) cholesterol, compared with 0.5% for the placebo group. Additionally, high-sensitivity C-reactive protein (CRP) was reduced by a median of 41% among ETC-1002 patients, whereas the placebo group only showed an 11% reduction.

Although the researchers reported no safety issues, there were 45 adverse events in 14 patients from the ETC-1002 group, compared to 52 adverse events in 21 patients from the placebo group. While the most common side effect was hyperglycemia, it was more frequent in the placebo group. No patients experienced adverse events so great that they had to withdraw from the trial.

Those who participated in the study also experienced significant weight loss. However, the authors speculated it was due to the number of obese patients who maintained healthier lifestyles during their 35 days in the clinic.

“ETC-1002 seems to provide a novel therapeutic approach to the prevention of vascular complications in T2DM in that it combines significant LDL lowering with improvements in the cross-linkages between subclinical inflammation and dysmetabolism in this disease,” Ronald Goldberg, MD, from the University of Miami School of Medicine, wrote in an accompanying editorial, as he was not affiliated with the study. “These properties may therefore also have application to the larger population with pre-diabetes and metabolic syndrome. Ultimately, as in the development of any new drug that influences central metabolic pathways, documenting long-term safety will be crucial. It is, however, somewhat reassuring that lengthy clinical experience with an agent known to increase adenosine monophosphate—activated protein kinase activity, namely metformin, has proven positive.”

The phase 1 trial of ETC-1002 in patients with T2DM and hypercholesterolemia for 12 weeks showed the drug lowered LDL-C by 27% in the 120 mg group, compared to 2% in the placebo group. Though the authors said its remains unclear why the phase 2 trial showed substantially greater LDL-C reduction, they speculated population differences — such as diabetics versus non-diabetics – contributed to the variation, in addition to inpatient versus outpatient trial design, baseline LDL, and the Hispanic population, which comprised 98% of the phase 2 trial.