ETC-1002 lowers LDL-c without worsening glycaemic control in hypercholesterolaemic T2DM

Gutierrez MJ, Rosenberg NL, Macdougall DE, et al.
Arterioscler Thromb Vasc Biol. 2014 Jan 2

Background

Many patients with type 2 diabetes mellitus (T2DM) fail to achieve LDL-c targets on statins [1-3]. Recent meta-analyses suggest an increased risk for worsening of glycaemic control and new onset diabetes mellitus associated with statin use [4-9]. The Food and Drug Administration required in 2012 that statin labels mentioned an increase in haemoglobin A1C and fasting serum glucose [10].
ETC-1002 (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is an agent currently in phase 2 clinical development to treat hypercholesterolaemia. Early evidence suggests that ETC-1002 has favourable effects on cardiometabolic biomarkers such as insulin sensitivity, inflammation and high blood pressure.
Nonclinical studies have demonstrated that ETC-1002 modulates two distinct molecular targets that regulate lipid homeostasis: hepatic ATP-citrate lyase and AMP-activated protein kinase [11]. Inhibition of the first target rapidly reduces acetyl-CoA levels; the final common substrate for fatty acid and sterol synthesis, upstream of the point of action of statins. Activation of AMP-activated protein kinase reduces lipid synthesis, regulates carbohydrate metabolism and reduces inflammation and adiposity [11,12]. Thus, ETC-1002 not only regulates hepatic lipid homeostasis, but also has favourable effects on glucose regulation in animal models [12-15].
In a phase 2 placebo-controlled trial in 177 patients with hypercholesterolaemia, 12 weeks of ETC-1002  showed a dose-related, significant lowering of LDL-c levels, as compared to placebo. This phase 2, placebo-controlled, double-blind trial was to evaluate the lipid-altering effects of ETC-1002 in patients with both elevated LDL-c (>100 mg/dL) and T2DM.

Main results

• At day 29, LDL-c was reduced by 42.9% (least squares mean % change from baseline) in the ETC-1002 group as compared to 4.0% in the placebo group (95%CI of difference: -46.2 to -31.7, P<0.0001). The LDL-c reduction was seen in all patients treated with ETC-1002 and across a broad range of baseline LDL-c and triglyceride values.
  Statistically significant mean % reductions with ETC-1002 were also seen at day 29 in non-HDL-c (difference: −31.4, 95% CI: −38.0 to −24.8; P<0.0001) and total cholesterol (difference: −24.6, 95% CI: −29.9 to −19.4; P<0.0001. Levels of triglycerides, HDL-c and free fatty acids did not change significantly with ETC-1002, as compared to placebo.
  High-sensitivity C-reactive protein was reduced by 40.% (median % reduction from baseline) with ETC-1002, as compared to 11.0% with placebo at day 29 (P=0.0011).
• A non-significant reduction of all prespecified glycaemic markers was seen at day 29, after treatment with ETC-1002, in comparison to placebo (including fasting plasma glucose, postprandial measures and a 24-hour-continuous glucose monitoring assessment that showed a trend of improved glycaemic control).
• ETC-1002 was generally safe and well tolerated. The number of reported adverse events and the percentage of patients affects were lower in the ETC-1002 group than in the placebo group. The majority of adverse events reported were  of mild severity, and all events were resolved by the end of the trial.
  Mild to moderate mean increases in uric acid and homocysteine and mild decreases in alkaline phosphatase and haemoglobin were the only clinical chemistry and haematology parameters that were different in ETC-1002 treated patients than in the placebo group. These laboratory findings did not lead to clinical sequelae or interventions.

Conclusion

This phase 2 proof-of-concept trial showed that ETC-1002 120 mg gives significant LDL-c lowering in hypercholesterolaemic patients with T2DM at day 29, as compared with placebo. Significant reductions in related lipid parameters such as non-HDL-c and total cholesterol were also seen with ETC-1002, as well as lower inflammatory biomarker high-sensitivity C-reactive protein.
ETC-1002 was well tolerated and did not worsen glycaemic control in these hypercholesterolaemic patients with T2DM. The potential benefits of ETC-1002 on LDL-c and other cardiometabolic risk factors support further clinical investigation in larger clinical trials.

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