Effect CETP inhibitor similar in vascular patients with or without diabetes
REVEAL - Effects of Anacetrapib on the Incidence of New-onset Diabetes Mellitus and on Vascular Events in People with Diabetes
Presented at AHA 2017 Scientific Sessions in Anaheim, CA, USA by Martin Landray (University of Oxford, Oxford, United Kingdom)Nov. 21, 2017 - news
The REVEAL study included 30000 patients over the age of 50 years with occlusive vessel disease, on a background therapy of atorvastatin 20 mg or 80 mg daily (in China: 10 or 20 mg), who were randomized to the CETP inhibitor anacetrapib (100 mg daily) or matching placebo. The follow-up of the study was longer than 4 years. The primary endpoint was major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization).
The main study results had been presented at ESC2017, namely 9% proportional reduction of major coronary events, with a greater effect in later years of treatment. The observed benefit was consistent with the anticipated effect from the observed reduction in non-HDL-C. There was no evidence of a significant impact of HDL-raising.
This analysis investigated the effect of anacetrapib in diabetes patients, because patients with diabetic dyslipidemia have low HDL-c and elevated triglycerides. The effects of anacetratpib on the development of diabetes was also evaluated. 19129 persons in the REVEAL population had diabetes and 11320 didn’t. Median follow-up time was 4.2 years in those with diabetes (99.7% completed) and 4.1 years (99.8%) in those without diabetes.
- LDL-c, HDL-c and non-HDL-c levels at baseline were comparable between patients with and without diabetes, but triglycerides were higher in patients with diabetes (137 mg/dL/1.5 mmol/l) than in those without (117 mg/dL/1.3 mmol/l).
- At trial midpoint, HDL-c was 41 mg/dL higher with anacetrapib in those with, and 45 mg/dL higher in those without diabetes. Apolipoprotein Ai was 42 mg/dL higher in anacetrapib treated diabetics and 43 mg/dL in non-diabetics.
- Placebo treated persons with diabetes (15.4%) had numerically fewer primary endpoints than the placebo group without diabetes (9.%). Anacetrapib treated patients with diabetes (13.9%) also showed numerically more primary events than those without diabetes (8.9%).
- no significant heterogeneity for the effect of anacetrapib on the primary endpoint was seen between persons with or without diabetes.
In the REVEAL study, individuals with diabetes were at higher absolute risk of major coronary events. Anacetrapib lowered non-HDL-c and reduced major coronary events with similar efficacy in patients with and without diabetes. Patients with diabetes had a numerically greater absolute risk reduction with anacetrapib treatment. A small reduction in risk of new-onset diabetes mellitus was observed.
Discussant Stephen Nicholls (Adelaide, Australië) summarized in his presentation what we know about CETP: it plays an important role in lipid metabolism, and genetic polymorphisms associated with low CETP activity associate with low CV risk. CETP inhibitors gained popularity primarily due to their ability to raise HDL-c levels and because CETP inhibition showed favorable effects on animal models of atherosclerosis. Favorable effects on HDL-c and LDL-c levels have indeed been demonstrated in humans, but torcetrapib also produced adverse effects on mortality and CV events. Dalcetrapib and evacetrapib trials were stopped early due to clinical futility.
Anacetrapib is a more potent CETP inhibitor. The CV benefit observed associated with the reduction in atherogenic apoB containing lipoproteins. The authors now demonstrate similar benefits in patients with and without diabetes and that a lower rate of new onset diabetes in patients treated with anacetrapib.
The modest CV benefit and prolonged half-life led to the decision to not bring anacetrapib to the clinic. However, he said, the benefit does keep the door slightly open with regard to potential clinical use of these agents in higher risk patients with higher baseline LDL-C levels. Genetic studies report that CETP inhibition may be of more value in the absence of statin therapy and that dalcetrapib may have benefits exclusively in patients with specific polymorphisms.
Considering lipid modifying therapy in the context of diabetes, evidence from genetics suggests that lowering LDL-C will associate with a greater risk of diabetes. The clinical relevance is unknown and are unlikely to change treatment of high risk patients in which the benefits of lipid lowering are well established. While CETP inhibitors in general have favurable effects on the risk of developing diabetes, it remains unknown how this influences clinical outcomes
- Our reporting is based on the information provided at the AHA 2017 congress –