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Cardiovascular Disease to Diabetes Prevention: The Potential of CETP Inhibition and Modulation

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

MEDICAL FRONTIERS - XVI International Symposium on Atherosclerosis

Sydney, Australia / March 25-29, 2012

Sydney - It is generally accepted that for every 0.1 mmol/L increase in HDL-C, there is an associated coronary artery disease risk reduction of ~10%. While raising HDL-C levels reduces the risk of atherosclerosis, a more specific focus on the quality of HDL-C, as opposed to quantity, is drawing more attention. The emerging importance of HDL-C in glucose metabolism was also discussed here at the meeting. Cholesteryl ester transfer protein modulators/inhibitors as agents to raise HDL-C, with their promising role as a risk reduction therapy for cardiovascular disease patients and perhaps the prevention and management of type 2 diabetes, also attracted wide interest.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Although statins clearly reduce the risk of cardiovascular disease (CVD) by about 30%, there is a large persisting residual risk. Studies have shown that HDL-C holds a predictive value for CVD in patients treated with statins. According to Prof. John Chapman, INSERM, Hôpital de la Pitié-Salpêtrière, Paris, France, it became clear during the International Symposium on Atherosclerosis that the association between low HDL-C and CV risk is widely accepted.

 HDL Action and Function

Critical to atherosclerotic plaque initiation and progress are endothelial dysfunction, cholesterol accumulation and immuno-inflammation, and in patients with cardiometabolic disease, HDL particles display defective cardioprotective anti-inflammatory, antithrombotic and antioxidative functions, Prof. Chapman noted. A literature evaluation reveals clear evidence that the function of HDL particles is attenuated in all clinical coronary artery disease (CAD) conditions involving the lipid triad with evidence of subnormal HDL-C.

Khera et al. showed the cholesterol efflux capacity from macrophages had a strong inverse association with carotid intima-media thickness (IMT) and angiographic CAD, independent of HDL-C (N Engl J Med 2011;364:127-35). However, cholesterol efflux is not the whole story. “Rather, the activity of HDL as an acceptor of both native and oxidized lipids is the key,” Prof. Chapman stated. Future therapies should target the modulation of the capacity of HDL as an acceptor of toxic pro-inflammatory lipids as well as cholesterol efflux.

“So it’s not just the quantity, it’s the quality,” Prof. Chapman emphasized. “The potential susceptibility of an individual to atherosclerosis may be more related to a specific function of HDL than to an assessment of HDL quantity. With regard to function,  cholesteryl ester transfer protein [CETP] plays a major role in the mechanism that underlies the formation of abnormal HDL.” This has driven the pursuit of HDL-C-raising therapies, including CETP inhibitors/modulators.

 Advances in CETP Inhibition/Modulation

Dr. Lawrence Leiter, University of Toronto, Ontario, agreed that CETP plays a key role in atherosclerosis because it is involved in the transfer of cholesteryl esters from HDL to LDL and VLDL. “Human trials are not totally consistent but in general, it would appear that genetic abnormalities associated with reduced levels of CETP are associated with reduced risk for atherosclerosis,” he stated.

However, development of this class of agents has met with a more prudent approach since the ILLUMINATE study. Findings showed that while torcetrapib raised HDL-C by about 70%, it was abruptly halted in 2006 because of increased CV events and mortality. It is now generally believed that its adverse effects were due to off-target effects, including increased blood pressure (BP) and increased aldosterone. However, “These adverse off-target effects have not been observed with the other drugs that target CETP,” Dr. Leiter noted.

For example, in the dal-VESSEL study, dalcetrapib (a CETP modulator) increased HDL-C by 31% and showed no adverse effect on nitric oxide-dependent endothelial function and no differences in diastolic or systolic BP compared to placebo. The primary end points were flow-mediated dilatation at 12 weeks and ambulatory BP at 4 weeks. The same end points were also assessed at 36 weeks.

In the dal-PLAQUE study, the CETP modulator showed no evidence of progression of plaque burden using magnetic resonance imaging (MRI) and no evidence of pro-inflammatory effects on the vessel wall at 6 months as assessed by positron emission tomography/computed tomography (PET/CT). “In addition, there was a suggestion of beneficial effect on atherosclerosis in that a significant reduction in total vessel area at 24 months was observed and there was no effect on BP,” Dr. Leiter told delegates.

The DEFINE study compared anacetrapib 100 mg with placebo, on top of statin therapy, in 1500 patients with coronary heart disease (CHD) or CHD risk equivalents. Active treatment was associated with a 40% reduction in LDL-C and a 138% increase in HDL-C, with no effect on BP and no increase in CV events.

Dr. Leiter cited first results of a study comparing evacetrapib 30 mg, 100 mg and 500 mg daily with placebo in 400 patients, originally released at the 2011 American Heart Association Scientific Sessions and subsequently published (JAMA 2011;306:2099-109). There was a dose response increase in HDL-C ranging from 54% to 130%. Details of future outcomes studies have not been announced.

Searching for Optimal Balance Between Inhibition and Modulation

Dr. Leiter noted that all agents were quite different from each other, both in terms of their effects on HDL-C levels and functionality. In terms of functionality, dalcetrapib appeared to increase the number of functional HDL particles. Moreover, phase II trial data showed that on top of background statin therapy, the addition of dalcetrapib increased the efflux of cholesterol from macrophages.

One of the important questions raised was whether there is a level to which HDL-C needs to be raised for optimal efficacy in the prevention of CVD and which might not necessarily be the maximum attainable. “That is the question—CETP inhibition vs. modulation—and the trials will give us the answer,” Dr. Leiter remarked. “The degree of inhibition is probably going to turn out to be important and it may well be that some inhibition is good but complete inhibition is bad. It is probably both quantitative and qualitative changes of HDL that are going to matter.”

 Future Outcomes

The ongoing phase III trial, dal-OUTCOMES, has recruited about 15,800 patients recently hospitalized for an acute coronary syndrome (ACS). The objective is to examine dalcetrapib 600 mg daily vs. placebo, in addition to best evidence-based practice management of LDL-C, for reduction in CV events and mortality after ACS. It will be the first of the outcomes studies on CETP modulators/inhibitors to report, with results expected next year.

Another large study is underway, dal-OUTCOMES-2, where some 20,000 patients with stable coronary heart disease, coronary disease risk equivalents or those at elevated risk for CVD will be randomized to receive dalcetrapib 600 mg or placebo.

In the dal-PLAQUE 2 phase III study, investigators have recruited over 900 patients with CAD or carotid artery disease. “It is the first study to measure the effect of an agent on both coronary atherosclerosis by intravascular ultrasound and carotid atherosclerosis by carotid IMT” Dr. Leiter emphasized. The results are expected next year.

The dal-ACUTE study has recruited 300 patients who will receive dalcetrapib within 1 week of an ACS event to ascertain the acute effects of the drug on lipid levels.

The REVEAL study is recruiting 30,000 patients with established vascular disease to compare anacetrapib 100 mg with placebo, in addition to atorvastatin, to determine if there is a risk reduction in major coronary events. Results are expected by 2017.

HDL-C and Diabetes

HDL-C-raising also holds promise for glycemic control, according to Prof. Bronwyn Kingwell, Baker IDI Heart and Diabetes Institute, Melbourne, Australia. There is a potential paradigm shift with HDL-C being shown in emerging data and literature as having a direct influence on glucose metabolism through multiple mechanisms. For one, a 24-year follow-up of the Framingham cohort showed a higher percentage of people with diabetes had low HDL-C levels compared with non-diabetic individuals (Figure 1).

Figure 1.

In major epidemiological studies and meta-analyses, low HDL-C in patients without diabetes predicts future diabetes. “This is true across a wide range of ethnic groups and age ranges, including children and adolescents,” Prof. Kingwell confirmed. Genetic studies provide some support for associations between low HDL-C and poor glycemic control plus development of type 2 diabetes. “The reverse is also true so those [genetic] variants causing higher HDL-C have been associated with improved glucose homeostasis,” she told delegates.

HDL-C has a potential involvement in non-insulin-mediated glucose uptake into skeletal muscle. “Non-insulin-dependent pathways are incredibly important, particularly in the context of exercise, and I don’t just mean when you go out for a run but in normal daily activities,” Prof. Kingwell stated. “If you have a mechanism that acts on muscle it is likely to have effects relevant to the whole body. If you can stimulate this mechanism, you can remove glucose from the blood. It is interesting because, of course, HDL-C goes up in athletes and it may be that it also contributes to them getting glucose into their muscles.”

The pathway involves AMP-activated protein kinase (AMPK), a metabolic enzyme that increases fatty acid oxidation, glucose uptake and glycolysis. “It mimics one particular aspect of exercise,” Prof. Kingwell explained.

Her group conducted a study in which they raised plasma HDL-C levels in unmedicated patients with type 2 diabetes by using an infusion of reconstituted HDL (rHDL), a disc-shaped, non-covalently associated particle resembling nascent HDL (CSL-111).

Plasma glucose was decreased by rHDL. Also, plasma insulin increased significantly after 2 hours. This could happen as a result of a reduced rate of degradation of insulin or an increased secretion rate, Prof. Kingwell suggested. “When we went back to look at animal studies, it appeared HDL was directly increasing insulin secretion from the pancreatic beta cells,” she added.

Some of the many mechanisms involved relate to the ability of HDL to release cholesterol from cells. “It is probably stopping accumulation of cholesterol in the beta cells and improving insulin secretion through that mechanism,” she told delegates.

Her group’s more recent work looked at whether HDL-C-raising therapies act on these mechanisms. A study of plasma in healthy patients treated acutely with the CETP inhibitor torcetrapib showed a significant rise in post-prandial insulin (Figure 2). Importantly, there was no effect on basal insulin. In addition, when the plasma was placed on pancreatic beta cells, there was an insulin secretion in response to a glucose stimulus. There was no effect when there was no glucose stimulus, again showing no effect on basal insulin.

Figure 2

A post-hoc analysis of ILLUMINATE reported a positive effect of torcetrapib on glycemic control. The results were from 6661 patients with type 2 diabetes (Barter et al. Circulation 2011;124:555-62). “Despite the off-target effects of torcetrapib, in diabetics there was lower glucose, lower HbA1c and their fasting insulin was reduced,” Prof. Kingwell reported (Figure 3). “The trial also raises the possibility that HDL is acting on another aspect of glucose function and that is the insulin sensitivity of the tissues themselves.” This was borne out by the homeostatic model assessment insulin resistance (HOMA-IR) results. “So you don’t need as much insulin for a given amount of glucose uptake because the resting insulin is actually down in these patients,” she explained.

Figure 3

Her group is conducting studies into 3 possible mechanisms by which HDL may increase glucose metabolism: 1) the non-insulin-dependent glucose uptake into muscle via the AMPK mechanism; 2) an increase in insulin sensitivity of the tissues; and 3) increased post-prandial insulin secretion. Prof. Kingwell said it is clear that HDL-C elevation in humans—either acutely via rHDL or chronically via CETP inhibition—reduces blood glucose. It raises the possibility that increasing HDL-C could be a novel therapy for protection against type 2 diabetes. In addition, CETP modulators/inhibitors as HDL-C-raising agents have the potential for rapid clinical translation if the clinical outcomes trials prove positive, she said. “If positive, such trials would provide a rationale for HDL-C-raising agents beyond vascular disease to manage or even prevent type 2 diabetes,” she told delegates.

“The exciting thing is that the co-occurrence of CVD and diabetes is very high, >50%. These patients already have a large number of medications that they have to take and if there are medications that have a dual effect on multiple risk factors, that would obviously be of benefit to these patients.”

Prof. Chapman agreed that CETP modulators/inhibitors have a very promising role to play in glucose control. “The indication is that HDL particles seem to gain function under CETP modulation/inhibition,” he noted. It also appears that HDL may protect the pancreatic beta cell and render insulin production highly efficient. As Prof. Chapman explained, the more the quantity and quality of HDL in patients with low HDL-C is normalized, the greater the chance of protecting pancreatic beta cells and perhaps preventing the patient from becoming diabetic.

Summary

There is growing interest in the potential use of HDL-C-raising agents such as the CETP modulators/inhibitors not only to prevent CV events but perhaps also type 2 diabetes. Some questions may be answered with the results of the current clinical outcomes trials, which are evaluating the efficacy and safety of CETP modulators/inhibitors. If they prove positive, it may be possible in the future to develop assays to measure the various functions of HDL, as opposed to a sole focus on HDL-C levels. As new therapies become available, therapeutic response could then be assessed via an improvement in HDL function.  

 

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