Issues in Emerging Health Technologies Anacetrapib for the Treatment of Dyslipidemia Issue 123 February 2013 [DRAFT] Summary Background Anacetrapib (Merck & Co., Inc) is a cholesterol Cardiovascular disease is one of the leading causes of ester transfer protein (CETP) inhibitor that morbidity and mortality in Canada.1,2 In 2009, almost blocks the transfer of cholesterol from high- 30% of all deaths in Canada were the result of density lipoprotein to other lipoproteins. This cardiovascular disease.2 The economic burden of results in an increase in high-density lipoprotein cholesterol (HDL-C) and a decrease in low- cardiovascular disease in Canada is substantial. The density lipoprotein cholesterol (LDL-C), which total cost for the use of health care resources and lost may reduce the development of atherosclerosis. productivity was estimated to be C$20.9 billion in Anacetrapib has not been approved for sale in 2005.3 This figure is expected to increase to Canada or the United States. C$28.3 billion in 2020.3 Statin therapy has been shown Clinical evidence to support the use of to decrease LDL-C by approximately 25% to 50%, with anacetrapib for dyslipidemia has been reported a corresponding 24% to 40% risk reduction in in two clinical trials. An eight-week phase 2b cardiovascular events.4 However, many patients remain dose-ranging study in patients with primary at risk for future cardiovascular events despite treatment hypercholesterolemia or mixed hyperlipidemia with statins.5-8 This may be explained by a low level of reported statistically significant increases in HDL-C, which has been shown to be a significant HDL-C of up to 139% and statistically predictor of coronary artery disease.9,10 Epidemiologic significant reductions in LDL-C of up to 40% compared with placebo. The DEFINE data have shown that the cardiovascular benefit from phase 3 clinical trial showed that, when used higher HDL-C levels is independent of the benefit 11-14 concomitantly with a statin in patients with associated with lower LDL-C levels. This suggests known coronary artery disease or who were at that strategies that increase HDL-C, when added to high-risk for coronary artery disease, those that lower LDL-C, may reduce cardiovascular risk anacetrapib produced a 39.8% reduction in more so than approaches that focus only on decreasing LDL-C and a 138.1% increase in HDL-C at LDL-C. 24 weeks compared with placebo. These lipid changes were sustained at 76 weeks. The Technology Adverse effects were mostly mild to moderate, and consisted of gastrointestinal symptoms Anacetrapib (Merck & Co. Inc., Whitehouse Station, (diarrhea, constipation, dyspepsia) and myalgias. New Jersey) is an orally active cholesterol ester transfer There was no evidence of effects on blood protein (CETP) inhibitor.15 CETP is a plasma protein pressure, serum levels of aldosterone, serum that facilitates the transfer of cholesterol and levels of electrolytes, or an increased risk of 16 cardiovascular events. triglycerides between various lipoprotein fractions. HDL particles play a central role in reverse cholesterol REVEAL is an ongoing, large-scale phase 3 trial transport, a process that removes excess cholesterol evaluating the effectiveness of anacetrapib with a from peripheral tissues and transports it to the liver for statin for the secondary prevention of major coronary events in patients who have a history of excretion. Pharmacologic inhibition of CETP blocks the cardiovascular disease. Results are anticipated in transfer of cholesterol from HDL to other lipoproteins January 2017. such as LDL and very low-density lipoprotein (VLDL). The result is an accumulation of cholesterol in the HDL The long-term safety and efficacy of anacetrapib for the primary or secondary prevention of fraction, which may reduce the development of cardiovascular morbidity and mortality needs to atherosclerosis (a narrowing of arteries due to an be clarified to determine the impact on clinical accumulation of fatty deposits or plaques in the practice. arterial wall). The Canadian Agency for Drugs and Technologies in Health (CADTH) is funded by Canadian federal, provincial, and territorial governments. (www.cadth.ca) The development of the previous investigational CETP dyslipidemia should be based on the risk of coronary inhibitors torcetrapib (Pfizer Inc., New York, New artery disease and lipid levels.25 Cardiovascular risk is York) and dalcetrapib (Roche, Basel, Switzerland) was estimated using the Framingham Risk Score based on discontinued. Despite a 72% increase in HDL-C and a the patient’s age, sex, and presence of comorbidities 25% decrease in LDL-C, development of torcetrapib such as diabetes, hypertension, familial hyperlipidemia, was stopped in 2006 after results from a pivotal trial family history of premature cardiovascular disease, and showed that torcetrapib was associated with an clinical evidence of atherosclerotic cardiovascular increased risk of cardiovascular events and mortality.17 disease. Treatment is considered in all high-risk patients These adverse events may have been the result of “off even if cholesterol levels are normal. Treatment is also target” effects on serum electrolyte levels, serum considered in moderate-risk or low-risk patients aldosterone levels, blood pressure, and prolongation of depending on the levels of LDL-C, apolipoprotein B the QT interval on electrocardiogram readings that (apo B), and non-HDL-C. The guidelines recommend were unrelated to CETP inhibition.18,19 Furthermore, LDL-C reduction with statins (e.g., simvastatin, three studies failed to show any effect on atorvastatin) as the primary target of therapy. The goal atherosclerotic plaque progression.20-22 Dalcetrapib of treatment is an LDL-C level of 2.0 mmol/L was a relatively weak CETP inhibitor that produced a (77.3 mg/dL) or less, or a 50% or greater reduction in 30% increase in HDL-C and did not significantly the LDL-C level. Alternate targets include a reduction in affect LDL-C.23 The development of dalcetrapib was apo B or non-HDL-C levels. terminated early in 2012 when a phase 3 trial in The goals of treating patients with low HDL-C levels patients with stable coronary artery disease failed to have not been established due to the absence of evidence show clinically meaningful efficacy when added to a showing an improvement in cardiovascular outcomes statin for a reduction in cardiovascular events.23,24 with therapies that increase HDL-C alone. Niacin is currently the most effective drug for increasing HDL-C, Regulatory Status but use is limited by adverse effects including skin flushing and liver toxicity. Fibrates (e.g., gemfibrozil) Anacetrapib is not currently approved for sale in have also been shown to increase HDL-C, but are Canada or the United States. associated with muscle toxicity when used with a statin. Furthermore, several clinical trials have suggested that Patient Group adding extended-release niacin27,28 or fibrates29 to a Dyslipidemia (an abnormal level of lipids and statin does not decrease the risk of cardiovascular events lipoproteins in the blood) is a major risk factor for relative to statin monotherapy. developing cardiovascular disease.1,25 Higher concentrations of LDL-C and lower concentrations of Methods HDL-C increase the risk for atherosclerosis.26 Progression of atherosclerosis may lead to coronary Literature Search Strategy A peer-reviewed literature search was conducted using artery disease, myocardial infarction, heart failure, the following bibliographic databases: MEDLINE, peripheral artery disease, and stroke. A substantial PubMed, Embase, and The Cochrane Library (2012, proportion of Canadians aged 20 to 79 years are Issue 12). Grey literature was identified by searching estimated to have a high level of LDL-C (36%) and a 26 relevant sections of the Grey Matters checklist low level of HDL-C (30%). An LDL-C level of (http://www.cadth.ca/en/resources/grey-matters). No 5.0 mmol/L (193.3 mg/dL) or greater is considered 25 methodological filters were applied. The search was high for most patients. An LDL-C level of limited to English language documents published 3.5 mmol/L (135.3 mg/dL) or greater is considered between January 1, 2007 and December 11, 2012. high for patients who are at increased risk of 25 Regular alerts were established to update the search cardiovascular disease. A low HDL-C level is less until the publication of the bulletin. Conference than 1.0 mmol/L (38.7 mg/dL) in men and less than 26 abstracts were excluded from the search results. 1.3 mmol/L (50.3 mg/dl) in women. Study Selection Criteria Current Practice Phase 2 and 3 studies evaluating the efficacy and safety Guidelines from the Canadian Cardiovascular Society of anacetrapib compared with placebo or pharmacologic recommend that the initiation of treatment for therapies for the treatment of dyslipidemia and cardiovascular disease were considered for inclusion in The Canadian Agency for Drugs and Technologies in Health (CADTH) is funded by Canadian federal, provincial, and territorial governments. (www.cadth.ca) the evidence section of this bulletin. Unpublished data, The baseline demographic and clinical characteristics case reports, editorials, letters, and narrative literature were similar across the 10 treatment groups. The mean reviews were excluded. age was 56.4 9.6 years and the majority (83.7%) of participants were Caucasian. The mean baseline levels The Evidence for LDL-C and apo B were 141.1 22.0 mg/dL and 142.5 23.8 mg/dL, respectively. The mean baseline Clinical data to support the use of anacetrapib in levels for HDL-C and apo A-I were 50.5 12.6 mg/dL dyslipidemia and coronary artery disease have been and 168.9 27.7 mg/dL, respectively. Overall, reported in a phase 2b dose-ranging study30,31 and a 32 26 (4.0%) patients had diabetes and 223 (37.9%) had phase 3 clinical trial.