Issues in Emerging Health Technologies

Anacetrapib for the Treatment of Dyslipidemia

Issue 123  February 2013 [DRAFT]

Summary Background

(Merck & Co., Inc) is a 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 . 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 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 or mixed hyperlipidemia with .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 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 , serum that facilitates the transfer of cholesterol and levels of electrolytes, or an increased risk of 16 cardiovascular events. 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 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 ( Inc., New York, New artery disease and lipid levels.25 Cardiovascular risk is York) and (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, , 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., , three studies failed to show any effect on ) 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. 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. (e.g., ) 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. The addition of anacetrapib to hypertension. After eight weeks of treatment, all statin therapy is being studied in two ongoing phase anacetrapib monotherapy doses produced statistically 3 trials in patients with heterozygous familial significant increases in HDL-C and statistically hypercholesterolemia33 and Japanese patients with 34 significant decreases in LDL-C compared with placebo dyslipidemia. A large-scale phase 3 clinical trial is (P < 0.001 versus placebo for all doses). While there evaluating whether anacetrapib reduces major coronary were statistically significant and incremental lipid events in patients with a history of cardiovascular 35 changes with increasing doses from 10 mg up to disease. 150 mg, there was no difference in response between the 150 mg and 300 mg doses. Decreases in LDL-C were Bloomfield et al. evaluated the efficacy, safety, and accompanied by significant decreases in apo B, tolerability of anacetrapib administered as monotherapy indicating a reduction in the concentration of circulating or with atorvastatin for the treatment of dyslipidemia in LDL particles. Similarly, increases in HDL-C were a multi-centre, randomized, double-blind, placebo- 30 accompanied by significant increases in the levels of controlled, dose-ranging study. Patients aged 18 to apo A-I, suggesting an increase in the concentration of 75 years with primary hypercholesterolemia or mixed circulating HDL particles. The peak effects on lipids and hyperlipidemia (LDL-C values ranging from 100 mg/dL lipoproteins were a 40% reduction in LDL-C, a 30% to 190 mg/dL, 100 mg/dL to 160 mg/dL for moderate- reduction in apo B, a 139% increase in HDL-C, and a risk patients, or 100 mg/dL to 130 mg/dL for diabetic 47% increase in apo A-I. patients) were eligible for inclusion. Patients were excluded if they had a history of coronary heart disease, Coadministration of atorvastatin with anacetrapib symptomatic carotid artery disease, uncontrolled cardiac produced significantly greater dose-dependent arrhythmias, uncontrolled hypertension, or uncontrolled reductions in LDL-C compared with atorvastatin diabetes. Following a screening and a placebo run-in monotherapy. The dose-dependent increases in HDL-C period, 589 patients were randomly allocated to one of with coadministration of atorvastatin were significantly ten groups: five groups received atorvastatin 20 mg in larger than those produced by atorvastatin monotherapy combination with anacetrapib 10 mg, 40 mg, 150 mg, or but similar to the increases observed with anacetrapib 300 mg (one group received atorvastatin alone); and monotherapy. Coadministration of atorvastatin with five groups received anacetrapib monotherapy at each anacetrapib reduced LDL-C by up to 70% and increased of the doses (one group received placebo alone). HDL-C by up to approximately 130%. All anacetrapib monotherapy and coadministration doses produced The primary outcome was the percentage change from significantly greater reductions of up to 50% in baseline in LDL-C with anacetrapib monotherapy lipoprotein (a) compared with placebo and atorvastatin, versus placebo, and with anacetrapib coadministered respectively. Anacetrapib administration did not affect with atorvastatin versus atorvastatin alone. Secondary the levels of triglycerides or C-reactive protein. outcomes included percentage change from baseline in Sustained effects on lipids were observed eight weeks HDL-C, triglycerides, apo B (a major protein following cessation of anacetrapib treatment in the component of LDL), and apo A-I (a major protein groups receiving 150 mg and 300 mg doses.31 component of HDL). Additional measurements included percentage change from baseline in other The DEFINE trial was a multi-centre, randomized, biomarkers for coronary artery disease including double-blind, placebo-controlled trial assessing the lipoprotein (a) and C-reactive protein. The safety efficacy and tolerability of anacetrapib for the treatment assessment included blood pressure measurements, of dyslipidemia in patients with known coronary artery serum aldosterone levels, and serum electrolyte disease or who were at high risk for coronary artery (sodium, potassium, chloride, bicarbonate) levels. disease (ten-year Framingham Risk Score > 20%).32

The Canadian Agency for Drugs and Technologies in Health (CADTH) is funded by Canadian federal, provincial, and territorial governments. (www.cadth.ca) Patients aged 18 years to 80 years were considered for treatment period. A 36.4% reduction in lipoprotein (a) inclusion if they had an LDL-C level ranging between levels beyond that seen in the placebo group was 50 mg/dL and 100 mg/dL while on a statin, an HDL-C reported, although this was not statistically significant. level less than 60 mg/dL, and a level of Anacetrapib did not significantly affect C-reactive protein 400 mg/dL or less. Patients were excluded if they had or triglyceride levels. Although the DEFINE study was severe chronic heart failure, uncontrolled hypertension, not designed to assess cardiovascular outcomes, a post or cardiac arrhythmias; active or chronic hepatobiliary hoc analysis showed a statistically significant difference or hepatic disease or severe renal impairment; and in the number of coronary revascularization procedures myocardial infarction, percutaneous coronary between groups during the 76-week treatment phase intervention, coronary artery bypass grafting, unstable (8 [1.0%] in the anacetrapib group versus 28 [3.5%] in angina, or stroke within the previous three months. the placebo group; P = 0.001). After a two-week screening and a placebo run-in period, 1,623 patients were randomly allocated to receive A two-year extension of the DEFINE trial is currently anacetrapib 100 mg or placebo once daily. All patients ongoing and will further evaluate the long-term safety received concomitant statin treatment with or without and efficacy of anacetrapib in patients with known, or at a other lipid-modifying agents. The primary efficacy high-risk for, coronary artery disease.36 Participants will outcomes were the percentage change from baseline in be assigned to the same treatment arm to which they were LDL-C after 24 weeks of treatment and safety assigned in the base study. The total duration of the measurements (including serum electrolyte and extension study will be up to 116 weeks, and will include aldosterone levels, blood pressure readings, and a two-year treatment period, followed by a 12-week off- electrocardiography) during the 76-week treatment drug phase. In addition, some participants will be period. Secondary efficacy outcomes included the evaluated in an extended off-drug phase, with a total change in LDL-C from baseline to week 76 and duration of one year. The estimated study completion changes in HDL-C, apo B, and apo A-I after 24 weeks date is November 2013. and 76 weeks of treatment. A pre-specified cardiovascular composite end point (including Whether the short-term effects of anacetrapib on lipid cardiovascular death, non-fatal myocardial infarction, levels translate into clinically meaningful reductions in non-fatal stroke, and hospitalization for unstable cardiovascular events and mortality is being investigated angina) was used to evaluate safety. Anacetrapib was in the ongoing REVEAL trial.35 The randomized, multi- discontinued if an LDL-C level of less than 25 mg/dL centre, double-blinded, placebo-controlled trial will was measured at two consecutive visits. recruit patients 50 years or older with a history of cardiovascular disease (e.g., myocardial infarction, The two groups were matched at baseline for cerebrovascular atherosclerotic disease, peripheral arterial demographic and clinical characteristics. The average disease, or diabetes with other evidence of symptomatic age was 63 years and the majority (83.5%) of coronary artery disease). All patients will receive participants were Caucasian. Most participants (54.7%) concomitant statin treatment. Patients allocated to receive had prior coronary artery disease. The majority of 100 mg anacetrapib will be compared to those on placebo patients had diabetes (53.1%) and hypertension to determine if the addition of anacetrapib reduces the (67.8%). There was a higher rate of discontinuation in risk of major coronary events (defined as coronary the anacetrapib group compared with placebo due to death, myocardial infarction, or coronary two consecutive measurements of LDL-C levels of less revascularization procedure). The trial is expected to than 25 mg/dL during the treatment period (142 patients enrol 30,000 participants, who will be followed for up to in the anacetrapib group [17.6%] versus one patient in five years. The estimated completion date is January the placebo group [0.1%]). At 24 weeks, statistically 2017. Anacetrapib, when added to ongoing statin therapy, significant changes in LDL-C and HDL-C beyond that is also being studied in two phase 3 trials in patients with seen with placebo were reported in the anacetrapib heterozygous familial hypercholesterolemia33 and in group ― a 39.8% reduction in LDL-C and a 138.1% Japanese patients with dyslipidemia.34 The primary increase in HDL-C; P < 0.001 for both (Table 1). outcome for both studies is the percentage change from Statistically significant changes in apo A-I and apo B baseline in LDL-C. The percentage change in HDL-C is levels beyond that with placebo were also reported being assessed as a secondary outcome. Each trial is (P < 0.001 for both). All lipid and lipoprotein changes expected to enrol 300 participants and results for both are were sustained during the course of the 76-week anticipated in 2014.

The Canadian Agency for Drugs and Technologies in Health (CADTH) is funded by Canadian federal, provincial, and territorial governments. (www.cadth.ca) Table 1: Summary of DEFINE Trial Results32 Variable* Baseline Week 24 Week 76 Level Level Placebo-adjusted % Level Placebo-adjusted % change from baseline change from baseline (95% CI) (95% CI) HDL-C (mg/dL) Placebo 40.4 45.5 138.1 44.9 138.8 (n = 797) (n = 744) (133.9 to 142.4)† (n = 664) (134.5 to 143.0)† Anacetrapib 40.5 101.2 102.3 (n = 797) (n = 686) (n = 541) LDL-C (mg/dL) Placebo 82.2 76.8 –39.8 76.7 –36.2 (n = 794) (n = 742) (–42.1 to –37.5)† (n = 663) (–38.7 to –33.6)† Anacetrapib 81.2 44.7 48.9 (n = 794) (n = 683) (n = 536) Apo A-I (mg/dL) Placebo 142.8 144.9 44.7 141.1 42.3 (n = 780) (n = 777) (42.8 to 46.5)† (n = 675) (40.5 to 44.1)† Anacetrapib 142.5 208.0 203.0 (n = 778) (n = 774) (n = 571) Apo B (mg/dL) Placebo 88.9 89.2 –21.0 85.5 –18.3 (n = 779) (n = 777) (–22.7 to –19.3)† (n = 675) (–20.2 to –16.4)† Anacetrapib 88.4 70.1 69.6 (n = 780) (n = 775) (n = 572) Triglycerides (mg/dL) Placebo 128.0 128.0 –6.8 124.0 –5.3 (n = 797) (n = 744) (–9.9 to –3.9) (n = 667) (–8.9 to –1.7) Anacetrapib 127.0 112.0 107.0 (n = 799) (n = 689) (n = 544) Lipoprotein (a) (nmol/L) Placebo 25.9 29.6 –36.4 31.3 –38.8 (n = 768) (n = 765) (–40.7 to –32.3) (n = 668) (–44.5 to –33.9) Anacetrapib 26.8 14.8 16.4 (n = 762) (n = 758) (n = 560) C-reactive protein (mg/L) Placebo 1.6 1.6 10.0 1.4 18.3 (n = 783) (n = 776) (3.2 to 16.7) (n = 681) (10.7 to 25.5) Anacetrapib 1.4 1.7 1.5 (n = 779) (n = 776) (n = 573)

Apo = apolipoprotein; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol. *Levels and placebo-adjusted percentage changes from baseline (changes from baseline beyond that with placebo) are means for all variables except for triglycerides, lipoprotein (a), and C-reactive protein for which medians are shown. †P < 0.001

The Canadian Agency for Drugs and Technologies in Health (CADTH) is funded by Canadian federal, provincial, and territorial governments. (www.cadth.ca) Adverse Effects Concurrent Developments Safety assessments from the two completed trials (Eli Lilly and Co., Indianapolis, Indiana) is show no evidence that anacetrapib has an effect on another CETP inhibitor currently under investigation. A blood pressure, serum aldosterone levels, or serum 12-week phase 2 trial in 398 patients with dyslipidemia electrolyte levels.30,32 The overall incidence of adverse showed that evacetrapib administered as monotherapy events of anacetrapib in the dose-ranging study were produced statistically significant increases in HDL-C of similar to placebo, and no dose-related trends were up to 128.8% and statistically significant decreases in identified.30 Constipation, diarrhea, dyspepsia, and LDL-C of up to 35.9% (P < 0.001 compared with myalgia were the most prevalent adverse events placebo for both).37 A statistically significant reduction attributed to treatment, and no patient experienced or in the level of triglycerides was also observed with the discontinued therapy due to serious adverse events.30 administration of the highest dose of evacetrapib Some non–dose-related incidences of clinically (10.8%; P = 0.006 compared with placebo). Compared relevant elevations in liver enzymes and creatine with evacetrapib monotherapy, the combination of a kinase were reported. However, there were no cases of statin and evacetrapib resulted in greater reductions in hepatitis, myopathy, or rhabdomyolysis.30 LDL-C but no greater increase in HDL-C. Evacetrapib had no effect on blood pressure or serum aldosterone During the DEFINE trial, no significant differences levels. A phase 3 trial is currently evaluating the were noted between the anacetrapib and placebo group efficacy of evacetrapib for the prevention of in the percentage of patients experiencing adverse cardiovascular events in patients with high-risk effects that were thought to be related to the study cardiovascular disease (those with a history of acute drug or that led to its discontinuation.32 There were no coronary syndrome, cerebrovascular atherosclerotic significant differences in the percentages of patients disease, peripheral arterial disease, or diabetes with with myalgias or elevations in creatine kinase. There documented coronary artery disease).38 The primary were no cases of rhabdomyolysis in either study outcome measure will be time to first occurrence of the group. Fewer patients in the anacetrapib group composite end point of cardiovascular death, myocardial compared with the placebo group had liver enzymes infarction, stroke, coronary revascularization procedure, greater than three times the upper reference limit or hospitalization for unstable angina. An estimated (0.1% versus 1%; P = 0.02). Death from any cause 11,000 participants will be enrolled and followed for an occurred in 11 (1.4%) patients in the anacetrapib estimated four years. The expected completion date is group and 8 (1.0%) patients in the placebo group September 2015. (P = 0.50). A minority of these deaths were due to cardiovascular causes (4 [36.4%] in the anacetrapib Another CETP inhibitor (DEZ-001, Dezima Pharma, group and 1 [12.5%] in the placebo group). Pre- Amsterdam, The Netherlands) is set to begin phase 3 specified adjudicated cardiovascular events testing.39 Three other CETP inhibitors ― BAY 60-5521 (cardiovascular death, non-fatal myocardial infarction, (Bayer, Leverkusen, Germany),40 JTT-302 (Japan non-fatal stroke, and hospitalization for unstable Tobacco Inc., Tokyo, Japan),41 and DRL-17822 angina) occurred in 16 (2.0%) patients treated with (Dr. Reddy’s Laboratories Limited, Andhra Pradesh, anacetrapib compared with 21 (2.6%) patients India)42 — have all undergone phase 2 testing but do not receiving placebo (P = 0.40). Additional analyses currently have any ongoing trials. suggested that anacetrapib would not be associated Other HDL-C-raising treatment strategies currently with an increase in cardiovascular events as previously under phase 2 investigation include reconstituted forms seen with torcetrapib.32 of HDL or apo A-I mimetics (the use of short peptides to mimic the function of native apo A-I and potentially Cost enhance the functions of HDL), apo A-I-based infusion therapies that may also enhance HDL functionality, and The manufacturer’s price for anacetrapib is currently RVX-208 (the first orally available compound that unavailable, as it has not been approved for sale in induces apo A-I transcription in hepatocytes).43 The Canada. Lipid Sciences Plasma Delipidation System-2 (Lipid Sciences Inc, Pleasanton, California) is an investigational device that selectively removes cholesterol from HDL in samples of human plasma collected by apheresis. A feasibility study has shown

The Canadian Agency for Drugs and Technologies in Health (CADTH) is funded by Canadian federal, provincial, and territorial governments. (www.cadth.ca) that autologous delipidated HDL plasma infusions CETP retain their protective function against were well-tolerated and resulted in a non-significant atherosclerosis. While investigators have reported that trend toward atherosclerotic plaque regression.44 pharmacologic CETP inhibition does not impair the Monoclonal antibodies targeted against the PCSK9 lipid mobilizing activities of HDL,49 the effect on other protein to reduce LDL-C are also in development.45 antiatherosclerotic properties (including antithrombotic, REGN727/SAR236553 (Sanofi New York, New antiinflammatory, antioxidative, antiplatelet, and York/Regeneron Pharmaceuticals Inc., Tarrytown, vasodilatory functions) has not been extensively New York) and AMG 145 (Amgen Inc., Thousand investigated. Current clinical assays that simply measure Oaks, California) are currently entering phase 3 the total cholesterol content in HDL particles cannot trials.46 Other investigational lipid-lowering assess qualitative functional differences in these therapies in phase 2 and 3 trials include activities. More research is needed to address not only (a microsomal transfer protein inhibitor that decreases HDL quantity but also the functional quality of the triglycerides and VLDL), (an mRNA resulting HDL particles. inhibitor of apo B that lowers LDL), and GFT505 (a peroxisome proliferator activator that decreases Whether the lipid modifications seen with anacetrapib triglycerides and increases HDL).47 translate into a clinically meaningful reduction in the risk of cardiovascular events remains an important Rate of Technology Diffusion question. A reduction in cardiovascular risk has not been consistently observed among patients with genetically The DEFINE trial was primarily designed to determine reduced CETP function.50-56 Furthermore, the effect of if the “off target” adverse effects observed with increasing HDL-C on the residual cardiovascular risk torcetrapib would also occur with anacetrapib.48 It after statin therapy remains uncertain. No trial to date lacked the sample size and study duration to assess the has shown that HDL-C-increasing therapies result in an long-term safety and efficacy of anacetrapib for the additional cardiovascular risk reduction when added to improvement of cardiovascular outcomes. Results statin therapy.17,23,27-29 It is possible that any benefit from the larger population in the REVEAL trial will observed in cardiovascular outcomes may be due to this help determine whether lipid modification with incremental lowering of LDL-C beyond that achieved anacetrapib, in addition to statin therapy, is effective with statins. Furthermore, there is some evidence to for the secondary prevention of major coronary events suggest that in the setting of primary prevention of in patients who have a history of cardiovascular cardiovascular disease and in the presence of very low disease. The diverse ethnic population and broad concentrations of LDL-C, HDL-C concentration might inclusion criteria for participation, combined with the not predict cardiovascular risk.57 To ensure appropriate large number of participants, will not only help patient selection for anacetrapib therapy, further evaluate the primary hypothesis that CETP inhibition research is needed to determine if certain subgroups reduces cardiovascular risk, but will also facilitate respond better to anacetrapib with or without subgroup analyses to determine if there are categories concomitant statin therapy. of patients who may benefit more from therapy with anacetrapib. Until the results of the REVEAL trial are reported and the effect on cardiovascular outcomes are made Implementation Issues available, the potential cost-consequences of introducing anacetrapib as a therapeutic option for dyslipidemia are Anacetrapib has been shown to significantly increase unknown. If adopted into clinical practice, anacetrapib HDL-C by over 130% and decrease LDL-C by 40% in may be considered an adjunctive therapy to statins and patients with dyslipidemia and coronary artery disease. other treatments for dyslipidemia. In summary, the long- In contrast to torcetrapib, anacetrapib does not appear term safety and efficacy of anacetrapib for the primary to affect serum levels of aldosterone or electrolytes, or or secondary prevention of cardiovascular morbidity and increase blood pressure. Although these results are mortality needs to be clarified to determine the impact promising, there is considerable controversy regarding on clinical practice. targeting HDL-C as a therapy. It is not yet clear whether the HDL particles generated by inhibition of

The Canadian Agency for Drugs and Technologies in Health (CADTH) is funded by Canadian federal, provincial, and territorial governments. (www.cadth.ca) 9. Sacks FM, Tonkin AM, Shepherd J, Braunwald E, References Cobbe S, Hawkins CM, et al. Effect of on coronary disease events in subgroups defined by 1. Genest J, McPherson R, Frohlich J, Anderson T, coronary risk factors: the Prospective Pravastatin Campbell N, Carpentier A, et al. 2009 Canadian Pooling Project. Circulation. 2000 Oct Cardiovascular Society/Canadian guidelines for 17;102(16):1893-900. the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult - 10. Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek 2009 recommendations. Can J Cardiol [Internet]. M, Grundy SM, et al. HDL cholesterol, very low 2009 Oct [cited 2013 Jan 22];25(10):567-79. levels of LDL cholesterol, and cardiovascular Available from: events. N Engl J Med. 2007 Sep 27;357(13):1301- http://www.ccs.ca/download/consensus_conferenc 10. e/consensus_conference_archives/2009_Dyslipide 11. Assmann G, Schulte H. The Prospective mia-Guidelines.pdf Cardiovascular Munster (PROCAM) study: 2. Statistics Canada. CANSIM [Internet]. Ottawa: prevalence of hyperlipidemia in persons with Statistics Canada. Table 102-05511: Deaths and hypertension and/or diabetes mellitus and the mortality rate, by selected grouped causes, age relationship to coronary heart disease. Am Heart J. group and sex, Canada annual; 2012 [cited 2013 1988 Dec;116(6 Pt 2):1713-24. Jan 22]. Available from: 12. Gordon T, Castelli WP, Hjortland MC, Kannel WB, http://www5.statcan.gc.ca/cansim/pick- Dawber TR. High density lipoprotein as a protective choisir?lang=eng&p2=33&id=1020551 factor against coronary heart disease. The 3. Thériault L, Stonebridge C, Browarski S. The Framingham Study. Am J Med. 1977 Canadian heart health strategy: risk factors and May;62(5):707-14. future cost implications [Internet]. Ottawa: 13. Goldbourt U, Yaari S, Medalie JH. Isolated low Conference Board of Canada; 2010 Jan. [cited HDL cholesterol as a risk factor for coronary heart 2013 Jan 22]. Available from: disease mortality. A 21-year follow-up of 8000 men. http://www.chhs.ca/sites/default/files/Conference Arterioscler Thromb Vasc Biol. 1997 %20Board%20Report%20English.pdf Jan;17(1):107-13. 4. Katz PM, Leiter LA. Drugs targeting high-density 14. Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, lipoprotein cholesterol for coronary artery disease Castelli WP, Knoke JD, et al. High-density management. Can J Cardiol. 2012;28(6):667-77. lipoprotein cholesterol and cardiovascular disease. 5. Baigent C, Keech A, Kearney PM, Blackwell L, Four prospective American studies. Circulation. Buck G, Pollicino C, et al. Efficacy and safety of 1989 Jan;79(1):8-15. cholesterol-lowering treatment: prospective meta- 15. Gutstein DE, Krishna R, Johns D, Surks HK, analysis of data from 90,056 participants in 14 Dansky HM, Shah S, et al. Anacetrapib, a novel randomised trials of statins. Lancet. 2005 Oct CETP inhibitor: pursuing a new approach to 8;366(9493):1267-78. cardiovascular risk reduction. Clin Pharmacol Ther. 6. Cannon CP, Braunwald E, McCabe CH, Rader 2012 Jan;91(1):109-22. DJ, Rouleau JL, Belder R, et al. Intensive versus 16. Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon moderate lipid lowering with statins after acute LT, Digenio AG, Clark RW, et al. Effects of an coronary syndromes. N Engl J Med. 2004 Apr inhibitor of cholesteryl ester transfer protein on 8;350(15):1495-504. HDL cholesterol. N Engl J Med. 2004 Apr 7. LaRosa JC, Grundy SM, Waters DD, Shear C, 8;350(15):1505-15. Barter P, Fruchart JC, et al. Intensive lipid 17. Barter PJ, Caulfield M, Eriksson M, Grundy SM, lowering with atorvastatin in patients with stable Kastelein JJ, Komajda M, et al. Effects of coronary disease. N Engl J Med. 2005 Apr torcetrapib in patients at high risk for coronary 7;352(14):1425-35. events. N Engl J Med. 2007 Nov 22;357(21):2109- 8. Pedersen TR, Faergeman O, Kastelein JJ, Olsson 22. AG, Tikkanen MJ, Holme I, et al. High-dose 18. Hu X, Dietz JD, Xia C, Knight DR, Loging WT, atorvastatin vs usual-dose simvastatin for Smith AH, et al. Torcetrapib induces aldosterone secondary prevention after myocardial infarction: and cortisol production by an intracellular calcium- the IDEAL study: a randomized controlled trial. mediated mechanism independently of cholesteryl JAMA. 2005 Nov 16;294(19):2437-45. ester transfer protein inhibition. Endocrinology. 2009 May;150(5):2211-9.

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The Canadian Agency for Drugs and Technologies in Health (CADTH) is funded by Canadian federal, provincial, and territorial governments. (www.cadth.ca) 52. Ridker PM, Pare G, Parker AN, Zee RY, Miletich JP, Chasman DI. Polymorphism in the CETP gene Cite as: Ndegwa S. Anacetrapib for the Treatment of region, HDL cholesterol, and risk of future Dyslipidemia [Issues in emerging health technologies, Issue 123]. Ottawa: Canadian Agency for Drugs and Technologies in myocardial infarction: Genomewide analysis Health; 2013. among 18 245 initially healthy women from the Women's Genome Health Study. Circ Cardiovasc CADTH thanks the external reviewer who kindly provided Genet [Internet]. 2009 Feb [cited 2013 Jan comments on an earlier draft of this bulletin.

23];2(1):26-33. Available from: ****************** http://www.ncbi.nlm.nih.gov/pmc/articles/PMC27 29193 Issues in Emerging Health Technologies is a series of concise bulletins describing drug and non-drug technologies that are not 53. Zhong S, Sharp DS, Grove JS, Bruce C, Yano K, yet used (or widely diffused) in Canada. The contents are based Curb JD, et al. Increased coronary heart disease in on information from early experience with the technology; however, further evidence may become available in the future. Japanese-American men with mutation in the These summaries are not intended to replace professional cholesteryl ester transfer protein gene despite medical advice. They are compiled as an information service for increased HDL levels. J Clin Invest [Internet]. those involved in planning and providing health care in Canada. 1996 Jun 15 [cited 2013 Jan 23];97(12):2917-23. While CADTH has taken care in the preparation of this Available from: publication to ensure that its contents are accurate, complete, and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC50 up to date as of February 2013, CADTH does not make any 7389 guarantee to that effect. CADTH is not responsible for any errors or omissions or injury, loss or damage arising from or relating to 54. Bruce C, Sharp DS, Tall AR. Relationship of the use (or misuse) of any information, statements, or HDL and coronary heart disease to a common conclusions contained in or implied by the information in this publication or in any of the source documentation. amino acid polymorphism in the cholesteryl ester transfer protein in men with and without This document and the information provided in this document hypertriglyceridemia. J Lipid Res. 1998 are prepared and intended for use in the context of the Canadian May;39(5):1071-8. health care system. Other health care systems are different; the issues, information related to the subject matter of this document 55. Agerholm-Larsen B, Nordestgaard BG, Steffensen may be different in other jurisdictions and, if used outside of Canada, it is at the user’s risk. This disclaimer and any questions R, Jensen G, Tybjaerg-Hansen A. Elevated HDL or matters of any nature arising from or relating to the content or cholesterol is a risk factor for ischemic heart use (or misuse) of this document will be governed by and disease in white women when caused by a interpreted in accordance with the laws of the Province of common mutation in the cholesteryl ester transfer Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the protein gene. Circulation. 2000 Apr courts of the Province of Ontario, Canada. 25;101(16):1907-12. CADTH is funded by Health Canada and the governments of 56. Borggreve SE, Hillege HL, Wolffenbuttel BH, de Alberta, British Columbia, Manitoba, New Brunswick, Jong PE, Zuurman MW, van der Steege G, et al. Newfoundland and Labrador, Northwest Territories, Nova An increased coronary risk is paradoxically Scotia, Nunavut, Ontario, Prince Edward Island, Saskatchewan, associated with common cholesteryl ester transfer and Yukon. CADTH takes sole responsibility for the final form and content of this report. The views expressed herein do not protein gene variations that relate to higher high- necessarily represent the views of Health Canada or any density lipoprotein cholesterol: a population-based provincial or territorial government. study. J Clin Endocrinol Metab. 2006 Sep;91(9):3382-8. Copyright © CADTH 2013. You are permitted to reproduce this document for non-commercial purposes, provided it is not 57. Ridker PM, Danielson E, Fonseca FA, Genest J, modified when reproduced and appropriate credit is given to CADTH. You may not otherwise copy, modify, translate, post on Gotto AM Jr, Kastelein JJ, et al. to a website, store electronically, republish, or redistribute any prevent vascular events in men and women with content from this document in any form or by any means without elevated C-reactive protein. N Engl J Med. 2008 the prior written permission of CADTH. Nov 20;359(21):2195-207. Please contact CADTH’s Vice-President of Corporate Services at [email protected] with any inquiries about this notice or other legal matters relating to CADTH’s services.

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The Canadian Agency for Drugs and Technologies in Health (CADTH) is funded by Canadian federal, provincial, and territorial governments. (www.cadth.ca)