The ezetimibe controversy: implications for clinical practice

Khanderia, Ujjaini; Regal, Randolph E.; Rubenfire, Melvyn; Boyden, Thomas F.

doi:10.1177/1753944711410099

Cited by 15 publications

(10 citation statements)

References 63 publications

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“…Ezetimibe, an NPC1L1 inhibitor, was reported to reduce circulating LDL-C levels and improve clinical outcomes in patients at increased risk for cardiovascular events when administered alone or in combination with a statin [107]. Unlike in rodents in which NPC1L1 is mainly expressed in the intestine, NPC1L1 is highly expressed in the liver in humans [108, 109].…”

Section: Pharmacotherapeutic Candidates For Multidisciplinary Treamentioning

confidence: 99%

Multidisciplinary Pharmacotherapeutic Options for Nonalcoholic Fatty Liver Disease

Nakajima

2012

International Journal of Hepatology

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Nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are multidisciplinary liver diseases that often accompany type 2 diabetes or metabolic syndrome, which are characterized by insulin resistance. Therefore, effective treatment of type 2 diabetes and metabolic syndrome should target not only the cardiometabolic abnormalities, but also the associated liver disorders. In the last decade, it has been shown that metformin, thiazolidinediones, vitamin E, ezetimibe, n-3 polyunsaturated fatty acids, renin-angiotensin system (RAS) blockers, and antiobesity drugs may improve hepatic pathophysiological disorders as well as clinical parameters. Accordingly, insulin sensitizers, antioxidative agents, Niemann-Pick C1-like 1 (NPC1L1) inhibitors, RAS blockers, and drugs that target the central nervous system may represent candidate pharmacotherapies for NAFLD and possibly NASH. However, the efficacy, safety, and tolerability of long-term treatment (potentially for many years) with these drugs have not been fully established. Furthermore, clinical trials have not comprehensively examined the efficacy of lipid-lowering drugs (i.e., statins, fibrates, and NPC1L1 inhibitors) for the treatment of NAFLD. Although clinical evidence for RAS blockers and incretin-based agents (GLP-1 analogs and dipeptidyl peptidase-4 inhibitors) is also lacking, these agents are promising in terms of their insulin-sensitizing and anti-inflammatory effects without causing weight gain.

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Section: Pharmacotherapeutic Candidates For Multidisciplinary Treamentioning

confidence: 99%

Multidisciplinary Pharmacotherapeutic Options for Nonalcoholic Fatty Liver Disease

Nakajima

2012

International Journal of Hepatology

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“…23 It has been in studies examining this latter outcome where the benefit of ezetimibe therapy has been most strongly called into question. 2, 3, 24 However, a number of recent studies cast doubt on the utility of CIMT as a predictive measure for AD events. 25 For example, in data from 41 trials representing 18,307 individuals using a variety of lipid lowering treatments, Costanzo et al .…”

Section: Discussionmentioning

confidence: 99%

Effect of Ezetimibe on Major Atherosclerotic Disease Events and All-Cause Mortality

Hayek

Escaro

Sattar

et al. 2013

The American Journal of Cardiology

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Despite ezetimibe’s ability to reduce serum cholesterol levels, there are concerns over its vascular effects and whether it prevents or ameliorates atherosclerotic disease (AD). Our objective was to estimate the effect of ezetimibe use on major AD events and all-cause mortality and to compare these associations to those observed for hydroxy-methylglutaryl-CoA reductase inhibitor (i.e., statin) use. We identified 367 new ezetimibe users between November 1, 2002 and December 31, 2009. These individuals were ≥18 years of age and had no prior statin use. One to four statin user matches were identified for each ezetimibe user resulting in a total of 1,238 closely matched statin users. Pharmacy data and drug dosage information were used to estimate a moving window of ezetimibe and statin exposure for each day of study follow-up. The primary outcome was a composite of major AD events (coronary heart disease, cerebrovascular disease, and peripheral vascular disease events) and all-cause death. Both ezetimibe use (odds ratio [OR] 0.33, 95% CI 0.13–0.86) and statin use (OR 0.61, 95% CI 0.36–1.04) were associated with reductions in the likelihood of the composite outcome. These protective associations were most significant for cerebrovascular disease events and all-cause death. Subgroup analyses by sex, race-ethnicity, prior history of AD, diabetes status, and estimated renal function showed consistent estimates across strata with no significant differences between ezetimibe and statin use. In conclusion, ezetimibe appeared to have a protective effect on major AD events and all-cause death which was not significantly different from that observed for statin use.

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“…Mixed results from RCTs and an association with increased cancer risk have made ezetimibe use controversial for many clinicians [90]. This will likely change in light of the positive results from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), which enrolled 18,000 patients who were at least 50 years of age (median age of 63 years) with a history of an acute coronary syndrome and an LDL-C B125 mg/dL [91].…”

Section: Ezetimibementioning

confidence: 96%

Current Drug Treatment of Hyperlipidemia in Older Adults

2015

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Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death, especially in older adults. Managing modifiable risk factors (e.g., hyperlipidemia, hypertension) remains the primary approach to prevent ASCVD events and ASCVD-related mortality. Statins are generally considered one of the most effective approaches to reduce ASCVD risk, especially for secondary prevention, yet remain underutilized in older adults. The evidence to support statin therapy in older adults is less robust than in their younger counterparts, especially in individuals aged 75 years and older. Recent lipid guidelines have raised this concern, yet statin therapy is recommended in 'at risk' older adults. Determining which older adults should receive statin therapy for primary prevention of ASCVD is challenging, as the currently available risk estimation tools are of limited use in those aged over 75 years. Furthermore, non-statin therapies have been de-emphasized in recent clinical practice guidelines and remain understudied in the older adult population. This is unfortunate given that older adults are less likely to tolerate moderate- to high-intensity statins. Non-statin therapies could be viable options in this population if more was understood about their ability to lower ASCVD risk and safety profiles. Nevertheless, lipid-lowering agents remain an integral component of the overall strategy to reduce atherogenic burden in older adults. Future research in this area should aim to enroll more older adults in clinical trials, determine the utility of ASCVD risk estimation for primary prevention, and investigate the role of non-statin therapies in this population.

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The ezetimibe controversy: implications for clinical practice

Cited by 15 publications

References 63 publications

Multidisciplinary Pharmacotherapeutic Options for Nonalcoholic Fatty Liver Disease

Multidisciplinary Pharmacotherapeutic Options for Nonalcoholic Fatty Liver Disease

Effect of Ezetimibe on Major Atherosclerotic Disease Events and All-Cause Mortality

Current Drug Treatment of Hyperlipidemia in Older Adults

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