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Background: The risk of cardiovascular disease in type 1 diabetes remains extremely high, despite marked advances in blood glucose control and even the widespread use of cholesterol synthesis inhibitors. Thus, a deeper understanding of insulin regulation of cholesterol metabolism, and its disruption in type 1 diabetes, could reveal better treatment strategies., Methods: To define the mechanisms by which insulin controls plasma cholesterol levels, we knocked down the insulin receptor, FoxO1, and the key bile acid synthesis enzyme, CYP8B1. We measured bile acid composition, cholesterol absorption, and plasma cholesterol. In parallel, we measured markers of cholesterol absorption and synthesis in humans with type 1 diabetes treated with ezetimibe and simvastatin in a double-blind crossover study., Results: Mice with hepatic deletion of the insulin receptor showed marked increases in 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol. This phenotype was entirely reversed by hepatic deletion of FoxO1 . FoxO1 is inhibited by insulin and required for the production of 12α-hydroxylated bile acids, which promote intestinal cholesterol absorption and suppress hepatic cholesterol synthesis. Knockdown of Cyp8b1 normalized 12α-hydroxylated bile acid levels and completely prevented hypercholesterolemia in mice with hepatic deletion of the insulin receptor (n=5-30), as well as mouse models of type 1 diabetes (n=5-22). In parallel, the cholesterol absorption inhibitor, ezetimibe, normalized cholesterol absorption and low-density lipoprotein cholesterol in patients with type 1 diabetes as well as, or better than, the cholesterol synthesis inhibitor, simvastatin (n=20)., Conclusions: Insulin, by inhibiting FoxO1 in the liver, reduces 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol levels. Thus, type 1 diabetes leads to a unique set of derangements in cholesterol metabolism, with increased absorption rather than synthesis. These derangements are reversed by ezetimibe, but not statins, which are currently the first line of lipid-lowering treatment in type 1 diabetes. Taken together, these data suggest that a personalized approach to lipid lowering in type 1 diabetes may be more effective and highlight the need for further studies specifically in this group of patients.

Background: Evidence regarding the primary prevention of coronary artery disease events by low-density lipoprotein cholesterol (LDL-C) lowering therapy in older individuals, aged ≥75 years, is insufficient. This trial tested whether LDL-C-lowering therapy with ezetimibe is useful for the primary prevention of cardiovascular events in older patients., Methods: This multicenter, prospective, randomized, open-label, blinded end-point evaluation conducted at 363 medical institutions in Japan examined the preventive efficacy of ezetimibe for patients aged ≥75 years, with elevated LDL-C without history of coronary artery disease. Patients, who all received dietary counseling, were randomly assigned (1:1) to receive ezetimibe (10 mg once daily) versus usual care with randomization stratified by site, age, sex, and baseline LDL-C. The primary outcome was a composite of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke., Results: Overall, 3796 patients were enrolled between May 2009 and December 2014, and 1898 each were randomly assigned to ezetimibe versus control. Median follow-up was 4.1 years. After exclusion of 182 ezetimibe patients and 203 control patients because of lack of appropriate informed consent and other protocol violations, 1716 (90.4%) and 1695 (89.3%) patients were included in the primary analysis, respectively. Ezetimibe reduced the incidence of the primary outcome (hazard ratio [HR], 0.66; 95% CI, 0.50-0.86; P =0.002). Regarding the secondary outcomes, the incidences of composite cardiac events (HR, 0.60; 95% CI, 0.37-0.98; P =0.039) and coronary revascularization (HR, 0.38; 95% CI, 0.18-0.79; P =0.007) were lower in the ezetimibe group than in the control group; however, there was no difference in the incidence of stroke, all-cause mortality, or adverse events between trial groups., Conclusions: LDL-C-lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals aged ≥75 years with elevated LDL-C. Given the open-label nature of the trial, its premature termination and issues with follow-up, the magnitude of benefit observed should be interpreted with caution. Clinical Registration: URL: https://www.umin.ac.jp. Unique identifier: UMIN000001988.

Background: Patients who experience an acute coronary syndrome are at heightened risk of recurrent ischemic events, including stroke. Ezetimibe improved cardiovascular outcomes when added to statin therapy in patients stabilized after acute coronary syndrome. We investigated the efficacy of the addition of ezetimibe to simvastatin for the prevention of stroke and other adverse cardiovascular events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), with a focus on patients with a stroke before randomization., Methods: Patients who experienced acute coronary syndrome were randomized to a placebo/simvastatin or ezetimibe/simvastatin regimen and followed for a median of 6 years. Treatment efficacy was assessed for the entire population and by subgroups for the first and total (first and subsequent) events for the end points of stroke of any etiology, stroke subtypes, and the primary trial end point at 7 years., Results: Of 18 144 patients, 641 (3.5%) experienced at least 1 stroke; most were ischemic (527, 82%). Independent predictors of stroke included prior stroke, older age, atrial fibrillation, congestive heart failure, diabetes mellitus, myocardial infarction, and renal dysfunction. There was a nonsignificant reduction in the first event of stroke of any etiology (4.2% versus 4.8%; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.73-1.00; P =0.052) with ezetimibe/simvastatin versus placebo/simvastatin, driven by a significant 21% reduction in ischemic stroke (3.4% versus 4.1%; HR, 0.79; 95% CI, 0.67-0.94; P =0.008) and a nonsignificant increase in hemorrhagic stroke (0.8% versus 0.6%; HR, 1.38; 95% CI, 0.93-2.04; P =0.11). Evaluating total events, including the first and all recurrent strokes, ezetimibe/simvastatin reduced stroke of any etiology (HR, 0.83; 95% CI, 0.70-0.98; P =0.029) and ischemic stroke (HR, 0.76; 95% CI, 0.63-0.91; P =0.003). Patients who had experienced a stroke prior to randomization were at a higher risk of recurrence and demonstrated an absolute risk reduction of 8.6% for stroke of any etiology (10.2% versus 18.8%; number needed to treat=12; HR, 0.60; 95% CI, 0.38-0.95; P =0.030) and 7.6% for ischemic stroke (8.7% versus 16.3%; number needed to treat=13; HR, 0.52; 95% CI, 0.31-0.86; P =0.011) with ezetimibe added to simvastatin therapy., Conclusions: The addition of ezetimibe to simvastatin in patients stabilized after acute coronary syndrome reduces the frequency of ischemic stroke, with a particularly large effect seen in patients with a prior stroke., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00202878., (© 2017 American Heart Association, Inc.)

Background: A continuous relationship between reductions in low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE) has been observed in statin and ezetimibe outcomes trials down to achieved levels of 54 mg/dL. However, it is uncertain whether this relationship extends to LDL-C levels <50 mg/dL. We assessed the relationship between additional LDL-C, non-high-density lipoprotein cholesterol, and apolipoprotein B100 reductions and MACE among patients within the ODYSSEY trials that compared alirocumab with controls (placebo/ezetimibe), mainly as add-on therapy to maximally tolerated statin., Methods: Data were pooled from 10 double-blind trials (6699 patient-years of follow-up). Randomization was to alirocumab 75/150 mg every 2 weeks or control for 24 to 104 weeks, added to background statin therapy in 8 trials. This analysis included 4974 patients (3182 taking alirocumab, 1174 taking placebo, 618 taking ezetimibe). In a post hoc analysis, the relationship between average on-treatment lipid levels and percent reductions in lipids from baseline were correlated with MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization) in multivariable analyses., Results: Overall, 33.1% of the pooled cohort achieved average LDL-C <50 mg/dL (44.7%-52.6% allocated to alirocumab, 6.5% allocated to ezetimibe, and 0% allocated to placebo). In total, 104 patients experienced MACE (median time to event, 36 weeks). For every 39 mg/dL lower achieved LDL-C, the risk of MACE appeared to be 24% lower (adjusted hazard ratio, 0.76; 95% confidence interval, 0.63-0.91; P=0.0025). Percent reductions in LDL-C from baseline were inversely correlated with MACE rates (hazard ratio, 0.71; 95% confidence interval, 0.57-0.89 per additional 50% reduction from baseline; P=0.003). Strengths of association materially similar to those described for LDL-C were observed with achieved non-high-density lipoprotein cholesterol and apolipoprotein B100 levels or percentage reductions., Conclusions: In a post hoc analysis from 10 ODYSSEY trials, greater percentage reductions in LDL-C and lower on-treatment LDL-C were associated with a lower incidence of MACE, including very low levels of LDL-C (<50 mg/dL). These findings require further validation in the ongoing prospective ODYSSEY OUTCOMES trial., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01507831, NCT01623115, NCT01709500, NCT01617655, NCT01644175, NCT01644188, NCT01644474, NCT01730040, NCT01730053, and NCT01709513., (© 2016 The Authors.)

Background: Statins lower low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hs-CRP); addition of ezetimibe to statins further reduces LDL-C and hs-CRP. An analysis of the relationship between achieved LDL-C and hs-CRP targets and outcomes for simvastatin and ezetimibe/simvastatin was prespecified in Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT)., Methods and Results: The IMPROVE-IT trial randomly assigned 18 144 patients stabilized after acute coronary syndrome to simvastatin or ezetimibe/simvastatin. LDL-C and hs-CRP were measured at baseline and 1 month after randomization. Outcomes were assessed in those achieving one or both of the prespecified targets of LDL-C<70 mg/dL and hs-CRP<2 mg/L versus achieving neither target, adjusting for differences in baseline characteristics. An exploratory analysis examined targets of LDL-C<50 mg/dL and hs-CRP<1 mg/L. Patients meeting both targets at baseline, with no 1-month values, or with end points before 1 month were excluded. Of 15 179 patients, 39% achieved the dual LDL-C (<70 mg/dL) and hs-CRP (<2 mg/L) targets at 1 month, 14% met neither target, 14% met only the hs-CRP target, and 33% met only the LDL-C target. Those achieving dual targets had lower primary end point rates than those meeting neither target (cardiovascular death, major coronary event, or stroke; 38.9% versus 28.0%; adjusted hazard ratio, 0.73; 0.66-0.81; P<0.001). More patients treated with ezetimibe/simvastatin met dual targets than those treated with simvastatin alone (50% versus 29%, P<0.001). The association of dual-target attainment with improved outcomes was similar irrespective of treatment assignment (P-interaction=0.65). Similar findings were observed using the exploratory targets., Conclusions: Significantly more patients treated with ezetimibe/simvastatin met prespecified and exploratory dual LDL-C and hs-CRP targets than patients treated with simvastatin alone. Reaching both LDL-C and hs-CRP targets was associated with improved outcomes after multivariable adjustment., Clinical Trial Registration: URL: http://www.clinicaltrials.gov; Unique identifier: NCT00202878., (© 2015 American Heart Association, Inc.)