Background The ODYSSEY COMBO I study ( http://clinicaltrials.gov/show/NCT01644175 ) evaluated efficacy and safety of alirocumab as add-on therapy to stable maximally tolerated daily statin with or ...without other lipid-lowering therapy in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia. Methods This multicenter, phase 3, randomized (2:1 alirocumab vs placebo), double-blind, 52-week trial enrolled 316 patients with established coronary heart disease or coronary heart disease risk equivalents and hypercholesterolemia. Alirocumab (75 mg every 2 weeks Q2W) or placebo Q2W was self-administered subcutaneously via 1 mL prefilled pen. The alirocumab dose was increased to 150 mg Q2W (also 1 mL) at week 12 if week 8 low-density lipoprotein cholesterol (LDL-C) was ≥70 mg/dL. The primary efficacy end point was percent change in LDL-C from baseline to week 24 (intention-to-treat analysis). Results At week 24, estimated mean (95% CI) changes in LDL-C from baseline were −48.2% (−52.0% to −44.4%) and −2.3% (−7.6% to 3.1%) for alirocumab and placebo, respectively, an estimated mean (95% CI) difference of −45.9% (−52.5% to −39.3%) ( P < .0001). Low-density lipoprotein cholesterol <70 mg/dL was achieved by 75% alirocumab versus 9% placebo patients at week 24. At week 12, 83.2% of evaluable alirocumab-treated patients remained on 75-mg Q2W. Treatment-emergent adverse events were comparable between groups. Conclusions Alirocumab treatment achieved a significantly greater reduction in LDL-C and allowed a greater proportion of patients to achieve LDL-C goals, versus placebo after 24 weeks in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia at baseline despite receiving maximally tolerated statin with or without other lipid-lowering therapy. The frequency of treatment-emergent adverse events and study medication discontinuations were generally comparable between treatment groups.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Cardiovascular disease (CVD) is the leading global cause of death, accounting for 17.3 million deaths per year. Preventive treatment that reduces CVD by even a small percentage can substantially ...reduce, nationally and globally, the number of people who develop CVD and the costs of caring for them. This American Heart Association presidential advisory on dietary fats and CVD reviews and discusses the scientific evidence, including the most recent studies, on the effects of dietary saturated fat intake and its replacement by other types of fats and carbohydrates on CVD. In summary, randomized controlled trials that lowered intake of dietary saturated fat and replaced it with polyunsaturated vegetable oil reduced CVD by ≈30%, similar to the reduction achieved by statin treatment. Prospective observational studies in many populations showed that lower intake of saturated fat coupled with higher intake of polyunsaturated and monounsaturated fat is associated with lower rates of CVD and of other major causes of death and all-cause mortality. In contrast, replacement of saturated fat with mostly refined carbohydrates and sugars is not associated with lower rates of CVD and did not reduce CVD in clinical trials. Replacement of saturated with unsaturated fats lowers low-density lipoprotein cholesterol, a cause of atherosclerosis, linking biological evidence with incidence of CVD in populations and in clinical trials. Taking into consideration the totality of the scientific evidence, satisfying rigorous criteria for causality, we conclude strongly that lowering intake of saturated fat and replacing it with unsaturated fats, especially polyunsaturated fats, will lower the incidence of CVD. This recommended shift from saturated to unsaturated fats should occur simultaneously in an overall healthful dietary pattern such as DASH (Dietary Approaches to Stop Hypertension) or the Mediterranean diet as emphasized by the 2013 American Heart Association/American College of Cardiology lifestyle guidelines and the 2015 to 2020 Dietary Guidelines for Americans.
To address concerns about cognitive decline with the use of PCSK9 inhibitors, automated neuropsychological testing was performed in patients who received evolocumab or placebo. Evolocumab was ...noninferior to placebo with respect to cognitive changes from baseline over 19 months.
In randomized trials and many observational studies, statins are associated with a modest excess of type 2 diabetes mellitus. High-intensity statins, such as atorvastatin 80 mg and rosuvastatin 20 ...mg, are associated with a higher excess risk of diabetes than moderate-intensity statins, such as atorvastatin 10 mg, simvastatin 20-40 mg, or pravastatin 40 mg.
Multiple mechanisms have been proposed for statin-associated diabetes risk, primarily related to increased insulin resistance or impaired insulin secretion. Genetic polymorphisms with reduced HMG CoA reductase function are associated with weight gain, insulin resistance, and diabetes. Animal models have shown that HMG CoA inhibition has multiple downstream effects that may increase diabetes risk. Statin impairment of insulin signaling, decreased adipocyte differentiation, decreased pancreatic β-cell insulin secretion, and other effects have also been found. The excess risk of diabetes appears to be confined to those who are already at risk for developing diabetes. Diabetes is diagnosed only 2-4 months earlier in statin-treated patients and therefore is unlikely to have no long-term adverse consequences.
The clinical impact of statin-associated diabetes is likely unimportant. The cardiovascular risk reduction benefit from statin far outweighs the potential for adverse effects in all but the very lowest risk individuals.
In a randomized trial, alirocumab (a monoclonal antibody that inhibits PCSK9), as compared with placebo, reduced LDL cholesterol levels by an additional 62 percentage points. In a post hoc analysis, ...the incidence of cardiovascular events was reduced with alirocumab.
Monoclonal antibodies to proprotein convertase subtilisin–kexin type 9 (PCSK9) have been shown to reduce low-density lipoprotein (LDL) cholesterol levels in patients who are being treated with statins. In phase 2 studies lasting 8 to 12 weeks, the PCSK9 inhibitor alirocumab lowered LDL cholesterol levels by 40 to 70% when added to background statin therapy.
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However, this new treatment needs to be evaluated in larger populations for longer periods of follow-up to establish its safety and efficacy.
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We conducted a 78-week trial comparing alirocumab (150 mg every 2 weeks) with placebo in 2341 patients at high risk for cardiovascular . . .
Symptoms during statin therapy are common and often attributed to statin intolerance. Recent data suggest few patients are truly intolerant to statins. Muscle symptoms are similar in statin and ...control groups in blinded treatment periods of clinical trials. The “nocebo” effect may occur during open-label statin treatment, when previously asymptomatic study participants report symptoms attributed to statin therapy, or during placebo-controlled trials. Most patients reporting statin intolerance can tolerate blinded moderate intensity statin therapy. In clinical practice the large majority of patients are willing to retry a statin, and of those who do, >80–90% successfully remain on statin therapy long-term. Emerging evidence from brain imaging studies and contemporary approaches to pain management suggests that building trust and managing patient expectations can minimize the “nocebo” effect in statin-treated patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Elevated lipoprotein(a) Lp(a) is independently associated with increased cardiovascular risk. However, treatment options for elevated Lp(a) are limited. Alirocumab, a monoclonal antibody to ...proprotein convertase subtilisin/kexin type 9, reduced low-density lipoprotein cholesterol (LDL-C) by up to 62% from baseline in phase 3 studies, with adverse event rates similar between alirocumab and controls. We evaluated the effect of alirocumab on serum Lp(a) using pooled data from the phase 3 ODYSSEY program: 4,915 patients with hypercholesterolemia from 10 phase 3 studies were included. Eight studies evaluated alirocumab 75 mg every 2 weeks (Q2W), with possible increase to 150 mg Q2W at week 12 depending on LDL-C at week 8 (75/150 mg Q2W); the other 2 studies evaluated alirocumab 150-mg Q2W from the outset. Comparators were placebo or ezetimibe. Eight studies were conducted on a background of statins, and 2 studies were carried out with no statins. Alirocumab was associated with significant reductions in Lp(a), regardless of starting dose and use of concomitant statins. At week 24, reductions from baseline were 23% to 27% with alirocumab 75/150-mg Q2W and 29% with alirocumab 150-mg Q2W (all comparisons p <0.0001 vs controls). Reductions were sustained over 78 to 104 weeks. Lp(a) reductions with alirocumab were independent of race, gender, presence of familial hypercholesterolemia, baseline Lp(a), and LDL-C concentrations, or use of statins. In conclusion, in addition to marked reduction in LDL-C, alirocumab leads to a significant and sustained lowering of Lp(a).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
IMPORTANCE: Effects on specific fatal and nonfatal end points appear to vary for low-density lipoprotein cholesterol (LDL-C)–lowering drug trials. OBJECTIVE: To evaluate whether baseline LDL-C level ...is associated with total and cardiovascular mortality risk reductions. DATA SOURCESAND STUDY SELECTION: Electronic databases (Cochrane, MEDLINE, EMBASE, TCTMD, ClinicalTrials.gov, major congress proceedings) were searched through February 2, 2018, to identify randomized clinical trials of statins, ezetimibe, and PCSK9-inhibiting monoclonal antibodies. DATA EXTRACTION AND SYNTHESIS: Two investigators abstracted data and appraised risks of bias. Intervention groups were categorized as “more intensive” (more potent pharmacologic intervention) or “less intensive” (less potent, placebo, or control group). MAIN OUTCOMES AND MEASURES: The coprimary end points were total mortality and cardiovascular mortality. Random-effects meta-regression and meta-analyses evaluated associations between baseline LDL-C level and reductions in mortality end points and secondary end points including major adverse cardiac events (MACE). RESULTS: In 34 trials, 136 299 patients received more intensive and 133 989 received less intensive LDL-C lowering. All-cause mortality was lower for more vs less intensive therapy (7.08% vs 7.70%; rate ratio RR, 0.92 95% CI, 0.88 to 0.96), but varied by baseline LDL-C level. Meta-regression showed more intensive LDL-C lowering was associated with greater reductions in all-cause mortality with higher baseline LDL-C levels (change in RRs per 40-mg/dL increase in baseline LDL-C, 0.91 95% CI, 0.86 to 0.96; P = .001; absolute risk difference ARD, −1.05 incident cases per 1000 person-years 95% CI, −1.59 to −0.51), but only when baseline LDL-C levels were 100 mg/dL or greater (P < .001 for interaction) in a meta-analysis. Cardiovascular mortality was lower for more vs less intensive therapy (3.48% vs 4.07%; RR, 0.84 95% CI, 0.79 to 0.89) but varied by baseline LDL-C level. Meta-regression showed more intensive LDL-C lowering was associated with a greater reduction in cardiovascular mortality with higher baseline LDL-C levels (change in RRs per 40-mg/dL increase in baseline LDL-C, 0.85 95% CI, 0.80 to 0.91; P < .001; ARD, −1.0 incident cases per 1000 person-years 95% CI, −1.51 to −0.45), but only when baseline LDL-C levels were 100 mg/dL or greater (P < .001 for interaction) in a meta-analysis. Trials with baseline LDL-C levels of 160 mg/dL or greater had the greatest reduction in all-cause mortality (RR, 0.72 95% CI, 0.62 to 0.84; P < .001; 4.3 fewer deaths per 1000 person-years) in a meta-analysis. More intensive LDL-C lowering was also associated with progressively greater risk reductions with higher baseline LDL-C level for myocardial infarction, revascularization, and MACE. CONCLUSIONS AND RELEVANCE: In these meta-analyses and meta-regressions, more intensive compared with less intensive LDL-C lowering was associated with a greater reduction in risk of total and cardiovascular mortality in trials of patients with higher baseline LDL-C levels. This association was not present when baseline LDL-C level was less than 100 mg/dL, suggesting that the greatest benefit from LDL-C–lowering therapy may occur for patients with higher baseline LDL-C levels.
Objectives To determine the relationship between non–high-density lipoprotein cholesterol (HDL-C) lowering and coronary heart disease (CHD) risk reduction for various lipid-modifying therapies. ...Background Non–HDL-C is the second lipid target of therapy after low-density lipoprotein cholesterol (LDL-C). Methods Randomized placebo or active-controlled trials were evaluated. The effect of mean non–HDL-C reduction on the relative risk of nonfatal myocardial infarction and CHD death was estimated using Bayesian random-effects meta-analysis models adjusted for study duration. Cochrane's Q was used to test for heterogeneity. Results Inclusion criteria were met by 14 statin (n = 100,827), 7 fibrate (n = 21,647), and 6 niacin (n = 4,445) trials, and 1 trial each of a bile acid sequestrant (n = 3,806), diet (n = 458), and ileal bypass surgery (n = 838). For statins, each 1% decrease in non–HDL-C resulted in an estimated 4.5-year CHD relative risk of 0.99 (95% Bayesian confidence interval: 0.98 to 1.00). The fibrate model did not differ from the statin model (Bayes factor K = 0.49) with no evidence of heterogeneity. The niacin model was moderately different from the statin model (K = 7.43), with heterogeneity among the trials (Q = 11.8, 5 df; p = 0.038). The only niacin monotherapy trial (n = 3,908) had a 1:1 relationship between non–HDL-C and risk reduction. No consistent relationships were apparent for the 5 small trials of niacin in combination. The 95% confidence intervals for the single trials of diet, bile acid sequestrants, and surgery also included the 1:1 relationship. Conclusions Non–HDL-C is an important target of therapy for CHD prevention. Most lipid-modifying drugs used as monotherapy have an ≈1:1 relationship between percent non–HDL-C lowering and CHD reduction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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