高龄老年混合型高脂血症患者联合调脂治疗的临床特点

目的探讨高龄老年混合型高脂血症患者联合调脂治疗的临床特点。方法选择我院接受联合调脂治疗的混合型高脂血症患者340例,根据年龄分为对照组140例(65～79岁),试验组200例(≥80岁)。常用联合调脂方案为烟酸+贝特、他汀+烟酸、他汀+贝特、他汀+多廿烷醇和他汀+依折麦布。观察2组患者用药前后TG、TC、LDL-C及HDL-C变化及不良反应情况。结果所有入选患者均表现为混合型高脂血症;试验组与对照组5种方案治疗后,方案烟酸+贝特降低TG和升高HDL-C幅度明显优于其他方案;他汀+烟酸、他汀+贝特、他汀+多廿烷醇和他汀+依折麦布降低TC、LDL-C水平明显优于烟酸+贝特(P<0.05,P<0.01)。试验组与对照组各方案疗效及治疗前后肝肾功能和肌酸激酶水平差异无统计学意义(P>0.05)。结论老年常用联合调脂方案主要有5类;烟酸+贝特降低TG及升高HDL-C的作用明显优于其他方案,其他4种方案降低TC、LDL-C水平均有较好疗效;各联合调脂方案对老年患者同样疗效确切,且安全性良好。     

What Combination Therapy with a Statin,If Any,Would You Recommend?

The latest recommended goals for blood lipid levels may require multiple lipid drugs. Lower doses in combination may render more efficacy and safety than highest doses of single agents. Except for isolated hypoalphalipoproteinemia (a low level of high-density lipoprotein cholesterol), therapies will start with a statin. All marketed statins are acceptable. The choice may be based on dose- efficacy and patient’s tolerability. High-potency statins (eg, atorvastatin, simvastatin, or rosuvastatin) are often chosen. Currently, generic statins, such as simvastatin, lovastatin, pravastatin, and fluvastatin, offer cost benefits. The choice of added agent depends on the “residual lipoprotein abnormalities” after statin therapy, efficacy, compliance issues, and cost. Approved “combined” preparations improve cost and compliance. To further lower low-density lipoprotein cholesterol, ezetimibe is a safe, efficacious choice, pending resolution of a controversial trial’s results. Colesevelam is moderately effective and the best tolerated bile acids sequestrant. In combined dyslipidemias, extended-release niacin is the best tolerated niacin preparation; other quality-controlled immediate-release preparations have similar safety and efficacy but produce more flushing of the skin. Niacin or fenofibrate is effective in normalizing high-density lipoprotein and triglyceride levels persisting after statin therapy. Agents approved by the US Food and Drug Administration and the latest guidelines of the National Cholesterol Education Program, American Heart Association/American College of Cardiology provide choices and indications of drug combinations.     

Ezetimibe: the first in a novel class of selective cholesterol-absorption inhibitors

Zetia (ezetimibe) is the first medication in the novel class of selective cholesterol-absorption inhibitors to be released in the United States. Ezetimibe selectively inhibits the uptake of cholesterol from the intestinal lumen at the level of the enterocyte in the intestinal brush border while having no effect on other sterols or lipid-soluble vitamins. Ezetimibe 10 mg daily produces a consistent reduction in low-density lipoprotein cholesterol (LDL-C) by approximately 15 to 20% when used as monotherapy or in combination with 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) or fenofibrate and a 4 to 9% increase in high-density lipoprotein cholesterol. Unlike other lipid-lowering medications that act in the gastrointestinal tract, ezetimibe does not appear to worsen hypertriglyceridemia. Ezetimibe also has an adverse-event profile that is similar to placebo when used as monotherapy or in combination with statins and fenofibrate. Studies of longer duration and with niacin, bile acid sequestrants, and gemfibrozil are warranted to more completely assess the safety of ezetimibe in combination therapy. To date, no clinically significant drug-drug interactions have been noted with the use of ezetimibe; however, further studies are warranted. Ezetimibe will be useful as monotherapy in patients who need modest reductions in LDL-C or are intolerant to other lipid-lowering medication, and in combination with a statin in patients who are unable to tolerate large doses of statins or need further reductions in LDL-C despite maximum doses of a statin. The long-term safety and the effect on cardiovascular morbidity and mortality of ezetimibe are unknown.     

LDL reduction: How low should we go and is it safe?

High-dose statin therapy or combination statin treatment is necessary for most patients to achieve aggressive lowdensity lipoprotein cholesterol goals. Adding ezetimibe or bile acid sequestrants appears unlikely to increase the risk of myopathy. Although the combination of niacin or fenofibrate with moderate-dose statins appears to be reasonably safe, the safety of combination with highdose statins has yet to be determined. To enhance patient outcomes, attention must be paid to characteristics that predict muscle and hepatic statin toxicity when considering using high-dose statin or combination statin therapy     

A review of trials evaluating nonstatin lipid-lowering therapies

Recently reported clinical trials raise doubts on the effectiveness of nonstatin lipid-lowering therapies in reducing the residual risk of cardiovascular events after statin monotherapy. Addition of torcetrapib to statin therapy increased overall mortality in coronary patients despite a marked increase in high-density lipoprotein cholesterol. Combining ezetimibe with statin therapy neither further reduces carotid atherosclerosis nor slows aortic stenosis, and it has not been shown to be superior to statin monotherapy in reducing cardiovascular events. Clinical trials currently in progress will more clearly delineate the cardiovascular effects of adding either ezetimibe or extended-release niacin/laropiprant to statin therapy.     

Pharmacoepidemiology safety study of fibrate and statin concomitant therapy

Combinations of statins and fibrates may be increasingly prescribed to achieve lipid goals in high-risk patients and those with other cardiovascular risk factors, such as mixed dyslipidemia. The purpose of this retrospective cohort study was to compare rates of hospitalization for specific diagnoses in a cohort of new users of statins or fibrates, using claims data from a large United States health insurer. New users of statin, fibrate, or statin-fibrate therapy from 2004 to 2007 were identified; followed for hospitalization with rhabdomyolysis, renal impairment, hepatic injury, or pancreatitis; and confirmed by medical record review. Incidence rates (IRs) were compared across categories of fibrate or statin use, with adjusted IR ratios estimated using Poisson regression. A total of 584,784 patients initiated statins or fibrates. The IR of rhabdomyolysis in statins was 3.30 per 100,000 patient-years; the adjusted IR ratio for statin-fenofibrate combinations compared to statins alone was 3.75 (95% confidence interval 1.23 to 11.40). The IRs of renal impairment and pancreatitis in statins were 108.87 per 100,000 patient-years and 45.76 per 100,000 patient-years, respectively; the adjusted IR ratios for statin-fenofibrate combinations compared to statins alone were 1.47 (95% confidence interval 1.12 to 1.93) and 2.87 (95% confidence interval 2.05 to 4.02), respectively. The IR of hepatic injury with statins was 8.57 per 100,000 patient-years, with no risk difference between exposure groups. In conclusion, the risk for rhabdomyolysis was low, although higher in patients newly treated with statin-fibrate concurrent therapy than those treated with either as monotherapy. The risk for pancreatitis was higher in patients treated with fenofibrate, whether in combination with statins or alone.     

Rediscovering bile acid sequestrants

Aim: In the recently published The Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) mega-trial, rosuvastatin significantly reduced cardiovascular events at the expense of a small but significant increase in the risk of developing type 2 diabetes. The increased risk of new-onset diabetes was in keeping with a recent meta-analysis which suggested that statins, with the possible exception of pravastatin, marginally increase the risk of developing type 2 diabetes.
Methods: Although the net effect of rosuvastatin was obviously very positive, we hypothesized that the addition of a bile aid sequestrant to a statin would not only further decrease lipid levels and potentially further decrease cardiovascular events but also protect against the development of diabetes. This is particularly relevant because the bile acid sequestrant, colesevelam, has recently been approved for therapy of diabetes.
Results: Colesevelam like other bile acid sequestrants lowers low-density lipoprotein levels by 16% and C-reactive protein by 22% beyond the reductions that occur with statin therapy alone. Bile acid sequestrants confer lipid-lowering, glucose-lowering, and anti-inflammatory benefits, and have been shown to reduce risk of cardiovascular events.
Conclusions: Therefore, colesevelam should be the most effective and logical agent to add to a statin in the diabetic and insulin-resistant patient, because in addition to lowering cardiac risk it may prevent the development of diabetes, as well as improving glycaemic control in the established diabetic patient.     

Efficacy of Combination Drug Pulse Therapy in Maintaining Lipid Levels in Patients Intolerant of Daily Statin Use

The objective of this study was to evaluate the efficacy of combination drug pulse therapy in maintaining lipid levels in patients intolerant of a daily dose of statins. Twenty‐three patients, previously receiving aggressive statin therapy, were treated twice weekly with rosuvastatin or atorvastatin in different dosages along with ezetimibe as well as daily doses of bile acid sequestrant for a mean period of 4.5 months. The recommended National Cholesterol Education Program Adult Treatment Panel III goals had already been achieved in 78% of patients (n=18) before starting combination pulse therapy. This combination therapy significantly increased high‐density lipoprotein cholesterol values by 5.82% (t=2.138, P=.044), while the increases in total cholesterol, low‐density lipoprotein cholesterol, triglyceride, and apolipoprotein B levels compared with baseline were not statistically significant. Overall, 3 of 23 patients (13%) discontinued the combination therapy because of muscle‐related symptoms over a mean course of 4.5 months of treatment.     

Is combined lipid-regulating therapy safe and feasible for the very old patients with mixed dyslipidemia?

Objectives To detect the efficacy and safety of combined lipid-regulating therapies in the very old patients with mixed dyslipidemia and determine an appropriate therapy for them. Methods Four hundred and fifty patients aged over 75 with mixed dyslipidemia were divided into five groups according to different combination therapies. Lipid levels and drug related adverse events were tested during the study. Results Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were reduced in every group compared to baseline: statin + ezetimibe: -30.0% and -55.5%; statin + policosanol: -31.1% and -51.2%; statin + fibrates: -23.7% and -44.6%; statin + niacin: -25.2% and -43.0%; and niacin + fibrates: -11.3% and -23.5%. The target achievement rates of LDL-C all exceeded 50%, except in niacin + fibrates (42.0%); statin + ezetimibe: 57.0%; statin + policosanol: 56.0%; statin + niacin: 52.0%; and statin + fibrates: 50.0%. However, overall, the niacin + fibrates group was the most effective in decreasing triglyceride (TG) and increasing high-density lipoprotein cholesterol (HDL-C) as follows: niacin + fibrates: -39.3% and 28.6%; statin + fibrates: -29.3% and 18.4%; statin + niacin: -18.5% and 16.7%; statin + ezetimibe: -17.1% and 7.1%; and statin + policosanol: -15.6% and 9.5%. The achievement rates of TG and HDL-C levels in niacin + fibrates (58.0% and 39.0%) were better than the other four groups: statin + niacin (34.0% and 34.0%), statin + fibrates (43.0% and 28.0%), statin + policosanol (30.0% and 24.0%) and statin + ezetimibe (28.0% and 25.0%). Patients in all five groups experiencing drug adverse events were only 2% and no severe adverse events occurred. Conclusions Statin + ezetimibe was the most effective group in lowering TC and LDL-C levels, while niacin + fibrates was the most effective in decreasing TG and increasing HDL-C levels. The commonly used combined lipid-regulating therapies with common dosages in this study were all quite safe and feasible for the very old patients with mixed hyperlipidemia.     

Management of Dyslipidemias in the Presence of the Metabolic Syndrome or Type 2 Diabetes

In the metabolic syndrome and type 2 diabetes, excess energy intake on the background of genetic predisposition and lifestyle factors leads to the dysregulation of fatty acid metabolism and acquired insulin resistance. These initial metabolic defects are reflected to both lipoprotein and glucose metabolism and contribute to increased risk for cardiovascular disease. However, even after controlling for the traditional cardiovascular risk factors, subjects with the metabolic syndrome and type 2 diabetes remain at high residual cardiovascular risk despite of low/normal LDL-cholesterol concentration. For 2 decades, statin therapy has been the cornerstone of treatment of dyslipidemia in these disorders. In the metabolic syndrome and type 2 diabetes, only statin treatment has demonstrated consistently a significant reduction in cardiovascular and all cause mortality in clinical trials. Lately, increased incidence of diabetes especially in the high-risk populations using statins has raised the debate whether statins are indicated for primary prevention especially in the metabolic syndrome. Guidelines recommend intensified lifestyle intervention to those in high risk groups on statin therapy to reduce the residual risk. Despite of the proven efficacy on plasma lipids, fibrate, or niacin as monotherapy, or in combination with statins has failed in reducing cardiovascular mortality. This underlies the fact that improvement in dyslipidemia or other biomarkers is not equal to the reduction in cardiovascular events. However, fibrates in combination with statins seem to be beneficial to reduce CVD events in subjects with low HDL-cholesterol (< 0.9?C1.1?mmol/L) and elevated triglycerides (> 2.3?mmol/L), but the data are derived from subgroup analysis of clinical trials. The position of niacin and ezetimibe and omega-3 fatty acids in treatment of dyslipidemia in the metabolic syndrome and type 2 diabetes is even less clear and remains to be established in future clinical trials.     

Effective use of combination lipid therapy

Despite the benefits of statin therapy, low-density lipoprotein (LDL) cholesterol management remains suboptimal and many patients do not achieve their recommended target goals. The aim of combination lipid drug therapy in high-risk patients is to achieve LDL cholesterol and non-high-density lipoprotein (HDL) cholesterol goals with a minimum of serious adverse effects. Although statins are the drug of first choice, statin monotherapy may be limited by intolerance of dose escalation or failure to attain non-HDL cholesterol goals in those with mixed hyperlipidemia. Statins plus bile acid resins or ezetimibe can achieve greater than 50% reduction in LDL cholesterol, with little or no increase in adverse effects. Fibrates, niacin, and omega-3 fatty acids, when added to statins, can reduce triglycerides, increase HDL cholesterol, and reduce non-HDL cholesterol to a greater extent than statin monotherapy. The safety profile of combination lipid therapy is acceptable if the global coronary heart disease risk of the patient is high, thus producing a favorable risk to benefit ratio. Careful surveillance of hepatic transaminases, avoidance of gemfibrozil in statin-fibrate combinations, and awareness of statin-concomitant drug interactions is key to safe and efficacious use of combination lipid drug therapy.     

Effective use of combination lipid therapy

Despite the benefits of statin therapy, low-density lipoprotein cholesterol (LDL-C) management remains suboptimal and many patients do not achieve their recommended target goals. The aim of combination lipid drug therapy in high-risk patients is to achieve LDL-C and non-high-density lipoprotein cholesterol (HDL-C) goals with a minimum of serious adverse effects. Although statins are the drug of first choice, statin monotherapy may be limited by intolerance of dose escalation or failure to attain non-HDL-C goals in those with mixed hyperlipidemia. Statins plus bile acid resins or ezetimibe can achieve greater than 50% reduction in LDL-C, with little or no increase in adverse effects. Fibrates, niacin, and omega-3 fatty acids, when added to statins, can reduce triglycerides, increase HDL-C, and reduce non-HDL-C to a greater extent than statin monotherapy. The safety profile of combination lipid therapy is acceptable, if the global coronary heart disease risk of the patient is high, thus producing a favorable risk to benefit ratio. Careful surveillance of hepatic transaminases, avoidance of gemfibrozil in statin-fibrate combinations, and awareness of statin-concomitant drug interactions is key to safe and efficacious use of combination lipid drug therapy.     

Comparison of pleiotropic effects of statins vs fibrates on laboratory parameters in patients with dyslipidemia: A retrospective cohort study

Differences in the mechanism of action and potential pleiotropic effects between statins and fibrates would potentially drive a different effect on various laboratory parameters, but this remains controversial because of a paucity of reports comparing them. Therefore, the aim of this study was to compare the effects of statins and fibrates on laboratory parameters in Japanese patients in routine clinical practice.This retrospective cohort study included patients with dyslipidemia who had been newly treated with statin or fibrate monotherapy between January 2005 and December 2017. Patients were randomly matched into two sets of pairs by sex, age, and baseline triglyceride (TG) or low-density lipoprotein (LDL) cholesterol level. The 830 patients in TG-matched pairs (415 fibrate users and 415 matched statin users) and 1172 patients in LDL cholesterol-matched pairs (586 fibrate users and 586 matched statin users) were included in this study. Generalized estimating equations were used to estimate the effects of the drugs on serum creatinine level, estimated glomerular filtration rate (eGFR), urea nitrogen, hemoglobin A_1c, aspartate aminotransferase, and alanine aminotransferase (ALT), in addition to LDL cholesterol and TG levels, and red blood cell (RBC) and platelet (PLT) counts, up to 12 months after the start of study drug administration.In TG-matched pairs, the increases in creatinine and urea nitrogen levels (P = .010 and P < .001, respectively) and the decreases in eGFR, ALT level and RBC count (P < .001, P = .003, and P = .014, respectively) were greater in fibrate users than in statin users. The decrease in PLT count was greater in statin users than in fibrate users (P < .001). The mean changes in aspartate aminotransferase and hemoglobin A_1c levels were not significantly different between statin users and fibrate users. In LDL cholesterol-matched pairs, the differences in changes of all laboratory parameter levels between statin users and fibrate users were similar to those in TG-matched pairs.We demonstrate here that fibrates have a greater effect of increasing creatinine and urea nitrogen levels and of reducing eGFR, ALT level, and RBC count than statins, and that the lowering effect on PLT count is greater with statins than with fibrates.     

The role of ezetimibe in the prevention of cardiovascular disease: Where do we stand after ARBITER 6-HALTS

Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, rapidly became one of the most widely drugs in the US following its approval by the FDA in 2002. Due to its capacity to significantly lower LDL-C with few side effects, ezetimibe has been very useful in enabling patients who were statin intolerant to reach their recommended therapeutic goal for LDL-C. In addition, ezetimibe also reduces non-HDL-C and raises HDL-C, further enhancing its effectiveness in clinical practice. A significant preponderance of evidence supports the reduction of LDL-C and non-HDL-C as the most effective therapy to prevent or reverse atherosclerotic cardiovascular disease (ASCVD). However 3 recent clinical trials, ENHANCE, SEAS, and ARBITER 6-HALTS have raised questions about the efficacy and safety of ezetimibe and have led to a re-examination of its clinical use as a drug for managing lipid risk factors to prevent or manage ASCVD. An in-depth analysis of these three trials reveals methodological deficiencies and concerns with the statistical methods used which significantly diminish their indictment of the clinical utility of ezetimibe. In contrast, The SANDS trial has confirmed the effectiveness of ezetimibe in managing both LDL-C and non-HDL-C, and also demonstrated this drug’s ability to improve carotid atherosclerosis by producing regression of CIMT. One of the important conclusions of the SANDS Trail is that ezetimibe remains an effective adjunctive medication for use in patients who do not reach their LDL-C goals on statin monotherapy. However, as a significant residual risk for ASCVD remains even after aggressive goals for LDL-C and non-HDL-C are reached, current treatment strategies should emphasize managing of all cardiac risk factors and increasing HDL in addition to the attainment and maintenance of recommended goals for LDL-C and non-HDL-C. Hence, ezetimibe should be considered as an important component of broad-spectrum management of lipid risk factors with therapy that includes statins, niacin, bile acid sequestrants, fibrates and Omega 3 fatty acids in appropriate combinations in addition to therapeutic life change.     

Effect of statin withdrawal on frequency of cardiac events after vascular surgery

The discontinuation of statin therapy in patients with acute coronary syndromes has been associated with an increase of adverse coronary events. Patients who undergo major surgery frequently are not able to take oral medication shortly after surgery. Because there is no intravenous formula for statins, the interruption of statins in the postoperative period is a serious concern. The objective of this study was to assess the effect of perioperative statin withdrawal on postoperative cardiac outcome. Also, the association between outcome and type of statin was studied. In 298 consecutive statin users who underwent major vascular surgery, detailed cardiac histories were obtained, and medication use was noted. Postoperatively, troponin levels were measured on days 1, 3, 7, and 30 and whenever clinically indicated by electrocardiographic changes. End points were postoperative troponin release, myocardial infarction, and a combination of nonfatal myocardial infarction and cardiovascular death. Multivariate analyses and propensity score analyses were performed to assess the influence of type of statin and the discontinuation of statins for these end points. Statin discontinuation was associated with an increased risk for postoperative troponin release (hazard ratio 4.6, 95% confidence interval 2.2 to 9.6) and the combination of myocardial infarction and cardiovascular death (hazard ratio 7.5, 95% confidence interval 2.8 to 20.1). Extended-release fluvastatin was associated with fewer perioperative cardiac events compared with atorvastatin, simvastatin, and pravastatin. In conclusion, the present study showed that statin withdrawal in the perioperative period is associated with an increased risk for perioperative adverse cardiac events. Furthermore, there seemed to be better outcomes in patients who received statins with extended-release formulas.     

Management of the Patient with Statin Intolerance

Current guidelines recommend statins as first-line therapy for reducing low-density lipoprotein cholesterol (LDL-C) and preventing cardiovascular events. Patients taking statins frequently experience adverse effects during therapy. The first step is to determine whether the adverse effects are indeed related to statin therapy by statin dechallenge and rechallenge. Strategies for managing statin intolerance include changing statins, intermittent dosing, intensification of lifestyle modifications, and using other LDL-C-lowering agents such as ezetimibe, bile acid sequestrants, and LDL apheresis in suitable patients. More controversial approaches include red yeast rice, coenzyme Q10, and vitamin D supplementation. New therapies for LDL-C lowering are in development.     

Treating mixed hyperlipidemia and the atherogenic lipid phenotype for prevention of cardiovascular events

Statins reduce cardiovascular events and cardiovascular and total mortality in persons at risk for and with coronary disease, but there remains a significant residual event rate, particularly in those with the atherogenic lipid phenotype that is characterized by a low high-density lipoprotein (HDL) cholesterol and increase in non-HDL cholesterol. Large outcome trials designed to assess the value of combining statins with other agents to target HDL cholesterol and non-HDL cholesterol will not be completed for a few years, but there is ample evidence for the clinician to consider combination therapy. The choices for therapies to supplement statins include niacin, fibrates, and omega-3 fatty acids. We present the argument that after therapeutic lifestyle changes, the first priority should be the maximally tolerated effective dose of a potent statin. Evidence supports the addition of niacin as the second agent. In some situations, high-dose omega-3 fatty acid therapy could be the first agent added to statins. Although fibrate monotherapy alone or in combination with non-statin low-density lipoprotein cholesterol-lowering agents can be effective in mixed hyperlipidemia when statins are not tolerated, the combination of statin + fibrate should be considered second-line therapy until the efficacy and safety are established.     

Triglycerides and atherogenic dyslipidaemia: extending treatment beyond statins in the high-risk cardiovascular patient

Although statins significantly decrease the incidence of cardiovascular disease (CVD), residual CVD risk remains high. This may partly be due to uncorrected atherogenic dyslipidaemia. The driving force behind atherogenic dyslipidaemia is hypertriglyceridaemia, which results from hepatic oversecretion and/or hypocatabolism of triglyceride-rich lipoproteins, and is typical of type 2 diabetes and metabolic syndrome. Persistent atherogenic dyslipidaemia in patients treated with a statin according to low-density lipoprotein-cholesterol goals may be corrected with niacin, fibrates or n-3 fatty acids. Clinical trial evidence to inform best practice is limited, but new data support adding fenofibrate to a statin. A consistent feature of fibrate clinical trials is the specific benefit of these agents in dyslipidaemic patients and the improvement in diabetic retinopathy with fenofibrate. Ongoing clinical trials may provide good evidence for adding niacin to a statin. Low-dose n-3 fatty acids could be used routinely after a myocardial infarction, but the value of higher doses of n-3 fatty acids in reducing CVD risk remains to be demonstrated.