Combination therapy in the management of mixed dyslipidaemia

Whilst statin monotherapy is often sufficient to reach LDL-C goals, treatment may not reach all lipid goals in individuals with mixed dyslipidaemia typically associated with metabolic syndrome or type 2 diabetes. Double or triple combination therapy, which provides the opportunity to address multiple lipid abnormalities simultaneously, may be required to achieve targets in some patients. Addition of fenofibrate or niacin (nicotinic acid) to statin therapy is likely to be the first option, as recommended by national treatment guidelines; omega-3 fatty acids may also be useful. Careful monitoring is required when adding additional agents given the increased potential for drug interactions and side effects.     

Pharmacotherapy of Dyslipidemia

Reducing elevated levels of low-density-lipoprotein cholesterol (LDL-C) significantly reduces the incidence of coronary heart disease (CHD) events and mortality in hypercholesterolemic patients. CHD risk reduction is proportional to LDL-C reduction. Despite this knowledge, many physicians are not applying existing treatment guidelines to the extent required to achieve target LDL-C levels. Target LDL-C levels are not achievable for most patients without drug therapy. Based on their lipid-lowering abilities, safety, and tolerability profiles, the HMG-CoA reductase inhibitors (statins) are the first-line pharmacotherapeutic agents for hypercholesterolemia. The ability of statins to reduce CHD events and total mortality in primary- and secondary-prevention patients also supports this assertion. For combined dyslipidemia, statin monotherapy is a reasonable initial approach in patients with moderate hypertriglyceridemia because statins effectively lower both LDL-C and triglycerides. Fibrates or niacin are effective therapies for severe hypertriglyceridemia. Resins are moderately effective in isolated hypercholesterolemia, and are a useful alternative to statins in pregnant women or patients with liver disease. For severe hyperlipidemia that does not respond to single drug therapy, combination drug therapy may be required. This article reviews the various manifestations of dyslipidemia and assesses the most efficacious treatments.     

小剂量氟伐他汀联合非诺贝特治疗老年混合型高脂血症的临床研究

目的观察小剂量氟伐他汀联合非诺贝特治疗老年混合型高脂血症的疗效及安全性。方法将入选的70例老年混合型高脂血症患者，随机分为氟伐他汀单药治疗组（12=35，20mg／d），氟伐他汀（20mg／d）、非诺贝特（200mg，隔日1次）联合治疗组（12=35），疗程均为12周。结果联合治疗组血脂参数变化最显著，降低低密度脂蛋白胆固醇、三酰甘油和升高高密度脂蛋白胆固醇的能力明显优于单药组（P〈0．01或P〈0．05），且未发现明显不良反应。结论小荆量氟伐他汀与非诺贝特联合治疗可以更有效地改善老年混合型高脂血症患者的血脂异常，具有良好的安全性和耐受性。     

Combination drug therapy for combined hyperlipidemia

Combination therapy for hyperlipidemia, especially combined hyperlipidemia, may have advantages over single drug therapy, affording better improvement in lipoprotein risk factors and possibly better prevention of atherothrombotic events. Although preliminary experience has been gained using treatment combinations of niacin with statins, and fibrates with statins, few studies have focused on angiographic or clinical outcomes. Both of these treatment combinations increase the risk of drug-induced myopathy and rhabdomyolysis. Current estimates of myopathy incidence are much lower than original estimates, but the relative safety of combined therapy might depend upon employing low or moderate statin doses. Safety depends critically upon educating the patient to respond appropriately to muscle symptoms, to intercurrent illness, and to concurrent use of certain other medications. Other useful drug combinations include those derived by addition of fish oil, bile acid binding resins, or stanol esters, as well as nonstatin combinations such as niacin-resin or fibrate-niacin.     

Combination statin–fibrate therapy: safety aspects

Patients with type 2 diabetes or metabolic syndrome remain at high residual risk of cardiovascular events even after intensive statin therapy. While treatment guidelines recommend the addition of a fibrate to statin therapy in this setting, concerns about the potential for myopathy may limit the use of this combination in clinical practice. These concerns are certainly justified for gemfibrozil, which interferes with statin glucuronidation, leading to elevation in statin plasma concentrations and an increased risk of myotoxicity in combination with a range of commonly prescribed statins. However, the available evidence refutes suggestions that this is a class effect for fibrates. Fenofibrate does not adversely influence the metabolism or pharmacokinetics of any of the commonly prescribed statins. This in turn translates to a reduced potential for myotoxicity in combination with a statin. Data are awaited from the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) study to evaluate the efficacy and safety of fenofibrate plus simvastatin combination therapy in type 2 diabetes patients.     

Combination drug therapy for familial combined hyperlipidemia

STUDY OBJECTIVE: To compare the efficacy of gemfibrozil and colestipol with gemfibrozil and lovastatin in patients with familial combined hyperlipidemia. DESIGN: A prospective, randomized trial. SETTING: An outpatient clinical research center in a tertiary care center. PATIENTS: Seventeen patients with familial combined hyperlipidemia documented by studies of first-degree relatives; nine patients with type 2b hyperlipoproteinemia, and eight patients with type 4 hyperlipoproteinemia. INTERVENTIONS: Baseline lipid, lipoprotein, and apolipoprotein levels were obtained during control periods on diet alone and on gemfibrozil therapy. Patients then received gemfibrozil and colestipol or gemfibrozil and lovastatin in a randomized order. MEASUREMENTS AND MAIN RESULTS: In patients with type 2b hyperlipoproteinemia, gemfibrozil alone significantly reduced total cholesterol by 11%, and low density lipoprotein (LDL)-apolipoprotein B by 18%, did not change LDL-cholesterol, and raised high density lipoprotein (HDL)-cholesterol levels by 26%. Addition of either colestipol or lovastatin reduced LDL-cholesterol levels by 17% and 25%, respectively, compared to gemfibrozil alone. However, colestipol mitigated the HDL-cholesterol raising effect of gemfibrozil and did not further reduce LDL-apolipoprotein B levels. In contrast, addition of lovastatin caused an additional reduction of LDL-apolipoprotein B 19% compared with gemfibrozil alone. In patients with type 4 hyperlipoproteinemia, gemfibrozil alone reduced triglycerides by 40%, raised HDL-cholesterol by 26%, and increased LDL-cholesterol levels by 29%. The addition of either colestipol or lovastatin reduced LDL-cholesterol levels by 34% and 33%, respectively (compared with gemfibrozil alone), but greater reductions of LDL-apolipoprotein B (30% with lovastatin compared with 15% with colestipol, compared with gemfibrozil alone), and increases in HDL-cholesterol levels (8% increase with lovastatin compared with 10% decrease with colestipol, compared to gemfibrozil alone) were seen with the lovastatin combination. CONCLUSIONS: Although gemfibrozil with either colestipol or lovastatin favorably altered lipoprotein levels in patients with hypertriglyceridemia and familial combined hyperlipidemia, the combination of gemfibrozil and lovastatin appeared superior overall.     

Low-dose combination therapy with colesevelam hydrochloride and lovastatin effectively decreases low-density lipoprotein cholesterol in patients with primary hypercholesterolemia

BACKGROUND: Colesevelam hydrochloride is a novel, lipid-lowering agent that binds bile acids with high affinity. A multicenter, randomized, double-blind, placebo-controlled, parallel-design study was conducted to assess the efficacy and tolerability of combination low-dose colesevelam and lovastatin treatment in patients with primary hypercholesterolemia. HYPOTHESIS: Combination therapy with low doses of colesevelam and lovastatin decreases low density (LDL) cholesterol with minimal adverse events. METHODS: Following a 4- to 6-week dietary lead in, 135 patients were randomized into five groups for a 4-week treatment period: placebo, colesevelam 2.3 g at dinner, lovastatin 10 mg at dinner, the combination of colesevelam and lovastatin given at dinner (dosed together), and combination treatment with colesevelam given at dinner and lovastatin administered at bedtime (dosed apart). RESULTS: Combination colesevelam and lovastatin treatment decreased LDL cholesterol by 34% (60 mg/dl, p < 0.0001) and 32% (53 mg/dl, p < 0.0001) when colesevelam and lovastatin were dosed together or dosed apart, respectively. Both combination therapies were superior to either agent alone (p < 0.05). Decreases in LDL cholesterol exceeded the combined decreases observed for colesevelam alone (13 mg/dl, 7%) and lovastatin alone (39 mg/dl, 22%). Both combination treatments reduced total cholesterol by 21% (p < 0.0001) and apolipoprotein B by 24% (p < 0.0001). Neither combination treatment significantly altered high-density lipoprotein cholesterol or triglycerides. Adverse side effects were not significantly different among randomized groups. CONCLUSIONS: Combination colesevelam and lovastatin was efficacious and well tolerated, resulting in additive decreases in LDL cholesterol levels whether or not both agents were administered simultaneously.     

A head-to-head comparison of the cost effectiveness of HMG-CoA reductase inhibitors and fibrates in different types of primary hyperlipidemia

Summary The objective of this study was to compare the lifetime cost-effectiveness of HMG-CoA reductase inhibitors and fibrates for the treatment of hyperlipidemia. Estimates of lipid modification achieved due to drug therapy were based on published head-to-head comparisons of specific HMG-CoA reductase inhibitors and fibrates in randomized, double-blind studies. We used a validated coronary heart disease (CHD) prevention computer model to estimate the costs and benefits of lifelong lipid modification. The patients were middle-aged men and women who were free of CHD, with either primary type IIa or IIb hyperlipidemia. The intervention used were specific HMG-CoA reductase inhibitors and fibrates at several dosages, which reduced total cholesterol 11–34% and increased high-density lipoprotein cholesterol 1–29%. The main outcome measure was the cost per year of life saved after discounting benefits and costs by 5% annually. The lifetime cost effectiveness of HMG-CoA reductase inhibitors (fluvastatin, lovastatin, pravastatin, simvastatin) and fibrates (bezafibrate, fenofibrate, gemfibrozil) for the treatment of primary hyperlipidemia varied according to patient population, the effectiveness of each drug in modifying lipid levels, and the price of each drug. The estimates of cost per year of life saved for HMG-CoA reductase inhibitors range from $19,886 to $73,632, and $16,955 to $59,488 for fibrates according to gender and type of primary hyperlipidemia. Fluvastatin 20 mg/day was significantly more cost effective than gemfibrozil 1200 mg/day for male patients with type IIa hyperlipidemia. Simvastatin 17.3 mg/day or 20 mg/day yielded similar cost-effectiveness ratios compared with fibrates among type II hyperlipidemic patients. However, micronized fenofibrate was more cost effective than simvastatin 20 mg/day among type IIb patients. The cost effectiveness of lipid therapy varies widely and can be maximized by selecting specific drugs for specific lipid abnormalities.     

Long-Term safety of pravastatin-gemfibrozil therapy in mixed hyperlipidemia

Background: Combined HMG-CoA reductase inhibitor and fibric acid derivative therapy is often necessary for the effective reduction of concentrations of low-density lipoprotein (LDL) cholesterol and triglycerides in patients with mixed hyperlipidemia; however, the potential risk of myopathy has limited the use of these agents. Hypothesis: This study evaluated long-term safety and efficacy of combined pravastatin and gemfibrozil therapy. Methods: Eighty-three patients with hyperlipidemia were treated with combined pravastatin and gemfibrozil therapy for a median of 44 months (range 9–78 months). Plasma lipids, serum liver function tests, creatinine, and creatinine kinase (CK) levels were measured every 3 to 4 months. Results: One patient developed myalgia with a normal CK level after 4 months of combination therapy. Three patients had transient elevations in CK levels that ranged from 3 to 5 times the upper limits of “normal” and that returned to normal upon repeat testing. Liver function tests did not change significantly from baseline. in a subset of 26 previously untreated patients, combined pravastatin (mean daily dose 22 mg) and gemfibrozil (mean daily dose 1,154 mg) therapy lowered total cholesterol by 25% (p<0.001), triglycerides by 53% (p = 0.0001), LDL cholesterol by 14% (p = 0.24), and increased high-density lipoprotein (HDL) cholesterol by 20% (p = 0.012). Conclusion: Pravastatin and gemfibrozil therapy is safe and efficacious in patients with mixed hyperlipidemia. The long-term safety results are consistent with other reports on follow-up of shorter duration.     

Physician extenders for cost-effective management of hypercholesterolemia

OBJECTIVE: Treatment of elevated cholesterol levels reduces morbidity and mortality from coronary heart disease in high-risk patients, but can be costly. The purpose of this study was to determine whether physician extenders emphasizing diet modification and, when necessary, effective and inexpensive drug algorithms can provide more cost-effective therapy than conventional care. DESIGN: Randomized controlled trial. SETTING: A Department of Veterans Affairs Medical Center. PATIENTS: Two hundred forty-seven veterans with type IIa hypercholesterolemia. INTERVENTIONS: Patients assigned to either a cholesterol treatment program (CTP) or usual health care provided by general internists (UHC). CTP included intensive dietary therapy administered by a registered dietitian utilizing individual and group counseling and drug therapy initiated by physician extenders for those failing to achieve goal low-density lipo-protein (LDL) levels with diet alone. A drug selection algorithm for CTP subjects utilized niacin as initial therapy followed by bile acid sequestrants and lovastatin. Subjects were followed prospectively for 2 years. MEASUREMENTS: Primary outcome measurements were effectiveness of therapy defined as reductions in LDL cholesterol (LDL-C), and whether goal LDL-C levels were achieved; costs of therapy; and cost-effectiveness defined as the cost per unit reduction in the LDL-C. MAIN RESULTS: Total program costs were higher for CTP patients than for UHC patients ($659±$43 vs $477±$42 per patient, p<.001). However, at 24 months the patients in CTP were more likely to achieve LDL goal levels (65% vs 44%,p<.005), and also achieved greater reductions in LDL-C 27%±2% vs 14%±2% at 24 months,p<.001). Program costs per unit (mmol/L) reduction in the LDL-C, a measure of cost-effectiveness, was significantly lower for CTP ($758±$58 vs $1,058±$70,p=.002). CONCLUSIONS: Although more expensive than usual care, the greater effectiveness of physician extenders implementing cholesterol treatment algorithms resulted in more cost-effective therapy. Supported by Health Services Research and Delivery grant 88-127, Department of Veterans Affairs.     

Combination therapy with anabolic and antiresorptive agents

Combination therapy, the use of an anabolic agent with an antiresorptive agent in some sequence, has been evaluated in a number of clinical trials. There is no fracture data on combination therapy except for a small trial using PTH and estrogen. It appears that simultaneous use of a bisphosphonate (alendronate 10 mg per day) with PTH offers no advantage (and appears to blunt PTH's effect) compared with the use of PTH alone based on bone density gains. Previous therapy with alendronate also blunts gains in bone density with PTH therapy. Estrogen and raloxifene, whether given before or with PTH, do not blunt its anabolic effect. Sequential therapy with PTH followed by an antiresorptive agent (alendronate) offers the greatest gains in bone mass. It is possible that alendronate or other bisphosphonates given in a different dosing regimes may have different effects on PTH's anabolic effect. More trial data on combination therapy is needed.     

慢性乙型肝炎联合抗病毒治疗研究进展

抗病毒治疗是慢性乙型肝炎治疗的重要手段。目前单一药物的疗效不令人满意,越来越多的研究数据表明药物联合抗病毒治疗,包括干扰素α和核苷（酸）类似物联合治疗以及两种核苷（酸）类似物联合治疗可以减少耐药发生、提高抗病毒疗效,因而联合抗病毒治疗可能是控制乙肝的有效策略。     

Clinical Relevance of hyperlipidemia

Summary This review concerns the clinical impact of treating hyperlipidemia. The U.S. Lipid Research Clinics Coronary Primary Prevention Trial, the Helsinki Heart Study, and the Olso Primary Prevention Trial all consistently showed that intensive and long-term (5–7 years) lipidlowering treatment is successful in reducing the incidence of fatal and nonfatal myocardial infarction. Secondary prevention trials (Coronary Drug Project, and the Stockholm Ischaemic Heart Disease Secondary Prevention Study) have overall confirmed this result. Assessment of progression/ regression of atherosclerosis by invasive or noninvasive methods has shown that an important mechanism underlying the reduction of coronary events with long-term lipidlowering treatment is that involving stabilization or regression of arterial lesions. An, additional advantage from lipidlowering treatment might come from useful hemodynamic changes, occurring shortly after the start of an intensive cholesterol-lowering treatment with low-density lipoprotein apheresis.     

Combination drug therapy for dyslipidemia

Effective treatment of dyslipidemia improves prognosis. Statin therapy has been documented to decrease the cardiovascular event rate in the setting of elevated low-density lipoprotein (LDL) cholesterol levels and coronary heart disease, but most patients are not treated to the target (LDL ≤100 mg/dL) set by the National Cholesterol Education Program. The triglyceride level is also being increasingly recognized as an important mediator in the process of progressive atherosclerosis and cardiovascular events. Studies suggest the target level for triglycerides should be the same as for LDL cholesterol levels— no more than 100 mg/dL. In order to achieve these LDL and triglyceride levels, combination therapy is required frequently. Probably the most effective combination for mixed dyslipidemia is a statin with niacin. The use of adjunctive omega-3 supplementation also should be considered especially for patients with elevated triglyceride levels. Other adjunctive agents including sitostanol ester (in the form of a margarine) and a well-tolerated second generation bile acid sequestrant that will lower LDL cholesterol an additional 10% to 18% and will be available soon.     

抗结核固定剂量复合剂与板式组合药治疗肺结核效果对比分析

目的研究国产抗结核FDC的有效性和安全性，探索适合深圳市结核病防治用药。方法从深圳市罗湖区和南山区登记的全部初治涂阳病例中随机抽取200例，其中FDC组、对照组（板式组合药）各100例，均采用全程督导的方式。对两组病人的用药剂量、临床表现、治疗效果、不良反应进行分析比较。结果（1）FDC组与对照组患者1、2、3、6个月末相关临床症状（如盗汗、发热、咳嗽、咯血、胸痛、呼吸困难、乏力）的出现率均逐渐下降，两组无显著性差异（P〉0．05）；（2）FDC组与对照组2个月末痰菌阴转率分别为88％、84％，6个月末痰菌阴转率提高到98％、97％，两组6个月末结核空洞闭合率分别为58．3％、48．6％，痰菌阴转率X线胸片吸收率和空洞闭合率均无显著性差异（P〉0．05）；（3）FDC组与对照组临床不良反应率分别为25％和18％，WBC异常率分别为18％和11％，AST异常率分别为16％和9％，TBIL异常率分别为19％和15％，临床和实验室检测的结果均无显著性差异（P〉0．05）；（4）FDC中利福平（R）的体质量与剂量相关系数为0．804，高于组合药中利福平（R）的体质量与剂量相关系数（0．781）。FDC组异烟肼（H）、利福平（R）、吡嗪酰胺（Z）、乙胺丁醇（E）的用药剂量低于对照组，有显著性差异（P〈0．05）。结论国产FDC与板武组合药的治疗效果相同，不良反应率相近，但FDC药物的用药剂量低，具有一定的推广应用前景。     

抗结核固定剂量复合剂与板式组合药治疗肺结核效果对比分析

目的研究国产抗结核FDC的有效性和安全性,探索适合深圳市结核病防治用药。方法从深圳市罗湖区和南山区登记的全部初治涂阳病例中随机抽取200例,其中FDC组、对照组(板式组合药)各100例,均采用全程督导的方式。对两组病人的用药剂量、临床表现、治疗效果、不良反应进行分析比较。结果(1)FDC组与对照组患者1、2、3、6个月末相关临床症状(如盗汗、发热、咳嗽、咯血、胸痛、呼吸困难、乏力)的出现率均逐渐下降,两组无显著性差异(P<0.05);(2)FDC组与对照组2个月末痰菌阴转率分别为88%、84%,6个月末痰菌阴转率提高到98%、97%,两组6个月末结核空洞闭合率分别为58.3%、48.6%,痰菌阴转率X线胸片吸收率和空洞闭合率均无显著性差异(P<0.05);(3)FDC组与对照组临床不良反应率分别为25%和18%,WBC异常率分别为18%和11%,AST异常率分别为16%和9%,TBIL异常率分别为19%和15%,临床和实验室检测的结果均无显著性差异(P<0.05);(4)FDC中利福平(R)的体质量与剂量相关系数为0.804,高于组合药中利福平(R)的体质量与剂量相关系数(0.781)。FDC组异烟肼(H)、利福平(R)、吡嗪酰胺(Z)、乙胺丁醇(E)的用药剂量低于对照组,有显著性差异(P<0.05)。结论国产FDC与板式组合药的治疗效果相同,不良反应率相近,但FDC药物的用药剂量低,具有一定的推广应用前景。     

Combination therapy with calcium-entry blockers and beta-adrenoceptor antagonists in hypertension

The use of more than one drug to control blood pressure may be necessary in up to 50% of hypertensive patients seen in clinical practice. A rational basis for combination therapy includes 1) the use of drugs that act on different physiological systems involved in blood-pressure control and 2) using a second drug to counteract reflex responses, which may limit the effectiveness of the first, and, 3) as is less commonly practiced, the use of low doses of two drugs that act on the same or different physiological systems to avoid the side effects encountered with higher doses of single agents.The hemodynamic effects of calcium-entry blocking druga and beta-adrenoceptor blockers are complementary and synergism might be anticipated, particularly with the dihydropyridines and beta-blockers, since the latter prevent the short-term reflex increase in sympathetic activity occurring as a consequence of vasodilation.     

Combination therapy with prostacyclin and tadalafil for severe pulmonary arterial hypertension: a pilot study

Despite the introduction of new drugs that have changed the course of pulmonary arterial hypertension (PAH), some patients are still refractory to treatment and deteriorate rapidly. Long-acting phosphodiesterase-5 inhibitors are a new class of drugs that are effective in PAH. This prospective study assessed the potential of combination therapy with prostacyclin and tadalafil for treatment of severe PAH. We report four cases of severe PAH that deteriorated despite prostacyclin therapy. Two patients had Eisenmenger syndrome, one had pulmonary hypertension associated with scleroderma and one had histiocytosis X. All were treated with tadalafil, 10-20 mg once daily, in addition to prostacyclin. After 3 months of treatment, all patients improved clinically, with an increase in mean 6MWD from 214 to 272 m. In three patients, the New York Heart Association functional class decreased from IV to III. Echocardiograms showed no significant changes in pulmonary arterial pressure. Although this study was limited by the small sample size, it suggests that tadalafil in combination with prostacyclin is an effective treatment for severe PAH. Tadalafil may be beneficial for the treatment of patients with advanced disease.