Drug therapies for HIV-related metabolic disorders

Introduction: Human immunodeficiency virus (HIV) has become a chronic disease often associated with dyslipidaemia and insulin resistance. Combination antiretroviral therapy (cART) may contribute to metabolic disturbances, eventually leading to increased cardiovascular disease (CVR) in this population.

Escalating interventions to decrease CVR include promoting a healthy lifestyle, such as quitting smoking, diet and regular exercise. If they do not achieve the goals, a change of cART should be considered, followed by or used concomitantly with the use of chemical therapies.

Areas covered: The aim of this article is to review the available drug therapies for the treatment of metabolic disorders in HIV-infected patients and to examine their safety and effectiveness in this population. A review of the literature was conducted, highlighting the most relevant articles.

Expert opinion: Switching strategies can be useful but its expected benefit is not high. Therefore, chemical intervention is often needed. Statins have been proven to reduce CVR in the general population and in HIV-infected patients. Simvastatin is contraindicated in patients treated with boosted PI due to interactions; atorvastatin is safe at submaximal dose and needs close monitoring, while pravastatin lacks lipid-lowering potency, and rosuvastatin and pitavastatin are safe. Ezetimibe and fibrates are also safe and effective in HIV-infected patients and can be used in combination with statins. The management of glucose homeostatic disorders in HIV-infected patients follows the same guidelines as in the general population. However, there are specific considerations with respect to the interactions of particular medications with cART. When drug therapy is needed, metformin is the first-line drug. Decisions regarding second- and third-line drugs should be carefully individualized.     

Effect of metformin on selected parameters of hemostasis in fenofibrate-treated patients with impaired glucose tolerance

BackgroundNo previous study has assessed whether the addition of metformin potentiates fibrate action on hemostasis in prediabetic subjects.MethodsOur study included 41 fenofibrate-treated patients with impaired glucose tolerance allocated to either metformin (3 g daily) or placebo.ResultsTwelve-week treatment with fenofibrate and metformin reduced plasma levels of fibrinogen and PAI-1 and tended to change the other hemostatic markers measured, as well as improved insulin sensitivity.ConclusionsOur results show that high-dose metformin exhibits beneficial effects on coagulation and fibrinolysis in isolated IGT patients treated with a fibrate.     

Peroxisome proliferator-activated receptor alpha-mediated drug toxicity in the liver

Introduction: Drug-induced hepatic injury is the most common cause of acute liver failure in the United States. Peroxisome proliferator-activated receptor alpha (PPARα)-mediated drugs are included among the approximately 900 natural and synthetic substances, which have shown hepatotoxicity.

Areas covered: This review will focus on fibrates – PPARα agonists and their implication in causing liver injury.

Expert opinion: Compelling evidence for fibrate-induced hepatotoxicity is not available. Results have been varying because several large randomized clinical trials have reported similar elevations of plasma transaminase levels in fibrate or placebo treated groups. On the other hand, one meta-analysis has reported an increased risk of hepatotoxicity when fibrates are combined with statins. Fibrate induced clinically apparent liver damage has been demonstrated in case reports. However, there is a wide spectrum of clinical phenotypic presentations of these cases (onset of injury, pattern of enzyme elevation and resolution of the symptoms), which reduces the ability to identify specific cause and effect of any putative fibrate-induced hepatotoxicity. Thus, the current recommendations for using fibrates include monitoring of aminotransferase levels especially if combined with statins and discontinuation of the treatment only if the levels persist above three times the upper limit of normal.     

PPARα配体对肌细胞的毒性作用研究

背景与目的： 探讨过氧化物酶体增殖物激活受体α(peroxisome proliferators-activated receptor α, PPARα)配体类降脂药物对人骨骼肌细胞的影响。 材料与方法： WST-1法测定苯扎贝特及与阿托伐他汀联合应用时对人横纹肌肉瘤(RD)细胞的毒性作用;全自动生化分析仪测定不同浓度的苯扎贝特及与阿托伐他汀联合作用RD细胞,细胞中乳酸脱氢酶(LDH)和肌酸激酶(CK)活性;Hoechest 33342染色法观察细胞凋亡的形态学改变。 结果： 苯扎贝特明显抑制RD细胞生长,明显降低CK活性,并引起细胞凋亡的典型变化,呈剂量-效应和时间-效应关系,与阿托伐他汀联合应用时对RD细胞的作用增强。 结论： 苯扎贝特作为PPARα配体对RD细胞具有明显的细胞毒性作用,与他汀类合用时细胞毒性增强。     

Successful pregnancy outcome in a patient with severe chylomicronemia due to compound heterozygosity for mutant lipoprotein lipase

OBJECTIVES: Familial chylomicronemia syndrome is characterized by massive accumulation of plasma chylomicrons, which typically results from an absolute deficiency of lipoprotein lipase (LPL). Chylomicronemia in pregnancy is a rare, but serious clinical problem and can be found in patients with underlying molecular defects in the LPL gene. We report the course and treatment of an 18 yr-old primigravida who had LPL deficiency and hypertriglyceridemia since birth. We also analyzed the molecular basis of her LPL deficiency. DESIGN AND METHODS: The patient's antenatal course was complicated by extreme elevations of plasma triglycerides. Her management included a very low fat diet, pharmacotherapy with gemfibrozil in the third trimester, and intermittent hospitalization with periods of fasting supplemented by IV glucose feeding. We used DNA sequencing to determine whether mutations in LPL were present. RESULTS: At 38 weeks of gestation, labor was induced, and the patient delivered a healthy 2.77 kilogram male. Postnatal triglycerides fell to prenatal levels. DNA sequencing showed that she was a compound heterozygote for mutant LPL: I > T194 and R > H243. CONCLUSIONS: This experience indicates that vigilance is required during pregnancy in patients with familial chylomicronemia due to mutant LPL. Gemfibrozil was used in this patient without apparent adverse effects. Compound heterozygosity for LPL mutations is an important underlying mechanism for LPL deficiency.     

Apolipoproteins AI and B as therapeutic targets

Currently the apolipoprotein B:AI ratio integrates information about the potential for cardiovascular disease (CVD) risk reduction better than any other lipid or lipoprotein index. Certainly it could, with benefit, replace serum cholesterol and HDL cholesterol in the estimation of CVD risk. Defining the therapeutic target of statin therapy in terms of serum apolipoprotein B (apo B) rather than LDL cholesterol could also help to optimize statin treatment. Deciding whether a therapeutic response is adequate also requires knowledge of whether there is persisting hypertriglyceridaemia, because this gives an indication of whether small dense LDL is likely to have been satisfactorily reduced. Raising low levels of HDL, probably best measured as apo AI, may also prove to be an important aim of treatment. This is, however, a more complex issue and also depends on the mechanism by which a particular therapy alters HDL levels and on whether the capacity of HDL to perform its anti-inflammatory and antioxidative functions is restored. A meta-analysis of randomized clinical trials of statins in which apo B and apo AI have been reported could provide valuable information.     

PPARalpha agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition

Angiogenesis and inflammation are central processes through which the tumor microenvironment influences tumor growth. We have demonstrated recently that peroxisome proliferator-activated receptor (PPAR)alpha deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of thrombospondin (TSP)-1 and prevents tumor growth. Hence, we speculated that pharmacologic activation of PPARalpha would promote tumor growth. Surprisingly, the PPARalpha agonist fenofibrate potently suppressed primary tumor growth in mice. This effect was not mediated by cancer-cell-autonomous antiproliferative mechanisms but by the inhibition of angiogenesis and inflammation in the host tissue. Although PPARalpha-deficient tumors were still susceptible to fenofibrate, absence of PPARalpha in the host animal abrogated the potent antitumor effect of fenofibrate. In addition, fenofibrate suppressed endothelial cell proliferation and VEGF production, increased TSP-1 and endostatin, and inhibited corneal neovascularization. Thus, both genetic abrogation of PPARalpha as well as its activation by ligands cause tumor suppression via overlapping antiangiogenic pathways. These findings reveal the potential utility of the well tolerated PPARalpha agonists beyond their use as lipid-lowering drugs in anticancer therapy. Our results provide a mechanistic rationale for evaluating the clinical benefits of PPARalpha agonists in cancer treatment, alone and in combination with other therapies.