Theodosios D. Filippatos

Orlistat-Associated Adverse Effects and Drug Interactions A Critical Review

Orlistat, an anti-obesity drug, is a potent and specific inhibitor of intestinal lipases. In light of the recent US FDA approval of the over-the-counter sale of orlistat (60 mg three times daily), clinicians need to be aware that its use may be associated with less well known, but sometimes clinically relevant, adverse effects. More specifically, the use of orlistat has been associated with several mild-to-moderate gastrointestinal adverse effects, such as oily stools, diarrhoea, abdominal pain and faecal spotting. A few cases of serious hepatic adverse effects (cholelithiasis, cholostatic hepatitis and subacute liver failure) have been reported. However, the effects of orlistat on non-alcoholic fatty liver disease are beneficial. Orlistat-induced weight loss seems to have beneficial effects on blood pressure. No effect has been observed on calcium, phosphorus, magnesium, iron, copper or zinc balance or on bone biomarkers. Interestingly, the use of orlistat has been associated with rare cases of acute kidney injury, possibly due to the increased fat malabsorption resulting from the inhibition of pancreatic and gastric lipase by orlistat, leading to the formation of soaps with calcium and resulting in increased free oxalate absorption and enteric hyperoxaluria. Orlistat has a beneficial effect on carbohydrate metabolism. No significant effect on cancer risk has been reported with orlistat.Orlistat interferes with the absorption of many drugs (such as warfarin, amiodarone, ciclosporin and thyroxine as well as fat-soluble vitamins), affecting their bioavailability and effectiveness.This review considers orlistat-related adverse effects and drug interactions. The clinical relevance and pathogenesis of these effects is also discussed.

Effect of ezetimibe monotherapy on the concentration of lipoprotein subfractions in patients with primary dyslipidaemia

ABSTRACT Background: Recent studies suggest that the distribution of lipoprotein subfractions is an independent predictor of vascular events. Therefore, we evaluated the effect of ezetimibe (a selective cholesterol transport inhibitor) on the concentrations of lipoprotein subfractions in patients with primary dyslipidaemia. Materials and methods: Patients (n = 50) with primary dyslipidaemias were recruited. The concentrations of the individual lipoprotein subfractions were measured using the Lipoprint system at baseline and after 16 weeks of treatment. Results: Ezetimibe reduced total, low-density lipoprotein cholesterol (LDL‑C) and non-high-density lipoprotein cholesterol (HDL‑C) values as well as apolipoprotein B concentrations. Subfractionation of apolipoprotein B-containing lipoproteins showed that the reduction in LDL‑C values was due to a fall in the concentrations of all LDL subfractions. However, a more pronounced trend towards a decrease in the concentrations of dense LDL subfractions was observed. Patients with triglyceride values >1.7 mmol/L had significantly greater reductions in the concentrations of small, dense LDL particles compared with those with normal triglyceride levels (49 vs. 19%, respectively; p < 0.05). Ezetimibe decreased the concentrations of HDL‑C mainly due to a fall in the concentration of dense HDL subfractions. Conclusion: Ezetimibe can favourably affect the distribution of LDL subfractions, especially in patients with elevated triglyceride values. Further studies are needed to clarify the significance of the ezetimibe-induced reduction in the concentrations of dense HDL particles.

A review of the metabolic effects of sibutramine.

ABSTRACT Background: Obesity is associated with an increased incidence of diabetes, hypertension, dyslipidaemia and coronary artery disease. Current management strategies of obesity include lifestyle interventions and pharmacotherapy. Sibutramine is a drug with established efficacy in weight reduction and maintenance of weight loss. It reduces food intake and attenuates the fall in metabolic rate associated with weight loss. Objective: To review the metabolic effects associated with sibutramine use. Methods: Relevant articles were identified through a Medline search (up to December 2004). Results: Weight loss with sibutramine treatment is associated with improved insulin sensitivity and a fall in glycosylated haemoglobin levels in type 2 diabetic patients. In most trials sibutramine exerted favourable effects on lipids, especially on high density lipoprotein (HDL) cholesterol and triglycerides, as well as on the total:HDL cholesterol ratio. Sibutramine also lowers serum uric acid concentrations. Furthermore, this drug seems to favourably influence adipocytokines; it reduces serum leptin and resistin levels and increases adiponectin levels. Sibutramine also exerts a beneficial effect on hyperandrogenaemia in obese women with polycystic ovary syndrome. Preliminary findings also suggest that weight loss following treatment with sibutramine is useful in patients with non-alcoholic fatty liver disease (NAFLD). Conclusion: Weight loss following sibutramine administration is associated with several favourable metabolic effects.

Effect of orlistat, micronised fenofibrate and their combination on metabolic parameters in overweight and obese patients with the metabolic syndrome: the FenOrli study

ABSTRACT Background: Obesity is becoming increasingly common worldwide and is strongly associated with the metabolic syndrome (MetS). MetS is considered to be a cluster of risk factors that increase the risk of vascular events. Objective: In an open-label randomised study (the FenOrli study) we assessed the effect of orlistat and fenofibrate treatment, alone or in combination on reversing the diagnosis of the MetS (primary end-point) as well as on anthropometric and metabolic parameters (secondary end-points) in overweight and obese patients with MetS but no diabetes. Methods: Overweight and obese patients (N = 89, body mass index (BMI) > 28 kg/m2) with MetS [as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III criteria] participated in the study. Patients were prescribed a low-calorie low-fat diet and were randomly allocated to receive orlistat 120 mg three times a day (tid) (O group), micronised fenofibrate 200 mg/day (F group), or orlistat 120 mg tid plus micronised fenofibrate 200 mg/day (OF group). Body weight, BMI, waist circumference, blood pressure, serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL‐C), high-density lipoprotein cholesterol (HDL‐C), non-HDL‐C, triglyceride, creatinine (SCr) and uric acid (SUA) levels, as well as homeostasis model assessment (HOMA) index and liver enzyme activities were measured at baseline and after 3 months of treatment. Results: Of the 89 patients enrolled, three (one in each group) dropped out during the study due to side effects. After the 3‐month treatment period, 43.5% of patients in the O group, 47.6% in the F group and 50% in the OF group no longer met the MetS diagnostic criteria (primary end-point, p < 0.0001 vs. baseline in all treatment groups). No significant difference in the primary end-point was observed between the three treatment groups. Significant reductions in body weight, BMI, waist circumference, blood pressure, TC, LDL‐C, non-HDL‐C, triglyceride and SUA levels, as well as gamma-glutamyl transpeptidase activity and HOMA index were observed in all treatment groups. In the OF group a greater decrease in TC (–26%) and LDL‐C (–30%) was observed compared with that in the O and F groups ( p < 0.01) and a more pronounced reduction of triglycerides (–37%) compared with that in the O group ( p < 0.05). SUA levels and alkaline phosphatase activity decreased more in the F and OF groups compared with the O group ( p < 0.05). Moreover, SCr significantly increased and estimated creatinine clearance decreased in the F and OF groups but they were not significantly altered in the O group ( p < 0.01 for the comparison between O and either F or OF groups). Glucose (in groups O and OF), as well as insulin levels and HOMA index (in all groups), were significantly reduced after treatment ( p < 0.05 vs. baseline). Conclusion: The combination of orlistat and micronised fenofibrate appears to be safe and may further improve metabolic parameters in overweight and obese patients with MetS compared with each monotherapy.

Increased plasma visfatin levels in subjects with the metabolic syndrome

Editor – The presence of the metabolic syndrome (MetS) increases the risk for cardiovascular disease (CVD) and type 2 diabetes mellitus [1]. A ‘new’ adipocytokine named ‘visfatin’ (pre-B cell colony-enhancing factor) is a cytokine highly expressed in visceral fat that exhibits insulin-mimetic properties [2]. We investigated the possible differences in plasma visfatin levels between subjects with and without MetS. Consecutive patients (n = 186, 81 men/105 women) without known CVD or diabetes mellitus attending the Outpatient Lipid Clinic of the University Hospital of Ioannina participated in the present study. Ninety of them fulfilled the National Cholesterol Educational Program Adult Treatment Panel III (NCEP ATP III) criteria for the diagnosis of MetS [3] and the remaining 96 subjects served as a control group (non-MetS). Plasma visfatin concentrations were measured using an enzyme-linked immunoabsorbent assay (EIA) kit (Phoenix Pharmaceuticals, Belmont, California, USA). Plasma visfatin concentrations were higher in MetS subjects compared with non-MetS individuals [24·6 (9·1–56·6) ng mL vs. 16·1 (6·7–48·7) ng mL, P < 0·01], even after adjustment for age, sex and body mass index. Visfatin levels increased proportionally to the number of MetS components (P for trend < 0·01) (Fig. 1). Plasma visfatin concentrations were correlated with waist circumference (rho = 0·3, P < 0·001), triglycerides (rho = 0·35, P < 0·001), systolic (rho = 0·28, P < 0·001) and diastolic (rho = 0·27, P < 0·001) blood pressure but not with high-density lipoprotein cholesterol levels. Plasma visfatin levels were marginally correlated with fasting glucose (rho = 0·144, P = 0·055) and insulin levels (rho 0·165, P = 0·035), as well as with the homeostasis model assessment (HOMA) index (rho = 0·16, P = 0·041). In conclusion, plasma visfatin levels are increased in patients with MetS compared with individuals that do not fulfil the criteria for this syndrome. Visfatin concentrations elevate in parallel with the number of MetS components. Gene expression of visfatin was recently found to be enhanced in macrophages of human unstable carotid and coronary atherosclerotic lesions; this finding suggests a potential role for visfatin as an inflammatory mediator and in plaque destabilisation process [4]. Larger clinical studies are needed in order to assess if the observed increase in visfatin levels in MetS subjects is a consequence of the involvement of the molecule in the pathogenesis of this syndrome, or it is just an epiphenomenon that might be a useful marker of abdominal fat deposition and cardiovascular risk.

Treating to target patients with primary hyperlipidaemia:comparison of the effects of ATOrvastatin and ROSuvastatin (the ATOROS study)

ABSTRACT Objectives: In a 24-week, open-label, randomized, parallel-group study, we compared the efficacy and metabolic effects, beyond low density lipoprotein cholesterol (LDL-C)-lowering, of atorvastatin (ATV) and rosuvastatin (RSV) in cardiovascular diseasefree subjects with primary hyperlipidaemia, treated to an LDL-C target (130 mg/dL). Methods: After a 6‐week dietary lead-in period, patients were randomized to RSV 10 mg/day ( n = 60) or ATV 20 mg/day ( n = 60). After 6 weeks on treatment the dose of the statin was increased (to RSV 20 mg/day or ATV 40 mg/day) if the treatment goal was not achieved. A control group of healthy volunteers ( n = 60) was also included for the validation of baseline serum and urinary laboratory parameters. The primary outcome was the percentage of patients reaching the LDL‐C goal; secondary outcomes were changes in lipid and non-lipid metabolic parameters. Results: A total of 45 patients (75.0%) in the RSV-treated group and 43 (71.7%) in the ATV-treated group achieved the treatment target at the initial dose. Both regimens were generally well tolerated and there were no withdrawals due to treatment-related serious adverse events. Similar significant reductions in total cholesterol, LDL‐C, apolipoprotein (apo) B, triglycerides, apoB/apoA1 ratio, fibrinogen and high-sensitivity C‐reactive protein levels were seen. RSV had a significant high density lipoprotein cholesterol (HDL‐C)-raising effect and showed a trend towards increasing apoA1 levels. Glycaemic control and renal function parameters were not influenced by statin therapy. ATV, but not RSV, showed a significant hypouricaemic effect. Conclusions: RSV and ATV were equally efficacious in achieving LDL‐C treatment goals in patients with primary hyperlipidaemia at the initial dose and following dose titration. RSV seems to have a significantly higher HDL‐C-raising effect, while ATV lowers serum uric acid levels.

The effects of orlistat on metabolic parameters and other cardiovascular risk factors

Orlistat is an antiobesity drug with a well documented efficacy in weight reduction and weight maintenance. Weight reduction with orlistat has been associated with a favourable effect on obesity-related cardiovascular risk factors. Orlistat treatment is associated with a reduction in serum insulin levels. Moreover, orlistat reduces the incidence of type 2 diabetes in patients with impaired glucose tolerance and lowers the required dose of metformin, sulfonylureas and insulin in patients with type 2 diabetes. Furthermore, orlistat can reduce total and low density lipoprotein (LDL) cholesterol levels and improve postprandial triglyceridemia, as well as the low density lipoprotein cholesterol/high density lipoprotein cholesterol ratio (LDL/HDL ratio). Moreover, orlistat appears to have a favourable effect on some inflammatory markers, such as TNF-alpha and interleukin-6 and has a time-depended effect on some haemostatic factors.

A review of the role of apolipoprotein C-II in lipoprotein metabolism and cardiovascular disease.

The focus of this review is on the role of apolipoprotein C-II (apoC-II) in lipoprotein metabolism and the potential effects on the risk of cardiovascular disease (CVD). We searched PubMed/Scopus for articles regarding apoC-II and its role in lipoprotein metabolism and the risk of CVD. Apolipoprotein C-II is a constituent of chylomicrons, very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein (HDL). Apolipoprotein C-II contains 3 amphipathic α-helices. The lipid-binding domain of apoC-II is located in the N-terminal, whereas the C-terminal helix of apoC-II is responsible for the interaction with lipoprotein lipase (LPL). At intermediate concentrations (approximately 4 mg/dL) and in normolipidemic subjects, apoC-II activates LPL. In contrast, both an excess and a deficiency of apoC-II are associated with reduced LPL activity and hypertriglyceridemia. Furthermore, excess apoC-II has been associated with increased triglyceride-rich particles and alterations in HDL particle distribution, factors that may increase the risk of CVD. However, there is not enough current evidence to clarify whether increased apoC-II causes hypertriglyceridemia or is an epiphenomenon reflecting hypertriglyceridemia. A number of pharmaceutical interventions, including statins, fibrates, ezetimibe, nicotinic acid, and orlistat, have been shown to reduce the increased apoC-II concentrations. An excess of apoC-II is associated with increased triglyceride-rich particles and alterations in HDL particle distribution. However, prospective trials are needed to assess if apoC-II is a CVD marker or a risk factor in high-risk patients.

Visfatin/PBEF and atherosclerosis-related diseases

Visfatin is highly expressed in adipose tissue (mainly by the stromal cells), but it is also ubiquitously present in most tissues. Visfatin, which plays a role in nicotinamide adenine dinucleotide (NAD) biosynthesis, has been implicated in inflammatory states. Controversial results exist about the expression, circulating levels and the role of visfatin in atherosclerosis-related diseases. Most studies showed increased levels of visfatin in diabetes mellitus, obesity, hypertension, renal and cardiovascular disease. However, other studies reported lower levels of visfatin in these diseases. The discrepancies in clinical studies may be attributed to the multifactorial regulation of visfatin. There is evidence that visfatin expression and circulating levels are influenced by fat area and distribution, inflammatory state, renal function, iron metabolism, hormones as well as several other factors. Furthermore, discrepancies and lack of correlation between commercially available visfatin assays have been reported. More research is needed to better understand the factors that control its synthesis/release and to evaluate the role of visfatin in atherosclerosis-related disease. Large studies with homogeneous populations will probably be needed to answer these questions. Whether visfatin will eventually become a therapeutic target remains to be established.

The effect of orlistat and ezetimibe, alone or in combination, on serum LDL and small dense LDL cholesterol levels in overweight and obese patients with hypercholesterolaemia

ABSTRACT Background: Increased concentrations of low density lipoprotein cholesterol (LDL-C), as well as of small dense LDL-C (sdLDL-C), are considered as cardiovascular risk factors. Objective: An assessment of the effects of ezetimibe and orlistat administration, alone or in combination, on LDL-C and sdLDL-C levels (primary endpoint), as well as on anthropometric variables and metabolic parameters (secondary endpoints) in overweight and obese patients [body mass index (BMI) > 28 kg/m2] with hypercholesterolaemia [total cholesterol > 200 mg/dL (5.2 mmol/L)]. Methods: Eighty six subjects were prescribed a low-fat low-calorie diet and were randomly allocated to receive orlistat 120 mg, 3 times daily (O group), ezetimibe 10 mg/day (E group) or both (OE group) for 6 months. Results: Significant reductions in LDL-C (−19%, −21%, −32% in groups O, E and OE, respectively, all p < 0.01 vs. baseline) and sdLDL-C levels (−45%, −48%, −76% in groups O, E, OE, respectively, all p < 0.01 vs. baseline) were observed. Group OE experienced a significantly greater reduction in LDL-C and sdLDL-C levels compared with groups O and E (p < 0.05). Furthermore, significant reductions of BMI, homeostasis model assessment (HOMA) index, serum uric acid, transaminase activities and plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) activity were observed in the O and OE groups. Gamma-glutamyl transpeptidase activity and Lp-PLA2 activity improved significantly more with the combination treatment compared with either orlistat or ezetimibe monotherapy. Conclusions: Orlistat and ezetimibe combination had a more favourable effect on LDL-C and sdLDL-C levels in overweight and obese hypercholesterolaemic patients than either drug alone. Furthermore, orlistat, alone or in combination with ezetimibe, additionally improved several anthropometric and metabolic variables.