Summary. One of the main goals of obesity treatment is to reduce the overall cardiometabolic risk, which is largely determined by atherogenic changes in the blood lipid spectrum. The data of scientific publications presented in this review confirm that orlistat 120 mg is an effective drug for treating obesity, the purpose of which significantly increases the proportion of patients achieving clinically significant results. The mechanism of action of orlistat 120 mg determines its effect on the blood lipid spectrum, which does not directly depend on weight loss during treatment. The improvement of cardiometabolic indices against the background of the use of orlistat allows us to consider this treatment option as one of the methods for correcting dyslipidemia.
Introduction
Reducing the prevalence of cardiovascular diseases, as the main cause of mortality, is a top priority for health care in Europe and the United States. Obesity is not only an independent risk factor for the development of cardiovascular diseases, but also leads to the development of metabolic disorders that potentiate the development of atherosclerosis.
The results of population studies confirm that among those with one or more cardiometabolic risk factors, most are obese or overweight. Thus, when analyzing an electronic database containing information about patients monitored by general practitioners in Wisconsin (USA), such risk factors as high levels of triglycerides (TG), low levels of high density lipoprotein cholesterol (HDL), arterial hypertension , type 2 diabetes. It turned out that the presence of at least two of these disorders increased by 5 times the probability that the patient’s body mass index (BMI) would be higher than 27.
The atherogenic effect of obesity is mediated by a number of mechanisms, the most important of which are dysregulation of lipid and lipoprotein metabolism at various levels, inhibition of the fibrinolysis system, secretion of pro-inflammatory cytokines by adipocytes.
The most characteristic disorders of lipid metabolism for people with obesity and overweight are hypertriglyceridemia and a decrease in HDL cholesterol levels. In the visceral type of obesity, the most atherogenic variants of dyslipidemia are observed, when hypertriglyceridemia and a decrease in HDL cholesterol are combined with an increase in the cholesterol concentration of low-density lipoproteins (LDL-C) and very low-density lipoproteins (VLDL), as well as an increase in the level of apolipoprotein B-B. -AT).
Obviously, dyslipidemia is one of the most adverse effects of obesity, since it is associated with a high incidence of IHD and other vascular complications. It should be taken into account that, in addition to the direct atherogenic action of dyslipidemia, the high risk of cardiovascular diseases is determined by the frequent combination of lipid metabolism disorders with other components of the metabolic syndrome: carbohydrate metabolism disorders, increased proinflammatory and prothrombotic markers, arterial hypertension.
Many studies conducted in recent decades demonstrate that a decrease in body weight against the background of calorie restriction and increased physical activity is accompanied by a decrease in triglyceride levels and an increase in HDL cholesterol levels. Moreover, these favorable changes in the lipid spectrum of blood are observed even with a moderate decrease in body weight – 5-10% of the original. According to the meta-analysis of FASHO A., CG-ESHEOP D., 1992), with a decrease in body weight per 1 kg, the level of total cholesterol (total cholesterol) decreases by 0.05 mmol/l, the level of LDL cholesterol – by 0.02 mmol/l, and the level of TG – 0,015 mmol/l.
Results of obesity treatment with orlistat 120 mg (xenical)
One of the drugs successfully used in clinical practice for the treatment of obesity is orlistat (Xenical, F. Hoffmann-La Roche Ltd., Switzerland). Since orlistat has been used in obesity pharmacotherapy for more than 10 years, the results of numerous randomized, placebo-controlled studies allow not only to evaluate the effectiveness of the drug for the treatment of obesity by the degree of weight loss, but also to evaluate the effect of orlistat on cardiometabolic risk factors, in particular, lipid levels blood.
In 2007, Rucker D. et al. The results of a meta-analysis of long-term obesity pharmacotherapy were published. This meta-analysis included only placebo-controlled clinical trials with a duration of at least 1 year, including 16 studies evaluating the effectiveness of orlistat. The total number of patients participating in these studies was 10,631. 4 of these 16 studies included patients with type 2 diabetes mellitus (T2DM), in 5 studies patients had at least one of the risk factors for cardiovascular diseases (arterial hypertension, dislipidemia). impaired glucose tolerance).
With orlistat treatment, weight loss was 2.9 kg more than in the placebo group (95% CI from 2.5 kg to 3.2 kg). Admission of orlistat increased the absolute number of patients who reduced their weight by 5% and 10% from the original by 21% and 12%, respectively. In patients with type 2 diabetes with orlistat therapy, compared with the placebo group, the weight loss was 2.6% greater. According to 4 studies, weight gain by patients receiving orlistat or placebo for 2 years was about the same, but the difference achieved at the stage of weight loss remained.
Compared with placebo, orlistat also resulted in a statistically significant decrease in waist circumference, BMI, systolic and diastolic blood pressure, total cholesterol and LDL cholesterol, fasting glucose and HbA1c in patients with diabetes. However, according to a meta-analysis, there were no significant differences in triglyceride levels between patients receiving orlistat and placebo.
Thus, in addition to the effect on body weight, therapy with orlistat has a positive effect on lipid metabolism. Moreover, the decrease in the levels of total cholesterol and cholesterol LDL is not only a consequence of reducing the amount of adipose tissue, but also the result of the influence of the drug on the absorption of lipids in the intestine.
Over the 10 years of successful use of orlistat in clinical practice, both studies related to the direct effect of xenical on postprandial blood lipids, and studies evaluating the effect of long-term therapy (from 8 weeks to 1 year) on blood lipid spectrum have been conducted.
Effect of therapy with orlistat 120 mg on postprandial lipid metabolism
Postprandial hyperlipidemia is a physiological phenomenon, the level of blood lipids naturally increases after eating and absorption of fat in the intestine. TG absorbed by enterocytes are transported to the liver as chylomicrons, and then from the liver as very low density lipoproteins (VLDL) enter the bloodstream.
Excessive increase in lipid levels after a meal is characterized by a powerful atherogenic effect. Atherogenicity of postprandial hyperlipidemia is determined primarily by lipoproteins with a high content of triglycerides, which are toxic to endothelial cells. Chylomicron remnants, rich in triglycerides, penetrate into the subendothelial space, where they are captured by macrophages, which, in fact, is the initial stage of atherosclerosis.
Prolonged postprandial hyperlipidemia leads to the formation of LDL cholesterol and HDL cholesterol containing a large amount of TG. Such lipoproteins under the action of hepatic lipase are transformed into small dense forms: small dense LDL with the most atherogenic, and small dense HDL, subject to rapid clearance. As a result of the formation of small dense forms, the level of HDL cholesterol in plasma rapidly decreases and it does not fully exert its protective action.
Obviously, the mechanism of action of orlistat – blocking intestinal lipases and reducing fat absorption by 30%, implies a change in postprandial lipid metabolism during treatment.
Changes in postprandial indicators of glucose, lipids and free fatty acids after taking orlistat were demonstrated by Tan K. et al. [nineteen]. This randomized, placebo-controlled crossover study included 63 patients with type 2 diabetes with overweight and obesity (average BMI 30.4). The levels of TG, free fatty acids (FFA), and cholesterol of lipoprotein remnants (cholesterol-X-RLP) were determined within 8 hours after patients receiving orlistat or placebo during a standard breakfast containing 70 g of fat. Postprandial levels of TG, FFA, and XC-RLP were significantly lower after taking orlistat, and this effect persisted for 4 hours.
Suter P. et al. (2005) studied the effect of orlistat on postprandial lipidemia and the formation of subclasses of lipoproteins in healthy individuals. Participants in this double-blind, randomized study were patients with normal body weight who did not have
leading to carbohydrate and lipid metabolism disorders. The patients were randomized into 3 groups: the first received orlistat 120 mg 3 times a day and food with a high fat content, the second – orlistat 120 mg 3 times a day and food with a moderate fat content, the third – a placebo and high fat food. In patients receiving orlistat, the maximum postprandial triglyceride level was significantly lower than in patients who received placebo. In addition, the area under the triglyceride level curve was the lowest in the groups of patients receiving orlistat, that is, the high postprandial level of triglycerides decreased to baseline values much faster.
The direct effect of orlistat on the absorption of cholesterol has also been confirmed using radioisotope techniques. In persons with abdominal obesity, after 3 days of treatment with orlistat, a 25% reduction in cholesterol absorption was recorded.
Thus, summing up the presented data, it can be concluded that taking orlistat reduces the absorption of cholesterol and affects the postpranial level of blood lipids, reducing the level of TG. chylomicrons and remnants of lipoproteins rich in TG. Taking into account the contribution of both of these factors — excess cholesterol intake from food and, in general, postgenital hyperlipidemia to the genesis of atherosclerosis, the prescription of orlistat can be considered as a therapy that reduces the risk of cardiovascular diseases.
The effect of therapy with orlistat 120 mg on blood lipid indices
The study Milee O. et al. (1999), as well as a number of other clinical studies, confirmed that with the same decrease in body weight in patients receiving orlistat, a more pronounced decrease in total cholesterol levels was observed, that is, a decrease in total cholesterol often exceeded the expected effect of weight loss.
Since the majority of patients participating in these studies had normal or slightly elevated levels of cholesterol, Mick E. et al. (2001) included in their study only patients with obesity and hypercholesterolemia (the LDL cholesterol level on an empty stomach was in the range of 4.1–6.7 mmol/l, the TG level was elevated, but did not exceed 4.5 mmol/l). The results, published by these authors, confirmed that in addition to the effect on body weight, long-term use of orlistat reduces the level of total cholesterol and LDL cholesterol. All participants were recommended a diet with an energy deficit of 600 kcal/day. and limiting fat to 30% of daily calories. After 2 weeks (starting period), randomization was performed, and for 24 weeks, patients received orlistat or placebo (double-blind phase of the study), after which the study was continued as open for 24 weeks.
For 2 weeks of the starting period, the total cholesterol level decreased by 6%. During the first 24 weeks of the study (phase of the double-blind study), treatment with orlistat was accompanied by a further decrease in the level of cholesterol cholesterol (–5.5%). In the placebo group, the total cholesterol level increased by 2.8%. By the end of the open period of the study (48 weeks), the level of total cholesterol in both groups was almost the same.
The level of LDL cholesterol in both groups decreased during the start-up period and continued to decline in the or-listat group during the double-blind period. In the placebo group, LDL cholesterol levels did not decrease during the double-blind period, despite continued weight loss. After 24 weeks, the decrease in the level of LDL cholesterol was significantly greater in the group of patients receiving orlistat, it reached 10.7%, in the placebo group the level of LDL cholesterol decreased only by 0.7%.
In the placebo group, the degree of decrease in LDL cholesterol levels correlated with loss of body weight, whereas no correlation was found during treatment with orlistat. Interestingly, during the double-blind study, the level of LDL cholesterol was significantly lower when receiving orlistat. This pattern was traced in various categories of patients: both among those who reduced body weight by more than 10% of the initial one, and among patients who gained weight.
Another major study on the impact of orlistat on the blood lipid spectrum (Lucas K. et al., 2001) included 444 patients who received orlistat or placebo for 1 year. All patients had hypercholesterolemia or combined hyperlipidemia. All participants in the study were recommended a low-calorie diet, after which the patients were randomly assigned to the orlistat treatment group at a dose of 360 mg per day and the placebo group. After a year, significant differences were found between the groups in the degree of weight loss, and these differences were approximately the same between patients with hypercholesterolemia and patients with hyperlipidemia. During treatment, there was a decrease in levels of LDL cholesterol, total cholesterol and a decrease in atherogenicity. However, no differences were found between the groups of patients receiving orlistat and placebo in terms of TG and HDL cholesterol levels.
A meta-analysis of 28 randomized controlled studies (Hutton B., Ferguson D., 2004) also confirmed that orlistat effectively reduces weight and improves blood lipid spectrum. Especially I want to note that according to this meta-analysis, the level of total cholesterol and LDL cholesterol decreased in all categories of patients suffering from obesity, regardless of the presence of concomitant diseases and baseline blood lipid disorders.
Thus, therapy with orlistat provides an additional reduction in LDL cholesterol levels in patients with obesity and hypercholesterolemia. In general, the difference in the degree of lowering LDL cholesterol levels compared to placebo is 10%. In persons with obesity and hypercholesterolemia while taking orlistat, even with the original weight, the level of LDL cholesterol is also reduced by 10%. Apparently, this effect of orlistat, which is not associated with a decrease in the amount of adipose tissue, is due to its ability to reduce the absorption of fat in the intestine. A decrease in fat absorption is accompanied by a decrease in cholesterol cholesterol in the liver and modifies the activity of liver LDL receptors and reduces the level of LDL cholesterol.
Of particular interest for practical public health are the results of the XXL study. This is a post-marketing study that involved more than 15,000 obese people (average BMI 34.7). All patients were observed on an outpatient basis by general practitioners. The purpose of this study was to evaluate the effect of therapy with orlistat not only on body weight, but also on various clinical parameters, primarily on the risk factors for cardiovascular diseases.
The maximum duration of treatment with orlistat in the XXL study did not exceed 9 months. With orlistat treatment, 87% of patients lost more than 5% of their initial body weight and 51% lost more than 10%. On average, a decrease in body weight was 10.7%.
At the time of the study, 34% of patients had different options for dyslipidemia. As a result of treatment, there was a decrease in cholesterol levels, levels of LDL cholesterol and TG, an increase in the content of HDL cholesterol in the blood. Positive dynamics of lipid metabolism was observed for the group as a whole, but to the greatest extent these changes concerned patients with dyslipidemia. So, if on average the level of total cholesterol decreased by 11%, then among patients with dyslipidemia, the changes in total cholesterol level reached 13.5%.
Almost a third of patients receiving hypolipidemic therapy, by the end of the study were able to cancel lipid-lowering drugs (31%), 15% of patients needed lower doses of lipid-lowering drugs.
Interestingly, the results of the XXL study, which was conducted on the basis of outpatient medical facilities of general practice, coincide with the results of controlled randomized studies, when all participants are given standardized recommendations for the correction of nutrition, and, in particular, to limit fat intake. The best results among the participants in the XXL study were achieved by those who followed a diet with reduced fat. However, those patients who did not change their lifestyle, managed to reduce body weight by 9.4%. Also, the improvements in blood lipid indices, which were maximal in individuals with initial dyslipidemia, did not practically differ from the results of studies on the effectiveness of orlistat in obesity and hypercholesterolemia.
The role of orlistat 120 mg in combination therapy for dyslipidemia
The effect of orlistat on the level of blood lipids and the potential to reduce the doses of hypolipid-ical preparations taken by overweight patients has made it important to administer orlistat in combination with drugs from the group of statins and fibrates.
The purpose of the study conducted by Derosa G. et al. (2003), it was possible to compare the results of treatment of patients with obesity and hypercholesterolemia, orlistat, flu-vastatin and a combination of these drugs. 99 patients were randomized into 4 groups: therapy with orlistat at a dose of 120 mg 3 times a day, therapy with fluvastatin at a dose of 80 mg per day, combination therapy (orlistat 120 mg 3 times a day and fluvastatin 80 mg/day) and the placebo group. All participants in the study were recommended low-calorie diet. The study continued throughout the year.
When examining patients at 12 months, there was a significant decrease in levels of cholesterol, LDL cholesterol and TG from baseline. These changes were comparable in the treatment groups with orlistat, fluvastatin and combined therapy. However, the level of HDL cholesterol was increased compared with basal values only in patients who received fluvastatin and the combination of fluvastatin with orlistat (p <0.02 and p <0.01, respectively). Against the background of monotherapy with orlistat, there was no significant increase in HDL cholesterol. It is also worth noting that the most pronounced dynamics of indicators of cholesterol and LDL cholesterol was observed in a group of patients who received 2 drugs. The data obtained in the course of the study of Derosa G. et al. Showed that both an improvement in clinical indicators (body weight dynamics, BMI, waist circumference) and an improvement in blood lipid spectrum can be achieved with any treatment option. However, against the background of the combined intake of fluvastatin and orlistat, the results of the treatment were optimal. In 2005, a group of scientists from Greece conducted a study comparing the effectiveness of orlistat, fenofibrate, and their combination in patients with metabolic syndrome (FenOrly study). This open, randomized study included patients with metabolic syndrome, which was diagnosed according to the NCEP ATP III criteria. Persons with obesity or overweight (n = 89, BMI> 28) were randomized into three groups: treatment with orlistat at a dose of 120 mg 3 times a day (group O), treatment with micronized fenofibrate at a dose of 200 mg/day. (group F) and combined treatment (Or-listat 120 mg 3 times a day and micronized fenofibrate 200 mg per day, OF group). A low-fat, low-fat diet was recommended for all patients. The results of different treatment options were evaluated after 3 months.
After a period of treatment of 3 months in each of the groups, almost half of the patients no longer met the diagnostic criteria for metabolic syndrome in terms of anthropometric and biochemical parameters. Moreover, according to this result of treatment, the differences between the groups were not significant: in the group O, the number of patients in whom the metabolic syndrome was no longer diagnosed was 43.5%, in the F group – 47.6%, in the OF group – 50%. In all groups, such lipid metabolism indicators as total cholesterol, LDL cholesterol, TT were significantly reduced. In the combined treatment group, a more pronounced decrease in total cholesterol (by 26%) and LDL cholesterol (by 30%) was observed in comparison with
the group O and group E Compared with the group O, the level of TG in patients in the combined treatment group decreased to a greater extent by 37%.
The results allowed the authors to conclude that the combination of orlistat and fenofibrate has certain advantages: co-administration of drugs is safe and has a more effective effect on metabolic parameters in patients with obesity and overweight compared to monotherapy.
Conclusion
The data of scientific publications presented in this review confirm that orlistat 120 mg (xenical) is an effective drug for the treatment of obesity, the purpose of which significantly increases the proportion of patients achieving clinically significant results.
The results of reducing the absorption of alimentary fat during xenical therapy are the improvement of postprandial indices of blood lipids and a decrease in the levels of total cholesterol and LDL cholesterol. The mechanism of action of Xenical determines its effect on the blood lipid spectrum, which does not directly depend on weight loss during treatment.
Improvement of cardiometabolic indices against the background of the use of orlistat 120 mg allows us to consider this treatment option as one of the methods for correcting dyslipidemia. The purpose of orlistat 120 mg in combination with lipid-lowering drugs from the group of statins and the group of fibrates makes it possible to achieve the maximum reduction in blood lipid spectrum, which are risk factors for cardiovascular diseases.