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The ORLIstat and CArdiovascular Risk Profile in Patients With Metabolic Syndrome and Type 2 DIAbetes (ORLICARDIA) Study

Posted on: Tuesday, 9 November 2004, 12:00 CST

Key words: Cardiovascular risk * Diabetes * Diet * Metabolic syndrome * Orlistat

SUMMARY

Background: Metabolic syndrome (MetSyn) is associated with a marked increase in the risk of cardiovascular disease, especially in patients with type 2 diabetes mellitus (DM).

Aim.-To investigate the effect of orlistat plus hypocaloric diet (HCD) vs HCD alone on the cardiovascular risk profile in patients with both MetSyn (National Cholesterol Educational Program - NCEP - Adult Treatment Panel III definition) and type 2 DM.

Methods: This was a prospective, multicentre, openlabel, randomized, controlled study. One hundred and twenty-six patients, free of cardiovascular disease at baseline, were included in the final analysis. Ninety-four (73%) patients were treated with orlistat (360mg/day) and HCD for a 6-month period, while 34 (27%) were on HCD alone. Analysis of covariance was used to assess differences between the treatment groups over time.

Main outcome measures: Components of the MetSyn criteria assessed were: waist circumference; systolic and diastolic blood pressure; fasting glucose, triglycerides; high-density lipoprotein cholesterol (HDL-C) plus body mass index; glycosylated haemoglobin (HbA^sub 1c^); homeostasis model for assessment of insulin resistance (HOMA) index; and total and low-density lipoprotein cholesterol (LDL-C).

Results: By protocol, all patients had MetSyn at baseline. After a 6 month treatment period there were significant differences between the orlistat plus HCD vs the HCD-alone groups in body weight (p- 0.0001), waist circumference (p < 0.0001), fasting glucose (p < 0.0001), HbA^sub 1c^ (p < 0.0001), systolic blood pressure (p = 0.024), total cholesterol (p < 0.0001), LDL-C (p = 0.034), and HOMA index (p = 0.022), while there were no significant differences in triglycrides and HDL-C. Orlistat was well tolerated. By the end of the study, 65% of the patients on orlistat plus HCD were still meeting the MetSyn criteria and 41% had four to five MetSyn components vs 91% (p < 0.0001) and 53% (p = 0.017), respectively, of those on HCD alone.

Conclusions: Orlistat plus HCD favourably modified several cardiovascular risk factors in patients with both MetSyn and type 2 DM. These effects might partly offset the excess cardiovascular risk and improve outcome in this patient population.

Introduction

Metabolic syndrome (MetSyn) is a clustering of risk factors that confer an increased risk of vascular morbidity and mortality1,2, and all-cause mortality2, even in the absence of clinically evident vascular disease and/or diabetes mellitus (DM)2,3. The presence of DM also significantly increases vascular risk4-6. Furthermore, there is a linear association between the number of MetSyn criteria that are present and vascular mortality4,7. For example, patients with four or five components of MetSyn have a > 5-fold increased risk of a cardiovascular event compared with those with only one7.

Several studies have shown that weight loss (as part of a comprehensive lifestyle intervention) appears to be beneficial with respect to improvement in metabolic aberrations and a reduction in cardiac morbidity in obese and glucose-intolerant subjects at high risk of vascular events8-12. However, weight reduction and the long- term maintenance of lower body weight can be difficult to achieve, and very few obese patients maintain the shortterm weight losses achieved following dietary restriction13-15. Pharmacological treatment aimed at long-term weight reduction and improving obesity- related risk factors may be an important adjunct to dietary and behavioural change for many overweight patients at risk of vascular events. Treatment with orlistat, in conjunction with diet, has been shown to result in significantly greater weight loss and improvement in risk factors than diet alone among obese patients at high risk of coronary events16,17.

To further assess the effect of orlistat we compared the effect of orlistat plus diet vs diet alone on vascular risk factors in patients with both MetSyn and type 2 DM.

Study population - methods

Study Design and Patients

This was a prospective, multicentre, open-label, controlled, randomized study, conducted in three Greek hospitals. The study duration was 2 years. In total, 134 patients aged 30 years-72 years were screened. One hundred and twenty-six cases were finally randomized [with a pattern of three on orlistat (120mg TID) to one on diet alone]. The study protocol and informed consent form was reviewed and approved by the Ethics Review Committee at each participating Hospital.

Inclusion Criteria

The patients were men or women aged 30 years72 years with type 2 DM treated with oral antidiabetic agents (metformin alone or in combination with sulfonylureas).

All patients had the MetSyn, according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) definition18. Subjects were considered to have MetSyn if they met at least three of the following criteria:

1. Abdominal obesity: waist circumference > 102 cm in men and > 88 cm in women.

2. Hypertriglyceridaemia: triglycerides ≥ 150mg/dL (1.69mmol/L).

3. Low high-density lipoprotein (HDL) cholesterol: < 40 mg/dL (1.04 mmol/L) in men and < 50 mg/dL (1.29 mmol/L) in women.

4. Raised blood pressure: ≥ 130/85 mm Hg.

5. Raised fasting glucose: ≥ 110mg/dL (6.1 mmol/L).

Exclusion Criteria

Insulin-dependent DM, symptomatic vascular disease, total cholesterol ≥ 350mg/dL (9.0mmol/L) or triglycerides ≥ 500 mg/dL (5.7 mmol/L), glycosylated haemoglobin (HbA^sub 1c^) ≤ 7.0% to ≥ 10.0%, major gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders, history of allergy, which were considered by the investigator relevant to the trial, and concomitant use of drugs that may affect body weight.

Withdrawals

Patients were excluded from further participation in the study for the following reasons: withdrawal of consent (without having to justify their decision), inability to continue participation due to other diseases not related with the study treatment, occurrence of serious adverse events during the trial, and lack of compliance to the protocol.

Hypocaloric Diet (HCD)

All 126 patients were on a hypocaloric diet (HCD) throughout the study. At baseline there was an interview with a qualified dietician. Dietary preferences were recorded, and a specific 7-day diet sheet was handed to the patient at every visit. Daily calorie intake was set at 500 calories below the needs of the patient, according to physical activity. The mean daily calorie intake of the patients was about 1300 calories. Moreover, a leaflet with general information about the diet was handed to the patient. Patient diet sheets were handed back to the investigating physician periodically to monitor the compliance to the HCD. This procedure was followed throughout the study.

Table 1. Demographic characteristics of the patients in the two treatment groups at day 1 of the study

Main Outcome Measures

Change in body weight, waist circumference, blood pressure, lipid profile, fasting glucose, fasting insulin, homeostasis model for assessment of insulin resistance (HOMA) index, and HbA^sub 1c^ were the main outcome measures. Physical examination was performed every 4 weeks and laboratory tests every 8 weeks. All laboratory tests from the 3 participating centres were performed at a central lab, participating in internal and external quality control schemes.

Safety

Clinical and laboratory investigation for adverse effects of the treatment (including gastrointestinal, liver and renal function) were performed at 4 week and 8 week intervals, respectively, throughout the study.

Medical Treatment

The baseline drug treatment (Table 1) remained unchanged throughout the study. No patient was excluded from the final analysis, because this was an intention-to-treat study.

Assessments

After an overnight fast, total cholesterol (TC), highdensity lipoprotein cholesterol (HDL-C), and triglycerides (TG) were assessed using an Olympus AU 560 autoanalyser and respective reagents (Olympus Diagnostica GmbH, Clare, Ireland). Low-density lipoprotein cholesterol (LDL-C) was calculated by the Friedewald formula [LDL-C mg/dL = TC in mg/dL-(TG mg/dL/5 + HDL-C mg/dL)]. The non-HDL-C value was obtained by subtracting the HDL-C value from that of TC. Fasting blood glucose was measured with the GOD-PAP method using an Olympus AU 560 autoanalyser and respective reagents (Medicon Hellas, Athens, Greece, reference range: 70mg/dL-110mg/dL; (3.9 mmol/L-6.1 mmol/L) and glycosylated haemoglobin (HbA^sub 1c^) was assessed by HPLC, using the Menarini Diagnostics (Menarini, Greece) reagents (reference range: 3.8%-5.5%). The lipid profile, fasting blood glucose, and HbA^sub 1c^ were assessed in both groups at the same time intervals as the safety measurements. Fasting plasma insulin levels were assessed using a selective RIA and the HOMA index was calculated using the formula previously described19. Serum uric acid (SUA) was assessed with an enzymatic colorimetric test (uricase); reference range 150l/L-415 mol/L (2.5 mg/dL-7.0 mg/ dL). Liver ultrasound examination was performed at the beginning and the end of the study to establish if non-alcoholic fatty liv\er disease was present. Fatty liver disease was graded as none, mild, moderate or severe. Ultrasound scanning accurately identifies fatty liver disease recording a hyperechogenic liver (sensitivity 0.90, specificity 0.82, positive predictive value 0.87, negative predictive value 0.87)20,21. Increased liver echogenicity together with high attenuation has even higher sensitivity and specificity20.

Vascular Event Risk Assessment

The UKPDS Risk Engine (http://www.dtu.ox.ac.uk/ index.html?maindoc=/ukpds/) was used to assess the risk of non- fatal and fatal coronary heart disease and stroke during the next 10- year period. This engine provides risk estimates in individuals with type 2 DM not known to have heart disease.

Table 2. Measured parameters at the beginning and the end of the study in the two treatment groups

Table 3. Prevalence of metabolic syndrome and its components at the end of the study (6th month of treatment)

Statistical Analyses

This was a prospective, multi-centre, open-label, comparative study. In statistical terms, the model was a factor repeated measures design over time (6 months). The following tests were used: analysis of covariance (ANCOVA) to investigate the significance of changes within and between treatment groups over time. The ANOVA, paired t-test, Wilcoxon signed rank sum test, Sign test, Pearson (r) correlation coefficient, Cochran-Mantel-Haenszel test, Chi-square tests were also used. Mean and standard deviation (SD) of the numerical variables are reported. A two tailed p < 0.05 was considered significant. The SPSS 11.0 program was used for all statistical analyses.

Results

Baseline Characteristics

All patients had type 2 DM and MetSyn by protocol (with a mean of 4.3 MetSyn components) - see Table 1. Concomitant drug treatment remained unchanged throughout the study.

Treatment Period

The change in main outcome measures during the study is reported in Table 2. At the 6th treatment month the mean weight loss was significantly greater with orlistat compared with diet alone (-6.0% [95% CI -7.0%, -5.1%] vs -2.5% [95% CI -4.0%, -1.0%], p < 0.0001). Moreover, significantly more orlistat-treated patients than those on diet alone maintained a weight loss of > 5% (67% vs 19%, p < 0.0001). The weight loss at the 1 st month of therapy was positively correlated with the weight loss observed at the end of the study (6th month) in both treatment groups (orlistat: r = 0.62, p < 0.0001; diet alone: r = 0.72, p < 0.0001). At the 6th treatment month the mean change in waist circumference was significantly greater with orlistat compared with diet alone (-7.2% [95% CI -9.0% to

-4.6%] vs -2.3% [95% CI -3.4% to -0.5%], p < 0.0001 ). Orlistat was also associated with significantly greater improvements than diet alone in TC (-11.2% vs -0.9%, p < 0.0001), LDL-C (-13.7% vs - 2.1%; p < 0.0001), fasting glucose (-24.5% vs -1.2%; p < 0.0001), HbA^sub 1c^. (-19.8% vs -10.3%; p < 0.0001), and SUA levels (-27.4% vs -11.1%; p = 0.0002) (Table 2). Moreover, 73% of all patients (n = 92) had non-alcoholic fatty liver disease at baseline. Ultrasound imaging showed no change during the study. Three orlistat treated patients were considered to change from moderate to mild fatty liver. The mean transaminases levels activity showed a non- significant reduction in both treatment groups.

Metabolic Syndrome

The percentage of patients in each treatment group having MetSyn (with 3 or 4-5 components) at the end of the study is reported in Table 3. By the end of the study 65% of the patients on orlistat plus diet still met the MetSyn criteria and 41% had 4-5 MetSyn components vs 91% (p < 0.0001) and 53% (p = 0.0173), respectively, of the patients on HCD alone. This was mainly due to the drastic reduction in the number of patients with waist circumference and blood pressure values above the cut-off points of the NCEP definition18 for MetSyn.

Vascular Event Risk Assessment

In the orlistat group there was a significant reduction in estimated 10-year risk of vascular events (-50% vs -4.5% in the HCD group, p < 0.0001) (Table 2).

Safety

Orlistat was well tolerated. Overall, orlistat had a similar safety profile to diet alone, with the exception of a higher incidence of generally mild and transient gastrointestinal events known to be associated with the mode of action of orlistat. One patient (1.1%) in the orlistat group had to discontinue drug treatment, because of diarrhoea.

Discussion

Our results show that treatment with orlistat benefits patients with MetSyn + type 2 DM, with improvements in glycaemic control and other vascular risk factors. At the end of 6-months follow-up, 35% of patients on orlistat plus diet no longer satisfied the criteria for MetSyn vs 9% of patients on diet alone (p < 0.0001). This, along with the lower percentage of patients with four to five MetSyn components (41% vs 53% of the diet-alone group, p = 0.0173), probably translates to a substantial reduction in vascular risk. This was confirmed by the significant reduction in estimated vascular event risk (using the UKPDS risk calculator) in the orlistat treated group (-50% vs -4.5% of the HCD group, p < 0.0001) (Table 2).

The cross-sectional, multicentre epidemiological study (MetS- GREECE)22 that included 4153 subjects representing the Greek urban, semi-urban, and rural population showed that 23.6% of adults have the MetSyn. The yet unpublished data of this survey on the prevalence of vascular disease among subjects with DM show significant differences in total vascular disease burden between patients with MetSyn in comparison to those without MetSyn. In patients with DM without MetSyn the risk of a vascular event is half that in subjects with both MetSyn and DM, after adjustment for conventional risk factors, [odds ratio 1.42 (95% CI 1.09-1.81) vs 2.91 (95% CI 1.89-3.98), respectively]. Moreover, the greater the number of MetSyn components for those continuing to have MetSyn the higher the vascular risk. Therefore, effective control of MetSyn in terms of reducing the number of diagnostic features as seen in the present study, should result in a substantial vascular risk reduction. The morbidity and mortality from DM-related vascular disease is preventable in Greek patients with CHD23,24. The development of macrovascular and microvascular complications of DM may also be preventable25.

In the present study, treatment with orlistat + diet produced a significantly greater weight loss than diet alone in patients with both MetSyn and DM. Orlistat-treated patients achieved a mean weight loss of 5.6 kg (6% of body weight) after 6 months. This was associated with a significant improvement in several metabolic variables, including TC, LDL-C, non-HDL-C, fasting glucose and HbA^sub 1c^. In contrast, a mean weight loss of 2.5% in the diet alone group had little effect, supporting the view that weight reduction of 5% is a critical threshold necessary to achieve meaningful clinical benefits17. Weight loss in the present study was similar to that recorded after using orlistat in the prevention of diabetes in obese subjects (the XENDOS trial)26, in obese subjects with impaired glucose tolerance (IGT)26, in patients with DM on oral hypoglycemic drugs27 and in patients with DM on insulin28.

Systolic blood pressure and central obesity were the MetSyn components that showed the greatest reduction in the orlistat- treated patients. Central obesity is a powerful risk factor for the development of insulin resistance, hypertension, hyperlipidaemia, and atherogenesis29-32. Weight reduction results in an improvement or elimination of these obesity-related co-morbid conditions33. Weight loss of 5% has been shown to reduce disease risks, and metabolic improvements are related to the magnitude of weight loss34. Lifestyle modifications with diet and orlistat have been shown to be associated with a reduction in blood pressure and with improvement of insulin sensitivity35. This medical approach also results in a reduction in LDL-C, without a significant change in HDL- C36. Abdominal adipose tissue is now known to release a variety of adipocytokines, such as leptin, resistin, and adiponectin, which have been implicated in the pathogenesis of insulin resistance and atherosclerosis37. A balanced production of adipocytokines plays an important role in maintaining homeostasis of glucose and lipid metabolism. Dysregulation of adipocytokine production is directly involved in the pathophysiology of the MetSyn. Modest weight loss and reduction of waist circumference (as in the present study) are associated with a rise in serum adiponectin and reduction in serum resistin levels, respectively38. The normalization of plasma concentrations of adipocytokines reverses the phenotype of the MetSyn39,40.

From a clinical perspective, the improvements in glycaemic control achieved in the orlistat-treated patients in the present study is comparable to those reported in studies of antidiabetic drugs such as acarbose, glibenclamide or metformin41-43. Moreover, these improvements were achieved despite the fact that the known duration of DM was long (9 years - Table 1) and all patients were on long-term treatment with oral antidiabetic agents (metformin alone or in combination with sulfonylureas).

Although LDL-C is not considered a component of MetSyn, many patients have raised levels. In the present study, the mean baseline LDL-C was 3.7 mmol/L (143 mg/dL] (Table 2), despite the fact that 39% of all patients were on lipid lowering treatment (Table 1). Probably elevated LDL-C, especially in the presence of elevated TGs (indicating small dense LDL particles with increased atherogenicity44] should be considered as contributing to the morbidity and mortality associated with MetSyn.

The contribution of high LDL-C levels to vascular risk in subjects with MetSyn has been highlighted by retrospective analyses of the landmark statin trials. The placebo data from the Scandinavian Simvastat\in Survival Study (4S) and the Air Force/ Texas Coronary Atherosclerosis Prevention Study (AFCAPS/ TexCAPS]45 showed that the MetSyn is associated with an increased risk of major coronary events in both hypercholesterolaemic patients with CHD in 4S and in those with 'average' LDL-C levels and low HDL-C but without CHD in AFCAPS/TexCAPS45. In the West of Scotland Coronary Prevention Study46 MetSyn continued to predict coronary events (HR = 1.30, 95% CI 1.00-1.67, p = 0.045] in a multivariate model incorporating conventional risk factors. Moreover, men with 4 or 5 features of the MetSyn had a 3.7-fold increase in risk for CHD compared with men with none46. This result was similar to that of a study which reported that patients with 4 or 5 MetSyn components have a > 5-fold increased vascular risk compared with those with only one7. A projection of pooled observational data47 suggested that optimal control of LDL-C to normal levels in subjects with the MetSyn would have prevented 46% and 38% of coronary events, in men and women, respectively. Since the reduction of serum LDL-C levels has been defined as the main lipid therapeutic target in type 2 DM, the most powerful drugs for these patients may well be statins48. In the present study LDL-C reduction was highly significant, and was probably related to the partial inhibition of fat absorption from the gastrointestinal tract by orlistat49. It has been reported that orlistat has a direct cholesterol lowering effect that is independent of weight loss49,50. Therefore, the reduction in LDL-C induced by orlistat in the present study may make a significant contribution to the reduction in vascular risk.

The reduction in SUA levels with orlistat recoded in the present study has been reported before51. Elevated SUA levels are considered by some authors as an independent vascular disease risk factor52 and their reduction is associated with clinical benefit53. This might be another potential mechanism for orlistat to improve clinical outcome.

Because of the small sample size, our results need to be confirmed by larger studies.

Conclusions

Weight management involving orlistat resulted in significant weight loss, improved glycaemic control and vascular risk factor profile in patients with MetSyn and type 2 DM. Moreover, orlistat reduced the number of MetSyn components and the calculated vascular risk. Orlistat should, therefore, be considered as an option for the treatment of these patients. The results of this study need to be confirmed by larger trials.

Acknowledgements

No Company or Institution supported the present study financially or otherwise and there is no conflict of interest. Some of the authors have attended conferences and participated in other trials sponsored by various pharmaceutical companies.

Support for the publication of the paper itself has been partially funded by Roche Hellas.

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T. P. Didangelos1, A. K. Thanopoulou2, S. H. Bousboulas3, C. L. Sambanis1, V. G. Athyros1, E. A. Spanou2, K. C. Dimitriou3, S. I. Pappas3, B. G. Karamanos2 and D. T. Karamitsos1

1 Diabetes Center, Aristotelian University, Hippocration Hospital, Thessaloniki, Greece

2 Diabetes Center, University of Athens, Hippocration Hospital, Athens, Greece

3 Diabetes Center, Nikea General Hospital, Piraeus, Greece

Address for correspondence: Dr Triandafillos P. Didangelos, 34 K. Paleologou Str., Panorama, Thessaloniki, 552 36, Greece. Tel.: +30- 2310-340-086; Fax: +30-2310-445-220; email: didang@med.auth.gr

Copyright Librapharm Sep 2004

Source: Current Medical Research and Opinion

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