A Review of the Metabolic Effects of Sibutramine

T. D. Filippatos; D. N. Kiortsis; E. N. Liberopoulos; D. P. Mikhailidis; M. S. Elisaf

Disclosures

Curr Med Res Opin. 2005;21(3):457-468. 

In This Article

Other Effects of Sibutramine

Given the increasing prevalence of obesity and diabetes mellitus, NAFLD has become the most common cause of chronic liver disease, affecting a third of the general population in the United States.[75] NAFLD includes a spectrum of liver damage, ranging from liver steatosis, which is usually associated with a benign prognosis, to non-alcoholic steatohepatitis (NASH), which has the potential to progress to cirrhosis and its complications of liver failure and liver cancer.[75] Weight loss in these patients may improve the features associated with NAFLD and NASH. Sabuncu et al .[76] investigated the effects of sibutramine treatment for 6 months plus a low-calorie diet in 13 obese patients with NASH and a mean BMI of 37.3 kg/m.2 At the end of this study, sibutramine significantly reduced body weight (-10.2%), insulin resistance (-47%), as well as the serum activities of aspartate aminotransferase (AST) (-41%), alanine amino transferase(ALT) (-59%) and gamma-glutamyltrans peptidase (γGT) (-27%). Ultrasonographic regression of steatosis was observed in 11 patients. During the treatment, an unexpectedly significant increase in total alkaline phosphatase (ALP) activity was found (+9%), but the authors, based on the reduction of γGT activity, concluded that the increased ALP activity probably did not originate from the liver. In another study,[54] sibutramine treatment resulted in a significant decrease in serum γGT activity (from 28 ± 12 U/L to 21 ± 8 U/L after 24 weeks of treatment, p < 0.05).

Preliminary results of a randomised, placebocontrolled, double-blind study 77 that evaluated the effectiveness of orlistat in the treatment of NASH, showed a biopsy-proven improvement in the degree of steatosis and severity of NASH in those taking orlistat compared to those in the placebo group. In another study,[78] orlistat therapy and dietary counselling were associated with a 10% or greater reduction in weight improved steatosis and fibrosis in the majority of patients treated for 6 months. A decline in transaminase activities and normalisation of ultrasonographic evidence of fatty liver were also observed on treatment with orlistat in overweight patients with hyperlipidaemia.[79]

Recent studies suggest that the serum uric acid concentration is an independent risk factor for cardiovascular events.[80] Sibutramine treatment significantly reduces serum uric acid levels.[29] In the study of Gokcel et al .[50] , after treatment for 6 months there was a 12% reduction in serum uric acid levels in the sibutramine group ( p < 0.01 vs. baseline). A similar reduction in serum uric acid levels (-9%) was also reported by Tambascia et al .[54] Furthermore, in the STORM study,[23] after treatment for 2 years there was a 6.5% reduction in uric acid levels in the sibutramine group vs. a 3% reduction in the placebo group ( p < 0.05 vs. treatment groups).

The fall in serum uric acid levels may be associated with the observed weight loss per se, improved renal function, a direct uricosuric effect of sibutramine or a decrease in insulin resistance. Unfortunately, we did not find any studies that assessed possible alterations in creatinine or uric acid clearance after sibutramine administration. The decrease in insulin resistance following sibutramine treatment may explain the observed fall in serum urate concentration. Indeed, metformin administration resulted in a significant reduction in serum uric acid levels in obese patients.[50] This effect was comparable to that induced by sibutramine, despite the fact that sibutramine caused more weight loss than metformin.[50] In this study, orlistat also lowered serum urate levels.[50] In this context, it is of interest that troglitazone, an insulin sensitising thiazolidinedione now withdrawn due to side effects, can lower serum uric acid levels without changing body weight.[81]

White adipose tissue is now recognised to have a major endocrine function secreting several hormones, as well as a variety of other protein factors, the 'adipocytokines'.[82]

In a 2-week study[83] sibutramine treatment (10 mg/ day) decreased plasma leptin levels from 48.8 ng/mL to 42.8 ng/mL ( p < 0.05) and HOMA-IR from 5.59 ng/ mL to 3.66 ng/mL ( p < 0.02). In this study there was no correlation between the fall in leptin levels and the decrease in insulin resistance. Yip et al .[84] evaluated insulin and leptin levels, as well as abdominal adiposity in relation to weight loss with sibutramine and diet in 18 patients with upper body obesity. At the end of this 6-month study, there was a 16% reduction in body weight ( p < 0.001) and a 22.5% ( p < 0.001) decrease in total body fat mass. Abdominal CT scans showed a 28.3% ( p < 0.001) reduction in total abdominal fat, a 26% reduction in subcutaneous fat ( p < 0.001) and a 31% reduction in visceral fat ( p < 0.001). There was a 32% ( p < 0.001) reduction in leptin levels and a 37.9% ( p < 0.001) reduction in insulin levels between baseline and week 4, but no further significant reduction in leptin and insulin levels was observed after that period. Further more, from baseline through to the end of the study there was a significant correlation between insulin and leptin concentrations ( p < 0.001). Significant associations between visceral abdominal fat, subcutaneous fat and leptin were also observed.

In a recent study,[85] Valsamakis et al . assessed the effects of modest weight loss with sibutramine on serum adipocytokines and their relationship with changes in anthropometric and metabolic parameters in 21 Caucasian non-diabetic women. After 6 months the patients had a mean weight loss of 5.4% ( p < 0.001), while their waist circumference was reduced by 4.5 cm. There was a decrease in serum resistin (16.8%, p = 0.02), leptin (22%, p = 0.02) and CRP (9.7%, p = 0.03) levels (a predictor of cardiovascular events)[86] and a rise in serum adiponectin (27%, p = 0.04). The percentage change in BMI was associated with percentage changes in insulin ( r = 0.53, p = 0.02) and leptin ( r = 0.58, p = 0.01) levels. More over, the change in waist circumference was associated with percentage changes in insulin ( r = 0.75, p = 0.005) and resistin ( r = 0.55, p = 0.03) levels. Furthermore, sibutramine improved fat distribution and insulin resist ance and increased serum adiponectin levels in Korean obese nondiabetic premenopausal women.[87]

Fibrinogen is a risk factor for cardiovascular events.[88] Tambascia et al .[54] reported that after sibutramine treatment for 6 months in 40 obese women there was no change in fibrinogen levels in the sibutramine or placebo group.

Obesity has been associated in some cases with PCOS.[89] The effectiveness of sibutramine therapy alone or in combination with ethinylestradiol-cyproterone acetate (EE-CPA) was evaluated in obese women with PCOS.[90] After treatment for 6 months, BMI, Ferriman-Gallwey hirsutism score, serum total testosterone, free testosterone and dihydroepiandrosterone sulphate (DHEAS) levels were significantly decreased, while sex hormonebinding globulin (SHBG) was significantly increased in all groups. Waist to hip ratio and serum TG level were significantly reduced only in the sibutramine group. Therefore, sibutramine may have a positive effect on hyperandrogenaemia in obese women with PCOS.

No study reporting the effect of sibutramine treatment on plasma homocysteine levels could be found. However, homocysteine levels tend to be increased in obese individuals[91] and hyperhomocysteinaemia is an emerging risk factor for vascular disease.[92] Therefore, it would be interesting to establish whether sibutramine-induced weight loss would result in a fall in homocysteine levels.

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