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

Effects on Glycaemic Control and Type 2 Diabetes

Weight gain is a risk factor for the development of type 2 diabetes and even modest weight reduction can reduce that risk.[51] Weight reduction is also a cornerstone of diabetes management, improving glycaemic control and improving other risk factors associated with this disease.[52] Sibutramine can contribute to the management of type 2 diabetes in overweight and obese patients.[53]

In a study,[54] 40 obese normal glucose tolerant women (BMI 34.3 kg/m2) were randomised to placebo or sibutramine, 10 mg once daily. After 24 weeks significant weight change was observed in the sibutramine group (-5.6 kg or -6.1% vs. +0.9 kg or +1.1%, p < 0.01). Sibutramine treatment was also associated with enhanced insulin sensitivity ( p < 0.05) and a reduction of homeostasis model assessment-insulin (HOMA-IR) resistance:

HOMA-IR = insulin (µU/mL) × glucose (mmol/L) ÷ 22.5

from 7.8 to 5.6 ( p < 0.05). Moreover, HOMA-β(β- pancreatic cell functional capacity) [20 × insulin (µU/ mL)/glucose (mmol/L) - 3.5] also decreased from 508 to 374 ( p < 0.05). No changes were observed in the placebo group regarding insulin sensitivity. McLaughlin et al .[55] studied the effect of sibutramine-assisted weight loss in healthy, normotensive, nondiabetic, obese women (BMI > 30 kg/m2). The 24 volunteers were divided into two groups, one being insulin-resistant (IR) and one being insulin-sensitive (IS) on the basis of their steady-state plasma glucose (SSPG) concentration in response to a 180 min continuous intravenous infusion of octreotide (synthetic somatostatin analogue), insulin and glucose. Weight loss after 4 months in response to an energy-restricted diet and sibutramine (15 mg/day) was compar able in the 2 experimental groups (8.6 kg vs. 7.9 kg). SSPG concentrations decreased significantly following weight loss [12.0 mmol/L-7.9 mmol/L (219 mg/dL-144 mg/dL), p < 0.001)] in the IR group, but there was no significant change in the SSPG in the IS group [3.8 mmol/L-4.0 mmol/L (69 mg/dL- 73 mg/dL)]. The improvement in insulin sensitivity in the IR group after weight loss was associated with a significant decline in plasma glucose ( p < 0.001) and insulin ( p = 0.02) concentrations. In contrast, there was no significant change in plasma glucose and insulin concentrations following weight loss in the IS group. Moreover, the results of the STORM study[23] showed that in obese patients (BMI 30 kg/m2-45 kg/m2) sibutramine treatment for 2 years led to a 22% reduction in plasma insulin levels and to a 26% reduction in C-peptide (a marker of endogenous insulin production) levels (both p < 0.01 vs. baseline).

A recent meta-analysis[56] of studies involving adults with type 2 diabetes ( n = 2231) showed that sibutramine reduced body weight (-3.3%) and glycosylated haemoglobin (HbA1c) (-0.7%) after 26 weeks of treatment. In another study[57] a 5-kg decrease in weight at 1 year of sibutramine treatment in obese diabetic patients was associated with a decrease of 0.4% in HbA1c ( p < 0.01). Finer et al[26] assessed the efficacy of sibutramine (15 mg/ day) for 12 weeks in 91 patients with treated (oral medication or insulin) or untreated type 2 diabetes. The mean peak blood glucose concentration after a standard test meal decreased by 1.1 mmol/L (20 mg/dL) in the sibutramine group but increased by 0.5 mmol/L (9 mg/dL) in the placebo group ( p < 0.05). In this trial both mean fasting blood glucose levels and mean HbA1c levels decreased in the sibutramine group but they were unchanged or increased in the placebo group. However, these differences did not reach statistical significance; this may be attributed to the relatively short duration (12 weeks) of this study. Nevertheless, more sibutramine-treated patients (33%) than placebotreated patients (5%) achieved decreases in HbA1c of 1% or more ( p < 0.05). Furthermore, Fujioka et al .[24] determined the efficacy of sibutramine treatment for 6 months in obese patients whose type 2 diabetes was poorly controlled on diet alone or with an oral antidiabetic agent. At the end of the study, the patients receiving sibutramine compared with patients receiving placebo showed significantly greater weight loss (-4.5% vs. -0.5%, p < 0.01). Weight loss ≥5% or ≥10% was achieved by 33% and 8% of sibutramine patients who completed the course, respectively, but by none of the patients receiving placebo. Improvement in glycaemic control correlated with weight loss ( p < 0.001). In 5% and 10% weight-loss responders, mean treatment differ ences were -0.53% and -1.65% ( p < 0.05), respectively, for HbA1c, and -1.4 mmol/L (25.5 mg/dL) and -3.8 mmol/L (69.0 mg/dL) ( p < 0.05), respectively, for fasting plasma glucose. In another trial,[58] sibutramine treatment for 6 months in combination with hypoglycaemic drugs in obese type 2 diabetic women, whose glucose levels were poorly regulated (HbA1c ≥8%), was associated with greater reductions in fasting blood glucose, second-hour postprandial blood glucose and HOMA-IR (all p < 0.001). Similar decreases in HbA1cand fasting plasma glucose were reported with sibutramine treatment in diabetic patients receiving metformin[59] or sulphonyl ureas.[60,61] In a study[62] comparing the efficacy and safety of sibutramine and orlistat in 144 obese diabetic patients, both drugs were effective on anthropometric variables and metabolic pattern during the 12-month treatment. In this study, orlistat appears to be slightly more efficacious as an anti-obesity drug, while sibutramine intake was not associated with any cardiovascular effect and was generally better tolerated than orlistat.

Obesity is frequently associated with the metabolic syndrome.[63] Sibutramine-induced weight loss and maintaining this effect leads to clinically relevant reductions in risk factors associated with the metabolic syndrome.[64] Furthermore, there is evidence that drug-induced weight loss in obese patients may prevent the onset of type 2 diabetes. Indeed, in the recent XENical in the prevention of Diabetes in Obese Subjects (XENDOS) study,[65] treatment with orlistat for 4 years significantly reduced the incidence of type 2 diabetes (6.2% vs. 9.0% in the lifestyle changes group, p = 0.0032, relative risk reduction = 37.3%).

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