Alteration of gastric functions and candidate genes associated with weight reduction in response to sibutramine.
OBJECTIVE
It is unclear whether weight loss with the noradrenergic (norepinephrine) and serotonergic (5-hydroxytryptamine) reuptake inhibitor, sibutramine, is associated with altered stomach functions and whether genetics influence treatment response.


METHODS
Forty-eight overweight and obese but otherwise healthy participants were randomized to placebo or sibutramine (15 mg/day for 12 weeks). At baseline and posttreatment we measured the following: gastric emptying for solids and liquids by scintigraphy, gastric volumes by single-photon emission computed tomography, maximum tolerated volume and 30-minute postnutrient challenge symptoms, and selected gastrointestinal hormones. All participants received structured behavior therapy for weight management. The influence of candidate gene polymorphisms involved in norepinephrine and 5-hydroxytryptamine or receptor function (phenylethanolamine N-methyltransferase, guanine nucleotide binding protein beta polypeptide 3, alpha2A adrenoreceptor, and solute carrier family 6 [neurotransmitter transporter, serotonin] member 4 [homo sapiens] [SLC6A4]) on weight loss and gastric functions was evaluated.


RESULTS
The overall average weight loss posttreatment was 5.4 +/- 0.8 (SEM) kg with sibutramine and 0.9 +/- 0.9 kg with placebo (P < .001). The sibutramine group showed significant retardation in gastric emptying of solids (P = .03), reduced maximum tolerated volume (P = .03), and increased postprandial peptide YY compared with the placebo group. Obese females showed greater effects of sibutramine on weight loss and gastric emptying of solids and liquids. Gastric volumes and postchallenge symptoms were not significantly different in the 2 treatment groups. The LS/SS genotype of the promoter for SLC6A4 was associated with enhanced weight loss with sibutramine.


CONCLUSIONS
Weight reduction with sibutramine is associated with altered gastric functions and increased peptide YY and is significantly associated with SLC6A4 genotype. The role of genetic variation in SLC6A4 on weight loss in response to sibutramine deserves further study.
Vazquez Roque
Maria I
MI
Clinical Enteric Neuroscience Translational and Epidemiological Research Group, Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Camilleri
Michael
M
Clark
Matthew M
MM
Tepoel
Debra A
DA
Jensen
Michael D
MD
Graszer
Karen M
KM
Kalsy
Sarah A
SA
Burton
Duane D
DD
Baxter
Kari L
KL
Zinsmeister
Alan R
AR
D000293:Adolescent; D000328:Adult; D000368:Aged; D001067:Appetite Depressants / Q000627:therapeutic use; D015992:Body Mass Index; D002851:Chromatography, High Pressure Liquid; D003503:Cyclobutanes / Q000627:therapeutic use*; D004247:DNA / Q000235:genetics*; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D050485:GABA Plasma Membrane Transport Proteins / Q000235:genetics*; D005746:Gastric Emptying / Q000187:drug effects* / Q000502:physiology; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D009929:Organ Size; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D013270:Stomach / Q000473:pathology* / Q000503:physiopathology; D016896:Treatment Outcome; D015431:Weight Loss / Q000187:drug effects* / Q000235:genetics / Q000502:physiology
D001067:Appetite Depressants; D003503:Cyclobutanes; D050485:GABA Plasma Membrane Transport Proteins; C493413:SLC6A1 protein, human; D004247:DNA; C058254:sibutramine