Comparison of combinations of drugs for treatment of obesity: body weight and echocardiographic status

Abstract

Background: Obesity treatment with single drugs produces weight losses of about 8-10% of initial body weight. Few studies of combinations of drugs for treating obesity have been published. The combination of phentermine, an adrenergic agent, and fenfluramine, a serotonergic agent, (phen-fen) produced weight losses of about 15% of initial body weight. Fenfluramine is no longer available because it was associated with cardiac valve lesions. Phentermine-fluoxetine (phen-flu) has been proposed as an alternative for phen-fen. Objective: To compare the efficacy of treatment and prevalence of cardiac valve abnormalities on phen-flu vs phen-fen. Design: Retrospective chart review of all patients treated for at least 3 months with phen-flu (N ¼ 97) to a random sample of patients treated with phen-fen (N ¼ 98) in the Clinical Nutrition Clinic at the University of Wisconsin. Comparison of echocardiograms in all patients treated solely with phen-flu (N ¼ 21) to a random sample of patients treated with phen-fen (N ¼ 47), and to a group of subjects never treated with obesity drugs (N ¼ 26). Results: With last observation carried forward analysis (LOCF), at 6 months of treatment the phen-fen patients lost 12.670.6% of baseline weight and phen-flu patients lost 9.070.6% (Po0.001). With completers analysis, there were no significant differences in weight loss as a percent of baseline weight at 6 months (14.470.6 vs 13.370.9%). LOCF decreases in body mass index (BMI) at 6 months were À5.3 and À3.6 kg/m 2 for phen-fen and phen-flu, respectively (Po0.001), and 6.270.3 vs 5.470.4 kg/m 2 , respectively, for the completers analysis (P -NS). Dropout rate at 6 months was higher in phen-flu subjects (44 vs 28%). In subjects without atherosclerosis of valves (presumably pre-existing), cardiac valve lesions occurred in eight of 38 phen-fen subjects and in none of 15 phen-flu subjects or 25 control subjects who had not been treated with drugs. Conclusions: The combination of phentermine and fluoxetine was not as effective as phen-fen, but was not associated with cardiac valve lesions. Longer term, larger scale studies of phen-flu are warranted.

Serotonergic drugs and valvular heart disease

“…These drugs included phentermine, fluoxetine and its metabolite norfluoxetine. Echocardiographic studies in humans support the assertion that fluoxetine (and other SSRIs) 65, phentermine 66 and sibutramine (a NE/5-HT uptake inhibitor) 67 do not cause VHD. We also tested the antidepressant trazodone and its active metabolite, m-chlorophenylpiperazine (mCPP), as negative controls 68, 69.…”

Adiposopathy: Treating pathogenic adipose tissue to reduce cardiovascular disease risk

“…Although trials of some combinations of antiobesity drug therapies have demonstrated variable results [30][31][32][33][34], the combination of phentermine with phenfluramine was not discontinued due to lack of clinical efficacy (which was significant), but rather was mostly abandoned due to finding of heart valve pathology with fenfluramine [35]. The potential and possibly somewhat unique efficacy benefits of adding phentermine to other antiobesity agents (coupled with its generic status) have prompted its incorporation into investigational combination antiobesity agents (see "Emerging Therapies" section).…”

Pharmacotherapies for Obesity: Past, Current, and Future Therapies

“…In clinical practice fluoxetine 10–20 mg has been used with phentermine (i.e., phen-pro or phen-flu ) but there are no RCTs of either the long-term efficacy or safety of this combination [50]. A retrospective chart review suggested this combination is not as effective as fenfluramine with phentermine [51]. Fluoxetine generally has a tolerable safety profile with reported adverse events of headache, asthenia, nausea, diarrhoea, somnolence, insomnia, nervousness, sweating, and tremor [47].…”