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

International Journal of Obesity volume 31, pages 850–857 (2007)Cite this article

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=97) to a random sample of patients treated with phen–fen (N=98) in the Clinical Nutrition Clinic at the University of Wisconsin. Comparison of echocardiograms in all patients treated solely with phen–flu (N=21) to a random sample of patients treated with phen–fen (N=47), and to a group of subjects never treated with obesity drugs (N=26).

Results:

With last observation carried forward analysis (LOCF), at 6 months of treatment the phen–fen patients lost 12.6±0.6% of baseline weight and phen–flu patients lost 9.0±0.6% (P<0.001). With completers analysis, there were no significant differences in weight loss as a percent of baseline weight at 6 months (14.4±0.6 vs 13.3±0.9%). LOCF decreases in body mass index (BMI) at 6 months were −5.3 and −3.6 kg/m2 for phen–fen and phen–flu, respectively (P<0.001), and 6.2±0.3 vs 5.4±0.4 kg/m2, 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.

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References

  1. Bray GA . Drug treatment of obesity. Am J Clin Nutr 1992; 55 (2 Suppl): 538S–544S.

    Article  CAS  Google Scholar 

  2. Weintraub M . Long-term weight control: the National Heart, Lung, and Blood Institute funded multimodal intervention study. Clin Pharmacol Ther 1992; 51: 581–646.

    Article  CAS  Google Scholar 

  3. Atkinson RL, Blank RC, Schumacher D, Dhurandhar NV, Ritch DL . Long-term drug treatment of obesity in a private practice setting. Obes Res 1997; 5 : 578–586.

    Article  CAS  Google Scholar 

  4. Wadden TA, Berkowitz RI, Silvestry F, Vogt RA, St John Sutton MG, Stunkard AJ et al. The fen–phen finale: a study of weight loss and valvular heart disease. Obes Res 1998; 6: 278–284.

    Article  CAS  Google Scholar 

  5. Dhurandhar NV, Blank RC, Schumacher D, Atkinson RL . Initial weight loss as a predictor of response to obesity drugs. Int J Obes Relat Metab Disord 1999; 23: 1333–13336.

    Article  CAS  Google Scholar 

  6. Alger SA, Malone M, Cerulli J, Fein S, Howard L . Beneficial effects of pharmacotherapy on weight loss, depressive symptoms, and eating patterns in obese binge eaters and non-binge eaters. Obes Res 1999; 7 : 469–476.

    Article  CAS  Google Scholar 

  7. Katz DA, Maloney MJ, Sutkamp JC, McConville BJ . Lower dosages of phentermine–fenfluramine given in the afternoon: five cases with significant weight loss. Int J Eat Disord 1999; 25: 469–474.

    Article  CAS  Google Scholar 

  8. Kolotkin RL, Crosby RD, Williams GR, Hartley GG, Nicol S . The relationship between health-related quality of life and weight loss. Obes Res 2001; 9: 564–571.

    Article  CAS  Google Scholar 

  9. Greenway FL, Ryan DH, Bray GA, Rood JC, Tucker EW, Smith SR . Pharmaceutical cost savings of treating obesity with weight loss medications. Obes Res 1999; 7 : 523–531.

    Article  CAS  Google Scholar 

  10. Steel JM, Munro JF, Duncan LJ . A comparative trial of different regimens of fenfluramine and phentermine in obesity. Practitioner 1973; 211: 232–236.

    CAS  PubMed  Google Scholar 

  11. Hudson KD . The anorectic and hypotensive effect of fenfluramine in obesity. JR Coll Gen Pract 1977; 27: 497–501.

    CAS  Google Scholar 

  12. Guy-Grand B, Apfelbaum M, Crepaldi G, Gries A, Lefebvre P, Turner P . International trial of long-term dexfenfluramine in obesity. Lancet 1989; 2: 1142–1145.

    Article  CAS  Google Scholar 

  13. Breum L, Astrup A, Andersen T, Lammert O, Nielsen E, Garby L et al. The effect of long-term dexfenfluramine treatment on 24-hr energy expenditure in man. A double-blind placebo controlled study. Int J Obesity 1990; 14: 613–621.

    CAS  Google Scholar 

  14. Mathus-Vliegen EMH, Van De Voore K, Kok AME, Res AMA . Dexfenfluramine in the treatment of severe obesity: a placebo-controlled investigation of the effects on weight loss, cardiovascular risk factors, food intake, and eating behaviour. J Intern Med 1992; 232: 119–127.

    Article  CAS  Google Scholar 

  15. Bray GA, Ryan DH, Gordon D, Heidingsfelder S, Cerise F, Wilson K . A double-blind randomized placebo-controlled trial of sibutramine. Obes Res 1996; 4: 263–270.

    Article  CAS  Google Scholar 

  16. Lean MEJ . Sibutramine – a review of clinical efficacy. Int J Obesity 1997; 21: S30–S36.

    CAS  Google Scholar 

  17. Ryan DH, Kaiser P, Bray GA . Sibutramine: a novel new agent for obesity treatment. Obes Res 1995; 3 (Suppl 4): 553S–559S.

    Article  CAS  Google Scholar 

  18. James WP, Avenell A, Broom J, Whitehead J . A one year trial to assess the value of orlistat in the management of obesity. Int J Obesity Relat Metab Disord 1997; 21 (Suppl 3): S24–S30.

    CAS  Google Scholar 

  19. Davidson MH, Hauptman J, DiGirolamo M, Foreyt JP, Halsted CH, Heber D et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA 1999; 281: 235–242.

    Article  CAS  Google Scholar 

  20. Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD et al. Valvular heart disease associated with fenfluramine–phentermine. N Engl J Med 1997; 337: 581–588.

    Article  CAS  Google Scholar 

  21. Graham DJ, Green L . Further cases of valvular heart disease associated with fenfluramine–phentermine. N Engl J Med 1997; 337: 635.

    Article  CAS  Google Scholar 

  22. Kurz X, Van Ermen A . Valvular heart disease associated with fenfluramine–phentermine. N Engl J Med 1997; 337: 1772–1773.

    Article  CAS  Google Scholar 

  23. Cannistra LB, Davis SM, Bauman AG . Valvular heart disease associated with dexfenfluramine. N Engl J Med 1997; 337: 636.

    Article  CAS  Google Scholar 

  24. Weissman NJ, Tighe Jr JF, Gottdiener JS, Gwynne JT . An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine, sustained-release dexfenfluramine, or placebo. Sustained-release dexfenfluramine study group. N Engl J Med 1998; 339: 725–732.

    Article  CAS  Google Scholar 

  25. Griffen L, Anchors M . Asymptomatic mitral and aortic valve disease is seen in half of the patients taking ‘phen–fen’. Arch Intern Med 1998; 158: 102.

    Article  CAS  Google Scholar 

  26. Khan MA, Herzog CA, St Peter JV, Hartley GG, Madlon-Kay R, Dick CD et al. The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite-suppressant drugs. N Engl J Med 1998; 339: 713–718.

    Article  CAS  Google Scholar 

  27. Wee CC, Phillips RS, Aurigemma G, Erban S, Kriegel G, Riley M et al. Risk for valvular heart disease among users of fenfluramine and dexfenfluramine who underwent echocardiography before use of medication. Annals Intern Med 1998; 129: 870–874.

    Article  CAS  Google Scholar 

  28. Ryan DH, Bray GA, Helmcke F, Sander G, Volaufova J, Greenway F et al. Serial echocardiographic and clinical evaluation of valvular regurgitation before, during, and after treatment with fenfluramine or dexfenfluramine and mazindol or phentermine. Obes Res 1999; 7: 313–322.

    Article  CAS  Google Scholar 

  29. Li R, Serdula MK, Williamson DF, Bowman BA, Graham DJ, Green L . Dose-effect of fenfluramine use on the severity of valvular heart disease among fen–phen patients with valvulopathy. Int J Obes Relat Metab Disord 1999; 23: 926–928.

    Article  CAS  Google Scholar 

  30. Kancherla MK, Salti HI, Mulderink TA, Parker M, Bonow RO, Mehlman DJ . Echocardiographic prevalence of mitral and/or aortic regurgitation in patients exposed to either fenfluramine–phentermine combination or to dexfenfluramine. Am J Cardiol 1999; 84: 1335–1338.

    Article  CAS  Google Scholar 

  31. Burger AJ, Sherman HB, Charlamb MJ, Kim J, Asinas LA, Flickner SR et al. Low prevalence of valvular heart disease in 226 phentermine–fenfluramine protocol subjects prospectively followed for up to 30 months. J Am Coll Cardiol 1999; 34: 1153–1158.

    Article  CAS  Google Scholar 

  32. Teramae CY, Connolly HM, Grogan M, Miller Jr FA . Diet drug-related cardiac valve disease: the Mayo Clinic echocardiographic laboratory experience. Mayo Clin Proc 2000; 75: 456–461.

    Article  CAS  Google Scholar 

  33. Jick H, Vasilakis C, Weinrauch LA, Meier CR, Jick SS, Derby LE . A population-based study of appetite-suppressant drugs and the risk of cardiac-valve regurgitation. N Engl J Med 1998; 339: 719–724.

    Article  CAS  Google Scholar 

  34. Rowland NE, Marshall M, Roth JD . Comparison of either norepinephrine-uptake inhibitors or phentermine combined with serotonergic agents on food intake in rats. Psychopharmacology (Berl) 2000; 149: 77–83.

    Article  CAS  Google Scholar 

  35. Anchors M . Safer Than Phen–Fen. Prima Publishing: Rocklin, CA, USA, 1997.

    Google Scholar 

  36. Devlin MJ, Goldfein JA, Carino JS, Wolk SL . Open treatment of overweight binge eaters with phentermine and fluoxetine as an adjunct to cognitive-behavioral therapy. Int J Eat Disord 2000; 28: 325–332.

    Article  CAS  Google Scholar 

  37. Reeve HL, Nelson DP, Archer SL, Weir EK . Effects of fluoxetine, phentermine, and venlafaxine on pulmonary arterial pressure and electrophysiology. Am J Physiol 1999; 276 (2 Part 1): L213–L219.

    CAS  PubMed  Google Scholar 

  38. Bostwick JM, Brown TM . A toxic reaction from combining fluoxetine and phentermine. J Clin Psychopharmacol 1996; 16: 189–190.

    Article  CAS  Google Scholar 

  39. Griffen L, Anchors M . The ‘phen-pro’ diet drug combination is not associated with valvular heart disease. Arch Intern Med 1998; 158: 1278–1279.

    Article  CAS  Google Scholar 

  40. Atkinson RL, Russ CS, Ciavarella PA, Owsley ES, Bibbs ML . A comprehensive approach to outpatient obesity management. J Am Diet Assoc 1984; 84: 439–444.

    CAS  PubMed  Google Scholar 

  41. Centers for Disease Control and Prevention (CDC). Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: US Department of Health and Human Services interim public health recommendations, November, 1997. MMWR Morb Mortal Wkly Rep 1997; 46: 1061–1066.

  42. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. The evidence report. National Institutes of Health. Obes Res 1998; 6 (Suppl 2): 51S–209S.

  43. Wadden TA, Berkowitz RI, Womble LG, Sarwer DB, Arnold ME, Steinberg CM . Effects of sibutramine plus orlistat in obese women following 1 year of treatment by sibutramine alone: a placebo-controlled trial. Obes Res 2000; 8: 431–437.

    Article  CAS  Google Scholar 

  44. Bowen RL, Atkinson RL . Addition of orlistat to long term phentermine treatment for obesity. Obes Res 2000; 8: 118.

    Google Scholar 

  45. Goldstein DJ, Rampey Jr AH, Dornseif BE, Levine LR, Potvin JH, Fludzinski LA . Fluoxetine: a randomized clinical trial in the maintenance of weight loss. Obes Res 1993; 1: 92–98.

    Article  CAS  Google Scholar 

  46. Goldstein DJ, Rampey Jr AH, Roback PJ, Wilson MG, Hamilton SH, Sayler ME et al. Efficacy and safety of long-term fluoxetine treatment of obesity – maximizing success. Obes Res 1995; 3 (Suppl 4): 481S–490S.

    Article  CAS  Google Scholar 

  47. Sussman N, Ginsberg DL, Bikoff J . Effects of nefazodone on body weight: a pooled analysis of selective serotonin reuptake inhibitor- and imipramine-controlled trials. J Clin Psychiatry 2001; 62: 256–260.

    Article  CAS  Google Scholar 

  48. Hansen D, Astrup A, Toubro S, Finer N, Kopelman P, Hilsted J, et al., Goulder For The STORM Study Group M. Predictors of weight loss and maintenance during 2 years of treatment by sibutramine in obesity Results from the European multi-centre STORM trial. sibutramine trial of obesity reduction and maintenance. Int J Obes Relat Metab Disord 2001; 25: 496–501.

    Article  CAS  Google Scholar 

  49. Wadden TA, Berkowitz RI, Sarwer DB, Prus-Wisniewski R, Steinberg C . Benefits of lifestyle modification in the pharmacologic treatment of obesity: a randomized trial. Arch Intern Med 2001; 161: 218–227.

    Article  CAS  Google Scholar 

  50. Foster GD, Wadden TA, Vogt RA, Brewer G . What is a reasonable weight loss? Patients' expectations and evaluations of obesity treatment outcomes. J Consult Clin Psychol 1997; 65: 79–85.

    Article  CAS  Google Scholar 

  51. Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ et al. Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation 2000; 102: 2836–2841.

    Article  CAS  Google Scholar 

  52. Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996; 335: 609–616.

    Article  CAS  Google Scholar 

  53. Rich S, Rubin L, Walker AM, Schneeweiss S, Abenhaim L . Anorexigens and pulmonary hypertension in the United States: results from the surveillance of North American pulmonary hypertension. Chest 2000; 117: 870–874.

    Article  CAS  Google Scholar 

  54. Ulus IH, Maher TJ, Wurtman RJ . Characterization of phentermine and related compounds as monoamine oxidase (MAO) inhibitors. Biochem Pharmacol 2000; 59: 1611–1621.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr E Shrago, H Walaski, E Freitick, and A Rettammel for clinical assistance; and J Hansen and V Schmidt for administrative assistance. Supported by grants from the Eli Lilly Company and funds from the Beers–Murphy Clinical Nutrition Center, University of Wisconsin, Madison.

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  1. Departments of Medicine and Nutritional Sciences, University of Wisconsin, Madison, WI, USA

    L D Whigham, N V Dhurandhar, P S Rahko & R L Atkinson

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Correspondence to R L Atkinson.

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Whigham, L., Dhurandhar, N., Rahko, P. et al. Comparison of combinations of drugs for treatment of obesity: body weight and echocardiographic status. Int J Obes 31, 850–857 (2007). https://doi.org/10.1038/sj.ijo.0803498

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