Pharmaceutical Cost Savings of Treating Obesity with Weight Loss Medications

GREENWAY, FRANK L., DONNA H. RYAN, GEORGE A. BRAY, JENNIFER C. ROOD, ELIZABETH W. TUCKER, AND STEVEN R. SMITH. Pharmaceutical cost savings of treating obesity with weight loss medications. Obes Res. Objective: To evaluate, in compliant patients, the pharmaceutical costs of treating obesity with fenfluraminel/mazindol, fenfluramine/phentermine, caffeine/ephedrine, or mazindol relative to the pharmaceutical costs of treating obesity-related comorbid conditions and reducing cardiovascular risk. Methods and Procedures: Subjects were between 18 and 60 years of age with a BMI of >30 kg/m². Pharmaceutical costs were evaluated in 73 of 220 subjects taking medications for diabetes, hyperlipidemia, or hypertension before and after treatment using fenfluramine with mazindol or phentermine. The pharmaceutical cost of weight loss, cardiac risk reduction, and low-density lipoprotein (LDL) cholesterol reduction was calculated for fenfluramine with mazindol or phentermine, caffeine with ephedrine, or mazindol alone, and compared to approved lipid-lowering medications. Results: Losses of 6% to 10% of initial body weight reduced pharmacy costs $122. 64/month for insulin treated diabetes, $42. 92/month for sulfonylurea-treated diabetes, $61. O7/month for hyperlipidemia treated with medication, and $0. 20/month for hypertension treated with medication. Blood pressure and laboratory evidence of insulin resistance improved in all medication groups. Caffeine/ephedrine was most cost-effective of the three treatments in reducing weight, cardiac risk, and LDL cholesterol. Discussion: Obesity medications produced a substantial weight loss in compliant patients and resulted in a net pharmaceutical cost savings compared to treating obesity related comorbid conditions.     

Combined Drug Treatment of Obesity

Pharmacological treatment of obesity has been neglected as a viable therapeutic option for many years. Recent long term studies with combinations of obesity drugs gives promise that drugs may play a role in weight maintenance, which classically has been the most difficult aspect of treating obesity. Currently available obesity drugs include centrally acting adrenergic agents and serotonin agonists. Drugs still in development include a lipase inhibitor that produces fat malabsorption, a combined adrenergic-serotonergic reuptake inhibitor, various gut-central nervous system peptides, and a number of beta-3 agonists. Any of these obesity drugs given alone produces modest weight loss, and for most, weight loss continues for as long as medication is given. The most successful drug regimens to date are combinations of phentermine and fenfluramine or of ephedrine, caffeine, and/or aspirin. The former combination produces reduction in body weight and complications of obesity for 2 to almost 4 years in clinical trials to date. More research is needed to document long term efficacy and particularly the long term safety of these and other combinations.     

Lifestyle Modification in the Pharmacologic Treatment of Obesity: A Pilot Investigation of a Potential Primary Care Approach

This study examined a new method of providing brief, individual lifestyle modification to obese individuals treated by pharmacotherapy. Twenty-six women with a mean (±SD) age of 47.0 ± 7.2 years, weight of 97.6 ± 13.0 kg, and body mass index of 36.5 ± 5.0 kg/m² were prescribed 60 mg/d of fenfluramine and 15 mg/d of phentermine for one year. In addition, half of the women were randomly assigned to traditional group behavior modification, conducted by a nutritionist, which included 32 75-minute sessions during the year. The other half were provided lifestyle modification by a physician during 10 15–20 minute structured visits. All participants received identical treatment manuals and comparable assignments for behavior change. At the end of one year, patients in the physician group achieved the same highly successful weight losses as those treated by group behavior modification (13.9 ± 9.6 kg vs. 15.4 ± 7.9 kg, respectively). Treatment was associated with highly significant improvements in lipids and lipoproteins, as well as in mood and several measures of appetite. Weight loss the first four weeks, as well as patient completion of daily food records during the first 18 weeks, correlated positively with weight loss at weeks 18, 26, and 52. Results of this study await replication using larger samples but strongly suggest that effective lifestyle modification can be provided during brief, structured physician visits. The findings are discussed in terms of their implications for the treatment of obesity in primary care practice.     

Plasma fenfluramine levels,weight loss,and side effects.

Fifty women with refractory obesity received fenfluramine for 20 weeks. Every two weeks details of weight change, drug dose, degree of anorexia, and any side effects were recorded and plasma was obtained for fenfluramine and norfenfluramine measurements. Of the 41 patients available for final analysis 26 achieved a maximum plateau dose of 160 mg/day. Plasma fenfluramine concentrations did not correlate with the degree of anorexia or with the incidence of side effects other than the severity of dream disturbance. There was a highly significant relation between weight loss and plasma fenfluramine and norfenfluramine concentrations and also between weight loss and the presence of sustained anorexia. Women who achieved mean plateau concentrations over 200 ng/ml lost a mean 8.8 kg while those with concentrations less than 100 ng/ml lost a mean of only 2.1 kg. When fenfluramine is prescribed in refractory obesity the dose should be increased stepwise until either satisfactory weight loss is achieved or troublesome side effects appear.     

Blood pressure and heart rate effects, weight loss and maintenance during long-term phentermine pharmacotherapy for obesity

There is a perception that phentermine pharmacotherapy for obesity increases blood pressure and heart rate (HR), exposing treated patients to increased cardiovascular risk. We collected data from phentermine‐treated (PT) and phentermine‐untreated (P0) patients at a private weight management practice, to examine blood pressure, HR, and weight changes. Records of 300 sequential returning patients were selected who had been treated with a low‐carbohydrate ketogenic diet if their records included complete weight, blood pressure, and HR data from seven office examinations during the first 12 weeks of therapy. The mean time in therapy, time range, and mode was 92 (97.0), 12–624, and 52 weeks. 14% were normotensive, 52% were prehypertensive, and 34% were hypertensive at their first visit or had a previous diagnosis of hypertension. PT subjects systolic blood pressure/diastolic blood pressure (SBP/DBP) declined from baseline at all data points (SBP/DBP ?6.9/?5.0 mm Hg at 26, and ?7.3/?5.4 at 52 weeks). P0 subjects' declines of SBP/DBP at both 26 and 52 weeks were ?8.9/?6.3 but the difference from the treated cohort was not significant. HR changes in treated/untreated subjects at weeks 26 (?0.9/?3.5) and 52 (+1.2/?3.6) were not significant. Weight loss was significantly greater in the PT cohort for week 1 through 104 (P = 0.0144). These data suggest phentermine treatment for obesity does not result in increased SBP, DBP, or HR, and that weight loss assisted with phentermine treatment is associated with favorable shifts in categorical blood pressure and retardation of progression to hypertension in obese patients.     

Beneficial Effects of Pharmacotherapy on Weight Loss,Depressive Symptoms,and Eating Patterns in Obese Binge Eaters and Non-Binge Eaters

ALGER, SHARON A., MARGARET MALONE, JENNIFER CERULLI, STEVEN FEIN, LYN HOWARD. Beneficial effects of pharmacotherapy on weight loss, depressive symptoms, and eating patterns in obese binge eaters and non-binge eaters. Obes Res. Objective: The purpose of this study was to compare the impact of drug therapy on weight loss, Beck Depression Inventory (BDI) scores, and binge eating patterns (BES) between obese binge eaters and non-binge eaters. Research Methods and Procedures: 22 severe binge eaters, 17 moderate binge eaters, and 16 non-binge eaters received phentermine resin 15mg/day and dl-fenfluramine 20mg three times daily over a 6 month period for weight loss. All data are reported as mean±S. Results: The percent weight loss compared to baseline within the 3 groups ranged from 8. 9% to 11. 3% at 3 months and 10. 6% to 14. 9% at 6 months. After 6 months, 73% of the severe binge eaters, 59% of moderate binge eaters and 69% of non-binge eaters had experienced more than 10% weight loss. BDI scores were significantly higher in the severe group at baseline when compared to non-binge eaters (p<0. 006). After 3 and 6 months BDI scores improved in all groups but remained significantly different between the severe and non-binge eaters until the 6-month assessment. BES scores declined in all groups over the 6-month period. Echocardiograms were performed in 35 of 55 subjects following reports of a possible association between fenfluramine and valvular changes. Fifteen (43%) of subjects had no abnormal findings and 20 (57%) had evidence of valvular insufficiency occurring in one or more valves. Seven patients (20%) had significant valve damage according to the DHHS and FDA criteria. Conclusion: After 24 weeks of treatment severe binge eaters improved their eating pattern, depression scores, and achieved weight loss similar to non-binge eaters. These data suggest that pharmacologic intervention for weight loss and subsequent weight maintenance can be as successful in binge eaters as non-binge eaters. A relationship was seen between duration of drug treatment and valvular insufficiency in subjects treated for an average of 52 weeks. These findings validate the FDA requirement for studies of at least 1 year duration to evaluate both the safety and efficacy of pharmacologic treatment for obesity.     

How Physician Obesity Specialists Use Drugs to Treat Obesity

Specialist physicians may have prescribing habits that are different from nonspecialist physicians. Little is known about the prescribing habits of physicians specializing in the treatment of obesity. An anonymous survey was given to the physician members of the American Society of Bariatric Physicians (ASBP). There was a 35% response rate (266 physicians) to the questionnaire that was represented nationally. Almost all prescribed medications and all of them recommended phentermine. The average maximal dose of phentermine was above that approved in the package insert, and these physicians disagreed with the National Institutes of Health (NIH) Obesity Treatment Guidelines. Phendimetrazine, metformin, and phentermine plus l ‐5‐hydroxytryptophan (5‐HTP) with carbidopa were all used more frequently than either orlistat or sibutramine. The combination of sibutramine and orlistat as well as 5‐HTP/carbidopa were prescribed by 14 and 20%, respectively. As 5‐HTP‐carbidopa was a combination not previously reported for the treatment of obesity, a retrospective chart review was performed in a single obesity practice, which may not be representative. Twenty‐two subjects had a 16% weight loss with phentermine over 6 months and an additional 1% weight loss with the addition of 5‐HTP/carbidopa for an additional 6 months. One subject who started on 5‐HTP/carbidopa alone lost 24.4% of initial body weight over 6 months. This questionnaire revealed that 20% of the obesity specialists responding to the survey used phentermine plus of 5‐HTP/carbidopa, an unreported combination. A controlled, randomized, clinical trial to evaluate the safety and efficacy of this combination in treating obesity should be considered.     

Pregnancy outcomes after first trimester exposure to phentermine/fenfluramine

BACKGROUND: Fenfluramine was withdrawn from the U.S. market in 1997 because of its association with cardiac-valve abnormalities in adults. The combination of fenfluramine and phentermine had been widely used to promote weight loss, and many women were inadvertently exposed during the first trimester of pregnancy. The possible effect on the developing fetus has not been studied. METHODS: Controlled prospective cohort study comparing 98 women who had taken phentermine/fenfluramine to 233 women who had not, all of whom contacted the California Teratogen Information Service during pregnancy. RESULTS: The proportion of liveborn infants with major structural anomalies was similar in the two groups (3.6% vs. 1.0%, relative risk (RR) 3.59; 95% confidence interval (CI) 0.61, 21.10), as was the proportion of infants with >or=3 minor anomalies (11.7% vs. 7.6%, RR 1.53; 95% CI 0.61, 3.82). Furthermore, no pattern of malformation was identified. There were no significant differences between the groups in spontaneous pregnancy loss (6.1% vs. 8.2%, P = 0.65) or premature delivery (8.6% vs. 7.7%, P = 0.95). Birth weight and head circumference were significantly increased in the exposed group; however, these differences were not associated with anorexiant use itself. The rate of gestational diabetes was significantly increased in pregnant women who took phentermine/fenfluramine during the first trimester of pregnancy. CONCLUSIONS: Although it is not possible from this study to rule out weak to moderate associations, the lack of an increased risk of spontaneous pregnancy loss, and major or minor anomalies in the offspring of women who took phentermine/fenfluramine at the recommended daily dose during the first trimester of pregnancy is reassuring.     

The Relationship between Health‐Related Quality of Life and Weight Loss

Objective: This is a report of health‐related quality of life (HRQOL) changes in obese patients completing at least 1 year of outpatient treatment in a weight reduction program combining phentermine‐fenfluramine and dietary counseling. Research Methods and Procedures: Participants were 141 women (87.6%) and 20 men (12.4%) who had an average body mass index at intake of 41.1 kg/m² (SD = 7.0, range = 29.5 to 67.0 kg/m²) and an average age of 44.9 years (SD = 9.3, range = 23 to 65 years). HRQOL was assessed at intake and at 1‐year follow‐up using the Impact of Weight on Quality of Life (IWQOL)‐Lite questionnaire. The relationship between HRQOL changes and weight loss was examined using Pearson correlations. Clinically meaningful change in HRQOL was defined as a 1.96 SEM reduction in IWQOL‐Lite total score. Results: On average, participants lost 20.2 kg or 17.6% of their weight over the 1‐year period. Of the participants, 15.5% lost <10% of their weight, 24.2% lost 10% to 14.9%, 23.6% lost 15% to 19.9%, and 36.6% lost 20% or more. All five IWQOL‐Lite scales and total score showed statistically significant improvement over the 1‐year period. Changes in IWQOL‐Lite scores from intake to 1 year showed statistically significant correlations with percentage of weight loss for all subscales and total score. Subscale correlations with weight loss ranged from 0.166 (Public Distress) to 0.396 (Physical Function) and was 0.370 for the total score. Forty‐four percent of participants losing <10% met the criterion of clinically meaningful change, compared with 51.3% losing 10% to 14.9%, 55.3% losing 15% to 19.95%, and 76.3% losing >20%. For total score and for three of the five IWQOL‐Lite scales (Physical Function, Self‐Esteem, and Sexual Life), the relationship between weight loss and clinically meaningful change was linear and was significant at p < 0.05. Physical Function and Self‐Esteem were most strongly affected by weight loss. Discussion: HRQOL changes, as measured by an obesity‐specific instrument (IWQOL‐Lite), are strongly related to weight reduction.     

Metformin Decreases Food Consumption and Induces Weight Loss in Subjects with Obesity with Type II Non-Insulin-Dependent Diabetes

Metformin often promotes weight loss in patients with obesity with non-insulin-dependent diabetes mellitus (NIDDM). The mechanism may be attributed to decreased food intake. This study has tested the effect of metformin on satiety and its efficacy in inducing weight loss. Twelve diet-treated NIDDM women with obesity were randomly given two dose levels (850 mg or 1700 mg) of metformin or placebo at 0800 for three consecutive days followed by a meal test on the third day on three occasions using a 3times3 Latin square design. The number of sandwich canapes eaten in three consecutive 10-minute periods beginning at 1400 hours was used to quantitate food intake, and the level of subjective hunger was rated just before the sandwich meal with a linear analogue hunger rating scale at 1400 after a 6-hour fast. The prior administration of metformin produced a reduction in calorie intake after each of the two doses of metformin treatment. The 1700-mg metformin dose had the most marked appetite suppressant action. Similarly, hunger ratings were significantly lowered after metformin, and the effect was most pronounced after the administration of 1700 mg of metformin. To assess the efficacy of metformin in reducing bodyweight, 48 diet-treated NIDDM women with obesity who had failed to lose weight by diet therapy were first placed on a 1200-kcal ADA (American Diabetes Association) diet before being randomized to receive either metformin (850 mg) or placebo twice daily in a double-blind fashion for 24 weeks. A 4-week single-blind placebo lead-in period preceded and a 6-week single-blind placebo period followed the 24-week double-blind treatment period. Subjects treated with metformin continued to lose weight throughout 24 weeks of treatment; their mean maximum weight loss was 8 kg greater than that of the placebo group, with corresponding lower HbA1C and fasting blood glucose levels at the end of the active treatment period. These results indicate that metformin decreases calorie intake in a dose-dependent manner and leads to a reduction in bodyweight in NIDDM patients with obesity.     

The Benefit of Short-Term Weight Loss with Anti-Obesity Medications in Real-World Clinical Practice

Objective: The effectiveness of anti-obesity medications (AOMs) outside of clinical trials is unclear. The objective of this study was to compare the short-term effectiveness of AOMs in real-world practice.Methods: This retrospective study included adults aged ≥18 years, with body mass index ≥30 kg/m² or ≥27 kg/m² with at least one obesity-related comorbidity who were prescribed phentermine hydrochloride, phenterminetopiramate, bupropion-naltrexone, or lorcaserin for 12 consecutive weeks between 2006 and 2016 at a large tertiary healthcare system. Propensity score–matched cohorts were created for each pair of AOMs. The primary outcomes were percent and absolute weight loss from baseline after 12 weeks. A prediction model was constructed to estimate weight loss with different AOMs based on demographic and clinical data.Results: Of the 3,411 patients included in this study, patients lost an average of 3.45% of body weight from baseline. All AOMs were associated with a significant weight loss from baseline (P<.0001). Patients lost the highest percentage of body weight on phentermine hydrochloride (3.75 ± 5.66%), followed by phentermine-topiramate (3.63 ± 5.7%), bupropion-naltrexone (2.66 ± 5.03%), and lorcaserin (1.84 ± 6.69%). In propensity-matched cohorts, patients taking phentermine hydrochloride lost more weight than those taking lorcaserin or bupropion-naltrexone, and patients taking phentermine topiramate lost more weight than patients taking lorcaserin.Conclusion: In real-world practice, AOMs are associated with clinically meaningful weight loss of 2 to 4% after 12 weeks. In this study, phentermine hydrochloride and phentermine topiramate produced the most weight loss. AOMs should be seriously considered as part of the armamentarium to treat patients with obesity.Abbreviations: AOM = anti-obesity medication; BMI = body mass index; EMR = electronic medical record; FDA = Food and Drug Administration; T2D = type 2 diabetes     

Impact of Weight Loss and Regain on Quality of Life: Mirror Image or Differential Effect?

Objective: To compare the impact of weight regain and weight loss on health‐related quality of life. Research Methods and Procedures: Subjects were 122 (106 women, 16 men) overweight and obese participants in a weight reduction program (phentermine‐fenfluramine and dietary counseling) who had initially lost at least 5% of their total body weight and then regained at least 5% of their weight during the follow‐up period. Follow‐up periods ranged from 10 to 41 months (mean, 28 months). Participants completed the Impact of Weight on Quality of Life‐Lite, an obesity‐specific health‐related quality of life (HRQOL) measure, at 3‐month intervals. Results: Mean BMI at baseline was 40.9 ± 6.6 kg/m² (range, 29.2 to 63.7 kg/m²). Average weight loss from entry was 18.8 ± 6.7% (range, 6.0% to 43.7%), and average regain was 10.1 ±4.4% of baseline weight (range, 5.0% to 30.6%). The effects of weight regain on HRQOL mirrored the effects of weight loss—rates of HRQOL change were similar in magnitude but different in direction for comparable weight loss and regain. Those with more severe initial impairments in HRQOL experienced greater improvements in HRQOL during weight loss as well as greater deterioration during weight regain than those with less severe impairments. Discussion: Weight loss and regain produced mirror image changes in HRQOL. The initial severity of HRQOL impairment had a greater impact on the magnitude of HRQOL change than the direction of weight change. Findings underscore the importance of maintaining weight loss for the purposes of retaining obesity‐specific HRQOL benefits.     

A Retrospective Study Examining Phentermine on Preconception Weight Loss and Pregnancy Outcomes

Objective: Obesity is a well-known risk factor for infertility. However, the use of weight loss medications prior to conception is underutilized. The objectives of our study are to describe weight loss, pregnancy rates, and live birth rates after short-term phentermine use in women with obesity and infertility.Methods: This was a retrospective analysis of 55 women (18 to 45 years old) who were overweight or obese, diagnosed with infertility, and prescribed phentermine for weight loss in an ambulatory endocrinology clinic at a single, tertiary level academic medical center. Main outcome measures were mean percent weight change at 3 months after starting phentermine, and pregnancy, and live birth rates from start of phentermine to June 30, 2017.Results: Median duration of phentermine use was 70 days (Q1, Q3 &lsqb;33, 129]). Mean ± SD percent weight change at 3 months after starting phentermine was -5.3 ± 4.1% (P<.001). The pregnancy rate was 60% and the live birth rate was 49%. There was no significant difference in pregnancy rates (52% versus 68%; P = .23) or live birth rates (44% versus 54%; P = .50) in women who lost ≥5% versus <5% of their baseline weight. The number of metabolic comorbidities was negatively associated with the pregnancy rate. Phentermine was generally well-tolerated with no serious adverse events.Conclusion: Phentermine can produce clinically significant weight loss in women with obesity during the preconception period. Higher pregnancy or live birth rates were not observed with a greater degree of weight loss with phentermine.     

Weight Loss,Weight Maintenance,and Improved Cardiovascular Risk Factors after 2 Years Treatment with Orlistat for Obesity

Objective: To determine the effect of orlistat, a new lipase inhibitor, on long‐term weight loss, to determine the extent to which orlistat treatment minimizes weight regain in a second year of treatment, and to assess the effects of orlistat on obesity‐related risk factors. Research Methods and Procedures: This was a 2‐year, multicenter, randomized, double‐blind, placebo‐controlled study. Obese patients (body mass index 28 to 43 kg/m²) were randomized to placebo or orlistat (60 or 120 mg) three times a day, combined with a hypocaloric diet during the first year and a weight maintenance diet in the second year of treatment to prevent weight regain. Changes in body weight, lipid profile, glycemic control, blood pressure, quality of life, safety, and tolerability were measured. Results: Orlistat‐treated patients lost significantly more weight (p < 0.001) than placebo‐treated patients after Year 1 (6.6%, 8.6%, and 9.7% for the placebo, and orlistat 60 mg and 120 mg groups, respectively). During the second year, orlistat therapy produced less weight regain than placebo (p = 0.005 for orlistat 60 mg; p < 0.001 for orlistat 120 mg). Several obesity‐related risk factors improved significantly more with orlistat treatment than with placebo. Orlistat was generally well tolerated and only 6% of orlistat‐treated patients withdrew because of adverse events. Orlistat leads to predictable gastrointestinal effects related to its mode of action, which were generally mild, transient, and self‐limiting and usually occurred early during treatment. Discussion: Orlistat administered for 2 years promotes weight loss and minimizes weight regain. Additionally, orlistat therapy improves lipid profile, blood pressure, and quality of life.     

The Impact of a Shipboard Weight Control Program

DENNIS, KAREN E., KAREN W. PANE, BRENDA K. ADAMS, AND BING BING QI. The impact of a shipboard weight control program. Obes Res. 1999;7:60–67. Objective : The specific aim was to determine whether a multifaceted approach to weight loss and physical readiness could be implemented onboard a deployed combatant ship of the U.S. Navy. Research Methods and Procedures : Thirty-nine men (31±6 years old, mean±standard deviation) assigned to the USS ENTERPRISE (CVN 65) during a 6-month Mediterranean deployment who had failed their previous Physical Readiness Test due to excessive body weight (108±11 kg overweight) were randomly assigned to nutrition, cognitivebehavioral obesity treatment plus exercise or to the Navy's usual treatment (control), which is exercise alone. Results : Outcomes for the treatment group were significantly better than the controls, with 8.6±5.0 vs. 5.0±4.1 kg weight loss, 8% vs. 5% reduction in original body weight, and body fat loss of 7% vs. 5%. Triglycerides declined significantly greater in the treatment group than the controls (145 mg/dL to 109 mg/dL vs. 146 mg/dL to 145 mg/dL, p<0.05), whereas depression and eating behaviors significantly improved among treated men. Problematic environmental factors were the limited variety of heart healthy foods in the galley, short meal breaks, and long mess hall lines that led to eating snacks from vending machines and frequent port calls. Discussion : Although greater weight loss than would be expected of a Navy usual care group diluted the treatment effect, the treated men still fared significantly better. The physical readiness implication of this research has the potential to impact Navy health promotion programs and policy, the health and well-being of its personnel, and the Navy's ability to meet mission requirements.     

Effects of fenfluramine and ritanserin on prolactin response to insulin-induced hypoglycemia in obese patients: evidence for failure of the serotoninergic system

In order to study the hypothesized impairment of the serotoninergic system in human obesity, an insulin tolerance test (ITT) was carried out on 12 obese normoprolactinemic women and on 6 normal-weight women before (A) and after (B) the administration of a serotoninergic drug, fenfluramine (60 mg twice a day per os for 7 days). After a washout period, a new ITT (C) followed the administration of fenfluramine at the same dose, associated with a specific S2 blocker receptor agent, ritanserin (30 mg/day for the first 2 days and 20 mg/day for a further 5 days). In obese subjects, the prolactin (PRL) response to ITT A was reduced as compared to the controls: in 6 patients ('nonresponders') the PRL levels did not change, while in the other 6 ('responders') they increased (p less than 0.003) but less than in the controls (p less than 0.02). In normal-weight subjects, the administration of fenfluramine alone or with ritanserin did not modify the PRL response to ITT. In the responders, the serotoninergic drug normalized the PRL response to ITT while significantly improving it in the nonresponders; these effects were not antagonized by ritanserin. In conclusion, our data suggest that the serotoninergic system of obese patients is impaired and that the different secretory pattern observed in the two groups before and after fenfluramine may reflect differing degrees of this impairment.     

Enhanced Weight Loss Following Coadministration of Pramlintide With Sibutramine or Phentermine in a Multicenter Trial

Preclinical evidence suggests that pharmacotherapy for obesity using combinations of agents targeted at distinct regulatory pathways may produce robust additive or synergistic effects on weight loss. This randomized placebo‐controlled trial examined the safety and efficacy of the amylin analogue pramlintide alone or in combination with either phentermine or sibutramine. All patients also received lifestyle intervention. Following a 1‐week placebo lead‐in, 244 obese or overweight, nondiabetic subjects (88% female; 41 ± 11 years; BMI 37.7 ± 5.4 kg/m²; weight 103 ± 19 kg; mean ± s.d.) received placebo subcutaneously (sc) t.i.d., pramlintide sc (120 µg t.i.d.), pramlintide sc (120 µg t.i.d.) + oral sibutramine (10 mg q.a.m.), or pramlintide sc (120 µg t.i.d.) + oral phentermine (37.5 mg q.a.m.) for 24 weeks. Treatment was single‐blind for subjects receiving subcutaneous medication only and open‐label for subjects in the combination arms. Weight loss achieved at week 24 with either combination treatment was greater than with pramlintide alone or placebo (P < 0.001; 11.1 ± 1.1% with pramlintide + sibutramine, 11.3 ± 0.9% with pramlintide + phentermine, ?3.7 ± 0.7% with pramlintide; ?2.2 ± 0.7% with placebo; mean ± s.e.). Elevations from baseline in heart rate and diastolic blood pressure were demonstrated with both pramlintide + sibutramine (3.1 ± 1.2 beats/min, P < 0.05; 2.7 ± 0.9 mm Hg, P < 0.01) and pramlintide + phentermine (4.5 ± 1.3 beats/min, P < 0.01; 3.5 ± 1.2 mm Hg, P < 0.001) using 24‐h ambulatory monitoring. However, the majority of subjects receiving these treatments remained within normal blood pressure ranges. These results support the potential of pramlintide‐containing combination treatments for obesity.     

The Fen-Phen Finale: A Study of Weight Loss and Valvular Heart Disease

Objective : To assess weight loss, as well as the prevalence of valvular heart disease, in 21 obese women who completed 2 years of treatment by fenfluramine and phentermine (fen-phen) in June 1997. Research Methods and Procedures : Patients were 21 of 22 women who had completed a 1-year, open-label trial of fen-phen combined with lifestyle modification. This study describes the results of a second year of treatment. The presence of valvular heart disease, defined as aortic regurgitation of mild or greater severity and/or mitral regurgitation of moderate or greater severity, was assessed using two-dimensional, color Doppler and pulsed- and continuouswave Doppler examinations. Results : At 2 years, the 21 patients had a mean reduction in initial weight of 13.9 ±10.1%, which was significantly (p<<0.001) smaller than their 1-year loss of 17.1 ±8.7%. Nine of 21 patients reported that they took fen-phen irregularly during the last 4 months of the study because of fears of developing health complications. These nine patients had a 2-year weight loss of 8.7 ± 7.5%, compared with a significantly (p<0.04) larger loss of 17.6 ± 10.5% for participants who reported taking medication regularly. Six of 20 (30%) patients met criteria for valvular heart disease. None of the six had signs or symptoms of this condition. Discussion : Fenfluramine was withdrawn from the market on September 15, 1997 because of concerns that it was associated with valvular heart disease. The present findings are discussed in terms of the potentially favorable long-term benefits of combining lifestyle modification with weight loss medications that are both safe and effective.     

Treatment of Hypothalamic Obesity with Caffeine and Ephedrine

ObjectiveTo investigate the hypothesis that the peripheral actions of caffeine and ephedrine to increase sympathetic tone and metabolic rate and to preserve lean tissue will cause weight loss in patients with hypothalamic obesity.MethodsWe present 3 case studies of consecutive patients who presented with hypothalamic obesity and were treated with caffeine (200 mg) and ephedrine hydrochloride (25 mg) 3 times a day.ResultsAll patients were gaining weight at the time of initial assessment. The first patient lost 8% to 9% of her body weight and maintained that loss for the subsequent 2 years. The second patient lost 18.8% of her body weight and was maintaining a 9.5% weight loss after 6 years. The third patient lost 14% of her body weight during a 6- month period and gradually returned to her baseline weight during a period of 5 years, after which she was referred for bariatric surgical treatment.ConclusionThese 3 patients with hypothalamic obesity, who had been steadily gaining weight, lost a mean of 13.9% of their body weight, and 2 of them maintained weight loss for a period of years. Thus, caffeine and ephedrine appeared to halt weight gain and maintain a clinically significant weight loss in 2 of our 3 patients. A randomized clinical trial to confirm these findings would be appropriate but difficult because of the rarity of this disorder. (Endocr Pract. 2008;14:697-703)     

Sibutramine Produces Dose-Related Weight Loss

BRAY, GEORGE A., GEORGE L. BLACKBURN, JAMES M. FERGUSON, FRANK L. GREENWAY, ADESH K. JAIN, CARL M. MENDEL, JOSEPH MEN-DELS, DONNA H. RYAN, SHERWYN L. SCHWARTZ, MONTE L. SCHEINBAUM, AND TIMOTHY B. SEATON. Sibutramine produces dose-related weight loss. Obes Res. Objective Sibutramine is a weight control drug that inhibits the reuptake of both serotonin and norepinephrine. In animals, it reduces food intake and increases thermogenesis and preliminary data in human beings showed weight loss. This paper reports a 24-week dose-ranging study to determine the effect of sibutramine on body weight of patients with obesity. Research Methods and Procedures Seven clinical centers screened 1463 patients with obesity and randomized 1047 to 24 weeks of treatment with 1 of 6 doses of sibutramine (1, 5, 10, 15, 20, or 30 mg) or placebo once daily. Six hundred eighty-three patients completed the study. A two-week placebo run-in period was used to initiate a standardized program of diet, physical activity, and lifestyle changes. Results Weight loss was dose-related and statistically significant vs. placebo (p <0.05) across all time-points for a 5 mglday to 30 mglday dosage of sibutramine. At week 24, percent weight loss from baseline for completers was: placebo, 1.2%; 1 mg, 2.7%; 5 mg, 3.9%; 10 mg, 6.1%; 15 mg, 7.4%; 20 mg, 8.8%; and 30 mg, 9.4%. Weight loss achieved at week 4 was predictive of weight loss achieved at week 24. Patients losing weight demonstrated an increase in serum high density lipoprotein cholesterol and reductions in serum triglycerides, total cholesterol, low density lipoprotein cholesterol, and uric acid. Small mean increases in blood pressure and pulse rate (with considerable individual variability) were observed in patients treated with sibutramine. The most frequent adverse events were dry mouth, anorexia, and insomnia. Discussion Sibutramine administered once daily for 24 weeks in the weight loss phase of treatment for uncomplicated obesity produced dose-related weight loss and was well tolerated. Improvements in serum lipids and uric acid accompany sibutramine-induced weight loss. Most of the adverse events observed on sibutramine are related to its pharmacology, including small mean increases in blood pressure and heart rate.