Pavur R Sundaresan

Long‐term weight control study I (weeks 0 to 34)

To investigate the value of anorexiant medications as an adjunct to other forms of weight control therapy, we studied 121 people in a 34‐week, double‐blind clinical trial of 60 mg extended‐release fenfluramine plus 15 mg phentermine resin versus placebo added to behavior modification, caloric restriction, and exercise. Participants weighed 130% to 180% (154% ± 1.2%, mean ± SEM) of ideal body weight (1983 Metropolitan Life tables) and were in good health. By week 34, participants receiving active medication lost an average of 14.2 ± 0.9 kg, or 15.9% ± 0.9% of initial weight (n = 58), versus a loss of 4.6 ± 0.8 kg or 4.9% ± 0.9% of initial weight by subjects taking placebo (n = 54; p < 0.001). On visual analog scales, participants rated fenfluramine plus phentermine as more helpful than placebo (50.3 ± 0.5 versus 20.3 ± 0.3) and not bothersome (fenfluramine plus phentermine, 17.4 ± 0.3 versus 13.5 ± 0.2). Blood pressure decreased and pulse remained unchanged in both groups. Dry mouth was the most common adverse effect in subjects receiving fenfluramine plus phentermine; all adverse effects decreased after 4 weeks. Only nine participants left the study in the first 34 weeks. Two subjects from each group left the study as a result of adverse effects. Overall, fenfluramine plus phentermine used in conjunction with behavior modification, caloric restriction, and exercise aided weight loss and continued to be efficacious for 34 weeks.

Long-term Weight Control Study VI

We analyzed the individual response patterns of all 121 participants who entered the study. Fifty‐one participants completed up to week 190. In 26 completers, the response pattern consisted of an initial beneficial effect (≥6 months of weight loss ≥10% from baseline) and later success (weight loss of ≥10% from baseline at week 160). These successful participants had lost 14.1 ± 1.0 kg (mean ± SEM); 15.9% ± 0.9% of initial weight) at week 160 and 8.1 ± 1.2 kg (9.1% ± 1.3% of initial weight) at week 190. A second pattern observed in 16 completers consisted of initial benefit and later partial success (loss of 0.1% to 9.9% at week 160). Other response patterns observed in completers included showing initial benefit only (n = 3) and no success (n = 6). Seventy of the 121 participants left: the study before week 190. There were 22 “dropout successes” who had consistent weight loss for 1 year or more and were ≥10% below their initial weights at time of dropout. Fifteen “dropouts with initial benefit” stayed in the study for ≥1 year with initial benefit (weight loss ≥10% from baseline maintained for ≥6 months). Medication‐related reasons accounted for only 10 of the 37 dropouts in the group with initial or later benefit. Minimal benefit was seen in 17 dropouts. Another 16 were in the study less than 1 year. Analysis of individual participant responses made some other generalizations possible. Participants receiving continuous medication lost more weight and had fewer adverse effects than those receiving targeted intermittent medication. Upward dose adjustment appeared to help 24 participants achieve the criteria for late or partial success. Analyses of individual participant responses can suggest ways to optimize anorectic medication use for individual patients.

Long‐term weight control study II (weeks 34 to 104)

Between weeks 34 and 104, we explored different schema for administering fenfluramine plus phentermine in open‐label fashion. At week 34, the original placebo group participants began taking fenfluramine plus phentermine (placebo‐to‐active group). Those receiving fenfluramine plus phentermine between weeks 6 and 34 either continued to receive medication or began targeted intermittent therapy. Participants who did not lose 10% of initial weight received an augmented dose (60 mg fenfluramine plus 30 mg phentermine. The placebo‐to‐active group lost an additional 9.1 ± 0.8 kg (mean ± SEM) in the period from week 34 to week 60. At week 60, they were assigned to either continue medication, intermittent therapy, or augmented therapy. More than 68% (83) of the original participants completed up to study week 104. At that point, overall weight loss was 10.8 ± 0.7 kg (11.6 ± 0.8% of initial weight); participants who continued to receive fenfluramine plus phentermine lost 11.6 ± 0.8 kg, participants receiving intermittent therapy lost 11.6 ± 1.3 kg, and participants receiving augmented therapy lost 6.5 ± 1.5 kg. Although 41% of the participants complained of dry mouth, neither serious adverse effects nor evidence of medication abuse appeared. There were 29 dropouts in the period from weeks 34 to 104. Sixteen of those were related to medication (adverse effects, lack of efficacy, and fear of medication). Overall, fenfluramine plus phentermine used in conjunction with behavior modification, caloric restriction, and exercise continued to be efficacious for up to 2 years.

Long-term weight control study IV (weeks 156 to 190)

To assess continued efficacy of anorexiants after 3 years of use, 52 participants (43% of those starting) entered a second double‐blind trial to compare 60 mg sustained‐release fenfluramine plus 15 mg phentermine resin versus placebo added to behavior modification, caloric restriction, and exercise. Although participants in both the active medication and placebo groups gained weight, participants receiving fenfluramine plus phentermine (n = 27) gained significantly (p < 0.01) less (4.4 ± 0.5 kg or 5.3% ± 0.5% of initial weight) than participants receiving placebo (n = 24) (6.9 ± 0.8 kg or 8.5% ± 1.1% of initial weight). At week 190, both groups were still below their initial weight (fenfluramine plus phentermine group, 5.0 ± 1.4 kg; placebo group, 2.1 ± 1.2 kg; p < 0.01). Overall, 12 participants (23.5% of those still in the study) were ≥10% below initial weight. One participant dropped out during this phase because of personal reasons and loss of medication efficacy. During the 30 weeks, participants receiving fenfluramine plus phentermine had 26 moderate or severe complaints versus eight participants receiving placebo. Fenfluramine plus phentermine provided better appetite control and only slightly more bother. Analysis of participant response in this phase by treatment assignment in the first double‐blind phase (weeks 6 to 34) indicated that initial receipt of medication did not have negative learning effects. Eleven participants receiving active medication between weeks 6 and 34 and receiving placebo between weeks 160 to 190 gained 5.1 ± 1.0 kg. In contrast, 13 participants originally taking placebo gained 8.3 ± 9 kg in this second double‐blind phase. Participants titrated to higher doses of medication in the period from weeks 104 to 156 had a greater increase in their weights during the second double‐blind study.

Long‐term weight control study V (weeks 190 to 210)

Participants who completed up to week 190 in the long‐term weight control study were monitored after cessation of medication between weeks 190 and 210. Caloric restriction, behavior modification sessions, exercise reinforcement, and physician visits continued. We assessed whether or not participants had reset their weight control mechanisms and compared the effect of stopping medication under open‐label conditions (weeks 190 to 210) with the results of stopping anorexiants under double‐blind conditions (weeks 160 to 190). At week 210, participants were, on average, 1.4 ± 1.0 kg (mean ± SEM, 1.5% ± 1.1%) below their weights at baseline (week 0). Of the 48 participants who remained in the study, 13 were still 5% or more and seven were 10% or more below their initial weights. On average, participants gained 2.7 ± 0.5 kg (3.2%) in the period from weeks 190 to 210. Those who had been taking medication in the period from weeks 160 to 190 gained weight at a somewhat faster rate than those who had been taking placebo. However, participants who had transferred from fenfluramine plus phentermine to no medication in this phase gained at a slower rate than participants who had changed from fenfluramine plus phentermine to placebo under double‐blind conditions at week 160 (0.195 kg per week versus 0.277 kg per week). The findings indicate that participants had difficulty maintaining weight loss without anorexiant medications. Despite long periods of time at weights much lower than baseline, permanent resetting of weight control mechanisms could not be shown for most participants.

Phenylpropanolamine OROS (Acutrim) vs. placebo in combination with caloric restriction and physician-managed behavior modification

We added phenylpropanolamine OROS (Acutrim; Ciba‐Geigy Corp.) or placebo to a physician‐managed behavior modification, mild caloric restriction, and exercise weight control program. One hundred six healthy, overweight (115% to 130% ideal body weight) women participated in this 14‐week double‐blind clinical trial. On average, the participants who took Acutrim lost significantly more weight (X̄ ± SE; 6.1 ± 0.6 kg; 8.0% ± 0.8%) than did those taking placebo (4.3 ± 0.7 kg; 5.5% ± 0.8%; P < 0.05). Those taking Acutrim continued to lose weight over the Christmas holiday, while the placebo group gained weight. Fifteen participants taking placebo withdrew, three because of adverse drug reactions (ADRs). Thirteen of 53 participants in the Acutrim group left the study, two because of ADRs. Dry mouth was the most frequent complaint from participants taking Acutrim. No serious cardiovascular effects occurred. Both complaints and the number of participants reporting ADRs decreased with continued dosing. We conclude that Acutrim is a safe, modestly effective adjunct to a physician‐managed, integrated weight control program.

Long‐term weight control study VII (weeks 0 to 210)

We analyzed serum total cholesterol, triglycerides, and lipoprotein profile changes occurring in the participants (N = 121) through 210 weeks of the study. On average, baseline lipid levels were within normal limits. The most consistent changes occurred in the high‐density lipoprotein cholesterol (HDL‐C), serum total cholesterol/HDL‐C ratios, and triglyceride levels. HDL‐C increased significantly (p < 0.01), compared with baseline, by 10% at week 34, 15% at week 54, 19% at week 104, and 27% at week 139. At week 210, 20 weeks after treatment had ended, HDL‐C was 15% higher than baseline. At weeks 34, 54, 104, and 139, the serum total cholesterol/HDL‐C ratio was significantly decreased, compared with baseline, by 9%, 19%, 17%, and 25%, respectively. At week 210, serum total cholesterol/HDL‐C ratio was 8% less than week 0. Compared with baseline, triglyceride levels decreased significantly by 21%, 31%, 29%, and 29% at weeks 34, 54, 104, and 139, respectively. At week 210, triglyceride levels were 16% below baseline. Total cholesterol levels and low‐density lipoprotein cholesterol (LDL‐C) showed less dramatic changes. Patterns of lipid and lipoprotein changes were qualitatively similar between men and women. However, greater decreases in serum total cholesterol, LDL‐C, and triglyceride levels were observed in participants with high (n = 10) compared with low (n = 10) baseline lipid levels. Cholesterol changes were not affected by anorexiant medications. However, triglyceride levels at week 34 were significantly (p < 0.025) less in the participants treated with anorexiants. Overall, participants in the long‐term weight control study had beneficial changes in their lipid profiles, thus decreasing their risk of coronary heart disease.

Platelet alpha‐2 adrenoceptors and the menstrual cycle

To clarify further the suggested influence of menstrual cycle phase on platelet α2‐adrenoceptors, we carried out cross‐sectional studies in 77 subjects in a clinical trial of weight control strategies. Blood samples were drawn at baseline and after 6 weeks of diet, behavior modification, and exercise, a program that resulted in a mean weight loss of 4.5 kg. For the analyses, 42 premenopausal women were divided into four groups according to the week of menstrual cycle at the time of blood sampling. At baseline, there was no significant difference in mean platelet α2‐adrenoceptor numbers among the four groups. At week 6 accompanying the weight loss, there was a significant increase in the platelet α2‐adrenoceptor number for all groups. Despite the fact that the women were at a different phase of the menstrual cycle than at baseline, there was again no significant difference in mean platelet α2‐adrenoceptor number. Mean baseline platelet α2‐adrenoceptor number in the premenopausal women (113.7 ± 5.5 fmol/mg protein) did not differ from values in 12 postmenopausal women (113.7 ± 12.0 fmol/mg protein), four women with hysterectomies (105.9 ± 8.9 fmol/mg protein), or 19 men (101.8 ± 6.2 fmol/mg protein). Numbers at 6 weeks also did not differ. We conclude that the menstrual cycle has minimal effects on platelet α2‐adrenoceptor number and should not confound clinical studies of platelet α2‐adrenoceptors.

Platelet alpha‐adrenergic receptors in obesity: Alteration with weight loss

We studied platelet α‐adrenergic receptor concentration and function in 19 subjects with simple obesity participating in a double‐blind, controlled clinical trial of diet and anorexiants (phentermine, fenfluramine, or a combination of the two) or placebo. From wk 1 to wk 8, weight loss for the group as a whole was 4.9 ± 0.7 kg (mean ± SE). Concomitant with this weight loss, the platelet α‐adrenergic receptor concentration rose from 85.7 ± 5.8 to 113 ± 5.8 fmol/mg protein. This increase moved the values for the obese subjects toward or beyond values in lean controls (100 ± 10.5 fmol/mg protein). The response in the different treatment groups was similar. The receptor concentration increase was accompanied by a corresponding increase in α‐adrenergic receptor–mediated platelet aggregation. For individual subjects the extent of weight loss over time generally correlated with percent receptor change. Altered adrenergic sensitivity occurring in obese subjects who are losing weight may have important implications in relation to external (therapeutic or inadvertent) administration of catecholamines.

Extended-release fenfluramine: patient acceptance and efficacy of evening dosing.

We compared the patient acceptance and efficacy of 60 mg extended‐release fenfluramine and placebo before the evening meal in a 10‐week, double‐blind clinical trial. All 51 participants were 130% to 180% of ideal body weight. They received instruction in diet and behavior modification for 2 wk before the beginning of and during the medication period. Mean weight loss was 5.9 kg (8.0 ± 4.6% of initial weight) in the fenfluramine group and 3.3 kg (5.5 ± 3.5%) in the placebo group. Fenfluramine‐treated participants reported lower hunger ratings and greater fullness in the target supper‐to‐bedtime period than participants receiving placebo. Both groups reported dry mouth, dizziness, drowsiness, fatigue, and diarrhea. Although the fenfluramine group reported more complaints, these diminished to less than half after 2 wk of treatment. Four of the fenfluramine and three of the placebo group dropped out for drug‐related reasons. In all, 10 fenfluramine and 8 placebo participants dropped out. Fenfluramine participants had a higher benefit score with no difference in risk scores. The fenfluramine groups global evaluation was better than that of the placebo group. Participants viewed the study and the dosing regimen positively but had negative ideas about anorexiants in general. Extended‐release fenfluramine taken in the evening was well tolerated and maintained its efficacy as measured by standard and novel techniques.