University Department of Medicine Infirmary, Leeds LSI 3EX,
The General
U. K.
THE EFFECT OF FENFLURAMINE ON
OBESE,
MATURITY-ONSET DIABETIC PATIENTS
By
John
K. Wales
ABSTRACT
maturity-onset diabetic patients the effect of fenfluramine carbohydrate tolerance was compared to placebo therapy in a double blind trial. Fenfluramine therapy did not affect weight loss, or fasting glucose levels but produced a slight but significant improvement in glucose tolerance. This improvement was not correlated with any change in body weight or insulin secretion. In 38 obese
therapy
on
an accepted adjunct to diet therapy in obesity (Craddock but mode of action is unclear. Both a central (Garrattini et al. 1973) its 1973) and a peripheral action on carbohydrate and lipid metabolism (Butterfield 8c Whichelow 1968; Inneset et al. 1973; Jergensen 1973; Turtle 8c Burgess 1973) have been suggested. It has also been reported that in diabetic patients fen¬ fluramine exerts an antidiabetic action which is not related to its ability to promote weight loss (Dykes 1973; Larsen et al. 1977; Turtle 8c Burgess 1973). In view of the caution now expressed about the use of biguanide therapy (Varma et al. 1972) this antidiabetic activity of fenfluramine may be useful in the treatment of the obese diabetic patient. This paper reports the results of the comparison of the activities of fen¬ fluramine and placebo therapy on carbohydrate tolerance in a doubble blind trial in maturity onset, obese diabetic patients treated with conventional anti¬ diabetic therapy, i. e. sulphonylureas or biguanides or diet alone.
Fenfluramine is
PATIENTS AND METHODS All the
patients
Infirmary at
studied were attending the Diabetic Outpatient Clinic at the General Leeds which was held in the morning. All had been receiving antidiabetic
therapy for more than one year and all were more than 15% above their ideal body weight as calculated from Kemsley's data (Kemsley 1951). Patients with renal or hepatic disease, advanced diabetic complications, such as nephropathy, amputations and severe retinopathy, who were pregnant, or were receiving other antiobesity therapy than diet
alone were excluded. After the purpose of the trial had been explained to the patients, including the ex¬ pected variation of weight loss, 59 patients taken at random from the Diabetic Clinic, and fulfilling the above criteria, agreed to enter the trial and 38 patients completed the trial. The clinical details of these 38 patients are shown in Table 1. Twenty-one patients did not complete the trial. Each patient was randomly allocated to fenflur¬ amine or placebo therapy using a pre-arranged random allocation plan unknown to patient or medical staff in the trial. As each patient dropped out of the trial, a new patient was assigned to that treament schedule to replace the omitted patient. Fenflur¬ amine was prescribed as 60 mg long-action capsules (lnnes et al. 1973) with identical placebo capsules. Each capsule was taken daily with breakfast, and the supply of cap¬ sules was such at to last until the next clinic visit, when the container was returned. In all patients, the same dietary therapy was maintained throughout the study as they were receiving before; in the majority this was a 1000 calorie diet. All the patients attended a regular morning clinic every 4 weeks. At each visit they were weighed without topcoat or shoes, visited the dietitians and a fasting morning urine sample was tested for sugar, protein and ketones. A fasting blood sample was taken for whole blood glucose and plasma insulin. As the patients were fasting on the morning when they attended the Clinic, they were instructed not to take their medica¬ tion before they attended. They were asked about side effects and symptoms by the same doctor using a standard symptom record sheet both before and during the trial. Further clinical investigations were performed as the symptoms or signs required. Wherever possible the reasons for dropping out of the trial were elicited, although this took months to determine in some cases. In the 10 patients on sulphonylurea drugs who completed the trial, 4 were receiving chlorpropamide, 3 glibenclamide and 3 tolbutamide as well as dietary therapy. In those 16 patients on biguanide drugs half were on phenformin and half on metformin. The dose levels of these drugs remained constant throughout the study. In these 26 patients the trial design was a double blind allocation of each patient to 2 consecutive 3 month period of either fenfluramine-placebo or placebo-fenfluramine; each patient allocated at random. Standard 50 g, 2 h glucose tolerance tests (GTT) were performed before the trial and after the first treatment period (at 3 months) and the second treatment period (6 months). Plasma insulin levels during each GTT were measured by double antibody radioimmunoassay (Morgan & Lazarow 1963) and the levels in the 3 GTT's in the same patient were measured in the same assay. The total area under the GTT was calculated and similarly total area of insulin response. In the 12 patients on diet alone, the trial design was of an ABAB or BABA type with the treatment periods being of 2 months. Patients were randomly allocated to one of these treatment schedules. GTT's were performed before and after 4 and 8 months'
therapy. Statistical analysis of the data was performed using non-parametric analysis, e. g. Mann-Whitney 'U' test, Wilcoxon matched pair signed rank test and the Spearman rank correlation test (Siegal 1956) using a significance level of 0.05.
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The General
U. K.
THE EFFECT OF FENFLURAMINE ON
OBESE,
MATURITY-ONSET DIABETIC PATIENTS
By
John
K. Wales
ABSTRACT
maturity-onset diabetic patients the effect of fenfluramine carbohydrate tolerance was compared to placebo therapy in a double blind trial. Fenfluramine therapy did not affect weight loss, or fasting glucose levels but produced a slight but significant improvement in glucose tolerance. This improvement was not correlated with any change in body weight or insulin secretion. In 38 obese
therapy
on
an accepted adjunct to diet therapy in obesity (Craddock but mode of action is unclear. Both a central (Garrattini et al. 1973) its 1973) and a peripheral action on carbohydrate and lipid metabolism (Butterfield 8c Whichelow 1968; Inneset et al. 1973; Jergensen 1973; Turtle 8c Burgess 1973) have been suggested. It has also been reported that in diabetic patients fen¬ fluramine exerts an antidiabetic action which is not related to its ability to promote weight loss (Dykes 1973; Larsen et al. 1977; Turtle 8c Burgess 1973). In view of the caution now expressed about the use of biguanide therapy (Varma et al. 1972) this antidiabetic activity of fenfluramine may be useful in the treatment of the obese diabetic patient. This paper reports the results of the comparison of the activities of fen¬ fluramine and placebo therapy on carbohydrate tolerance in a doubble blind trial in maturity onset, obese diabetic patients treated with conventional anti¬ diabetic therapy, i. e. sulphonylureas or biguanides or diet alone.
Fenfluramine is
PATIENTS AND METHODS All the
patients
Infirmary at
studied were attending the Diabetic Outpatient Clinic at the General Leeds which was held in the morning. All had been receiving antidiabetic
therapy for more than one year and all were more than 15% above their ideal body weight as calculated from Kemsley's data (Kemsley 1951). Patients with renal or hepatic disease, advanced diabetic complications, such as nephropathy, amputations and severe retinopathy, who were pregnant, or were receiving other antiobesity therapy than diet
alone were excluded. After the purpose of the trial had been explained to the patients, including the ex¬ pected variation of weight loss, 59 patients taken at random from the Diabetic Clinic, and fulfilling the above criteria, agreed to enter the trial and 38 patients completed the trial. The clinical details of these 38 patients are shown in Table 1. Twenty-one patients did not complete the trial. Each patient was randomly allocated to fenflur¬ amine or placebo therapy using a pre-arranged random allocation plan unknown to patient or medical staff in the trial. As each patient dropped out of the trial, a new patient was assigned to that treament schedule to replace the omitted patient. Fenflur¬ amine was prescribed as 60 mg long-action capsules (lnnes et al. 1973) with identical placebo capsules. Each capsule was taken daily with breakfast, and the supply of cap¬ sules was such at to last until the next clinic visit, when the container was returned. In all patients, the same dietary therapy was maintained throughout the study as they were receiving before; in the majority this was a 1000 calorie diet. All the patients attended a regular morning clinic every 4 weeks. At each visit they were weighed without topcoat or shoes, visited the dietitians and a fasting morning urine sample was tested for sugar, protein and ketones. A fasting blood sample was taken for whole blood glucose and plasma insulin. As the patients were fasting on the morning when they attended the Clinic, they were instructed not to take their medica¬ tion before they attended. They were asked about side effects and symptoms by the same doctor using a standard symptom record sheet both before and during the trial. Further clinical investigations were performed as the symptoms or signs required. Wherever possible the reasons for dropping out of the trial were elicited, although this took months to determine in some cases. In the 10 patients on sulphonylurea drugs who completed the trial, 4 were receiving chlorpropamide, 3 glibenclamide and 3 tolbutamide as well as dietary therapy. In those 16 patients on biguanide drugs half were on phenformin and half on metformin. The dose levels of these drugs remained constant throughout the study. In these 26 patients the trial design was a double blind allocation of each patient to 2 consecutive 3 month period of either fenfluramine-placebo or placebo-fenfluramine; each patient allocated at random. Standard 50 g, 2 h glucose tolerance tests (GTT) were performed before the trial and after the first treatment period (at 3 months) and the second treatment period (6 months). Plasma insulin levels during each GTT were measured by double antibody radioimmunoassay (Morgan & Lazarow 1963) and the levels in the 3 GTT's in the same patient were measured in the same assay. The total area under the GTT was calculated and similarly total area of insulin response. In the 12 patients on diet alone, the trial design was of an ABAB or BABA type with the treatment periods being of 2 months. Patients were randomly allocated to one of these treatment schedules. GTT's were performed before and after 4 and 8 months'
therapy. Statistical analysis of the data was performed using non-parametric analysis, e. g. Mann-Whitney 'U' test, Wilcoxon matched pair signed rank test and the Spearman rank correlation test (Siegal 1956) using a significance level of 0.05.
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