Therapeutic benefit of benfluorex in type II diabetic patients treated with sulfonylureas.

The objective of this study was to evaluate the effect of benfluorex in type II diabetic patients already treated with sulfonylureas (SU) in a randomized placebo-controlled trial. After a 4-week placebo run-in, 68 patients (49 men and 19 women; age range 40-70 years; known duration of diabetes 0.5-19 years) were randomized to double-blind 12-week treatment with benfluorex (B) or placebo (P). Primary end points were HbA1c and fasting blood glucose (FBG). Secondary end points were glucose tolerance (meal test over 120 min), plasma insulin, C-peptide, and lipid profile. Results were analyzed using both intention-to-treat analysis (ITT) in patients completing at least one treatment visit and per protocol analysis in those completing the whole study. There were no baseline differences between the two groups in any study parameter. Fifty-eight patients completed the study (28 B, 30 P), and 66 patients (33 B, 33 P) were eligible for ITT analysis. Over the 12-week treatment period, FBG decreased by 14.9% in the B group (-1.39 mmol/L, p < 0.001), and 3.2% in the P group (-0.28 mmol/L, NS) according to the ITT analysis and by 17.4% (p < 0.001) and 3.8% (NS), respectively, in the per protocol analysis. The difference in FBG outcome between the two groups was significant (p = 0.009 and p = 0.004, respectively). In patients completing the study, mean HbA1c decreased in the B group (-0.66%, p = 0.005) and remained stable in the P group (+0.14%, NS). HbA1c outcome differed between the two groups (p = 0.007). The decrease in AUCglucose was greater in the B group than in the P group (-210 +/- 220 versus -60 +/- 270 mmol/L x 120 min, p = 0.026). Plasma insulin and C-peptide changes did not differ between the two groups. Low-density lipoprotein (LDL) cholesterol decreased in B patients and was stable in P patients (-0.43 versus -0.05 mmol/L, p = 0.026). Of the 68 randomized patients, six on B and four on P reported at least one adverse event, causing dropout in five and two patients, respectively. In conclusion, benfluorex is an effective agent for combination therapy in type II diabetic patients poorly controlled on SUs alone.

Chronobiometric identification of disorders of hunger sensation in essential obesity: therapeutic effects of dexfenfluramine.

In human beings, hunger is a proprioceptive signal that shows intraday (circadian components) and within-day (ultradian components) recursivity. Both periodic components can be investigated by chronobiometric procedures by combining the Cosinor method with spectral analysis. A 24-hour profile of hunger sensation (HS) can be plotted on a 1-to-10 scale of intensity using self-rated scores performed every half-hour of the day. Circadian and ultradian components were studied in 60 patients affected by essential obesity (20 men and 40 women; mean age, 38.4 years; mean body weight, 101 kg) before and after treatment with dexfenfluramine (Isomeride; Servier, Orléans, France) 15 mg orally twice daily, for 30 days. The control group consisted of 30 clinically healthy subjects (15 men and 15 women; mean age, 37.5 years; mean body weight, 69 kg). Chronobiometric analysis shows three patterns in obese patients, which suggests that HS may be normal (eurectic obesity), exaggerated (hyperrectic obesity), or diminished (hyporectic obesity). After dexfenfluramine administration, HS was showed a substantial decrease in the daily mean level. The spectrum of resolution in circadian and ultradian components was found to be maintained in eurectic obesity and partially readjusted in hyperrectic and hyporectic obesities. This demonstrates that dexfenfluramine acts not only as an anorectic but also as a chronizer by interfering with the recursive components of HS. The anorectic and chronizing effects suggest that dexfenfluramine is a "chronoanorectic drug" that interacts with the chronobiologic properties of the serotoninergic system.

Influence of short-term dexfenfluramine therapy on glucose and lipid metabolism in obese non-diabetic patients.

In a short-term (eight days) double-blind crossover study involving 10 obese patients, the effects of dexfenfluramine on glucose and lipid metabolism were examined. The protocol comprised whole body in vivo measurements (hyperinsulinemic euglycemic clamp in combination with indirect calorimetry) and in vitro studies of isolated adipocytes (lipolysis and glucose transport). All study participants were weight stable during the study period (103.1 +/- 3.2, placebo vs 103.3 +/- 3.1 kg, dexfenfluramine, NS). The following parameters were significantly reduced after dexfenfluramine treatment: fasting levels of plasma glucose (6.2 +/- 0.2 vs 5.7 +/- 0.2 mmol/l, p < 0.01), serum insulin (168.0 +/- 14.5 vs 138.9 +/- 7.9 pmol/l, p < 0.05), serum C-peptide (0.68 +/- 0.03 vs 0.58 +/- 0.02 nmol/l, p < 0.05) and total serum cholesterol (6.07 +/- 0.41 vs 5.48 +/- 0.38 mmol/l, p < 0.01). In the basal state glucose oxidation rate was significantly reduced by 36% (p < 0.001), whereas non-oxidative glucose disposal was significantly increased by 41% (p < 0.01), following dexfenfluramine treatment. Insulin-stimulated (2 mU.kg-1 x min-1) glucose disposal rate tended to be increased (18%, p = 0.10) after dexfenfluramine. In conclusion, dexfenfluramine possesses beneficial regulatory effects on glucose and lipid metabolism in non-diabetic obese patients, independently of weight loss.

Turnover and oxidation rates of plasma-free fatty acids in obese patients treated with dexfenfluramine.

In order to assess a possible direct metabolic effect of dexfenfluramine (dF) apart from its action on food intake reduction, 10 obese postmenopausal women and 10 obese men (BMI = 32.19 +/- 1.99 kg/m2) were studied in a single-blind fashion: 4 weeks on placebo (D-28 to D0) and 4 weeks on dF (D0 to D28). A balanced diet, computed on the basis of basal metabolic rate x 1.4, was followed throughout the study. The patients' alimentary diary was checked for compliance. FFA turnover and oxidation rate, using 1-14C palmitate intravenous infusion, was determined basally (D0), after single high-dose (30 mg, D1) and after long-term (15 mg b.i.d., D28) administration. Indirect calorimetric measurements were performed using a mass spectrometer, and the usual metabolic parameters were computed. The isotope method was used in order to assess plasma FFA oxidation rate. Plasma FFA were analyzed by high-performance liquid chromatography (HPLC) and specific activity was determined at 55, 60, 65 and 70 min by counting dpm in HPLC eluates corresponding to the retention time of palmitate. The turnover rate was not significantly modified after single high-dose dF administration when compared to basal values (6.24 +/- 1.62 at D1 vs. 5.63 +/- 2.07 mmol/kg/min at D0), but was significantly increased at D28 compared with D0 (6.35 +/- 1.96 mmol/kg/min; p < 0.05). A significant increase in FFA oxidation rate was observed with respect to basal values after dF administration both at D1 (0.81 +/- 0.33 at D1 vs. 0.61 +/- 0.21 mmol/kg/min at D0; p < 0.01) and at D28 (0.77 +/- 0.34 mmol/kg/min; p < 0.015).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and chronic effects of dexfenfluramine on glucose and insulin response to intravenous glucose in diabetic and non-diabetic obese subjects.

Fenfluramine improves glucose tolerance in obese subjects independently of its anorectic effect. Increased insulin action has been reported, but such an effect may be secondary to reduced hyperglycemia following augmented insulin secretion. For this reason, we investigated whether the dextro-enantiomer of fenfluramine (dexfenfluramine, dF) has a direct effect on insulin secretion using the glucose infusion test, a technique that can also be used to indirectly evaluate insulin action. Ten lean controls (BMI 21 +/- 0.4 kg/m2), 9 non-diabetic obese subjects (BMI 32.3 +/- 1.1) and 10 obese mild non-insulin dependent diabetics (BMI 36 +/- 2.6, fasting plasma glucose (FPG) 7.9 +/- 0.9 mmol/l) were studied with a random, double blind cross-over protocol. Each subject received 15 mg dF (or placebo) twice daily for 3 days prior to glucose infusion; 30 mg dF (or placebo) were given 90 min before the test. Obese control and diabetic subjects continued treatment with either dF or placebo for one month after which they were retested. There was no significant change in weight or fasting plasma glucose or insulin in any group. Biphasic insulin secretion was demonstrated in both non-diabetic groups, whereas a complete lack of first-phase and a delayed and reduced second phase insulin response was demonstrated in the diabetic subjects. There was no acute or chronic (obese subjects) effect of dF on insulin secretion in any group. In lean control subjects, plasma glucose curves during glucose infusion were unchanged by dF, whereas in non-diabetic obese subjects the glucose slope was improved after both acute and chronic dF, implying augmented glucose disposal. In diabetic patients, no significant acute or chronic effect of dF on glucose response was registered. When all obese subjects were re-grouped according to fasting plasma insulin levels (FPI) and not glucose tolerance, those with relative fasting hyperinsulinemia (> 100 pmol/l, mean +/- SE = 144 +/- 12 pmol/l) showed significant improvement of insulin action after dF, whereas those with low FPI (< 100 pmol/l, mean +/- SE = 65 +/- 7 pmol/l) did not. These findings, together with previously published results of improved insulin action in diabetics during hyperinsulinemic clamps, suggest that dF-mediated improvement in glucose clearance may require substantial plasma insulin concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)

The mode of action and clinical pharmacology of gliclazide: a review.

Gliclazide is a sulphonylurea drug with an intermediate half-life of around 11 hours. It is extensively metabolised, and renal clearance accounts for only 4% of total drug clearance. The molecule contains an azabicyclo-octyl group which confers special properties on the basic sulphonylurea moiety. Gliclazide stimulates insulin secretion through the beta cell sulphonylurea receptor, and possibly through a direct effect on intracellular calcium transport. It specifically improves the abnormal first phase insulin release in type 2 diabetes, and also has an effect on the second phase. This pattern of insulin release is thought to explain the lower incidence of hypoglycaemic episodes and weight gain compared with some other sulphonylureas. There is also a reduction in hepatic glucose production and improvement in glucose clearance, without changes in insulin receptors. This suggests a possible post-receptor effect on insulin action, perhaps by stimulation of hepatic fructose-2,6-bisphosphatase and muscle glycogen synthase. Gliclazide reduces platelet adhesion, aggregation and hyperactivity and increases fibrinolysis. These actions, thought to be independent of its hypoglycaemic activity, may make gliclazide useful in halting the progression of diabetic microangiopathy.

History and evolution of the concept of oral therapy in diabetes.

The object of diabetes treatment is to restore adequate carbohydrate, protein and lipid metabolism. The cornerstone of this treatment has been diet since the end of the 18th century, but true antidiabetic therapy started only with the identification and purification of insulin. Pressure for oral therapy then quickly built up. The hypoglycemic effect of guanidines was discovered in 1919, leading to their therapeutic use, but they were withdrawn in 1932 due to their hepatotoxic effects. The related biguanides appeared in the 1950s but have since diminished in importance so that metformin is practically the only representative still used today. Work in the 1940s and 1950s led to the discovery and development of hypoglycemic sulfonylureas (SU), a therapeutic class unique for its specificity and safety. These products were found to stimulate insulin secretion by the endocrine pancreas. In vitro studies have shown that they bind specifically to an ATP-dependent K+ channel of the beta cell membrane. This binding closes the channel so that K+ outflow ceases, the beta cell membrane depolarizes and voltage-dependent Ca2+ channels open to allow an influx of extracellular calcium. The result is migration and extrusion of insulin granules. Although this mechanism of action has been demonstrated in vitro, it cannot account for all the clinical actions of various SU. They thus appear to have extrapancreatic actions, probably potentiating the peripheral effects of insulin at a postreceptor site in target cells. Other effects involve fibrinolytic activity of the blood, platelet behavior and vascular reactivity. The future of oral diabetes therapy thus seems to lie with the sulfonylureas.

Effect of 6 months therapy with dexfenfluramine in obese patients: studies in the United Kingdom.

The efficacy of dexfenfluramine in inducing weight loss and its clinical acceptability were assessed in two studies carried out in a hospital obesity clinic and general practitioner's office. Seventeen patients who had gained an average of 0.7 +/- 1.9 kg during 12 weeks treatment with diet and placebo lost a mean of 2.9 +/- 0.5 kg after 12 weeks sequential treatment with dexfenfluramine 15 mg twice daily (p less than 0.001). In a second trial, 29 patients treated for 24 weeks with dexfenfluramine showed significantly increased, and continuing, weight loss after 24 weeks (7.0 +/- 0.8 kg) compared to that after 12 weeks of treatment (5.7 +/- 0.1 kg; p = 0.05). The incidence of side effects in both trials was lower than that reported in previous studies of racemic dl-fenfluramine. The clinically significant weight loss and low incidence of unwanted effects suggest that dexfenfluramine has a role in the treatment of refractory obesity.

Prolonged weight loss with dexfenfluramine treatment in obese patients.

17 patients with refractory obesity, who had gained an average of 0.7 +/- 1.9 kg during 12 weeks treatment with diet and placebo, lost a mean of 2.9 +/- 0.5 kg after 12 weeks sequential treatment with dexfenfluramine 15 mg twice daily (p less than 0.001). In a second trial, 29 patients were treated for 24 weeks with dexfenfluramine; average cumulative weight loss after 12 weeks in these patients (5.7 +/- 0.1 kg) was significantly greater than in the patients who had been treated initially with placebo. After 24 weeks of dexfenfluramine treatment there was a further significant increase in cumulative weight loss (7.0 +/- 0.8 kg; p = 0.05). The incidence of side effects in both trials was lower than that reported in previous studies of racemic dlfenfluramine. The clinically significant weight loss, and low incidence of unwanted effects, suggest that dexfenfluramine has a role in the treatment of refractory obesity.

Is sulphonylurea therapy effective long term? A 3-year study with gliclazide.

Fifty non-insulin-dependent diabetic patients, aged 59.06 +/- 1.37 years and overweight (119.3% of ideal body weight), with an impaired daily glycaemic profile despite a carbohydrate restrictive diet were treated with gliclazide (40 to 320 mg per day) for 36 months. Forty-four patients completed the full study (3 drop-outs for secondary failure, 3 others for reasons not related to the treatment). Mean daily plasma glucose levels (fasting, 10.00, 12.00 and 16.00 hours) decreased significantly from 15.2 +/- 0.7 to 6.9 +/- 0.2 mmol/l after 36 months. Mean fasting plasma glucose level decreased significantly from 12.7 +/- 0.5 to 8.2 +/- 0.2 mmol/l after 3 months and continued to decrease to 6.9 +/- 0.3 mmol/l after 36 months (p less than 0.01). Fatty acids, cholesterol, and triglycerides plasma levels also decreased significantly from 0.53 +/- 0.06 mmol/l, 6.3 +/- 0.2 mmol/l and 1.9 +/- 0.2 mmol/l, respectively to 0.32 +/- 0.01 mmol/l, 5.8 +/- 0.1 mmol/l and 1.6 +/- 0.1 mmol/l, respectively. No weight gain was observed: mean body weight decreased significantly from 68.2 +/- 1.7 to 64.0 +/- 1.4 kg, indicating that gliclazide did not interfere with diet-induced weight loss. Importantly, platelet adhesiveness, abnormal before treatment 77.2 +/- 1.3% (normal less than 70%), improved throughout the study to 57.8 +/- 1.3% after 36 months of gliclazide. Treatment was well tolerated and no hypoglycaemic attacks or other side-effects were reported.