Efficacy of Benfluorex in Combination with Sulfonylurea in Type 2
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Clinical Care/Education/Nutrition ORIGINAL ARTICLE Efficacy of Benfluorex in Combination With Sulfonylurea in Type 2 Diabetic Patients An 18-week, randomized, double-blind study 1 6 PHILIPPE MOULIN, MD, PHD DRAGOMIR KOEV, MD apy is being recognized as desirable in 2 7 MARIE ANDRE, MD RAY MOORE, MRCP type 2 diabetes. According to the patho- 3 8 HASAN ALAWI, MD VIOREL SERBAN, MD 4 2 physiological mechanism of the disease, LELITA C. DOS SANTOS, MD BRIGITTE PICANDET, MD 5 2 the combination of an insulin secreta- ABDUL K. KHALID, MD MARIE FRANCILLARD, MD, PHD gogue with an insulin sensitizer is the most common drug treatment proposed for type 2 diabetic patients, in addition to OBJECTIVE — The aim of this study was to demonstrate the superiority of benfluorex over diet, lifestyle counseling, and exercise. In- placebo as an add-on therapy in type 2 diabetic patients in whom diabetes is insufficiently sulin sensitizers are not a homogenous controlled by sulfonylurea monotherapy and who have a limitation for the use of metformin. drug class. For many years, metformin was the only drug of this type on the RESEARCH DESIGN AND METHODS — Type 2 diabetic patients with HbA1c (A1C) (7–10%) who were receiving the maximum tolerated sulfonylurea dose and had a contraindi- market; now thiazolidinediones are an cation to or poor tolerance of metformin were randomly assigned (double blind) to receive alternative. Both metformin and thiazo- benfluorex 450 mg/day (n ϭ 165) or placebo (n ϭ 160) for 18 weeks. The main efficacy criterion lidinediones have limitations on their use: was A1C, analyzed as the change from baseline to the end of treatment using ANCOVA with gastrointestinal intolerance is common with baseline and country as covariates. Secondary criteria were fasting plasma glucose (FPG), insulin metformin, and although serious complica- resistance, and plasma lipid level. tions such as lactic acidosis are very infre- quent, caution should be exercised in RESULTS — Both groups were similar at baseline in the intention-to-treat population. A1C significantly decreased with benfluorex from 8.34 Ϯ 0.83 to 7.52 Ϯ 1.04% (P Ͻ 0.001) and patients with cardiovascular, pulmonary, or tended to increase with placebo from 8.33 Ϯ 0.87 to 8.52 Ϯ 1.36% (NS), resulting in a mean renal insufficiency, which may be associ- adjusted difference between groups of Ϫ1.01% (95% CI Ϫ1.26 to Ϫ0.76; P Ͻ 0.001). The target ated with hypoxia or drug accumulation A1C (Յ7%) was achieved in 34% of patients receiving benfluorex versus 12% of patients (3). In prescribing thiazolidinediones, cau- receiving placebo. Significant between-group differences in favor of benfluorex were observed tion is required in patients with fluid reten- for mean FPG (Ϫ1.65 mmol/l) (P Ͻ 0.001) and for homeostasis model assessment of insulin tion, mildly elevated liver enzyme levels, or resistance. Overall tolerance was similar in both groups. Serious adverse events were more underlying cardiac insufficiency. Thus, al- frequent in the benfluorex group, without evidence of causality relationship. ternative drugs can be useful in patients CONCLUSIONS — Benfluorex as an add-on therapy was superior to placebo in lowering with intolerance of or contraindications to A1C with a between-group difference of 1% in type 2 diabetic patients whose disease was metformin and/or thiazolidinediones. insufficiently controlled with sulfonylurea alone and in whom metformin was contraindicated or Benfluorex (2-[[(1RS)-1-methyl-2-[3-(tri- not tolerated. fluoromethyl)phenyl]ethyl]-amino]ethyl benzoate hydrochloride) is a compound Diabetes Care 29:515–520, 2006 with both lipid-lowering and antihypergly- cemic actions. Benfluorex is almost com- he incidence and progression of mi- tes Study (UKPDS) in 1998, recom- pletely absorbed after oral administration. It crovascular complications in type 2 mended target values for HbA1c (A1C) in is fully metabolized by a circulating esterase T diabetes are strongly associated with type 2 diabetes were reduced from 7 to and mainly eliminated in urine. It was ini- the degree of hyperglycemia. Following 6.5% or even lower (1,2). To achieve such tially developed in patients with metabolic the results of the U.K. Prospective Diabe- goals, early initiation of combined ther- syndrome, mainly for European market. In ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● further preclinical and clinical studies, ben- From the 1Endocrinology Department, Cardiovascular Hospital, University Claude Bernard, Lyon, France; fluorex has been shown to improve insulin the 2Institut de Recherches Internationales Servier, Courbevoie, France; 3Schwerpunkt Diabetologie Klinik, sensitivity, decrease hepatic glucose pro- Saarlouis, Germany; the 4University Hospital of Coimbra, Coimbra, Portugal; the 5Universiti Kebangsaan, 6 7 duction, and improve aerobic glucose utili- Kuala Lumpur, Malaysia; the University of Sofia, Sofia, Bulgaria; the Umhlanga Hospital, Durban, South zation in skeletal muscle (4–7). Benfluorex Africa; and the 8Spitalul Judetean, Timisoara, Romania. Address correspondence and reprint requests to Prof. P. Moulin, Service d’Endocrinologie—Unite 11, decreases gluconeogenesis by affecting the Hoˆpital Cardio-Vasculaire Louis Pradel, 28 avenue Doyen Lepine, 69677 Bron Cedex, France. E-mail: expression of genes encoding enzymes in- [email protected]. volved in both glucose and fatty acid metab- Received for publication 2 August 2005 and accepted in revised form 20 November 2005. olism. The mechanisms of these metabolic Abbreviations: FPG, fasting plasma glucose; FSI, fasting serum insulin; HOMA-IR, homeostasis model assessment of insulin resistance; ITT, intention to treat; NCEP, National Cholesterol Education Program; actions in liver and muscle differ from those UKPDS, U.K. Prospective Diabetes Study. of metformin: in particular, benfluorex de- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion creases gluconeogenesis by inhibition of factors for many substances. -oxidation (4). These findings prompted © 2006 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby the development of the product in overt marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. type 2 diabetes. A small-scale exploratory DIABETES CARE, VOLUME 29, NUMBER 3, MARCH 2006 515 Benfluorex in combination with sulfonylurea trial demonstrated that in overweight dia- ing either placebo or 150 mg benfluorex using a two-sided Student’s t test for in- betic patients whose diabetes was poorly (Les Laboratoires Servier Industrie, Gidy, dependent samples with 90% power, a controlled by a sulfonylurea as mono- France), the dose being gradually in- type 1 error of 5%, and a 10% drop-out therapy, the combination with benfluorex creased over the first 3 weeks from one rate. The intention-to-treat (ITT) popula- over 3 months led to a significant improve- tablet per day to the recommended dose tion was defined as all randomly assigned ment in blood glucose control (8). A recent of one tablet three times daily. The dose of patients exposed to the study drug with a large-scale, 6-month trial in diet-failed type sulfonylurea was to be maintained baseline value and at least one A1C value 2 diabetic patients demonstrated the effi- throughout the study, except in patients during treatment. Per-protocol patients cacy of benfluorex versus placebo in mono- with severe or repeated hypoglycemia. were defined as patients who completed therapy, with a significant 0.86% reduction Subjects were asked to maintain their the study without a deviation affecting the in A1C and a good safety profile (9). The usual diet and physical activity. The pri- A1C evaluation. For efficacy analyses, the most common side effects are gastrointesti- mary efficacy end point was A1C. The difference between benfluorex and pla- nal disorders, asthenia, somnolence, dizzi- secondary end points were FPG, fasting cebo treatment was studied as the change ness, and headache. These data, together serum insulin (FSI), and lipid profile, from baseline to last value with treatment with the assumption of a potential benefit of each assessed at inclusion and at weeks 4, using ANCOVA with baseline and geo- benfluorex in combination with a sulfonyl- 10, and 18, and insulin resistance index graphic area as covariates. The within- urea, led to the design of the present study evaluated at baseline and week 18. An in- group evolution between baseline and the to confirm the antidiabetic properties of teractive voice response system was used last value during treatment was studied in benfluorex and to demonstrate its superior- for centralized randomization, stratified each treatment group using a two-sided ity over a placebo as add-on therapy in type by baseline A1C (Յ8orϾ8%) and geo- paired Student’s t test. Nonparametric ap- 2 diabetic patients whose diabetes is insuf- graphic area. The protocol was approved proaches were performed for triglyceride- ficiently controlled with sulfonylurea by each institution’s ethics committee. mia and HOMA-IR analyses. Three monotherapy. In Europe the first-line ther- The trial was conducted in accordance subgroups were predefined according to apy for this group of patients involves the with the ethical principles stated in the regulatory requirements (12): A1C at in- combination of a sulfonylurea and met- Declaration of Helsinki 1964, as revised clusion Ͼ8%, age at selection Ͼ65 years, formin;