Clinical Care/Education/Nutrition ORIGINAL ARTICLE Repaglinide Versus Nateglinide Monotherapy A randomized, multicenter study 1 6 JULIO ROSENSTOCK, MD NAUM KHUTORYANSKY, PHD epaglinide (Prandin) and nategli- 2 6 DAVID R. HASSMAN, DO PAULA M. HALE, MD nide (Starlix) are short-acting insu- 3 ROBERT D. MADDER, DO FOR THE REPAGLINIDE VERSUS NATEGLINIDE 4 lin secretagogues that are approved HARI RAZINSKY MD R S A. B , COMPARISON STUDY GROUP* 5 for the treatment of type 2 diabetes (1,2). JAMES FARRELL, MD Both of these agents have relatively short elimination half-lives (1 h for repaglinide and 1.5 h for nateglinide). When admin- istered at mealtimes, both agents produce OBJECTIVE — A randomized, parallel-group, open-label, multicenter 16-week clinical trial peak insulin stimulation during the post- compared efficacy and safety of repaglinide monotherapy and nateglinide monotherapy in type prandial period, when physiological insu- 2 diabetic patients previously treated with diet and exercise. lin needs are maximal. Clinical trials have demonstrated that both agents increase RESEARCH DESIGN AND METHODS — Enrolled patients (n ϭ 150) had received insulin response to postprandial glucose, Ͼ Յ treatment with diet and exercise in the previous 3 months with HbA1c 7 and 12%. Patients resulting in reductions of HbA1c and fast- were randomized to receive monotherapy with repaglinide (n ϭ 76) (0.5 mg/meal, maximum ing plasma glucose (FPG) levels. ϭ dose 4 mg/meal) or nateglinide (n 74) (60 mg/meal, maximum dose 120 mg/meal) for 16 Although both repaglinide and nateg- weeks. Primary and secondary efficacy end points were changes in HbA and fasting plasma 1c linide stimulate insulin secretion by inhi- glucose (FPG) values from baseline, respectively. Postprandial glucose, insulin, and glucagon bition of the ATP-dependent potassium were assessed after a liquid test meal (baseline, week 16). Safety was assessed by incidence of ␤ adverse events or hypoglycemia. channels of -cells, the molecular binding site of repaglinide is different from that of RESULTS — Mean baseline HbA1c values were similar in both groups (8.9%). Final HbA1c nateglinide and sulfonylureas (3–5). Clin- values were lower for repaglinide monotherapy than nateglinide monotherapy (7.3 vs. 7.9%). ical trial comparisons of repaglinide ver- Mean final reductions of HbA1c were significantly greater for repaglinide monotherapy than sus sulfonylurea monotherapy have been nateglinide monotherapy (Ϫ1.57 vs. Ϫ1.04%; P ϭ 0.002). Mean changes in FPG also demon- conducted in mixed populations of pa- Ϫ Ϫ Ͻ strated significantly greater efficacy for repaglinide than nateglinide ( 57 vs. 18 mg/dl; P tients (treatment naive and previously 0.001). HbA values Ͻ7% were achieved by 54% of repaglinide-treated patients versus 42% for 1c treated) for periods up to 1 year. In a non- nateglinide. Median final doses were 6.0 mg/day for repaglinide and 360 mg/day for nateglinide. There were 7% of subjects treated with repaglinide (five subjects with one episode each) who had inferiority trial, repaglinide provided im- minor hypoglycemic episodes (blood glucose Ͻ50 mg/dl) versus 0 patients for nateglinide. Mean provements in glycemic control that were weight gain at the end of the study was 1.8 kg in the repaglinide group as compared with 0.7 kg similar in efficacy to glyburide (6). In an- for the nateglinide group. other 1-year direct comparison clinical trial, repaglinide treatment showed sig- CONCLUSIONS — In patients previously treated with diet and exercise, repaglinide and nificantly greater efficacy than glipizide as nateglinide had similar postprandial glycemic effects, but repaglinide monotherapy was signif- measured in reductions of HbA1c and icantly more effective than nateglinide monotherapy in reducing HbA1c and FPG values after 16 FPG values (7). A clinical trial directly weeks of therapy. comparing postprandial effects of nategli- Diabetes Care 27:1265–1270, 2004 nide and glipizide reported comparable reductions of postprandial glucose levels ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● by these two agents (8). From the 1Dallas Diabetes and Endocrine Center, Dallas, Texas; the 2Comprehensive Clinical Research, Direct comparison trials of the meal- 3 4 Berlin, New Jersey; the Tri-State Medical Group, Beaver, Pennsylvania; the Institute of Health Care As- time secretagogues repaglinide and nateg- sessment, San Diego, California; 5Midwest Pharmaceutical Research, St. Peters, Missouri; and 6Novo Nordisk Pharmaceuticals, Princeton, New Jersey. linide have been lacking, and in the Address correspondence and reprint requests to Dr. Julio Rosenstock, Dallas Diabetes and Endocrine absence of such clinical trials, it has been Center, 7777 Forest Ln., Suite C618, Dallas, TX 75230. E-mail: [email protected]. very difficult to assess their clinical effi- Received for publication 18 September 2003 and accepted in revised form 26 February 2004. cacy. Assessment of their blood glucose– *A complete list of the Repaglinide Versus Nateglinide Comparison Study Group can be found in the lowering potency could only be estimated APPENDIX. J.R. and D.R.H. have received grant support from Novo Nordisk Pharmaceuticals, and J.R. has received from interpretation of repaglinide or na- honoria from Novo Nordisk Pharmaceuticals. teglinide monotherapy trials, frequently Abbreviations: AUC, area under the curve; FPG, fasting plasma glucose; IMI, incremental mean impu- having differences in study design (9– tation; LOCF, last observation carried forward; SMBG, self-monitoring of blood glucose. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion 12). A review of such insulin secretagogue factors for many substances. literature by Inzucchi (13) concluded that © 2004 by the American Diabetes Association. nateglinide appeared to be somewhat less DIABETES CARE, VOLUME 27, NUMBER 6, JUNE 2004 1265 Comparison of repaglinide vs. nateglinide potent a secretagogue than repaglinide or Table 1—Characteristics of randomized population at baseline and completion status sulfonylureas. A recently published direct comparison trial of repaglinide and nateg- Repaglinide Nateglinide linide, under conditions of combination therapy with metformin, demonstrated Population characteristics that repaglinide/metformin combination n 76 74 therapy was significantly more effective Age (years) 50.9 Ϯ 12.2 54.0 Ϯ 13.4 than nateglinide/metformin therapy in 16 Sex (men/women) 41/35 42/32 weeks of treatment (with mean reduc- BMI (kg/m2) 33.0 Ϯ 5.6 32.9 Ϯ 5.7 tions of HbA1c of 1.28 vs. 0.67%, respec- Ethnic group (C/B/H/A/O) 60/6/9/0/1 59/3/9/1/2 tively) (14). However, that clinical trial Time since diabetes diagnosis (years) 3.5 Ϯ 4.6 4.3 Ϯ 5.6 did not examine the relative efficacy of Completion status repaglinide monotherapy versus nategli- Completed week 16 70 (92) 62 (84) nide monotherapy. Did not complete week 16 6 (8) 12 (16) This clinical trial was conducted to Reasons for discontinuation: provide a direct comparative assessment Adverse event 2 (3) 0 (0.0) of the relative efficacy and safety of repag- Lack of efficacy* 1 (1) 6 (8) linide versus nateglinide in patients who Noncompliance 1 (1) 1 (1) had received only diet and exercise ther- Other 2 (3) 5 (7) apy in the previous 3 months. Data are means Ϯ SEM or n (%). C, Caucasian; B, black; H, Hispanic; A, Asian; O, other. *Lack of efficacy RESEARCH DESIGN AND was determined by the investigator. Patients were to be withdrawn from the study because of unacceptable Ͼ Ͼ METHODS — This clinical trial was persistent hyperglycemia, FPG 270 mg/dl, in the absence of a treatable intercurrent illness. If FPG 270 mg/dl, it was to be rechecked at least once within 1–3 days. If the FPG was still Ͼ270 mg/dl, the subject was conducted in accordance with the provi- to be withdrawn from the trial if no obvious treatable intercurrent cause for the hyperglycemia could be sions of the Declaration of Helsinki for found, and the maximum allowed dose of repaglinide (4 mg before each main meal, maximum dose 16 participation of subjects in human re- mg/day) or nateglinide (120 mg before each main meal, maximum dose 360 mg/day) was being given. search. The protocol received approval of relevant institutional review boards before initiation of any trial-related activities. needed. Patients initiated repaglinide administered 10 min before the liquid test This study was a multicenter, ran- treatment at doses of 0.5 mg before each meal. domized, parallel-group, open-label meal, and doses were increased stepwise Patients were requested to record an comparison of repaglinide and nategli- from 0.5 to 1.0, to 2.0, and to 4.0 mg at 8-point SMBG profile (before breakfast, nide treatment for a period of 16 weeks. weekly visits based upon the results of an 2 h after breakfast, before lunch, 2 h after The primary efficacy end points for com- 8-point SMBG (maximum dose 16 mg/ lunch, before dinner, 2 h after dinner, parison were final HbA1c values (HPLC day). Doses of nateglinide were started at bedtime, and at 2:00 A.M.) at each visit. assay; Icon Laboratories, Tinton Falls, NJ) 60 mg/meal and increased to 120 mg/ Patients were provided instructions that and changes in HbA1c values from base- meal after 1 week if target glycemic con- included regular calibration of the meter line. Secondary efficacy end points in- trol was not achieved. Doses were as recommended by the manufacturer. cluded changes in FPG values. Enrolled determined by the labeling of each agent. Ն Adverse events and reports of hypo- patients were adults (age 18 years) who The labeling for nateglinide allows for a glycemic episodes were recorded at all had type 2 diabetes for at least 3 months maximum dose of 360 mg/day, corre- study visits. Hypoglycemic episodes were with BMI values in the range of 24–42 sponding to three meals at the maximum defined as follows.