Repaglinide Versus Nateglinide Monotherapy a Randomized, Multicenter Study

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 administered 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. Major hypoglycemic kg/m2. Subjects were stratified by baseline dose of 120 mg/meal. The labeling for re- episodes were events having severe cen- HbA value (Ͻ9% or Ն9%), and were paglinide allows for a total of up to 16 1c tral nervous system symptoms consistent asked to conduct self-monitoring of their mg/day, corresponding to as many as four with hypoglycemia in which the subject blood glucose levels (SMBG) from the ran- meals at the 4-mg dose. The number of was unable to treat him/herself, having domization visit onward. meals was not recorded by patients, so Ͻ Enrolled patients had been treated average doses per meal were not calcu- blood glucose readings 50 mg/dl and/or reversal of symptoms by treatment (food with only diet and exercise during the lated. HbA1c values were determined at Ͻ intake, glucagon, or intravenous glucose). previous 3 months (HbA1c values 7 and baseline and at weeks 4, 8, 12, and 16. Ն12%). Subjects were randomly assigned A liquid test meal evaluation (two Minor hypoglycemic episodes included to either mealtime repaglinide therapy cans of Boost equal 480 kcal; 67% carbo- events having hypoglycemia symptoms Ͻ (n ϭ 76) or mealtime nateglinide mono- hydrate, 17% protein, and 16% fat) was and confirmed blood glucose levels 50 therapy (n ϭ 74) with an initial 3-week conducted at the baseline and week 16 mg/dl and events with asymptomatic dose titration. Both agents were to be visits with determination of plasma glu- blood glucose levels Ͻ50 mg/dl. given 1–30 min before daily meals. Target cose (hexokinase assay), insulin (immu- Missing values of HbA1c and FPG af- glycemic control during the initial 3-week nometric assay), and glucagon ter baseline were substituted by imputed period was SMBG preprandial values of (radioimmunoassay) from Ϫ10 min to data (calculated by the incremental mean 80–140 mg/dl, with dose adjustments 240 min (Icon Laboratories). At week 16, imputation [IMI] method) (15). Simula- possible in the following 13 weeks if doses of repaglinide or nateglinide were tions of datasets resembling the output of

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Efficacy Mean HbA1c values during treatment are graphically represented in Fig. 1A. The mean baseline HbA1c value was 8.9% in both groups. From week 8 onward, mean HbA1c values were significantly lower for repaglinide than nateglinide, and by week 16, such treatment-related differences appeared to have stabilized. The mean end of study reductions in HbA1c values from baseline was significantly greater for repaglinide than nateglinide (IMI method, 1.57 vs. 1.04%, P ϭ 0.002; last observation carried forward (LOCF) method, 1.55 vs. 1.02%, P ϭ 0.003). At the end of the study, 54% of repaglinide-treated patients had HbA1c values of Յ7 vs. 42% of nateglinide-treated patients (P ϭ 0.18 between treatments). Only 11% of nateglinide-treated patients Ͼ having initial HbA1c values 8% had fi- Յ nal HbA1c values of 7%. In contrast, 40% of repaglinide-treated patients with Ͼ initial HbA1c values 8% had final HbA1c values of Յ7% (P ϭ 0.004 between treatments). By week 16 of treatment, only nine repaglinide-treated patients (12%) had escalated mealtime doses to the maximal level of 16 mg/day (mean time at maximum dose was 44 days). However, 57 (77%) nateglinide monotherapy patients had remained at the highest dosage level Figure 1—A: Mean HbA1c values during treatment. SE values are indicated by bars. B: Mean FPG values during treatment. SE values are indicated by bars. of 360 mg/day up to the end of the study (mean time at maximum dose was 94 days). Median daily doses of secretagogues were 6.0 mg/day for repaglinide this clinical trial have demonstrated that agnosed diabetes. None of these variables and 360 mg/day for nateglinide. A sub- the IMI method is more precise than the differed significantly by treatment group. analysis of subjects on the maximum dose last observation carried forward method Only 8% of the patients in the repaglinide of nateglinide showed that the mean (15). Differences between the mono- group and 16% of the patients of the na- HbA1c reduction (adjusted for baseline therapy groups in the change in HbA1c or teglinide group failed to complete 16 difference with the repaglinide group) FPG values were compared by ANOVA weeks of therapy (Table 1). The nategli- was 1.08% versus a mean HbA1c reduc- (with and without adjustment for baseline nide monotherapy group had a slightly tion for subjects treated with repaglinide ϳ imbalance). An enrollment of 150 pa- higher rate of discontinuation due to lack (all doses) of 1.67% (P ϭ 0.0031). tients was calculated based upon the as- of efficacy (at the judgment of the inves- The subset of subjects who received a sumption of a 10% drop-out rate and an tigator; patients were to be withdrawn for nateglinide dose of 60 mg/meal had mean intent-to-treat analysis with 80% power unacceptable persistent hyperglycemia baseline HbA values significantly lower Ͼ 1c to detect an HbA1c difference of 0.6%. [two FPG readings 270 mg/dl, in the than those treated at 120 mg/meal (7.32 absence of a treatable intercurrent illness, vs. 9.41%). The lower dose was thus used in 3 days] when the maximum allowed in patients who had near-goal HbA1c RESULTS dose of repaglinide [4 mg before each when treatment was initiated, as recom- main meal, maximum dose 16 mg/day] or mended in the nateglinide package insert Subjects nateglinide [120 mg before each main (2). Demographic and baseline characteristics meal, maximum dose 360 mg/day] was Mean FPG values over time are pre- of the 150 enrolled patients are summa- being given) and other reasons. Two sub- sented by treatment group in Fig. 1B. The rized in Table 1. The repaglinide and na- jects discontinued in the repaglinide repaglinide group had significantly lower teglinide therapy groups were very group due to adverse events: one due to FPG values than the nateglinide group af- comparable in age, sex, ethnic back- right side pain and one due to diarrhea ter 1 week of therapy with FPG values ground, BMI values, and duration of di- and cramping after dosing. reaching a steady state by week 4. FPG

DIABETES CARE, VOLUME 27, NUMBER 6, JUNE 2004 1267 Comparison of repaglinide vs. nateglinide

Table 2—Changes in glycemic control during 16 weeks of treatment

Repaglinide Nateglinide

HbA1c (%) 71 69 Baseline 8.9 Ϯ 1.34 8.9 Ϯ 1.74 16 weeks 7.3 Ϯ 1.30 7.9 Ϯ 1.36 Change in 16 weeks* Ϫ1.57 Ϯ 0.15† Ϫ1.04 Ϯ 0.14 FPG (mg/dl) 70 71 Baseline 211 Ϯ 53.6 206 Ϯ 62.2 16 weeks 154 Ϯ 40.2 188 Ϯ 62.9 Change in 16 weeks* Ϫ57 Ϯ 5.7‡ Ϫ18 Ϯ 5.3 Mealtime test glucose AUC (mg ϫ min/dl) 65 59 Baseline 15.9 ϫ 103 Ϯ 6.8 ϫ 103 15.8 ϫ 103 Ϯ 7.4 ϫ 103 End of study 9.6 ϫ 103 Ϯ 7.3 ϫ 103 10.0 ϫ 103 Ϯ 8.1 ϫ 103 Change by end of study* Ϫ6.3 ϫ 103 Ϯ 0.8 ϫ 103 Ϫ5.9 ϫ 103 Ϯ 0.8 ϫ 103 Mealtime test insulin AUC (␮IU ϫ min/ml) 66 56 Baseline 6.8 ϫ 103 Ϯ 7.6 ϫ 103 7.2 ϫ 103 Ϯ 7.8 ϫ 103 End of study 11.1 ϫ 103 Ϯ 8.3 ϫ 103 13.3 ϫ 103 Ϯ 18.0 ϫ 103 Change by end of study* ϩ4.3 ϫ 103 Ϯ 1.2 ϫ 103 ϩ6.0 ϫ 103 Ϯ 1.3 ϫ 103 Mealtime test glucagon AUC (pg ϫ min/ml) 61 53 Baseline 3.8 ϫ 104 Ϯ 1.5 ϫ 104 3.7 ϫ 104 Ϯ 1.7 ϫ 104 End of study 1.8 ϫ 104 Ϯ 1.5 ϫ 104 2.5 ϫ 104 Ϯ 1.8 ϫ 104 Change by end of study* Ϫ1.9 ϫ 104 Ϯ 0.2 ϫ 104§ Ϫ1.2 ϫ 104 Ϯ 0.2 ϫ 104 Data are n and means Ϯ SD or *SEM. AUC values were adjusted for baseline (the level at the time of the start of the meal). Change refers to change from baseline in least squared mean. †Statistically significant treatment group difference (P ϭ 0.002). ‡Statistically significant treatment group difference (P Ͻ 0.001). §Statistically significant treatment group difference (P ϭ 0.005). values remained lower in the repaglinide creased levels of postprandial glucagon cantly different for repaglinide and nateg- group for the following 12 weeks until the (Fig. 3B; Table 2). Changes in the area linide. Changes in postprandial insulin end of the study. Mean final FPG values under the postprandial plasma glucose AUC0–240min were likewise comparable ⌬ were 156 mg/dl for repaglinide and 183 curve ( AUC0–240min) were not signifi- for the two treatments (Table 2). Gluca- mg/dl for nateglinide (Table 2). Mean final reductions in FPG values from baseline were significantly greater for repaglinide (Ϫ57 mg/dl) than nateglinide therapy (Ϫ18 mg/dl, P Ͻ 0.001) (LOCF method, Ϫ57 and Ϫ19 mg/dl, respectively). A subanalysis of subjects on the maximum dose of nateglinide showed that the mean FPG reduction (adjusted for baseline difference with the repaglinide group) was 20 mg/dl compared with the mean FPG reduction for repaglinide (all doses) of 59 mg/dl (P Ͻ 0.0001). The mean 8-point SMBG profiles col- lected by patients at the end of the study are presented in Fig. 2 and were consistent with observed differences in the FPG response of the two treatments. Repagli- nide monotherapy showed significantly lower mean SMBG values than nateglinide at all time points measured (P Ͻ 0.05). Liquid meal challenge testing resulted in the plasma glucose profiles shown in Fig. 3A. From baseline to the end of the study, both treatments showed decreased Figure 2—Mean 8-point blood glucose profiles at end of study. SE values are indicated by bars. levels of postprandial glucose, increased The two treatment groups were significantly different in blood glucose values at all time points (P levels of postprandial insulin, and de- Ͻ 0.05).

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of adverse events for the two treatment groups.

CONCLUSIONS — With an increas- ing number of therapeutic choices for oral therapy of type 2 diabetes, the comparative efficacy of various agents and their optimal conditions for use are important considerations. Such comparisons have numerous implications regarding the best therapy to institute in a particular patient population, including the choice of agents to begin monotherapy when diet and exercise fail or the choice of agents to add to monotherapy to potentiate glucose- lowering effects. In a 1-year comparison trial, repaglinide had similar efficacy to glyburide, but a direct comparison of the efficacy of repaglinide with nateglinide has not previously been reported (6). This clinical trial demonstrated that under conditions of dose titration to the same glycemic targets, repaglinide had significantly greater reductions of glycemic parameters than nateglinide when used as monotherapy in patients who had been treated with diet and exercise therapy in the previous 3 months. Efficacy differences between the two treatments were evident in changes in FPG or HbA1c within the first 4 weeks. Greater glycemic efficacy of repaglinide (with a lowering of HbA1c values from baseline by 1.57%) was not attributable to an inadequacy of nateglinide dosage, because the majority (77%) of nateglinide-treated patients received the maximal recommended daily dosage of 360 mg/day, whereas 12% of patients using repaglinide were at the maximal dose. The observed efficacy of Figure 3—A: Postprandial plasma glucose levels following a liquid meal challenge at baseline and nateglinide in this clinical trial of a 1.04% end of study. SE values are indicated by bars. B: Postprandial plasma insulin levels following a reduction of HbA1c relative to baseline in liquid meal challenge at baseline and end of study. SE values are indicated by bars. 16 weeks was comparable with previous reports of nateglinide monotherapy of a gon AUC0 –240min showed reductions month for subjects treated with repagli- 0.6% reduction in 16 weeks (16) or a 0.8% from week 0 to week 16 that were signif- nide, as compared with 0 events per pa- reduction in 24 weeks in the oral antidia- icantly greater for repaglinide than nateg- tient per month (P ϭ 0.3 based on the betic drug–naive subset of patients (12). linide (P ϭ 0.005). Poisson rare-event model.) It is of interest to note that effects of Mean weight gains (adjusted for base- these short-acting secretagogues upon Safety line and age) from baseline to end of study postprandial hyperglycemia has typically There were no major hypoglycemic epi- were ϩ1.8 kg for repaglinide and ϩ0.7 kg been emphasized as the mechanism of ac- sodes (requiring the assistance of another for nateglinide (IMI method calculation, tion, but in this study, the glycemic effects person) in either treatment group. There P ϭ 0.04; LOCF method calculation, P ϭ of the two agents on postprandial glucose were five patients (7%) receiving repagli- 0.034). or insulin AUC values were similar. This nide treatment who had events of minor The most common adverse events finding underscores the value of control- hypoglycemia (two in the absence of (between 3 and 10% of patients in both ling nocturnal and fasting hyperglycemia symptoms), and no reported minor hypo- treatment groups) were upper respiratory in which repaglinide effects appeared glycemic events during nateglinide ther- tract infection, sinusitis, constipation, ar- greater, suggesting a longer duration of apy. The frequency of hypoglycemic thralgia, headache, and vomiting. There action for this compound. Because the events is 0.016 events per patient per were no notable differences in the pattern two treatment groups had similar reduc-

DIABETES CARE, VOLUME 27, NUMBER 6, JUNE 2004 1269 Comparison of repaglinide vs. nateglinide tions of postprandial glucose peaks after a and FPG values than nateglinide mono- paglinide and glipizide in type 2 diabetes liquid test meal, the greater reduction of therapy with similar postprandial effects. mellitus: a 1-year multicentre study. Dia- HbA , FPG, or SMBG values for repagli- bet Med 18:395–401, 2001 1c 8. Carroll MF, Ahmad I, Riboni K, Burge nide is likely to be due to subtle differ- Acknowledgments— This study was sup- MR, Schade DS: Control of postprandial ences in repaglinide performance during ported by Novo Nordisk Pharmaceuticals of hyperglycemia: optimal use of short-act- the night and at late postprandial times or Princeton, New Jersey. ing secretagogues. Diabetes Care 25:2147– between meals. Effects of such differences 2152, 2002 might culminate rapidly in a mealtime APPENDIX 9. Moses RG, Gomis R, Frandsen KB, dosing regimen: although the two agents Schlienger JL, Dedov I: Flexible meal-re- have similar elimination half-lives (1 h for Members of the Repaglinide Versus lated dosing with repaglinide facilitates glycemic control in therapy-naive type 2 repaglinide and 1.5 h for nateglinide), Nateglinide Comparison Study ␤ Group diabetes. Diabetes Care 24:11–15, 2001 their affinity for their -cell receptors is 10. Van Gaal LF, Van Acker KL, de Leeuw IH: dramatically different (half-maximal in- Steven S. Bimson, Jonathon Bortz, Shari Repaglinide improves blood glucose con- hibitory concentration for ATP-sensitive A. Brazinky, Dennis Buth, John Capple- trol in sulphonylurea-naive type 2 diabe- ϩ K channel-blocking effect in rat ␤-cells man, James Farrell, Vincente Florida, tes. Diabetes Res Clin Pract 53:141–148, is 5 nmol/l for repaglinide vs. 7.4 ␮mol/l David R. Hassman, Priscilla Hollander, C. 2001 for nateglinide) (1,2,17). Preclinical ex- Scott Horn, Edward Kerwin, Allen King, 11. Hanefield M, Bouter KP, Dickinson S, Nelson Kopyt, Robert Madder, Janet Guitard C: Rapid and short-acting meal- perimental data have indicated that the McGill, Joseph Milburn, Jorge Pino, Larry time insulin secretion with nateglinide inhibitory effects of nateglinide upon ATP- ϩ Popeil, Julio Rosenstock, Don Schuma- controls both prandial and mean glycae- sensitive K channels are reversed more cher, Barry Seidman, Richard Sievers, Ste- mia. Diabetes Care 23:202–207, 2000 rapidly than those of repaglinide (17). phen A. South, and Scott Touger. 12. Horton ES, Clinkingbeard C, Gatlin M, Postprandial insulin measurements Foley J, Mallows S, Shen S: Nateglinide indicate that the two secretagogues are alone and in combination with metformin clinically similar in their stimulation of References improves glycemic control by reducing 1. Novo Nordisk Pharmaceuticals: Repa- mealtime glucose levels in type 2 diabetes. mealtime insulin release. In this clinical glinide product labeling, 2003 Diabetes Care 23:1660–1665, 2000 trial, the two secretagogues had no obvi- 2. Novartis Pharmaceuticals: Nateglinide 13. Inzucchi SE: Oral antihyperglycemic ous differences in their effects upon the product labeling, 2003 therapy for type 2 diabetes. JAmMed early stages of insulin secretion. The clin- 3. Gromada J, Dissing S, Kofod H, Frokjaer- Assoc 287:360–372, 2002 ical significance of a significantly greater Jensen J: Effects of the hypoglycaemic 14. Raskin P, Klaff L, McGill J, South SA, Hol- reduction of postprandial glucagon levels drugs repaglinide and glibenclamide on lander P, Khutoryansky N, Hale PM: Effi- for repaglinide monotherapy remains to ATP-sensitive potassium channels and cy- cacy and safety of combination therapy: tosolic calcium levels in bTC3 cells and repaglinide plus metformin versus nateg- be established. rat pancreatic ␤-cells. Diabetologia 38: linide plus metformin. Diabetes Care 26: Regarding hypoglycemia, both agents 1025–1032, 1995 2063–2068, 2003 showed a desirable hypoglycemic episode 4. Chachin M, Yamada M, Fujita A, Mat- 15. Khutoryansky NM, Huang WC: Imputa- profile in this clinical trial with no re- suoka T, Matsushita K, Kurachi Y: Nateg- tion techniques using SAS software for in- ported events of major hypoglycemia. It linide, a D-phenylalanine derivative lacking complete data in diabetes clinical trials. In should be noted that any treatment that either a sulfonylurea or benzamido moi- Pharmaceutical Industry SAS Users Group ␤ results in an improvement in glycemic ety, specifically inhibits pancreatic -cell- Conference Proceedings, Boston, MA, 20–23 type K(ATP) channels. J Pharmacol Exp May 2001. p. 334–337 control might also lead to an increase in Ther 304:1025–1032, 2003 16. Rosenstock J, Gatlin MR, Shen SG, Foley hypoglycemic events. The mean weight 5. Hansen AM, Christensen IT, Hansen IB, JE: Combination therapy with nateglinide changes associated with repaglinide or na- Carr RD, Ashcroft FM, Wahl P: Differen- and a thiazolidinedione improves glyce- teglinide were statistically different, and tial actions of nateglinide and repaglinide mic control in type 2 diabetes. Diabetes the clinical importance of this difference on the human ␤-cell sulphonylurea re- Care 25:1529–1533, 2002 is unknown. Both drugs were generally ceptor. Diabetes 51:2789–2795, 2002 17. Hu S, Wang S, Fanelli B, Bell PA, Dunning well tolerated. 6. Marbury T, Huang WC, Strange P, Lebo- RE, Geisse S, Schmitz R, Boettcher BR: vitz H: Repaglinide versus glyburide: a Pancreatic ␤-cell channel activity and In patients having inadequate glyce- 1-year comparison trial. Diabetes Res Clin membrane-binding studies with nategli- mic control in a regimen of diet and exer- Pract 43:155–166, 1999 nide: a comparison with sulfonylureas cise, repaglinide monotherapy led to 7. Madsbad S, Kilhovd B, Lagert I, Mustajoki and repaglinide. J Pharmacol Exp Ther significantly greater reductions in HbA1c P, Dejgaard A: Comparison between re- 293:444–452, 2000

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