Clinical Care/Education/Nutrition ORIGINAL ARTICLE

Comparison of the Effects of Three Insulinotropic Drugs on Plasma Insulin Levels After a Standard Meal

1 2 LAWRENCE S. COZMA, MRCP KIRSTEN W. LANGENDORG, MSC both chronic (6) and acute hyperglycemia 1 3 STEPHEN D. LUZIO, PHD THOMAS PIEBER (7) have been shown to worsen the func- 1 1 GARETH J. DUNSEATH, BSC DAVID R. OWENS, MD, FRCP tion of the endothelium. Recent prospective studies have at- tempted to assess the effects of fasting and postprandial hyperglycemia independent OBJECTIVE — To compare the effects of repaglinide, glipizide, and glibenclamide on insulin of each other. Postprandial hyperglyce- secretion and postprandial glucose after a single standard 500-kcal test meal. mia might be more important than fasting RESEARCH DESIGN AND METHODS — A total of 12 type 2 diabetic patients with hyperglycemia in predicting CVD (8). However, despite indisputable evidence early diabetes (mean HbA1c of 6.1%) and 12 matched control subjects were enrolled in this randomized, double-blind, crossover trial. Subjects received placebo, 2 mg repaglinide, 5 mg that better diabetes control reduces the glipizide, and 5 mg glibenclamide in a random fashion during the trial. Administration of each incidence of microvascular complica- drug was followed by a single standard 500-kcal test meal. A washout period of 7–12 days existed tions, a reduction in the risk of developing between the four study visits. CVD has not been proven convincingly. Hemoglobin glycosylation is influ- RESULTS — All three drugs were equally effective on the total prandial insulin secretion (area enced by both fasting and postprandial under the curve [AUC] –15 to 240 min). However, clear differences were noted in the early glucose; the latter is more strongly corre- insulin secretion (AUC –15 to 30 min); both repaglinide and glipizide increased secretion in lated with HbA values (9). Therefore, nondiabetic subjects by ϳ61 and 34%, respectively, compared with placebo. In the diabetic 1c patients, the difference versus placebo was 37 and 47%, respectively. The difference between targeting the postprandial glucose level glipizide and glibenclamide reached significance in both groups of subjects, whereas repaglinide when elevated seems logical and has been was more effective than glibenclamide only in the healthy nondiabetic subject group. All three shown to achieve better control than fo- drugs were effective in decreasing total glucose AUC in the nondiabetic and diabetic population. cusing on the fasting glucose level alone In the nondiabetic subjects, however, repaglinide was significantly more effective than gliben- (10). clamide. The differences disappeared in the diabetic subjects, probably as a result of increased Postprandial hyperglycemia is gener- prevalence of insulin resistance in this group. ated by a combination of impaired pan- creatic insulin secretion, unsuppressed CONCLUSIONS — Repaglinide and glipizide but not glibenclamide significantly enhanced ␤ hepatic glucose production, and reduced the early insulin secretion in both nondiabetic and diabetic subjects with preserved -cell glucose uptake in the periphery (11). In- function after a single standard meal. sulin secretion in normal subjects has a Diabetes Care 25:1271–1276, 2002 characteristic biphasic pattern, with an early phase lasting Ͻ10 min after food ingestion followed by a more sustained later phase of insulin release, which par- ardiovascular disease (CVD) is the (3). Dysfunction of the vascular endothe- allels the glucose absorption from the gut most important cause of morbidity lium is present early in the history of dia- (12). In type 2 diabetes, there is a loss of and mortality in type 2 diabetes (1). betes (4) and has been implicated in C the early phase and a delayed, blunted, The classical risk factors of hypertension, atherogenesis. Insulin resistance and its smoking, increased LDL, and reduced associated features are a major determi- and consequently more prolonged late HDL with increased triglycerides (2) ac- nant of the abnormal endothelial function phase (13). These changes occur very count for Ͻ50% of the excess risk of CVD in the prediabetic stages (5). However, early in the natural history of this syn- drome, and the degree of blunting relates ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● to the fasting plasma glucose, the so- From the 1Diabetes Research Unit, University Hospital of Wales, College of Medicine, South Glamorgan, called “Starling curve” of the pancreas Wales; 2Novo Nordisk A/S, Bagsvaerd, Denmark; and 3Med Universitatsklinik Graz, Graz, Austria. (14). The early-phase loss contributes to a Address correspondence and reprint requests to Dr. L. S. Cozma, Diabetes Research Unit, University lack of early suppression of the glucagon Hospital of Wales, College of Medicine, First Floor, Academic Centre, Llandough Hospital and Community NHS Trust, Penlan Rd., Penarth, South Glamorgan CF642XX. E-mail: [email protected]. secretion after ingestion of carbohydrates Received for publication 4 November 2001 and accepted in revised form 26 March 2002. (15), which in turn leads to continuing Thomas R. Pieber has received honoraria for speaking engagements from Novo Nordisk A/S. hepatic glucose production and an accen- Abbreviations: AUC, area under the curve; CVD, cardiovascular disease; KATP, ATP-sensitive potas- tuation of the hyperglycemia (16). A loss sium. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion of the early phase of secretion has been factors for many substances. shown to cause postprandial glucose in- See accompanying editorial on p. 1472. tolerance in nondiabetic subjects (17). In

DIABETES CARE, VOLUME 25, NUMBER 8, AUGUST 2002 1271 Effects of insulinotropic drugs on plasma insulin levels

Table 1—Baseline characteristics cross-reacted Ͻ2% with insulin and ϳ100% with proinsulin. Type 2 diabetic subjects Nondiabetic subjects Statistical analysis n 12 12 Data were analyzed using SAS 6.11 soft- Age (years) 57.0 Ϯ 8.7 56.3 Ϯ 9.3 ware on a UNIX platform. Metabolic pa- Men/women (n) 7 (58) / 5 (42) 7 (58) / 5 (42) rameters with a normal distribution are BMI 29.5 Ϯ 3.2 29 Ϯ 1.9 presented as means with SD or 95% CI. Ϯ Ϯ ϭ HbA1c baseline 6.1 1.2* 4.6 0.4 (n 11)* Nonnormally distributed data parameters Duration of diabetes (years min–max) 2.6 (0.5–6.6) N/A are shown as median with minimum and Fasting glucose baseline (mmol/l) 7.83 Ϯ 0.7* 4.84 Ϯ 0.2* maximum also given. Area under the Data are means Ϯ SD and n (%). *P Ͻ 0.05. curve (AUC) was calculated using the trapezoidal rule. Fasting levels for glu- cose, insulin, and C-peptide were calcu- Ϫ type 2 diabetes, restoration of the early tients had good control with HbA1c lated by averaging premeal values ( 30, phase using short-acting insulin analogs Յ6.5%, two had borderline control with Ϫ20, Ϫ15, and 0 min). Insulin secretion significantly improves the glucose toler- HbA1c between 6.5 and 7.5%, and two was analyzed as early phase, terminal Ͼ ance by reducing the endogenous glucose had poor control with HbA1c 7.5%. phase, and total insulin secretion by cal- output (18). However, despite the inhib- The treatment period started within culating insulin AUCs for the first 30 min, itory effects on the hepatic glucose pro- 30 days after the screening visit and con- the last 120 min, and the total 240 min, duction, the impaired glucose utilization sisted of four visits with washout periods respectively. AUC and the maximal by the insulin-resistant tissues remains of 7–12 days between them. A follow-up plasma concentration (Cmax) were loga- unchanged. visit was conducted 7–12 days after the rithmically transformed to obtain nor- Among the agents available for man- last treatment day. The maximum dura- mally distributed data. The transformed agement of type 2 diabetes, only ␣-glyco- tion of participation for each subject was end points were compared across groups sidase inhibitors (19) and short-acting 77 days from the first visit to the last visit. using ANOVA for a crossover design ac- insulinotropic agents such as repaglinide After a 10-h overnight fast, an intra- counting for sequence of treatment, sub- (20) and nateglinide (21) have definitely venous cannula was inserted and saline ject (within a treatment sequence), visit been shown to impact the postprandial infusion was started. Each subject re- (period), and treatment. Wilcoxon’s glucose levels. ceived placebo, 2 mg repaglinide, 5 mg signed-rank test was used to compare the The purpose of this study was to com- glipizide, and 5 mg glibenclamide in a individual groups. To account for multi- pare the effects on the ␤-cell function of random fashion. Administration of the ple comparisons, the Bonferroni method three insulinotropic agents available for drug was followed 15 min later by a stan- was applied. Using an overall level of sig- the treatment of patients with type 2 dia- dard 500-kcal meal tolerance test (55% nificance of 0.05, the nominal level of sig- betes: repaglinide, glipizide, and gliben- carbohydrate, 30% fat, and 15% protein). nificance was 0.05/3 ϭ 0.02 with three clamide. Blood sampling for glucose, insulin, and comparisons. C-peptide was performed at –30, –20, RESEARCH DESIGN AND –15, and 0 min before the meal. Postmeal RESULTS — All 24 subjects who were METHODS samples were collected every 10 min dur- recruited completed the study. Demo- ing the first hour, every 15 min during the graphic and glycemic parameters of the Study design second hour, and hourly thereafter for a study population are shown in Table 1. This study was a randomized, double- total of 4 h. The only significant differences between blind, crossover trial performed at two the diabetic population and the control centers, one in the U.K. and the second in group were in the fasting glucose and the Austria. A total of 12 diet-treated type 2 Analytical methods HbA1c levels. diabetic patients and 12 nondiabetic con- All specimens were centralized and pro- Glucose, insulin, and C-peptide trol subjects matched for age, sex, and cessed in a single laboratory in the U.K. AUCs in the diabetic and nondiabetic weight were enrolled in the study. The The samples were taken into fluoride- control subjects are shown in Table 2. Austrian center recruited four diabetic oxalate for assay of blood glucose (YSI Mean Cmax and the time to maximal con- subjects. All healthy control subjects and 2300; YSI, Aldershot, Hants, U.K.). Blood centrations (Tmax) are shown in Table 3. eight diabetic patients were recruited in samples for assay of insulin and C-peptide The AUC –15 to 240 min for glucose, the U.K. center. All subjects gave written were taken into lithium heparin and cen- insulin, and C-peptide was significantly informed consent to participate in the trifuged, and the plasma was stored at different with all three secretagogues ver- trial. The study received approval of the –20°C before assay. Insulin was measured sus placebo in both groups of subjects. local ethics committee and was con- by a specific immunoassay (MLT Re- Maximum insulin and C-peptide concen- ducted in accordance with the Declara- search, Cardiff, S. Glam, U.K.) and the trations (Cmax) were significantly higher tion of Helsinki. The diabetic population cross-reactivity of proinsulin in the insu- with all active drugs compared with pla- recruited in our study had early type 2 lin assay was Ͻ2%. C-peptide was mea- cebo. Glucose Cmax, however, was de- diabetes with a mean HbA1c of 6.1% (lab- sured by immunoassay (Dako creased significantly only by repaglinide oratory normal range Յ6.4%). Eight pa- Diagnostics, Ely, Cambs, U.K.), which and glipizide. In addition, in nondiabetic

1272 DIABETES CARE, VOLUME 25, NUMBER 8, AUGUST 2002 Cozma and Associates

Table 2—Comparison of the glucose, insulin and C-peptide AUCs in type 2 diabetic and nondiabetic subjects

Glucose AUC Insulin AUC* Insulin AUC* Insulin AUC* C-peptide AUC (mmo/l ϫ hϪ1) (mU/l ϫ hϪ1) (mU/l ϫ hϪ1) (mU/l ϫ hϪ1) (pmol/1/ϫ hϪ1) (Ϫ15 to 240 min) (Ϫ15 to 30 min) (120 to 240 min) (Ϫ15 to 240 min) (Ϫ15 to 240 min) Type 2 diabetic subjects Placebo 34.0 (28.0–41.4) 13.0 (8.5–19.9) 58.1 (41.3–82.0) 158.5 (113.3–221.7) 6.2 (5.3–7.4) Repaglinide 27.6 (22.7–33.5)† 17.8 (11.7–27.2)† 91.2 (64.7–128.5)† 244.4 (174.8–341.9)† 9.1 (7.7–10.8)† Glipizide 27.0 (22.2–32.8)† 19.2 (12.6–29.3)†‡ 88.4 (62.7–124.6)† 233.9 (167.3–327.1)† 8.7 (7.4–10.3)† Glibenclamide 27.8 (22.9–33.9)† 14.0 (9.2–21.4) 112.2 (79.6–158.1)† 254.5 (182.0–355.9)† 8.9 (7.5–10.5)† Nondiabetic subjects Placebo 21.3 (20.1–22.6) 16.8 (12.7–22.3) 31.4 (24.1–41.0) 137.3 (110.6–170.3) 5.9 (5.0–7.0) Repaglinide 15.7 (14.8–16.6)†‡ 27.2 (20.5–36.0)†‡ 52.4 (40.3–68.6)‡ 236.5 (190.6–293.4)† 8.8 (7.4–10.3)† Glipizide 16.6 (15.6–17.6)† 22.5 (17.0–29.8)‡ 62.3 (47.8–81.3) 247.4 (199.4–307.0)† 8.4 (7.1–9.9)† Glibenclamide 17.5 (16.5–18.6)† 17.3 (13.1–22.9) 76.2 (58.4–99.5)† 238.6 (192.2–296.0)† 8.5 (7.3–10.0)† Data are mean (95% CI). *ANOVA significance level at P Ͻ 0.02 across both nondiabetic and type 2 diabetic groups; †significant difference against placebo (P Ͻ 0.02); ‡ significant difference against glibenclamide (P Ͻ 0.02). subjects, the AUC –15 to 240 min for glu- cant difference was noted with In the nondiabetic group, repaglinide cose was smaller, and glucose Cmax was glibenclamide in nondiabetic subjects. increased the early-phase ␤-cell secretion significantly lower with repaglinide com- The difference between glipizide and glib- by ϳ61% compared with placebo (P Ͻ pared with glibenclamide. The mean con- enclamide was also significant in these 0.02) and reached significance against centration-time profiles for glucose and subjects, suggesting that the latter has a glibenclamide. Glipizide increased the se- insulin are shown in Figs. 1 and 2. more protracted action on the ␤-cell than cretion by ϳ34% (not significant versus There was no difference between the glipizide. placebo) but reached significance com- active treatment groups in the total insu- Separate analysis of the insulin secre- pared with glibenclamide. lin (AUC –15 to 240 min) secreted over tion over the first 30 min (AUC –15 to 30 Glibenclamide, but not the other two 4 h after the meal, confirming the equiv- min) and the last 120 min (AUC 120–240 drugs, significantly increased the insulin alence between the doses used in the min) after the meal is shown in Table 2. output in the late phase in nondiabetic study with respect to overall prandial in- There were clear interdrug differ- subjects (142% increase relative to place- sulin secretion. There were nonsignificant ences in the early-phase insulin output bo). These effects were notably higher differences in the Tmax for insulin be- (AUC –15 to 30 min). Therefore, in the compared with repaglinide in this group tween the active treatment and placebo in diabetic subjects, insulin AUC –15 to 30 of subjects. In type 2 diabetic subjects, all both groups. The difference between glib- min was significantly higher with both re- three drugs significantly increased the in- enclamide and repaglinide in the control paglinide (ϩ37%) and glipizide (ϩ47%) sulin secretion in the late phase compared group became significant, suggesting that compared with placebo. In addition, with placebo: glipizide by ϳ52%, repa- glibenclamide has a delayed effect on the glipizide reached significance against glinide by 57%, and glibenclamide by pancreatic secretion. Tmax for C-peptide glibenclamide. Glibenclamide had only a 93%. was increased by all secretagogues com- minor effect on this phase of secretion The rates of insulin secretion (ISR) pared with placebo, but the only signifi- (3% increase versus placebo). were reconstructed from plasma C-

Table 3—Comparison of the Cmax and Tmax in type 2 diabetic and nondiabetic subjects

Glucose Glucose* Insulin Insulin* C-peptide C-peptide* (mmol/l) Cmax (mmol/l) (Tmax) (mU/l) (Cmax) (mU/l) (Tmax) (pmol/l) (Cmax) (pmol/l) (Tmax) Type 2 diabetic subjects Placebo 11.1 (9.3–13.2) 50.0 (30.0–75.0) 73.8 (51.5–105.7) 75.0 (30.0–120) 2.1 (1.8–2.6) 97.5 (75.0–120) Repaglinide 10.0 (8.4–11.9)† 40.0 (30.0–90.0) 108.6 (75.8–155.6)† 82.5 (50.0–120) 3.2 (2.7–3.8)† 120 (75.0–120) Glipizide 9.8 (8.2–11.7)† 50.0 (0.0–90.0) 111.0 (77.4–59.0)† 82.5 (30.0–120) 3.1 (2.5–3.7)† 105 (50.0–180) Glibenclamide 10.3 (8.6–12.3) 50.0 (30.0–75.0) 111.4 (77.8–159.7)† 90.0 (40.0–120) 3.0 (2.5–3.6)† 113 (60.0–240) Nondiabetic subjects Placebo 7.5 (6.9–8.2) 30.0 (30.0–50.0) 92.8 (73.4–117.4) 50.0 (30.0–90.0) 2.6 (2.2–3.0) 55.0 (50.0–120) Repaglinide 6.4 (5.9–7.0)†‡ 30.0 (0.0–40.0) 149.2 (118.0–188.7)† 50.0 (30.0–75.0)‡ 3.9 (3.3–4.6)† 60.0 (50.0–105) Glipizide 6.7 (6.2–7.3)† 30.0 (20.0–40.0) 158.5 (125.3–200.5)† 40.0 (30–120) 3.6 (3.0–4.2)† 60.0 (50.0–120)‡ Glibenclamide 7.2 (6.6–7.8) 40.0 (20.0–50.0) 125.1 (98.9–158.2)† 55.0 (30.0–90.0) 3.3 (2.8–3.9)† 75.0 (50.0–180)† Data are means (95% CI). *Median with minimum-maximum interval (brackets); †significant difference against placebo (P Ͻ 0.02); ‡significant difference against glibenclamide (P Ͻ 0.02).

DIABETES CARE, VOLUME 25, NUMBER 8, AUGUST 2002 1273 Effects of insulinotropic drugs on plasma insulin levels

intravenous glucose tolerance test in both nondiabetic and diabetic subjects (28). In a study using hyperglycemic clamp tech- nique in nondiabetic volunteers, gliben- clamide had no effect on the first phase of insulin secretion (29). Glibenclamide was also less effective than nateglinide in re- ducing the incremental glucose AUC after a liquid meal (30). Our study confirmed that the three test drugs—repaglinide, glipizide, and glibenclamide—were all powerful insulin secretagogues. An increase of Ͼ47% Figure 1—Mean concentration-time profiles of glucose in type 2 diabetic and nondiabetic sub- (47% glipizide, 54% repaglinide, and jects. 61% glibenclamide) in the total insulin (AUC –15 to 240 min) secretion was peptide concentration and demographic clamide and glipizide have a much slower noted in diabetic patients when com- data, using ISEC (Insulin SECretion) soft- absorption with Tmax over 120 min pared with placebo. The diabetic subjects ware developed by Hovorka et al. (version (23,24). Although all secretagogues lead in our study had relatively preserved 3.4a, 1994). This software package allows to inhibition of the KATP channel and de- ␤-cell function, and therefore, a good se- an estimation of the pancreatic insulin se- polarization of the ␤-cell with subsequent cretory response was expected. In a real cretion (before hepatic extraction) by us- insulin exocytosis, the duration and mag- clinical context, however, this group of ing the point-area deconvolution method nitude of this effect are variable among patients represents a minority of the type in a mathematical model. The temporal the antidiabetic agents. Therefore, repa- 2 diabetic population requiring pharma- profiles relative to placebo in both groups glinide has been shown to inhibit the cological intervention. An extrapolation of subjects are presented in Fig. 3. KATP channels more potently than glib- of these results to all diabetic populations Secretion rates in the diabetic group enclamide in animal models (25), with a requiring drug treatment should be un- were significantly higher with repaglinide higher stimulation of the insulin release in dertaken with care. and glipizide compared with placebo at vitro and in vivo (26). We found that repaglinide, as previ- any time point beginning with 10 min af- We have previously shown that repa- ously reported (20), significantly in- ter consuming the meal (repaglinide from glinide increased the insulin secretion creased the insulin secretion in the early 0 min). Glibenclamide, however, became rate within 30 min after a solid meal and phase both in diabetic and nondiabetic significant only 30 min after the meal. improved the early phase of secretion in subjects. Interestingly, glipizide was very Moreover, both repaglinide and glipizide diabetic subjects (20). Similarly, nateglin- similar to repaglinide with respect to the were significantly more potent than glib- ide, another member of the meglitinide effects on the early phase. Moreover, enclamide at the 20- and 30-min time family, improved the early insulin secre- glipizide reached significance against points; glipizide was higher than gliben- tion and reduced the prandial glucose ex- glibenclamide in both groups of subjects, clamide, even at the 40-min point. cursions after a liquid meal (21) and after whereas repaglinide was significantly In the nondiabetic subjects, the secre- an intravenous glucose challenge (27). more effective than glibenclamide only in tion rates with repaglinide became signif- The effects of the sulfonylureas on the the nondiabetic group. icant against placebo after the 0-min time early insulin secretion have been studied Due to its pharmacokinetic proper- point. Glipizide reached significance ver- less. Gliclazide has been shown to in- ties, the effects of repaglinide become ap- sus placebo slightly later than repaglinide crease the early insulin response after an parent within 30 min after intake (22). (after 20 min). Furthermore, both drugs were significantly more potent than glib- enclamide between 30 and 50 min after the meal; repaglinide was still notably higher than glibenclamide at the 60-min time point.

CONCLUSIONS — Insulin secreta- gogues have different effects on the insu- lin secretion, largely conditioned by their individual pharmacokinetic profiles and their actions on the pancreatic ATP- sensitive potassium channels (KATP). For instance, repaglinide is rapidly absorbed from the gut and the time to peak (Tmax) plasma concentration in humans is 30–50 min (22). By contrast, gliben- Figure 2—Mean concentration-time profiles of insulin in type 2 diabetic and nondiabetic subjects.

1274 DIABETES CARE, VOLUME 25, NUMBER 8, AUGUST 2002 Cozma and Associates

AUC (AUC –15 to 240 min) versus pla- cebo was smaller in the diabetic popula- tion compared with their nondiabetic peers. These data suggest a reduction in the insulin action with an effacement of the interdrug differences in the diabetic subjects, most likely due to increased re- sistance to insulin in this population. Our study compared the effects of a single dose of each of the three drugs on the insulin and glucose profiles after a sin- gle meal. This scenario, however, could be different in the clinical practice situa- tion. Therefore, whereas repaglinide has a Figure 3—Mean estimated insulin secretion rates relative to placebo for the first 60 min after the short half-life and the effects of one dose meal. Significant difference against placebo: P Ͻ 0.05 (†), P Ͻ 0.01 (*). Significant difference would have entirely disappeared before against glibenclamide: P Ͻ 0.05 (‡), P Ͻ 0.01 (§). the next meal, the other two drugs have a long duration of action. The effects of glipizide and glibenclamide on subse- Calculated insulin secretion rates in our acute exposure (glucose Cmax) with re- quent meals during a 24-h period cannot study confirmed these observations. Re- spect to harmful consequences. Gliben- be assumed to be identical to the observa- paglinide boosted the secretion signifi- clamide was significantly less effective tions after a single meal. cantly more than placebo, as early as 15 than repaglinide in decreasing the total In summary, our data show that repa- min after drug ingestion (0 min on the glucose AUC in this group of subjects. glinide significantly enhanced the early ISEC profiles). Glipizide, on the other Glipizide also seemed to have greater ef- phase of insulin secretion in both nondi- hand, increased the secretion rates fects than glibenclamide on the total glu- abetic and diabetic subjects. This resulted slightly later (after the 10-min point in cose AUC, although it did not reach in a significant reduction in the postpran- diabetics and after the 20-min point in statistical significance on direct compari- dial glucose peaks compared with pla- nondiabetic control subjects) but well be- son. Interestingly, these differences were cebo. fore glibenclamide had any significant ef- noted despite significantly more insulin We also showed that glipizide, a fect. Our findings were confirmed by a being secreted by glibenclamide in the second-generation sulfonylurea, has sim- recent study done in rats (31). Repaglin- late phase (AUC –120 to 240 min). ilar effects to repaglinide on the early ide and nateglinide stimulated an early in- Insulin resistance and reduced ␤-cell phase of insulin secretion. Therefore, in crease in the insulin secretion with a insulin secretory capacity are important both groups of subjects, insulin levels subsequent decrease of the prandial glu- factors in the pathogenesis of type 2 dia- were significantly higher than with glib- cose excursions after the meal (powdered betes. Glucose toxicity accentuates and enclamide. Postprandial glucose peaks rodent diet), whereas glibenclamide had compounds the secretory defect and also were significantly lower compared with no significant effect. Glipizide, on the other enhances the insulin resistance (32). The placebo. hand, had intermediate effects, with less effects of various insulin secretagogues Glibenclamide had no significant ef- early insulin secretion than repaglinide are expected, therefore, to be less evident fect on the early phase of insulin secretion and nateglinide but still significant de- in the diabetic patients compared with the and consequently failed to significantly creasing the glucose excursions com- normal subjects. Our study showed that change the postprandial glucose peaks. pared with the vehicle (control). both repaglinide and glipizide main- Its action became evident only on the late The differences in the insulin secre- tained their efficacy on decreasing the phase of insulin secretion. However, total tion were partly associated with corre- postprandial glucose peaks (glucose postprandial glucose-lowering effect sponding effects on blood glucose in the Cmax) in type 2 diabetic patients with (AUC –15 to 240 min) was similar to the nondiabetic subjects. Therefore, repaglin- preserved ␤-cell function compared with other two drugs in the diabetic patients. ide was more effective than glibenclamide placebo (mean reduction 1.1 mmol/l with in reducing postmeal glucose peaks (glu- repaglinide and 1.3 mmol/l with glipiz- cose Cmax). Furthermore, whereas both ide). Again, similar to the effects in non- References repaglinide and glipizide significantly diabetic subjects, glibenclamide did not 1. Panzram G: Mortality and survival in type lowered the peaks compared with pla- significantly impact the peak postpran- 2 (non-insulin-dependent) diabetes mel- cebo (mean reduction 1.1 mmol/l with re- dial glucose. All study drugs, on the other litus. Diabetologia 30:123–131, 1987 paglinide and 0.8 mmol/l with glipizide), hand, similarly reduced total glucose 2. Turner RC, Millns H, Neil HA, Stratton glibenclamide had no significant effect. AUC (AUC –15 to 240 min). 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