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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 11 5248-5254
Copyright © 2003 by The Endocrine Society

Targeting Postprandial Hyperglycemia: A Comparative Study of Insulinotropic Agents in Type 2 Diabetes

Mary F. Carroll, Absalon Gutierrez, Marygrace Castro, Dechen Tsewang and David S. Schade

Internal Medicine/Endocrinology, University of New Mexico, Albuquerque, New Mexico 87131

Address all correspondence and requests for reprints to: Mary F. Carroll, M.D., Internal Medicine/Endocrinology, MSC10 5550, 1 University of New Mexico, Albuquerque, New Mexico 87131. E-mail: mcarroll{at}salud.unm.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
This study was designed to compare the efficacy of three insulinotropic agents in the control of postprandial hyperglycemia in type 2 diabetes. Fifteen subjects with noninsulin-requiring type 2 diabetes were admitted to the General Clinical Research Center on four separate occasions. During the control study and following 7–10 d on each study medication, daylong glucose profiles were performed to investigate the effects of the assigned medication on postprandial hyperglycemia. During each admission, placebo or study medications were administered before three isocaloric meals as follows: immediate-release glipizide 30 min before breakfast and 30 min before supper, glipizide gastrointestinal therapeutic system (GITS) 30 min before breakfast, or nateglinide 120 mg 10 min before breakfast, before lunch, and before supper. Blood was drawn for analysis of glucose, insulin, and C-peptide at -0.05, 0, 0.25, 0.5, 1, 2, 3, and 4 h relative to each test meal. Immediate-release glipizide, nateglinide, or glipizide GITS administration resulted in significantly lower integrated daylong (glucose area under the curve) and peak glucose levels, compared with placebo. There were no significant differences in the daylong integrated glucose levels among the three study medications. The peak postbreakfast glucose level (but not glucose area under the curve) was lower with nateglinide, compared with either immediate-release glipizide or glipizide GITS. Postlunch and postdinner integrated glucose levels were significantly lower with immediate-release glipizide or glipizide GITS, compared with nateglinide. C-peptide levels were significantly higher with immediate-release glipizide, compared with glipizide GITS. Insulin levels did not differ among the three study medications. Once-daily glipizide GITS, twice-daily immediate-release glipizide, or three-times-a-day administration of nateglinide results in equivalent control of postmeal hyperglycemia in type 2 diabetes. The decision to prescribe one of these three insulinotropic agents should be based on factors such as the patient’s ability to comply with complex dosing regimens, the need to control fasting hyperglycemia, the risk of interprandial hypoglycemia, and pharmacoeconomic considerations, rather than postprandial glucose-lowering efficacy.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
POSTPRANDIAL HYPERGLYCEMIA IS a prominent and early defect in type 2 diabetes. Studies have shown that postchallenge hyperglycemia is associated with increased cardiovascular mortality in type 2 diabetes (1, 2, 3) and have focused attention on antidiabetic treatments designed to limit postmeal glucose excursions. Postprandial hyperglycemia occurs in 40% of subjects at recommended hemoglobin A1C (HbA1C) targets (<7%) and in 10% of diabetic subjects who have normal fasting blood glucose levels (4). Postmeal glucose spikes are estimated to account for 54% of glucose increments in diabetic subjects (5) and are highly correlated with HbA1C (6). The postprandial state has a duration of 2–8 h after each meal, depending on the nutrient content and the parameter measured (7, 8). The reported influence of postmeal hyperglycemia on overall glycemic control fits with the observation that a large part of the day is spent in the postprandial state. Postprandial hyperglycemia is predominantly due to loss of insulin secretion in the first 30 min after eating (9). This ß-cell defect results in inadequate suppression of hepatic glucose production and subsequent late hyperinsulinemia (10). The ideal agent to treat postprandial hyperglycemia should restore early-phase insulin secretion without delayed hyperinsulinemia or hypoglycemia. The current study compares the prandial glucose-lowering efficacy of three insulinotropic agents.

Glipizide is a potent, easily absorbed, rapid-acting, second-generation sulfonylurea with the shortest effect duration in its class (11). Immediate-release glipizide, which is available in a generic form, achieves peak blood concentrations within 1–3 h after administration and has a half-life of 3 h. When administered 30 min before a meal, glipizide is effective in reducing postprandial glucose levels (12). The maximum recommended total daily dose of immediate-release glipizide is 40 mg, with doses above 15 mg divided twice daily. Extended-release glipizide delivers active drug by a membrane-controlled osmotic process (gastrointestinal therapeutic system). Once-daily administration of glipizide gastrointestinal therapeutic system (GITS) results in sustained plasma drug concentrations without a pronounced peak (13). The maximally effective dose of glipizide GITS is 20 mg daily; thus, it may be more effective on a dose for dose basis than immediate-release glipizide (14). Glipizide GITS has been shown to ameliorate postmeal hyperglycemia (15) and be more effective than immediate-release glipizide in reducing fasting plasma glucose levels (16).

Nateglinide is a rapidly acting and rapidly reversible phenylalanine derivative, which specifically targets postprandial hyperglycemia (17). Nateglinide raises insulin levels by binding to the sulfonylurea receptor on the pancreatic ß-cell but does not possess a sulfonylurea moiety (18). Nateglinide reaches peak plasma levels 1 h after administration and has an elimination half-life of 1.5 h (19). The optimal dose of nateglinide is 120 mg three times daily 10 min preprandially (19). A fourth dose with a bedtime snack maintains the insulinotropic and glucose-lowering effects of nateglinide overnight (17).

It is important to improve postprandial glucose control, in addition to optimizing fasting glycemic levels, in type 2 diabetes. The aim of this study was to compare the efficacy of immediate-release glipizide vs. glipizide GITS vs. nateglinide in the control of postmeal glucose excursions in subjects with type 2 diabetes who were previously well controlled on a single oral hypoglycemic agent.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The study enrolled 15 subjects with non-insulin-requiring type 2 diabetes of at least 6 months duration. Volunteers attended a screening visit at which a history and physical, electrocardiogram, and screening laboratory tests were performed. Eligible patients were taking a single oral hypoglycemic agent, had reasonable glycemic control (HbA1C < 8%), and a body mass index of less than 40 kg/m2. Subjects were excluded if they had significantly abnormal vital signs; electrocardiogram tracings; or hematological, electrolyte, or liver laboratory results at screening. Other important exclusion criteria were pregnancy, chronic insulin treatment, medications that affect liver metabolism, active substance abuse, use of oral corticosteroids, known sensitivity to nateglinide or glipizide, or a history of gastroparesis. All patients gave written informed consent before participating in the study. The study protocol received approval from the University of New Mexico Institutional Review Board.

Study protocol

The study used a randomized, placebo-controlled, crossover design. Participants were admitted to the General Clinical Research Center (GCRC) for daylong glucose profiles on four separate occasions as depicted in Fig. 1Go. Upon admission, subjects were fed a standardized snack at 2200 h and then fasted until morning. To control for the effects of varying fasting glucose levels on postprandial glucose excursions (20), euglycemia was maintained overnight using an infusion of regular insulin (21). The insulin infusion was titrated based on hourly blood glucose measurements and discontinued at 0700 h. On the second day of each admission, subjects were fed three standardized test meals: breakfast at 0800 h, lunch at 1300 h, and supper at 1800 h. Test meals had an energy content of 7 kcal/kg and a nutrient content of 50% carbohydrate, 30% fat, and 20% protein. Meals were prepared in the GCRC metabolic kitchen and were identical during each admission. All test meals were consumed over 15 min. Arterialized venous blood was drawn for glucose, insulin, and C-peptide analysis at -0.5, 0, +0.25, 0.5, 1, 2, 3, and 4 h relative to the test meals.



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  		FIG. 1. Study protocol

 
Existing antidiabetic therapy was discontinued for 48 h before admission for the baseline daylong glucose profile and was withheld for the duration of the studies. During the initial control study (admission 1), placebo pills were administered 10 and 30 min before the test meals. After the control study, subjects were randomly assigned to receive immediate-release glipizide twice daily (30 min before breakfast and 30 min before supper), glipizide GITS once daily (30 min before breakfast), or nateglinide 120 mg four times daily (10 min before breakfast, lunch, supper, and bedtime snack) for 7–10 d. The bedtime dose of nateglinide was included to limit fasting hyperglycemia (17). Subjects were instructed to perform home capillary glucose checks four times daily and record hypoglycemic episodes. Initial doses of glipizide were based on the doses of patients’ maintenance oral hypoglycemic agents. The dose was increased after 3 d if the fasting capillary glucose level remained above 6 mmol/liter, and there were no episodes of hypoglycemia. Because of varying timing of administration and number of pills and to facilitate rapid and safe dose titration, neither participants nor investigators were blinded to outpatient study medication assignments. Following 7–10 d on each study medication, subjects were readmitted for daylong glucose profiles to investigate the effects of the assigned medication on postprandial hyperglycemia (admissions 2, 3, and 4). During each admission, the study medications were administered before the test meals in a placebo-controlled, double-blind fashion; immediate-release glipizide 30 min before breakfast and 30 min before supper, glipizide GITS 30 min before breakfast, or nateglinide 120 mg 10 min before breakfast, lunch, and supper.

Study measurements

All assays were performed in the GCRC laboratory. Plasma was separated from blood elements by centrifugation immediately after sampling and frozen at -70 C for later determination. If blood glucose values were less than 4.4 mmol/liter (80 mg/dl) as measured with a bedside glucometer, plasma glucose levels were determined immediately. Plasma glucose was measured using the glucose oxidase method (Analox Instruments USA, Lunenburg, MA), serum free insulin using radioimmunoassy, and C-peptide using chemiluminescence with an Immulite instrument (DPC Cirrus Inc., Randolph, NJ).

Statistical methods

Area under the curve (AUC) for glucose, insulin, and C-peptide was calculated using the linear trapezoidal rule. The primary efficacy variables assessed were overall postprandial hyperglycemia, as determined by the glucose AUC, and peak postprandial glucose. Secondary variables included plasma insulin and C-peptide levels. Data were analyzed using SAS (SAS Institute Inc., Cary, NC). Parameters were compared among the various groups using ANOVA for repeated measures with post hoc t test for paired data. All data are reported as mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Subject characteristics

Seven men and eight women (six Caucasian, six Hispanic, three Native American) were studied. Mean (±SD) age, body mass index, and duration of diabetes were 54 ± 15 yr, 32 ± 6 kg/m2, and 10 ± 11 yr, respectively. The subjects had a mean (±SD) HbA1c of 6.9 ± 0.7%. Preexisting antidiabetic medications were distributed as follows: six sulfonylureas, eight metformin, and one thiazolidinedione. No changes were made to the participants’ medications during the study period, apart from changing to the assigned antidiabetic study medication. The mean (±SD) doses of glipizide used during the daylong glucose profiles were 9 ± 4 mg of immediate-release glipizide twice daily and 10 ± 6 mg of glipizide GITS daily. The nateglinide dose was not titrated because only one dose is recommended by the manufacturer.

Plasma glucose levels

The fasting plasma glucose levels were similar between the study medications. For all study conditions, postprandial hyperglycemia (glucose AUC5 h) was most marked following breakfast and least prominent in the postlunch period (Fig. 2Go). Immediate-release glipizide, nateglinide, or glipizide GITS administration resulted in significantly lower integrated daylong glucose levels (glucose AUC11 h) and significantly lower peak glucose levels, compared with placebo (P < 0.05) (Table 1Go). There were no significant differences in the daylong peak or integrated glucose levels among the three active study medications. Postprandial glucose levels of 11 mmol/liter (200 mg/dl) or more were detected in 73% of study participants during the control studies, 40% with immediate-release glipizide, 27% with nateglinide, and 40% following glipizide GITS. Postlunch and postdinner glucose levels (glucose AUC5 h) were significantly lower with immediate-release glipizide (P < 0.05) and showed a trend toward lower values with glipizide GITS (P = 0.09 for lunch, P = 0.05 for dinner), compared with nateglinide (Table 1Go and Fig. 2Go). Nateglinide administration significantly blunted the postbreakfast glucose peak, compared with either immediate-release glipizide (P = 0.02) or glipizide GITS (P = 0.02). However, the integrated overall glucose levels were not different among the three agents during the postbreakfast period. The glucose profiles were not affected by the sequences in which the study arms were performed or the class of antidiabetic agent (sulfonylurea vs. nonsulfonlyurea) the subjects were taking before participating in this study.



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  		FIG. 2. Plasma glucose levels during daylong profiles with placebo (open circle), immediate-release glipizide (closed circle), glipizide GITS (open triangle), and nateglinide (closed triangle).

 

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  		TABLE 1. Plasma glucose, insulin, and C-peptide parameters

 
Insulin and C-peptide levels

The daylong integrated insulin levels (AUC11 h) were significantly higher for all three insulinotropic drugs, compared with placebo, but did not differ according to which drug was used (Fig. 3Go). Peak postmeal insulin levels were higher for nateglinide (P < 0.05). Glipizide GITS resulted in significantly lower overall (insulin AUC5 h) and early insulin levels (insulin AUC30 min) after breakfast, compared with the other two drugs (P < 0.05) (Table 1Go). Nateglinide resulted in higher overall, peak, and early insulin levels post lunch compared with either glipizide formulation (P < 0.05). C-peptide peak and AUC11 h levels for the entire day and during each of the postmeal periods were significantly higher with immediate-release glipizide, compared with glipizide GITS (P < 0.05) (Fig. 4Go). There were no differences between the insulin or C-peptide levels between immediate-release glipizide and nateglinide.



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  		FIG. 3. Plasma insulin levels during daylong profiles with placebo (open circle), immediate-release glipizide (closed circle), glipizide GITS (open triangle), and nateglinide (closed triangle).

 


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  		FIG. 4. Plasma C-peptide levels during daylong profiles with placebo (open circle), immediate-release glipizide (closed circle), glipizide GITS (open triangle), and nateglinide (closed triangle).

 
Adverse events

During the outpatient phases of the study, no episodes of severe hypoglycemia (requiring third-party assistance) were recorded. During the daylong glucose profiles, postprandial hypoglycemia was defined as a plasma glucose less than 3.3 mmol/liter or symptoms suggestive of hypoglycemia with a plasma glucose less than 3.9 mmol/liter. There were no episodes of hypoglycemia in the placebo or nateglinide arms. One participant experienced hypoglycemia 30 min before lunch following administration of immediate-release glipizide (10 mg). Another subject experienced hypoglycemia 30 min before lunch and 15 min after lunch following administration glipizide GITS (15 mg). None of these hypoglycemic episodes required treatment with oral glucose. There were no episodes of severe hypoglycemia (plasma glucose < 2.2 mmol/liter) during the inpatient studies.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study demonstrates that the three insulinotropic agents, immediate-release glipizide, extended-release glipizide, and nateglinide, have equivalent efficacy in the control of postprandial hyperglycemia when administered at the optimal time and dose before standardized meals. Similar glycemic control was observed despite the obvious differences in frequency of administration of these antidiabetic agents. Insulin levels were similar for the three drugs. Peak and integrated overall C-peptide levels were higher with immediate-release glipizide, compared with glipizide GITS. All three insulin secretagogues were well tolerated without serious hypoglycemia in the inpatient or outpatient setting.

The results of the current study contrast with previous studies that compared the efficacy of sulfonylureas with the newer nonsulfonylurea insulin secretagogues as prandial glucose regulators. Hollander et al. (22) reported that nateglinide provided better mealtime glucose control with less overall glucose exposure than glyburide. Landgraf et al. (23) reported that patients treated with repaglinide had lower 2-h postprandial glucose than patients treated with glibenclamide. The study populations in these previous reports were similar to ours and comprised healthy type 2 diabetes patients who were considered still responsive to oral hypoglycemic agents. However, we chose to compare nateglinide with glipizide, which is the second-generation sulfonylurea with the most rapid onset and shortest duration of action (11). Studies suggest that glipizide may be more effective in controlling postprandial hyperglycemia and that the incidence of hypoglycemia may be less with glipizide, compared with glyburide (24, 25). Moreover, we previously demonstrated that acute premeal administration of immediate-release glipizide has equal efficacy to nateglinide in controlling postbreakfast hyperglycemia (12). The present study expands this finding by prolonging the sampling period over the course of three standardized meals and including the extended-release formulation of glipizide. Studies have shown that glipizide GITS is as effective as immediate-release glipizide in lowering HbA1C levels but is more effective at reducing fasting glucose levels (16). The glipizide GITS tablet employs a membrane-controlled, osmotically powered process to release glipizide into the gastrointestinal lumen at a steady rate (13). Once-daily administration of glipizide GITS results in constant plasma glipizide concentration and smaller peaks and troughs than once- or twice-daily administration of immediate-release glipizide (13). We found that the two glipizide formulations provide similar postprandial glycemic control despite previously described markedly different plasma concentration time profiles. Overall insulin exposure was also similar between immediate- vs. extended-release glipizide, although we did observe slightly higher C-peptide levels with the immediate-release drug.

Consistent with a similar degree of overall insulin exposure, we found a low incidence of hypoglycemia resulting from administration of the three insulinotropic agents compared in the present study. One episode of hypoglycemia occurred during treatment with each formulation of glipizide, although none of these episodes required treatment with oral glucose. Nateglinide did not cause hypoglycemia during the study, but this may be due to waning glucose-lowering effectiveness at lunch and supper. As has been previously reported (22), nateglinide showed maximal antihyperglycemic effects in the early part of the day, whereas glipizide and glipizide GITS were most effective at lunch and supper. Nateglinide selectively enhanced early-phase insulin production (AUC30 min), compared with glipizide at lunch only. Of the insulin secretagogues studied, glipizide GITS appeared to have the lowest peak and integrated overall insulin levels (AUC11 h). The incidence of hypoglycemia was too low to allow statistical comparison among the three drugs in the present study. However, previous studies have demonstrated that nateglinide, immediate-release glipizide, and glipizide GITS have a low incidence of hypoglycemia and are well tolerated in patients with type 2 diabetes (11, 14, 16, 23).

The fasting plasma glucose is an important determinant of postmeal glucose excursions in type 2 diabetes patients (20, 26). Differential effects on fasting glycemic control could obscure accurate investigation of the prandial glucose-lowering efficacy of oral hypoglycemia agents. In the current study, we eliminated the confounding effect of varying fasting glucose levels by using an overnight insulin infusion to achieve normoglycemia before administration of the test meals to the study subjects (21). Use of an overnight insulin infusion may be analogous to the use of bedtime sc insulin to normalize fasting blood glucose levels at home. Although artificial, an iv insulin infusion was necessary to ensure reliable absorption and allow rapid titration in the current research setting. Furthermore, to reduce possible detrimental effects of chronic glucotoxicity or inadequate endogenous insulin secretory capacity on early-phase insulin secretion, eligible subjects had reasonable glycemic control (HbA1C = 6.9 ± 0.7%) on a single oral hypoglycemic medication at the time of enrollment into the study. A fourth daily dose of nateglinide was administered with a bedtime snack during the assigned outpatient period of this study protocol to prevent early-morning hyperglycemia during the week before the associated inpatient glucose profile (17). Thus, we sought to minimize factors that might interfere with the accurate assessment of the postprandial glycemic control provided by the insulinotropic agents under comparison.

The exaggerated postbreakfast glycemic response previously described in type 2 diabetes (5) was clearly demonstrated in the current study. This was most marked when placebo only was administered before the test meals (admission 1) but was also observed in the setting of insulin secretagogue administration. This circadian pattern of glucose response to meals was seen to occur despite identical calorific content and nutrient composition of the test meals and carefully supervised study conditions. Plasma insulin and C-peptide levels were not significantly lower at breakfast, compared with other mealtimes, and do not provide a mechanism for this diurnal mealtime glucose excursions. The glycemic pattern observed is most likely due to impaired hepatic insulin sensitivity resulting in inadequate suppression of hepatic glucose output in the morning hours (27). A similar mechanism is thought to cause fasting hyperglycemia due to the dawn phenomenon (28). It has been demonstrated that hepatic glucose production peaks after an overnight fast and declines progressively to reach a nadir in the afternoon in type 2 diabetes patients (27). The current study demonstrates that a variety of insulinotropic agents are not completely effective in overcoming the hepatic insulin resistance that magnifies postbreakfast, compared with postlunch and postsupper glycemic excursions.

There are obvious differences in the complexity of dosing regimen among the three insulinotropic agents employed in the current study. The frequency of antidiabetic drug dosing has been shown to be an important determinant of adherence and persistence with therapy in type 2 diabetes. In a population-based study, Donnan et al. (29) showed that only one in three patients with type 2 diabetes had adequate adherence to oral hypoglycemic drugs. There is a linear trend of poorer compliance with each increase in the daily number of tablets taken in the type 2 diabetes population (29). In particular, for glipizide, once-daily pharmacotherapy with glipizide GITS is associated with higher adherence and persistence than twice-daily dosing of immediate-release glipizide, despite a greater daily pill burden (30). Therefore, simpler once-a-day regimens may be more successful in the majority of patients with type 2 diabetes. However, for patients with variable eating and lifestyle habits, once-daily sulfonylurea administration may introduce restriction because of a small increased risk of hypoglycemia with missed meals or increased activity (25). The risk of hypoglycemia may be of particular concern in patients with modest fasting hyperglycemia or isolated postprandial hyperglycemia. Prandial dosing of a short-acting agent such as nateglinide may be more flexible for selected patients (31).

In conclusion, this study demonstrated that once-daily glipizide GITS, twice-daily immediate-release glipizide, or three times-a-day administration of nateglinide results in equivalent control of postmeal hyperglycemia in a group of patients with well-controlled type 2 diabetes. The decision to prescribe one of these three insulinotropic agents should be based on factors such as the patient’s ability to comply with complex dosing regimens, the need to control fasting hyperglycemia, the risk of interprandial hypoglycemia, and pharmacoeconomic considerations, rather than postprandial glucose-lowering efficacy.


   Acknowledgments
 
We acknowledge the editorial assistance of Ms. Carolyn King in the preparation of this manuscript for publication.


   Footnotes
 
This work was supported by the University of New Mexico General Clinical Research Center (National Institutes of Health NCCR GCRC Grant 5 Mo1-RR00997).

Abbreviations: AUC, Area under the curve; GCRC, General Clinical Research Center; GITS, gastrointestinal therapeutic system; HbA1C, hemoglobin A1C.

Received April 15, 2003.

Accepted July 28, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Hanefeld M, Fischer S, Julius U, Schulze J, Schwanebeck U, Schmechel H, Ziegelasch HJ, Lindner J, the DIS group 1996 Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Intervention Study, 11-year follow-up. Diabetologia 39:1577–1583[CrossRef][Medline]
  2. DECODE Study Group, European Diabetes Epidemiology Group 1999 Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. Lancet 354:617–621[CrossRef][Medline]
  3. Tominaga M, Eguchi H, Manaka H, Igarashi K, Kato T, Sekikawa A 1999 Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose: the Fungata Diabetes study. Diabetes Care 22:920–924[Abstract]
  4. Erlinger TP, Brancati FL 2001 Postchallenge hyperglycemia in a national sample of U.S. adults with type 2 diabetes. Diabetes Care 24:1734–1738[Abstract/Free Full Text]
  5. Monnier L, Colette C, Rabasa-Lhoret R, Lapinski H, Caubel C, Avignon A, Boniface H 2002 Morning hyperglycemic excursions: a constant failure in the metabolic control of non-insulin-using patients with type 2 diabetes. Diabetes Care 25:737–741[Abstract/Free Full Text]
  6. Avignon A, Radauceanu A, Monnier L 1997 Non-fasting plasma glucose is a better marker of diabetic control then fasting plasma glucose in type 2 diabetes. Diabetes Care 20:1822–1826[Abstract]
  7. Dinneen S, Gerich JE, Rizza R 1992 Carbohydrate metabolism in non-insulin-dependent diabetes mellitus. N Engl J Med 327:707–713[Medline]
  8. Reaven GM, Hollenbeck C, Jeng CY, Wu MS, Chen YD 1988 Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with NIDDM. Diabetes 37:1020–1024[Abstract]
  9. Ward WK, Beard JC, Halter JB, Pfeiffer MA, Porte D 1984 Pathophysiology of insulin secretion in non-insulin-dependent diabetes mellitus. Diabetes Care 7:491–502[Abstract]
  10. Bruttomesso D, Pianta A, Mari A, Valerio A, Marescotti M, Avogaro A, Tiengo A, Del Prato S 1999 Restoration of early rise in plasma insulin levels improves the glucose tolerance of type 2 diabetic patients. Diabetes 48:99–105[Abstract]
  11. Wahlin-Boll E, Almer L-O, Melander A 1982 Bioavailability, pharmacokinetics and effects of glipizide in type 2 diabetics. Clin Pharmacokin 7:363–372[Medline]
  12. Carroll MF, Izard A, Riboni K, Burge M, Schade DS 2002 Control of postprandial hyperglycemia: optimal use of short-acting insulin secretagogues. Diabetes Care 25:2147–2152[Abstract/Free Full Text]
  13. Chung M, Kourides I, Canovatchel W, Sutfin T, Messig M, Chaiken RL 2002 Pharmacokinetics and pharmacodynamics of extended-release glipizide GITS compared with immediate release glipizide in patients with type II diabetes mellitus. J Clin Pharmacol 42:651–657[Abstract]
  14. Simonson DC, Kourides IA, Feinglos M, Shamoon H, Fischette CT 1997 Efficacy, safety, and dose-response characteristics of glipizide gastrointestinal therapeutic system on glycemic control and insulin secretion in NIDDM. Diabetes Care 20:597–606[Abstract]
  15. Mooradian AD, Albert SG, Bernbaum M, Plummer S 1996 The effect of glipizide gastrointestinal therapeutic system on islet cell hormonal responses to a test meal in NIDDM. Diabetes Care 19:883–884[Abstract]
  16. Berelowitz M, Fischette C, Cefalu W, Schade DS, Sutfin R, Kourides IA 1994 Comparative efficacy of once-daily controlled-release formulation of glipizide and immediate release glipizide in patients with NIDDM. Diabetes Care 17:1460–1464[Abstract]
  17. Walter YH, Spratt DI, Garreffa S, McLeod JF 2000 Mealtime glucose regulation by nateglinide in type 2 diabetes mellitus. Eur J Clin Pharmacol 56:129–133[Medline]
  18. Hu S, Wang S, Fanelli B, Bell PA, Dunning B, Geisse S, Schmitz R, Boettcher BR 2000 Pancreatic ß-cell KATP channel activity and membrane binding studies with nateglinide: a comparison with sulfonylureas and repaglinide. J Pharmacol Exp Ther 293:444–452[Abstract/Free Full Text]
  19. Luzio SD, Anderson DM, Owens DR 2001 Effects of administration and meal composition on the pharmacokinetic and pharmacodynamic characteristics of the short-acting oral hypoglycemic agent nateglinide in healthy subjects. J Clin Endocrinol Metab 86:4874–4880[Abstract/Free Full Text]
  20. Carroll MF, Izard A, Riboni K, Burge M, Schade DS 2002 Fasting hyperglycemia predicts the magnitude of postprandial hyperglycemia: implications for diabetes therapy. Diabetes Care 25:1247–1248[Free Full Text]
  21. Mokan M, Gerich JE 1992 A simple insulin infusion algorithm for establishing and maintaining overnight near-normoglycemia in type 1 and type 2 diabetes. J Clin Endocrinol Metab 74:943–945[Abstract]
  22. Hollander PA, Schwartz SL, Gatlin MR, Haas SJ, Zheng H, Foley JE, Dunning BE 2001 Importance of early insulin secretion: comparison of nateglinide and glyburide in previously diet-treated patients with type 2 diabetes. Diabetes Care 24:983–988[Abstract/Free Full Text]
  23. Landgraf R, Bilo JG, Muller PG 1999 A comparison of regaglinide and glibenclamide in the treatment of type 2 diabetic patients previously treated with sulphonylureas. Eur J Clin Pharmacol 55:165–171[CrossRef][Medline]
  24. Kitabchi AE, Kaminska E, Fisher JN, Sherman A, Pitts K, Bush A, Bryer-Ash M 2000 Comparative efficacy and potency of long-term therapy with glipizide or glyburide in patients with type 2 diabetes mellitus. Am J Med Sci 319:143–148[CrossRef][Medline]
  25. Burge MR, Schmidt-Fiorentino K, Fischette C 1998 A prospective trial of risk factors for sulfonylurea-induced hypoglycemia in type 2 diabetes mellitus. JAMA 279:137–143[Abstract/Free Full Text]
  26. Abbasi F, Reaven GM 2002 Relationship between fasting and daylong glucose concentrations in diet-treated patients with type 2 diabetes. Metabolism 51:457–459[Medline]
  27. Boden G, Chen X, Urbain JL 1996 Evidence for a circadian rhythm of insulin sensitivity in patients with NIDDM caused by cyclic changes in hepatic glucose production. Diabetes 45:1044–1050[Abstract]
  28. Bolli GB, Gerich JE 1984 The "dawn phenomenon"—a common occurrence in both non-insulin-dependent and insulin-dependent diabetes mellitus. N Engl J Med 310:746–750[Abstract]
  29. Donnan PT, MacDonald TM, Morris AD for the DARTS/MEMO Collaboration 2002 Adherence to prescribed oral hypoglycemic medication in a population of patients with type 2 diabetes: a retrospective cohort study. Diabet Med 19:279–284[CrossRef][Medline]
  30. Dezii CM, Kawabata H, Tran M 2002 Effects of once-daily and twice-daily dosing on adherence with prescribed glipizide oral therapy for type 2 diabetes. Southern Med J 95:68–71[Medline]
  31. Saloranta C, Hershon K, Ball M, Dickinson S, Holmes D 2002 Efficacy and safety of nateglinide in type 2 diabetic patients with modest fasting hyperglycemia. J Clin Endocrinol Metab 87:4171–4176[Abstract/Free Full Text]



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