A Prospective Trial of Risk Factors for Sulfonylurea-Induced Hypoglycemia in Type 2 Diabetes Mellitus

Transcription

1 Clinical Investigation Prospective Trial of Risk Factors for Sulfonylurea-Induced Hypoglycemia in Type 2 Diabetes Mellitus Mark R. urge, MD; Kristen Schmitz-Fiorentino, MD; Christine Fischette, PhD; Clifford R. Qualls, PhD; David S. Schade, MD Context. Retrospective studies have identified oral sulfonylureas, age, and fasting as major risk factors for hypoglycemia in patients with type 2 diabetes. Sulfonylureas may be withheld from elderly patients out of concern for hypoglycemia. Objective. To evaluate the hypoglycemic effects of maximum doses of oncedaily second-generation sulfonylureas administered to fasting elderly patients. Design. prospective, randomized, double-blind clinical trial. Setting. The University of New Mexico General Clinical Research Center. Patients. Fifty-two sulfonylurea-treated subjects with type 2 diabetes with a mean (SD) age of 65.1 (5.7) years. Interventions. Subjects were randomly assigned to glyburide or glipizide gastrointestinal therapeutic system (GITS). Each subject participated in three 23-hour fasting studies after the sequential administration of 1 week of placebo and 1 week of 1 mg and 1 week of 2 mg of the assigned sulfonylurea. Main Outcome Measures. Occurrence of hypoglycemia (defined as plasma glucose level 3.33 mmol/l [6 mg/dl]) and hormonal parameters during the final 9 hours of the 23-hour fast in patients who had taken sulfonylureas vs placebo. Results. No hypoglycemia was observed during 156 fasting studies. Plasma glucose level was decreased (nadir, 4.9 mmol/l [88 mg/dl] for a 2-mg dose of glyburide vs 8.3 mmol/l [15 mg/dl] for placebo; nadir, 5.8 mmol/l [15 mg/dl] for a 2-mg dose of glipizide GITS vs 8.7 mmol/l [157 mg/dl] for placebo), and serum insulin was increased in the sulfonylurea studies compared with placebo (P.1). Plasma glucose parameters did not differ between the 2 sulfonylureas, but C peptide concentrations were increased in the glyburide group compared with glipizide GITS in the 2-mg study (P=.5). Concentrations of epinephrine were increased in the sulfonylurea studies compared with placebo (P.1). Epinephrine secretion increased when glucose concentration fell below the mean (SD) level of 9.1 (2.66) mmol/l (164 [48] mg/dl) in the 1-mg study and 8.77 (2.83) mmol/l (158 [51] mg/ dl) in the 2-mg study. Conclusions. Fasting was well tolerated among these elderly patients with type 2 diabetes treated with sulfonylureas. Older age should not be considered a contraindication to sulfonylurea treatment for diabetes. Stimulation of epinephrine secretion at normal or elevated plasma glucose levels appears to be the primary mechanism of protection against hypoglycemia in this study. JM. 1998;279: From the Department of Medicine/Endocrinology, University of New Mexico School of Medicine, lbuquerque (Drs urge, Schmitz-Fiorentino, and Schade); Pfizer Inc, New York, NY (Dr Fischette); and the University of New Mexico General Clinical Research Center, Computerized Database Management and nalysis Systems, lbuquerque (Dr Qualls). Drs urge and Schade received a grant from Pfizer Inc for this study and have received honoraria from Pfizer in the past. Reprints: Mark R. urge, MD, University of New Mexico School of Medicine, Department of Medicine/ Endocrinology, 5CC, lbuquerque, NM ( mburge@salud.unm.edu). DESPITE the availability of new agents for the treatment of type 2 diabetes mellitus, oral sulfonylureas remain a cornerstone of therapy. Sulfonylureas are appealing in the treatment of type 2 diabetes because they are relatively inexpensive and are well tolerated. Hypoglycemia, however, is a major safety concern with the sulfonylureas. 1 Jennings et al 2 demonstrated that up to 2% of patients taking oral sulfonylurea agents experience symptoms consistent with hypoglycemia over a 6-month period, but hypoglycemia was not corroborated by plasma glucose determination in this study. Moreover, in a comprehensive review of 1418 cases of severe drug-inducedhypoglycemia,seltzer 3 retrospectively identified sulfonylurea ingestion, advanced age, and fasting as the major risk factors for the development of hypoglycemia requiring hospitalization. Specifically, sulfonylurea ingestion was a factor in 65% of adult cases, 86% of cases were older than 5 years, and the omission of 1 or more meals was implicated in 8% of cases. This report is flawed, however, by the lack of a control group, by its inclusion of intentional overdoses, and by its retrospective design. Thus, despite concern over the risk of hypoglycemia associated with sulfonylureas, the role of perceived risk factors in the pathogenesis of hypoglycemia has not been rigorously examined. In fact, avoidance of sulfonylureas out of fear of inducing hypoglycemia may unnecessarily deprive elderly patients with type 2 diabetes of an affordable and effective treatment option. 4 The recently published interim results of the United Kingdom Prospective Diabetes Study reported severe hypoglycemia occurring at a rate of.7% per year among 922 patients newly di- JM, January 14, 1998 Vol 279, No. 2 Sulfonylurea-Induced Hypoglycemia in Type 2 Diabetes urge et al 137 Downloaded From: on 1/2/219

2 Received : 29 Followed Up at 1 and 2 wk: 27 Withdraw for Personal Reasons: 2 Eligible Subjects: 58 Not Randomized: Randomized: 58 Received : 29 Followed Up at 1 and 2 wk: 25 Withdraw for Personal Reasons: 4 Completed Trial: 27 Completed Trial: 25 Figure 1. Randomization of eligible patients. GITS indicates gastrointestinal therapeutic system. agnosed as having type 2 diabetes assigned to treatment with sulfonylureas. 5 The cumulative incidence of severe hypoglycemia occurring in this group over the 6 years of the study is reported to be 3.3%, suggesting that approximately 3 episodes of hypoglycemia requiring medical assistance were documented. Unfortunately, hypoglycemia was not corroborated by blood glucose determination in this study, and details of the episodes are not provided. dditionally, this study did not specifically focus on elderly patients with type 2 diabetes and did not exclude patients who were abusing alcohol or using other drugs that have been associated with hypoglycemia. Interestingly, an incidence of severe hypoglycemia of.3% per year was reported among patients who were treated with diet alone. This raises questions about the cause of these episodes and reinforces the importance of carefully documenting plasma glucose concentrations during apparent hypoglycemia in type 2 diabetes. ased on the observation that most elderly patients with type 2 diabetes have intact glucose counterregulatory mechanisms, 6 we hypothesized that the development of hypoglycemia would be acceptably low in elderly patients with type 2 diabetes taking maximal doses of once-daily second-generation oral sulfonylurea agents during a short-term fast. This study reports the glucose and hormonal responses of 52 elderly subjects with type 2 diabetes receiving submaximal and maximal doses of once-daily second-generation sulfonylureas during a 23-hour fast compared with placebo. The results suggest that healthy elderly subjects with type 2 diabetes who take sulfonylureas do not develop hypoglycemia Table 1. Demographic and Descriptive Characteristics of the 52 Subjects With Type 2 Diabetes Studied* Characteristics (n=27) Glipizide GITS (n=25) Sex 16 M, 11 F 19 M, 6 F ge, y 65.5 (5.5) 64.7 (6.) Duration of diabetes, y 6.5 (6.2) 7.3 (7.6) Glycosylated hemoglobin.82 (.18).85 (.17) (reference range,.4-.68) ody mass index, kg/m (4.4) 28.7 (3.4) Ethnicity, No. Non-Hispanic white Hispanic 7 11 Other 1 1 *Data are mean (SD) unless indicated otherwise. GITS indicates gastrointestinal therapeutic system. P.5 for all comparisons. during a short-term fast and, further, that such patients may be protected against the development of hypoglycemia by the incremental secretion of epinephrine. METHODS Study Subjects Fifty-eight subjects with type 2 diabetes were enrolled in a sequential, randomized, double-blind, placebo-controlled, 3-week study of 2 different oncedaily sulfonylureas (glyburide and glipizide gastrointestinal therapeutic system [GITS]) (Figure 1). employs the principle of an osmotic pump to effect a steady release of glipizide from the tablet over 24 hours. Inclusion criteria consisted of type 2 diabetes treated with oral sulfonylureas alone for at least 2 months, an age between 55 and 75 years, a glycosylated hemoglobin level between.68 and.12 (normal range,.4-.68), and a body mass index (weight in kilograms divided by the square of height in meters) of less than 35 kg/m 2. Patients were excluded from the study by the presence of severe cardiovascular, gastrointestinal, renal, or hepatic disease, concurrent medications that interfere with glucose homeostasis, malignancy, or substance abuse. Patients were recruited through a combination of database searches and local advertising, and all subjects received compensation for time and expenses for participating in the study. Descriptive characteristics for the participants are summarized in Table 1. ll tabular results are expressed as mean (SD), and in the figures, mean and SE are depicted. Of the 58 subjects who enrolled in the study, 6 subjects dropped out for personal reasons, and 52 completed the protocol. None of the dropouts completed more than the placebo study or experienced hypoglycemia, and these data are not included in the analysis. ll participants gave informed consent for the protocol as approved by the University of New Mexico s Institutional Review oard. Study Protocol On enrollment, all treatment with diabetes medications was discontinued, and subjects were randomized to receive either glyburide or glipizide GITS during the study. Subjects received 2 sets of study medication each week that were identical in appearance. One set of study medication consisted of placebo and the other contained active drug, except duringthefirstweekofthestudy,whenboth sets of study medication contained placebo. Patients were instructed to take both medications daily in the morning before breakfast. ll subjects were provided with a capillary blood glucose monitor and were instructed to monitor their glucose twice daily and whenever hypoglycemic symptoms occurred. ll subjects received placebo for 7 to 9 days, followed by 1 mg of glyburide or glipizide GITS for 7 to 9 days, followed by 2 mg of glyburide or glipizide GITS (maximal dose) for 7 to 9 days. Pharmacologic data indicate that steady-state concentrations of sulfonylureas are achieved within 1 week of therapy. 7,8 fter 7 to 9 days of each sequential dose, patients were admitted to the University of New Mexico General Clinical Research Center for a 23-hour fasting study. ntecubital intravenous access was established to obtain blood samples, and subjects were fed a 33.5-kJ (8 kcal)/ kg merican Diabetes ssociation supper at 18 on the evening prior to study. No energy-containing food was provided for the next 23 hours. t 8 the following morning, subjects ingested their final dosage of that week s medication. lood was collected for glucose, insulin, C peptide, glucagon, epinephrine, and norepinephrine determinations at 75 and 8 (baseline determinations) and then every 3 minutes during the final 9 hours of study. lood was sampled for serum sulfonylurea concentrations at 8 on the day of the placebo study and at 8, 1, 12, 14, 16, and 17 during the 2 sulfonylurea studies. dditionally, all subjects completed a 43-item hypoglycemia symptom questionnaire at 8, 1, 12, 14, 16, and 17 during the study period. Symptoms evaluated included drowsiness, hunger, nervousness, blurred vision, weakness, light-headedness, trembling, sweating, palpitations, tachycardia, dyspnea, and difficulty concentrating. Subjects rated each of the symptoms on a scale of 1 (no symptoms) to 7 (severe symptoms). On completion of each study, supper was provided, and the next week s medication was dispensed. 138 JM, January 14, 1998 Vol 279, No. 2 Sulfonylurea-Induced Hypoglycemia in Type 2 Diabetes urge et al Downloaded From: on 1/2/219

3 Subjects were allowed free access to non energy-containing beverages during the fast, and all subjects drank a single caffeinated beverage (coffee or diet cola) at 8 on the morning of the fast. Furthermore, all subjects participated in a supervised walk around the hospital grounds between 8 and 83 to simulate normal activity. The study protocol is summarized in Figure 2. Study Variables Development of hypoglycemia during the final 9 hours of the 23-hour fast was the primary study outcome variable. Hypoglycemia was prospectively defined as a plasma glucose level less than 3.33 mmol/l (6 mg/dl) with typical hypoglycemic symptoms or any plasma glucose level less than 2.78 mmol/l (5 mg/dl). Secondary analyses included comparison of plasma glucose, insulin, C peptide, glucagon, and catecholamine concentrations between placebo and the 2 doses of sulfonylurea therapy, as well as between glyburide and glipizide GITS. Summary measures of these parameters that were analyzed include the baseline value (mean of 75 and 8 results), the mean value over the entire 9-hour study, and the peak and nadir values during each 9-hour study. Serum sulfonylurea concentrations were analyzed by comparing the 1-mg and 2-mg studies using a repeated-measures analysis of variance (NOV) within each treatment group. dditionally, plasma glucose thresholds for the secretion of epinephrine were determined. To summarize the data obtained from the hypoglycemia symptom questionnaire, 14 of the 43 symptoms were profiled by subtracting the baseline score (8) from the peak score obtained during the subsequent 9 hours of fasting. Sample nalysis Plasma glucose concentrations were determined with a glucose oxidase based analyzer (eckman Instruments, Fullerton, Calif). Plasma was separated from blood elements by centrifugation immediately after sampling and frozen at 2 C for later determination unless capillary blood glucose values were less than 4.44 mmol/l (8 mg/dl), at which time plasma glucose levels were determined immediately. Serum insulin concentrations were determined using an insulin radioimmunoassay kit (Coat-a- Count, Diagnostic Products Corp, Los ngeles, Calif). For 8 patients who had previously received exogenous insulin (none within 3 months of study), free insulin concentrations were determined after treatment of the serum with 25% polyethylene glycol. 9 C peptide concentrations were determined using radioimmunoassay (INCSTR, Stillwater, Minn). Serum glucagon concentrations were determined by the core laboratory at Washington University(St Louis, Mo) using radioimmunoassay. 1 Samples for plasma epinephrine and norepinephrine were placed on ice immediately after sampling and stored at 7 C until being assayed radioenzymatically. 11 Plasma samples for sulfonylurea concentration were frozen at 2 C until assay by highperformanceliquidchromatography(hazelton Laboratories, Madison, Wis). 12,13 Sample Size and Statistical nalysis Our original power analysis was based on the rates of hypoglycemia expected to occur with sulfonylurea therapy during a short-term fast, but surprisingly, no hypoglycemia was observed. ccordingly, we performed a post hoc analysis using the plasma glucose nadir as a surrogate variable for our estimate of power. Since the observed common SD in this parameter was 2.22 mmol/l (4 mg/dl), our sample size is adequate to detect a difference between the 2 sulfonylurea preparations and/or between active treatment and placebo therapy of 1.78 mmol/l (32 mg/dl) with 8% power and equal to.5. Comparisons for an effect of treatment group (glyburide vs glipizide GITS) as a grouping factor and dosage (placebo vs 1 mg vs 2 mg) as a repeated factor were performed using a repeatedmeasures NOV with the Fisher least significant difference method of post hoc pairwise comparisons using SS software for the summary measures previously described. Plasma glucose thresholds for epinephrine secretion were determined using a 2-segment piecewise linear model of the individual data from each study. This was accomplished using a modification of the methods of Clutter et al 14 by analyzing plasma epinephrine concentrations against the concomitant plasma glucose concentration and deriving the glucose level at which the slope changed from zero. This nonlinear model was implemented with the SS PROC NLIN program using an intercept, a slope, and a glucose threshold where the slope changed. 15 RESULTS Plasma Glucose and Hypoglycemia For comparisons within any of the dosages studied, plasma glucose concentrations did not differ between the treatment groups with respect to any of the 4 summary measures (baseline, average, peak, or nadir) by NOV. These data are shown in Table 2. s expected, plasma glucose was significantly decreased when comparing active drug Week 1 Week 2 Week 3 52 Subjects With Type 2 Diabetes, ged y Randomized to or Double-blind ssignment Discontinue Existing Therapy 1 wk of Placebo (n=52) 23-h Day Day 7 Fasting Study or 1 mg Every Morning Day 8 Day 15 or 2 mg Every Morning Day 16 Day h Fasting Study 23-h Fasting Study Figure 2. Study protocol. GITS indicates gastrointestinal therapeutic system. treatment with placebo (Figure 3). dditionally, a significant difference was observed between the 1-mg and 2-mg doses for both drugs. No hypoglycemia occurred during any of the 156 studies. Serum Insulin and C Peptide s expected, insulin concentrations were increased with sulfonylurea therapy as compared with placebo. Specifically, as shown in Table 2, baseline, mean, peak, and nadir concentrations of insulin were significantly higher than placebo in the glyburide group at both 1-mg and 2-mg doses, but only mean and nadir insulin levels were increased with sulfonylurea treatment in the glipizide GITS group. aseline levels of C peptide were higher than placebo for the 1-mg dose of glyburide (P.1) and for the 2-mg dose of both glyburide (P.1) and glipizide GITS (P.5). Mean and peak C peptide levels were significantly increased compared with placebo for both treatment groups at the 1-mg and 2-mg doses (Figure 4). Finally, mean C peptide concentrations (a surrogate for endogenous insulin secretion) were increased in the glyburide group compared with the glipizide GITS group during the 2-mg study by nonpaired Student t test (P=.5). Counterregulatory Hormones Since there was no effect of treatment group with respect to any of the measured counterregulatory hormones (Table 2), the data are summarized by dosage in Figure 5, with the data from both treatment groups being combined for a given dosage (n=52). Concentrations of glucagon and norepinephrine did not differ according to treatment group or dosage (Table 2, Figure 5, and ). There were no differences in plasma epinephrine concentrations according to treatment group in any of the 3 studies. Moreover, baseline and nadir levels of epinephrine did not differ from placebo with active sulfonyl- JM, January 14, 1998 Vol 279, No. 2 Sulfonylurea-Induced Hypoglycemia in Type 2 Diabetes urge et al 139 Downloaded From: on 1/2/219

4 Table 2. Study Results for Each of the 3 Fasting Studies by Treatment Group a (n=27) (n=25) Variable and Dose aseline Mean Peak Nadir aseline Mean Peak Nadir Plasma glucose, mmol/l b Placebo 11.4 (2.6) 1. (2.5) 1.9 (2.8) 8.3 (2.1) 12.5 (3.5) 1.6 (3.4) 12.7 (3.6) 8.7 (3.) 1 mg 9.5 (3.2) c 7.4 (2.4) c 1. (3.1) c 5.5 (1.6) c 1.2 (3.3) c 8.2 (2.7) c 1.6 (3.2) c 6.2 (2.3) c 2 mg 8.7 (2.7) cd 6.9 (2.2) cd 9.3 (2.9) cd 4.9 (1.7) cd 9.6 (3.5) c 7.7 (2.9) cd 1. (3.5) c 5.8 (2.4) de Insulin, pmol/l f Placebo 68 (37) 67 (34) 111 (63) 38 (19) 65 (38) 58 (32) 99 (62) 35 (2) 1 mg 83 (42) e 93 (53) c 146 (92) c 6 (34) g 71 (38) 76 (43) g 112 (62) 47 (29) g 2 mg 82 (46) e 91 (47) c 127 (72) e 56 (27) g 71 (47) 72 (4) e 12 (52) 48 (28) e C peptide, nmol/l Placebo.93 (.4) 1.1 (.43) 1.37 (.59).71 (.32).88 (.34).89 (.34) 1.19 (.49).63 (.25) 1 mg 1.12 (.44) c 1.32 (.53) c 1.74 (.7) c.97 (.35).97 (.37) 1.8 (.42) c 1.4 (.67) c.81 (.34) 2 mg 1.14 (.42) c 1.34 (.5) c 1.77 (.75) c.95 (.33) 1.2 (.34) e 1.9 (.39) c 1.46 (.62) e.82 (.31) Glucagon, ng/l Placebo 19 (28) 18 (23) 131 (3) 86 (19) 118 (5) 19 (51) 135 (58) 87 (48) 1 mg 11 (31) 11 (28) 136 (38) 9 (22) 117 (46) 116 (5) 144 (65) 94 (44) 2 mg 112 (36) 11 (33) 134 (44) 91 (3) 113 (45) 11 (43) 132 (52) 9 (35) Norepinephrine, nmol/l i Placebo 1.92 (1.) 2. () 3.21 (1.71) 1.33 (.82) 1.92 (.7) 2.7 (.77) 3.46 (1.46) 1.31 (.44) 1 mg 2.5 (1.8) 2.5 (.82) 3.47 (1.34) 1.31 (.66) 2.17 (.87) 2.22 (.84) 3.68 (1.48) 1.42 (.5) 2 mg 2.13 (1.16) 2.11 (.98) 3.65 (2.3) 1.3 (.65) 2.29 (1.15) 2.19 (.71) 3.72 () 1.41 (.51) Epinephrine, pmol/l j Placebo 142 (17) 143 (87) 236 (115) 81 (58) 156 (162) 168 (133) 324 (288) 87 (75) 1 mg 142 (86) 222 (14) k 529 (389) k 8 (38) 139 (143) 24 (139) k 579 (89) k 93 (74) 2 mg 115 (57) 241 (165) k 574 (418) k 82 (36) 123 (9) 222 (134) k 534 (34) k 8 (46) a Values are expressed as mean (SD). GITS indicates gastrointestinal therapeutic system. b To convert to milligrams per deciliter, divide by c P.1 vs placebo. d P.5 vs 1-mg study. e P.5 vs placebo. f To convert to microunits per milliliter, divide by g P.1 vs placebo. h To convert to nanograms per milliliter, divide by.333. i To convert to picograms per milliliter, divide by j To convert to picograms per milliliter, divide by k P.1 vs placebo when treatment groups are combined. urea treatment, as shown in Table 2 and Figure 5, C. oth mean and peak levels of epinephrine, however, were significantly increased compared with placebo during both the 1-mg and 2-mg studies when the treatment groups were combined (P.1). There was no difference in epinephrine response between the 1-mg and 2-mg studies. Glucose Thresholds for Epinephrine Secretion No glucose threshold for epinephrine secretion could be determined from the placebo study using nonlinear regression. During active sulfonylurea treatment, however, this model derived mean (SD) glucose thresholds of 9.1 (2.66) mmol/l (164 [48] mg/dl) for incremental epinephrine secretion during the 1- mg study and 8.77 (2.83) mmol/l (158 [51] mg/dl) during the 2-mg study between subjects. There was no difference between these thresholds by pairwise post hoc analysis. Serum Sulfonylurea Concentrations Serum sulfonylurea levels were below therapeutic ( 1 ng/ml) for both glyburide and glipizide GITS after the week of placebo therapy. On average, glipizide concentrations approximately doubled during active sulfonylurea treatment over baseline, while concentrations of glyburide increased approximately 6-fold over baseline after dosing (Figure 6). Serum sulfonylurea concentrations were significantly increased during the 2-mg study compared with those obtained during the 1-mg study for both drugs. Hypoglycemic Symptom Questionnaire Study subjects did not differ between treatment group or dosage with respect to any of the 14 hypoglycemia symptom variables (data not shown). In general, symptom scores remained very low throughout the studies, except for hunger, for which scores increased similarly during all 3 studies. COMMENT Type 2 diabetes is common in the elderly, with approximately 1% of individuals older than 65 years having a diagnosis of diabetes and another 1% having occult diabetes. 16 n additional 23% of this population meet criteria for impaired glucose tolerance, so 4% to 5% of individuals older than 65 years manifest some abnormality of carbohydrate metabolism. 16 ecause the proportion of the merican population older than 65 years is projected to increase from the current level of 12% to 22% by the year 24, the burden of type 2 diabetes will become increasingly prevalent in the near future. 17 s such, the dilemma of how best to care for these patients must be considered. Previous retrospective reports have suggested that long-acting sulfonylureas (such as chlorpropamide and glyburide) are more likely to cause hypoglycemia and should be avoided in elderly patients, 1,4,7 but there are insufficient prospective, controlled data to support these claims. lthough alternatives to sulfonylurea therapy have recently become available, these agents have the drawbacks of potential adverse gastrointestinal effects (eg, metformin, acarbose) and high cost (eg, metformin, troglitazone, acarbose). Thus, although hypoglycemia remains an appropriate concern for the elderly diabetic patients who use them, sulfonylureas are likely to remain a cornerstone of type 2 diabetes therapy. This placebo-controlled prospective study demonstrates that hypoglycemia does not normally occur in otherwise 14 JM, January 14, 1998 Vol 279, No. 2 Sulfonylurea-Induced Hypoglycemia in Type 2 Diabetes urge et al Downloaded From: on 1/2/219

5 Placebo Study Placebo Placebo Placebo Study Placebo Placebo Placebo Study Placebo Placebo Plasma Glucose, mmol/l mg Study Serum Insulin, pmol/l mg Study C C Peptide, nmol/l mg Study D 14 2-mg Study C (8) (123) (17) mg Study (8) (123) (17) E mg Study (8) (123) (17) F Figure 3. Plasma glucose during the final 9 hours of a 23-hour fast among elderly subjects with type 2 diabetes receiving glyburide (circles, n=27) or glipizide gastrointestinal therapeutic system (GITS) (triangles, n=25). There were no differences between treatment groups after 7 to 9 days of () placebo, () 1 mg of the assigned drug, or (C) 2 mg of the assigned drug (P=.32). Data points indicate mean values; error bars, SE. To convert glucose values to milligrams per deciliter, divide by healthy elderly patients with type 2 diabetes who receive maximal doses of a once-daily second-generation sulfonylurea agent during a short-term fast. Thus, although fasting is likely to remain a factor in the pathogenesis of hypoglycemia in a small percentage of patients with type 2 diabetes treated with sulfonylureas, this risk is not sufficient to withhold the use of these agents in otherwise healthy elderly patients. These results are contrary to the conclusions of numerous retrospective uncontrolled studies on the subject of sulfonylureainduced hypoglycemia, which have identified age and energy restriction as the primary factors associated with hypoglycemia among type 2 diabetic patients. 2,3,18 Other known associations with sulfonylurea-induced hypoglycemia include polypharmacy, alcohol Figure 4. Serum levels of insulin (, C, E) and C peptide (, D, F) during the final 9 hours of a 23-hour fast among elderly subjects with type 2 diabetes receiving glyburide (circles, n=27) or glipizide gastrointestinal therapeutic system (GITS) (triangles, n=25). Results were obtained after 7 to 9 days of placebo ( and ), 1 mg (C and D) of the assigned drug, and 2 mg (D and E) of the assigned drug. Data points indicate mean values; error bars, SE. To convert glucose values to milligrams per deciliter, divide by abuse, and liver or kidney dysfunction. 3 These data further suggest that healthy elderly sulfonylurea-receiving patients with type 2 diabetes are protected against the development of hypoglycemia during a short-term fast. Enhanced counterregulatory hormone secretion is a potential mechanism to explain this finding. Much published data are available describing the physiological response to hypoglycemia in type 1 diabetes, but the data are inconclusive with respect to type 2 diabetes. ecause most patients with type 1 diabetes lose their ability to secrete glucagon in response to hypoglycemia shortly after developing diabetes, incremental secretion of epinephrine assumes a primary role in the hormonal response to hypoglycemia in this disease. 19 ecause the ability to secrete epinephrine is also impaired in approximately 25% of patients with long-standing type 1 diabetes mellitus, such patients may manifest the syndrome of hypoglycemic unawareness, resulting in a tendency to develop frequent, severe, and prolonged hypoglycemia. 2 Healthy nondiabetic subjects begin to exhibit increments in epinephrine secretion at plasma glucose levels between 2.27 and 3.77 mmol/l (41 and 68 mg/dl). 21,22 The fact that the subjects with type 2 diabetes in our study secreted epinephrine during hyperglycemia suggests that glucoregulatory centers in the hypothalamus are sensing neuroglycopenia and are responding by stimulating epinephrine secretion prior to the onset of global cortical dysfunction. 23 This is consistent with observations in type 1 diabetes, where patients with poor glycemic control have been demonstrated to exhibit elevated glycemic thresholds for the development of hypoglycemic symptoms compared with nondiabetic subjects. 24 The inability to demonstrate a clear glycemic threshold for epinephrine release during the placebo arm of the current study probably reflects the fact that plasma glucose con- JM, January 14, 1998 Vol 279, No. 2 Sulfonylurea-Induced Hypoglycemia in Type 2 Diabetes urge et al 141 Downloaded From: on 1/2/219

6 Plasma Norepinephrine, nmol/l Plasma Glucagon, ng/l P >.5 P >.5 Serum, ng/ml mg of 2 mg of P<.1 vs 1-mg Dose 1 mg of 2 mg of Plasma Epinephrine, pmol/l mg Study Placebo 1-mg Study 5 P<.1, Placebo vs Sulfonylurea (8) (123) (17) Figure 5. Plasma levels of () glucagon, () norepinephrine, or (C) epinephrine during the final 9 hours of a 23-hour fast among elderly subjects with type 2 diabetes receiving placebo (circles, n=52), 1 mg of glyburide or glipizide gastrointestinal therapeutic system (GITS) (triangles, n=52), or 2 mg of glyburide or glipizide GITS (squares, n=52). Data points indicate mean values; error bars, SE. centrations did not drop below this threshold (about 8.9 mmol/l [16 mg/ dl]) in most patients during the placebo study. In sum, our results suggest that enhanced incremental secretion of epinephrine protects against the development of cerebral neuroglycopenia in type 2 diabetes and may effectively preclude clinical hypoglycemia. Interpretation of this study is limited by the fact that many of the participants exhibited suboptimal diabetes control, and as a result, these findings may not be applicable to patients with type 2 diabetes who achieve near-normal glycemic control. Many patients with type 2 diabetes do not achieve near-normal glycemia, however, and the glycosylated hemoglobin levels obtained at study entry are typical of patients with type 2 diabetes encountered in clinical practice. 25 Moreover, when the subjects are analyzed by quartile according to fasting C Serum Glipizide, ng/ml (8) (123) (17) (8) (123) (17) Hours fter Dosing (Clock Hours) plasma glucose concentrations, it is evident that subjects in the lowest quartile had normal glycemia during the highdose study (mean [SD] fasting glucose, 5.8 [.8] mmol/l [14 (14 mg/dl); mean (SD) nadir glucose, 3.9 [.6] mmol/l [71 (11) mg/dl]; n=13), and these subjects did not develop hypoglycemia. lthough the observed epinephrine increase may, theoretically, be attributable to factors other than the decline in plasma glucose, the fact that baseline epinephrine levels did not differ between the placebo and sulfonylurea studies suggests that the decline in plasma glucose was the primary stimulus for incremental epinephrine secretion. Concentrations of growth hormone and cortisol were not determined in this study, but these hormones have been shown not to be involved in P<.1 vs 1-mg Dose Figure 6. Serum sulfonylurea concentrations as determined by high-performance liquid chromatography for () glyburide and () glipizide gastrointestinal therapeutic system (GITS) after 1 week of daily therapy during the 1-mg (dashed line) and 2-mg (solid line) studies. Time corresponds to 8 and 14 hours of fasting. Significant P values demonstrate the presence of an effect of dose on serum sulfonylurea concentrations and imply neither dose proportionality nor pharmacokinetic analysis. Data points indicate mean values; error bars, SE. the acute response to hypoglycemia. 26 Finally, all of the subjects were receiving stable sulfonylurea treatment prior to study enrollment, so these results do not directly pertain to the risk of hypoglycemia among patients with type 2 diabetes with diet failure who fast shortly after initiating sulfonylurea therapy. Similarly, the rate of occurrence of hypoglycemia may be higher in actual clinical practice than was observed in this carefully controlled clinical trial. One unresolved issue regards the pathogenesis of severe sulfonylurea-induced hypoglycemia, which, although uncommon, does occur in clinical practice. lthough many of the reported cases of sulfonylurea-induced hypoglycemia are attributable to intentional overdose or otherwise inappropriate sul- 142 JM, January 14, 1998 Vol 279, No. 2 Sulfonylurea-Induced Hypoglycemia in Type 2 Diabetes urge et al Downloaded From: on 1/2/219

7 fonylurea ingestion, the mechanism of life-threatening hypoglycemia in appropriately treated patients with type 2 diabetes remains to be elucidated. It may be that other causes of hypoglycemia, such as ethanol ingestion or strenuous exercise, play a significant role in these cases, although a recent report suggests that moderate exercise is well tolerated among fasted, sulfonylurea-receiving patients with type 2 diabetes. 27 Other known factors, such as the presence of underlying renal disease, hepatic dysfunction, or intercurrent illness, are also likely to be important in the pathogenesis of hypoglycemia secondary to sulfonylureas. lternatively, it is possible References 1. Gerich JE. Oral hypoglycemic agents. N Engl J Med 1989;321: Jennings M, Wilson RM, Ward JD. Symptomatic hypoglycemia in NIDDM patients treated with oral hypoglycemic agents. Diabetes Care. 1989;12: Seltzer HS. Drug-induced hypoglycemia: a review of 1418 cases. Endocrinol Metab Clin. 1989; 18: Clinical practice recommendations of the merican Diabetes ssociation. Diabetes Care. 1997;2 (suppl 1):S UK Prospective Diabetes Study Group. UK Prospective Diabetes Study 16: overview of 6 years therapy of type II diabetes: a progressive disease. Diabetes. 1995;44: oden G, Soriano M, Hoeldke RD, Owen OE. Counterregulatory hormone release and glucose recoveryafterhypoglycemiainnon-insulin-dependent diabetic patients. Diabetes. 1983;32: Groop LC. Sulfonylureas in NIDDM. Diabetes Care. 1992;15: In: Physician s Desk Reference. Montvale, NJ: Medical Economics Press; Nakagawa S, Nakayama H, Sasaki T, et al. simple method for the determination of serum free insulin levels in insulin-treated patients. Diabetes. 1973;22: Ensinck JW. Immunoassays for glucagon. In: Glucagon: Handbook of Experimental Pharmacology. New York, NY: Verlag; 1983; Shah SD, Clutter WE, Cryer PE. External and internal standards in the single isotope derivative (radioenzymatic) assay of plasma norepinephrine and epinephrine in normal humans and persons with that type 2 diabetes is analogous to type 1 diabetes in that those patients who are unable to secrete epinephrine in response to a hypoglycemic stimulus are at an increased risk for the development of severehypoglycemia. 28 Ifthisisthecase, then prospective identification of these patients may be useful in determining appropriate treatment goals for these patients. In summary, our study emphasizes that hypoglycemia is rare among healthy, sulfonylurea-receiving, elderly patients with type 2 diabetes during a short-term fast. Moreover, these data suggest that incremental secretion of epinephrine at elevated glucose thresholds may play a pivotal role in the prevention of sulfonylurea-induced hypoglycemia. From a clinical standpoint, the second-generation oral sulfonylurea agents should be considered safe for use in elderly, fasted patients with type 2 diabetes provided that the presence of other hypoglycemia risk factors, such as alcohol, are excluded. This research was supported by a grant from Pfizer Inc and by the University of New Mexico Clinical Research Center (NIH NCRR GCRC grant 5MO1-RR997). One-Touch II capillary blood glucose meters and supplies were supplied by Lifescan Inc, Milpitas, Calif. diabetes mellitus or chronic renal failure. J Lab Clin Med. 1985;16: Rydberg T, Wahlin-oll E, Melander. Determinationofglibenclamideanditstwomajormetabolites in human serum and urine by column liquid chromatography. J Chromatogr. 1991;564: Wahlin-oll E, Melander. High performance liquid chromatographic determination of glipizide andsome other sulfonylurea drugs in serum. J Chromatogr. 1979;164: Clutter WE, ier DM, Shah SD, Cryer PE. Epinephrine plasma metabolic clearance rates and physiologic thresholds for metabolic and hemodynamic actions in man. J Clin Invest. 198;66: SS/STT User s Guide Volume 2, Version 6. Cary, NC: SS Institute Inc; 199: Harris MI, Hadden WC, Knowler WC, ennett PH. Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in U.S. population aged 2-74 yr. Diabetes. 1987;36: Siegel JS. Recent and prospective trends for the elderly population and some implications for health care. In: Haynes S, Feinleib M, eds. Second Conference on the Epidemiology of ging. Washington, DC: US Government Printing Office; 198. DHHS NIH publication splund K, Wilholm -E, Lithner F. Glibenclamide-associated hypoglycaemia: a report on 57 cases. Diabetologia. 1983;24: Popp D, Shah SD, Cryer PE. The role of epinephrine mediated -adrenergic mechanisms in hypoglycemicglucosecounterregulationandpost-hypoglycemic hyperglycemia in insulin-independent diabetes mellitus. J Clin Invest. 1982;69: Mokan M, Mitrakou, Veneman T, et al. Hypoglycemic awareness in IDDM. Diabetes Care. 1994;17: Garber J, Cryer PE, Santiago JV, Haymond MW, Pagliara S, Kipnis DM. The role of adrenergic mechanisms in the substrate and hormonal response to insulin-induced hypoglycemia in man. J Clin Invest. 1976;58: Mitrakou T, Ryan C, Veneman T, et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. m J Physiol. 1991;26:E67-E org WP, During MJ, Sherwin RS, org M, rines ML, Schulman GI. Ventromedial hypothalamic lesions in rats suppress counterregulatory responses to hypoglycemia. J Clin Invest. 1994;93: oyle PJ, Schwartz NS, Shah SD, Clutter WE, Cryer PE. Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and nondiabetics. N Engl J Med. 1988;318: Klein R. Hyperglycemia and microvascular and macrovascular disease in diabetes. Diabetes Care. 1995;18: Gerich J, Davis J, Lorenzi M, et al. Hormonal mechanisms of recovery from insulin-induced hypoglycemia in man. m J Physiol. 1979;236:E38-E Riddle MC, McDaniel P, Tive L. Glipizide GITS does not increase the hypoglycemic effect of mild exercise during fasting in NIDDM. Diabetes Care. 1997;2: Santiago JV, White NH, Skor D, Levandoski L, ier DM, Cryer PE. Defective glucose counterregulation limits intensive therapy of diabetes mellitus. m J Physiol. 1984;247:E215-E22. JM, January 14, 1998 Vol 279, No. 2 Sulfonylurea-Induced Hypoglycemia in Type 2 Diabetes urge et al 143 Downloaded From: on 1/2/219