Interaction of Ethanol and Glipizide in Humans - Diabetes Care

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nteraction of Ethanol and Glipizide in Humans

SVEND G. HARTLING, MD, OLE K. FABER, MD, PhD, MARIE-LOUISE WEGMANN, MD, ELISABETH WAHLIN-BOLL, PhD, AND ARNE MELANDER, MD, PhD

The hypoglycemic effect of 2.5 mg glipizide and the potentiation of this effect by ethanol were studied in 10 normal-weight nondiabetic subjects. The reductions in blood glucose concentrations were similar in time of onset and extent (2 mM) whether glipizide was taken alone or in combination with ethanol. However, the return of blood glucose toward fasting level was delayed by ethanol. P-Cell secretory activity, evaluated from the concentrations of insulin and C-peptide, was unchanged by ethanol. The serum glipizide concentrations were reproducible within subjects, whereas there was a considerable interindividual variation. This heterogeneity in the rise in glipizide concentration was strongly correlated with blood glucose fall and insulin secretion. Thus, ethanol can prolong but does not augment the hypoglycemia induced by glipizide. The heterogeneity in glipizide concentration seems to be caused by an interindividual variation in kinetics. Diabetes Care 10:683-86, 1987

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thanol induces hypoglycemia (1), but not until 1963 was ethanol shown to be effective as ethanol rather than via denatured additives (2). The hypoglycemic effect of ethanol is particularly common in chronic alcoholism but has also been described in nonalcoholic fasting subjects regardless of weight and presence of diabetes (3,4). Even occasional drinkers who miss one or two meals have developed ethanol-induced hypoglycemia (5). The significance of hypoglycemia associated with sulfonylureas and ethanol is emphasized by reports that 80% of all severe hypoglycemic episodes are caused either by sulfonylurea and/ or excessive alcohol intake (5,6). There has been renewed concern about this problem with the introduction of the second-generation sulfonylureas (7). The mechanism of potential interaction of ethanol and sulfonylureas has not been elucidated. Therefore, we studied the acute effect of a secondgeneration sulfonylurea and ethanol, alone and in combination, on blood glucose and insulin secretion.

SUBJECTS AND METHODS

Ten clinically healthy volunteers (6 men, 4 women) of age range 25-39 yr (median 32 yr) who were within 10% of ideal body weight gave informed consent to participate in the study. None had a history of alcohol abuse. Three studies

separated by at least 3 days were performed with each subject, who served as his/her own control. The study protocol was approved by the local committee on ethics. All studies were performed in the morning after a 10-h fast. For 3 days before each study, the subjects consumed a normal diet containing at least 250 g carbohydrate/day. At the start of the study the subject assumed a supine position, and an intravenous catheter was inserted into the forearm for blood sampling. The catheter was kept open by a saline drip during the study. After a 30-min rest the subjects were randomly chosen to receive either 2.5 mg glipizide (Minidiab, Farmatalia Carlo Erba, Milan), 2.5 mg glipizide and 0.4 g pure ethanol/kg body wt 30 min later, or a placebo and 0.4 g pure ethanol/ kg body wt 30 min later. Ethanol was taken orally in the form of Danish schnapps (Red Aalborg 45% vol/vol). Venous blood samples were collected every 15 min for blood glucose and every 30 min for insulin, C-peptide, ethanol, and glipizide determinations from — 30 to 180 min. On the first study day, each subject received a bolus injection of 1 mg i.v. glucagon at 180 min, followed by blood sampling after 6 and 10 min for determination of blood glucose, insulin, and Cpeptide. Blood glucose concentrations were determined by the glucose oxidase method. Plasma insulin concentrations were measured radioimmunologically (8), and C-peptide concentrations were measured by the method of Heding (9)

DIABETES CARE, VOL. 10 NO. 6, NOVEMBER-DECEMBER 1987

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INTERACTION OF ETHANOL AND GLIPIZIDE/S. G. HARTLING AND ASSOCIATES

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FIG. 1. Blood glucose concentrations (mean ± SE) in healthy volunteers after intake of placebo plus ethanol (•), glipizide without ethanol (O), or glipizide plus ethanol (•). Glipizide (2.5 mg) or placebo was given at —30 min; ethanol or water was given at time 0. with antibody Ml230 (10). Ethanol was measured by gas chromatography, and glipizide was measured by high-performance liquid chromatography (11). All values are reported as means ± SE. The results were analyzed with the Pratt matched-pair signed-ranks test. Correlations were sought with the Spearman ranked-correlation test. The risk of type I error was set at 2P < .05. RESULTS

Blood glucose concentration declined steadily after ethanol ingestion and continuous fasting (Fig. 1). The reduction was significant after 45 min compared with time 0, and the mean maximum individual decrease was 0.56 mM (range 0.1-0.8 mM), The corresponding C-peptide values were unaltered until 90 min compared with time 0 (0.32 ± 0.02 pM). Thereafter, a slight reduction was seen that reached statistical significance at 180 min (0.27 ± 0.02 pM). The pattern for insulin was similar. The blood glucose reductions after glipizide were unaffected by ethanol addition insofar as onset and degree were concerned. However, recovery was delayed when ethanol was added (Fig. 1), and the differences at 90, 105, 120, and 135 min were significant (P < .05). Also, analyzing the area under the curve in relation to the value at time 0 showed a statistically significant difference (P < .01). Glipizide evoked a mean maximum blood glucose reduction of 2.03 mM (range 1.2-3.3 mM) with a great variation; nadir was reached within 30 min in some subjects and not until 180 min in others. However, the time at which the glipizide concentration exceeded the threshold concentration of 50 ng/ml (112 nM) correlated closely with the time at which blood glucose reached its nadir, regardless of whether glipizide was taken alone (r = .96, P < .001) or with ethanol (r = .97, P < .001; Fig. 2). Similar correlations to blood glucose decrease were found when the time to maxi-

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mum concentration of glipizide instead of the threshold concentration was used. The average glipizide concentrations did not differ when ethanol was taken. By comparing times to reach the glipizide threshold concentration of >50 ng/ml with and without ethanol, Fig. 3 shows that the heterogeneity in the absorption of glipizide (and thereby in blood glucose responses) was due to interindividual variation rather than day-to-day variation within individuals. It appears that there are individuals who are slow or fast absorbers of glipizide. C-peptide and insulin concentrations rose quickly after glipizide intake with or without ethanol. There were no differences in C-peptide or insulin levels with or without ethanol. The individual time to reach maximum concentration correlated with the time when glipizide exceeded the threshold concentration of 50 ng/ml (r = .79, P < .02) with or without ethanol. Ethanol concentrations peaked at 30 min; peak values with and without glipizide were 11.7 ± 1.2 mM (53 ± 5 mg/dl) and 10.8 ± 0 . 6 mM (50 ± 3 mg/dl), respectively. There was no observable influence of the sulfonylurea on ethanol kinetics. After glucagon injection, blood glucose increased in all 10 subjects, independent of the previous regimen, from 2.93 ± 0.15 to 4.22 ± 0.29 mM at 10 min. C-peptide levels rose from 0.34 ± 0.03 mM to 1.09 ± 0.13 mM, and insulin levels rose from 0.09 ± 0.00 mM to 0.39 ± 0.05 mM. DISCUSSION

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ur findings indicate that a moderate amount of ethanol and/or 10-12 h of fasting will reduce blood glucose concentrations by ~0.5 mM in normal subjects. Because no control day with con-

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FIG. 2. Correlation of time at which glipizide concentration exceeds threshold concentration of 50 ng/ml with time to reach lowest blood glucose concentration. O, Glipizide without ethanol (r = .96); • , glipizide plus ethanol (r = .97).


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tinuous fasting was included and the literature is controversial about the decline in blood glucose after 10 h of fasting, it cannot be concluded which factor is more important. However, we found that ethanol can prolong, but does not seem to augment, the hypoglycemia induced by glipizide. The effects of ethanol on carbohydrate metabolism vary, depending on species, dose, route of administration, and whether it is given in the fasting or nonfasting state or whether it is administered acutely or chronically (12,13). In vitro, animal, and human studies indicate that ethanol inhibits gluconeogenesis (4,14-16). The inhibition of gluconeogenesis would also inhibit glycogen formation (17), but the rise in blood glucose after glucagon injection that we found at the end of the study indicated that glycogen stores were still present in the liver. Accordingly, ethanol probably not only inhibits gluconeogenesis but also counteracts glycogenolysis. In support of this assumption, it has been shown that ethanol suppresses the rebound phase after an insulintolerance test (18). The ethanol-induced inhibition of glycogenolysis could be a direct effect or secondary to suppression of counterregulatory hormones. It has been shown that the growth hormone response to hypoglycemia is impaired during ethanol infusion (4,19). Although ethanol prolonged the hypoglycemia induced by glipizide, there was no influence on the release or availability of insulin. Ethanol augments the insulin-releasing effects of tolbutamide, glucose, and arginine (20,21) but not glipizide, unless the clearance of insulin is also changed, which seems unlikely. This suggests the possibility that glipizide releases insulin by a mechanism different at least in part from that of tolbutamide. Alternatively, ethanol augments glipizide-

induced insulin release but only at higher doses and plasma levels than those found in this study. Glipizide is completely absorbed, but its absorption rate varies greatly between subjects, probably because of differences in the rate of gastric emptying and hence in glipizide dissolution rate (11). The pronounced interindividual variation in the rate of glipizide absorption seen in our study explained the considerable interindividual difference in the rate of blood glucose reduction. There was a close correlation between the time to reach the minimum effective (threshold) concentration of serum glipizide (50 ng/ml; 11) and the time to reach the minimum concentration of blood glucose. Moreover, there was very little intraindividual but substantial interindividual variation in glipizide absorption rate. This finding of individuals who are rapid or slow absorbers could have clinical implications and requires further elucidation. Even though the mean glipizide curves were comparable, ethanol may delay glipizide absorption and elimination. An absorption delay could be secondary to slower gastric emptying when ethanol was added; a substantially prolonged effect of glipizide is, however, not likely. When only ethanol was ingested, most subjects felt sleepy but otherwise well. After glipizide without ethanol, only one subject had hypoglycemic symptoms (tremor and tachycardia), which lasted —-10—15 min. When glipizide was combined with ethanol, five subjects felt mildly inebriated, but their symptoms were probably partly accounted for by hypoglycemia because ethanol levels were low. At no time did blood ethanol concentration exceed the Danish legal limit for automobile driving (17.4 mM or 80 mg/dl). This study shows that ethanol can prolong but may not augment the hypoglycemia induced by glipizide. Ethanol might delay glipizide absorption, adding to but not being the initial cause of the prolonged hypoglycemia. A pronounced interindividual variation in glipizide absorption rate explains the considerable variation in the rate of blood glucose reduction. Studies on the influence of ethanol during treatment with sulfonylurea are in progress to evaluate the clinical relevance of the interaction in long-term sulfonylurea-treated diabetic patients. ACKNOWLEDGMENTS: We thank Jane Falk and Marianne Beve for skillful technical assistance and Bente Kjar for preparing the manuscript.

From the Medical Department, H0rsholm Hospital, H0rsholm (S.G.H., O.K.F., M.-L.W.), and Hagedorn Research Laboratory, Gentofte (O.K.F.), Denmark; and Division of Clinical Pharmacology, Lund University Health Sciences Centre, Dalby, Sweden (E.W.-B., A.M.). Address correspondence and reprint requests to Ole K. Faber, MD, PhD, Medical Department, H0rsholm Hospital, DK-2970 H0rsholm, Denmark. REFERENCES

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