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Dose-Response Profile of Acarbose in Older Subjects with Type 2 Diabetes
Dose-Response Profile of Acarbose in Older Subjects with Type 2 Diabetes ARSHAG D. MOORADIAN, MD; STEWART G. ALBERT, MD; SUSAN WITTRY, BSN, RN; JOE CHEHADE, MD; JOOHEE KIM, MD; BRENDA BELLRICHARD, RD;
ABSTRACT: Objective: To examine the dose-response relationship of acarbose, an a-glucosidase inhibitor, in older subjects with type 2 diabetes. Research Oesign: Fourteen subjects with type 2 diabetes who were over 65 years old were studied. Five subjects had been treated with diet alone and 9 were receiving a sulfonylurea. The subjects underwent a meal tolerance test in the presence of varying doses of acarbose (0, 25, 50, and 100 mg) on 4 occasions, each 1 week apart. The test meal was chosen to include food items commonly consumed during breakfast in the United States. The 483kcal meal consisted of 51 % of calories in the form of carbohydrates, 14% protein, and 35% fat. The serum glucose, insulin, and triglyceride levels were measured
at 0, 1, and 2 hours after the meal. Results: The postprandial hyperglycemic response to the test meal was significantly reduced with 25 mg of acarbose compared with baseline values. Increasing doses of acarbose to 50 or 100 mg had no significant additional ameliorating effects on postprandial hyperglycemia. Postprandial insulin or triglyceride levels were not significantly altered with single dose acarbose treatment. Conclusions: It is concluded that the acute efficacy of acarbose is near maximal at 25 mg when the meal size does not exceed 483 kcal and contains only 61 gm of carbohydrates. KEY INDEXING TERMS: Aging; Acarbose; Elderly; Type 2 diabetes; Postprandial [Am J Med Sci 2000;319(5):
T
type 2 diabetes and postprandial hyperglycemia are very common.
he efficacy and safety of a-glucosidase inhibitors in subjects with type 2 diabetes have been previously demonstrated in several clinical trials. 1- 9 The post hoc analysis of the data from these trials has found no significant age-related difference in the efficacy or safety of these agents in the elderly population. In addition, controlled prospective studies, as well as surveys conducted after a drug has been put on the market, have also established the efficacy of these agents in the elderly.1O,ll However, an acute dose-response relationship of a-glucosidase inhibitors has not been previously established. The various determinants of postprandial glycemia, including the rate of gastric emptying, the small intestinal absorption capacity, and the insulin response, may be altered with age. 12 Therefore, it is important to establish the dose-res'ponse relationship of a-glucosidase inhibitors in this patient population in which
From the Division of Endocrinology, Department of Internal Medicine, St. Louis University Medical School, St. Louis, Missouri. Submitted May 20, 1999; accepted in revised form August 30, 1999. This study was supported by The Bayer Corporation (West Haven, CT). Correspondence: Arshag D. Mooradian, M.D., Division of Endocrinology, St. Louis University, Medical School, 1402 S. Grand Blvd., St. Louis, MO 63104.
334
334-7.]
Research Design and Methods
Subjects A total of21 subjects with type 2 diabetes over the age of 65 years were recruited from Saint Louis University Diabetes clinics. All subjects who met the criteria for the diagnosis of type 2 diabetes 13 signed an informed consent form approved by the Institutional Review Board of Saint Louis University. Of the original 21 subjects recruited, 5 were excluded for having hemoglobin (Hb) AlC of less than 6.9%, one was excluded for having HbA lC of more than 12.5%, and one subject was excluded because of scheduled back surgery during the course of the study. The mean [± standard error of the mean (SEM)] age of the 14 subjects enrolled was 70.4 ± 1.2 years. There were 7 men and 7 women. The mean body weight was 190.3 ± 6.4lb and the mean body mass index was 29.2 ± 0.93 kg/m2 . The mean HbA lC was 7.97 ± 0.23%. Nine subjects were on sulfonylurea (5-15 mg glipizide or 5-20 mg glyburide) and 5 were treated with diet only. None of the subjects had undergone prior gastrointestinal surgery or had any clinical evidence of gastropathy, such as postprandial bloating, nausea, May 2000 Volume 319 Number 5
Mooradian et al
vomiting, or abdominal pain. None were on medications known to alter gastrointestinal motility.
300
Study Plan and Measurements The subjects were given a test meal with or without acarbose on 4 occasions, each 1 week apart. After completion of the first test meal without acarbose, 3 additional tests were done in which each subject was given either 25 mg, 50 mg, or 100 mg of acarbose in random order. The pill was taken with the first bite of the meal. The serum glucose, insulin, and triglyceride levels were measured at 0, 1, and 2 hours after the meal. The 483-kcal meal consisted of 51% of calories in the form of carbohydrate (61 g), 14% protein (17 g) and 35% fat (19 g). The test meal included the following food items: 1 cup (8 oz) of Tropicana unsweetened orange juice, 1 cup (8 oz) of skim milk, 3/4 cup cereal (Rice Krispies for low fiber), and Swanson microwavable scrambled eggs with home fries. All the carbohydrate in this test meal, with the exception of 5 g of glucose, 5 g of fructose, and 11 g of lactose, is amenable to the effects of acarbose. All the tests were done in the morning after at least 9 hours of overnight fast. Those subjects on sulfonylurea therapy did not take their daily doses on the morning of testing. The subjects consumed the meal within 20 minutes and indicated that the meal size was somewhat larger than the size of any meal they would ordinarily consume.
280
Statistical Analysis Results are reported as mean (± SEM) unless specified otherwise. Parametric group mean data were analyzed by the student's t-test or analysis of variance. Paired data were analyzed by paired ttests or one-way analysis of variance for repeated measures. When there was a significant difference demonstrated by analysis of variance, post hoc analysis was performed by the Newman-Keuls procedure for subgroup analysis. Statistical procedures were performed with the statistical package Statistica for Windows (Statsoft Inc, Tulsa, OK). Significance was defined as a 2-tailed P < 0.05. Results and Discussion
The I-hour postprandial hyperglycemic response to the test meal was significantly reduced with 25 mg of acarbose (Figure 1). The mean I-hour postprandial serum glucose value decreased from a baseline of 273.9 ± 12.9 mg/dL to 249.6 ± 14.5 mg/dL when 25 mg acarbose was given (P < 0.008). The mean 2-hour postprandial serum glucose value decreased from a baseline of 258.5 ± 12.4 mg/dL to 213.0 ± 16.5 mg/dL (P < 0.0002). The area under the serum glucose curve when 25 mg of acarbose was given with the test meal (603.9 ± 48.9 mg/hr/dL) was significantly smaller than the area of the curve THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
260
!i!Cl .§. 240 QI
1*--~o:::---.J,[*
til
0
U
:::J
220
..
200
c;
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E :::J
QI !I)
180 160 0
1 2
0 Time (hours)
Figure 1. The mean (:!:: SEM) of serum glucose concentrations at baseline and at 1 and 2 hours after ingestion of a test meal without acarbose (e) or when acarbose was given with the first bite of the meal at 25-mg (.), 50-mg (~), and 100-mg (T) doses. (N = 14) *, P < 0.01 compared with corresponding values when the test meal was ingested without acarbose.
when the test meal was given without acarbose (696.8 ± 30.2 mg/hr/dL; P < 0.0005). Increasing doses of acarbose to 50 mg or 100 mg had no significant additional effects on postprandial serum glucose concentrations compared with 25 mg of acarbose. It is possible that if a larger number of subjects were studied, some of the differences in response could have achieved statistical significance. Twentyfive milligrams of acarbose achieves a maximum glucose lowering effect after this test meal, probably because a maximal inhibitory effect on brush border glucosidase activity is achieved with this dose. The postprandial serum insulin concentration was not altered compared with baseline values with the administration of any of the three doses of acarbose (Figure 2). The lack of reduction in maximal insulin values despite the lower postprandial plasma glucose concentrations could be caused either by altered insulin secretory dynamics in older type 2 diabetic subjects or by the presence of a residual sulfonylurea effect. The latter is less likely because the postprandial insulin response to the test meal and acarbose was similar in subjects on sulfonylurea therapy (n = 9) compared with those on diet only (n = 5). There was a modest yet significant rise in postprandial serum triglyceride concentrations from a mean baseline value of 167.9 ± 25.4 mg/dL to 184.9 ± 26.7 mg/dL at 2 hours after the test meal
335
Acorbose in Older Subjects
60
220
55
210 :::- 200
50
:!2 C)
:::-
E
E
45
::::I
U)
CI)
.,2; 40 C
"0
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c 30
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·c CI)
170
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150
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25
E 140 :::l
20
en
CI)
~
en
CI)
0
1
1 2
0
Time (hours) Figure 2. The mean (± SEM) of serum insulin concentrations at baseline and at 1 and 2 hours after ingestion of a test meal without acarbose (e) or when acarbose was given with the first bite of the meal at 25-mg (.), 50-mg (.), and 100-mg (T) doses. (N = 14)
< 0.003). Acarbose administration at 25, 50, or
100 mg ameliorated the postprandial hypertriglyceridemia such that the one- or two-hour postprandial serum triglyceride concentrations were not significantly different from basal serum levels when acarbose was given with the test meal (Figure 3). During the acute dose-response studies, none of the subjects (n = 14) reported any gastrointestinal discomfort after the administration of a single dose of acarbose with the test meal. This acarbose dose-response study indicates that the efficacy of acarbose is near maximal at 25 mg when the meal size does not exceed 483 kcal and contains only 61 g of carbohydrates. Because acarbose is a competitive inhibitor of carbohydrate digestion,14 it is likely that the dose-response relationship for such an agent will vary with the size and composition of the meal, notably with the carbohydrate content. Thus, it is likely that if larger amounts of carbohydrates were consumed, higher doses of acarbose would have additional antihyperglycemic effects. However, in this study, the test meal was chosen to represent a balanced diet and to include items typical of the American diet. The size ofthe meal was chosen to simulate the average meal size consumed by an elderly population. 15 The subjects enrolled in the study indicated that they would rarely consume a meal larger than the one provided. As expected from previous experience with acarbose, the amelioration of postprandial hyperglyce-
336
130 120
15
(P
*
180
u >- 160 '51
35
:::l
190
1
01 2
0
Time (hours) Figure 3. The mean (± SEM) of serum triglyceride concentrations at baseline and at 1 and 2 hours after ingestion of a test meal without acarbose (e) or when acarbose was given with the first bite of the meal at 25-mg (.), 50-mg (.), and 100-mg (T) doses. (N = 14) *, P < 0.01 compared with baseline (time 0) value.
mia occurred without aggravation of hyperinsulinemia. 2 In addition, the postprandial lipemia also seemed to be ameliorated with 25 mg acarbose, although the effect was somewhat modest. The potential role of postprandial hyperlipidemia in atherogenesis has been suggested and the beneficial effect of a-glucosidase inhibitors in ameliorating postprandial lipemia has been previously documented.1 6 ,17 The present study confirms and extends these observations to the older patient population. Recently, it has been suggested that the measurement of blood glucose before and after administration of a test meal may be useful in clinical practice to guide acarbose dosage.1 8 ,19 A large cohort of subjects treated with various doses of acarbose in parallel fashion over at least 1 year is required to better address this issue. Overall, it seems that in older subjects with type 2 diabetes when carbohydrate intake is limited to only 61 g per meal, maximal acute antihyperglycemic efficacy can be achieved with 25 mg of acarbose. Larger studies are needed to determine if the acute response to acarbose can predict long-term efficacy in this population. References 1. Hoffman J, Spengler M. Efficacy of 24-week monotherapy with acarbose, glibenclamide, or placebo in NIDDM patients. Diabetes Care 1990;17:561-6. 2. Chiasson JL, Josse RG, Hunt JA, et al. The efficacy of acarbose in the treatment of patients with non-insulin-depenMay 2000 Volume 319 Number 5
Mooradian et 01
3. 4.
5.
6. 7.
8.
9. 10.
dent diabetes mellitus: a multicenter controlled clinical trial. Ann Intern Med 1994;121:928-35. Hanefeld M, Fischer S, Schulze J, et aI. Therapeutic potentials of acarbose as first-line drug in NIDDM insufficiently treated with diet alone. Diabetes Care 1991;14:732-8. Coniff RF, Shapiro JA, Seaton TB, et al. Multicenter, placebo-controlled trial comparing acarbose (BAY g 5421) with placebo, tolbutamide, and tolbutamide-plus-acarbose in non-insulin-dependent diabetes mellitus. Am J Med 1995;98: 443-5l. Coniff RF, Shapiro JA, Robbins D, et aI. Reduction of glycosylated hemoglobin and postprandial hyperglycemia by acarbose in patients with NIDDM. Diabetes Care 1995;18: 817-24. Johnston PS, Coniff RF, Hoogwerf BJ, et al. Effects of the carbohydrate inhibitor miglitol in sulfonylurea-treated NIDDM patients. Diabetes Care 1994;17:20-9. Schnack C, Prager RJF, Winkler J, et aI. Effects of 8-wk alpha glucosidase inhibition on metabolic control, C-peptide secretion, hepatic glucose output, and peripheral insulin sensitivity in poorly controlled type II diabetic patients. Diabetes Care 1989;12:537-43. Segal P, Feig PU, Schernthaner G, et al. The efficacy and safety of miglitol therapy compared with glibenclamide in patients with NIDDM inadequately controlled by diet alone. Diabetes Care 1997;20:687-9l. Johnston PS, Feig PU, Coniff RF, et aI. Chronic treatment of Mrican-American type 2 diabetic patients with a-glucosidase inhibition. Diabetes Care 1998;21:416-22. Johnston PS, Lebovitz HE, Coniff RF, et aI. Advantages of alpha glucosidase inhibition as monotherapy in elderly type 2 diabetic patients. J Clin Endocrinol Metab 1998;83: 1515-22.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
11. Mooradian A, Neumann C. PRECOSE resolution of optimal titration to enhance current therapies (PROTECT) study: experience in the elderly. J Am Geriatr Soc 1997;45: S49. 12. Mooradian AD. Biology of aging. In: Rehabilitation of the aging and elderly patient. Felsenthal G, GarrisonSG, Steinberg FU, editors. Baltimore: Williams & Wilkins; 1994. p. 3-10. 13. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20:1183-97. 14. Clissold SP, Edwards C. Acarbose: a preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. Drugs 1988;35:214-43. 15. Carroll MD, Dresser CM, ·Johnson CL, et al. Dietary intake of persons 1-74 years of age in the United States. Advance data from vital and health statistics ofthe National Center for Health Statistics No.6. Publication no. (HRA) 77-1250. Rockville (MD): Health Resources Administration, Public Health Service; 1977. 16. Hanefeld M, Temelkova-Kurktschiev T. The postprandial state and the risk of atherosclerosis. Diabet Med 1997; 14(Suppl 3):S6-S11. 17. Patsch JR, Miesenbock G, Hopferwieser T, et al. Relation of triglyceride metabolism and coronary artery disease. Studies in the postprandial state. Arterioscl Thromb 1992;12: 1336-45. 18. Wolever TMS. Assessing the antihyperglycemic effect of acarbose. Solid or liquid test meal? Diabetes Care 1998; 21:667-8. 19. Herman BL, Scbatz H, Pfeiffer A. Continuous blood glucose monitoring: the acute effect of acarbose on blood glucose variations. Med Klin 1998;93:651-5.
337
ABSTRACT: Objective: To examine the dose-response relationship of acarbose, an a-glucosidase inhibitor, in older subjects with type 2 diabetes. Research Oesign: Fourteen subjects with type 2 diabetes who were over 65 years old were studied. Five subjects had been treated with diet alone and 9 were receiving a sulfonylurea. The subjects underwent a meal tolerance test in the presence of varying doses of acarbose (0, 25, 50, and 100 mg) on 4 occasions, each 1 week apart. The test meal was chosen to include food items commonly consumed during breakfast in the United States. The 483kcal meal consisted of 51 % of calories in the form of carbohydrates, 14% protein, and 35% fat. The serum glucose, insulin, and triglyceride levels were measured
at 0, 1, and 2 hours after the meal. Results: The postprandial hyperglycemic response to the test meal was significantly reduced with 25 mg of acarbose compared with baseline values. Increasing doses of acarbose to 50 or 100 mg had no significant additional ameliorating effects on postprandial hyperglycemia. Postprandial insulin or triglyceride levels were not significantly altered with single dose acarbose treatment. Conclusions: It is concluded that the acute efficacy of acarbose is near maximal at 25 mg when the meal size does not exceed 483 kcal and contains only 61 gm of carbohydrates. KEY INDEXING TERMS: Aging; Acarbose; Elderly; Type 2 diabetes; Postprandial [Am J Med Sci 2000;319(5):
T
type 2 diabetes and postprandial hyperglycemia are very common.
he efficacy and safety of a-glucosidase inhibitors in subjects with type 2 diabetes have been previously demonstrated in several clinical trials. 1- 9 The post hoc analysis of the data from these trials has found no significant age-related difference in the efficacy or safety of these agents in the elderly population. In addition, controlled prospective studies, as well as surveys conducted after a drug has been put on the market, have also established the efficacy of these agents in the elderly.1O,ll However, an acute dose-response relationship of a-glucosidase inhibitors has not been previously established. The various determinants of postprandial glycemia, including the rate of gastric emptying, the small intestinal absorption capacity, and the insulin response, may be altered with age. 12 Therefore, it is important to establish the dose-res'ponse relationship of a-glucosidase inhibitors in this patient population in which
From the Division of Endocrinology, Department of Internal Medicine, St. Louis University Medical School, St. Louis, Missouri. Submitted May 20, 1999; accepted in revised form August 30, 1999. This study was supported by The Bayer Corporation (West Haven, CT). Correspondence: Arshag D. Mooradian, M.D., Division of Endocrinology, St. Louis University, Medical School, 1402 S. Grand Blvd., St. Louis, MO 63104.
334
334-7.]
Research Design and Methods
Subjects A total of21 subjects with type 2 diabetes over the age of 65 years were recruited from Saint Louis University Diabetes clinics. All subjects who met the criteria for the diagnosis of type 2 diabetes 13 signed an informed consent form approved by the Institutional Review Board of Saint Louis University. Of the original 21 subjects recruited, 5 were excluded for having hemoglobin (Hb) AlC of less than 6.9%, one was excluded for having HbA lC of more than 12.5%, and one subject was excluded because of scheduled back surgery during the course of the study. The mean [± standard error of the mean (SEM)] age of the 14 subjects enrolled was 70.4 ± 1.2 years. There were 7 men and 7 women. The mean body weight was 190.3 ± 6.4lb and the mean body mass index was 29.2 ± 0.93 kg/m2 . The mean HbA lC was 7.97 ± 0.23%. Nine subjects were on sulfonylurea (5-15 mg glipizide or 5-20 mg glyburide) and 5 were treated with diet only. None of the subjects had undergone prior gastrointestinal surgery or had any clinical evidence of gastropathy, such as postprandial bloating, nausea, May 2000 Volume 319 Number 5
Mooradian et al
vomiting, or abdominal pain. None were on medications known to alter gastrointestinal motility.
300
Study Plan and Measurements The subjects were given a test meal with or without acarbose on 4 occasions, each 1 week apart. After completion of the first test meal without acarbose, 3 additional tests were done in which each subject was given either 25 mg, 50 mg, or 100 mg of acarbose in random order. The pill was taken with the first bite of the meal. The serum glucose, insulin, and triglyceride levels were measured at 0, 1, and 2 hours after the meal. The 483-kcal meal consisted of 51% of calories in the form of carbohydrate (61 g), 14% protein (17 g) and 35% fat (19 g). The test meal included the following food items: 1 cup (8 oz) of Tropicana unsweetened orange juice, 1 cup (8 oz) of skim milk, 3/4 cup cereal (Rice Krispies for low fiber), and Swanson microwavable scrambled eggs with home fries. All the carbohydrate in this test meal, with the exception of 5 g of glucose, 5 g of fructose, and 11 g of lactose, is amenable to the effects of acarbose. All the tests were done in the morning after at least 9 hours of overnight fast. Those subjects on sulfonylurea therapy did not take their daily doses on the morning of testing. The subjects consumed the meal within 20 minutes and indicated that the meal size was somewhat larger than the size of any meal they would ordinarily consume.
280
Statistical Analysis Results are reported as mean (± SEM) unless specified otherwise. Parametric group mean data were analyzed by the student's t-test or analysis of variance. Paired data were analyzed by paired ttests or one-way analysis of variance for repeated measures. When there was a significant difference demonstrated by analysis of variance, post hoc analysis was performed by the Newman-Keuls procedure for subgroup analysis. Statistical procedures were performed with the statistical package Statistica for Windows (Statsoft Inc, Tulsa, OK). Significance was defined as a 2-tailed P < 0.05. Results and Discussion
The I-hour postprandial hyperglycemic response to the test meal was significantly reduced with 25 mg of acarbose (Figure 1). The mean I-hour postprandial serum glucose value decreased from a baseline of 273.9 ± 12.9 mg/dL to 249.6 ± 14.5 mg/dL when 25 mg acarbose was given (P < 0.008). The mean 2-hour postprandial serum glucose value decreased from a baseline of 258.5 ± 12.4 mg/dL to 213.0 ± 16.5 mg/dL (P < 0.0002). The area under the serum glucose curve when 25 mg of acarbose was given with the test meal (603.9 ± 48.9 mg/hr/dL) was significantly smaller than the area of the curve THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
260
!i!Cl .§. 240 QI
1*--~o:::---.J,[*
til
0
U
:::J
220
..
200
c;
*
E :::J
QI !I)
180 160 0
1 2
0 Time (hours)
Figure 1. The mean (:!:: SEM) of serum glucose concentrations at baseline and at 1 and 2 hours after ingestion of a test meal without acarbose (e) or when acarbose was given with the first bite of the meal at 25-mg (.), 50-mg (~), and 100-mg (T) doses. (N = 14) *, P < 0.01 compared with corresponding values when the test meal was ingested without acarbose.
when the test meal was given without acarbose (696.8 ± 30.2 mg/hr/dL; P < 0.0005). Increasing doses of acarbose to 50 mg or 100 mg had no significant additional effects on postprandial serum glucose concentrations compared with 25 mg of acarbose. It is possible that if a larger number of subjects were studied, some of the differences in response could have achieved statistical significance. Twentyfive milligrams of acarbose achieves a maximum glucose lowering effect after this test meal, probably because a maximal inhibitory effect on brush border glucosidase activity is achieved with this dose. The postprandial serum insulin concentration was not altered compared with baseline values with the administration of any of the three doses of acarbose (Figure 2). The lack of reduction in maximal insulin values despite the lower postprandial plasma glucose concentrations could be caused either by altered insulin secretory dynamics in older type 2 diabetic subjects or by the presence of a residual sulfonylurea effect. The latter is less likely because the postprandial insulin response to the test meal and acarbose was similar in subjects on sulfonylurea therapy (n = 9) compared with those on diet only (n = 5). There was a modest yet significant rise in postprandial serum triglyceride concentrations from a mean baseline value of 167.9 ± 25.4 mg/dL to 184.9 ± 26.7 mg/dL at 2 hours after the test meal
335
Acorbose in Older Subjects
60
220
55
210 :::- 200
50
:!2 C)
:::-
E
E
45
::::I
U)
CI)
.,2; 40 C
"0
U)
c 30
E
:::l ~
·c CI)
170
·c
150
l-
25
E 140 :::l
20
en
CI)
~
en
CI)
0
1
1 2
0
Time (hours) Figure 2. The mean (± SEM) of serum insulin concentrations at baseline and at 1 and 2 hours after ingestion of a test meal without acarbose (e) or when acarbose was given with the first bite of the meal at 25-mg (.), 50-mg (.), and 100-mg (T) doses. (N = 14)
< 0.003). Acarbose administration at 25, 50, or
100 mg ameliorated the postprandial hypertriglyceridemia such that the one- or two-hour postprandial serum triglyceride concentrations were not significantly different from basal serum levels when acarbose was given with the test meal (Figure 3). During the acute dose-response studies, none of the subjects (n = 14) reported any gastrointestinal discomfort after the administration of a single dose of acarbose with the test meal. This acarbose dose-response study indicates that the efficacy of acarbose is near maximal at 25 mg when the meal size does not exceed 483 kcal and contains only 61 g of carbohydrates. Because acarbose is a competitive inhibitor of carbohydrate digestion,14 it is likely that the dose-response relationship for such an agent will vary with the size and composition of the meal, notably with the carbohydrate content. Thus, it is likely that if larger amounts of carbohydrates were consumed, higher doses of acarbose would have additional antihyperglycemic effects. However, in this study, the test meal was chosen to represent a balanced diet and to include items typical of the American diet. The size ofthe meal was chosen to simulate the average meal size consumed by an elderly population. 15 The subjects enrolled in the study indicated that they would rarely consume a meal larger than the one provided. As expected from previous experience with acarbose, the amelioration of postprandial hyperglyce-
336
130 120
15
(P
*
180
u >- 160 '51
35
:::l
190
1
01 2
0
Time (hours) Figure 3. The mean (± SEM) of serum triglyceride concentrations at baseline and at 1 and 2 hours after ingestion of a test meal without acarbose (e) or when acarbose was given with the first bite of the meal at 25-mg (.), 50-mg (.), and 100-mg (T) doses. (N = 14) *, P < 0.01 compared with baseline (time 0) value.
mia occurred without aggravation of hyperinsulinemia. 2 In addition, the postprandial lipemia also seemed to be ameliorated with 25 mg acarbose, although the effect was somewhat modest. The potential role of postprandial hyperlipidemia in atherogenesis has been suggested and the beneficial effect of a-glucosidase inhibitors in ameliorating postprandial lipemia has been previously documented.1 6 ,17 The present study confirms and extends these observations to the older patient population. Recently, it has been suggested that the measurement of blood glucose before and after administration of a test meal may be useful in clinical practice to guide acarbose dosage.1 8 ,19 A large cohort of subjects treated with various doses of acarbose in parallel fashion over at least 1 year is required to better address this issue. Overall, it seems that in older subjects with type 2 diabetes when carbohydrate intake is limited to only 61 g per meal, maximal acute antihyperglycemic efficacy can be achieved with 25 mg of acarbose. Larger studies are needed to determine if the acute response to acarbose can predict long-term efficacy in this population. References 1. Hoffman J, Spengler M. Efficacy of 24-week monotherapy with acarbose, glibenclamide, or placebo in NIDDM patients. Diabetes Care 1990;17:561-6. 2. Chiasson JL, Josse RG, Hunt JA, et al. The efficacy of acarbose in the treatment of patients with non-insulin-depenMay 2000 Volume 319 Number 5
Mooradian et 01
3. 4.
5.
6. 7.
8.
9. 10.
dent diabetes mellitus: a multicenter controlled clinical trial. Ann Intern Med 1994;121:928-35. Hanefeld M, Fischer S, Schulze J, et aI. Therapeutic potentials of acarbose as first-line drug in NIDDM insufficiently treated with diet alone. Diabetes Care 1991;14:732-8. Coniff RF, Shapiro JA, Seaton TB, et al. Multicenter, placebo-controlled trial comparing acarbose (BAY g 5421) with placebo, tolbutamide, and tolbutamide-plus-acarbose in non-insulin-dependent diabetes mellitus. Am J Med 1995;98: 443-5l. Coniff RF, Shapiro JA, Robbins D, et aI. Reduction of glycosylated hemoglobin and postprandial hyperglycemia by acarbose in patients with NIDDM. Diabetes Care 1995;18: 817-24. Johnston PS, Coniff RF, Hoogwerf BJ, et al. Effects of the carbohydrate inhibitor miglitol in sulfonylurea-treated NIDDM patients. Diabetes Care 1994;17:20-9. Schnack C, Prager RJF, Winkler J, et aI. Effects of 8-wk alpha glucosidase inhibition on metabolic control, C-peptide secretion, hepatic glucose output, and peripheral insulin sensitivity in poorly controlled type II diabetic patients. Diabetes Care 1989;12:537-43. Segal P, Feig PU, Schernthaner G, et al. The efficacy and safety of miglitol therapy compared with glibenclamide in patients with NIDDM inadequately controlled by diet alone. Diabetes Care 1997;20:687-9l. Johnston PS, Feig PU, Coniff RF, et aI. Chronic treatment of Mrican-American type 2 diabetic patients with a-glucosidase inhibition. Diabetes Care 1998;21:416-22. Johnston PS, Lebovitz HE, Coniff RF, et aI. Advantages of alpha glucosidase inhibition as monotherapy in elderly type 2 diabetic patients. J Clin Endocrinol Metab 1998;83: 1515-22.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
11. Mooradian A, Neumann C. PRECOSE resolution of optimal titration to enhance current therapies (PROTECT) study: experience in the elderly. J Am Geriatr Soc 1997;45: S49. 12. Mooradian AD. Biology of aging. In: Rehabilitation of the aging and elderly patient. Felsenthal G, GarrisonSG, Steinberg FU, editors. Baltimore: Williams & Wilkins; 1994. p. 3-10. 13. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20:1183-97. 14. Clissold SP, Edwards C. Acarbose: a preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. Drugs 1988;35:214-43. 15. Carroll MD, Dresser CM, ·Johnson CL, et al. Dietary intake of persons 1-74 years of age in the United States. Advance data from vital and health statistics ofthe National Center for Health Statistics No.6. Publication no. (HRA) 77-1250. Rockville (MD): Health Resources Administration, Public Health Service; 1977. 16. Hanefeld M, Temelkova-Kurktschiev T. The postprandial state and the risk of atherosclerosis. Diabet Med 1997; 14(Suppl 3):S6-S11. 17. Patsch JR, Miesenbock G, Hopferwieser T, et al. Relation of triglyceride metabolism and coronary artery disease. Studies in the postprandial state. Arterioscl Thromb 1992;12: 1336-45. 18. Wolever TMS. Assessing the antihyperglycemic effect of acarbose. Solid or liquid test meal? Diabetes Care 1998; 21:667-8. 19. Herman BL, Scbatz H, Pfeiffer A. Continuous blood glucose monitoring: the acute effect of acarbose on blood glucose variations. Med Klin 1998;93:651-5.
337