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Triple Oral Antidiabetic Therapy
Triple Oral Antidiabetic Therapy Todd B. Kaye
ABSTRACT Our objective was to determine the efficacy of adding acarbose to the combination of metformin and a sulfonylurea in the treatment of type II diabetes mellitus. Acarbose was added to the treatment regimen of 11 type II diabetic patients who were not adequately controlled on the combination of a sulfonylurea and metformin. Glycosylated hemoglobin before and after the addition of acarbose was compared to assess the efficacy of this additional therapy. One patient did not tolerate acarbose therapy. Of the remaining ten patients, the mean improvement in
glycosylated hemoglobin with the addition of acarbose was 1.4 percentage points, p 5 0.01. Eight patients had improvements in glycosylated hemoglobin; mean improvement, 2.0 percentage points. Two patients’ glycohemoglobin values worsened. Thus, the addition of acarbose to the treatment regimen of type II diabetic patients presently on a combination of a sulfonylurea and metformin improves glycemic control. (Journal of Diabetes and Its Complications 12; 6: 311–313, 1998.) 1998 Elsevier Science Inc.
INTRODUCTION
by combination therapy with a sulfonylurea medication, metformin, and acarbose.
S
ince 1995, there have been four new oral antidiabetic agents approved for the use in the United States in treating type II diabetes mellitus—metformin, acarbose, miglitol, and troglitazone. This advance has afforded physicians the opportunity to use combinations of oral medications to treat type II diabetic patients who are not properly controlled with one medication. Studies have established the beneficial effects on glycemic control of adding metformin,1,2 acarbose,3,4 and troglitazone5 to sulfonylurea therapy. A study has also demonstrated that glycemic control improves with the addition of acarbose to metformin therapy.4 However, there are no studies to date assessing the efficacy of combining three different classes of anti-diabetic agents. This study reports the changes in glycemic control achieved
Camino Medical Group, Sunnyvale, California, USA Reprint requests to be sent to: Dr. Todd B. Kaye, Camino Medical Group, 301 Old San Francisco Road, Sunnyvale, CA 94086, USA. Data from this manuscript has been published as an abstract in Diabetes, Abstract Book, 57th Annual Meeting and Scientific Sessions, American Diabetes Association, 1997, abstract 1112. Journal of Diabetes and Its Complications 1998; 12:311–313 1998 Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
METHODS Eleven Caucasian patients (seven men, four women; mean age, 64 years; range, 46–77 years) with type II diabetes mellitus did not have proper glycemic control, despite education about a diabetic meal plan and exercise, maximal sulfonylurea therapy, and maximal tolerated metformin therapy. Acarbose was added to the treatment regimen of these 11 patients. Dosing was initiated at 25 mg at the beginning of each meal, and increasing to 50 mg three times daily and then 100 mg three times daily at 4-week intervals, if tolerated. Patients’ baseline characteristics and doses of medications are summarized in Table 1. Total glycosylated hemoglobin [assayed by electrophoresis (Helena REp), reference range, 5.0%–7.9%) and weight were measured at the initiation of acarbose therapy and after 3 months of maximal acarbose therapy. Statistical differences were analyzed by paired t-test. RESULTS The results of the changes in glycohemoglobin and weight measurements with the addition of acarbose to 1056-8727/98/$19.00 PII S1056-8727(98)00013-0
312
KAYE
J Diab Comp 1998; 12:311–313
TABLE 1. PATIENT CHARACTERISTICS Patient 1 2 3 4 5 6 7 8 9 10 11 a
Age/Gender
Sulfonylurea
Metformin Dose
51 yo M 75 yo F 69 yo M 46 yo F 62 yo M 73 yo M 66 yo M 56 yo M 77 yo F 67 yo M 65 yo F
glyburide 10 mg b.i.d. glyburide 10 mg b.i.d. glucotrol XL 20 mg q.d. glyburide 10 mg b.i.d. glyburide 10 mg b.i.d. glyburide 10 mg b.i.d. glyburide 10 mg b.i.d. glyburide 10 mg b.i.d. glyucotrol XL 20 mg q.d. glyburide 10 mg b.i.d. glyburide 10 mg b.i.d.
850 mg t.i.d. 850 mg t.i.d. 850 mg b.i.d. 850 mg b.i.d. 850 mg b.i.d. 850 mg t.i.d. 850 mg b.i.d. 850 mg t.i.d. 850 mg t.i.d. 850 mg t.i.d. 850 mg t.i.d.
Maximal Acarbose Dose 50 mg t.i.d. 50 mg b.i.d. 50 mg t.i.d. 100 mg t.i.d. 100 mg t.i.d. 50 mg t.i.d. 25 mg t.i.d. 200 mg t.i.d. 50 mg t.i.d. 100 mg b.i.d. a
Patient did not tolerate acarbose.
sulfonylurea and metformin treatment are summarized in Table 2. Eight patients had an improvement in the glycohemoglobin measurement, two patients had a worsening of glycohemoglobin, and one patient did not tolerate acarbose (due to flatulence). Of the ten patients who continued with acarbose treatment, mean glycohemoglobin decreased by 1.4 percentage points, from 13.6% 6 2.8% before acarbose to 12.2% 6 3.1% after 3 months of maximal acarbose therapy (p 5 0.01). The mean improvement in glycohemoglobin in the eight responders was 2.0 percentage points, ranging from 1.0% to 2.6%. The mean weight before acarbose was 91.6 6 23.1 kg; mean weight after 3 months of maximal acarbose therapy was 89.5 6 22.0 kg, p 5 0.044. DISCUSSION Sulfonlylurea medications improve glycemic control by increasing insulin production. Metformin decreases hepatic glucose production and peripheral glucose up-
take. Acarbose delays digestion of complex carbohydrates. Given these different mechanisms of action, using combinations of these agents should have beneficial effects on glycemic control. This benefit has been established for combinations of two of these agents.1–5 This study demonstrates the improvement in glycosylated hemoglobin with the triple combination of a sulfonylurea medication, metformin, and acarbose. The major limitation of this study is the lack of a placebo control group. It is possible that the beneficial changes in glycohemoglobin may have been due to changes in diet and exercise, and not from the effects of acarbose. Acarbose therapy is not associated with weight loss. However, patients only weighed 2.1 kg less (a 2.3% decrease) after using acarbose compared to their weight before starting acarbose. The mean improvement in glycosylated hemoglobin in this study was 1.4 percentage points. This degree of improvement is clinically relevant as well as statistically significant. Klein6 has calculated that a 1 percent-
TABLE 2. GLYCOHEMOGLOBIN AND WEIGHTS BEFORE AND AFTER THE ADDITION OF ACARBOSE Patient 1 2 3 4 5 6 7 8 9 10
Glycohemoglobin Before Acarbose
Glycohemoglobin After Acarbose
Weight Before Acarbose (kg)
Weight After Acarbose (kg)
13.5% 16.3% 12.4% 11.1% 12.1% 13.0% 11.3% 20.0% 13.2% 13.4%
11.4% 12.4% 10.3% 8.9% 10.0% 10.4% 9.0% 19.0% 14.7% 14.0%
99 101 78 90 82 117 79 135 52 83
94 98 79 87 82 118 76 128 50 84
Patient 11 did not tolerate acarbose.
J Diab Comp 1998; 12:311–313
age point difference in glycohemoglobin translates into a 50% difference in the risk of developing retinopathy and a 10% difference in the risk of developing ischemic heart disease. This study demonstrates the beneficial effects of triple antidiabetic therapy, by adding acarbose to the treatment regimen of type II diabetic patients not adequately controlled on combination sulfonylurea and metformin therapy. REFERENCES 1. DeFronzo RA, Goodman AM, and the Multicenter Metformin Study Group: Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 333:541–549, 1995. 2. Haupt E, Knick B, Koschinsky T, Liebermeister H, Schneider J, Hirche H: Oral antidiabetic combination
TRIPLE ORAL ANTIDIABETIC THERAPY
3.
4.
5.
6.
313
therapy with sulphonylureas and metformin. Diabete Metab 17:224–231, 1991. Coniff RF, Shapiro JA, Seaton TB, Bray GA: Multicenter, place-controlled trial comparing acarbose (BAY g 5421) with placebo, tolbutamide, and tolbutamide-plus-acarbose in non–insulin-dependent diabetes mellitus. Am J Med 98:443–451, 1995. Chiasson JL, Josse RG, Hunt JA, Palmason C, Rodger NW, Ross SA, Ryan EA, Tan MH, Wolever TMS: The efficacy of acarbose in the treatment of patients with non–insulin-dependent diabetes mellitus. Ann Intern Med 121:928–935, 1994. Iwamoto Y, Kosaka K, Kuzuya T, Akanuma Y, Shigeta Y, Kaneko T: Effect of combination therapy of troglitazone and sulphonylureas in patients with type 2 diabetes who were poorly controlled by sulphonylurea therapy alone. Diabetic Med 13:365–370, 1996. Klein R: Hyperglycemia and microvascular and macrovascular disease in diabetes. Diabetes Care 18:258–268, 1995.
ABSTRACT Our objective was to determine the efficacy of adding acarbose to the combination of metformin and a sulfonylurea in the treatment of type II diabetes mellitus. Acarbose was added to the treatment regimen of 11 type II diabetic patients who were not adequately controlled on the combination of a sulfonylurea and metformin. Glycosylated hemoglobin before and after the addition of acarbose was compared to assess the efficacy of this additional therapy. One patient did not tolerate acarbose therapy. Of the remaining ten patients, the mean improvement in
glycosylated hemoglobin with the addition of acarbose was 1.4 percentage points, p 5 0.01. Eight patients had improvements in glycosylated hemoglobin; mean improvement, 2.0 percentage points. Two patients’ glycohemoglobin values worsened. Thus, the addition of acarbose to the treatment regimen of type II diabetic patients presently on a combination of a sulfonylurea and metformin improves glycemic control. (Journal of Diabetes and Its Complications 12; 6: 311–313, 1998.) 1998 Elsevier Science Inc.
INTRODUCTION
by combination therapy with a sulfonylurea medication, metformin, and acarbose.
S
ince 1995, there have been four new oral antidiabetic agents approved for the use in the United States in treating type II diabetes mellitus—metformin, acarbose, miglitol, and troglitazone. This advance has afforded physicians the opportunity to use combinations of oral medications to treat type II diabetic patients who are not properly controlled with one medication. Studies have established the beneficial effects on glycemic control of adding metformin,1,2 acarbose,3,4 and troglitazone5 to sulfonylurea therapy. A study has also demonstrated that glycemic control improves with the addition of acarbose to metformin therapy.4 However, there are no studies to date assessing the efficacy of combining three different classes of anti-diabetic agents. This study reports the changes in glycemic control achieved
Camino Medical Group, Sunnyvale, California, USA Reprint requests to be sent to: Dr. Todd B. Kaye, Camino Medical Group, 301 Old San Francisco Road, Sunnyvale, CA 94086, USA. Data from this manuscript has been published as an abstract in Diabetes, Abstract Book, 57th Annual Meeting and Scientific Sessions, American Diabetes Association, 1997, abstract 1112. Journal of Diabetes and Its Complications 1998; 12:311–313 1998 Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
METHODS Eleven Caucasian patients (seven men, four women; mean age, 64 years; range, 46–77 years) with type II diabetes mellitus did not have proper glycemic control, despite education about a diabetic meal plan and exercise, maximal sulfonylurea therapy, and maximal tolerated metformin therapy. Acarbose was added to the treatment regimen of these 11 patients. Dosing was initiated at 25 mg at the beginning of each meal, and increasing to 50 mg three times daily and then 100 mg three times daily at 4-week intervals, if tolerated. Patients’ baseline characteristics and doses of medications are summarized in Table 1. Total glycosylated hemoglobin [assayed by electrophoresis (Helena REp), reference range, 5.0%–7.9%) and weight were measured at the initiation of acarbose therapy and after 3 months of maximal acarbose therapy. Statistical differences were analyzed by paired t-test. RESULTS The results of the changes in glycohemoglobin and weight measurements with the addition of acarbose to 1056-8727/98/$19.00 PII S1056-8727(98)00013-0
312
KAYE
J Diab Comp 1998; 12:311–313
TABLE 1. PATIENT CHARACTERISTICS Patient 1 2 3 4 5 6 7 8 9 10 11 a
Age/Gender
Sulfonylurea
Metformin Dose
51 yo M 75 yo F 69 yo M 46 yo F 62 yo M 73 yo M 66 yo M 56 yo M 77 yo F 67 yo M 65 yo F
glyburide 10 mg b.i.d. glyburide 10 mg b.i.d. glucotrol XL 20 mg q.d. glyburide 10 mg b.i.d. glyburide 10 mg b.i.d. glyburide 10 mg b.i.d. glyburide 10 mg b.i.d. glyburide 10 mg b.i.d. glyucotrol XL 20 mg q.d. glyburide 10 mg b.i.d. glyburide 10 mg b.i.d.
850 mg t.i.d. 850 mg t.i.d. 850 mg b.i.d. 850 mg b.i.d. 850 mg b.i.d. 850 mg t.i.d. 850 mg b.i.d. 850 mg t.i.d. 850 mg t.i.d. 850 mg t.i.d. 850 mg t.i.d.
Maximal Acarbose Dose 50 mg t.i.d. 50 mg b.i.d. 50 mg t.i.d. 100 mg t.i.d. 100 mg t.i.d. 50 mg t.i.d. 25 mg t.i.d. 200 mg t.i.d. 50 mg t.i.d. 100 mg b.i.d. a
Patient did not tolerate acarbose.
sulfonylurea and metformin treatment are summarized in Table 2. Eight patients had an improvement in the glycohemoglobin measurement, two patients had a worsening of glycohemoglobin, and one patient did not tolerate acarbose (due to flatulence). Of the ten patients who continued with acarbose treatment, mean glycohemoglobin decreased by 1.4 percentage points, from 13.6% 6 2.8% before acarbose to 12.2% 6 3.1% after 3 months of maximal acarbose therapy (p 5 0.01). The mean improvement in glycohemoglobin in the eight responders was 2.0 percentage points, ranging from 1.0% to 2.6%. The mean weight before acarbose was 91.6 6 23.1 kg; mean weight after 3 months of maximal acarbose therapy was 89.5 6 22.0 kg, p 5 0.044. DISCUSSION Sulfonlylurea medications improve glycemic control by increasing insulin production. Metformin decreases hepatic glucose production and peripheral glucose up-
take. Acarbose delays digestion of complex carbohydrates. Given these different mechanisms of action, using combinations of these agents should have beneficial effects on glycemic control. This benefit has been established for combinations of two of these agents.1–5 This study demonstrates the improvement in glycosylated hemoglobin with the triple combination of a sulfonylurea medication, metformin, and acarbose. The major limitation of this study is the lack of a placebo control group. It is possible that the beneficial changes in glycohemoglobin may have been due to changes in diet and exercise, and not from the effects of acarbose. Acarbose therapy is not associated with weight loss. However, patients only weighed 2.1 kg less (a 2.3% decrease) after using acarbose compared to their weight before starting acarbose. The mean improvement in glycosylated hemoglobin in this study was 1.4 percentage points. This degree of improvement is clinically relevant as well as statistically significant. Klein6 has calculated that a 1 percent-
TABLE 2. GLYCOHEMOGLOBIN AND WEIGHTS BEFORE AND AFTER THE ADDITION OF ACARBOSE Patient 1 2 3 4 5 6 7 8 9 10
Glycohemoglobin Before Acarbose
Glycohemoglobin After Acarbose
Weight Before Acarbose (kg)
Weight After Acarbose (kg)
13.5% 16.3% 12.4% 11.1% 12.1% 13.0% 11.3% 20.0% 13.2% 13.4%
11.4% 12.4% 10.3% 8.9% 10.0% 10.4% 9.0% 19.0% 14.7% 14.0%
99 101 78 90 82 117 79 135 52 83
94 98 79 87 82 118 76 128 50 84
Patient 11 did not tolerate acarbose.
J Diab Comp 1998; 12:311–313
age point difference in glycohemoglobin translates into a 50% difference in the risk of developing retinopathy and a 10% difference in the risk of developing ischemic heart disease. This study demonstrates the beneficial effects of triple antidiabetic therapy, by adding acarbose to the treatment regimen of type II diabetic patients not adequately controlled on combination sulfonylurea and metformin therapy. REFERENCES 1. DeFronzo RA, Goodman AM, and the Multicenter Metformin Study Group: Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 333:541–549, 1995. 2. Haupt E, Knick B, Koschinsky T, Liebermeister H, Schneider J, Hirche H: Oral antidiabetic combination
TRIPLE ORAL ANTIDIABETIC THERAPY
3.
4.
5.
6.
313
therapy with sulphonylureas and metformin. Diabete Metab 17:224–231, 1991. Coniff RF, Shapiro JA, Seaton TB, Bray GA: Multicenter, place-controlled trial comparing acarbose (BAY g 5421) with placebo, tolbutamide, and tolbutamide-plus-acarbose in non–insulin-dependent diabetes mellitus. Am J Med 98:443–451, 1995. Chiasson JL, Josse RG, Hunt JA, Palmason C, Rodger NW, Ross SA, Ryan EA, Tan MH, Wolever TMS: The efficacy of acarbose in the treatment of patients with non–insulin-dependent diabetes mellitus. Ann Intern Med 121:928–935, 1994. Iwamoto Y, Kosaka K, Kuzuya T, Akanuma Y, Shigeta Y, Kaneko T: Effect of combination therapy of troglitazone and sulphonylureas in patients with type 2 diabetes who were poorly controlled by sulphonylurea therapy alone. Diabetic Med 13:365–370, 1996. Klein R: Hyperglycemia and microvascular and macrovascular disease in diabetes. Diabetes Care 18:258–268, 1995.