Pilot Study of Miglitol and Sitagliptin for T2DM
Background Glucose fluctuations including robust postprandial hyperglycemia are a risk for promoting atherosclerosis and diabetic complications. The α-glucosidase inhibitors and the dipeptidyl peptidase-4 (DPP-4) inhibitors have been found to effectively decrease postprandial hyperglycemia independently. Therefore, glycemic control with the combination of these drugs is warranted.
Methods Continuous glucose monitoring (CGM) was performed for 3 patients with type 2 diabetes and 1 control subject from the beginning to the end of the study. Medications were not administered to any of the subjects on the first day of the study. From the second day to the end of study (days 2–5), the subjects received miglitol (150 mg per day) and on days 4 and 5, sitagliptin (50 mg per day) was added to the treatment regimen. On the first, third, and fifth days of the study, blood was drawn at 0, 30, 60, 120, 180, and 240 min after breakfast for measurements of serum insulin, 1,5-anhydroglucitol (1,5-AG), plasma glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP).
Results Measurements of CGM and 1,5-AG levels showed that miglitol attenuated the escalation and fluctuation of glucose levels, and this was even more pronounced with the combination of miglitol and sitagliptin. The patterns of insulin secretion and glucagon secretion with miglitol alone or with a combination of miglitol and sitagliptin were various in the study subjects. Miglitol alone enhanced the release of GLP-1 in 1 patient with type 2 diabetes and the control subject, whereas the combination of miglitol and sitagliptin increased GLP-1 levels to varying degrees in all the subjects. Except for 1 subject, none of the subjects showed any change in GIP levels after the addition of sitagliptin, compared to the administration of miglitol alone.
Conclusions In conclusion, CGM measurements revealed that a combination of the α-GI miglitol and the DPP-4 inhibitor sitagliptin effectively reduced postprandial glucose fluctuation and stabilized blood glucose levels. Completely different response patterns of insulin, glucagon, GLP-1, and GIP were observed among the study subjects with either medication alone or in combination, suggesting that individual hormone-dependent glycemic responses to the α-GI and DPP-4 inhibitors are complicated and multifactorial.
Patients with type 2 diabetes mellitus are at an increased risk for cardiovascular disease. Recent studies have indicated that glycemic variability plays a role in the pathogenesis of atherosclerosis, because acute fluctuations of glucose levels lead to oxidative stress and have more deleterious effects on the development of cardiovascular complications in patients with diabetes than sustained hyperglycemia. Therefore, improved clinical outcomes in patients with diabetes may be related to the effort to reduce the fluctuations of glucose levels.
α-Glucosidase inhibitors (α-GIs), a promising class of glycemic control agents delay the absorbance of carbohydrates and decrease both postprandial hyperglycemia and hyperinsulinemia. These agents inhibit the activity of α-glucosidase, which is a membrane-bound enzyme located in the epithelium of the small intestine and is involved in the digestion of carbohydrates. By competitively inhibiting the breakdown of carbohydrates, α-GIs delay the absorption of digested carbohydrates from the small intestine and thus lower both postprandial glucose and insulin levels. Results of the STOP-NIDDM randomized trial showed that the α-GI acarbose could be used, either as an alternative or in addition to a change in lifestyle, to delay the development of type 2 diabetes in patients with impaired glucose tolerance.
Another promising class of therapeutic targets for decreasing glucose fluctuations is the incretin-related agents. There has been a recent increased appreciation for the role of incretins in controlling the postprandial metabolic milieu. The incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from enteroendocrine cells and enhance insulin secretion. Incretins are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4), resulting in a very short half-life. DPP-4 inhibitors, such as sitagliptin, increase active GLP-1 and GIP levels by inhibiting DPP-4 enzymatic activity and improve hyperglycemia in a glucose-dependent fashion by increasing serum insulin and decreasing serum glucagon levels in diabetic patients. In addition, the α-GIs reportedly enhance GLP-1 responses and reduce total GIP responses. The combination of an α-GI and a DPP-4 inhibitor has been reported to increase active GLP-1 levels and additively improve glucose tolerance in mice, compared to DPP-4 inhibitor alone. Considering the different but complementary mechanisms of action by which α-GIs and DPP-4 inhibitors lower glucose levels and increase GLP-1 action, a combination therapy with these agents may provide a valuable means of treating diabetes.
The aim of the present study is to evaluate the efficacy of miglitol alone and in combination with sitagliptin on changes in blood glucose levels, precisely evaluated by a continuous glucose-monitoring system (CGMS), and determine the effect of these agents on changes in insulin, 1,5-anhydroglucitol (1,5 AG), glucagon, GLP-1, and GIP levels in subjects with type 2 diabetes.
Abstract and Introduction
Abstract
Background Glucose fluctuations including robust postprandial hyperglycemia are a risk for promoting atherosclerosis and diabetic complications. The α-glucosidase inhibitors and the dipeptidyl peptidase-4 (DPP-4) inhibitors have been found to effectively decrease postprandial hyperglycemia independently. Therefore, glycemic control with the combination of these drugs is warranted.
Methods Continuous glucose monitoring (CGM) was performed for 3 patients with type 2 diabetes and 1 control subject from the beginning to the end of the study. Medications were not administered to any of the subjects on the first day of the study. From the second day to the end of study (days 2–5), the subjects received miglitol (150 mg per day) and on days 4 and 5, sitagliptin (50 mg per day) was added to the treatment regimen. On the first, third, and fifth days of the study, blood was drawn at 0, 30, 60, 120, 180, and 240 min after breakfast for measurements of serum insulin, 1,5-anhydroglucitol (1,5-AG), plasma glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP).
Results Measurements of CGM and 1,5-AG levels showed that miglitol attenuated the escalation and fluctuation of glucose levels, and this was even more pronounced with the combination of miglitol and sitagliptin. The patterns of insulin secretion and glucagon secretion with miglitol alone or with a combination of miglitol and sitagliptin were various in the study subjects. Miglitol alone enhanced the release of GLP-1 in 1 patient with type 2 diabetes and the control subject, whereas the combination of miglitol and sitagliptin increased GLP-1 levels to varying degrees in all the subjects. Except for 1 subject, none of the subjects showed any change in GIP levels after the addition of sitagliptin, compared to the administration of miglitol alone.
Conclusions In conclusion, CGM measurements revealed that a combination of the α-GI miglitol and the DPP-4 inhibitor sitagliptin effectively reduced postprandial glucose fluctuation and stabilized blood glucose levels. Completely different response patterns of insulin, glucagon, GLP-1, and GIP were observed among the study subjects with either medication alone or in combination, suggesting that individual hormone-dependent glycemic responses to the α-GI and DPP-4 inhibitors are complicated and multifactorial.
Introduction
Patients with type 2 diabetes mellitus are at an increased risk for cardiovascular disease. Recent studies have indicated that glycemic variability plays a role in the pathogenesis of atherosclerosis, because acute fluctuations of glucose levels lead to oxidative stress and have more deleterious effects on the development of cardiovascular complications in patients with diabetes than sustained hyperglycemia. Therefore, improved clinical outcomes in patients with diabetes may be related to the effort to reduce the fluctuations of glucose levels.
α-Glucosidase inhibitors (α-GIs), a promising class of glycemic control agents delay the absorbance of carbohydrates and decrease both postprandial hyperglycemia and hyperinsulinemia. These agents inhibit the activity of α-glucosidase, which is a membrane-bound enzyme located in the epithelium of the small intestine and is involved in the digestion of carbohydrates. By competitively inhibiting the breakdown of carbohydrates, α-GIs delay the absorption of digested carbohydrates from the small intestine and thus lower both postprandial glucose and insulin levels. Results of the STOP-NIDDM randomized trial showed that the α-GI acarbose could be used, either as an alternative or in addition to a change in lifestyle, to delay the development of type 2 diabetes in patients with impaired glucose tolerance.
Another promising class of therapeutic targets for decreasing glucose fluctuations is the incretin-related agents. There has been a recent increased appreciation for the role of incretins in controlling the postprandial metabolic milieu. The incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from enteroendocrine cells and enhance insulin secretion. Incretins are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4), resulting in a very short half-life. DPP-4 inhibitors, such as sitagliptin, increase active GLP-1 and GIP levels by inhibiting DPP-4 enzymatic activity and improve hyperglycemia in a glucose-dependent fashion by increasing serum insulin and decreasing serum glucagon levels in diabetic patients. In addition, the α-GIs reportedly enhance GLP-1 responses and reduce total GIP responses. The combination of an α-GI and a DPP-4 inhibitor has been reported to increase active GLP-1 levels and additively improve glucose tolerance in mice, compared to DPP-4 inhibitor alone. Considering the different but complementary mechanisms of action by which α-GIs and DPP-4 inhibitors lower glucose levels and increase GLP-1 action, a combination therapy with these agents may provide a valuable means of treating diabetes.
The aim of the present study is to evaluate the efficacy of miglitol alone and in combination with sitagliptin on changes in blood glucose levels, precisely evaluated by a continuous glucose-monitoring system (CGMS), and determine the effect of these agents on changes in insulin, 1,5-anhydroglucitol (1,5 AG), glucagon, GLP-1, and GIP levels in subjects with type 2 diabetes.
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