Original Article
Endocrinol Metab 2015;30:509-513 http://dx.doi.org/10.3803/EnM.2015.30.4.509 pISSN 2093-596X · eISSN 2093-5978
Clinical Characteristics of Subjects with SulfonylureaDependent Type 2 Diabetes Se Hee Min, Soo Heon Kwak, Young Min Cho, Kyong Soo Park, Hye Seung Jung Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea Background: Even though several oral anti-diabetic drugs (OAD) with various modes of action are replacing sulfonylurea (SU), some patients seem to be dependent on SU for adequate glycemic control. Therefore, we evaluated the clinical characteristics of such patients. Methods: We selected the patients with type 2 diabetes who met following criteria from 2009 to 2014 at Seoul National University Hospital: glycated hemoglobin (HbA1c) was maintained below 7.5% for at least 6 months under small dose of SU (glimepiride ≤2 mg/day or equivalent dose); after discontinuation of SU, HbA1c increased ≥1.2% within 3 months or ≥1.5% within 6 months; and after resuming SU, HbA1c reduction was ≥0.8% or reduction of fasting plasma glucose was ≥40 mg/dL within 3 months. Patients with impaired hepatic or renal function, and steroid users were excluded. Results: Nineteen subjects were enrolled: after averaged 4.8±1.5 months of SU-free period, HbA1c increased from 6.7%±0.4% to 8.8%±0.8% even though adding other OAD such as gliptins. However, HbA1c decreased to 7.4%±0.7% after resuming SU within 2.4±0.8 months. There was no sexual predominance. Despite their old age (67±11 years) and long duration of diabetes (18±10 years), fasting C-peptide was relatively well-reserved (3.9±2.6 ng/mL), and nephropathy was not observed (albumincreatinine ratio 21.2±16.6 mg/g and estimated glomerular filtration rate 75.8±18.0 mL/min/1.73 m2). Strong family history was also noted (73.7%). Conclusion: Despite hypoglycemia risk of SU, it seemed indispensable for a subset of patients with regard to insulin secretion. Genetic influences would be evaluated. Keywords: Sulfonylurea; Diabetes mellitus; Insulin secretion
INTRODUCTION It is necessary to control serum glucose tightly to prevent microvascular complications in type 2 diabetes mellitus (T2DM), and many guidelines recommend target glycated hemoglobin (HbA1c) less than 6.5% to 7% [1,2]. However, in several studies, intensive glycemic control was reported to increase mortal-
Received: 20 March 2015, Revised: 20 May 2015, Accepted: 2 July 2015 Corresponding author: Hye Seung Jung Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: +82-2-2072-0240, Fax: +82-2-762-9662, E-mail: [email protected]
ity, without significant reduction in cardiovascular events [3]. Although mechanisms for association between intensive glycemic control and increased mortality are not yet established, one possibility is hypoglycemia [4]. Even though hypoglycemia might not directly cause fatal outcome, it is known to induce hypoglycemia unawareness and to decrease quality of life [5,6]. So not only glucose lowering effects but also risk of hy-
Copyright © 2015 Korean Endocrine Society This is an Open Access article distributed under the terms of the Creative Com mons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribu tion, and reproduction in any medium, provided the original work is properly cited.
www.e-enm.org 509
Min SH, et al.
METHODS
poglycemia should be an important factor in the treatment of T2DM. Among oral anti-diabetic drugs (OAD), sulfonylureas (SU), glinides and incretin based therapy stimulate insulin secretion, and can cause hypoglycemia. SU is one of the most prescribed OAD and has strong glycemic control effects. However, it has risk of severe hypoglycemia, and higher mortality has been reported to be associated with SU compared with metformin [7,8]. In addition, several OAD have been developed with different modes of actions, what can replace SU. Therefore, SU is losing ground as monotherapy, although it is still actively prescribed for combination with other OAD [9]. But we detected that some patients seemed to be extremely dependent on SU for glycemic control. They were very responsive to just small doses of SU and demonstrated stable glycemic control, but when the SU were stopped, glucose levels dramatically deteriorated and were not recovered until SU were resumed. Therefore, we researched those subjects and evaluated their clinical characteristics.
We retrospectively sorted patients with T2DM under SU from 2009 to 2014 by searching electrical medical record. Among these patients, we selected patients who met following criteria: (1) subjects whose HbA1c was maintained below 7.5% for at least 6 months under small dose of SU (glimepiride ≤2 mg/day or equivalent dose); (2) after discontinuation of SU with/without compensation by adding or dosing-up of other OAD, HbA1c increased ≥1.2% within 3 months or ≥1.5% within 6 months; and (3) within 3 months of SU resuming, HbA1c reduction was ≥0.8% or fasting plasma glucose reduction was ≥40 mg/dL. Conversion of SU into glimepiride-equivalent dose is presented in Table 1 [10,11]. Exclusion criteria were as follows: impaired renal function (serum creatinine >1.4 mg/dL or estimated glomerular filtration rate [eGFR]
Endocrinol Metab 2015;30:509-513 http://dx.doi.org/10.3803/EnM.2015.30.4.509 pISSN 2093-596X · eISSN 2093-5978
Clinical Characteristics of Subjects with SulfonylureaDependent Type 2 Diabetes Se Hee Min, Soo Heon Kwak, Young Min Cho, Kyong Soo Park, Hye Seung Jung Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea Background: Even though several oral anti-diabetic drugs (OAD) with various modes of action are replacing sulfonylurea (SU), some patients seem to be dependent on SU for adequate glycemic control. Therefore, we evaluated the clinical characteristics of such patients. Methods: We selected the patients with type 2 diabetes who met following criteria from 2009 to 2014 at Seoul National University Hospital: glycated hemoglobin (HbA1c) was maintained below 7.5% for at least 6 months under small dose of SU (glimepiride ≤2 mg/day or equivalent dose); after discontinuation of SU, HbA1c increased ≥1.2% within 3 months or ≥1.5% within 6 months; and after resuming SU, HbA1c reduction was ≥0.8% or reduction of fasting plasma glucose was ≥40 mg/dL within 3 months. Patients with impaired hepatic or renal function, and steroid users were excluded. Results: Nineteen subjects were enrolled: after averaged 4.8±1.5 months of SU-free period, HbA1c increased from 6.7%±0.4% to 8.8%±0.8% even though adding other OAD such as gliptins. However, HbA1c decreased to 7.4%±0.7% after resuming SU within 2.4±0.8 months. There was no sexual predominance. Despite their old age (67±11 years) and long duration of diabetes (18±10 years), fasting C-peptide was relatively well-reserved (3.9±2.6 ng/mL), and nephropathy was not observed (albumincreatinine ratio 21.2±16.6 mg/g and estimated glomerular filtration rate 75.8±18.0 mL/min/1.73 m2). Strong family history was also noted (73.7%). Conclusion: Despite hypoglycemia risk of SU, it seemed indispensable for a subset of patients with regard to insulin secretion. Genetic influences would be evaluated. Keywords: Sulfonylurea; Diabetes mellitus; Insulin secretion
INTRODUCTION It is necessary to control serum glucose tightly to prevent microvascular complications in type 2 diabetes mellitus (T2DM), and many guidelines recommend target glycated hemoglobin (HbA1c) less than 6.5% to 7% [1,2]. However, in several studies, intensive glycemic control was reported to increase mortal-
Received: 20 March 2015, Revised: 20 May 2015, Accepted: 2 July 2015 Corresponding author: Hye Seung Jung Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: +82-2-2072-0240, Fax: +82-2-762-9662, E-mail: [email protected]
ity, without significant reduction in cardiovascular events [3]. Although mechanisms for association between intensive glycemic control and increased mortality are not yet established, one possibility is hypoglycemia [4]. Even though hypoglycemia might not directly cause fatal outcome, it is known to induce hypoglycemia unawareness and to decrease quality of life [5,6]. So not only glucose lowering effects but also risk of hy-
Copyright © 2015 Korean Endocrine Society This is an Open Access article distributed under the terms of the Creative Com mons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribu tion, and reproduction in any medium, provided the original work is properly cited.
www.e-enm.org 509
Min SH, et al.
METHODS
poglycemia should be an important factor in the treatment of T2DM. Among oral anti-diabetic drugs (OAD), sulfonylureas (SU), glinides and incretin based therapy stimulate insulin secretion, and can cause hypoglycemia. SU is one of the most prescribed OAD and has strong glycemic control effects. However, it has risk of severe hypoglycemia, and higher mortality has been reported to be associated with SU compared with metformin [7,8]. In addition, several OAD have been developed with different modes of actions, what can replace SU. Therefore, SU is losing ground as monotherapy, although it is still actively prescribed for combination with other OAD [9]. But we detected that some patients seemed to be extremely dependent on SU for glycemic control. They were very responsive to just small doses of SU and demonstrated stable glycemic control, but when the SU were stopped, glucose levels dramatically deteriorated and were not recovered until SU were resumed. Therefore, we researched those subjects and evaluated their clinical characteristics.
We retrospectively sorted patients with T2DM under SU from 2009 to 2014 by searching electrical medical record. Among these patients, we selected patients who met following criteria: (1) subjects whose HbA1c was maintained below 7.5% for at least 6 months under small dose of SU (glimepiride ≤2 mg/day or equivalent dose); (2) after discontinuation of SU with/without compensation by adding or dosing-up of other OAD, HbA1c increased ≥1.2% within 3 months or ≥1.5% within 6 months; and (3) within 3 months of SU resuming, HbA1c reduction was ≥0.8% or fasting plasma glucose reduction was ≥40 mg/dL. Conversion of SU into glimepiride-equivalent dose is presented in Table 1 [10,11]. Exclusion criteria were as follows: impaired renal function (serum creatinine >1.4 mg/dL or estimated glomerular filtration rate [eGFR]
