Acta Diabetol DOI 10.1007/s00592-013-0553-z
ORIGINAL ARTICLE
The effect of glargine versus glimepiride on pancreatic b-cell function in patients with type 2 diabetes uncontrolled on metformin monotherapy: open-label, randomized, controlled study Jun Sung Moon • Kyoung Soo Ha • Ji Sung Yoon Hyoung Woo Lee • Hyun Chul Lee • Kyu Chang Won • BETA study group
•
Received: 3 October 2013 / Accepted: 30 December 2013 Ó Springer-Verlag Italia 2014
Abstract The aim of present study is to assess whether if basal insulin, glargine, could improve insulin secretory function of b-cells compared with glimepiride when metformin alone was failed. This was an open-label and multicenter study for 52 weeks in Korean patients with uncontrolled type 2 diabetes by metformin monotherapy. Subjects were randomized to glargine or glimepiride groups (n = 38 vs. 36, respectively). The primary endpoint was to compare changes in c-peptide via glucagon test after 48 weeks. Glycemic efficacy and safety endpoints (glycated hemoglobin (HbA1c), HOMA-B, fasting plasma glucose (FPG), lipid profiles, and hypoglycemic events) were also checked. The mean disease duration of all subjects was 88.2 months. Changes in C-peptide was no significant different between groups (P = 0.73), even though insulin secretion was not worsened in both groups at the
endpoint. Glargine was not superior to glimepiride in other b-cell function indexes such as HOMA-B (P = 0.28). HbA1c and FPG reduced significantly in each groups but not different between two groups. Although, severe hypoglycemia did not occur, symptomatic hypoglycemia was more frequent in glimepiride group (P = 0.01). Insulin glargine was as effective as glimepiride in controlling hyperglycemia and maintaining b-cell function in Korean patients with type 2 diabetes during 48 weeks study period, after failure of metformin monotherapy. Hypoglycemic profile was favorable in the insulin glargine group and less weight gain was observed in the glimepiride group. Our results suggest that glargine and glimepiride can be considered after failure of metformin monotherapy. Keywords Glargine Glimepiride Metformin Treatment failure b-cell
Communicated by Massimo Porta. Hyun Chul Lee and Kyu Chang Won are equally contributed to this manuscript as corresponding authors. This study was conducted on behalf of the ‘BETA study group’. Please refer the ‘‘Appendix’’ section for the BETA study group members. ClinicalTrials.gov Identifier: NCT00562172. J. S. Moon J. S. Yoon H. W. Lee K. C. Won (&) Department of Internal Medicine, Yeungnam University College of Medicine, 170 Hyunchung-ro, Nam-gu, Daegu 705-717, Republic of Korea e-mail: [email protected] K. S. Ha Sanofi Korea, Seoul, Republic of Korea H. C. Lee Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
Introduction Type 2 diabetes is characterized by a progressive decline of pancreatic b-cell function in the presence of insulin resistance. Since declining insulin production and treatment failure serve as stumbling blocks in management of diabetes, strategies for preservation or rejuvenation of b-cell function are important [1, 2]. According to current guidelines, after treatment failure with metformin alone as a first-line drug, most patients with type 2 diabetes need combination therapy [3, 4]. However, the next best option remains unclear. Sulfonylureas (SUs) have often been chosen as the next step in treatment, because of their potent efficacy in glycemic control. However, previous in vitro [5–7] and clinical studies [8–10] indicate concern over the low durability and
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unfavorable effects of SU on pancreatic b-cell function. An earlier study [10] reported that a high proportion of patients remained uncontrolled, even after adding SU to metformin. In addition, other treatment options, including newly developed incretin-based therapies, have yet to prove their effect in the improvement of b-cell function [11–13]. Recently, intensive insulin therapy—either multiple daily insulin injection (MDI) or continuous subcutaneous insulin infusion (CSII)—has been shown to improve b-cell function along with extended glycemic remissions, and only lifestyle modification was needed to maintain nearnormal glycemia [14]. Despite their remarkable effects, these intensive insulin therapies have not been used widely, because of psychological barriers of physicians and patients to initiate insulin, frequency of injection, and the risk of hypoglycemia [15]. A long-acting basal insulin, glargine, is reported to have good glycemic control, with convenience of once-a-day injection and low risk of hypoglycemia [16]. Benefits of insulin glargine are well known, especially in patients uncontrolled with metformin monotherapy. However, little is known about the role of insulin glargine vis-a`-vis SUs in the functioning of pancreatic b-cells. Hence, in the present study, we attempt to compare the effect of insulin glargine and glimepiride on the b-cell secretory function in patients with type 2 diabetes uncontrolled on metformin monotherapy.
of metformin was kept unchanged during the 48-week study period. The dose of glargine was titrated every three days by 2 IU after starting at 0.2 U/kg of body weight to target a fasting blood glucose (FBG) level of 90–130 mg/ dL. The starting dose of glimepiride was 1 mg/day and was increased to 2 mg/day at the second week, and then up to 8 mg/day at week 3, 5, and 7 with target FBG of 90–130 mg/dL, as per the investigator’s discretion. When FBG levels were controlled at 90–130 mg/dL with insulin glargine (B8 IU) or glimepiride (B0.25 mg/day), medication was discontinued. For consistency in data reporting and analysis, all BG values were converted to plasmareferenced glucose values. Patients received instructions on self-injecting insulin and self-monitoring of BG (SMBG). Glucagon tests were performed at randomization, week 24, and week 48, in the morning after fasting for 8 h. Glargine or glimepiride was withdrawn 72 h before testing. Blood samples were taken immediately before an intravenous injection of 1 mg glucagon (Dalim BioTech, Seoul, Korea) and 6 min thereafter. Ethics and good clinical practice
Materials and methods
All participants provided written informed consent. The protocol was approved by an independent ethics committee/institutional review board, and the study was conducted using good clinical practice in accordance with the Declaration of Helsinki.
Overall study design and study subjects
Study endpoints
This multi-center, randomized, active-competitor, parallel group, 52-week study compared efficacy and safety of insulin glargine and glimepiride, in Korean patients with type 2 diabetes uncontrolled on metformin monotherapy. Patients with type 2 diabetes, aged 18–75 years, with glycated hemoglobin (HbA1c) 7.5–12.0 % (58–108 mmol/ mol), body mass index (BMI) \ 35 kg/m2, and who received metformin treatment at a dose of [1,000 mg/day for [3 months, prior to enrollment, were eligible. We excluded patients who had type 1 diabetes, gestational diabetes or diabetes with identifiable secondary causes, significant renal impairment (serum creatinine C 1.5 mg/ dL [133 lmol/L] in men, and 1.4 mg/dl [124 lmol/L] in women), or alanine aminotransferase/aspartate aminotransferase (ALT/AST) [3 times the upper limit of its normal range at study entry. Patients taking medications (other than antidiabetic medications) known to affect glycemic control, such as glucocorticoids, were also excluded. After the 4-week screening phase, the patients were randomly assigned to groups using glargine or glimepiride in addition to metformin therapy. The dose and regimen
The primary endpoint of the study was to compare changes in glucagon-stimulated C-peptide release 48 weeks after glargine or glimepiride was added to metformin. Secondary efficacy endpoints were (1) HbA1c, (2) fasting plasma glucose (FPG), (3) homeostasis model assessment of b-cell function (HOMA-B), (4) lipid profile, including total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol, (5) episodes of hypoglycemia (symptomatic or severe hypoglycemia), and (6) 3-point SMBG values. Hypoglycemia was classified as symptomatic hypoglycemia (symptoms consistent with hypoglycemia and resolved shortly after oral glucose ingestion) or severe hypoglycemia (any episode requiring the assistance of another party accompanied by plasma glucose value \2.0 mmol/L [36 mg/dL] or symptom resolved after oral or intravenous glucose or intravenous glucagon ingestion). Patients were educated to measure their BG concentration and record it along with time of event, last meal time, and last insulin or oral hypoglycemic agent dose, whenever they experienced a severe hypoglycemic symptom.
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Safety endpoints were adverse events (AEs), serious adverse events (SAEs), and change in weight. An SAE was defined as an AE that resulted in death, threat to life, admission to hospital, or the prolongation of in-patient treatment, de novo cancer, or any other medical events important in the opinion of the investigators and a data safety monitoring board. Severe hypoglycemic events were classified as SAEs. Sample size Based on a previous study [9], in this trial, we determined that 74 patients were required to obtain difference in glucagon-induced C-peptide release of 0.26 ng/mL, after 48 weeks of treatment to achieve a 95 % confidence interval. These patients were further split into a glargine group and glimepiride group (a-error = 5 %; b-error = 80 %). After the screening period, we allocated 38 participants to the glargine group and 36 to the glimepiride group. The withdrawal rate was assumed to be 10 %.
at least one dose of study medication and had at least one follow-up C-peptide measurement, were included in the analysis. Table 1 presents data on demographic and baseline metabolic characteristics of the randomized patients. The insulin glargine and glimepiride groups did not differ with respect to baseline characteristics: age, BMI, HbA1c, FPG, lipid profile, duration of disease (79.0 ± 59.9 vs. 95.6 ± 72.2 months, respectively), duration of metformin use (18.9 ± 7.0 vs. 21.7 ± 17.1 months, respectively), daily metformin dose, and fasting C-peptide (2.44 ± 0.92 vs. 2.39 ± 0.9, respectively). Efficacy
Results
Table 2 shows data on efficacy at baseline and at the end of the treatment (at 48 weeks). In the insulin glargine group, the mean C-peptide 6 min after glucagon challenge increased from 4.8 ± 1.9 ng/ml at baseline to 5.2 ± 2.2 ng/ml at week 48; whereas, in the glimepiride group, it increased from 4.8 ± 2.0 ng/ml at baseline to 5.4 ± 2.2 ng/ml at week 48. The increase in C-peptide after glucagon challenge was similar in both groups (P = 0.51). There was also no significant between-group difference in the change in HOMA-B (P = 0.28). During the study, HbA1c and FPG decreased in both groups with no between-group differences. The changes in HbA1c and FPG from baseline to end of the study were statistically significant (P = 0.43 and P = 0.19, respectively). At week 48, the mean daily doses of insulin glargine and glimepiride were 22.8 ± 9.4 IU and 4.3 ± 2.3 mg, respectively. Figure 2 shows three-point SMBG, especially before meal-time glucose level, profiles during the study. SMBG profiles showed significant decrease in both the groups with no intergroup difference (P = 0.06 before breakfast, 0.40 before lunch, and 0.31 before dinner). Table 3 shows comparison of change in b-cell function during the study, stratified by duration of diabetes. In patients having diabetes for the past \5 years, the insulin glargine group showed higher C-peptide after glucagon challenge than the glimepiride group at week 24 (P = 0.05), but not at week 48 (P = 0.30). There was no significant between-group difference in changes in HOMAB during the study period (data not shown).
Participants studied
Safety profile
Participants flow throughout the study is shown in Fig. 1. Of 82 patients screened at 10 hospitals in Korea from September 2007 to October 2009, 75 were recruited. The patients were randomized to receive either insulin glargine or glimepiride. Finally, 74 (98.7 %) patients, who received
The change in body weight in the insulin glargine group and the glimepiride group was 1.7 ± 2.7 and 0.0 ± 3.1 kg, respectively, and the between-group difference was statistically significant (P = 0.02) (Table 4). There were no significant changes in other measured biochemical
Statistical analysis All data are presented as the mean ± standard deviation (SD) or n (%) and were analyzed using SAS version 9.2 (SAS Institute Inc., Cary, NC). Changes in baseline parameters were evaluated using paired t-tests. Efficacy analyses were performed in all randomized patients who received at least one dose of study medication and who had both baseline and follow-up measurement. Analysis of covariance (ANCOVA) was used for all efficacy variables to test the primary and secondary endpoints, wherein treatment was regarded as a classification variable and the baseline measure as the covariate. Missing data were imputed using the last-observation-carried-forward method. Symptomatic hypoglycemia and severe hypoglycemia were described using n (%) and were analyzed by chi-square test or Fisher’s exact test. Statistical significance was determined on the basis of two-sided P values from the ANCOVA models; P \ 0.05 was considered to be statistically significant.
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Enrollment
Assessed for eligibility (n=82)
Excluded ♦ Not meeting inclusion criteria (n=7)
Randomized (n=75)
Allocation Metformin + Insulin Glargine (n=39)
Metformin + Glimepiride (n=36)
♦
Received allocated intervention (n=38)
♦
♦
Did not receive allocated intervention
Received allocated intervention (n=36)
-Do not take study medication (n=1)
Follow-Up ♦ Lost
♦ Efficacy
to follow-up (n=0)
♦ Discontinued
measure is missing (n=2)
intervention (n=0)
Analysis Analysed (n=34)
Analysed (n=30)
♦
♦
Excluded from analysis (n=4)
Excluded from analysis (n=4 )
- Violation of inclusion/exclusion criteria (n=1)
- Investigator`s judgment (n=1)
- Use of prohibited medication (n=1)
- Violation of protocol (n=1)
- Violation of Protocol (n=1)
- Withdrawal of consent (n=2)
- Withdrawal of consent (n=1)
Fig. 1 Patient disposition and flow throughout the study
parameters in either group, including lipid profile (data not shown). Hypoglycemic events were experienced by 26.3 and 55.9 % of patients in the insulin glargine and the glimepiride groups, respectively (P = 0.01). There were no severe hypoglycemic events reported (Table 4). The overall frequency of AEs in the insulin glargine group (47.4 %) was similar to that in the glimepiride group (52.8 %) (Table 4). The SAEs were experienced by a similar number of patients in the insulin glargine group and the glimepiride group. In both the groups, no patient discontinued the treatment because of an AE. Other than hypoglycemia and severe hypoglycemia (detailed above), all other specific AEs were reported by \5 % of the patients in either group, and there were no remarkable
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differences between the two groups in the incidence of any specific AE.
Discussion In this study, we observed no between-group differences in b-cell function or glycemic control. We reported a more favorable hypoglycemic profile in the glargine group, but lesser weight gain in the glimepiride group. From prior studies showing the benefits of insulin therapy on b-cell function [2, 17], we hypothesized that insulin glargine may improve and/or preserve the insulin secretory function as compared to SUs, which are suspected to decline b-cell function [5–10]. A few head-to-head
Acta Diabetol Table 1 Baseline clinical characteristics of subjects a
Insulin glargine (N = 38)
Glimepiride (N = 34)
Age (years)
51.3 ± 8.1
54.9 ± 8.6
Men ( %)
31.6
47.1
DM duration (month)
79.0 ± 59.9
95.6 ± 72.2
Height (cm)
160.2 ± 7.8
160.7 ± 7.2
Weight (kg)
62.7 ± 9.1
66.0 ± 11.1
BMI (kg/m2)
24.4 ± 2.7
25.5 ± 3.6
Systolic blood pressure (mm Hg)
125.7 ± 11.1
123.7 ± 14.7
Diastolic blood pressure (mm Hg)
75.1 ± 8.8
77.4 ± 9.9
Parameters
HbA1c (%)
8.8 ± 1.2
8.9 ± 1.3
Fasting plasma glucose (mg/dL) Total cholesterol (mg/dL)
168.3 ± 44.7
168.9 ± 38.9
167.5 ± 38.7
166.7 ± 30.7
Triglyceride (mg/dL)
123.5 ± 55.9
127.2 ± 74.3
HDL-cholesterol (mg/dL)
50.8 ± 11.4
49.1 ± 8.9
LDL cholesterol (mg/dL)
92.0 ± 34.0
92.1 ± 27.8
Fasting
2.44 ± 0.9
2.39 ± 0.9
At min 6 after glucagon challenge
4.83 ± 1.9
4.75 ± 2.0
AST (IU/L)
25.8 ± 13.7
21.3 ± 7.8
ALT (IU/L)
26.7 ± 16.0
25.2 ± 13.9
Cr (mg/dL)
0.8 ± 0.1
0.9 ± 0.1
C-peptide (ng/mL)
Metformin daily dose (mg) 1,365.1 ± 448.0 Diabetic complication, n (%)
1,426.5 ± 449.5
Diabetic retinopathy
5 (41.7)
7 (63.6)
Diabetic neuropathy
7 (58.3)
4 (36.4)
ALT alanine aminotransferase, AST aspartate aminotransferase, BMI body mass index, Cr creatinine, DM diabetes mellitus, HbA1c glycosylated hemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein a
Values are mean ± standard deviation, unless otherwise specified
studies were conducted to compare the effect of insulin treatment on b-cell function with that of sulfonylureas. Alvarsson et al. [9] demonstrated that insulin (NPH 30/70), in comparison with SU (glibenclamide), was beneficial for insulin secretion in recently diagnosed (\2 years) patients with type 2 diabetes, and the effect was most prominent after the first year of the study. They found that the positive effect of insulin lasted for 6 years following study inception and also provided evidence for long-term negative effects from sulfonylurea, especially glibenclamide [18, 19]. Comparing basal insulin plus oral agent (glimepiride or metformin) to oral agent alone (glimepiride and metformin), Mu et al. [15] reported that b-cell function was more improved in the glargine treatment group even if both group increased HOMA-b. Weng et al. [14] also emphasized early intensive insulin therapy
had an advantage over oral hypoglycemic agents in recovering and maintaining b-cell function in addition to glycemic remission. In another study [20], glargine showed greater b-cell function improvement than metformin in patients with early-stage diabetes. However, the present results were different from what we expected on the basis of these studies. Differences from previous studies can be explained by several considerations: Firstly, duration of diabetes in the patients analyzed in the current study was longer than that in the previous studies. It is well known that onset of diabetes is preceded by the impairment of insulin secretion. In the UKPDS [21], b-cell function decreased by approximately 50 % at diagnosis and deteriorated progressively thereafter. Early rigorous glycemic control is reported to improve b-cell function by delaying the progression of metabolic abnormalities to irreversible cellular and epigenetic alterations [14, 22]. Studies showing benefits of intensive insulin therapy included patients with early stage of diabetes— usually within 2 years [14, 15, 20]. In an earlier study in patients with mean duration of diabetes of 4.6 years, insulin glargine improved b-cell function [23]. The longer mean duration of diabetes in the current study (7.4 years) than those of previous studies is a plausible explanation of the observed lack of improvement of b-cell function by insulin glargine in late stages of diabetes when damage to b-cells is irreversible. We also could find transiently improved b-cell function by insulin glargine compared with glimepiride in patients with mean duration of diabetes \5 years (Table 3). Thus, we assume that early treatment may be helpful to preserve b-cell function and delay diabetes progression [24]. Secondly, the current study included Korean patients with higher possibility of overt b-cell dysfunction than that of Caucasian patients with similar duration of diabetes. This can be explained by the fact that in Korean patients with type 2 diabetes, insulin secretory defect is the predominant abnormality in the development of diabetes; whereas, in Caucasian patients, insulin resistance is predominant [25–27]. It has been suggested that Korean patients with type 2 diabetes have lower b-cell capacity than Caucasians [26], and an early-phase insulin secretory defect is the more important factor resulting in abnormal glucose metabolism than insulin resistance [27–29]. According to Rhee et al. [26], an early-phase insulin secretion was reduced by more than 50 % of the normal glucose tolerance (NGT) in Korean patients with ‘‘prediabetes’’; thus, endogenous insulin secretory dysfunction may be overt at diagnosis. From the context of progressive b-cell dysfunction, we concluded that both basal insulin and SUs are not sufficient to change insulin secretory function when irreversible changes happen.
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Acta Diabetol Table 2 Changes in variables related to glucose metabolism at baseline and week 48, in patients receiving insulin glargine or glimepiride
Baseline
Week 48
LS mean change
P
Daily dose Insulin glargine (IU)
12.2 ± 1.9
22.8 ± 9.4
10.5 ± 8.7
1.0 ± 0.2
4.3 ± 2.3
3.3 ± 2.3
Insulin glargine
8.8 ± 1.2
7.0 ± 0.7
-1.8 ± 1.3
Glimepiride
8.9 ± 1.3
7.2 ± 1.0
-1.8 ± 1.2
Insulin glargine
168.3 ± 44.7
136.1 ± 26.3
-32.6 ± 42.9
Glimepiride
168.9 ± 38.9
143.7 ± 26.9
-25.2 ± 37.2
Glimepiride (mg) HbA1c (%)
0.43
Fasting plasma glucose (mg/dl) 0.19
C-peptide (ng/ml) Fasting Insulin glargine
2.4 ± 0.9
2.6 ± 1.1
0.2 ± 1.5
Glimepiride
2.4 ± 0.9
2.6 ± 0.9
0.2 ± 0.8
0.33
5.2 ± 2.2 5.4 ± 2.2
0.4 ± 2.2 0.7 ± 1.8
0.51
0.28
At min 6 after glucagon challenge
HbA1c glycosylated hemoglobin, HOMA-B homeostatic model assessment of pancreatic b cell, LS least square
Insulin glargine Glimepiride
4.8 ± 1.9 4.8 ± 2.0
HOMA-B (%) Insulin glargine
8.67 ± 7.84
10.62 ± 5.13
1.73 ± 8.74
Glimepiride
7.42 ± 4.57
13.16 ± 14.14
5.70 ± 13.95
Fig. 2 Self-monitoring blood glucose (SMBG) during the 48-week study period at 3 time points. Fasting blood glucose significantly reduced at end of the study in each agent, but there was no difference between glargine and glimepiride groups. Metformin ? Insulin glargine, closed circle; Metformin ? Glimepiride, open square. Data were expressed as mean value and standard deviations
Thirdly, the difference in insulin regimen may also be the reason for the difference in results. Most studies showing favorable effects of insulin on b-cell function used an intensive regimen such as CSII or MDI. Such intensive regimens are very close to physiologic insulin secretion and are effective in controlling not only fasting but also prandial hyperglycemia and minimizing the exposure of glucotoxicity, which is known to deteriorate b-cell function [2, 14, 30–33]. As in the current study, prandial BG contributes more to the overall hyperglycemia than to FBG in poorly controlled patients (HbA1c [ 8.5 %) [34]; rapid acting insulin will be needed for appropriate glycemic control in these patients. ‘‘Premixed insulin,’’ containing short acting insulin proportionally, also showed greater
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insulin secretory function than with SUs [9]. Thus, strict normoglycemia is required for improved b-cell function, which was not obtained in this study (and neither will often occur in real-life situations). Insulin glargine might be limited to maintaining b-cell dysfunction for its ‘‘peakless’’ pharmacologic action which mainly controls fasting hyperglycemia. That the proportion of patients achieving glycemic goal (HbA1c \ 7 %) was about 60 % and similar between groups (data were not shown) explains why there were no differences between groups in our study. Fourthly, glimepiride used in the current study is known to have weaker binding affinity to b-cells [17], whereas other SUs, such as glibenclamide or glyburide, used in previous studies reported worsening effect on b-cell
Acta Diabetol Table 3 Changes in insulin secretary function at week 24 and week 48, in patients stratified by duration of diabetes DM duration \5 years
Insulin glargine (n = 14)
Glimepiride (n = 12)
P
LS mean change at week 24 C-peptide at min 6 (ng/ml)
-0.5 ± 1.4
HOMA-B (%)
8.1 ± 13.8
0.3 ± 2.6
0.41
0.3 ± 5.1
0.05
LS mean change at week 48 C-peptide at min 6 (ng/ml)
0.2 ± 2.2
0.4 ± 1.5
0.86
HOMA-B (%)
3.5 ± 5.0
10.2 ± 19.6
0.30
DM duration C 5 years
(n = 24)
(n = 22)
LS mean change at week 24 C-peptide at min 6 (ng/ml)
0.3 ± 2.0
0.2 ± 1.5
0.94
HOMA-B (%)
3.3 ± 11.2
5.6 ± 11.8
0.67
C-peptide at min 6 (ng/ml)
0.4 ± 2.1
0.7 ± 2.1
0.66
HOMA-B (%)
1.1 ± 9.8
3.2 ± 9.3
0.71
LS mean change at week 48
DM diabetes mellitus, HOMA-B homeostatic model assessment of pancreatic b cell, LS least square
Table 4 Safety profiles Insulin glargine
Glimepiride
P
Change in body weight (kg), mean ± SD
1.7 ± 2.7
0.0 ± 3.1
0.02
Patients who experienced symptomatic hypoglycemia, n (%)
10 (26.3)
19 (55.9)
0.01
Patients who experienced severe hypoglycemia, n
0
0
N/A
Adverse events, n (%)
18 (47.4)
19 (52.8)
0.64
Severe adverse events, n (%)
4 (10.5)
3 (8.3)
1.00
SD standard deviation
function [9]. Several in vitro studies [5, 7, 35] suggest that the continuous use of SUs leading to sustained Ca2? influx, resulting in ‘‘b-cell exhaustion’’ by oxidative stress is the main possible mechanism. Some clinical trials also support these results. Alvarsson et al. [9, 18, 19] reported association of SUs with worsening of b-cell function in their 2-, 4- and 6-year studies. In another retrospective study [36], longer treatment with SUs was reported to be related with a rapid decline in b-cell function. The current study showed that glimepiride was effective in glycemic control for almost 1 year without signs of b-cell exhaustion, and even numerically better than insulin glargine. This inconsistency may be partly explained by the differences between SUs. Glimepiride, which has lower binding affinity to b-cell receptors, was reported to have milder disturbance to human islet, resulting in lower incidence of hypoglycemia compared to other SUs, including glibenclamide and
chlorpropamide, in clinical studies [17]. Therefore, we can speculate that all SUs are not the same in terms of effect on b-cell and that, after failure of metformin monotherapy, glimepiride can be a valid option that does not harm b-cell. Further studies are needed to assess long-term durability of glimepiride. The current study has several limitations. Firstly, the presence of pancreatic islet autoantibodies, such as islet cell autoantibody (ICA), insulin autoantibody (IAA), or glutamic acid decarboxylase antibody (GADA), has not been checked in the current study. Pancreatic islet autoantibodies are related with gradual b-cell destruction and, therefore, may influence b-cell function in both the groups, if patients having these autoantibodies are not distributed evenly. However, prevalence of GADA positive-non-insulindependent diabetes mellitus (NIDDM) patients was reported as 4.7 % in Korea, which is up to 12 % lower than that of Western countries [37–40]. Therefore, the influence of pancreatic auto-antibody may be limited. Secondly, generalization of the results of our study to other populations may be limited, because the current study included only Korean patients in a relatively small number. As stated above, the pathophysiology of Korean patients with type 2 diabetes is different from that of Caucasians, in which insulin glargine may demonstrate different results. Larger multi-national studies are needed in the future for assessing improvement of b-cell function. Thirdly, data on the specific time of the day when hypoglycemic events occurred or 7/8-point blood glucose profile were not collected in this study. Even though glimepiride has been known to be safer than other SUs for a relatively short half-life, we do not know exactly why hypoglycemia was more frequent. In summary, insulin glargine was as effective as glimepiride in controlling hyperglycemia and maintaining b-cell function in Korean patients with type 2 diabetes during a 48-week study period, after failure of metformin monotherapy. The hypoglycemic profile was favorable in the insulin glargine group, and less weight gain was observed in the glimepiride group. Our results suggest that both drugs can be considered after failure of metformin monotherapy, and further, larger studies are needed to assess improvement of b-cell function in patients with type 2 diabetes. Acknowledgments K.S.H is employed as a medical advisor of Sanofi Korea. No potential conflicts of interest relevant to this article were reported. K.S.H performed statistical analysis, and wrote and edited the manuscript. J.S.M and K.C.W contributed to the interpretation of results, and wrote and edited the manuscript. J.S.Y, H.W.L, and H.C.L contributed to discussion and reviewed the manuscript. K.C.W is the guarantor of this work and had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Conflict of interest
None.
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Acta Diabetol Human and Animal Rights disclosure All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for being included in the study.
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Appendix: BETA study group Bong-Soo Cha, 2Chang Won Lee, 3Choon Hee Chung, Chul Woo Ahn, 5Dae Jung Kim, 1Eun Seok Kang, 5Hae Jin Kim, 1Hyun Chul Lee, 6Ji Hyun Lee, 4Jong Suk Park, 5 Kwan Woo Lee, 7Kyu Chang Won, 8Moonsuk Nam, 9 Seok Won Park, 8Seong Bin Hong, 5Seung Jin Han, 8So Hun Kim, 9Soo Kyung Kim, 8Yong Seong Kim, 9Yong Wook Cho. ,from 1Department of Internal Medicine, Yonsei university College of Medicine, Seoul 2 Department of Internal Medicine, Busan St.Mary‘s Medical Center, Busan. 3 Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju 4 Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul 5 Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 6 Department of Internal Medicine, Catholic University of Daegu, Daegu 7 Department of Internal Medicine, Yeungnam University College of Medicine, Daegu 8 Department of Internal Medicine, Inha University School of Medicine, Incheon 9 Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
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16.
17.
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insulin glargine improves first- and second-phase insulin secretion in patients with type 2 diabetes. Diabetes Care 34:2048–2053 Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA (2008) 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359:1577–1589 Chung JO, Cho DH, Chung DJ, Chung MY (2012) Associations among body mass index, insulin resistance, and pancreatic betacell function in Korean patients with new-onset type 2 diabetes. Korean J Intern Med 27:66–71 Rhee SY, Kim JY, Chon S, Hwang YC, Jeong IK, Oh S, Ahn KJ, Chung HY, Woo JT, Kim SW, Kim JW, Kim YS (2010) The changes in early phase insulin secretion in newly diagnosed, drug naive korean prediabetes subjects. Korean Diabetes J 34:157–165 Kim DJ, Lee MS, Kim KW, Lee MK (2001) Insulin secretory dysfunction and insulin resistance in the pathogenesis of korean type 2 diabetes mellitus. Metabolism 50:590–593 Kim J, Choi S, Kong B, Oh Y, Shinn S (2001) Insulin secretion and sensitivity during oral glucose tolerance test in Korean lean elderly women. J Korean Med Sci 16:592–597 Rhee SY, Chon S, Oh S, Kim SW, Kim JW, Kim YS, Woo JT (2007) Insulin secretion and insulin resistance in newly diagnosed, drug naive prediabetes and type 2 diabetes patients with/ without metabolic syndrome. Diabetes Res Clin Pract 76:397–403 Ilkova H, Glaser B, Tunckale A, Bagriacik N, Cerasi E (1997) Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients by transient intensive insulin treatment. Diabetes Care 20:1353–1356 McFarlane SI, Chaiken RL, Hirsch S, Harrington P, Lebovitz HE, Banerji MA (2001) Near-normoglycaemic remission in AfricanAmericans with Type 2 diabetes mellitus is associated with recovery of beta cell function. Diabet Med 18:10–16 Ryan EA, Imes S, Wallace C (2004) Short-term intensive insulin therapy in newly diagnosed type 2 diabetes. Diabetes Care 27:1028–1032
33. Li Y, Xu W, Liao Z, Yao B, Chen X, Huang Z, Hu G, Weng J (2004) Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients is associated with improvement of beta-cell function. Diabetes Care 27:2597–2602 34. Monnier L, Lapinski H, Colette C (2003) Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care 26:881–885 35. Iwakura T, Fujimoto S, Kagimoto S, Inada A, Kubota A, Someya Y, Ihara Y, Yamada Y, Seino Y (2000) Sustained enhancement of Ca(2?) influx by glibenclamide induces apoptosis in RINm5F cells. Biochem Biophys Res Commun 271:422–428 36. Shin MS, Yu JH, Jung CH, Hwang JY, Lee WJ, Kim MS, Park JY (2012) The duration of sulfonylurea treatment is associated with beta-cell dysfunction in patients with type 2 diabetes mellitus. Diabetes Technol Ther 14:1033–1042 37. Park Y, Lee H, Koh CS, Min H, Rowley M, Mackay IR, Zimmet P, McCarthy B, McCanlies E, Dorman J, Trucco M (1996) The low prevalence of immunogenetic markers in Korean adult-onset IDDM patients. Diabetes Care 19:241–245 38. Lee S, Kim E, Kim E, Jeong J, Jeong E, Kim D, Cho E, Koh E, Kim M, Park J, Lee K (2009) Anti-GAD Antibody in Patients with Adult-Onset Diabetes in Korea. Korean Diabetes J 33:16–23 39. Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR, Shattock M, Bottazzo GF, Holman R (1997) UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group. Lancet 350:1288–1293 40. Castleden HA, Shields B, Bingley PJ, Williams AJ, Sampson M, Walker M, Gibson JM, McCarthy MI, Hitman GA, Levy JC, Hattersley AT, Vaidya B, Pearson ER (2006) GAD antibodies in probands and their relatives in a cohort clinically selected for Type 2 diabetes. Diabetes Med 23:834–838
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ORIGINAL ARTICLE
The effect of glargine versus glimepiride on pancreatic b-cell function in patients with type 2 diabetes uncontrolled on metformin monotherapy: open-label, randomized, controlled study Jun Sung Moon • Kyoung Soo Ha • Ji Sung Yoon Hyoung Woo Lee • Hyun Chul Lee • Kyu Chang Won • BETA study group
•
Received: 3 October 2013 / Accepted: 30 December 2013 Ó Springer-Verlag Italia 2014
Abstract The aim of present study is to assess whether if basal insulin, glargine, could improve insulin secretory function of b-cells compared with glimepiride when metformin alone was failed. This was an open-label and multicenter study for 52 weeks in Korean patients with uncontrolled type 2 diabetes by metformin monotherapy. Subjects were randomized to glargine or glimepiride groups (n = 38 vs. 36, respectively). The primary endpoint was to compare changes in c-peptide via glucagon test after 48 weeks. Glycemic efficacy and safety endpoints (glycated hemoglobin (HbA1c), HOMA-B, fasting plasma glucose (FPG), lipid profiles, and hypoglycemic events) were also checked. The mean disease duration of all subjects was 88.2 months. Changes in C-peptide was no significant different between groups (P = 0.73), even though insulin secretion was not worsened in both groups at the
endpoint. Glargine was not superior to glimepiride in other b-cell function indexes such as HOMA-B (P = 0.28). HbA1c and FPG reduced significantly in each groups but not different between two groups. Although, severe hypoglycemia did not occur, symptomatic hypoglycemia was more frequent in glimepiride group (P = 0.01). Insulin glargine was as effective as glimepiride in controlling hyperglycemia and maintaining b-cell function in Korean patients with type 2 diabetes during 48 weeks study period, after failure of metformin monotherapy. Hypoglycemic profile was favorable in the insulin glargine group and less weight gain was observed in the glimepiride group. Our results suggest that glargine and glimepiride can be considered after failure of metformin monotherapy. Keywords Glargine Glimepiride Metformin Treatment failure b-cell
Communicated by Massimo Porta. Hyun Chul Lee and Kyu Chang Won are equally contributed to this manuscript as corresponding authors. This study was conducted on behalf of the ‘BETA study group’. Please refer the ‘‘Appendix’’ section for the BETA study group members. ClinicalTrials.gov Identifier: NCT00562172. J. S. Moon J. S. Yoon H. W. Lee K. C. Won (&) Department of Internal Medicine, Yeungnam University College of Medicine, 170 Hyunchung-ro, Nam-gu, Daegu 705-717, Republic of Korea e-mail: [email protected] K. S. Ha Sanofi Korea, Seoul, Republic of Korea H. C. Lee Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
Introduction Type 2 diabetes is characterized by a progressive decline of pancreatic b-cell function in the presence of insulin resistance. Since declining insulin production and treatment failure serve as stumbling blocks in management of diabetes, strategies for preservation or rejuvenation of b-cell function are important [1, 2]. According to current guidelines, after treatment failure with metformin alone as a first-line drug, most patients with type 2 diabetes need combination therapy [3, 4]. However, the next best option remains unclear. Sulfonylureas (SUs) have often been chosen as the next step in treatment, because of their potent efficacy in glycemic control. However, previous in vitro [5–7] and clinical studies [8–10] indicate concern over the low durability and
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unfavorable effects of SU on pancreatic b-cell function. An earlier study [10] reported that a high proportion of patients remained uncontrolled, even after adding SU to metformin. In addition, other treatment options, including newly developed incretin-based therapies, have yet to prove their effect in the improvement of b-cell function [11–13]. Recently, intensive insulin therapy—either multiple daily insulin injection (MDI) or continuous subcutaneous insulin infusion (CSII)—has been shown to improve b-cell function along with extended glycemic remissions, and only lifestyle modification was needed to maintain nearnormal glycemia [14]. Despite their remarkable effects, these intensive insulin therapies have not been used widely, because of psychological barriers of physicians and patients to initiate insulin, frequency of injection, and the risk of hypoglycemia [15]. A long-acting basal insulin, glargine, is reported to have good glycemic control, with convenience of once-a-day injection and low risk of hypoglycemia [16]. Benefits of insulin glargine are well known, especially in patients uncontrolled with metformin monotherapy. However, little is known about the role of insulin glargine vis-a`-vis SUs in the functioning of pancreatic b-cells. Hence, in the present study, we attempt to compare the effect of insulin glargine and glimepiride on the b-cell secretory function in patients with type 2 diabetes uncontrolled on metformin monotherapy.
of metformin was kept unchanged during the 48-week study period. The dose of glargine was titrated every three days by 2 IU after starting at 0.2 U/kg of body weight to target a fasting blood glucose (FBG) level of 90–130 mg/ dL. The starting dose of glimepiride was 1 mg/day and was increased to 2 mg/day at the second week, and then up to 8 mg/day at week 3, 5, and 7 with target FBG of 90–130 mg/dL, as per the investigator’s discretion. When FBG levels were controlled at 90–130 mg/dL with insulin glargine (B8 IU) or glimepiride (B0.25 mg/day), medication was discontinued. For consistency in data reporting and analysis, all BG values were converted to plasmareferenced glucose values. Patients received instructions on self-injecting insulin and self-monitoring of BG (SMBG). Glucagon tests were performed at randomization, week 24, and week 48, in the morning after fasting for 8 h. Glargine or glimepiride was withdrawn 72 h before testing. Blood samples were taken immediately before an intravenous injection of 1 mg glucagon (Dalim BioTech, Seoul, Korea) and 6 min thereafter. Ethics and good clinical practice
Materials and methods
All participants provided written informed consent. The protocol was approved by an independent ethics committee/institutional review board, and the study was conducted using good clinical practice in accordance with the Declaration of Helsinki.
Overall study design and study subjects
Study endpoints
This multi-center, randomized, active-competitor, parallel group, 52-week study compared efficacy and safety of insulin glargine and glimepiride, in Korean patients with type 2 diabetes uncontrolled on metformin monotherapy. Patients with type 2 diabetes, aged 18–75 years, with glycated hemoglobin (HbA1c) 7.5–12.0 % (58–108 mmol/ mol), body mass index (BMI) \ 35 kg/m2, and who received metformin treatment at a dose of [1,000 mg/day for [3 months, prior to enrollment, were eligible. We excluded patients who had type 1 diabetes, gestational diabetes or diabetes with identifiable secondary causes, significant renal impairment (serum creatinine C 1.5 mg/ dL [133 lmol/L] in men, and 1.4 mg/dl [124 lmol/L] in women), or alanine aminotransferase/aspartate aminotransferase (ALT/AST) [3 times the upper limit of its normal range at study entry. Patients taking medications (other than antidiabetic medications) known to affect glycemic control, such as glucocorticoids, were also excluded. After the 4-week screening phase, the patients were randomly assigned to groups using glargine or glimepiride in addition to metformin therapy. The dose and regimen
The primary endpoint of the study was to compare changes in glucagon-stimulated C-peptide release 48 weeks after glargine or glimepiride was added to metformin. Secondary efficacy endpoints were (1) HbA1c, (2) fasting plasma glucose (FPG), (3) homeostasis model assessment of b-cell function (HOMA-B), (4) lipid profile, including total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol, (5) episodes of hypoglycemia (symptomatic or severe hypoglycemia), and (6) 3-point SMBG values. Hypoglycemia was classified as symptomatic hypoglycemia (symptoms consistent with hypoglycemia and resolved shortly after oral glucose ingestion) or severe hypoglycemia (any episode requiring the assistance of another party accompanied by plasma glucose value \2.0 mmol/L [36 mg/dL] or symptom resolved after oral or intravenous glucose or intravenous glucagon ingestion). Patients were educated to measure their BG concentration and record it along with time of event, last meal time, and last insulin or oral hypoglycemic agent dose, whenever they experienced a severe hypoglycemic symptom.
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Safety endpoints were adverse events (AEs), serious adverse events (SAEs), and change in weight. An SAE was defined as an AE that resulted in death, threat to life, admission to hospital, or the prolongation of in-patient treatment, de novo cancer, or any other medical events important in the opinion of the investigators and a data safety monitoring board. Severe hypoglycemic events were classified as SAEs. Sample size Based on a previous study [9], in this trial, we determined that 74 patients were required to obtain difference in glucagon-induced C-peptide release of 0.26 ng/mL, after 48 weeks of treatment to achieve a 95 % confidence interval. These patients were further split into a glargine group and glimepiride group (a-error = 5 %; b-error = 80 %). After the screening period, we allocated 38 participants to the glargine group and 36 to the glimepiride group. The withdrawal rate was assumed to be 10 %.
at least one dose of study medication and had at least one follow-up C-peptide measurement, were included in the analysis. Table 1 presents data on demographic and baseline metabolic characteristics of the randomized patients. The insulin glargine and glimepiride groups did not differ with respect to baseline characteristics: age, BMI, HbA1c, FPG, lipid profile, duration of disease (79.0 ± 59.9 vs. 95.6 ± 72.2 months, respectively), duration of metformin use (18.9 ± 7.0 vs. 21.7 ± 17.1 months, respectively), daily metformin dose, and fasting C-peptide (2.44 ± 0.92 vs. 2.39 ± 0.9, respectively). Efficacy
Results
Table 2 shows data on efficacy at baseline and at the end of the treatment (at 48 weeks). In the insulin glargine group, the mean C-peptide 6 min after glucagon challenge increased from 4.8 ± 1.9 ng/ml at baseline to 5.2 ± 2.2 ng/ml at week 48; whereas, in the glimepiride group, it increased from 4.8 ± 2.0 ng/ml at baseline to 5.4 ± 2.2 ng/ml at week 48. The increase in C-peptide after glucagon challenge was similar in both groups (P = 0.51). There was also no significant between-group difference in the change in HOMA-B (P = 0.28). During the study, HbA1c and FPG decreased in both groups with no between-group differences. The changes in HbA1c and FPG from baseline to end of the study were statistically significant (P = 0.43 and P = 0.19, respectively). At week 48, the mean daily doses of insulin glargine and glimepiride were 22.8 ± 9.4 IU and 4.3 ± 2.3 mg, respectively. Figure 2 shows three-point SMBG, especially before meal-time glucose level, profiles during the study. SMBG profiles showed significant decrease in both the groups with no intergroup difference (P = 0.06 before breakfast, 0.40 before lunch, and 0.31 before dinner). Table 3 shows comparison of change in b-cell function during the study, stratified by duration of diabetes. In patients having diabetes for the past \5 years, the insulin glargine group showed higher C-peptide after glucagon challenge than the glimepiride group at week 24 (P = 0.05), but not at week 48 (P = 0.30). There was no significant between-group difference in changes in HOMAB during the study period (data not shown).
Participants studied
Safety profile
Participants flow throughout the study is shown in Fig. 1. Of 82 patients screened at 10 hospitals in Korea from September 2007 to October 2009, 75 were recruited. The patients were randomized to receive either insulin glargine or glimepiride. Finally, 74 (98.7 %) patients, who received
The change in body weight in the insulin glargine group and the glimepiride group was 1.7 ± 2.7 and 0.0 ± 3.1 kg, respectively, and the between-group difference was statistically significant (P = 0.02) (Table 4). There were no significant changes in other measured biochemical
Statistical analysis All data are presented as the mean ± standard deviation (SD) or n (%) and were analyzed using SAS version 9.2 (SAS Institute Inc., Cary, NC). Changes in baseline parameters were evaluated using paired t-tests. Efficacy analyses were performed in all randomized patients who received at least one dose of study medication and who had both baseline and follow-up measurement. Analysis of covariance (ANCOVA) was used for all efficacy variables to test the primary and secondary endpoints, wherein treatment was regarded as a classification variable and the baseline measure as the covariate. Missing data were imputed using the last-observation-carried-forward method. Symptomatic hypoglycemia and severe hypoglycemia were described using n (%) and were analyzed by chi-square test or Fisher’s exact test. Statistical significance was determined on the basis of two-sided P values from the ANCOVA models; P \ 0.05 was considered to be statistically significant.
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Enrollment
Assessed for eligibility (n=82)
Excluded ♦ Not meeting inclusion criteria (n=7)
Randomized (n=75)
Allocation Metformin + Insulin Glargine (n=39)
Metformin + Glimepiride (n=36)
♦
Received allocated intervention (n=38)
♦
♦
Did not receive allocated intervention
Received allocated intervention (n=36)
-Do not take study medication (n=1)
Follow-Up ♦ Lost
♦ Efficacy
to follow-up (n=0)
♦ Discontinued
measure is missing (n=2)
intervention (n=0)
Analysis Analysed (n=34)
Analysed (n=30)
♦
♦
Excluded from analysis (n=4)
Excluded from analysis (n=4 )
- Violation of inclusion/exclusion criteria (n=1)
- Investigator`s judgment (n=1)
- Use of prohibited medication (n=1)
- Violation of protocol (n=1)
- Violation of Protocol (n=1)
- Withdrawal of consent (n=2)
- Withdrawal of consent (n=1)
Fig. 1 Patient disposition and flow throughout the study
parameters in either group, including lipid profile (data not shown). Hypoglycemic events were experienced by 26.3 and 55.9 % of patients in the insulin glargine and the glimepiride groups, respectively (P = 0.01). There were no severe hypoglycemic events reported (Table 4). The overall frequency of AEs in the insulin glargine group (47.4 %) was similar to that in the glimepiride group (52.8 %) (Table 4). The SAEs were experienced by a similar number of patients in the insulin glargine group and the glimepiride group. In both the groups, no patient discontinued the treatment because of an AE. Other than hypoglycemia and severe hypoglycemia (detailed above), all other specific AEs were reported by \5 % of the patients in either group, and there were no remarkable
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differences between the two groups in the incidence of any specific AE.
Discussion In this study, we observed no between-group differences in b-cell function or glycemic control. We reported a more favorable hypoglycemic profile in the glargine group, but lesser weight gain in the glimepiride group. From prior studies showing the benefits of insulin therapy on b-cell function [2, 17], we hypothesized that insulin glargine may improve and/or preserve the insulin secretory function as compared to SUs, which are suspected to decline b-cell function [5–10]. A few head-to-head
Acta Diabetol Table 1 Baseline clinical characteristics of subjects a
Insulin glargine (N = 38)
Glimepiride (N = 34)
Age (years)
51.3 ± 8.1
54.9 ± 8.6
Men ( %)
31.6
47.1
DM duration (month)
79.0 ± 59.9
95.6 ± 72.2
Height (cm)
160.2 ± 7.8
160.7 ± 7.2
Weight (kg)
62.7 ± 9.1
66.0 ± 11.1
BMI (kg/m2)
24.4 ± 2.7
25.5 ± 3.6
Systolic blood pressure (mm Hg)
125.7 ± 11.1
123.7 ± 14.7
Diastolic blood pressure (mm Hg)
75.1 ± 8.8
77.4 ± 9.9
Parameters
HbA1c (%)
8.8 ± 1.2
8.9 ± 1.3
Fasting plasma glucose (mg/dL) Total cholesterol (mg/dL)
168.3 ± 44.7
168.9 ± 38.9
167.5 ± 38.7
166.7 ± 30.7
Triglyceride (mg/dL)
123.5 ± 55.9
127.2 ± 74.3
HDL-cholesterol (mg/dL)
50.8 ± 11.4
49.1 ± 8.9
LDL cholesterol (mg/dL)
92.0 ± 34.0
92.1 ± 27.8
Fasting
2.44 ± 0.9
2.39 ± 0.9
At min 6 after glucagon challenge
4.83 ± 1.9
4.75 ± 2.0
AST (IU/L)
25.8 ± 13.7
21.3 ± 7.8
ALT (IU/L)
26.7 ± 16.0
25.2 ± 13.9
Cr (mg/dL)
0.8 ± 0.1
0.9 ± 0.1
C-peptide (ng/mL)
Metformin daily dose (mg) 1,365.1 ± 448.0 Diabetic complication, n (%)
1,426.5 ± 449.5
Diabetic retinopathy
5 (41.7)
7 (63.6)
Diabetic neuropathy
7 (58.3)
4 (36.4)
ALT alanine aminotransferase, AST aspartate aminotransferase, BMI body mass index, Cr creatinine, DM diabetes mellitus, HbA1c glycosylated hemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein a
Values are mean ± standard deviation, unless otherwise specified
studies were conducted to compare the effect of insulin treatment on b-cell function with that of sulfonylureas. Alvarsson et al. [9] demonstrated that insulin (NPH 30/70), in comparison with SU (glibenclamide), was beneficial for insulin secretion in recently diagnosed (\2 years) patients with type 2 diabetes, and the effect was most prominent after the first year of the study. They found that the positive effect of insulin lasted for 6 years following study inception and also provided evidence for long-term negative effects from sulfonylurea, especially glibenclamide [18, 19]. Comparing basal insulin plus oral agent (glimepiride or metformin) to oral agent alone (glimepiride and metformin), Mu et al. [15] reported that b-cell function was more improved in the glargine treatment group even if both group increased HOMA-b. Weng et al. [14] also emphasized early intensive insulin therapy
had an advantage over oral hypoglycemic agents in recovering and maintaining b-cell function in addition to glycemic remission. In another study [20], glargine showed greater b-cell function improvement than metformin in patients with early-stage diabetes. However, the present results were different from what we expected on the basis of these studies. Differences from previous studies can be explained by several considerations: Firstly, duration of diabetes in the patients analyzed in the current study was longer than that in the previous studies. It is well known that onset of diabetes is preceded by the impairment of insulin secretion. In the UKPDS [21], b-cell function decreased by approximately 50 % at diagnosis and deteriorated progressively thereafter. Early rigorous glycemic control is reported to improve b-cell function by delaying the progression of metabolic abnormalities to irreversible cellular and epigenetic alterations [14, 22]. Studies showing benefits of intensive insulin therapy included patients with early stage of diabetes— usually within 2 years [14, 15, 20]. In an earlier study in patients with mean duration of diabetes of 4.6 years, insulin glargine improved b-cell function [23]. The longer mean duration of diabetes in the current study (7.4 years) than those of previous studies is a plausible explanation of the observed lack of improvement of b-cell function by insulin glargine in late stages of diabetes when damage to b-cells is irreversible. We also could find transiently improved b-cell function by insulin glargine compared with glimepiride in patients with mean duration of diabetes \5 years (Table 3). Thus, we assume that early treatment may be helpful to preserve b-cell function and delay diabetes progression [24]. Secondly, the current study included Korean patients with higher possibility of overt b-cell dysfunction than that of Caucasian patients with similar duration of diabetes. This can be explained by the fact that in Korean patients with type 2 diabetes, insulin secretory defect is the predominant abnormality in the development of diabetes; whereas, in Caucasian patients, insulin resistance is predominant [25–27]. It has been suggested that Korean patients with type 2 diabetes have lower b-cell capacity than Caucasians [26], and an early-phase insulin secretory defect is the more important factor resulting in abnormal glucose metabolism than insulin resistance [27–29]. According to Rhee et al. [26], an early-phase insulin secretion was reduced by more than 50 % of the normal glucose tolerance (NGT) in Korean patients with ‘‘prediabetes’’; thus, endogenous insulin secretory dysfunction may be overt at diagnosis. From the context of progressive b-cell dysfunction, we concluded that both basal insulin and SUs are not sufficient to change insulin secretory function when irreversible changes happen.
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Acta Diabetol Table 2 Changes in variables related to glucose metabolism at baseline and week 48, in patients receiving insulin glargine or glimepiride
Baseline
Week 48
LS mean change
P
Daily dose Insulin glargine (IU)
12.2 ± 1.9
22.8 ± 9.4
10.5 ± 8.7
1.0 ± 0.2
4.3 ± 2.3
3.3 ± 2.3
Insulin glargine
8.8 ± 1.2
7.0 ± 0.7
-1.8 ± 1.3
Glimepiride
8.9 ± 1.3
7.2 ± 1.0
-1.8 ± 1.2
Insulin glargine
168.3 ± 44.7
136.1 ± 26.3
-32.6 ± 42.9
Glimepiride
168.9 ± 38.9
143.7 ± 26.9
-25.2 ± 37.2
Glimepiride (mg) HbA1c (%)
0.43
Fasting plasma glucose (mg/dl) 0.19
C-peptide (ng/ml) Fasting Insulin glargine
2.4 ± 0.9
2.6 ± 1.1
0.2 ± 1.5
Glimepiride
2.4 ± 0.9
2.6 ± 0.9
0.2 ± 0.8
0.33
5.2 ± 2.2 5.4 ± 2.2
0.4 ± 2.2 0.7 ± 1.8
0.51
0.28
At min 6 after glucagon challenge
HbA1c glycosylated hemoglobin, HOMA-B homeostatic model assessment of pancreatic b cell, LS least square
Insulin glargine Glimepiride
4.8 ± 1.9 4.8 ± 2.0
HOMA-B (%) Insulin glargine
8.67 ± 7.84
10.62 ± 5.13
1.73 ± 8.74
Glimepiride
7.42 ± 4.57
13.16 ± 14.14
5.70 ± 13.95
Fig. 2 Self-monitoring blood glucose (SMBG) during the 48-week study period at 3 time points. Fasting blood glucose significantly reduced at end of the study in each agent, but there was no difference between glargine and glimepiride groups. Metformin ? Insulin glargine, closed circle; Metformin ? Glimepiride, open square. Data were expressed as mean value and standard deviations
Thirdly, the difference in insulin regimen may also be the reason for the difference in results. Most studies showing favorable effects of insulin on b-cell function used an intensive regimen such as CSII or MDI. Such intensive regimens are very close to physiologic insulin secretion and are effective in controlling not only fasting but also prandial hyperglycemia and minimizing the exposure of glucotoxicity, which is known to deteriorate b-cell function [2, 14, 30–33]. As in the current study, prandial BG contributes more to the overall hyperglycemia than to FBG in poorly controlled patients (HbA1c [ 8.5 %) [34]; rapid acting insulin will be needed for appropriate glycemic control in these patients. ‘‘Premixed insulin,’’ containing short acting insulin proportionally, also showed greater
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insulin secretory function than with SUs [9]. Thus, strict normoglycemia is required for improved b-cell function, which was not obtained in this study (and neither will often occur in real-life situations). Insulin glargine might be limited to maintaining b-cell dysfunction for its ‘‘peakless’’ pharmacologic action which mainly controls fasting hyperglycemia. That the proportion of patients achieving glycemic goal (HbA1c \ 7 %) was about 60 % and similar between groups (data were not shown) explains why there were no differences between groups in our study. Fourthly, glimepiride used in the current study is known to have weaker binding affinity to b-cells [17], whereas other SUs, such as glibenclamide or glyburide, used in previous studies reported worsening effect on b-cell
Acta Diabetol Table 3 Changes in insulin secretary function at week 24 and week 48, in patients stratified by duration of diabetes DM duration \5 years
Insulin glargine (n = 14)
Glimepiride (n = 12)
P
LS mean change at week 24 C-peptide at min 6 (ng/ml)
-0.5 ± 1.4
HOMA-B (%)
8.1 ± 13.8
0.3 ± 2.6
0.41
0.3 ± 5.1
0.05
LS mean change at week 48 C-peptide at min 6 (ng/ml)
0.2 ± 2.2
0.4 ± 1.5
0.86
HOMA-B (%)
3.5 ± 5.0
10.2 ± 19.6
0.30
DM duration C 5 years
(n = 24)
(n = 22)
LS mean change at week 24 C-peptide at min 6 (ng/ml)
0.3 ± 2.0
0.2 ± 1.5
0.94
HOMA-B (%)
3.3 ± 11.2
5.6 ± 11.8
0.67
C-peptide at min 6 (ng/ml)
0.4 ± 2.1
0.7 ± 2.1
0.66
HOMA-B (%)
1.1 ± 9.8
3.2 ± 9.3
0.71
LS mean change at week 48
DM diabetes mellitus, HOMA-B homeostatic model assessment of pancreatic b cell, LS least square
Table 4 Safety profiles Insulin glargine
Glimepiride
P
Change in body weight (kg), mean ± SD
1.7 ± 2.7
0.0 ± 3.1
0.02
Patients who experienced symptomatic hypoglycemia, n (%)
10 (26.3)
19 (55.9)
0.01
Patients who experienced severe hypoglycemia, n
0
0
N/A
Adverse events, n (%)
18 (47.4)
19 (52.8)
0.64
Severe adverse events, n (%)
4 (10.5)
3 (8.3)
1.00
SD standard deviation
function [9]. Several in vitro studies [5, 7, 35] suggest that the continuous use of SUs leading to sustained Ca2? influx, resulting in ‘‘b-cell exhaustion’’ by oxidative stress is the main possible mechanism. Some clinical trials also support these results. Alvarsson et al. [9, 18, 19] reported association of SUs with worsening of b-cell function in their 2-, 4- and 6-year studies. In another retrospective study [36], longer treatment with SUs was reported to be related with a rapid decline in b-cell function. The current study showed that glimepiride was effective in glycemic control for almost 1 year without signs of b-cell exhaustion, and even numerically better than insulin glargine. This inconsistency may be partly explained by the differences between SUs. Glimepiride, which has lower binding affinity to b-cell receptors, was reported to have milder disturbance to human islet, resulting in lower incidence of hypoglycemia compared to other SUs, including glibenclamide and
chlorpropamide, in clinical studies [17]. Therefore, we can speculate that all SUs are not the same in terms of effect on b-cell and that, after failure of metformin monotherapy, glimepiride can be a valid option that does not harm b-cell. Further studies are needed to assess long-term durability of glimepiride. The current study has several limitations. Firstly, the presence of pancreatic islet autoantibodies, such as islet cell autoantibody (ICA), insulin autoantibody (IAA), or glutamic acid decarboxylase antibody (GADA), has not been checked in the current study. Pancreatic islet autoantibodies are related with gradual b-cell destruction and, therefore, may influence b-cell function in both the groups, if patients having these autoantibodies are not distributed evenly. However, prevalence of GADA positive-non-insulindependent diabetes mellitus (NIDDM) patients was reported as 4.7 % in Korea, which is up to 12 % lower than that of Western countries [37–40]. Therefore, the influence of pancreatic auto-antibody may be limited. Secondly, generalization of the results of our study to other populations may be limited, because the current study included only Korean patients in a relatively small number. As stated above, the pathophysiology of Korean patients with type 2 diabetes is different from that of Caucasians, in which insulin glargine may demonstrate different results. Larger multi-national studies are needed in the future for assessing improvement of b-cell function. Thirdly, data on the specific time of the day when hypoglycemic events occurred or 7/8-point blood glucose profile were not collected in this study. Even though glimepiride has been known to be safer than other SUs for a relatively short half-life, we do not know exactly why hypoglycemia was more frequent. In summary, insulin glargine was as effective as glimepiride in controlling hyperglycemia and maintaining b-cell function in Korean patients with type 2 diabetes during a 48-week study period, after failure of metformin monotherapy. The hypoglycemic profile was favorable in the insulin glargine group, and less weight gain was observed in the glimepiride group. Our results suggest that both drugs can be considered after failure of metformin monotherapy, and further, larger studies are needed to assess improvement of b-cell function in patients with type 2 diabetes. Acknowledgments K.S.H is employed as a medical advisor of Sanofi Korea. No potential conflicts of interest relevant to this article were reported. K.S.H performed statistical analysis, and wrote and edited the manuscript. J.S.M and K.C.W contributed to the interpretation of results, and wrote and edited the manuscript. J.S.Y, H.W.L, and H.C.L contributed to discussion and reviewed the manuscript. K.C.W is the guarantor of this work and had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Conflict of interest
None.
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Acta Diabetol Human and Animal Rights disclosure All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for being included in the study.
6.
7.
Appendix: BETA study group Bong-Soo Cha, 2Chang Won Lee, 3Choon Hee Chung, Chul Woo Ahn, 5Dae Jung Kim, 1Eun Seok Kang, 5Hae Jin Kim, 1Hyun Chul Lee, 6Ji Hyun Lee, 4Jong Suk Park, 5 Kwan Woo Lee, 7Kyu Chang Won, 8Moonsuk Nam, 9 Seok Won Park, 8Seong Bin Hong, 5Seung Jin Han, 8So Hun Kim, 9Soo Kyung Kim, 8Yong Seong Kim, 9Yong Wook Cho. ,from 1Department of Internal Medicine, Yonsei university College of Medicine, Seoul 2 Department of Internal Medicine, Busan St.Mary‘s Medical Center, Busan. 3 Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju 4 Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul 5 Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 6 Department of Internal Medicine, Catholic University of Daegu, Daegu 7 Department of Internal Medicine, Yeungnam University College of Medicine, Daegu 8 Department of Internal Medicine, Inha University School of Medicine, Incheon 9 Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
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