diabetes research and clinical practice 108 (2015) 273–279
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Risk factors for the development of glucocorticoid-induced diabetes mellitus Takayuki Katsuyama, Ken-Ei Sada *, Sayaka Namba, Haruki Watanabe, Eri Katsuyama, Toshio Yamanari, Jun Wada, Hirofumi Makino Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama City 700-8558, Japan
article info
abstract
Article history:
Aims: To evaluate the incidence of glucocorticoid-induced diabetes mellitus (GC-DM) by
Received 14 May 2014
repeated measurements of the postprandial glucose and detect predictors for the develop-
Received in revised form
ment of GC-DM.
9 October 2014
Methods: Inpatients with rheumatic or renal disease who received glucocorticoid therapy
Accepted 6 February 2015
were enrolled in this study. We compared the clinical and laboratory parameters of the GC-
Available online 21 February 2015
DM group with the non-GC-DM group and performed a multivariate analysis to identify risk factors.
Keywords:
Results: During a four-week period, 84 of the 128 patients (65.6%) developed GC-DM. All
Glucocorticoid-induced diabetes
patients were diagnosed based on the detection of postprandial hyperglycemia. The GC-DM
mellitus
group had an older age (65.2 vs. 50.4 years, p < 0.0001), higher levels of fasting plasma
Risk factor
glucose (93.3 vs. 89.0 mg/dl, p = 0.027) and HbA1c (5.78 vs. 5.50%, 39.7 vs. 36.6 mmol/mol,
Rheumatic disease
p = 0.001) and lower eGFR values (54.0 vs. 77.1 ml/min/1.73 m2, p = 0.0003) than the non-GC-
Renal disease
DM group. According to the multivariate analysis, an older age (more than or equal to 65 years), higher HbA1c level (more than or equal to 6.0%) and lower eGFR (65 years or less than or equal to 65 years). Candidate risk factors were selected according to the results of the univariate analysis and the findings of previous reports. A p value of less than 0.05 was considered to indicate a statistically significant difference. All statistical analyses were performed using the JMP 9.0 software package (SAS Institute Inc., Cary, NC, USA). The patient background data are presented as the mean SD, and the data in the table comparing the characteristics of the groups are given as the mean SE.
Ethical considerations
3.
Results
3.1.
Patient background characteristics
We recruited 184 inpatients treated with glucocorticoid therapy. Of these patients, 56 were excluded because their postprandial glucose measurements were taken less than three times. Therefore, 128 patients were enrolled in this study. The mean frequency of postprandial glucose measurements during the first two weeks after the initiation of glucocorticoid therapy was 10.6 8.0 times. The patient population comprised 79 (61.7%) females and 49 (38.3%)
275
diabetes research and clinical practice 108 (2015) 273–279
Table 1 – Baseline characteristics of the patients. Patients (no)
128 (Female 79, male 49)
Age (years) Family history of DM BMI Complication of hypertension Fasting plasma glucose (mg/dl) HbA1c (%) WBC (ml) RBC (104/ml) eGFR (ml/min/1.73 m2) AST (IU/l) ALT (IU/l) Total cholesterol (mg/dl) LDL-cholesterol (mg/dl) Triglyceride (mg/dl) mPSL pulse therapy (%) Maximum dose of PSL (mg/day) Maximum dose of PSL (mg/kg/day) Total dose of PSL for 28 days (mg)* The dose of PSL at 28th day
60.1 16.8 21 (16.4%) 22.7 4.16 51 (40.2%) 91.8 10.9 5.68 0.49 7260 3890 376 70.7 62.0 34.6 58.0 167 34.7 48.9 232 112 147 87.6 155 81.9 25 (19.5%) 38.5 12.3 0.70 0.23 1380 1040 31.2 11.7
Mean SD DM: diabetes mellitus, BMI: body mass index, WBC: white blood cell, RBC: red blood cell, eGFR: estimated glomerular filtration rate, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDL: low-density lipoprotein, mPSL: methylprednisolone, PSL: prednisolone. * Includes the dose of glucocorticoids used in mPSL pulse therapy.
males. The clinical and laboratory characteristics of the patients are summarized in Table 1. The mean age of the patients was 60.1 16.8 years (range: 14–88 years), and the underling diseases included systemic vasculitis (31 patients), inflammatory myositis (17 patients), SLE (14 patients) and MCNS (10 patients) (Table 2). The daily maximum dose of prednisolone (PSL) was 38.5 12.3 mg (7.5–75 mg) and 0.7 0.23 mg/kg (0.1–1.3 mg/kg), and 25 patients (19.5%) received methylprednisolone pulse therapy. The dose of methylprednisolone was 500 mg/day in 22 patients and 1000 mg/day in three patients. The administration for three consecutive days was defined as one course of methylprednisolone pulse therapy. Sixteen patients received one course, eight patients received two courses and one patient received three courses of the methylprednisolone pulse therapy. The oral prednisolone was withdrawn during the pulse therapy.
3.2. group
Comparison of the GC-DM group and the non-GC-DM
During the four-week period after the initiation of glucocorticoid therapy, 84 patients (65.6%) developed GC-DM. All patients diagnosed with GC-DM exhibited a postprandial
glucose level exceeding 200 mg/dl at least twice, whereas only five patients showed a fasting glucose level exceeding 126 mg/ dl. During the four-week period, 42 of the 84 patients with GCDM (50.0%) received medications for GC-DM. Oral hypoglycemic agents were given in 35 patients; 26 patients received alpha-glucosidase inhibitors (a-GI) alone, two patients received dipeptidyl peptidase-4 (DPP-4) inhibitors alone, two patients received glinide class agents alone, three patients received a-GI and DPP-4 inhibitors and two patients received a-GI and glinide class agents. Insulin therapy was initiated in 11 patients. Compared with the patients who did not develop GC-DM (non-GC-DM group), those who developed GC-DM (GC-DM group) were older (65.2 vs. 50.4 years, p < 0.0001) and more frequently exhibited hypertension (47.6 vs. 25.6%, p = 0.015). Meanwhile, the GC-DM group demonstrated significantly higher levels of fasting plasma glucose and HbA1c prior to the initiation of glucocorticoid therapy (93.3 vs. 89.0 mg/dl, p = 0.027, 5.78 vs. 5.50%, p = 0.001, respectively), with lower eGFR values (54.0 vs. 77.1 ml/min/1.73 m2, p = 0.0003) (Table 3). The serum levels of AST and ALT were significantly lower in the GC-DM group than in the non-GC-DM group (36.1 vs. 99.9 IU/l, p = 0.0002 and 28.2 vs. 47.2 IU/l, p = 0.0001, respectively). These differences were dependent on the fact that some young patients with myositis who did not develop GC-DM presented markedly elevated levels of AST and ALT in association with the increase of myogenic enzymes. No significant differences were found between the two groups in the distribution of gender, BMI, a family history of DM, serum levels of LDL-cholesterol or triglycerides and maximum or total dose of glucocorticoids. There were no significant differences in the WBC and RBC counts between the two groups. We also analyzed the differential count of WBC; however, we could not detect significant differences in the WBC subtypes between the GC-DM group and the non-GCDM group. The GC-DM group tended to receive methylprednisolone pulse therapy more frequently than the non-GC-DM group, without statistical differences (22.6 vs. 13.6%, p = 0.213). Among the patients with rheumatic diseases, those with systemic vasculitis showed a significantly higher incidence of GC-DM (77.4%) than those with SLE (21.4%) and inflammatory myositis (52.9%) ( p = 0.004). However, the patients with systemic vasculitis were older (68.8 vs. 38.5 vs. 55.3 years, p < 0.0001) and exhibited higher levels of fasting plasma glucose (90.7 vs. 85.6 vs. 87.9 mg/dl, p = 0.195) and HbA1c (5.82 vs. 5.44 vs. 5.71%, p = 0.109) and lower values of eGFR (55.0 vs. 76.5 vs. 100.0 ml/min/1.73 m2, p < 0.0001)) than the patients with myositis and SLE.
Table 2 – Underlying diseases. Underlying diseases Patients number
Vasculitis
Myositis
SLE
MCNS
MN
MPGN
IN
FGS
Others
31
17
14
10
8
7
6
5
30
SLE: systemic lupus erythematosus, MCNS: minimal change nephrotic syndrome, MN: membranous nephropathy, MPGN: membranoproliferative glomerulonephritis, IN: interstitial nephritis, FGS: focal glomerular sclerosis.
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diabetes research and clinical practice 108 (2015) 273–279
Table 3 – Comparison of the baseline characteristics of the patients with and without GC-DM.
Patients (no) Gender (female, %) Age (years)* Family history of DM BMI Complication of hypertension* Fasting plasma glucose (mg/dl)* HbA1c (%)* WBC (/ml) RBC (104/ml) eGFR (ml/min/1.73 m2)* AST (IU/l) ALT (IU/l) Total cholesterol (mg/dl) LDL-cholesterol (mg/dl) Triglyceride (mg/dl) mPSL pulse therapy (%) Maximum dose of PSL (mg/day) Maximum dose of PSL (mg/kg/day) Total dose of PSL for 28 days (mg) The dose of PSL at 28th day
Non GC-DM
GC-DM
p Value
44 (34.4%) 28 (63.6%) 50.4 2.8 5 (11.4%) 23.2 0.7 11 (25.6%) 89.0 1.3 5.50 0.09 6900 3800 392 75.7 77.1 5.5 99.9 278 47.2 70.0 221 14.7 139 12.4 163 12.8 6 (13.6%) 40.8 2.1 0.71 0.04 1360 151 33.4 1.8
84 (65.6%) 51 (60.7%) 65.2 1.5 16 (19.1%) 22.4 0.4 40 (47.6%) 93.3 1.3 5.78 0.04 7440 3950 368 67.0 54.0 3.5 36.1 32.0 28.2 31.5 237 14.1 151 10.7 151 9.3 19 (22.6%) 37.3 1.2 0.69 0.02 1400 116 30.1 1.2
0.746
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Risk factors for the development of glucocorticoid-induced diabetes mellitus Takayuki Katsuyama, Ken-Ei Sada *, Sayaka Namba, Haruki Watanabe, Eri Katsuyama, Toshio Yamanari, Jun Wada, Hirofumi Makino Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama City 700-8558, Japan
article info
abstract
Article history:
Aims: To evaluate the incidence of glucocorticoid-induced diabetes mellitus (GC-DM) by
Received 14 May 2014
repeated measurements of the postprandial glucose and detect predictors for the develop-
Received in revised form
ment of GC-DM.
9 October 2014
Methods: Inpatients with rheumatic or renal disease who received glucocorticoid therapy
Accepted 6 February 2015
were enrolled in this study. We compared the clinical and laboratory parameters of the GC-
Available online 21 February 2015
DM group with the non-GC-DM group and performed a multivariate analysis to identify risk factors.
Keywords:
Results: During a four-week period, 84 of the 128 patients (65.6%) developed GC-DM. All
Glucocorticoid-induced diabetes
patients were diagnosed based on the detection of postprandial hyperglycemia. The GC-DM
mellitus
group had an older age (65.2 vs. 50.4 years, p < 0.0001), higher levels of fasting plasma
Risk factor
glucose (93.3 vs. 89.0 mg/dl, p = 0.027) and HbA1c (5.78 vs. 5.50%, 39.7 vs. 36.6 mmol/mol,
Rheumatic disease
p = 0.001) and lower eGFR values (54.0 vs. 77.1 ml/min/1.73 m2, p = 0.0003) than the non-GC-
Renal disease
DM group. According to the multivariate analysis, an older age (more than or equal to 65 years), higher HbA1c level (more than or equal to 6.0%) and lower eGFR (65 years or less than or equal to 65 years). Candidate risk factors were selected according to the results of the univariate analysis and the findings of previous reports. A p value of less than 0.05 was considered to indicate a statistically significant difference. All statistical analyses were performed using the JMP 9.0 software package (SAS Institute Inc., Cary, NC, USA). The patient background data are presented as the mean SD, and the data in the table comparing the characteristics of the groups are given as the mean SE.
Ethical considerations
3.
Results
3.1.
Patient background characteristics
We recruited 184 inpatients treated with glucocorticoid therapy. Of these patients, 56 were excluded because their postprandial glucose measurements were taken less than three times. Therefore, 128 patients were enrolled in this study. The mean frequency of postprandial glucose measurements during the first two weeks after the initiation of glucocorticoid therapy was 10.6 8.0 times. The patient population comprised 79 (61.7%) females and 49 (38.3%)
275
diabetes research and clinical practice 108 (2015) 273–279
Table 1 – Baseline characteristics of the patients. Patients (no)
128 (Female 79, male 49)
Age (years) Family history of DM BMI Complication of hypertension Fasting plasma glucose (mg/dl) HbA1c (%) WBC (ml) RBC (104/ml) eGFR (ml/min/1.73 m2) AST (IU/l) ALT (IU/l) Total cholesterol (mg/dl) LDL-cholesterol (mg/dl) Triglyceride (mg/dl) mPSL pulse therapy (%) Maximum dose of PSL (mg/day) Maximum dose of PSL (mg/kg/day) Total dose of PSL for 28 days (mg)* The dose of PSL at 28th day
60.1 16.8 21 (16.4%) 22.7 4.16 51 (40.2%) 91.8 10.9 5.68 0.49 7260 3890 376 70.7 62.0 34.6 58.0 167 34.7 48.9 232 112 147 87.6 155 81.9 25 (19.5%) 38.5 12.3 0.70 0.23 1380 1040 31.2 11.7
Mean SD DM: diabetes mellitus, BMI: body mass index, WBC: white blood cell, RBC: red blood cell, eGFR: estimated glomerular filtration rate, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDL: low-density lipoprotein, mPSL: methylprednisolone, PSL: prednisolone. * Includes the dose of glucocorticoids used in mPSL pulse therapy.
males. The clinical and laboratory characteristics of the patients are summarized in Table 1. The mean age of the patients was 60.1 16.8 years (range: 14–88 years), and the underling diseases included systemic vasculitis (31 patients), inflammatory myositis (17 patients), SLE (14 patients) and MCNS (10 patients) (Table 2). The daily maximum dose of prednisolone (PSL) was 38.5 12.3 mg (7.5–75 mg) and 0.7 0.23 mg/kg (0.1–1.3 mg/kg), and 25 patients (19.5%) received methylprednisolone pulse therapy. The dose of methylprednisolone was 500 mg/day in 22 patients and 1000 mg/day in three patients. The administration for three consecutive days was defined as one course of methylprednisolone pulse therapy. Sixteen patients received one course, eight patients received two courses and one patient received three courses of the methylprednisolone pulse therapy. The oral prednisolone was withdrawn during the pulse therapy.
3.2. group
Comparison of the GC-DM group and the non-GC-DM
During the four-week period after the initiation of glucocorticoid therapy, 84 patients (65.6%) developed GC-DM. All patients diagnosed with GC-DM exhibited a postprandial
glucose level exceeding 200 mg/dl at least twice, whereas only five patients showed a fasting glucose level exceeding 126 mg/ dl. During the four-week period, 42 of the 84 patients with GCDM (50.0%) received medications for GC-DM. Oral hypoglycemic agents were given in 35 patients; 26 patients received alpha-glucosidase inhibitors (a-GI) alone, two patients received dipeptidyl peptidase-4 (DPP-4) inhibitors alone, two patients received glinide class agents alone, three patients received a-GI and DPP-4 inhibitors and two patients received a-GI and glinide class agents. Insulin therapy was initiated in 11 patients. Compared with the patients who did not develop GC-DM (non-GC-DM group), those who developed GC-DM (GC-DM group) were older (65.2 vs. 50.4 years, p < 0.0001) and more frequently exhibited hypertension (47.6 vs. 25.6%, p = 0.015). Meanwhile, the GC-DM group demonstrated significantly higher levels of fasting plasma glucose and HbA1c prior to the initiation of glucocorticoid therapy (93.3 vs. 89.0 mg/dl, p = 0.027, 5.78 vs. 5.50%, p = 0.001, respectively), with lower eGFR values (54.0 vs. 77.1 ml/min/1.73 m2, p = 0.0003) (Table 3). The serum levels of AST and ALT were significantly lower in the GC-DM group than in the non-GC-DM group (36.1 vs. 99.9 IU/l, p = 0.0002 and 28.2 vs. 47.2 IU/l, p = 0.0001, respectively). These differences were dependent on the fact that some young patients with myositis who did not develop GC-DM presented markedly elevated levels of AST and ALT in association with the increase of myogenic enzymes. No significant differences were found between the two groups in the distribution of gender, BMI, a family history of DM, serum levels of LDL-cholesterol or triglycerides and maximum or total dose of glucocorticoids. There were no significant differences in the WBC and RBC counts between the two groups. We also analyzed the differential count of WBC; however, we could not detect significant differences in the WBC subtypes between the GC-DM group and the non-GCDM group. The GC-DM group tended to receive methylprednisolone pulse therapy more frequently than the non-GC-DM group, without statistical differences (22.6 vs. 13.6%, p = 0.213). Among the patients with rheumatic diseases, those with systemic vasculitis showed a significantly higher incidence of GC-DM (77.4%) than those with SLE (21.4%) and inflammatory myositis (52.9%) ( p = 0.004). However, the patients with systemic vasculitis were older (68.8 vs. 38.5 vs. 55.3 years, p < 0.0001) and exhibited higher levels of fasting plasma glucose (90.7 vs. 85.6 vs. 87.9 mg/dl, p = 0.195) and HbA1c (5.82 vs. 5.44 vs. 5.71%, p = 0.109) and lower values of eGFR (55.0 vs. 76.5 vs. 100.0 ml/min/1.73 m2, p < 0.0001)) than the patients with myositis and SLE.
Table 2 – Underlying diseases. Underlying diseases Patients number
Vasculitis
Myositis
SLE
MCNS
MN
MPGN
IN
FGS
Others
31
17
14
10
8
7
6
5
30
SLE: systemic lupus erythematosus, MCNS: minimal change nephrotic syndrome, MN: membranous nephropathy, MPGN: membranoproliferative glomerulonephritis, IN: interstitial nephritis, FGS: focal glomerular sclerosis.
276
diabetes research and clinical practice 108 (2015) 273–279
Table 3 – Comparison of the baseline characteristics of the patients with and without GC-DM.
Patients (no) Gender (female, %) Age (years)* Family history of DM BMI Complication of hypertension* Fasting plasma glucose (mg/dl)* HbA1c (%)* WBC (/ml) RBC (104/ml) eGFR (ml/min/1.73 m2)* AST (IU/l) ALT (IU/l) Total cholesterol (mg/dl) LDL-cholesterol (mg/dl) Triglyceride (mg/dl) mPSL pulse therapy (%) Maximum dose of PSL (mg/day) Maximum dose of PSL (mg/kg/day) Total dose of PSL for 28 days (mg) The dose of PSL at 28th day
Non GC-DM
GC-DM
p Value
44 (34.4%) 28 (63.6%) 50.4 2.8 5 (11.4%) 23.2 0.7 11 (25.6%) 89.0 1.3 5.50 0.09 6900 3800 392 75.7 77.1 5.5 99.9 278 47.2 70.0 221 14.7 139 12.4 163 12.8 6 (13.6%) 40.8 2.1 0.71 0.04 1360 151 33.4 1.8
84 (65.6%) 51 (60.7%) 65.2 1.5 16 (19.1%) 22.4 0.4 40 (47.6%) 93.3 1.3 5.78 0.04 7440 3950 368 67.0 54.0 3.5 36.1 32.0 28.2 31.5 237 14.1 151 10.7 151 9.3 19 (22.6%) 37.3 1.2 0.69 0.02 1400 116 30.1 1.2
0.746
