Abstract
Objective
The administration of glucocorticoids usually causes a mild increase in fasting glucose levels and a greater dose-dependent increase in postprandial values in patients without pre-existing diabetes mellitus. Patients with persistent hyperglycemia due to glucocorticoid therapy sometimes require insulin therapy, which might result in increased weight gain and more episodes of hypoglycemia, some of which are severe. On the other hand, scant evidence is available on the efficacy of oral hypoglycemic agents in treating glucocorticoid-induced diabetes. In this study, we evaluated the efficacy of dipeptidyl peptidase (DPP)-4 inhibitors in patients with glucocorticoid-induced diabetes by continuous glucose monitoring (CGM).
Methods
We examined the glycemic profiles using CGM at baseline and 1-4 weeks after initiating DPP-4 inhibitor treatment in patients with newly developed glucocorticoid-induced diabetes.
Results
Eleven patients who had been diagnosed with kidney disease or other diseases with renal involvement were recruited for the present retrospective study. After starting DPP-4 inhibitors, the mean and standard deviation (SD) of the glucose level, and the mean amplitude of glycemic excursion (MAGE) were significantly improved in comparison to baseline. Furthermore, the area over the curve (AOC) for the glucose levels <70 mg/dL was not increased in comparison to baseline after the initiation of DPP-4 inhibitor treatment. The results indicate that the treatment of patients with glucocorticoid-induced diabetes using DPP-4 inhibitors can minimize the risk of hypoglycemia and reduce glucose variability.
Conclusion
DPP-4 inhibitors are potentially useful for blood glucose control in patients with glucocorticoid-induced diabetes.
Keywords: dipeptidyl peptidase-4 inhibitor, glucocorticoid-induced diabetes, continuous glucose monitoring
Introduction
The administration of glucocorticoids usually causes a mild increase in fasting glucose levels. Glucocorticoids also induce a dose-dependent increase in postprandial blood glucose levels, even in patients without pre-existing diabetes mellitus. The mechanism by which glucocorticoids cause hyperglycemia is multifactorial and includes the augmentation of hepatic gluconeogenesis, the inappropriate secretion of glucagon, the inhibition of the glucose uptake in adipose tissue, and the alteration of insulin receptor and post-receptor signals (1-4). Patients with persistent hyperglycemia due to glucocorticoid therapy sometimes require insulin therapy. In fact, insulin therapy is recommended for patients with glucocorticoid-induced diabetes by the Endocrine Society guidelines for the management of hyperglycemia in hospitalized patients (5). However, insulin therapy itself can result in increased weight gain and may cause more episodes of hypoglycemia, some of which are severe. Recent trials have demonstrated the efficacy of thiazolidinediones and acarbose in patients with glucocorticoid-induced diabetes (6, 7); however, there is little evidence on the efficacy of oral hypoglycemic agents for glucocorticoid-induced diabetes. Furthermore, if patients with glucocorticoid-induced diabetes are also diagnosed with chronic kidney disease (CKD), the use of oral hypoglycemic agents such as sulfonylureas, biguanides, or both, is associated with the risk of developing medication-associated adverse events such as prolonged hypoglycemia and lactic acidosis. Dipeptidyl peptidase (DPP)-4 inhibitors are a new class of oral antidiabetic drugs that increase the action of the incretin hormones. With dose adjustment, DPP-4 inhibitors can also be administered to CKD patients. In addition, a meta-analysis by Kim et al. showed that DPP-4 inhibitors are particularly effective in Asian patients with type 2 diabetes (8). However, there is little evidence of their efficacy in patients with glucocorticoid-induced diabetes.
The precise circadian variations in the blood glucose levels of patients with glucocorticoid-induced diabetes have not been clarified. A continuous glucose monitoring (CGM) system can evaluate the changes in a patient's interstitial glucose throughout the day. It is highly accurate, easy to use, and useful in the daily management of diabetes. In the present study, we evaluated the efficacy of DPP-4 inhibitors, as determined by CGM, in the treatment of patients with glucocorticoid-induced diabetes.
Materials and Methods
Patients
We retrospectively analyzed 15 Japanese patients, who were diagnosed as having glucocorticoid-induced diabetes and who were evaluated by CGM at the Division of Clinical Nephrology and Rheumatology of Niigata University Medical and Dental Hospital and the Division of Internal Medicine in Itoigawa General Hospital, Japan, between April 2012 and March 2013. The study protocol was approved by the human research ethics committees at both institutions and in accordance with the principles embodied in the Declaration of Helsinki, and written informed consent was obtained from all participants. We excluded 2 patients who were finally confirmed to have type 2 diabetes: 1 patient with a poor CGM recording, and 1 patient who had only received DPP-4 inhibitor treatment for 2 days at the second CGM test. Eleven patients (male, n=5 female, n=6 mean age, 62.2±11.7 years) were admitted to either of the hospitals, mainly for kidney disease or other diseases with renal involvement (Table 1). They were glucocorticoid-naive and had not previously been diagnosed with diabetes mellitus. They also fulfilled the following criteria: hemoglobin A1c (HbA1c) level <6.5 % and fasting plasma glucose level <126 mg/dL prior to the administration of glucocorticoid. The patients received glucocorticoids according to the guidelines for each basic disease. No patients had a family history of diabetes.
Table 1.
Summary of Patient Characteristics.
| Case | Age (years) | Sex | Dx | BH (cm) | BW (kg) | BMI (kg/m2) | HbA1c (%) | eGFR (mL/min/ 1.73 m2) | UP (g/gCr) | Prednisolone dose (mg) | Diet therapy (kcal/kg) | DPP-4 inhibitor | Number of days of diet therapy before first CGM test (days) | Number of days of DPP-4 inhibitor before second CGM test (days) | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Initial | Before | After | Before | After | Name | Initial dose (mg) | ||||||||||||
| 1 | 60 | M | IgAN | 161.2 | 67.2 | 25.9 | 5.7 | 61.3 | 4.7 | 30*, ## | 25, # | 25, # | 31.5 | 31.5 | Alo | 25 | 14 | 6 |
| 2 | 47 | F | LDKT | 158.4 | 47.8 | 19.1 | 5.8 | 59.8 | 0.1 | 25*, ## | 15, ## | 5, # | 32.6 | 32.6 | Lina | 5 | 60 | 4 |
| 3 | 65 | M | MCNS | 164.3 | 61.5 | 22.8 | 6.1 | 53.8 | 5.9 | 50, ## | 50, ## | 50, ## | 30.3 | 33.7 | Lina | 5 | 32 | 5 |
| 4 | 60 | F | MPA | 152.7 | 45.6 | 19.6 | 6.3 | 77.4 | 0.1 | 50, ## | 45, ## | 40, ## | 27.3 | 27.3 | Teneli | 20 | 43 | 12 |
| 5 | 42 | F | NS | 152.0 | 38.7 | 16.8 | 6.4 | 107.0 | 7.2 | 50*, ## | 50, ## | 40, ## | 23.6 | 31.5 | Vilda | 100 | 15 | 12 |
| 6 | 65 | F | MN | 157.5 | 53.7 | 21.6 | 5.9 | 88.5 | 6.9 | 40, # | 40, # | 40, # | 29.3 | 29.3 | Sita | 50 | 39 | 14 |
| 7 | 74 | F | CSS | 157.1 | 52.9 | 21.4 | 5.2 | 55.5 | 0.0 | 55, ## | 50, ## | 40, ## | 27.6 | 27.6 | Alo | 25 | 56 | 25 |
| 8 | 74 | F | MPA | 149.0 | 41.2 | 18.6 | 6.2 | 7.0 | 2.5 | 25, # | 25, # | 25, # | 32.8 | 32.8 | Vilda | 100 | 18 | 4 |
| 9 | 57 | M | DM | 174.7 | 62.7 | 20.5 | 5.9 | 74.5 | 0.2 | 60, ## | 60, ## | 55, ## | 29.8 | 29.8 | Vilda | 100 | 13 | 8 |
| 10 | 82 | M | IP | 156.0 | 46.0 | 18.9 | 5.8 | 36.5 | 0.1 | 30*, ## | 20, # | 20, # | 29.9 | 29.9 | Sita | 25 | 7 | 10 |
| 11 | 58 | M | MCNS | 178.0 | 78.5 | 24.8 | 6.3 | 66.3 | 7.8 | 60, ## | 60, ## | 60, ## | 25.8 | 25.8 | Alo | 25 | 7 | 9 |
*These patients received methyl-prednisolone pulse therapy prior to maintenance glucocorticoid therapy, #Single daily dosing after breakfast, ##Twice daily dosing after breakfast and lunch, Alo: alogliptin, After: after DPP-4 inhibitor treatment, Before: before DPP-4 inhibitor treatment, BH: body height, BMI: body mass index, BW: body weight, CSS: Churg-Strauss syndrome, CGM: continuous glucose monitoring, DM: dermatomyositis, DPP: dipeptidyl peptidase, Dx: diagnosis, eGFR: estimated glomerular filtration rate, F: female, IgAN: immunoglobulin A nephropathy, IP: interstitial pneumonia, LDKT: living-donor kidney transplantation, Lina: linagliptin, M: male, MAGE: mean amplitude of glycemic excursion, MCNS: minimal change nephrotic syndrome, MN: membranous nephropathy, MPA: microscopic polyangiitis, MPGN: membranoproliferative glomerulonephritis, NS: nephrotic syndrome, Sita: sitagliptin, Teneli: teneligliptin, UP: urine protein, Vilda: vildagliptin
Patients took glucocorticoids once or twice a day. Newly developed glucocorticoid-induced diabetes was defined as an elevation of casual plasma glucose levels to >200 mg/dL at least twice during the course of glucocorticoid treatment. Each patient was prescribed an energy-restricted diet (approximately 30 kcal/kg) before glucocorticoid-induced diabetes was diagnosed.
CGM
The patients' glucose profiles were assessed using the iProⓇ2 CGM system (Medtronic, Northridge, USA). The first CGM test was carried out at least 1 week after starting energy-restricted diet therapy. This CGM device measures and records a patient's interstitial glucose levels every 5 minutes, and is calibrated with capillary blood glucose samples 4 times per day. After baseline glucose monitoring for 72 hours by CGM, the patients were prescribed a DPP-4 inhibitor (sitagliptin, vildagliptin, alogliptin, linagliptin, or teneligliptin) by the attending physician. The following values were calculated from the CGM data: 1) the mean 24 hours glucose level, 2) the standard deviation (SD) of the glucose level, 3) the mean amplitude of glycemic excursion (MAGE), 4) the area under the curve for the glucose level (AUC) >180 mg/dL per 24 hours (24 hours AUC), 5) the area over the curve for the glucose level (AOC) <70 mg/dL per 24 hours (24 hours AOC), 6) the mean, AUC>180 mg/dL, the highest glucose level within 3 hours postprandially (breakfast, 8:00-11:00 AM; lunch, 12:00-3:00 PM; supper, 6:00-9:00 PM), and 7) the preprandial glucose level (defined as the lowest glucose levels within 1 hour before each meal; breakfast, 7:00-8:00 AM; lunch, 11:00 AM-12:00 PM; supper, 5:00-6:00 PM). The glycemic AUCs and AOCs were calculated according to the rule of the trapezoidal area. At 1 to 4 weeks after the initiation of DPP-4 inhibitor treatment, the patients underwent CGM for another 72 hours.
Statistical analysis
The results are presented as the mean ± SD. The effects of DPP-4 inhibitors were analyzed using a paired t-test and a one-way repeated analysis of variance (ANOVA) with the Student-Newman-Keuls method as a post hoc test. The unpaired t-test was used for comparisons within the group in which the glucocorticoid dose was reduced and in the group in which it was not. Changes in the HbA1c level during treatment with DPP-4 inhibitors were assessed using by an ANOVA. Statistical analyses were performed using the SPSS software program (version 17.0). p values of <0.05 were considered to indicate statistical significance.
Results
For the 11 patients, the HbA1c was 6.0±0.4%, the fasting plasma glucose level was 93.3±9.2 mg/dL, the body mass index was 20.9±2.8 kg/m2, and the estimated glomerular filtration rate (eGFR) was 62.5±26.3 mL/min/1.73 m2. All of the patients had been diagnosed with kidney disease or other diseases with renal involvement. The patients' clinical characteristics are summarized in Table 1. Four patients had received methylprednisolone pulse therapy before receiving maintenance glucocorticoid therapy. The patients received an initial dose of prednisolone that ranged from 25 to 60 mg/day. After the first CGM test, vildagliptin or alogliptin was prescribed to 3 patients each; sitagliptin or linagliptin was prescribed to 2 patients each; and teneligliptin was prescribed to 1 patient.
After treatment with DPP-4 inhibitors, the mean glucose levels determined by CGM showed significant improvement from 139.6±22.9 mg/dL to 124.7±12.4 mg/dL (p=0.003), the SD of the glucose levels improved from 43.6±13.1 mg/dL to 35.1±13.9 mg/dL (p=0.007), the MAGE improved from 127.7±37.5 mg/dL to 99.7±40.2 mg/dL (p=0.02), and the 24 hours AUC (>180 mg/dL) improved from 172.5±216.6 mg·24 h/dL to 50.3±62.9 mg·24 h/dL (p=0.01). However, the 24 hours AOC (<70 mg/dL) was not significantly changed: 14.4±31.9 mg·24 h/dL to 7.7±15.7 mg·24 h/dL (p=0.4) (Fig. 1, Table 2). Table 3 summarizes the data at baseline and after treatment with DPP-4 inhibitors. Severe treatment-related hypoglycemia was not observed in any of the patients.
Figure 1.
Daily variation of blood glucose levels as determined by CGM before or after treatment with DPP-4 inhibitors. Gray line: Before treatment with DPP-4 inhibitors±SD. Black line: After treatment with DPP-4 inhibitors±SD
Table 2.
Comparison of CGM Data before and after Treatment with DPP-4 Inhibitors in 24 Hours.
| Before | After | p value | |
|---|---|---|---|
| Mean glucose (mg/dL) | 139.6±22.9 | 124.7±12.4 | 0.003 |
| Glucose SD (mg/dL) | 43.6±13.1 | 35.1±13.9 | 0.007 |
| MAGE (mg/dL) | 127.7±37.5 | 99.7±40.2 | 0.02 |
| 24 h AUC>180 (mg·24h/dL) | 172.5±216.6 | 50.3±62.9 | 0.01 |
| 24 h AOC<70 (mg·24h/dL) | 14.4±31.9 | 7.7±15.7 | 0.4 |
AOC: area over the curve for plasma glucose levels, AUC: area under the curve for plasma glucose levels, DPP: dipeptidyl peptidase, MAGE: mean amplitude of glycemic excursions
p value: paired t-test
Table 3.
Summary of Continuous Glucose Monitoring Data.
| Case | Mean glucose concentration, (mg/dL) | Maximum glucose concentration, (mg/dL) | Minimum glucose concentration, (mg/dL) | SD(mg/dL) | MAGE(mg/dL) | 24 h AUC>180 (mg·24h/dL) | 24 h AOC<70 (mg·24h/dL) | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Before | After | Before | After | Before | After | Before | After | Before | After | Before | After | Before | After | |
| 1 | 152.5 | 141.2 | 303 | 296 | 40 | 40 | 61.7 | 58.0 | 172.0 | 179.0 | 310.9 | 187.6 | 10.3 | 14.7 |
| 2 | 138.0 | 118.6 | 223 | 193 | 82 | 77 | 26.8 | 25.4 | 80.8 | 75.5 | 58.6 | 2.3 | 0.0 | 0.0 |
| 3 | 127.1 | 115.7 | 191 | 208 | 59 | 76 | 45.8 | 25.8 | 144.1 | 78.5 | 94.1 | 6.2 | 2.1 | 0.0 |
| 4 | 111.6 | 108.4 | 260 | 194 | 40 | 63 | 49.9 | 35.9 | 144.8 | 104.1 | 38.0 | 5.9 | 100.9 | 6.1 |
| 5 | 138.2 | 127.6 | 244 | 242 | 64 | 59 | 49.0 | 44.8 | 136.6 | 128.1 | 203.1 | 76.7 | 1.6 | 9.2 |
| 6 | 128.2 | 115.4 | 207 | 208 | 57 | 61 | 32.4 | 38.7 | 96.2 | 107.9 | 14.6 | 31.7 | 9.8 | 3.0 |
| 7 | 144.7 | 147.0 | 278 | 225 | 78 | 79 | 42.6 | 32.2 | 127.3 | 93.3 | 141.5 | 72.0 | 0.0 | 0.0 |
| 8 | 136.6 | 132.1 | 219 | 189 | 92 | 66 | 23.4 | 20.0 | 63.3 | 60.0 | 20.0 | 4.1 | 0.0 | 0.7 |
| 9 | 120.8 | 120.0 | 263 | 238 | 66 | 40 | 47.6 | 47.0 | 135.7 | 138.6 | 87.0 | 79.7 | 2.4 | 37.7 |
| 10 | 141.3 | 122.7 | 268 | 164 | 46 | 79 | 41.1 | 13.7 | 131.3 | 44.5 | 108.8 | 0.0 | 24.1 | 0.0 |
| 11 | 196.6 | 126.8 | 375 | 269 | 95 | 59 | 58.0 | 44.6 | 163.7 | 130.9 | 745.0 | 64.2 | 0.0 | 9.5 |
After: after DPP-4 inhibitor treatment, AOC: area over the curve, AUC: area under the curve, Before: before DPP-4 inhibitor treatment, MAGE: mean amplitude of glycemic excursion
DPP-4 inhibitors further improved the patient's postprandial glucose levels; the 3 hours mean glucose levels were significantly reduced after each meal (breakfast, 137.1±37.5 mg/dL to 123.9±19.5 mg/dL, p=0.047; lunch, 177.5±43.2 mg/dL to 157.5±28.9 mg/dL, p=0.046; and supper, 188.5±38.2 mg/dL to 155.7±34.4 mg/dL, p=0.005). The AUCs (>180 mg/dL) within 3 hours were also significantly smaller after each meal (breakfast: 3.9±7.9 mg·min/dL vs. 0.2±0.5 mg·min/dL, p=0.04; lunch: 19.0±24.1 mg/dL/min vs. 8.0±10.0 mg/dL/min, p=0.03; and supper: 23.7±30.4 mg·min/dL vs. 8.9±16.8 mg·min/dL, p=0.04). The administration of DPP-4 inhibitors significantly improved the highest postprandial glucose levels after lunch (219.0±43.1 mg/dL to 192.9±34.3 mg/dL, p=0.004) and supper (230.1±53.6 mg/dL to 192.3±41.8 mg/dL, p=0.006), while the highest postprandial glucose levels after breakfast did not differ to a statistically significant extent (161.7±40.2 mg/dL vs. 150.7±26.7 mg/dL, p=0.2). In contrast, the preprandial glucose levels did not change before breakfast (87.0±25.0 mg/dL vs. 81.7±15.5 mg/dL, p=0.4) or before lunch (111.3±30.3 mg/dL vs. 110.9±16.4 mg/dL, p=0.9), but those before supper (131.3±24.7 mg/dL vs. 118.7±16.5 mg/dL, p=0.04) were slightly reduced (Table 4).
Table 4.
Comparison of CGM Data before and after Treatment with DPP-4 Inhibitors at Meal Time.
| Before | After | p value | |
|---|---|---|---|
| Mean of glucose levels within 3 h after each meal (mg/dL) | |||
| Breakfast | 137.1±37.5 | 123.9±19.5 | 0.047 |
| Lunch | 177.5±43.2a | 157.5±28.9a | 0.046 |
| Supper | 188.5±38.2a | 155.7±34.4a | 0.005 |
| The AUC (>180 mg/dL) within 3 h after each meal (mg·min/dL) | |||
| Breakfast | 3.9±7.9 | 0.2±0.5 | 0.04 |
| Lunch | 19.0±24.1a | 8.0±10.0b | 0.03 |
| Supper | 23.7±30.4a | 8.9±16.8b | 0.04 |
| Highest glucose levels within 3 h after each meal (mg/dL) | |||
| Breakfast | 161.7±40.2 | 150.7±26.7 | 0.2 |
| Lunch | 219.0±43.1a | 192.9±34.3a | 0.004 |
| Supper | 230.1±53.6a | 192.3±41.8a | 0.006 |
| Pre-prandial glucose levels (mg/dL) | |||
| Breakfast | 87.0±25.0 | 81.7±18.5 | 0.4 |
| Lunch | 111.3±30.3a | 110.9±16.4a | 0.9 |
| Supper | 131.3±24.7ac | 118.7±16.5ad | 0.04 |
p value: paired t-test
a: p<0.01 vs. Breakfast. b: p<0.05 vs. Breakfast. c: p<0.01 vs. Lunch. d: p<0.05 vs. Lunch. (ANOVA and Student-Newman-Keuls)
The comparison between the group in which the glucocorticoid dose was reduced and the group in which it was not reduced prior to the initiation of DPP-4 inhibitor treatment revealed that both groups showed the same tendency toward the amelioration of the mean glucose level (6.3±9.2 mg/dL vs. 22.8±24.2 mg/dL, p=0.06), the maximum glucose level (25.4±25.3 mg/dL vs. 50.4±53.3 mg/dL, p=0.2), the SD of the glucose level (6.2±7.0 mg/dL vs. 10.6±16.7 mg/dL, p=0.5), the MAGE (14.3±23.5 mg/dL vs. 35.7±54.0 mg/dL, p=0.3), and the 24 hours AUC (>180 mg/dL) (58.3±59.6 mg·24 h/dL vs. 180.3±267.5 mg·24 h/dL, p=0.2) (Table 5).
Table 5.
Comparison of CGM Data between the Group in which the Glucocorticoid Dose was Reduced and the Group in which It was Not.
| Δ Mean glucose concentration (mg/dL) | Δ Maximum glucose concentration (mg/dL) | Δ SD(mg/dL) | Δ MAGE(mg/dL) | Δ 24 h AUC (mg·24h/dL) | |
|---|---|---|---|---|---|
| Reduction of glucocorticoid dose (+) (n=5) | 6.3±9.2 | 25.4±25.3 | 6.2±7.0 | 14.3±23.5 | 58.3±59.6 |
| Reduction of glucocorticoid dose (-) (n=6) | 22.8±24.2 | 50.4±53.3 | 10.6±16.7 | 35.7±54.0 | 180.3±267.5 |
| p value | 0.06 | 0.2 | 0.5 | 0.3 | 0.2 |
AUC: area under the curve, DPP: dipeptidyl peptidase, MAGE: mean amplitude of glycemic excursion
p value: unpaired t-test
Moreover, the HbA1c level was not aggravated after treatment with DPP-4 inhibitors during the six-month follow-up period (Fig. 2).
Figure 2.
Changes in HbA1c level after the patients started DPP-4 inhibitors. During the follow-up period of 6 months, the level of HbA1c was not aggravated by glucocorticoids after treatment with DPP-4 inhibitors.
Discussion
In the present study, we retrospectively investigated the effect of DPP-4 inhibitors on the blood glucose levels of patients with glucocorticoid-induced diabetes. After starting DPP-4 inhibitors, the glycemic profiles, as observed by CGM, were significantly improved in comparison to baseline. The measurements of MAGE and SD are widely used to evaluate the variability of blood glucose levels. In our study, we found that the level of MAGE in patients with glucocorticoid-induced diabetes was 127.7±37.5 mg/dL, which is extremely high in comparison to the level reported in healthy controls (25.2 mg/dL) (9). The actual daily variations of the blood glucose levels of patients with glucocorticoid-induced diabetes before and after DPP-4 inhibitor treatment are shown in Fig. 1. Treatment with DPP-4 inhibitors significantly improved not only the patients' CGM findings during 24 hours, such as the mean glucose level, SD, MAGE, 24 hours AUC (>180 mg/dL), but also the mean, AUC>180 mg/dL, the highest glucose level within 3 hours postprandially in comparison to baseline. It has been reported that glucocorticoid-induced diabetes is characterized by an increase in postprandial glucose levels (10-12). In our study, as well as a previous study, there was a tendency for blood glucose levels to rise in the evening. Furthermore, because DPP-4 inhibitors stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner (13, 14), they can improve postprandial hyperglycemia. Our study showed that we might be able to detect glucose variability in glucocorticoid-induced diabetes, and the glucose-dependent effect of DPP-4 inhibitors using CGM.
Recent studies have demonstrated that high levels of MAGE are strongly correlated with vascular endothelial dysfunction and the induction of oxidative stress, abnormalities which directly increase the risk of developing diabetic complications including cardiovascular diseases and diabetic micro-vascular diseases (15, 16). DPP-4 inhibitors are known to improve glycemic variability in diabetic patients (17). Our data obtained from CGM showed that DPP-4 inhibitors improve glucose variability in patients with glucocorticoid-induced diabetes by lowering the postprandial glucose levels. Moreover, the hypoglycemic episodes related to treatment with DPP-4 inhibitors were negligible, since the AOC (<70 mg/dL) did not change in comparison to baseline. Taken together, the treatment of glucocorticoid-induced diabetes with DPP-4 inhibitors appears to reduce the variability in glucose levels and minimize the risk of developing hypoglycemia. These favorable effects have the potential to modify the patient outcome by reducing the incidence of cardiovascular events.
To investigate the effects of glucocorticoid reduction on the patients' glycemic profiles, we divided the patients into two groups: in the first group, the glucocorticoid dose was reduced; in the second, the glucocorticoid dose was not reduced. Both groups demonstrated the same tendency toward the amelioration of the mean glucose level, SD, MAGE, and 24 hours AUC (>180 mg/dL) (Table 5). We also divided the patients into two groups according to the duration of diet therapy before the first CGM test (<30 days vs. ≥30 days), according to the frequency of taking glucocorticoids (a single daily dose after breakfast vs. twice daily after breakfast and lunch), and according to the duration of DPP-4 inhibitor treatment before the second CGM test (<7 days vs. ≥7 days). There were no significant differences in the amelioration of the glycemic profiles in these groups (data not shown). These data suggest that administration of DPP-4 inhibitors leads to the improvement of CGM data.
In general, the long-term administration of glucocorticoids tends to worsen blood glucose control. Recent studies have demonstrated that two-thirds of patients with rheumatic or renal disease who received glucocorticoid therapy developed glucocorticoid-induced diabetes (18). However, in our study, the exacerbation of HbA1c was not observed during the 6-month follow-up period because DPP-4 inhibitors were started after the onset of glucocorticoid-induced diabetes. Thus, DPP-4 inhibitors might be expected to prevent the aggravation of glucocorticoid-induced diabetes.
Glucocorticoid-induced insulin resistance and impaired glucose tolerance are both associated with a progressive decline in the incretin effect, and an increase in glucocorticoid-induced insulin resistance was associated with an inappropriate increase in glucagon secretion in the first-degree relatives of patients with type 2 diabetes (4). DPP-4 inhibitors promote insulin secretion via glucagon-like peptide-1 (GLP-1) and inhibit glucagon secretion (19), actions that should be beneficial for the treatment of glucocorticoid-induced diabetes.
Exenatide, an injectable GLP-1 receptor (GLP-1R) agonist, has similar pharmacologic functions to DPP-4 inhibitors and also improves hyperglycemia in patients with glucocorticoid-induced diabetes (20). However, there is little evidence to support the superiority of either DPP-4 inhibitors or GLP-1R agonists in the treatment of glucocorticoid-induced diabetes. A recent report indicated that GLP-1R agonists are superior to DPP-4 inhibitors in their capacity to lower the HbA1c level (21). In contrast, gastrointestinal side effects, particularly nausea, are often reported after treatment with GLP-1R agonists, but such adverse events occur infrequently with DPP-4 inhibitors (19). In addition, DPP-4 inhibitors can be orally administered, whereas GLP-1R agonists must be injected. In this regard, the administration of DPP-4 inhibitors for the treatment of glucocorticoid-induced diabetes is simpler and more convenient in comparison to GLP-1R agonists.
A previous study showed that linagliptin lowered the HbA1c levels in all patients in a group with a normal renal function and a group with mild-to-moderate renal impairment, and there was no inter-group difference in the HbA1c reduction (22). Another study showed that vildagliptin lowered the level of HbA1c in patients with moderate to severe renal impairment without an increased frequency of hypoglycemic events (23). The present study shows that DPP-4 inhibitors can be used to safely improve glycemic control in patients with glucocorticoid-induced diabetes regardless of their renal function. However, the accumulation of further evidence from prospective studies is needed.
The present study was associated with some limitations, including the small number of cases, the short duration of follow-up and the absence of a control group. Since this study was retrospective in nature, 5 types of DPP-4 inhibitors were selected for 11 patients. Craddy et al. recently reported that DPP-4 inhibitors have equivalent effects across the class in terms of their key efficacy and safety outcomes (24). Thus, we decided to analyze these 11 patients together in the present study.
Conclusion
In 11 patients with glucocorticoid-induced diabetes, who were also diagnosed with kidney disease or other diseases with renal involvement and treated with DPP-4 inhibitors, the glycemic profiles (as assessed by CGM) improved without an increase in the number of hypoglycemic episodes during the 6-month follow-up period. The oral hypoglycemic agents that are available for CKD patients are limited; thus, DPP-4 inhibitors would be useful for patients with glucocorticoid-induced diabetes.
Author's disclosure of potential Conflicts of Interest (COI).
Ichiei Narita: Honoraria, Novartis Pharma K.K., Daiichi Sankyo Co., Ltd, MSD K.K., Mitsubishi Tanabe Pharma Corporation and Kyowa Hakko Kirin Co.,Ltd.
References
- 1.van Raalte DH, Ouwens DM, Diamant M. Novel insights into glucocorticoid-mediated diabetogenic effects: towards expansion of therapeutic options? Eur J Clin Invest 39: 81-93, 2009. [DOI] [PubMed] [Google Scholar]
- 2.Wise JK, Hendler R, Felig P. Influence of glucocorticoids on glucagon secretion and plasma amino acid concentrations in man. J Clin Invest 52: 2774-2782, 1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Clement S, Braithwaite SS, Magee MF, et al. . Management of diabetes and hyperglycemia in hospitals. Diabetes Care 27: 553-591, 2004. [DOI] [PubMed] [Google Scholar]
- 4.Jensen DH, Aaboe K, Henriksen JE, et al. . Steroid-induced insulin resistance and impaired glucose tolerance are both associated with a progressive decline of incretin effect in first-degree relatives of patients with type 2 diabetes. Diabetologia 55: 1406-1416, 2012. [DOI] [PubMed] [Google Scholar]
- 5.Umpierrez GE, Hellman R, Korytkowski MT, et al. . Management of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 97: 16-38, 2012. [DOI] [PubMed] [Google Scholar]
- 6.Willi SM, Kennedy A, Brant BP, Wallace P, Rogers NL, Garvey WT. Effective use of thiazolidinediones for the treatment of glucocorticoid-induced diabetes. Diabetes Res Clin Pract 58: 87-96, 2002. [DOI] [PubMed] [Google Scholar]
- 7.Ito S, Ogishima H, Kondo Y, et al. . Early diagnosis and treatment of steroid-induced diabetes mellitus in patients with rheumatoid arthritis and other connective tissue diseases. Mod Rheumatol 24: 52-59, 2014. [DOI] [PubMed] [Google Scholar]
- 8.Kim YG, Hahn S, Oh TJ, Kwak SH, Park KS, Cho YM. Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis. Diabetologia 56: 696-708, 2013. [DOI] [PubMed] [Google Scholar]
- 9.Hill NR, Oliver NS, Choudhary P, Levy JC, Hindmarsh P, Matthews DR. Normal reference range for mean tissue glucose and glycemic variability derived from continuous glucose monitoring for subjects without diabetes in different ethnic groups. Diabetes Technol Ther 13: 921-928, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Uzu T, Harada T, Sakaguchi M, et al. . Glucocorticoid-induced diabetes mellitus: prevalence and risk factors in primary renal diseases. Nephron Clin Pract 105: c54-c57, 2007. [DOI] [PubMed] [Google Scholar]
- 11.van Raalte DH, Diamant M, Ouwens DM, et al. . Glucocorticoid treatment impairs microvascular function in healthy men in association with its adverse effects on glucose metabolism and blood pressure: a randomised controlled trial. Diabetologia 56: 2383-2391, 2013. [DOI] [PubMed] [Google Scholar]
- 12.Iwamoto T, Kagawa Y, Naito Y, Kuzuhara S, Kojima M. Steroid-induced diabetes mellitus and related risk factors in patients with neurologic diseases. Pharmacotherapy 24: 508-514, 2004. [DOI] [PubMed] [Google Scholar]
- 13.Drucker DJ. Glucagon-like peptides. Diabetes 47: 159-169, 1998. [DOI] [PubMed] [Google Scholar]
- 14.Vilsboll T, Krarup T, Madsbad S, Holst JJ. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept 114: 115-121, 2003. [DOI] [PubMed] [Google Scholar]
- 15.Torimoto K, Okada Y, Mori H, Tanaka Y. Relationship between fluctuations in glucose levels measured by continuous glucose monitoring and vascular endothelial dysfunction in type 2 diabetes mellitus. Cardiovasc Diabetol 12: 1, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Monnier L, Mas E, Ginet C, et al. . Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA 295: 1681-1687, 2006. [DOI] [PubMed] [Google Scholar]
- 17.Mori Y, Taniguchi Y, Miyazaki S, Yokoyama J, Utsunomiya K. Effects of add-on treatment with sitagliptin on narrowing the range of glucose fluctuations in Japanese type 2 diabetes patients receiving insulin therapy. Diabetes Technol Ther 15: 237-240, 2013. [DOI] [PubMed] [Google Scholar]
- 18.Katsuyama T, Sada KE, Namba S, et al. . Risk factors for the development of glucocorticoid-induced diabetes mellitus. Diabetes Res Clin Pract 108: 273-279, 2015. [DOI] [PubMed] [Google Scholar]
- 19.Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368: 1696-1705, 2006. [DOI] [PubMed] [Google Scholar]
- 20.van Raalte DH, van Genugten RE, Linssen MM, Ouwens DM, Diamant M. Glucagon-like peptide-1 receptor agonist treatment prevents glucocorticoid-induced glucose intolerance and islet-cell dysfunction in humans. Diabetes Care 34: 412-417, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Aroda VR, Henry RR, Han J, et al. . Efficacy of GLP-1 receptor agonists and DPP-4 inhibitors: meta-analysis and systematic review. Clin Ther 34: 1247-1258.e1222, 2012. [DOI] [PubMed] [Google Scholar]
- 22.Groop PH, Del Prato S, Taskinen MR, et al. . Linagliptin treatment in subjects with type 2 diabetes with and without mild-to-moderate renal impairment. Diabetes Obes Metab 16: 560-568, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Kothny W, Shao Q, Groop PH, Lukashevich V. One-year safety, tolerability and efficacy of vildagliptin in patients with type 2 diabetes and moderate or severe renal impairment. Diabetes Obes Metab 14: 1032-1039, 2012. [DOI] [PubMed] [Google Scholar]
- 24.Craddy P, Palin HJ, Johnson KI. Comparative effectiveness of dipeptidylpeptidase-4 inhibitors in type 2 diabetes: a systematic review and mixed treatment comparison. Diabetes Ther 5: 1-41, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]