Comparison of Vildagliptin and Pioglitazone in Korean Patients with Type 2 Diabetes Inadequately Controlled with Metformin.

BACKGROUND: We compared the efficacies of vildagliptin (50 mg twice daily) relative to pioglitazone (15 mg once daily) as an add-on treatment to metformin for reducing glycosylated hemoglobin (HbA1c) levels in Korean patients with type 2 diabetes. METHODS: The present study was a multicenter, randomized, active-controlled investigation comparing the effects of vildagliptin and pioglitazone in Korean patients receiving a stable dose of metformin but exhibiting inadequate glycemic control. Each patient underwent a 16-week treatment period with either vildagliptin or pioglitazone as an add-on treatment to metformin. RESULTS: The mean changes in HbA1c levels from baseline were -0.94% in the vildagliptin group and -0.6% in the pioglitazone group and the difference between the treatments was below the non-inferiority margin of 0.3%. The mean changes in postprandial plasma glucose (PPG) levels were -60.2 mg/dL in the vildagliptin group and -38.2 mg/dL in the pioglitazone group and these values significantly differed (P=0.040). There were significant decreases in the levels of total, low density lipoprotein, high density lipoprotein (HDL), and non-HDL cholesterol in the vildagliptin group but increases in the pioglitazone group. The mean change in body weight was -0.07 kg in the vildagliptin group and 0.69 kg in the pioglitazone group, which were also significantly different (P=0.002). CONCLUSION: As an add-on to metformin, the efficacy of vildagliptin for the improvement of glycemic control is not inferior to that of pioglitazone in Korean patients with type 2 diabetes. In addition, add-on treatment with vildagliptin had beneficial effects on PPG levels, lipid profiles, and body weight compared to pioglitazone.

Morphologic Changes in Autonomic Nerves in Diabetic Autonomic Neuropathy.

Diabetic neuropathy is one of the major complications of diabetes, and it increases morbidity and mortality in patients with both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Because the autonomic nervous system, for example, parasympathetic axons, has a diffuse and wide distribution, we do not know the morphological changes that occur in autonomic neural control and their exact mechanisms in diabetic patients with diabetic autonomic neuropathy (DAN). Although the prevalence of sympathetic and parasympathetic neuropathy is similar in T1DM versus T2DM patients, sympathetic nerve function correlates with parasympathetic neuropathy only in T1DM patients. The explanation for these discrepancies might be that parasympathetic nerve function was more severely affected among T2DM patients. As parasympathetic nerve damage seems to be more advanced than sympathetic nerve damage, it might be that parasympathetic neuropathy precedes sympathetic neuropathy in T2DM, which was Ewing's concept. This could be explained by the intrinsic morphologic difference. Therefore, the morphological changes in the sympathetic and parasympathetic nerves of involved organs in T1DM and T2DM patients who have DAN should be evaluated. In this review, evaluation methods for morphological changes in the epidermal nerves of skin, and the intrinsic nerves of the stomach will be discussed.

Insulin Initiation in Insulin-Naïve Korean Type 2 Diabetic Patients Inadequately Controlled on Oral Antidiabetic Drugs in Real-World Practice: The Modality of Insulin Treatment Evaluation Study.

BACKGROUND: The Modality of Insulin Treatment Evaluation (MOTIV) study was performed to provide real-world data concerning insulin initiation in Korean type 2 diabetes mellitus (T2DM) patients with inadequate glycemic control with oral hypoglycemic agents (OHAs). METHODS: This multicenter, non-interventional, prospective, observational study enrolled T2DM patients with inadequate glycemic control (glycosylated hemoglobin [HbA1c] ≥7.0%) who had been on OHAs for ≥3 months and were already decided to introduce basal insulin by their physician prior to the start of the study. All treatment decisions were at the physician's discretion to reflect real-world practice. RESULTS: A total of 9,196 patients were enrolled, and 8,636 patients were included in the analysis (mean duration of diabetes, 8.9 years; mean HbA1c, 9.2%). Basal insulin plus one OHA was the most frequently (51.0%) used regimen. After 6 months of basal insulin treatment, HbA1c decreased to 7.4% and 44.5% of patients reached HbA1c <7%. Body weight increased from 65.2 kg to 65.5 kg, which was not significant. Meanwhile, there was significant increase in the mean daily insulin dose from 16.9 IU at baseline to 24.5 IU at month 6 (P<0.001). Overall, 17.6% of patients experienced at least one hypoglycemic event. CONCLUSION: In a real-world setting, the initiation of basal insulin is an effective and well-tolerated treatment option in Korean patients with T2DM who are failing to meet targets with OHA therapy.

The Relationship between Anemia and the Initiation of Dialysis in Patients with Type 2 Diabetic Nephropathy.

BACKGROUND: Anemia is associated with various poor clinical outcomes in chronic kidney disease patients. The aim of this study was to investigate the relationship between anemia and the initiation degree and time of dialysis in type 2 diabetic nephropathy patients. METHODS: This observational retrospective study included 130 type 2 diabetic nephropathy patients in Korea. The existence of anemia, the degree and time of dialysis initiation were reviewed. Clinical characteristics and variables were also compared. RESULTS: The levels of hemoglobin and serum creatinine were significantly correlated with the dialysis initiation (P<0.05) during the 10-year follow-up period. Patients with anemia showed rapid decline of renal function, causing significantly more dialysis initiation (54.1% vs. 5.4%, P<0.05) compare to the patients without anemia. Average time to initiate dialysis in patients with anemia was 45.1 months (range, 8.0 to 115.8 months), which was significantly faster than that (68.3 months [range, 23.3 to 108.8 months]) in patients without anemia (P<0.01). The risk to dialysis initiation was significantly increased in patients with anemia compared to the patients without anemia (adjusted hazard ratio, 8.1; 95% confidence interval, 2.4 to 27.0; P<0.05). CONCLUSION: Anemia is associated with rapid decline of renal dysfunction and faster initiation of dialysis in diabetic nephropathy patients. Therefore, clinicians should pay an earlier attention to anemia during the management of diabetes.

Relationship between the Korean Version Survey of the Autonomic Symptoms Score and Cardiac Autonomic Neuropathy Parameters in Patients with Diabetic Peripheral Neuropathy.

BACKGROUND: The Survey of Autonomic Symptom (SAS) scale was reported as an easy instrument to assess the autonomic symptoms in patients with early diabetic neuropathy. In this study, we investigated the relationship between the SAS scale and the parameters of cardiac autonomic neuropathy (CAN) in Korean patients with diabetic peripheral neuropathy (DPN). METHODS: The SAS scale was tested in 30 healthy controls and 73 patients with DPN at Chonbuk National University Hospital, in Korea. The SAS score was compared to the parameters of the CAN test and the total symptom score (TSS) for DPN in patients with DPN. RESULTS: The SAS symptom score and total impact score were increased in patients with DPN compared to the control group (P=0.01), particularly in sudomotor dysfunction (P=0.01), and vasomotor dysfunction (P=0.01). The SAS score was increased in patients with CAN compared to patients without CAN (P<0.05). Among the diverse CAN parameters, the valsalva ratio and postural hypotension were associated with the SAS score (P<0.05). However, there was no association between the SAS scale and TSS for DPN, and TSS for DPN did not differ between patients with and without CAN. CONCLUSION: SAS is a simple instrument that can be used to assess autonomic symptoms in patients with diabetes and can be used as a screening tool for autonomic neuropathy, particularly for CAN.

Clinical characteristics of diabetic patients transferred to korean referral hospitals.

BACKGROUND: We evaluated the disease profile and clinical management, including the status of both glycemic control and complications, in patients with diabetes who were transferred to referral hospitals in Korea. METHODS: Patients referred to 20 referral hospitals in Gyeongsangnam/Gyeongsangbuk-do and Jeollanam/Jeollabuk-do with at least a 1-year history of diabetes between January and June 2011 were retrospectively reviewed using medical records, laboratory tests, and questionnaires. RESULTS: A total of 654 patients were enrolled in the study. In total, 437 patients (67%) were transferred from clinics and 197 (30%) patients were transferred from hospitals. A total of 279 patients (43%) visited higher medical institutions without a written medical request. The main reason for the referral was glycemic control in 433 patients (66%). Seventy-three patients (11%) had received more than one session of diabetic education. Only 177 patients (27%) had been routinely self-monitoring blood glucose, and 146 patients (22%) were monitoring hemoglobin A1c. In addition, proper evaluations for diabetic complications were performed for 74 patients (11%). The most common complication was neuropathy (32%) followed by nephropathy (31%). In total, 538 patients (82%) had been taking oral hypoglycemic agents. A relatively large number of patients (44%) had been taking antihypertensive medications. CONCLUSION: We investigated the clinical characteristics of diabetic patients and identified specific problems in diabetic management prior to the transfer. We also found several problems in the medical system, which were divided into three medical institutions having different roles in Korea. Our findings suggested that the relationships among medical institutions have to be improved, particularly for diabetes.

Efficacy and safety of weekly alendronate plus vitamin D3 5600 IU versus weekly alendronate alone in Korean osteoporotic women: 16-week randomized trial.

Vitamin D (vit-D) is essential for bone health, although many osteoporosis patients have low levels of 25-hydroxy-vit-D [25(OH)D]. This randomized, open-label study compared the effects of once weekly alendronate 70 mg containing 5600 IU vit-D3 (ALN/D5600) to alendronate 70 mg without additional vit-D (ALN) on the percent of patients with vit-D insufficiency [25(OH)D <15 ng/mL, primary endpoint] and serum parathyroid hormone (PTH, secondary endpoint) levels in postmenopausal, osteoporotic Korean women. Neuromuscular function was also measured. A total of 268 subjects were randomized. Overall, 35% of patients had vit-D insufficiency at baseline. After 16-weeks, there were fewer patients with vit-D insufficiency in the ALN/D5600 group (1.47%) than in the ALN group (41.67%) (p<0.001). Patients receiving ALN/D5600 compared with ALN were at a significantly decreased risk of vit-D insufficiency [odds ratio=0.02, 95% confidence interval (CI) 0.00-0.08]. In the ALN/D5600 group, significant increases in serum 25(OH)D were observed at weeks 8 (9.60 ng/mL) and 16 (11.41 ng/mL), where as a significant decrease was recorded in the ALN group at week 16 (-1.61 ng/mL). By multiple regression analysis, major determinants of increases in serum 25(OH)D were ALN/D5600 administration, seasonal variation, and baseline 25(OH)D. The least squares mean percent change from baseline in serum PTH in the ALN/D5600 group (8.17%) was lower than that in the ALN group (29.98%) (p=0.0091). There was no significant difference between treatment groups in neuromuscular function. Overall safety was similar between groups. In conclusion, the administration of 5600 IU vit-D in the ALN/D5600 group improved vit-D status and reduced the magnitude of PTH increase without significant side-effects after 16 weeks in Korean osteoporotic patients.

Duration of diabetes and effectiveness of insulin in the management of insulin-naïve Korean patients uncontrolled on oral antidiabetic drugs: a sub-analysis of the MOdaliTy of Insulin treatment eValuation (MOTIV) registry results.

To investigate whether duration of diabetes has an impact on the effectiveness of insulinization in diabetes management. This open-label, noninterventional, observational registry was conducted at >500 centers in Korea. Patients with diabetes, on oral antidiabetic drugs, with HbA1c ≥7 % (53 mmol/mol) in the preceding 3 months, being considered for initiation of basal insulin by their physicians, were included. Data were collected at baseline and at 3 and 6 months. Of 6,616 patients evaluated, 62.5 % had diabetes for <10 years, while only 6.5 % patients had diabetes for ≥20 years. At the end of study, average HbA1c in patients with diabetes for <10 years, for 10 to <20 years, and for ≥20 years was 7.3 ± 1.0 % (56 ± 10.9 mmol/mol), 7.4 ± 1.0 % (57 ± 10.9 mmol/mol), and 7.6 ± 1.1 % (60 ± 12.0 mmol/mol), respectively. Over half the patients (50.7 %) with diabetes <10 years achieved HbA1c <7 % (53 mmol/mol) by the end of study, while only 42.1 and 35.1 % patients with diabetes for 10 to <20 and ≥20 years, respectively, achieved their target. The average insulin dosage required for per unit HbA1c reduction was significantly different among the groups according to duration of type 2 diabetes mellitus (p < 0.05). Among patients who achieved HbA1c <7 %, proportion of patients with hypoglycemia in the ≥20 years group was higher than that in the <10 years, 10 to <20 years groups. Early insulin administration provided a better glycemic control with less insulin dosage and lower frequency of hypoglycemic events. Thus, early insulinization might hold the key to better management of type 2 diabetes mellitus.

The neuroprotective benefit from pioglitazone (PIO) addition on the alpha lipoic acid (ALA)-based treatment in experimental diabetic rats.

In this study, we investigated the combined effect of pioglitazone (PIO) with alpha lipoic acid (ALA) on the peripheral nerves of diabetic rats. Animals were divided into 8 groups (N = 6-8) and designated according to ALA (100 mg/kg/day) and PIO (10 mg/kg/day) treatment: Normal, Normal + ALA, Normal + PIO, Normal + ALA + PIO, DM, DM + ALA, DM + PIO, and DM + ALA + PIO. After 24 weeks, current perception threshold, mechanical allodynia, oxidative stresses, intraepidermal nerve fiber density (IENFD), and axonal morphology in the sciatic nerve were compared among groups. IENFD in the DM + ALA + PIO group was significantly less reduced than in other DM groups (7.61 ± 0.52 vs. 5.62 ± 0.96, 5.56 ± 0.60, and 7.10 ± 0.70 for DM, DM + ALA, and DM + PIO, respectively P < 0.05). The mean myelinated axonal area in the sciatic nerves was significantly higher in the DM + ALA + PIO group compared with non-treated DM group (70.2 ± 3.46 vs. 61.1 ± 2.91, P < 0.05) although significant differences were not present between combination therapy and monotherapy independent of ALA or PIO. Our results demonstrated that combination therapy using PIO based on ALA can give an additional benefit in peripheral nerve preservation in diabetes. Moreover, PIO can be preferentially considered when additional glucose-lowering agent is required in DPN patients treated with ALA.

Clinical implication of elevated CA 19-9 level and the relationship with glucose control state in patients with type 2 diabetes.

The aim is to investigate whether there is a difference in CA 19-9 levels between diabetes and healthy subjects except malignancies and associated factors with CA 19-9 in diabetes. We performed a retrospective analysis in 146 type 2 diabetes and 154 healthy subjects who visited our medical institution from 2005 to 2009. We compared the CA 19-9 in each group, and analyzed clinical and biochemical variables in diabetes. The average value of CA 19-9 in diabetes was higher than that of healthy subjects significantly (14.1 vs 8.1 U/mL, p < 0.01). CA 19-9 had a positive correlation with HbA1c (r = 0.22), fasting plasma glucose (r = 0.24), and C-reactive protein (r = 0.38) in diabetes (p < 0.05). 48 type 2 diabetes who showed decreased CA 19-9 during follow-up of 1.8 ± 1.0 years were also improved in glucose control state. The proportion of insulin use for glucose control was significantly higher in the group of CA 19-9 ≥ 37 U/mL (75.0 %) as compared with the group of CA 19-9 < 37 U/mL (34.0 %). CA 19-9 was significantly higher in the patients with diabetic peripheral neuropathy (DPN) as compared with those without DPN (p = 0.02). However, after excluding the influences from glycemic control state, significant difference was not observed. Our results indicate not only that CA 19-9 is influenced by glycemic control state but also can be elevated irrespective of any malignancy in diabetes. Therefore, CA 19-9 should be interpreted carefully in diabetic patients when CA 19-9 is used as the tool for malignancy screening.

Neuroprotective effects of Vitis vinifera extract on prediabetic mice induced by a high-fat diet.

BACKGROUND/AIMS: Vitis vinifera grape seed extract (VVE) contains oligomeric proanthocyanidins that show antioxidant and free radical-scavenging activities. We evaluated VVE for its neuroprotective effect in prediabetic mice induce by a high-fat diet (HD). METHODS: Mice were divided into four groups according to VVE dose: those fed a normal diet (ND; n = 10), HD (n = 10), HD with 100 mg/kg VVE (n = 10), and HD with 250 mg/kg VVE (n = 10). After 12 weeks, immunohistochemical analyses were carried out using a polyclonal antibody against antiprotein gene product 9.5 (protein-gene-product, 9.5), and intraepidermal innervation was subsequently quantified as nerve fiber abundance per unit length of epidermis (intraepidermal nerve fiber, IENF/mm). RESULTS: Daily administration of VVE at doses of 100 or 250 mg/kg for 12 weeks protected HD mice from nerve fiber loss compared to untreated mice, as follows (IENF/mm): controls (40.95 ± 5.40), HD (28.70 ± 6.37), HD with 100 mg/kg (41.14 ± 1.12), and HD with 250 mg/kg (48.98 ± 7.01; p < 0.05, HD with VVE vs. HD). CONCLUSIONS: This study provides scientific support for the therapeutic potential of VVE in peripheral neuropathy in an HD mouse model. Our results suggest that VVE could play a role in the management of peripheral neuropathy, similar to other antioxidants known to be beneficial for diabetic peripheral neuropathy.

Effect of granulocyte colony-stimulating factor on the peripheral nerves in streptozotocin-induced diabetic rat.

There are controversial reports about the effect of granulocyte colony-stimulating factor (G-CSF) in peripheral nerve protection. Therefore, the present study aimed to investigate the effect of G-CSF on peripheral nerves in streptozotocin (STZ) induced diabetic rats. After STZ or vehicle injection, rats were divided into five groups (n=6) as follows: normal+vehicle, normal+G-CSF (50 µg/kg for 5 days), diabetes mellitus (DM)+vehicle, DM+G-CSF (50 µg/kg for 5 days), and DM+G-CSF extension (50 µg/kg for 5 days and followed by two injections per week up to 24 weeks). Our results showed that the current perception threshold was not significantly different among experimental groups. G-CSF treatment inhibited the loss of cutaneous nerves and gastric mucosal small nerve fibers in morphometric comparison, but statistical significance was not observed. The present results demonstrated that G-CSF has no harmful but minimal beneficial effects with respect to peripheral nerve preservation in diabetic rats.

Therapeutic Potential of Dioscorea Extract (DA-9801) in Comparison with Alpha Lipoic Acid on the Peripheral Nerves in Experimental Diabetes.

DA-9801, a mixture of extracts from Dioscorea japonica Thunb. and Dioscorea nipponica Makino, was reported to have neurotrophic activity. Therefore, we investigated the therapeutic potential of DA-9801, in comparison with alpha lipoic acid (ALA), for peripheral nerves preservation in experimental diabetes. Experimental animals were divided into 4 groups, and each group was designated according to the type of treatment administered as follows: normal, DM, DM+DA-9801, and DM+ALA. After 16 weeks, response thresholds to tactile and thermal stimuli were higher in DM+DA-9801 group than in nontreated DM group. This degree of increase in DM+DA-9801 group indicates more therapeutic potency of DA-9801 than ALA. Western blot analysis showed more significant increase in NGF and decrease in TNF-α and IL-6 in DM+DA-9801 group than in DM or DM+ALA groups (P < 0.05). IENF density was reduced less significantly in the DM+DA-9801 group than in other DM groups (7.61 ± 0.32, 4.2 ± 0.26, and 6.5 ± 0.30 in DM+DA-9801, DM, and DM+ALA, resp., P < 0.05). Mean myelinated axonal area in the sciatic nerves was significantly greater in DM+DA-9801 group than in other DM groups (69.2 ± 5.76, 54.0 ± 6.32, and 63.1 ± 5.41 in DM+DA-9801, DM, and DM+ALA, resp., P < 0.05). Results of this study demonstrated potential therapeutic applications of DA-9801 for the treatment of diabetic peripheral neuropathy.