Tae Keun Oh

Comparison of Vildagliptin-Metformin and Glimepiride-Metformin Treatments in Type 2 Diabetic Patients

Background The present study investigated the efficacy and safety of vildagliptin-metformin treatment compared to those of glimepiride-metformin treatment for type 2 diabetes. Methods In a randomized, open-label, comparative study, 106 patients with type 2 diabetes were enrolled. The primary endpoint was a reduction in HbA1c from baseline and secondary endpoints included fasting plasma glucose (FPG) or 2-hour postprandial glucose (2h-PPG) reduction from baseline, as well as HbA1c responder rate and HbA1c reduction according to baseline HbA1c category. Results Comparable HbA1c reduction was observed with a mean±standard deviation change from baseline to the 32-week endpoint of -0.94±1.15% in the vildagliptin group and -1.00±1.32% in the glimepiride group. A similar reduction in 2h-PPG (vildagliptin group 3.53±4.11 mmol/L vs. the glimepiride group 3.72±4.17 mmol/L) was demonstrated, and the decrements in FPG (vildagliptin group 1.54±2.41 mmol/L vs. glimepiride group 2.16±2.51 mmol/L) were not different between groups. The proportion of patients who achieved an HbA1c less than 7% at week 32 was 50.1% in the vildagliptin group and 56.0% in the glimepiride group. An average body weight gain of 2.53±1.21 kg in the glimepiride group was observed in contrast with the 0.23±0.69 kg weight gain noted in the vildagliptin group. A 10-fold lower incidence of hypoglycemia was demonstrated in the vildagliptin group, in addition to an absence of severe hypoglycemia. Conclusion Vildagliptin-metformin treatment provided blood glucose control efficacy comparable to that of glimepiride-metformin treatment and resulted in better adverse event profiles with lower risks of hypoglycemia and weight gain.

Correction of anemia in uremic rats by intramuscular injection of lentivirus carrying an erythropoietin gene

Background: Anemia is an inevitable consequence of chronic renal failure. Gene therapy using lentiviral vector (LV) would be an effective tool to treat anemia associated with renal failure. Methods: A LV carrying the erythropoietin (EPO) cDNA was administered to skeletal muscle of partially nephrectomized rats, which is a model of uremia. The red blood cell production and serum EPO levels were temporally monitored in these rats. Polymerase chain reaction assays were done to validate the presence of the LV in the experimental rats. Results: After a single intramuscular injection of LV at a dose of 55 µg p24 Gag antigen (∼5 × 107 transducing units), blood hematocrit (Hct) levels increased and peaked at 3 weeks (47.8 ± 4.2%, p < 0.01, n = 8) with the levels being maintained for at least 20 weeks (duration of study; 44.9 ± 3.3%, p < 0.01, n = 3). The control rats receiving LV expressing lacZ had Hct levels of 36.9 ± 4.1% (n = 8) at 3 weeks and 33.1 ± 3.7% (n = 4) at 20 weeks, respectively. The serum EPO levels in the rats injected with the LV expression EPO significantly increased (p < 0.01) to 156.3 ± 3.0 mU/ml compared to the control rats (63.9 ± 1.7 mU/ml). Polymerase chain reaction analysis of the isolated genomic DNA from the LV-injected rats showed specific positive detection of the LV in only the skeletal muscle tissue at the site of injection, whereas the other tissues, including the liver, spleen, and kidney, were negative. Conclusions: This study demonstrates that intramuscular injection of LV can produce highly efficient and sustained EPO secretion in uremic rats, and suggests that this approach could be an effective tool to deliver secretable proteins at therapeutic levels in various animal disease models.

Delivery of Factor VIII Gene into Skeletal Muscle Cells Using Lentiviral Vector

Purpose This study was designed to investigate whether transduction of lentiviral vectors (LV) carrying human coagulation factor VIII (hFVIII) cDNA into skeletal muscle could increase circulating hFVIII concentrations. Materials and Methods A LV containing bacterial LacZ gene as a control or human FVIII gene was intramuscularly administered into the thigh muscle of 5 weeks old Sparague-Dawley rats. The plasma human FVIII concentration and neutralizing anti-FVIII antibodies were measured for up to 12 weeks in these experimental animals. Results The plasma human FVIII levels in the rats injected with LV carrying FVIII cDNA peaked at post-injection 1st week (5.19 ± 0.14 ng/mL vs. 0.21 ± 0.05 ng/mL in control rats , p < 0.05). Elevated hFVIII concentrations were maintained for 4 weeks (2.52 ± 0.83 ng/mL vs. 0.17 ± 0.08 ng/mL in control rats, p < 0.05) after a single intramuscular injection. In the Bethesda assay, neutralizing antibodies for FVIII protein were detected only in FVIII-LV injected rats by the 10th week, but not in control rats. Conclusion This study suggested that a single administration of an advanced generation LV carrying the human FVIII cDNA resulted in elevation of FVIII level in immune competent rats, and that this gene transfer approach to the skeletal muscle could be an effective tool in treatment of hemophilia A.

Prospective Observation of 5-Year Clinical Course of Subclinical Hypothyroidism in Korean Population

Subclinical hypothyroidism (SCH) is a common clinical condition, whereas its natural course has not been identified distinctly. We evaluated the natural history of 169 SCH patients over 5-yr and the prognostic factors including thyroid autoantibodies and thyroid ultrasonographic (USG) findings related to develop overt hypothyroidism. After 5 yr, 47.3% of patients showed normalization of TSH, while 36.7% of patients remained persistence of high level of TSH, and overt hypothyroidism developed in 11.2% of patients. There were painless thyroiditis (2.9%) and hyperthyroidism (1.7%) during 5 yr follow-up. The thyroid nodule was seen in 48.6% of patients. Most of patients had 1 to 2 nodules whereas only 3% of patients with thyroid nodule had more than 6 nodules. Overt hypothyroidism patients had more heterogenous echogenecity in USG compared to patients with normalization or persistent SCH (76.5% vs 50.0% vs 35.0%, P = 0.048) and higher prevalence positive anti-thyroid peroxidase (anti-TPO Ab) and anti-thyroglobulin antibody (anti-Tg Ab) and titer of anti-TPO Ab than other two groups. The cut off values for prediction of overt hypothyroidism were TSH > 7.45 µIU/mL, free T4 < 1.09 ng/dL and Anti-TPO Ab > 560 IU/mL. SCH has various courses and initial TSH, free T4, presence of thyroid autoantibody, titer of thyroid autoantibody; and thyroid USG findings can serve as a prognostic factor for progression of overt hypothyroidism. These parameters suggest consideration to initiate thyroid hormone treatment in SCH.

Increased Anti-tumor Effect by a Combination of HSV Thymidine Kinase Suicide Gene Therapy and Interferon-γ/GM-CSF Cytokine Gene Therapy in CT26 Tumor Model

The potential therapeutic benefit of introducing IFN-γ and GM-CSF genes in combination with the HSVtk suicide gene into subcutaneously implanted CT26 tumor cells was compared with that from each treatment alone. Cells, unmodified or retrovirally transduced with HSVtk or IFN-γ/GM-CSF genes, were inoculated subcutaneously into syngeneic BALB/c mice in various combinations. HSVtk gene, with intraperitoneal ganciclovir treatment, reduced tumor volume by 81% at locally inoculated tumor sites (p<0.01) and by 25% at distantly inoculated tumor sites (p=0.052). IFN-γ/GM-CSF genes showed a 56% tumor volume reduction at local tumor sites (p<0.01) and 15% volume reduction at remote tumor sites, although this was not statistically significant. The combination of HSVtk (with GCV) and IFN-γ/GM-CSF genes showed an 81% volume reduction at local tumor sites (p<0.01) and a 43% volume reduction at remote tumor sites (p<0.01). Thus, the combination of HSVtk and IFN-γ/GM-CSF gene therapy produced greater therapeutic efficacy than either treatment alone.

Dapagliflozin improves blood glucose in diabetes on triple oral hypoglycemic agents having inadequate glucose control

AIMS The aim of this study was to evaluate whether a combination drug therapy that consists of dapagliflozin with three other oral hypoglycemic agents (OHAs) would have a beneficial safety and efficacy profile in T2DM patients who have uncontrolled glucose levels compared to a treatment regimen that contains of basal insulin with two different OHAs. METHODS A total of 162 type 2 diabetic patients who are unable to control glucose on their current therapy consisting of 3 OHAs were enrolled in dapagliflozin group and 148 patients in insulin glargine group for the 24-week study period. RESULTS The mean changes in HbA1c level were comparable as -0.97 ± 1.29% in dapagliflozin group and -0.95 ± 1.41% in insulin glargine group (p = 0.911). Also, the fasting plasma glucose or post-prandial 2 h glucose were comparably decreased in dapagliflozin or insulin glargine. In terms of the body-weight, there was a significant decrease of -2.36 ± 0.51 kg following treatment of dapagliflozin, whereas the increment of 1.93 ± 0.49 kg was in insulin glargine (p < 0.001). In terms of adverse events, hypoglycemic events were higher in insulin glargine rather than dapagliflozin (15.1% vs. 1.6%, p < 0.05). CONCLUSIONS Our findings demonstrated that the addition of dapagliflozin to an existing drug regimen consisting of three different OHAs in patients exhibiting inadequate blood glucose control could be alternate treatment modality in T2D who hesitate to initiate insulin therapy.

Association of Adiponectin 45T/G Polymorphism with Diabetic Cardiovascular Complications in Korean Type 2 Diabetes

Background Adiponectin is an adipokine that regulates lipid and glucose metabolism and has been shown to have anti-inflammatory and anti-atherogenic effects. It also plays an important role in the development of cardiovascular disease (CVD). Methods This study evaluated the association between adiponectin 45T/G polymorphism and cardiovascular complication in type 2 diabetes in Koreans. Results The present study included 758 patients with type 2 diabetes. The distribution of the adiponectin 45T/G polymorphism was 3.56% (n = 27) for GG, 42.35% (n = 321) for TG, and 54.09% (n = 410) for TT in patients with type 2 diabetes. The prevalence of CVD was significantly higher in subjects with the GG + TG genotype compared to those with the TT genotype (17.5% vs. 9.8%, P = 0.002). The G allele was associated with a higher risk of CVD (P = 0.002). Conclusion Our findings suggest that the adiponectin 45T/G polymorphism is associated with diabetic cardiovascular complication in type 2 diabetes.

Effectiveness and safety of empagliflozin-based quadruple therapy compared with insulin glargine-based therapy in patients with inadequately controlled type 2 diabetes: An observational study in clinical practice

This open‐label, prospective study evaluated the effectiveness and safety of empagliflozin as add‐on therapy in inadequately controlled type 2 diabetes (T2D) patients (glycated haemoglobin [HbA1c], 7.5‐12%) who were already using three other types of orally active antidiabetic agents. A total of 268 T2D patients were enrolled and divided into two groups, empagliflozin (EMPA 25 mg/d, n = 142) or insulin glargine (INS, n = 126), respectively. After the treatment period of 24 weeks, HbA1c and fasting plasma glucose (FPG) were significantly reduced (HbA1c, P = 0.004; FPG, P = 0.008, respectively) in the EMPA group compared to the INS group. Also, EMPA treatment evoked a significant reduction in body weight (P < 0.001) and systolic blood pressure (P = 0.017) compared to the INS group. Hypoglycaemic adverse events were significantly higher in the INS group compared to the EMPA group (P = 0.001). In conclusion, this study demonstrated that a regimen comprising four different orally active antidiabetic agents, including EMPA, was effective and safe as a therapeutic strategy for treating T2D patients for glycaemic control and improvement of other cardiovascular and metabolic indices.