Optimal LDL cholesterol levels in young and old patients with type 2 diabetes for secondary prevention of cardiovascular diseases are different.

Objective: Real-world-based population data about the optimal low-density lipoprotein cholesterol (LDL-C) level for preventing cardiovascular disease in very high-risk populations is scarce. Methods: From 2009 to 2012, 26,922 people aged ≥ 40 years with type 2 diabetes mellitus (T2DM) who had a history of percutaneous coronary intervention (PCI) were analyzed. Data from the Korean National Health Insurance System were used. They were followed up to the date of a cardiovascular event or the time to death, or until December 31, 2018. Endpoints were recurrent PCI, newly stroke or heart failure, cardiovascular death, and all-cause death. Participants were divided into the following categories according to LDL-C level: <55 mg/dL, 55-69 mg/dL, 70-99 mg/dL, 100-129 mg/dL, 130-159 mg/dL, and ≥ 160 mg/dL. Results: Compared to LDL-C < 55 mg/dL, the hazard ratios (HR) for re-PCI and stroke increased linearly with increasing LDL-C level in the population < 65 years. However, in ≥ 65 years old, HRs for re-PCI and stroke in LDL-C = 55-69 mg/dL were 0.97 (95% CI: 0.85-1.11) and 0.96 (95% CI: 0.79-2.23), respectively. The optimal range with the lowest HR for heart failure and all-cause mortality were LDL-C = 70-99 mg/dL and LDL-C = 55-69 mg/dL, respectively, in all age groups (HR: 0.99, 95% CI: 0.91-1.08 and HR: 0.91, 95% CI: 0.81-1.01). Conclusion: LDL-C level below 55 mg/dL appears to be optimal in T2DM patients with established cardiovascular disease aged < 65 years, while an LDL-C level of 55-69 mg/dL may be optimal for preventing recurrent PCI and stroke in patients over 65 years old.

Anagliptin twice-daily regimen improves glycaemic variability in subjects with type 2 diabetes: A double-blind, randomized controlled trial.

AIM: To determine whether the twice-daily (BID) regimen is superior to the once-daily (QD) regimen for managing glycaemic variability by comparing the effects of anagliptin 100 mg BID versus sitagliptin 100 mg QD. MATERIALS AND METHODS: A double-blinded, randomized, multicentre study was performed in 89 patients with type 2 diabetes treated with metformin alone (6.5% < HbA1c < 8.5%). Subjects were randomly assigned to anagliptin 100 mg BID or sitagliptin 100 mg QD in a 1:1 ratio for 12 weeks. Continuous glucose monitoring was used to measure the mean amplitude of glycaemic excursion (MAGE) and postprandial time in range (TIR) before and after dipeptidyl peptidase-4 (DPP-4) inhibitor treatment to compare glycaemic variability. RESULTS: The decrease from baseline in MAGE at 12 weeks after DPP-4 inhibitor treatment was significantly greater in the anagliptin BID group than in the sitagliptin QD group (P < .05); -30.4 ± 25.6 mg/dl (P < .001) in the anagliptin group versus -9.5 ± 38.0 mg/dl (P = .215) in the sitagliptin group. The TIR after dinner increased by 33.0% ± 22.0% (P < .001) in the anagliptin group and by 14.6% ± 28.2% (P = .014) in the sitagliptin group, with a statistically significant difference (P = .009). No statistically significant differences were observed between the groups in the changes in HbA1c and fasting plasma glucose (FPG). CONCLUSIONS: The anagliptin BID regimen for the treatment of type 2 diabetes was superior in blood glucose control after dinner to improve glycaemic variability, as indicated by MAGE and TIR, but was equivalent to the QD regimen in terms of HbA1c and FPG.

Efficacy and Safety of a New Sustained-release Pregabalin Formulation Compared With Immediate-release Pregabalin in Patients With Peripheral Neuropathic Pain: A Randomized Noninferiority Phase 3 Trial.

OBJECTIVE: This study investigated whether a new sustained-release (SR) pregabalin formulation is noninferior to immediate-release (IR) pregabalin in alleviating peripheral neuropathic pain in Korean patients. MATERIALS AND METHODS: This was a randomized, double-blind, active-controlled phase 3 study of patients with diabetic peripheral neuropathy or postherpetic neuralgia from 41 sites in South Korea in 2017-2018. Eligible patients were randomized (1:1) to receive once-daily SR pregabalin or twice-daily IR pregabalin (150 to 600 mg/d) in a double-dummy manner for 12 weeks according to a stratified permuted block randomization scheme. The primary endpoint was the Daily Pain Rating Scale score at the end of treatment, averaged from the last 7 available scores. RESULTS: A total of 319 of 371 (86.0%) randomized patients completed the 12-week treatment (SR pregabalin: n=154; IR pregabalin: n=165; per-protocol set: n=296). The least square mean difference between both groups for the primary endpoint was 0.06 (SE 0.19); (95% confidence interval -0.31 to 0.42), with the lower limit of the confidence interval above the pre-specified margin (-0.78; Pnoninferiority<0.0001). Drug-related treatment-emergent adverse events (TEAEs) were comparable between both groups. The incidence of drug-related TEAEs leading to treatment discontinuation was low (SR pregabalin: 2.7%; IR pregabalin: 1.1%). No serious drug-related TEAEs or deaths occurred. DISCUSSION: The results demonstrate that the new once-daily SR pregabalin formulation is noninferior to twice-daily IR pregabalin in reducing peripheral neuropathic pain and is well tolerated in Korean patients with diabetic peripheral neuropathy or postherpetic neuralgia after 12 weeks of treatment.

Efficacy and Safety of Voglibose Plus Metformin in Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Trial.

BACKGROUND: Combination of metformin to reduce the fasting plasma glucose level and an α-glucosidase inhibitor to decrease the postprandial glucose level is expected to generate a complementary effect. We compared the efficacy and safety of a fixed-dose combination of voglibose plus metformin (vogmet) with metformin monotherapy in drug-naïve newly-diagnosed type 2 diabetes mellitus. METHODS: A total of 187 eligible patients aged 20 to 70 years, with a glycosylated hemoglobin (HbA1c) level of 7.0% to 11.0%, were randomized into either vogmet or metformin treatments for 24 weeks. A change in the HbA1c level from baseline was measured at week 24. RESULTS: The reduction in the levels of HbA1c was -1.62%±0.07% in the vogmet group and -1.31%±0.07% in the metformin group (P=0.003), and significantly more vogmet-treated patients achieved the target HbA1c levels of <6.5% (P=0.002) or <7% (P=0.039). Glycemic variability was also significantly improved with vogmet treatment, estimated by M-values (P=0.004). Gastrointestinal adverse events and hypoglycemia (%) were numerically lower in the vogmet-treated group. Moreover, a significant weight loss was observed with vogmet treatment compared with metformin (-1.63 kg vs. -0.86 kg, P=0.039). CONCLUSION: Vogmet is a safe antihyperglycemic agent that controls blood glucose level effectively, yields weight loss, and is superior to metformin in terms of various key glycemic parameters without increasing the risk of hypoglycemia.

Identification and functional analysis of a novel CaSR mutation in a family with familial hypocalciuric hypercalcemia.

The calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that plays an essential role in maintaining calcium homeostasis. In the present study, we analyzed the CaSR gene in a Korean family with familial hypocalciuric hypercalcemia (FHH). Genetic studies were performed by direct sequence analysis of the CaSR gene in genomic DNA obtained from peripheral leukocytes. A novel heterozygous G to T substitution at nucleotide position 1711 in exon 6, resulting in the G571W mutation, was identified in the CaSR gene in a 26-year-old female with asymptomatic hypercalcemia, a low calcium/creatinine clearance ratio, and normal intact parathyroid hormone. To study CaSR expression, the mutation was introduced by site-directed mutagenesis into a wild-type (WT) CaSR-expressing pCR3.1 vector, and COS-7 cells were transfected with either the WT or mutant CaSR-containing vector. Transfected cells loaded with Fura-2/AM, a fluorescent indicator of Ca2+, were assessed for CaSR function by the change in intracellular calcium [as measured by the 340 nm/380 nm fluorescence intensity ratio (F340/F380)] made in response to challenge with extracellular Ca2+. Both WT and G571W cells had equivalent amounts of CaSR protein in the cell membrane. However, after challenge with extracellular Ca2+, cells transfected with G571W CaSR responded with a lower F340/F380 ratio than those transfected with WT CaSR and showed decreased sensitivity to extracellular Ca2+ concentrations. The G571W mutation had therefore impaired the CaSR function. In conclusion, we identified a novel loss-of-function mutation, G571W, in the CaSR gene in a Korean family with FHH.

Diabetes epidemics in Korea: reappraise nationwide survey of diabetes "diabetes in Korea 2007".

There are many studies on the prevalence, clinical characteristics, and economic burden of diabetes across the past four decades in Korea. Nonetheless, there is a dearth of nationwide study regarding diabetes encompassing all age group. Eight years ago, the Committee on the Epidemiology of Diabetes Mellitus of Korean Diabetes Association collaborated with Health Insurance Review & Assessment Service to evaluate the status of diabetes care and characteristics in diabetic patients in Korea. In 2007, the collaborative task force team published a comprehensive survey titled "Diabetes in Korea 2007." In this review, we reappraise the diabetic epidemics from the joint report and suggest further studies that are needed to be investigated in the future.

Efficacy and safety of biphasic insulin aspart 30/70 in type 2 diabetes suboptimally controlled on oral antidiabetic therapy in Korea: a multicenter, open-label, single-arm study.

BACKGROUND: The purpose of this study was to evaluate change in glycosylated hemoglobin (HbA1c), side effects, and quality of life (QOL) after a 16-week treatment period with Biphasic insulin aspart 30/70 (BIasp30) in patients with type 2 diabetes mellitus (T2DM) who had been suboptimally controlled with oral antidiabetic drugs (OADs). METHODS: The study consisted of a 4-week titration period when concurrent OAD(s) were replaced with BIasp30 and followed by a 12-week maintenance period. All patients completed the Diabetes Treatment Satisfaction Questionnaire at the beginning and the end of the trial. Hypoglycemic episodes were recorded by the patient throughout the trial. RESULTS: Sixty patients were included, of whom 55 patients (92%) completed the full 16-week treatment period. Seven-point blood glucose was significantly improved as compared with the baseline, except for the postlunch blood glucose level. HbA1c at the end of period was significantly improved from 9.2% to 8.2% (P<0.001). Eleven percent (n=6) of patients achieved HbA1c values ≤6.5% and 22% (n=12) of patients achieved <7.0%. There were 3.4 episodes/patients-year of minor hypoglycemia and 0.05 episodes/patients-year of major hypoglycemia. QOL showed significant changes only in the acceptability of high blood glucose category (P=0.003). CONCLUSION: Treatment with once or twice daily BIasp30 may be an option for the patients with T2DM suboptimally controlled with OADs in Korea. However, considering the low number of patients achieving the HbA1c target and the high postlunch blood glucose levels, additional management with another modality may be required for optimal control.

Severe hypoglycemia is a serious complication and becoming an economic burden in diabetes.

BACKGROUND: The prevalence of hypoglycemia is increasing due to the growing incidence of diabetes and the latest strict guidelines for glycated hemoglobin (HbA1c) levels under 7%. This study examined the clinical characteristics, causal factors, and medical costs of severely hypoglycemic patients in an emergency room (ER) of Uijeongbu St. Mary's Hospital. METHODS: The study consisted of a retrospective analysis of the characteristics, risk factors, and medical costs of 320 severely hypoglycemic patients with diabetes who presented to an ER of Uijeongbu St. Mary's Hospital from January 1, 2006 to December 31, 2009. RESULTS: Most hypoglycemic patients (87.5%, 280/320) were over 60 years old with a mean age of 69.5±10.9 years and a mean HbA1c level of 6.95±1.46%. Mean serum glucose as noted in the ER was 37.9±34.5 mg/dL. Renal function was decreased, serum creatinine was 2.0±2.1 mg/dL and estimated glomerular filtration rate (eGFR) was 48.0±33.6 mL/min/1.73 m(2). In addition, hypoglycemic patients typically were taking sulfonylureas or insulin and a variety of other medications, and had a long history of diabetes. CONCLUSION: Severe hypoglycemia is frequent in older diabetic patients, subjects with low HbA1c levels, and nephropathic patients. Therefore, personalized attention is warranted, especially in long-term diabetics with multiple comorbidities who may not have been properly educated or may need re-education for hypoglycemia.

Diabetic peripheral neuropathy is highly associated with nontraumatic fractures in Korean patients with type 2 diabetes mellitus.

OBJECTIVE: Patients with type 2 diabetes mellitus are at greater risk of bone fractures than nondiabetics. However, the risk factors for fractures in patients with diabetes have not been fully evaluated. This study was designed to evaluate the relative frequency of fractures at different sites and the diabetes-associated factors that affect nontraumatic bone fracture in patients with type 2 diabetes. PATIENTS AND DESIGN: This retrospective case-control study recruited 144 patients with type 2 diabetes, who presented with nontraumatic fractures between March 2004 and March 2009 and 150 age-, gender-, body mass index (BMI)- and duration of diabetes-matched control subjects. Nontraumatic fractures were confirmed using patients' medical records and radiological findings. All subjects were examined for their diabetes status and associated factors for fracture, including bone mineral density (BMD). RESULTS: Of 150 reported bone fractures, the hip was the most frequent fracture site (32·7%), followed by the upper extremity (19·3%). Nontraumatic fractures were associated with diabetic retinopathy, diabetic peripheral neuropathy, stroke history, previous fracture and insulin treatment (P < 0·05). In multivariate analyses, independently associated factors for bone fracture were diabetic peripheral neuropathy [odds ratio (OR) = 37·3, 95% confidence interval (CI) = 1·46-652·57] and previous fracture (OR = 9·54, 95% CI = 1·18-77·37; P < 0·05). CONCLUSIONS: The hip was the most frequent site of nontraumatic fracture, and diabetic peripheral neuropathy was significantly associated with an increased risk of nontraumatic fractures in patients with type 2 diabetes.

Serum 25-hydroxyvitamin D concentration and arterial stiffness among type 2 diabetes.

AIM: To evaluate the association between serum 25-hydroxyvitamin D [25(OH)D] and arterial stiffness in patients with type 2 diabetes. METHODS: Serum 25(OH)D was measured in a cross-sectional sample of 131 men and 174 women aged 30 years and over in Korea. Arterial stiffness was assessed by pulse wave velocity (PWV) obtained with a VP-2000 pulse wave unit. Fasting plasma glucose, insulin, lipid profile, HbA1c, calcium, phosphorous, and HS-CRP were measured. RESULTS: The prevalence of vitamin D deficiency was high (85.9%). Those with lower vitamin D levels had increased PWV. Using multivariate regression analysis, low 25(OH)D concentrations independently predicted PWV (p<0.001) in people with type 2 diabetes after adjustment for other risk factors such as age, smoking, hypertension, HS-CRP, diabetes duration, hypertension duration, HbA1c, and BMI. CONCLUSIONS: Vitamin D deficiency is common in type 2 diabetes, and a low 25(OH)D level is significantly associated with increased arterial stiffness in these patients. Vitamin D may influence the development of cardiovascular disease. Clinical intervention studies are needed to clarify whether treatment with vitamin D decreases the risk of cardiovascular disease in patients with type 2 diabetes.

A case of Mayer-Rokitansky-Küster-Hauser syndrome presenting as Graves disease.

The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital disorder characterized by aplasia of the uterus and the upper part of the vagina in an XX individual with normal development of secondary sexual characteristics. Individuals with this syndrome may also present with renal and skeletal abnormalities. We report a case of a 16-year-old girl presenting with thyrotoxicosis and primary amenorrhea. After being diagnosed with Graves disease, this patient was placed on antithyroid medication. Although her thyroid function normalized, she did not start to menstruate. Therefore, we assessed her primary amenorrhea and diagnosed the patient with MRKH syndrome through pelvic imaging. To our knowledge, an association between Graves disease and MRKH syndrome has not yet been reported.

Angiotensin II Inhibits Insulin Binding to Endothelial Cells.

BACKGROUND: Insulin-mediated glucose uptake in insulin target tissues is correlated with interstitial insulin concentration, rather than plasma insulin concentration. Therefore, insulin delivery to the interstitium of target tissues is very important, and the endothelium may also play an important role in the development of insulin resistance. METHODS: After treating bovine aortic endothelial cells with angiotensin II (ATII), we observed the changes in insulin binding capacity and the amounts of insulin receptor (IR) on the cell membranes and in the cytosol. RESULTS: After treatment of 10(-7)M ATII, insulin binding was decreased progressively, up to 60% at 60 minutes (P<0.05). ATII receptor blocker (eprosartan) dose dependently improved the insulin binding capacity which was reduced by ATII (P<0.05). At 200 µM, eprosartan fully restored insulin binding capacity, althogh it resulted in only a 20% to 30% restoration at the therapeutic concentration. ATII did not affect the total amount of IR, but it did reduce the amount of IR on the plasma membrane and increased that in the cytosol. CONCLUSION: ATII decreased the insulin binding capacity of the tested cells. ATII did not affect the total amount of IR but did decrease the amount of IR on the plasma membrane. Our data indicate that ATII decreases insulin binding by translocating IR from the plasma membrane to the cytosol. The binding of insulin to IR is important for insulin-induced vasodilation and transendothelial insulin transport. Therefore, ATII may cause insulin resistance through this endothelium-based mechanism.

The effect of an Angiotensin receptor blocker on arterial stiffness in type 2 diabetes mellitus patients with hypertension.

BACKGROUND: Hypertension and type 2 diabetes mellitus are major risk factors for cardiovascular disease. This study analyzed the changes in central aortic waveforms and pulse wave velocity as well as related parameters after treatment with valsartan, an angiotensin II type 1 receptor blocker, in patients with type 2 diabetes and hypertension. METHODS: We used pulse wave analysis to measure central aortic waveform in a total of 98 subjects. In 47 of these patients, pulse wave velocity measurements were obtained before and after 12 weeks of treatment with valsartan. RESULTS: In the central aortic waveform analysis, the aortic pulse pressure and augmentation index were significantly decreased after valsartan treatment, as was the aortic pulse wave velocity. Factors contributing to the improvement in pulse wave velocity were the fasting blood glucose and haemoglobin A1c levels. CONCLUSION: Short-term treatment with valsartan improves arterial stiffness in patients with type 2 diabetes and hypertension, and the glucose status at baseline was associated with this effect.