Time- and Dose-Dependent Association of Statin Use With Risk of Clinically Relevant New-Onset Diabetes Mellitus in Primary Prevention: A Nationwide Observational Cohort Study.

Background Given that statins are increasingly being used for primary-prevention, the public concerns regarding the risk of new-onset diabetes mellitus associated with statin use may be an issue. Methods and Results Using healthcare data from the national health insurance examinees, our study comprised a cohort of adults aged ≥40 years with hypercholesterolemia who would be eligible for statin therapy for primary prevention from 2005 to 2012. The primary outcome was the occurrence of clinically relevant new-onset diabetes mellitus requiring medical therapy. Among 2 162 119 adults with hypercholesterolemia who might be eligible for statin therapy, 638 625 (29.5%) ever used statins and 1 523 494 (70.5%) never used statins. In the propensity-matched cohort of 518 491 pairs, during mean follow-up of 3.9 years, being an ever-user of statin was significantly associated with diabetes mellitus risk compared with being a never-user of statin (13.4 versus 6.9 per 1000 person-years; adjusted hazard ratio [ HR ], 1.88; 95% CI , 1.85-1.93). With increasing duration of statin use, the risk of diabetes mellitus was proportionally increased ( HR 1.25 <1 year, HR 2.22 for 1-2 years, and HR 2.62 >2 years). An excess risk of diabetes mellitus was also associated with a higher intensity ( HR 1.75 for low-to-moderate potency and HR 2.31 for high potency) and a cumulative dosing of statin ( HR 1.06 for low-tertile, HR 1.74 for middle-tertile, and HR 2.52 for high-tertile of defined-daily-disease). Conclusions In patients receiving statin therapy for primary prevention, there was a time- and dose-dependent association of statin use with an increasing risk of new-onset diabetes mellitus.

Association between metformin use and mortality in patients with type 2 diabetes mellitus and localized resectable pancreatic cancer: a nationwide population-based study in korea.

BACKGROUND: Preclinical studies support an antitumor effect of metformin. However, clinical studies have conflicting results and metformin's effect remains controversial. The aim of this study was to evaluate metformin's effect on clinical outcomes in diabetic patients with pancreatic cancer treated with curative resection. RESULTS: A total of 764 patients underwent curative resection, met none of the exclusion criteria, and were prescribed oral hypoglycemic agents. The cancer-specific survival (5-year, 31.9% vs. 22.2%, p < 0.001) was significantly higher in the 530 metformin users than in the 234 diabetic metformin non-users. After multivariable adjustments, metformin users had significantly lower cancer-specific mortality as compared with metformin non-users (hazard ratio, 0.727; 95% confidence interval, 0.611-0.868). Cubic spline regression analysis demonstrated significantly decreased cancer-specific mortality with increasing dose of metformin (p = 0.0047). MATERIALS AND METHODS: Data were provided from the Korea Central Cancer Registry and the National Health Insurance Service in the Republic of Korea. The study cohort consisted of 28,862 patients newly diagnosed with pancreatic cancer between 2005 and 2011. Metformin exposure was determined from prescription information from 6 months before the first diagnosis of pancreatic cancer to last follow-up. The main outcome was cancer-specific survival. CONCLUSIONS: This large study indicates that metformin might decrease cancer-specific mortality rates in localized resectable pancreatic cancer patients with pre-existing diabetes, independently of other factors, with a dose-response relationship.

Influence of Myopia on Size of Optic Nerve Head and Retinal Nerve Fiber Layer Thickness Measured by Spectral Domain Optical Coherence Tomography.

PURPOSE: To investigate optic nerve head size and retinal nerve fiber layer (RNFL) thickness according to refractive status and axial length. METHODS: In a cross-sectional study, 252 eyes of 252 healthy volunteers underwent ocular biometry measurement as well as optic nerve head and RNFL imaging by spectral-domain optical coherence tomography. Correlation and linear regression analyses were performed for all subjects. The magnification effect was adjusted by the modified axial length method. RESULTS: Disc area and spherical equivalent were positively correlated (r = 0.225, r2 = 0.051, p = 0.000). RNFL thickness showed significant correlations with spherical equivalent (r = 0.359, r2 = 0.129, p = 0.000), axial length (r = -0.262, r2 = 0.069, p = 0.000), disc radius (r = 0.359, r2 = 0.129, p = 0.000), and radius of the scan circle (r = -0.262, r2 = 0.069, p = 0.000). After adjustment for the magnification effect, those relationships were reversed; RNFL thickness showed negative correlation with spherical equivalent and disc radius, and positive correlation with axial length and radius of the scan circle. The distance between the disc margin and the scan circle was closely correlated with RNFL thickness (r = -0.359, r2 = 0.129, p = 0.000), which showed a negative correlation with axial length (r = -0.262, r2 = 0.069, p = 0.000). CONCLUSIONS: Optic disc radius and RNFL thickness decreased in more severely myopic eyes, but they increased after adjustment for magnification effect. The error due to the magnification effect and optic nerve head size difference might be factors that should be considered when interpreting optical coherence tomography results.

Association of Metformin Use With Cancer-Specific Mortality in Hepatocellular Carcinoma After Curative Resection: A Nationwide Population-Based Study.

Many preclinical reports and retrospective population studies have shown an anticancer effect of metformin in patients with several types of cancer and comorbid type 2 diabetes mellitus (T2DM). In this work, the anticancer effect of metformin was assessed in hepatocellular carcinoma (HCC) patients with T2DM who underwent curative resection.A population-based retrospective cohort design was used. Data were obtained from the National Health Insurance Service and Korea Center Cancer Registry in the Republic of Korea, identifying 5494 patients with newly diagnosed HCC who underwent curative resection between 2005 and 2011. Crude and adjusted hazard ratios (HRs) were calculated using Cox proportional hazard models to estimate effects. In the sensitivity analysis, we excluded patients who started metformin or other oral hypoglycemic agents (OHAs) after HCC diagnosis to control for immortal time bias.From the patient cohort, 751 diabetic patients who were prescribed an OHA were analyzed for HCC-specific mortality and retreatment upon recurrence, comparing 533 patients treated with metformin to 218 patients treated without metformin. In the fully adjusted analyses, metformin users showed a significantly lower risk of HCC-specific mortality (HR 0.38, 95% confidence interval [CI] 0.30-0.49) and retreatment events (HR 0.41, 95% CI 0.33-0.52) compared with metformin nonusers. Risks for HCC-specific mortality were consistently lower among metformin-using groups, excluding patients who started metformin or OHAs after diagnosis.In this large population-based cohort of patients with comorbid HCC and T2DM, treated with curative hepatic resection, metformin use was associated with improvement of HCC-specific mortality and reduced occurrence of retreatment events.

Clinical application and potential effects of 2014 hypertension guidelines on incident cardiovascular events.

BACKGROUND: The applicability to real-world hypertensive patients and the potential effects on future cardiovascular events of the 2014 hypertension guidelines of the Eighth Joint National Committee (JNC-8) remain to be determined. METHODS: Using the Korean National Health and Nutrition Examination Survey of 2008 to 2012 (n = 30,697), we estimated the proportion of Korean adults eligible for hypertension therapy under the 2014 JNC-8 and previous JNC-7 guidelines and the changes affected by the 2014 guidelines. Using the validation cohort (n = 116,767) from the 2003 National Health Examination with 7 years of follow-up, we determined the clinical effects of recent recommendations changes on incident cardiovascular events (composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). RESULTS: Compared with the JNC-7 guidelines, the 2014 guidelines would decrease the number of adults eligible for hypertension therapy from 10.1 million (28.2%) to 9.3 million (25.9%). In the validation cohort, compared with nonhypertensive adults, those eligible for hypertension therapy under the JNC-7 or JNC-8 guidelines had significantly higher risks of cardiovascular events (hazard ratio [HR], 5.05; 95% confidence interval [CI], 4.58-5.57, P < 0.001; and HR, 5.11; 95% CI, 4.63-5.64, P < 0.001, respectively). In addition, adults newly ineligible for treatment under the 2014 guidelines had an increased risk of cardiovascular events relative to nonhypertensive adults (HR, 4.36; 95% CI, 3.65-5.20; P < 0.001). CONCLUSIONS: The 2014 hypertension guidelines would modestly decrease the proportion of Korean adults eligible for hypertension therapy. Adults newly ineligible for hypertension therapy by the 2014 guidelines have a higher risk of cardiovascular events compared to nonhypertensive adults. Our observations should be confirmed or refuted through large, randomized clinical trials.

A case of Behçet's disease complicated by bilateral posterior ischemic optic neuropathy.

We report a case involving bilateral posterior ischemic optic neuropathy with Behçet's disease in a 49-year-old woman. The patient presented because of abrupt visual disturbances. An ophthalmic examination, including fluorescein angiography, visual field testing, and visual-evoked potentials, was performed. Her visual acuity was 20/100 bilaterally and posterior ischemic optic neuropathy was suspected. She was treated with systemic methylprednisolone; however, disc pallor developed and the visual acuity remained 20/200 bilaterally. Optic neuropathy can be bilateral, affect both eyes simultaneously, and lead to severe visual loss despite high doses of systemic steroid treatment. Optic neuropathy in Behçet's disease is very rare. This case provides clinical insight into the neuro-ophthalmologic manifestations of Behçet's disease.

Korean normative database for time domain optical coherence tomography to detect localized retinal nerve fiber layer defects (preliminary study).

PURPOSE: To establish a Korean normative database of retinal nerve fiber layer (RNFL) thickness. METHODS: Data was collected from 103 healthy volunteers. Total ophthalmologic examinations, including fast RNFL thickness analysis by time domain optical coherence tomography (STRATUS OCT) were performed. The RNFL thickness of 64 glaucoma patients with localized RNFL defects and 48 independent healthy subjects were collected. The RNFL thickness of both the glaucoma patients and the healthy subjects was evaluated using both normative databases. RESULTS: The average RNFL thickness of Koreans was 108.3 +/- 10.3 microm. The sensitivity rates recorded in the Korean normative database with 5% and 1% significance were 0.984 and 0.984, with specificity values of 0.938 and 1.000. By comparison, the sensitivity rates in the conventional normative database with 5% and 1% significance are 0.984 and 0.953, and the specificity values are 1.000 and 1.000. CONCLUSION: In detecting localized RNFL defects, the Korean database showed higher sensitivity than the conventional database.

Effect of myopia on the thickness of the retinal nerve fiber layer measured by Cirrus HD optical coherence tomography.

PURPOSE: To evaluate the effect of myopia on the peripapillary retinal nerve fiber layer (RNFL) thickness measured by Cirrus HD optical coherence tomography (OCT). METHODS: Comprehensive ophthalmic examinations were performed, including measurement of visual acuity, refraction, and axial length on 269 subjects (age, 19-26 years) with no ophthalmic abnormality. Further, 200 x 200-cube optic disc scans of the subjects' eyes were obtained with Cirrus HD OCT. The RNFL thickness at 256 points of the RNFL thickness profile and the average RNFL thickness were recorded. The correlations between these values and the axial length and spherical equivalent (SE) of refractive errors were then analyzed by simple linear regression, before and after adjustment of the ocular magnification. RESULTS: Before ocular magnification adjustment, the uncorrected average RNFL thickness decreased as the axial length increased and as the SE decreased. However, after the adjustment, the corrected average RNFL thickness exhibited no correlation with the spherical equivalent and a weak positive correlation with the axial length. Myopia also affected the RNFL thickness distribution. As the axial length increased and the spherical equivalent decreased, the thickness of the temporal peripapillary RNFL increased and that of the superior, superior nasal, inferior, and inferior nasal peripapillary RNFL decreased. CONCLUSIONS: The axial length affected the average RNFL thickness, and myopia affected the RNFL thickness distribution. High myopes are likely to exhibit different RNFL distribution patterns. Since ocular magnification significantly affects the RNFL measurement in such patients, it should be considered in diagnosing glaucoma.

Analysis of peripapillary retinal nerve fiber distribution in normal young adults.

PURPOSE. To determine the anatomic variations in the peripapillary retinal nerve fiber layer (RNFL) thickness distribution and the relationship between these anatomic variations and other ocular variables. METHODS. A complete ophthalmic examination, including measurement of visual acuity, refraction, and axial length, was performed on 269 subjects with no ophthalmic abnormalities. Further, fundus photographs and optic disc cube scans of the subjects' eyes were obtained with a fundus camera and spectral domain OCT (Cirrus HD-OCT; Carl Zeiss Meditec, Inc., Dubin, CA), respectively. The distance between the foveola and the center of the optic nerve head was measured. The correlations of the angles of the peaks in the RNFL thickness profile with the axial length, spherical equivalent of refractive error (SE), and distance between the foveola and optic disc center were analyzed by simple linear regression. RESULTS. Considerable interindividual variations were found in the angles of the peaks in the RNFL thickness profile. Further, the angles in the eyes in each individual showed significant differences. The angles of the superior and inferior first peak correlated significantly with the SE, axial length, and distance between the foveola and optic disc center. CONCLUSIONS. Subjects with increased distance between the foveola and optic disc center are likely to have a temporal shift in peak RNFL thickness. RNFL profiles with horizontally deviated peak RNFL thickness differ considerably from the normative data provided with the HD-OCT system. The variations in RNFL thickness profiles should be taken into account.

Optic disc hemorrhage may be associated with retinal nerve fiber loss in otherwise normal eyes.

PURPOSE: To evaluate quantitatively the structural damage of the peripapillary retinal nerve fiber layer (RNFL) in eyes with disc hemorrhage (DH). DESIGN: Prospective cross-sectional study. PARTICIPANTS: Seventy patients with DH (70 eyes; mean age +/- standard deviation, 60.0+/-11.8 years) and 100 healthy control subjects (100 eyes; mean age +/- standard deviation, 57.7+/-8.0 years) were enrolled from the Glaucoma Clinic of Seoul National University Hospital. METHODS: Normal eyes without DH (group 1: normal control group) served as controls. Eyes with DH were divided into the following groups: (1) eyes with a DH, accompanied by no visible RNFL defect according to red-free fundus photography and normal visual fields (group 2: DH only group); (2) eyes with a DH and a localized RNFL defect in the same quadrant, accompanied by normal visual fields (group 3: DH-preperimetric group); and (3) eyes with a DH and a localized RNFL defect in the same quadrant, accompanied by glaucomatous visual field defect in the corresponding hemifield location (group 4: DH-perimetric group). Optical coherence tomography (OCT)-measured RNFL thicknesses were compared. MAIN OUTCOME MEASURES: Average and segmental (4 quadrants and 12 clock-hours) OCT-measured RNFL thicknesses. RESULTS: The number of eyes in groups 1, 2, 3, and 4 was 100, 25, 22, and 23 eyes, respectively. The OCT-measured RNFL thickness was significantly different among the 4 groups in average RNFL thickness and in inferior, superior, and nasal quadrants (P<0.01, 1-way analysis of variance). On post hoc analysis, the eyes of groups 2 and 3 showed thinner average RNFL thickness than those of group 1, and the average RNFL thickness of group 4 was significantly lower than that of groups 2 and 3 (P<0.001, 1-way analysis of variance and Tukey's test). The OCT-measured RNFL thickness revealed a topographic relationship with the DH location. CONCLUSIONS: Significant RNFL loss was already present in the DH only eyes with apparently normal RNFL configuration by red-free fundus photography, indicating that preperimetric changes of the RNFL are already present. These results suggest that OCT has the potential to detect subclinical or preperimetric RNFL loss in the eyes with DH. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Assessing intraocular pressure by rebound tonometer in rats with an air-filled anterior chamber.

PURPOSE: To compare rebound tonometer and cannulation as methods for measuring intraocular pressure (IOP) in rats. METHODS: The accuracy of the TonoLab rebound tonometer was determined in eight cannulated rat eyes. IOP was manipulated by changing air pressure from 20 to 100 mmHg at 10-mmHg intervals, and the IOP was measured with the rebound tonometer at each level. The average value of three repeated pressure readings was recorded. Correlation analysis and comparison with the Bland and Altman method were performed. The intraclass correlation coefficient was calculated to assess intraoperator variability. RESULTS: The IOP values measured with the TonoLab rebound tonometer were well correlated with the actual IOP (r (2) = 0.963, P = 0.01). The mean of the difference between the rebound tonometer and actual (cannulation) IOP was 7.41 +/- 7.87%. The intraclass correlation coefficient was 0.9, indicating low intraoperator variability. CONCLUSIONS: The rebound tonometer showed high accuracy and reliability for IOP measurement in rat eyes.

Differences in the histopathology and matrix metalloproteinase expression in Tenon's tissue of primary open-angle glaucoma and primary angle-closure glaucoma.

PURPOSE: To investigate the differences in the histopathology and matrix metalloproteinase (MMP) expression in the Tenon's tissue of primary open-angle glaucoma (POAG) patients, primary angle-closure glaucoma (PACG) patients, and non-glaucomatous patients. METHODS: POAG and PACG patients, who underwent a trabeculectomy and had no history of ocular disease except glaucoma, were enrolled. The number and instillation period of topical eye drops were reviewed. For the controls, which were patients without glaucoma or a history of ocular surgery, the Tenon's tissue was obtained in the course of retinal detachment surgery. For glaucoma patients, the Tenon's tissue was obtained during the trabeculectomy. H&E and Masson's trichrome staining and immunohistochemistry for MMP-1, MMP-2, and MMP-9 were performed. A total of six eyes of POAG, six eyes of PACG, and four control eyes were evaluated. RESULTS: The duration of topical anti-glaucoma medication and the mean number of anti-glaucoma medications were similar in the POAG and PACG groups. The levels of MMP-1 and 2 were elevated in the POAG and PACG groups compared to the control group (p=0.03, 0.01, respectively). Compared with the control group, the MMP-2 level was higher in the POAG patients (p=0.01), whereas the MMP-1 was higher in the PACG patients (p=0.04). The levels of MMP-9 in the POAG and PACG patients were not significantly different from that of the control patients (p=0.48, 0.26). The levels of MMP-2 were significantly lower in the PACG patients than in the POAG patients (p=0.02). CONCLUSIONS: The MMP expression was altered in the Tenon's tissue of glaucoma patients compared to the control group. The levels of MMP-2 were lower in the PACG patients than in the POAG patients. These results suggest that there may be histopathological differences in the Tenon's tissue of POAG and PACG patients.