Empagliflozin for Type 2 Diabetes Mellitus: An Overview of Phase 3 Clinical Trials.

INTRODUCTION: Sodium glucose cotransporter 2 (SGLT2) inhibitors have a unique mechanism of action leading to excretion of glucose in the urine and subsequent lowering of plasma glucose. This mechanism is independent of ß-cell function; thus, these agents are effective treatment for type 2 diabetes mellitus (T2DM) at theoretically any disease stage. This class should not confer an additional risk of hypoglycemia (unless combined with insulin or an insulin secretagogue) and has the potential to be combined with other classes of glucose-lowering agents. Empagliflozin is one of three currently approved SGLT2 inhibitors in the United States, and has shown a favorable benefit-risk ratio in phase 3 clinical trials as monotherapy and as add-on to other glucose-lowering therapy in broad patient populations. In addition to its glucose-lowering effects, empagliflozin has been shown to reduce body weight and blood pressure without a compensatory increase in heart rate. Moreover, on top of standard of care, empagliflozin is the first glucoselowering agent to demonstrate cardiovascular risk reduction in patients at high risk of cardiovascular disease in a prospective outcomes trial: a 14% reduction in risk of the 3-point composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Like other SGLT2 inhibitors, empagliflozin is associated with a higher rate of genital mycotic infections than placebo and has the potential for volume depletion-associated events. CONCLUSION: This review summarizes the empagliflozin phase 3 clinical trials program and its potential significance in the treatment of patients with T2DM. Evidence from these clinical trials show reductions in glycated hemoglobin (-0.59 to -0.82%) with a low risk of hypoglycemia except when used with insulin or insulin secretagogues, and moderate reductions in body weight (-2.1 to - 2.5 kg) and systolic blood pressure (-2.9 to -5.2 mm Hg), thus supporting the use of empagliflozin as monotherapy or in addition to other glucose-lowering agents. In addition, evidence from the recent EMPA-REG OUTCOME study, which demonstrated relative risk reductions in major adverse cardiac events (14%), cardiovascular mortality (38%) and all-cause mortality (32%), as well as hospitalization for heart failure (36%), supports use of empagliflozin in patients with T2DM and increased cardiovascular risk.

Mechanisms of failure of locked-plate fixation of the proximal humerus: acoustic emissions as a novel assessment modality.

OBJECTIVES: Locking plates are the predominant implants used for proximal humerus fractures. Despite a preponderance of good clinical outcomes, failures continue to occur. The purpose of this study was to investigate the failure mechanism of locked proximal humeral plate fixation and its relationship with bone density and screw length. METHODS: Human cadaveric humeri were subjected to cyclic bending loads after an unstable 2-part fracture (Orthopedic Trauma Association classification 11 A-3) was created and stabilized with a locking proximal humeral plate. Acoustic emission (AE) sensors were mounted on the specimens to detect fracture displacement and generation of microcracks. The data were analyzed to evaluate construct failure. RESULTS: Eight of 10 locking plate constructs in cadaver specimens failed in varus collapse. The primary influences on failure were cancellous bone density and cancellous bone screw length. AE monitoring demonstrated patterns of microcrack progression, predominantly along the inferior screws. The progression trends according to AE were similar to their respective actuator displacement versus time curves. CONCLUSIONS: Cancellous bone density and total cancellous screw depth penetration seem to be critical variables. Although the patients' bone density cannot be controlled, surgeons may decrease the risk of failure by maximizing the length of the screws within the cancellous bone. Analysis of microcrack formation revealed that failures begin at the midportion and tips of the inferior screws and at the bone-plate interface of the inferior screws.

An In Vivo Lapine Model for Impact-Induced Injury and Osteoarthritic Degeneration of Articular Cartilage.

OBJECTIVE: In this study, we applied a spring-loaded impactor to deliver traumatic forces to articular cartilage in vivo. Based on our recent finding that a 0.28-J impact induces maximal catabolic response in adult bovine articular cartilage in vitro using this device, we hypothesize that this impact will induce the formation of a focal osteoarthritic defect in vivo. DESIGN: The femoral condyle of New Zealand White rabbits was exposed and one of the following procedures performed: 0.28 J impact, anterior cruciate ligament transection, articular surface grooving, or no joint or cartilage destruction (control). After 24 hours, 4 weeks, or 12 weeks (n = 3 for each time point), wounds were localized with India ink, and tissue samples were collected and characterized histomorphometrically with Safranin O/Fast green staining and Hoechst 33342 nuclear staining for cell vitality. RESULTS: The spring-loaded device delivered reproducible impacts with the following characteristics: impact area of 1.39 ± 0.11 mm(2), calculated load of 326 ± 47.3 MPa, time-to-peak of 0.32 ± 0.03 ms, and an estimated maximal displacement of 25.1% ± 4.5% at the tip apex. The impact resulted in immediate cartilage fissuring and cell loss in the surface and intermediate zones, and it induced the formation of a focal lesion at 12 weeks. The degeneration was defined and appeared more slowly than after anterior cruciate ligament transection, and more pronounced and characteristic than after grooving. CONCLUSION: A single traumatic 0.28 J impact delivered with this spring-loaded impactor induces focal cartilage degeneration characteristic of osteoarthritis.

Assessment of the test characteristics of C-reactive protein for septic arthritis in children.

The purpose of this study was to determine the test characteristics of C-reactive protein (CRP) in the diagnosis of septic arthritis in children and to compare with erythrocyte sedimentation rate (ESR). The authors reviewed patients with synovial fluid aspiration sent for culture and Gram stain for whom a CRP was drawn within 24 hours of presentation. Descriptive statistics and univariate analyses were performed. Results for CRP were compared with ESR. Thirty-nine of 133 patients had septic arthritis. Sensitivity of CRP ranged from 41% to 90%, specificity from 29% to 85%. Positive predictive values ranged from 34% to 53%, negative predictive values from 78% to 87%. In comparison to ESR, CRP is a better independent predictor of disease. CRP is a better negative predictor than a positive predictor of disease. Indeed, if the CRP is <1.0 mg/dL, the probability that the patient does not have septic arthritis is 87%.