Long-term safety and effectiveness of biosimilar insulin glargine in Japanese patients with diabetes mellitus in routine clinical practice: results of a post-marketing safety study

Abstract

Objective: To evaluate the long-term safety and effectiveness of biosimilar insulin glargine (GLY) in real-world clinical practice.

Methods: This prospective, non-interventional, multicenter, observational, post-marketing safety study (PMSS) enrolled Japanese patients with type 1 or 2 diabetes mellitus (T1DM or T2DM) starting GLY therapy, and was required by Japanese Pharmaceutical Affairs Law mandating post-marketing safety surveillance to acquire safety and effectiveness data of biosimilar products. Data collected from the 12-month observation included patient characteristics, adverse events, and blood glucose control.

Results: The study enrolled 141 patients with T1DM and 1104 patients with T2DM. Pre-study insulin was used by 94.1% of patients with T1DM and 75.0% with T2DM. 65.4% of patients with T1DM and 64.3% with T2DM switched from the reference product (GLY-switched), while 25.0% with T2DM were insulin-naive. Adverse events were reported by 5.7% and 8.5% in T1DM and T2DM, respectively. Similar incidences were reported in GLY-switched. Adverse events were reported by 10.7% in insulin-naive T2DM. Baseline mean hypoglycemic events/month were 1.8 and 0.1 in T1DM and T2DM, respectively: the mean change from baseline (CFB) was –1.2 (p?=?.066) and 0.0 (p?=?.915), respectively. Baseline mean HbA1c was 8.4% and 8.7% in T1DM and T2DM, respectively; the mean CFB was –0.5% (p?<?.001) and –0.9% (p?<?.001), respectively, and –1.5% (p?<?.001) in insulin-naive T2DM.

Conclusions: This first long-term Japanese PMSS of GLY demonstrated adverse events, hypoglycemia, and glycemic control consistent with the known GLY profile for T1DM and T2DM patients, in routine clinical practice.     

Medallion‐like dermal dendrocyte hamartoma: A rare congenital CD34‐positive dermal lesion clinically and pathologically overlapping with fibroblastic connective tissue nevus

Both medallion‐like dermal dendrocyte hamartoma and fibroblastic connective tissue nevus are rare benign dermal lesions composed of CD34‐positive spindle cells. Although regarded as different diseases, it is sometimes difficult to distinguish between them due to their clinical and pathological similarities. We present a case of medallion‐like dermal dendrocyte hamartoma that could also be diagnosed as fibroblastic connective tissue nevus and propose the possibility of overlap in these diseases.     

Real‐Time Observation of Thrombus Growth Process in an Impeller of a Hydrodynamically Levitated Centrifugal Blood Pump by Near‐Infrared Hyperspectral Imaging

Understanding the thrombus formation in cardiovascular devices such as rotary blood pumps is the most important issue in developing more hemocompatible devices. The objective of this study was to develop a hyperspectral imaging (HSI) method to visualize the thrombus growth process within a rotary blood pump and investigate the optical properties of the thrombus. An in vitro thrombogenic test was conducted using fresh porcine blood and a specially designed hydrodynamically levitated centrifugal blood pump with a transparent bottom. The pump rotating at 3000 rpm circulated the blood at 1.0 L/min. The bottom surface of the pump was illuminated with white light pulsed at the same frequency as the pump rotation, and the backward‐scattered light was imaged using the HSI system. Using stroboscopic HSI and an image construction algorithm, dynamic spectral imaging at wavelengths ranging from 608 to 752 nm within the rotating pump was achieved. After completing the experiment, we collected the red thrombus formed in the pump impeller and quantified the thrombus hemoglobin concentration (Hb_thrombus). The spectrum changed around the center of the impeller, and the area of change expanded toward the impeller flow path. The shape corresponded approximately to the shape of the thrombus. The spectrum change indicated that the light scattering derived from red blood cells decreased. The Hb_thrombus was 4.7 ± 1.3 g/dL versus a total hemoglobin of 13 ± 0.87 g/dL. The study revealed that Hb_thrombus was reduced by the surrounding blood flow.     

Does hard insertion and space improve shock absorption ability of mouthguard?

Abstract – Mouthguards are expected to reduce sports‐related orofacial injuries. Numerous studies have been conduced to improve the shock absorption ability of mouthguards using air cells, sorbothane, metal wire, or hard material insertion. Most of these were shown to be effective; however, the result of each study has not been applied to clinical use. The aim of this study was to develop mouthguards that have sufficient prevention ability and ease of clinical application with focus on a hard insertion and space. Ethylene vinyl acetate (EVA) mouthguard blank used was Drufosoft and the acrylic resin was Biolon (Dreve‐Dentamid GMBH, Unna, Germany). Three types of mouthguard samples tested were constructed by means of a Dreve Drufomat (Type SO, Dreve‐Dentamid) air pressure machine: the first was a conventional laminated type of EVA mouthguard material; the second was a three layer type with acrylic resin inner layer (hard‐insertion); the third was the same as the second but with space that does not come into contact with tooth surfaces (hard + space). As a control, without any mouthguard condition (NOMG) was measured. A pendulum type impact testing machine with interchangeable impact object (steel ball and baseball) and dental study model (D17FE‐NC.7PS, Nissin, Tokyo, Japan) with the strain gages (KFG‐1‐120‐D171‐11N30C2: Kyowa, Tokyo, Japan) applied to teeth and the accelerometer to the dentition (AS‐A YG‐2768 100G, Kyowa) were used to measure transmitted forces. Statistical analysis (anova , P < 0.01) showed significant differences among four conditions of NOMG and three different mouthguards in both objects and sensor. About acceleration: in a steel ball which was a harder impact object, shock absorption ability of about 40% was shown with conventional EVA and hard‐insertion and about 50% with hard + space. In a baseball that was softer compared with steel ball, a decrease rate is smaller, reduction (EVA = ～4%, hard‐insertion = ～12%, hard + space = ～25%) was admitted in the similar order. A significant difference was found with all the combinations except for between EVA and hard‐insertion with steel ball (Tukey test). About distortion: both buccal and lingual, distortions had become small in order of EVA, hard‐insertion, and hard + space, too. The decrease rate is larger than acceleration, EVA = ～47%, hard‐insertion = 80% or more, and hard +space = ～98%, in steel ball. EVA = ～30%, hard‐insertion =～75%, and hard + space = ～98% in baseball. And a significant difference was found with all the combinations (Tukey test). Especially, hard + space has decreased the distortion of teeth up to several percentages. Acceleration of the maxilla and distortions of the tooth became significantly smaller when wearing any type of mouthguard, in both impact objects. But the effect of mouthguard was clearer in the distortion of the tooth and with steel ball. Considering the differences of mouthguards, the hard‐insertion and the hard + space had significantly greater buffer capacity than conventional EVA. Furthermore, hard + space shows quite high shock absorption ability in the tooth distortion. Namely, hard + space has decreased the distortion of teeth up to several percentages in both impact objects.     

A vacuum technique to increase anterior thickness of athletic mouthguards to achieve a full-balanced occlusion.

A full-balanced occlusion is essential for mouthguards. It has been reported that a balanced occlusion for upper and lower anterior teeth is essential for prevention of injuries occurring to the maxillary anterior teeth and alveolar bone caused by horizontal direct impact. The support of the mandibular teeth through the mouthguard is critical to prevent maxillary front tooth injury from a direct impact force. However, some vacuum mouthguard designs may not achieve a full-balanced occlusion. For example, when a player has a malocclusion, an elongated molar or premolar tooth, an open bite, a large over jet or a maxillary protrusion. An improved vacuum fabrication method is necessary to obtain full balanced occlusion in these cases as opposed to conventional vacuum type single-layer mouthguard technique.     

Shear-dependent platelet aggregation size

Nonsurgical bleeding is the most frequent complication of left ventricular assist device (LVAD) support. Supraphysiologic shear rates generated in LVAD causes impaired platelet aggregation, which increases the risk of bleeding. The effect of shear rate on the formation size of platelet aggregates has never been reported experimentally, although platelet aggregation size can be considered to be directly relevant to bleeding complications. Therefore, this study investigated the impact of shear rate and exposure time on the formation size of platelet aggregates, which is vital in predicting bleeding in patients with an LVAD. Human platelet-poor plasma (containing von Willebrand factor, vWF) and fluorochrome-labeled platelets were subjected to a range of shear rates (0-10 000 s⁻¹) for 0, 5, 10, and 15 minutes using a custom-built blood-shearing device. Formed sizes of platelet aggregates under a range of shear-controlled environment were visualized and measured using microscopy. The loss of high molecular weight (HMW) vWF multimers was quantified using gel electrophoresis and immunoblotting. An inhibition study was also performed to investigate the reduction in platelet aggregation size and HMW vWF multimers caused by either mechanical shear or enzymatic (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13—ADAMTS13, the von Willebrand factor protease) mechanism under low and high shear conditions (360 and 10 000 s⁻¹). We found that the average size of platelet aggregates formed under physiological shear rates of 360-3000 s⁻¹ (200-300 μm²) was significantly larger compared to those sheared at >6000 s⁻¹ (50-100 μm²). Furthermore, HMW vWF multimers were reduced with increased shear rates. The inhibition study revealed that the reduction in platelet aggregation size and HWM vWF multimers were mainly associated with ADAMTS13. In conclusion, the threshold of shear rate must not exceed >6000 s⁻¹ in order to maintain the optimal size of platelet aggregates to “plug off” the injury site and stop bleeding.     

Detection of thrombosis in a magnetically levitated blood pump by vibrational excitation of the impeller

The use of contactless support technology for the impeller has led to an increase in the durability of ventricular assist devices (VADs), and these have been in clinical use worldwide. However, pump thrombosis and stroke are still issues to be solved. We have developed a method for detecting the thrombosis in a magnetically levitated blood pump without the need for additional sensors or other equipment. In the proposed method, a sinusoidal current is applied to the electromagnets used for the magnetic bearing, resulting in vibration of the impeller. The phase difference between the current and displacement of the impeller increases with pump thrombosis. First, we describe the principle by which the pump thrombosis is detected. Pump thrombosis reduces the narrowest fluid gap in the pump and this gives rise to a change in the phase difference. Second, we report on experiments in which we changed the narrowest fluid gap using oriented polypropylene tape and showed that decreasing the narrowest fluid gap resulted in an increase in phase difference. For these experiments, the measurements were repeated three times for each condition. Third, we examine the relationship between the pump thrombosis and the phase difference evaluated by observations of the underside of the impeller when operating the pump with porcine blood. Since light was unable to penetrate the blood layer, the erythrocytes were removed for this observation. Only one observation was made. The results showed the phase difference rapidly increased at the same moment when the pump thrombosis was observed. This implies the proposed method has the potential to detect the early stages of pump thrombosis. Finally, in vitro experiments to detect thrombosis when using whole porcine blood in the pump were conducted. The experiment was carried out five times. To intentionally form a thrombus inside the pump, the activated clotting time was controlled to be less than 200 s. In every case, the phase difference increased by more than one degree after tens of minutes. Then, the pump was disassembled and a small amount of pump thrombosis was observed. We conclude that real-time diagnosis of pump thrombosis may be realized by measuring the phase difference without the need for additional sensors.