Combination Glucose-Lowering Therapy Plans in T2DM: Case-Based Considerations

Type 2 diabetes mellitus (T2DM) is a complex disease, and while lifestyle interventions remain the cornerstone of therapy, most patients will also require pharmacotherapy. Current diabetes treatment guidelines and algorithms recommend an individualized approach to setting glycemic goals and selecting treatment. Although a single antihyperglycemic agent may be appropriate as the initial T2DM pharmacotherapy, the progressive nature of the disease due to declining pancreatic β-cell function will result in the vast majority of T2DM patients eventually requiring two or more antihyperglycemic agents. The American Association of Clinical Endocrinologists/American College of Clinical Endocrinology T2DM management algorithm recommends initial dual agent combination therapy when a single agent is unlikely to achieve their target glycemia, i.e., for those patients with an HbA1c?≥?7.5 and an individualized HbA1c target of <?7.5%. The American Diabetes Association Standards of Care recommend combination pharmacotherapy for those patients presenting with very elevated HbA1c levels (e.g., ≥?9% and <?10%). Metformin (if well tolerated and not contraindicated) is the initial pharmacologic choice for most patients; selection of another antihyperglycemic agent to the regimen will depend on the presence of atherosclerotic cardiovascular disease and other patient-specific factors (e.g., age, known duration of T2DM, history of or risk for hypoglycemia and/or adverse consequences from hypoglycemia, other comorbidities, and available resources), along with drug-specific factors (e.g., risk for hypoglycemia, potential effects on weight, drug adverse event profiles, and cost). Combination therapy may be administered as a multi-pill regimen, a single-pill combination (i.e., fixed-dose combination oral therapy), or as a combination of oral and/or injectable therapies. This paper provides two illustrative case presentations to demonstrate how current treatment recommendations and algorithms can be used to guide the selection of non-insulin-based combination therapy for patients with T2DM in primary care settings and discusses the relative merits of several possible approaches for each patient.Funding: Boehringer Ingelheim Pharmaceuticals, Inc.     

The Effect of Dapagliflozin on Albuminuria in DECLARE-TIMI 58

OBJECTIVESodium–glucose cotransporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report albuminuria change in the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) cardiovascular outcome trial, which included populations with lower cardiorenal risk.RESEARCH DESIGN AND METHODSDECLARE-TIMI 58 randomized 17,160 patients with type 2 diabetes, creatinine clearance >60 mL/min, and either atherosclerotic cardiovascular disease (CVD; 40.6%) or risk-factors for CVD (59.4%) to dapagliflozin or placebo. Urinary albumin-to-creatinine ratio (UACR) was tested at baseline, 6 months, 12 months, and yearly thereafter. The change in UACR over time was measured as a continuous and categorical variable (≤15, >15 to <30, ≥30 to ≤300, and >300 mg/g) by treatment arm. The composite cardiorenal outcome was a ≥40% sustained decline in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m², end-stage kidney disease, and cardiovascular or renal death; specific renal outcome included all except cardiovascular death.RESULTSBaseline UACR was available for 16,843 (98.15%) participants: 9,067 (53.83%) with ≤15 mg/g, 2,577 (15.30%) with >15 to <30 mg/g, 4,030 (23.93%) with 30–300 mg/g, and 1,169 (6.94%) with >300 mg/g. Measured as a continuous variable, UACR improved from baseline to 4.0 years with dapagliflozin, compared with placebo, across all UACR and eGFR categories (all P < 0.0001). Sustained confirmed ≥1 category improvement in UACR was more common in dapagliflozin versus placebo (hazard ratio 1.45 [95% CI 1.35–1.56], P < 0.0001). Cardiorenal outcome was reduced with dapagliflozin for subgroups of UACR ≥30 mg/g (P < 0.0125, P_interaction = 0.033), and the renal-specific outcome was reduced for all UACR subgroups (P < 0.05, P_interaction = 0.480).CONCLUSIONSIn DECLARE-TIMI 58, dapagliflozin demonstrated a favorable effect on UACR and renal-specific outcome across baseline UACR categories, including patients with normal albumin excretion. The results suggest a role for SGLT2i also in the primary prevention of diabetic kidney disease.     

Severe Hypoglycemia Attributable to Intensive Glucose-Lowering Therapy Among US Adults With Diabetes: Population-Based Modeling Study, 2011-2014

ObjectiveTo estimate the contemporary prevalence of intensive glucose-lowering therapy among US adults with diabetes and model the number of hypoglycemia-related emergency department (ED) visits and hospitalizations that are attributable to such intensive treatment.Patients and MethodsUS adults with diabetes and glycated hemoglobin (HbA_1c) levels less than 7.0% who were included in the National Health and Nutrition Examination Survey (NHANES) between 2011 and 2014. Participants were categorized as clinically complex if 75 years or older or with 2 or more activities of daily living limitations, end-stage renal disease, or 3 or more chronic conditions. Intensive treatment was defined as any glucose-lowering medications with HbA_1c levels of 5.6% or less or 2 or more with HbA_1c levels of 5.7% to 6.4%. First, we quantified the proportion of clinically complex and intensively treated individuals in the NHANES population. Then, we modeled the attributable hypoglycemia-related ED visits/hospitalizations over a 2-year period based on published data for event risk.ResultsAlmost half (48.8% [10,719,057 of 21,980,034]) of US adults with diabetes (representing 10.7 million US adults) had HbA_1c levels less than 7.0%. Among them, 32.3% (3,466,713 of 10,719,057) were clinically complex, and 21.6% (2,309,556 of 10,719,057) were intensively treated, with no difference by clinical complexity. Over a 2-year period, we estimated 31,511 hospitalizations and 30,954 ED visits for hypoglycemia in this population; of these, 4774 (95% CI, 954-9714) hospitalizations and 4804 (95% CI, 862-9851) ED visits were attributable to intensive treatment.ConclusionIntensive glucose-lowering therapy, particularly among vulnerable clinically complex adults, is strongly discouraged because it may lead to hypoglycemia. However, intensive treatment was equally prevalent among US adults, irrespective of clinical complexity. Over a 2-year period, an estimated 9578 hospitalizations and ED visits for hypoglycemia could be attributed to intensive diabetes treatment, particularly among clinically complex patients. Patients at risk for hypoglycemia may benefit from treatment deintensification to reduce hypoglycemia risk and treatment burden.     

Bioequivalence of Dapagliflozin/Metformin Extended-release Fixed-combination Drug Product and Single-component Dapagliflozin and Metformin Extended-release Tablets in Healthy Russian Subjects

Purpose

Fixed-combination drug products (FCDPs) combining dapagliflozin and metformin extended release (XR) may provide patients with type 2 diabetes mellitus with an alternative antihyperglycemic treatment, which could improve adherence by reducing tablet burden. This study evaluated the bioequivalence of dapagliflozin/metformin XR FCDP versus the co-administration of the individual monotherapy tablets currently available for use in the Russian Federation.

如何根据临床指南进行个体化治疗——从脓毒症与感染性休克治疗国际指南说起

脓毒症一直是全球死亡的主要原因。基于循证医学证据的脓毒症治疗指南推动了全球对脓毒症的认知,持续强化了医务人员对脓毒症发生发展的理解,不断规范临床治疗,为临床医疗行为标准的建立提供了依据,是“个体化”治疗实施的前提。当面对患者个体时,指南推荐意见不能完全代替临床医生的决策能力,所有诊疗决策需根据患者自身的病理生理特点进行定量干预。本文通过对2021年版《拯救脓毒症运动：脓毒症与感染性休克治疗国际指南》推荐意见进行分析,浅谈“个体化”治疗与指南之间的相关性,如何在临床干预中坚持“目标与目的”“连续与动态”“治疗与再损伤”三大原则,如何根据指南进行“个体化”治疗。     

Multiphysics Modelling of Background Dose by Systemic Targeted Alpha Therapy

IntroductionNontargeted molecules of alpha-immunoconjugate (AIC) intravenously injected in clinical trials of targeted alpha therapy (TAT) could be transported by convection and diffusion along with blood or lymphatic circulation.Materials and MethodsA coupled model based on the Geant4 Monte Carlo microdosimetry technique and computational fluid dynamics was established. The transient drug delivery process and background dose to the cells along the pathway were investigated using the model. A mesoscale numerical simulation in a simple 2D capillary was performed to determine the transient toxicity of the alpha-immunoconjugate to the DNA of a targeted cell.ResultsThe simulation results indicate that the multiphysics simulation is essential to improve the accuracy of TAT simulation.ConclusionIn this work, a solution strategy for modelling AIC delivery in a blood vessel at a mesoscale level has been established. This work is the first to model different phenomena through the multiphysics simulation to investigate the whole picture of TAT.     

血液流变学指标对骨性关节炎的疗效评价

目的：探讨骨性关节炎性患者血液流变学特点。方法：对36例骨性关节炎患者与正常人，患者治疗前后的血液流变学指标进行比较分析，结果：骨性关节炎患的血流变学指标与正常人相比明显异常（P＜0．01），经治疗症状明显减轻或消失,在液流变学指标得到改善（P＜0．01，0．05）。结论：骨性关节炎患者的血流流变学指标异常，血液流变学指标可作为骨性关节患者治疗效果评价的指标之一。     

园艺疗法对慢性精神分裂症病人的康复效果

为证实园艺疗法对慢性精神分裂症病人的康复效果,对19例慢性精神分裂症病人在药物治疗的同时,给予园艺疗法,并与单纯药物治疗病人进行对比观察,治疗前后应用BPRS,NORS,IPROS量表综合评价病人的康复情况,资料应用SAS统计软件进行分析。结果显示：实验组在生活自理能力和社会适应能力等方面优于对照组（P＜0．001）。提示：园艺疗法对慢性精神分裂症病人的康复是有效的。     

心理治疗对哮喘常规干预的影响

目的：在哮喘常规干预的前提下对病人增加心理治疗，观察其对哮喘治疗疗效的影响。方法：住院哮喘病人40例，对照组、实验组各20例，入院后均予常规药物治疗、健教育等；实验组增加心理治疗，比较两组病人的焦虑、抑郁评分，哮喘发作次数，肺功能指标。结果：实验组哮喘发作次数减少，焦虑、抑郁减轻，肺功能改善，其差异有统计学意义。结论：心理治疗可有效改善哮喘病人的转归，促进哮喘病人的康复。     

强制性诱导运动在偏瘫型脑瘫患儿作业治疗中的应用

目的探讨强制性诱导运动疗法在偏瘫型脑瘫患儿上肢作业疗法中的疗效。方法 30例偏瘫型脑瘫患儿分为对照组(n=15)和观察组(n=15),两组均进行常规作业治疗,观察组在此基础上采用强制性诱导运动疗法,治疗前后对所有患儿上肢功能进行评定并比较。结果两组患儿治疗后上肢功能评分较治疗前均明显提高(P<0.01),治疗组的评分高于对照组(P<0.05)。结论强制性诱导运动疗法可提高偏瘫型脑瘫患儿上肢作业治疗的康复疗效。     

儿童语言治疗中的"互动"作用

目的观察儿童语言治疗中“互动”的作用。方法采用中国康复研究中[S-S]法语言发育迟缓评价和构音障碍评价诊断和治疗儿童语言障碍患儿90例。结果本组患儿在其原有的基础上都有不同的进步，目前正在康复治疗中。结论语言治疗“互动”方法方便、经济，可激发患儿学习言语的乐趣，达到巩固训练的目的。     

Characterization of Renal Glucose Reabsorption in Response to Dapagliflozin in Healthy Subjects and Subjects With Type 2 Diabetes

OBJECTIVE

To examine the effect of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on the major components of renal glucose reabsorption (decreased maximum renal glucose reabsorptive capacity [T_mG], increased splay, and reduced threshold), using the pancreatic/stepped hyperglycemic clamp (SHC) technique.

RESEARCH DESIGN AND METHODS

Subjects with type 2 diabetes (n = 12) and matched healthy subjects (n = 12) underwent pancreatic/SHC (plasma glucose range 5.5–30.5 mmol/L) at baseline and after 7 days of dapagliflozin treatment. A pharmacodynamic model was developed to describe the major components of renal glucose reabsorption for both groups and then used to estimate these parameters from individual glucose titration curves.

RESULTS

At baseline, type 2 diabetic subjects had elevated T_mG, splay, and threshold compared with controls. Dapagliflozin treatment reduced the T_mG and splay in both groups. However, the most significant effect of dapagliflozin was a reduction of the renal threshold for glucose excretion in type 2 diabetic and control subjects.

CONCLUSIONS

The SGLT2 inhibitor dapagliflozin improves glycemic control in diabetic patients by reducing the T_mG and threshold at which glucose is excreted in the urine.The current study was undertaken to examine the mechanism (decreased maximum renal glucose reabsorptive capacity [T_mG], increased splay, and reduced threshold) through which sodium-glucose transporter 2 (SGLT2) inhibition induces glucosuria in diabetic and nondiabetic subjects. In humans, the kidney filters ∼162 g of glucose per day (glomerular filtration rate [GFR] = 180 L/day × fasting plasma glucose [FPG] = ∼5 mmol/L [90 mg/dL]), and virtually all the filtered glucose is reabsorbed (1). The high-capacity, low-affinity SGLT2 in the proximal tubule reabsorbs ∼80–90% of filtered glucose (2,3). T_mG varies among individuals and averages ∼375 mg/min (2–4). Because the filtered glucose load does not exceed T_mG in nondiabetic individuals, all filtered glucose is reabsorbed and returned to the circulation. If the filtered glucose load exceeds the T_mG, all glucose in excess of the T_mG is excreted. The plasma glucose concentration at which the filtered glucose load reaches 375 mg/min is ∼10 mmol/L (180 mg/dL) (2–4). Above the T_mG, the glucose excretion rate increases linearly and parallels the increase in filtered glucose load. Glucose reabsorption and excretion curves display a nonlinear transition as T_mG is approached. This rounding of the curves is termed splay (Fig. 1). The plasma glucose concentration at which glucose first appears in the urine is termed threshold and corresponds to the beginning of the splay.Open in a separate windowFigure 1Relationship between the rate of urinary glucose reabsorption/renal glucose filtration and the plasma glucose concentration during SHC in type 2 diabetic and healthy subjects at baseline and after 7 days of dapagliflozin treatment. Thin line, rate of glucose filtration; ○, observed rate of reabsorption; thick line, predicted rate of reabsorption; dashed line, geometric mean of T_mG.In patients with poorly controlled type 1 or 2 diabetes, T_mG is increased (5,6). Similar observations have been made in diabetic animal models (7,8). At the molecular level, increased T_mG may be explained by increased SGLT2 mRNA and protein in the proximal tubule (9–11).SGLT2 inhibitors have been developed for the treatment of type 2 diabetes (4,12–14) and have proven to be efficacious in reducing glycated hemoglobin (HbA_1c) (12–16). Because their mechanism of action is independent of severity of insulin resistance and β-cell failure, they can be used at any stage of type 2 diabetes (14,16,17). Clinical trials with SGLT2 inhibitors have demonstrated that treatment in healthy subjects results in continuously excreted glucose in the absence of hyperglycemia (18,19), suggesting that factors other than a reduction in T_mG must account for the drug’s glucosuric effect. Because no previous study to our knowledge has comprehensively characterized the changes in renal glucose handling through which SGLT2 inhibitors augment renal glucose excretion in humans, the current study was undertaken to examine the mechanisms through which dapagliflozin produces its glucosuric effect in individuals with type 2 diabetes and those with normal glucose tolerance.     

The Effect of Vibroacoustic Therapy

This paper reports an experimental study to determine the possible effects of a music chair on people with cerebral palsy. The effect of vibroacoustic treatment was evaluated in a double-blind trial. Members of six matched pairs, aged 27–48 years, were randomly allocated to experimental and control groups. The experimental group received two weekly treatments with music plus vibroacoustic waves (low frequency sounds), and the control group received treatment with music alone. Before and after the nine-week project, individuals were videotaped performing gross and fine muscular movements.Four independent assessors evaluated each movement. Both groups improved their performances on the post-test evaluation. Although there was a tendency towards better performances within the experimental group, the differences were not significant (p > 0.05). No significant differences were found in results from the Nic Waals muscle test, pulse oximetry and drawing/writing tests.Although users found vibroacoustic treatment pleasant and some individuals showed short-term improvement, there was no unequivocal evidence to support anecdotal reports of beneficial effects from vibroacoustic treatment. Not only is further research needed in order to identify criteria for selecting clients who may benefit and describe protocols of treatment but, as demand commonly follows introduction of a new intervention, caution is advised until risk of adverse effects has been evaluated.     

行为矫正疗法对男性精神分裂症病人康复的作用

长期住院的精神分裂症病人由于疾病本身的因素 ,又加上封闭式的环境及旧的看管式的护理模式 ,可发生不同程度的行为改变———始动性缺乏 ,产生对住院的依赖性。为了促进病人的康复 ,延缓其衰退 ,探索改变旧的护理模式 ,发挥护士在精神病康复中的作用 ,本文对此进行了观察。现介绍如下。1　对象与方法1.1　对象。 (1)符合中国精神疾病分类方案与诊断标准第2版修订版 (ＣＣＤＭ— 2—Ｒ)中精神分裂症、分裂样情感性精神病的诊断标准 ;(2 )临床特征为急性症状控制 ,病情基本稳定 ,精神症状以阴性为主 ;(3)病程 5ａ以上 ,无其他并发症 ;(4) 6 0…     

应用降纤酶个体化治疗下肢深静脉血栓形成临床分析

目的观察降纤酶治疗下肢深静脉血栓形成的临床疗效并探讨个体化的治疗方案。方法 65例下肢深静脉血栓形成的患者随机分为对照组31例。观察组34例．对照组与观察组均予阿司匹林、低分子肝素等常规治疗。观察组加用降纤酶10U 0．9％生理盐水100mL静滴。每日一次,根据凝血六项指标调整个体化剂量,以14d为1个疗程进行疗效比较。结果观察组总有效率88．2％,对照组74．2％,两组比较差异有显著性(P<0．05)。结论应用降纤酶治疗下肢深静脉血栓形成疗效显著、副作用小,且剂量应个体化。