Initial Dual Therapy Research Articles

Trends in Initial Antihypertensive Medication Prescribing Among >2.8 Million Veterans Newly Diagnosed With Hypertension, 2000 to 2019.

Among patients diagnosed with high blood pressure (BP), initial dual therapy has been recommended for patients with high pretreatment systolic BP (≥160 mm Hg) since 2003, and first-line β-blocker use without a compelling condition has fallen out of favor in US guidelines. This serial cross-sectional study of national Veterans Health Administration data included adult Veterans with incident hypertension initiating antihypertensive medication between January 1, 2000, and December 31, 2019. We assessed annual trends in initial regimens dispensed (index date: first antihypertensive dispense date) by number of classes and unique class combinations used overall and by pretreatment systolic BP (<140, 140 to <160, and ≥160 mm Hg), as well as trends in subgroups (age, sex, race and ethnicity, and comorbidities warranting β-blocker use). Among 2 832 684 eligible Veterans (average age 61 years, 95% men, 65% non-Hispanic White, and 8% with cardiovascular disease), from 2000-2004 to 2015-2019, initial monotherapy increased across all pretreatment systolic BP levels (<140 mm Hg: 62.1% to 66.4%; 140 to <160 mm Hg: 70.7% to 76.8%; ≥160 mm Hg: 64.2% to 69.7%). Initiation of dual therapy decreased across all pretreatment systolic BP levels (<140 mm Hg: 25.0% to 24.2%; 140 to <160 mm Hg: 20.4% to 17.6%; ≥160 mm Hg: 22.7% to 22.0%). Among 2 521 696 Veterans (89% of overall) without a β-blocker-indicated condition in 2015 to 2019, 20% initiated a β-blocker, most commonly as monotherapy. More than half of US Veterans diagnosed with hypertension with a pretreatment systolic BP ≥160 mm Hg were started on antihypertensive monotherapy. There are disparities between guideline-recommended first-line treatments and the actual regimens initiated for newly diagnosed Veterans with hypertension.

Comparative Effectiveness of Dual- Versus Mono-Sedative Therapy on Opioid Administration, Sedative Administration, and Sedation Level in Mechanically Ventilated, Critically Ill Children.

We estimated the effect of early initiation of dual therapy vs monotherapy on drug administration and related outcomes in mechanically ventilated, critically ill children. We used the electronic medical record at a single tertiary medical center to conduct an active comparator, new user cohort study. We included children <18 years of age who were exposed to a sedative or analgesic within 6 hours of intubation. We used stabilized inverse probability of treatment weighting to account for confounding at baseline. We estimated the average effect of initial dual therapy vs monotherapy on outcomes including cumulative opioid, benzodiazepine, and dexmedetomidine dosing; sedation scores; time to double the opioid or benzodiazepine infusion rate; initiation of neuromuscular blockade within the first 7 days of follow-up; time to extubation; and 7-day all-cause in-hospital death. The cohort included 640 patients. Children receiving dual therapy received 0.03 mg/kg (95% CI, 0.02-0.04) more dexmedetomidine over the first 7 days after initiation of mechanical ventilation than did monotherapy patients. Dual therapy patients had similar sedation scores, time to double therapy, initiation of neuromuscular blockade, and time to extubation as monotherapy patients. Dual therapy patients had a lower incidence of death. In this study, initial dual therapy compared with monotherapy does not reduce overall drug administration during mechanical ventilation. The identified effect of dual therapy on mortality deserves further investigation.

Cardiovascular outcomes of β-blocker-calcium channel blocker initial dual therapy vs. other initial dual therapies in Chinese patients with hypertension: A real-world retrospective study.

This retrospective study compared cardiovascular (CV) outcomes between initial β-blocker (BB)+calcium channel blocker (CCB) dual therapy ("B+C") and other initial dual therapies in Chinese newly diagnosed hypertensive patients. In this study, all patients in a regional electronic database with newly diagnosed hypertension from January 01, 2012 to December 31, 2016 who received any initial optimal dual therapy recommended by the Chinese hypertension guideline were included. 1:2 propensity score matching (PSM) was used to balance baseline characteristics between patients receiving B+C and patients receiving other initial dual therapies ("Others"). The primary outcome was major adverse cardiovascular events (MACE) that occurred from January 01, 2012 to December 31, 2017, consisting of non-fatal stroke, non-fatal myocardial infarction (MI), non-fatal chronic heart failure (CHF), and all-cause death. Cox proportional hazard models were used to compare these CV outcomes in the 2 matched cohorts. After the PSM, 6227 patients receiving B+C and 12454 patients receiving Others were included. Compared to patients receiving Others, patients receiving B+C had a significantly lower risk of MACE (hazard ratio [HR] 0.85; 95% confidential interval [CI] 0.78-0.92; p<.001), non-fatal stroke (HR 0.89; 95% CI 0.81-0.98; p=.018) and non-fatal CHF (HR 0.74; 95% CI 0.63-0.86; p<.0001). Additionally, differences in risks of non-fatal MI and all-cause death between the 2 treatment cohorts were not statistically significant. In conclusion, BB+CCB initial dual therapy was associated with a lower risk of MACE, stroke, and CHF than other optimal initial dual therapies recommended by the Chinese hypertension guideline in Chinese newly diagnosed hypertensive patients.

CARDIOVASCULAR OUTCOMES OF INITIAL BETA-BLOCKER + CALCIUM CHANNEL BLOCKER THERAPY VS OTHER DUAL THERAPIES IN CHINESE PATIENTS WITH NEWLY DIAGNOSED HYPERTENSION: A REAL-WORLD STUDY

Objective: This study aimed to compare cardiovascular (CV) outcomes associated with initial beta-blocker (BB) + calcium channel blocker (CCB) dual therapy and other initial dual therapies in Chinese patients with newly diagnosed hypertension. Design and method: In this retrospective study, all patients in a regional electronic database with newly diagnosed hypertension from January 01, 2012 to December 31, 2016 who received initial dual therapy recommended by the 2018 Chinese Guidelines for Prevention and Treatment of Hypertension were included. The recommended dual therapies included BB+CCB (B+C), ARB/ACEI+C (A+C), A+Diuretic (A+D) and C+D. 1:2 PSM was used to balance baseline characteristics between patients receiving B+C and patients receiving other initial dual therapies (Others). Primary outcome was major adverse cardiovascular events (MACE) consisting of non-fatal stroke, non-fatal myocardial infarction (MI), non-fatal chronic heart failure (CHF) and all-cause death during a median follow-up of 2.02 years (IQR: 1.07–3.36 years). Cox proportional hazard models were used to compare these CV outcomes in the 2 matched cohorts. Results: After the PSM, 6,227 patients in the B+C group and 12,454 patients in the Others group were included. The B+C group and the Others group had comparable age (59.5 ± 12.7 years vs. 59.8 ± 12.3 years) and diastolic blood pressure (91.2 ± 6.7 mmHg vs. 91.2 ± 6.9 mmHg), although their heart rate (88.0 ± 6.8 vs. 88.4 ± 7.1) and systolic blood pressure (156.2 ± 7.0 mmHg vs. 155.9 ± 7.1 mmHg) still had differences. Compared to the Others group, the B+C group had significantly lower risks of MACE (HR 0.85; 95%CI 0.78–0.92; P &lt; 0.001), non-fatal stroke (HR 0.89; 95% CI 0.81–0.98; P = 0.018) and non-fatal CHF (HR 0.74; 95% CI 0.63–0.86; P &lt; 0.0001) (Figure 1). Differences in risks of non-fatal MI and all-cause death in the 2 groups were statistically insignificant. Additionally, A+D (HR 1.71; 95% CI 1.52–1.92) and C+D (HR 1.77; 95% CI 1.45–2.15) were associated with significantly higher risk of MACE than B+C, and the difference between A+C (HR 1.04; 95% CI 0.96–1.14) and B+C was small. Conclusions: BB+CCB initial dual therapy was associated with lower risks of MACE, stroke and CHF than other recommended initial dual therapies in Chinese patients with newly diagnosed hypertension.

Starting Antihypertensive Drug Treatment With Combination Therapy

Starting Antihypertensive Drug Treatment With Combination Therapy

Outcomes of adults with congenital heart disease and pulmonary hypertension in the advanced pulmonary vasodilator era. A regional multicenter registry (RACCA)

Abstract The objective of this study is to evaluate mortality, causes and risk factors of death in adults with congenital heart disease (ACHD) and PHT on Pulmonary vasodilator therapy (PVT). Methods 170 cases with PHT were identified in RACCA (Left heart disease were excluded (n=20)). We examined mortality, causes of death and complications during a mean follow-up (FU) of 7.9+4.6 years. For each patient demographic data, shunt location, clinical PHT group and functional class (FC) were collected. In an unselected sample of 103 patients, O2Sat, NT-proBNP, right ventricle function (RV) and 6-minute-test (6min) were retrospectively reviewed at 2 data collection time points: evaluation at baseline and the most recent data preceding death or at last clinical visit. Survival was assessed with Kaplan-Meier curves and differences between groups using the log-rank test. To look for predictors of death, Cox regression analysis was performed. Results Patients with PHT were predominantly women (61%), aged 45 years (IQR 33–58.5). The distribution of PHT group by underlying defects were 58 Eisenmenger (ES) (Complex 50%) and 45 non-ES (pretricuspid 46.7% (p=0,0002). PHT-pretricuspid defects occurred more in women with unrepaired simple defects and at older ages. In the sample, 85% were commenced on therapy with PVT (5% on initial dual therapy). The treated patients presented worse functional situation, more desaturation of O2 and worse TAPSE. In the group of treatment, 53% required treatment escalation during the FU. Initially, 82% were in sinus rhythm, in FC I-II 53% and in FC III-IV 39%. 10% had moderate-severe RV dysfunction. At the last visit, 38% were on monotherapy, 40% on dual therapy and 22% on triple therapy. FC improved from III-IV to I-II in 35% and 79% remained in FC-I-II without clinical deterioration. The Δ6min was +53±72 mts in those patients alive at the end of FU, and −126±26 mts in exitus cases (p=0,003), but O2 saturation did not change significantly. Over the FU, 29 patients died. The main cause of death was heart failure, followed by sudden death. The event-free survival was 84% at 5 years. Survival was significantly worst for patients presenting with arrhythmias and more advanced FC at initiation of PVT and for those who developed RV dysfunction over FU. At multivariate analysis, syndromic forms, pretricuspid shunt, non-ES physiology, PVT and monotherapy at baseline, FC III-IV and desaturation were independent predictors for death. Conclusions Although a positive clinical response was observed, mortality of PHT in CHD under advanced PVT remains high at mid-term FU. Heart failure is the leading cause of death. In terms of mortality, non ES patients and pretricuspid shunts were less responsive to treatment than patients with ES. Our results may suggest that patients with more advanced disease at the initiation of therapies do not respond properly and support the need for early treatment and initial dual therapy. Funding Acknowledgement Type of funding source: None

Prescribing Pathways to Triple Therapy: A Multi-Country, Retrospective Observational Study of Adult Patients with Chronic Obstructive Pulmonary Disease

IntroductionMaintenance treatment strategies in COPD recommend inhaled corticosteroid (ICS) + long-acting muscarinic antagonist (LAMA) + long-acting β2-agonist (LABA) triple therapy after initial dual therapy. Little is known about how treatment pathways to triple therapy vary across countries in clinical practice.MethodsThis multi-country, retrospective cohort study (conducted 1 January 2005–1 May 2016) included patients with a COPD diagnosis, and (UK only) evidence of smoking history, or (France, Italy, Germany, and Australia) an indicator confirming COPD diagnosis, a first instance of triple therapy recorded during the study period and ≥ 12 months of data prior to this date. Treatment pathways to triple therapy were analyzed in patients whose first instance of triple therapy was on or after the initial COPD diagnosis. The proportion of patients who initiated triple therapy prior to initial COPD diagnosis was also estimated. Meta-analyses of the main results were performed.ResultsIn 130,729 patients across all countries, mean age (standard deviation) ranged from 63.4 (10.4) years (Germany) to 69.8 (9.9) years (Italy), and median time (interquartile range) from initial COPD diagnosis to first prescription of triple therapy ranged from 16.9 (5.7–36.2) months (Australia) to 42.5 (13.9–87.4) months (UK). ICS + LABA was the most common treatment pathway prior to triple therapy in the UK, Germany, and Italy (27.3%–31.6%); no previous maintenance therapy prior to triple therapy was the most common pathway in France and Australia (32.5% and 37.9%, respectively). Meta-analyses provided a pooled estimate of 20.4% (95% confidence interval: 13.8%–29.1%) for the proportion of patients initiating triple therapy at or before initial COPD diagnosis.ConclusionsIn this retrospective cohort study, treatment pathways to triple therapy were diverse within and between countries. The differing impact of treatments may affect quality of life and disease control in patients with COPD. Further analyses should investigate factors influencing pathways to triple therapy.

Analysis of the Authorized Target Populations for Fixed Dose Combination Products Between 2000 and 2017 Reveals Discrepancies Between EMA's and FDA's Views on Initial Dual-Therapy.

A fixed dose combination (FDC) product containing two components can be authorized for the use in 3 conceptual scenarios (1) as substitution for a treatment regimen containing both components given separately (substitution therapy) or (2) as replacement for a treatment regimen where the patient currently receives one of the components (add-on therapy) or (3) initial treatment of patients naïve to both components (initial combination therapy). Trends in European Medicine Agency (EMA) and Food and Drug Administration (FDA) approvals of FDC products for the 3 scenarios were explored by comparing the therapeutic indications retrieved from the EMA and FDA websites for FDCs approved between January 2000 and April 2017 within 5 selected therapeutic areas: type 2 diabetes mellitus (T2DM), asthma, chronic obstructive pulmonary disease, hypertension, and human immunodeficiency virus (HIV) infection. Approval decisions between EMA and FDA were largely aligned for the substitution therapy and add-on therapy scenarios. Discrepancies were found for the initial combination therapy scenario. Since EMA and FDA rely on similar conceptional models when approving FDCs, the reasons behind this general disparity are not clear, but may be found in the lack of evidence from the registration studies. Sponsors and health authorities should work collaboratively on closing that gap.

Analysis of the Authorized Target Populations for Fixed Dose Combination Products Between 2000 and 2017 Reveals Discrepancies Between EMA’s and FDA’s Views on Initial Dual-Therapy

A fixed dose combination (FDC) product containing two components can be authorized for the use in 3 conceptual scenarios (1) as substitution for a treatment regimen containing both components given separately (substitution therapy) or (2) as replacement for a treatment regimen where the patient currently receives one of the components (add-on therapy) or (3) initial treatment of patients naïve to both components (initial combination therapy). Trends in European Medicine Agency (EMA) and Food and Drug Administration (FDA) approvals of FDC products for the 3 scenarios were explored by comparing the therapeutic indications retrieved from the EMA and FDA websites for FDCs approved between January 2000 and April 2017 within 5 selected therapeutic areas: type 2 diabetes mellitus (T2DM), asthma, chronic obstructive pulmonary disease, hypertension, and human immunodeficiency virus (HIV) infection. Approval decisions between EMA and FDA were largely aligned for the substitution therapy and add-on therapy scenarios. Discrepancies were found for the initial combination therapy scenario. Since EMA and FDA rely on similar conceptional models when approving FDCs, the reasons behind this general disparity are not clear, but may be found in the lack of evidence from the registration studies. Sponsors and health authorities should work collaboratively on closing that gap.

A1C Goal Attainment with Initial Dual Therapy with Metformin (MET)/Sitagliptin (SITA) Compared with Met Monotherapy—Impact of Baseline A1C and Target A1C

While MET is generally recommended as initial pharmacologic therapy for T2D, the substantial proportion of patients who do not achieve glycemic targets with monotherapy argues for initial use of dual therapy in patients with high A1C levels (e.g., &amp;gt;7.5% per AACE and &amp;gt;9.0% per ADA guidelines). The individualization of glycemic targets based on patient characteristics adds an additional complexity to treatment decision-making. This analysis was designed to identify the baseline A1C range from which patients benefitted the most with initial dual therapy (compared with monotherapy) across a range of A1C goals. Data from 3 randomized clinical trials containing treatment arms of both initial MET monotherapy (1700-2000 mg qd, n=778) and initial MET + SITA dual therapy (1700-2000 mg + 100 mg qd, n=789) were pooled. Patients in all 3 trials had an entry A1C of at least 7.5% (mean = 9.4% in both groups). Demographic and disease-related baseline characteristics were well balanced in both groups. Rates of achieving various A1C goals after 18-24 weeks of treatment were assessed across a range of baseline A1C, and odds ratios for goal attainment were calculated (Table). Initial combination therapy with MET + SITA was generally more effective than MET monotherapy in achieving treatment targets across a broad range of individualized glycemic goals and baseline A1C values. Post-treatment A1C goalGoal achieved, % (n/n) MET/SITA, N = 789Goal achieved, % (n/n) MET, N = 778Odds ratio (95% CI)Baseline A1C 7 - 7.5%&amp;lt; 6.5%74.1 (43/58)44.8 (26/58)1.9 (1.27, 2.78)&amp;lt; 7.0%91.4 (53/58)75.9 (44/58)1.8 (1.06, 3.18)Baseline A1C 7.5 - 8%&amp;lt; 6.5%60.7 (65/107)31.8 (41/129)1.8 (1.39, 2.38)&amp;lt; 7.0%82.2 (88/107)65.9 (85/129)1.5 (1.14, 2.11)&amp;lt; 7.5%90.7 (97/107)80.6 (104/129)1.5 (1.03, 2.26)Baseline A1C 8 - 8.5%&amp;lt; 6.5%43.2 (54/125)24.8 (27/109)1.5 (1.15, 2.01)&amp;lt; 7.0%69.6 (87/125)47.7 (52/109)1.6 (1.21, 2.07)&amp;lt; 7.5%81.6 (102/125 )66.1 (72/109)1.5 (1.12, 2.04)&amp;lt; 8.0%89.6 (112/125)80.7 (88/109)1.4 (0.99, 2.08)Baseline A1C 8.5 - 9%&amp;lt; 6.5%46.5 (47/101)17.4 (16/92)2.0 (1.46, 2.84)&amp;lt; 7.0%67.3 (68/101)41.3 (38/92)1.7 (1.28, 2.30)&amp;lt; 7.5%80.2 (81/101)60.9 (36/92)1.6 (1.17, 2.23)&amp;lt; 8.0%86.1 (87/101)77.2 (71/92)1.4 (0.93, 1.97)Baseline A1C 9 - 9.5%&amp;lt; 6.5%32.2 (29/90)15.9 (13/82)1.6 (1.10, 2.30)&amp;lt; 7.0%52.2 (47/90)32.9 (27/82)1.5 (1.09, 2.03)&amp;lt; 7.5%71.1 (64/90)58.5 (48/82)1.3 (0.96, 1.81)&amp;lt; 8.0%82.2 (74/90)75.6 (62/82)1.2 (0.84, 1.77)Baseline A1C 9.5- 10%&amp;lt; 6.5%32.8 (21/64)15.1 (11/73)1.7 (1.10, 2.51)&amp;lt; 7.0%53.1 (34/64)23.3 (17/73)1.9 (1.34, 2.79)&amp;lt; 7.5%60.9 (39/64)35.6 (26/73)1.7 (1.19, 2.38)&amp;lt; 8.0%68.8 (44/64)50.7 (37/73)1.5 (1.03, 2.08)Baseline A1C &amp;gt;10.0%&amp;lt; 6.5%19.0 (46/242)11.3 (26/230)1.4 (1.05, 1.76)&amp;lt; 7.0%32.6 (79/242)22.6 (52/230)1.3 (1.05, 1.58)&amp;lt; 7.5%44.6 (108/242)33.9 (78/230)1.3 (1.04, 1.51)&amp;lt; 8.0%56.6 (137/242)42.6 (98/230)1.3 (1.10, 1.59) Disclosure A. Raji: Employee; Self; Merck &amp; Co., Inc. M.C. Ellison: Employee; Self; Merck &amp; Co., Inc. R.L.H. Lam: Employee; Self; Merck &amp; Co., Inc. E.A. O'Neill: Employee; Self; Merck &amp; Co., Inc. S.S. Engel: Employee; Self; Merck &amp; Co., Inc.. Stock/Shareholder; Self; Merck &amp; Co., Inc..

40-Year-Old Woman With Breathlessness and Fatigue

40-Year-Old Woman With Breathlessness and Fatigue

Approaches to treatment 2: Comparison of American Association of Clinical Endocrinologists (AACE) and American Diabetes Association (ADA) type 2 diabetes treatment guidelines

摘要 总的来说,2015年美国糖尿病协会(American Diabetes Association,ADA)1与美国临床内分泌学家协会(American Association of Clinical Endocrinologists,AACE)2推荐的2型糖尿病治疗指南都对当前控制糖尿病高血糖的方法与概念进行了深刻的分析。 ADA的方法是以选择血糖控制目标为起点,在控制血糖目标之前强调要控制HbA1c,建议通常的HbA1c目标应该设定为7%,虽然也指出了对于一名特定的患者来说更高或者更低水平的HbA1c目标也可能是合适的,这主要依赖于患者的医疗条件(疾病病程、预期寿命、合并疾病,特别是强调了血管并发症),并且还依赖于患者的态度、预期的努力程度以及可用的资源,这些因素都是可改变的,除此之外还有药物不良反应的风险,特别是低血糖。二甲双胍是推荐的首选初始用药,间隔3个月后可以增加到2种药物的联合使用,接着是3种药物的联合使用。另外还对6类治疗药物进行了陈述,其中胰岛素被认为具有“最高”效能;胰高血糖素样肽-1(GLP-1)受体激动剂(RA)、噻唑烷二酮类(TZD)以及磺脲类(SU)具有“高”效能;而二肽基肽酶(DPP)-4抑制剂与钠-葡萄糖共转运体(SGLT)-2抑制剂具有“中等”效能1。提到了将后面这两类药物引入推荐指南是“治疗方法的主要变化”1,但是没有推荐联合使用GLP-1 RAs进行治疗,这主要是因为缺乏临床试验证据。特别是明确提到了膀胱癌与吡格列酮并不相关,以及心脏衰竭在理论上与使用DPP-4抑制剂无关1;但假设根据一项新的来源于临床试验的证据这个结论将被修改3。在特定的治疗方案中,为了使治疗费用最小化需要将DPP-4抑制剂、SGLT2抑制剂、GLP-1 RAs以及胰岛素类似物排除在外;为了避免低血糖需要将SU与胰岛素排除在外;而为了避免体重增加还需将TZDs排除在外1。 如果HbA1c> 9%,推荐启用一种基础胰岛素进行治疗,剂量为10个单位或者0.1-0.2 U/kg体重,根据自我监测的空腹血糖每周调整剂量1到2次1。根据ADA临床实践标准定义的空腹血糖推荐目标为130 mg/dL(7.2 mmol/L),餐后峰值(假定为餐后1小时)血糖目标为180 mg/dL(10.0 mmol/L])4。对于使用基础胰岛素治疗后空腹血糖达标但是总体血糖控制却没有达标的患者来说,推荐的治疗方法有3种:(i)加用一种GLP-1 RA;(ii)在进食最多的餐前加用一针速效胰岛素;或者(iii)改成一种每日注射两次的预混胰岛素,而每餐前注射一次速效胰岛素是最终的选择1。 AACE推荐的(治疗策略)2纳入了所有已被批准的降糖药。4组药物的区别如下:(i)主要降低空腹血糖的药物(例如二甲双胍、TZDs与基础胰岛素);(ii)主要降低餐后血糖的药物(例如α-葡萄糖苷酶抑制剂[AGI]、胰淀素类似物普兰林肽、DPP-4抑制剂、格列奈类以及短效和/或速效胰岛素);(iii)具有两种作用的药物(例如GLP-1 RA、SU、SGLT2抑制剂以及混合性胰岛素制剂;(iv)适度有效的药物如胆汁酸螯合剂考来维仑以及一种多巴胺D2受体激动剂溴隐亭的快速吸收剂型(BCR)。AACE的治疗策略聚焦于安全性以及降糖获益:SU、格列奈类与胰岛素的低血糖问题;胰岛素、SU与TZDs的体重增加效应;以及GLP-1 RA与SGLT2抑制剂的体重减少效应2。中度肾功能受损导致二甲双胍的禁忌使用,而重度肾功能受损可导致艾塞那肽的禁忌使用。其他安全性问题包括使用SGLT2抑制剂治疗后的泌尿生殖道感染与血容量下降,以及使用GLP1 RAs治疗后的恶心、呕吐与腹泻。使用二甲双胍、AGI、考来维仑与BCR治疗后也可能出现胃肠道不良反应。心血管问题,特别是心脏衰竭,是引证过的TZDs不良效应;SU有可能会导致心血管不良效应(并且提到了SGLT2抑制剂可导致低密度脂蛋白胆固醇水平升高,虽然它的真实临床影响还尚未明确);而TZDs与SGLT2抑制剂还有潜在的导致骨量丢失的副作用2。 AACE在推荐治疗策略时有一个重要原则,就是要制定个体化的治疗计划,主要是根据基线HbA1c来确定。与ADA以及欧洲糖尿病研究协会(European Association for the Study of Diabetes,EASD)不同的是,AACE将药物选择按照以下方案进行了分级。如果HbA1c水平 7.5%并且 9.0%,推荐进行二联治疗或者三联治疗,除非患者出现了高血糖症状,对于这些病例来说需要使用胰岛素联用或不联用其他降糖药进行治疗2。 在AACE治疗方法中推荐的胰岛素使用策略是:HbA1c 8%的启始基础胰岛素剂量分别为0.1-0.2与0.2-0.3 U/kg。推荐每3日根据空腹血糖水平进行基础胰岛素剂量的滴定:>180 mg/dL(10.0 mmol/L)增加20%,140-180 mg/dL(7.8-10.0 mmol/L)增加10%,110-139 mg/dL(6.1-7.8 mmol/L)增加1个单位,而低血糖时如果血糖< 70 mg/dL(3.9 mmol/L)或< 40 mg/dL(2.2 mmol/L)则每日剂量分别要减少20%或40%。再次提到了SUs2,建议如果加用胰岛素治疗就要停用SUs或者减量,并且还认为使用基础胰岛素类似物治疗优于中效胰岛素(NPH)。如果加用基础胰岛素治疗后仍然不能达到血糖控制目标,有2种推荐的治疗方法:(i)加用非胰岛素类的治疗药物,建议加用GLP-1 RA或SGLT2抑制剂或DPP-4抑制剂;或者(ii)加用餐时胰岛素,开始时的每日胰岛素总剂量为0.3-0.5 U/kg/天,使用人胰岛素与预混胰岛素治疗是不太理想的治疗方法。如果餐后2小时的血糖水平超过180 mg/dL(10.0 mmol/L)就要对加用的治疗药物剂量进行滴定。 这些推荐的治疗方法都很复杂,并且ADA与AACE的方法具有许多相似性与差异性(表1)。两者都推荐了3个不同的HbA1c目标,通常来说AACE的方法都更为严格;两者都推荐改变生活方式与治疗药物一样重要;两者都强调了启动药物治疗后同时需要每3个月监测一次HbA1c目标,而这也是强化治疗所需。虽然两者都需要使用自我监测血糖(SMBG)水平来调整胰岛素剂量,但是AACE推荐的血糖治疗目标更低,并且AACE还推荐使用SMBG来判断一名特定患者的治疗方案是否最佳,包括空腹或者餐后血糖都要达标。虽然AACE与ADA/EASD都明确表明治疗必须以患者为中心并且要遵循个体化原则,但是ADA/EASD推荐的治疗方案一直都是使用二甲双胍作为初始治疗药物,然而AACE却是根据基线HbA1c水平进行分层治疗,允许一开始就是二联治疗或者三联治疗,更加强调要将那些不适合一开始就使用二甲双胍治疗的亚组患者识别出来(例如晚期肾病患者;在它的2015年更新部分中5,ADA/EASD提到了如果HbA1c超过9%,需要考虑一开始就使用二联治疗)。AACE推荐的治疗药物包括了所有经美国食品与药品管理局(FDA)批准的降糖药物并且将药物选择进行了排名,然而ADA/EASD指南仅仅罗列了主要的6类药物而没有推荐药物的排名顺序。AACE推荐指南明确聚焦于降低空腹与餐后血糖的差异,列出了更多种类的药物,并且对更多不同的潜在药物不良效应作出了评论;AACE与ADA的优化胰岛素使用方法在某种程度上有些差异。 最后,ADA与AACE的治疗方法代表的都是专家共识,因此具有其局限性,因为对于特定的患者来说其特征具有无数种可能性,缺乏来自随机对照试验的证据证实什么才是最佳的治疗方案。对于一名特定的患者来说,我们还缺乏患者水平的meta分析来帮助我们预测何种药物或者是哪一类药物最为安全或是最为有效,特别是在联合用药时。因此我们在治疗高血糖时应该谨慎用药,小心地根据HbA1c与SMBG来明确高血糖情况,逐步调整治疗药物的种类与剂量,并且还要聚焦于潜在的药物不良效应。有些治疗方法可能还具有额外获益(体重、血压以及血脂),因此对于一名特定的患者来说这些药物可能就会显得更加合适或者更加不合适。也许心血管结果数据将可以最终帮助我们提高药物分层选择的特异性6。ADA与AACE推荐的治疗方法都为我们提供了重要的见解。在未来的岁月里随着新型药物以及新研究结果的问世,我们期待会有进一步的变化。

Dipeptidyl Peptidase-4 Inhibitors in Diverse Patient Populations With Type 2 Diabetes.

The purpose of this review is to discuss the clinical evidence for dipeptidyl peptidase-4 (DPP-4) inhibitors and to better define their use in treating type 2 diabetes mellitus (T2DM), including in special populations, such as the elderly. DPP-4 inhibitors are incretin-based therapies that can be used as monotherapy or in combination with other antidiabetes medications to treat T2DM. As monotherapy, DPP-4 inhibitors have demonstrated a modest and comparable glycated hemoglobin-lowering effect. As initial dual therapy with other antidiabetes agents, DPP-4 inhibitors significantly improved glycated hemoglobin when compared with monotherapy arms. Similarly, in triple combinations, DPP-4 inhibitors consistently provided additive glycemic benefits. In patients who were continuing insulin, glycemic parameters were improved with the addition of a DPP-4 inhibitor, and they required less insulin uptitration. In clinical trials, the overall occurrence of adverse events was similar between DPP-4 inhibitor groups and controls, and a low occurrence of hypoglycemia was observed, except when used in combination with a sulfonylurea. A neutral effect on weight was maintained, even in combination with insulin. Similar to outcomes observed in younger patients, DPP-4 inhibitors significantly improved glycemic efficacy in older patients, without increasing the risk for hypoglycemia. Efficacy and safety in patients with renal insufficiency are also documented. DPP-4 inhibitors are therapeutically beneficial for a diverse population of patients with T2DM, including elderly patients, based on demonstrated efficacy, tolerability, and a low risk for hypoglycemia.

Benefit of initial dual-therapy on stroke prevention in Chinese hypertensive patients: a real world cohort study.

Studies have shown that combination anti-hypertensive therapy is superior to mono-therapy in blood pressure control and prevention of cardiovascular events. However, whether such advantage exists in the prevention of stroke in Chinese hypertensive patients remains unclear. This study aimed to compare the impact of initial combination versus mono-therapy on stroke events in a large cohort of Chinese hypertensive patients. Hypertensive patients with uncontrolled blood pressure and without a history of stroke were screened from the Shanghai Community-dwelling Hypertensive Population Follow-up Database. Based on the initial treatment, individuals were divided into an initial mono-therapy group and initial dual combination group. Patients were followed for 42 months. 32,682 and 4,926 patients were included in the initial mono- and dual-therapy group. The achieved target blood pressure control rates of mono vs. combination groups at 6, 12, 24, and 42 months of follow-up, were 59.47% vs. 60.05%, 78.23% vs. 77.06%, 85.51% vs. 84.02%, and 86.90% vs. 85.44%, respectively. Their corresponding incidence densities of stroke were 0.792 vs. 0.489, 1.49 vs. 1.15, 2.79 vs. 2.38, and 4.25 vs. 4.32 (cases per 100 person-year), respectively. The 6-month incidence of stroke in dual-therapy group was significantly lower than mono-therapy group (adjusted HR 0.64; 95% CI: 0.30-0.93). However, no significant group differences in the incidence density were observed at 12, 24, and 42 months. Our study demonstrates that, for patients with uncontrolled hypertension, initial dual therapy is more effective in the prevention of stroke during the first 6 months of treatment, but not thereafter. Combination antihypertensive therapy may be a beneficial initial strategy for early stroke prevention.

Assessment of AACE/ACE Recommendations for Initial Dual Antihyperglycemic Therapy Using the Fixed-Dose Combination of Sitagliptin and Metformin Versus Metformin

The American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) diabetes algorithm recommends a stratified approach to initial therapy to achieve a glycated hemoglobin (HbA1c) goal of ≤6.5% in patients with type 2 diabetes mellitus (T2DM) who have inadequate glycemic control. Data from a double-blind study in drug-naïve T2DM patients comparing initial monotherapy with metformin (MET) with initial dual therapy with a fixed-dose combination of sitagliptin and MET (SITA/MET FDC) was used to determine AACE/ACE HbA1c goal attainment in these treatment groups. A total of 1,250 patients (mean baseline HbA1c = 9.9%) were randomized 1:1 to SITA/MET FDC 50/500 mg twice daily (b.i.d.) or MET 500 mg b.i.d. for 18 weeks. SITA/MET FDC and MET were uptitrated over 4 weeks to 50/1,000 mg b.i.d. and 1,000 mg b.i.d., respectively. At week 18, a higher percentage of patients receiving SITA/MET FDC had HbA1c levels ≤6.5% and <7% than those receiving MET alone within each of the 3 AACE/ACE HbA1c categories (6.5-7.5%, >7.5-9.0%, and >9.0%). Of patients with a baseline HbA1c >7.5-9.0% who initiated SITA/MET FDC, 48.6% achieved an HbA1c ≤6.5% at week 18 compared with 23.1% of patients who initiated MET monotherapy (P<.001). In patients with a baseline HbA1c >9.0%, 24.0% on SITA/MET FDC achieved an HbA1c ≤6.5% compared with 12.8% on MET alone (P<.001). In T2DM patients with a baseline HbA1c >7.5-9.0%, substantially more achieved the HbA1c goal of ≤6.5% with initial dual therapy (SITA/MET FDC) than with initial monotherapy (MET), which is in agreement with the AACE/ACE diabetes algorithm.

Virologic Outcome of Using Tenofovir/Emtricitabine to Treat Hepatitis B in HIV-Coinfected Patients

Goal. To study the effect of combination antiviral therapy with tenofovir and emtricitabine or lamivudine with and without prior monotherapy with lamivudine. Study. We reviewed charts of 31 HIV-/HBV-coinfected patients. Twelve 3TC-naïve patients initially received tenofovir plus emtricitabine. Nineteen epivir experienced patients who had previously failed epivir were given tenofovir plus emtricitabine. Results. Baseline median HBV DNA was similar in the epivir-naïve (5.8×107 copies/mL) and experienced group (7.3×107 copies/mL, P = .65). The median time to complete suppression of HBV was 466 days in the naïve group and 877 days in the experienced (P = .001). After 12 months, 6/10 (60%) naïve patients and 3/14 (21%) experienced patients had HBV DNA below the detectionlimit (P = .067). After 24 months, 5/5 (100%) naïve patients and 4/13 (31%) experienced patients had an undetectable HBV DNA level (P = .015). Conclusions. The median time to suppression of HBV DNA was significantly shorter among treatment naïve patients. There was a significantly greater proportion of naïve patients with suppressed HBV DNA at 24 months. Our results support using initial dual therapy in those with HIV/HBV coinfection.