比特派钱包app下载安装|dpp
作者： 比特派钱包app下载安装
2024-03-07 18:20:36
下载与支持 – 服务与支持 - 佳能（中国）
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Digital Photo Professional 4.12.60 for Windows
最近更新 ： 31-Jul-2020
发行编号 ： 0200618605
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操作系统
Windows 10 (x64)
Windows 8.1 (x64)
要点
Digital Photo Professional 4 是一款真正佳能研发的应用程序，用于浏览,选择和开发 RAW 图像。 它在 图片样式 格式方面配备了多种图像调整功能，使得用户可以自由地进行快速图像调整。
更新历史记录
Digital Photo Professional 4.12.60 for Windows的变更 : - 支持EOS R5, EOS R6。 - 支持之前机型的深度合成功能。 - 支持剪辑和保存RAW影片的任意范围。 - 支持显示和保存RAW图像:“速度优先模式”(适用图像: EOS-1D X Mark III、EOS R5、和EOS R6图像)。
系统要求
欲使用此软件，您的计算机必须满足以下系统要求。 1.支持的操作系统 Windows 10 64位, Windows 8.1 64位 2.支持的计算机 预装了上述系统之一的个人计算机(不支持升级过的机器) CPU: - 使用EOS-1D X Mark III, EOS R5, EOS R6拍摄的图像: 英特尔 酷睿-i 系列 (推荐使用英特尔 酷睿-i7 或更高) - 使用EOS-1D X Mark III, EOS R5, EOS R6以外的相机拍摄的图像: 英特尔 酷睿 2 双核 2.0 GHz 或更高 (推荐使用英特尔 酷睿-i 系列或更高) 内存: - 使用EOS-1D X Mark III, EOS R5, EOS R6拍摄的图像: 4GB或更大 (推荐使用8GB或更大) - 使用EOS-1D X Mark III, EOS R5, EOS R6以外的相机拍摄的图像: 2GB或更大 (推荐使用4GB或更大) 硬盘驱动器; - 安装: 最少300 MB 可用空间 - 操作: 最少600 MB 可用空间 推荐播放短片的环境; - 8K (29.97/25/24/23.976fps) MP4: 英特尔 至强 E5-2687W v3 3.10GHz x2 或更快，内存16GB或更大 - 4K/ Full HD (60/50/29.97/25/24/23.976fps) MOV/MP4(Canon Log录制/HDR PQ录制): 英特尔 至强 E5-2687W v3 3.10GHz x2 或更快，内存8GB或更大 - 4K (60/50/29.97/25/24/23.976fps) MP4: 第八代智能 英特尔 酷睿-i7 8700 或更快，内存4GB或更大 - 4K (29.97/25/24/23.976fps) MOV/MP4: 第六代智能 英特尔 酷睿-i7 4.0GHz 4Core 或更快，内存4GB或更大 - 全高清 (59.94/50/30/29.97/25/24/23.976/20fps) MOV/MP4: 第四代智能 英特尔 酷睿-i7 3.0GHz 4Core 或更快，内存4GB或更大 注意:要以 8K / 4K 分辨率显示和播放短片，推荐使用由 AMD 或 NVIDIA 生产的 GPU。 即使满足了系统要求，也可能无法顺利播放。 3.显示器 - 分辨率: 1,024 x 720 或以上(推荐使用1,600 x 1,200 或以上) 4. 支持机型 EOS R5, EOS R6, EOS Kiss X10i / EOS REBEL T8i / EOS 850D, EOS-1D X Mark III, EOS M200, EOS 90D, EOS M6 Mark II, PowerShot G5 X Mark II, PowerShot G7 X Mark III, EOS Kiss X10 / EOS REBEL SL3 / EOS 250D / EOS 200D II, EOS RP, EOS R, PowerShot SX70 HS, EOS D2000 *, EOS D6000 *, EOS D30, EOS D60, EOS 10D, EOS Kiss Digital / EOS Digital REBEL / EOS 300D Digital, EOS Kiss M / EOS M50, EOS REBEL T100 / EOS 4000D / EOS 3000D, EOS Kiss X90 / EOS REBEL T7 / EOS 2000D / EOS 1500D, EOS-1Ds Mark III, EOS-1Ds Mark II, EOS-1Ds, EOS-1D X Mark II, EOS-1D X, EOS-1D Mark IV, EOS-1D Mark III, EOS-1D Mark II N, EOS-1D Mark II, EOS-1D C, EOS-1D, EOS 80D, EOS 7D Mark II, EOS 7D, EOS 70D, EOS 6D Mark II, EOS 6D, EOS 60Da, EOS 60D, EOS 5DS R, EOS 5DS, EOS 5D Mark IV, EOS 5D Mark III, EOS 5D Mark II, EOS 5D, EOS 50D, EOS 40D, EOS 30D, EOS 20Da, EOS 20D, EOS 9000D / EOS 77D, EOS 8000D / EOS REBEL T6s / EOS 760D, EOS Kiss X9i / EOS REBEL T7i / EOS 800D, EOS Kiss X9 / EOS REBEL SL2 / EOS 200D, EOS Kiss X8i / EOS REBEL T6i / EOS 750D, EOS Kiss X80 / EOS REBEL T6 / EOS 1300D, EOS Kiss X7i / EOS REBEL T5i / EOS 700D, EOS Kiss X70 / EOS REBEL T5 / EOS 1200D / EOS Hi, EOS Kiss X7 / EOS REBEL SL1 / EOS 100D, EOS Kiss X6i / EOS REBEL T4i / EOS 650D, EOS Kiss X50 / EOS REBEL T3 / EOS 1100D, EOS Kiss X5 / EOS REBEL T3i / EOS 600D, EOS Kiss X4 / EOS REBEL T2i / EOS 550D, EOS Kiss X3 / EOS REBEL T1i / EOS 500D, EOS Kiss X2 / EOS REBEL XSi / EOS 450D, EOS Kiss F / EOS REBEL XS / EOS 1000D, EOS Kiss Digital X / EOS Digital REBEL XTi / EOS 400D Digital, EOS Kiss Digital N / EOS Digital REBEL XT / EOS 350D Digital, EOS M100, EOS M10, EOS M6, EOS M5, EOS M3, EOS M2, EOS M, PowerShot G16, PowerShot G15, PowerShot G12, PowerShot G11, PowerShot G10, PowerShot G9 X Mark II, PowerShot G9 X, PowerShot G9, PowerShot G7 X Mark II, PowerShot G7 X, PowerShot G5 X, PowerShot G3 X, PowerShot G1 X Mark III, PowerShot G1 X Mark II, PowerShot G1 X, PowerShot SX60 HS, PowerShot SX50 HS, PowerShot SX1 IS, PowerShot S120, PowerShot S110, PowerShot S100V, PowerShot S100, PowerShot S95, PowerShot S90 * :现在可以处理用CR2 Converter转换过来的CR2文件。
注意
- 将视频导入电脑时务必使用佳能应用程序。 - Digital Photo Professional 4系列无法与Digital Photo Professional 1至3互换配方使用。 - Digital Photo Professional 4系列和Digital Photo Professional 3.15可安装在同一台计算机。 - 通过使用图形处理器(GPU)来处理在进行预览的图像，从而改进了显示速度。 要进行转换和保存以及打印，则使用传统的CPU处理方式。 要使用此功能，需要一个拥有1.0GB或以上的内置视频内存，并且支持NVIDIA出品的CUDA (计算能力2.0或更高版本)的GPU。 还必须安装NVIDIA出品的最新驱动程序。 - 以HDR PQ进行图像显示的推荐系统要求如下所示。 支持的型号: EOS-1D X Mark III, EOS R5, EOS R6, EOS R, EOS 5D Mark IV CPU: 英特尔 酷睿-i 系列 3.4GHz或更高 内存: 4GB或更大 (推荐使用8GB或更大) - 以下为在HDR显示屏上启用HDR图像显示的系统要求。 操作系统:必须在Windows 10操作系统显示设置中，将HDR显示设置为 [ON]。 请在使用前安装最新的显卡驱动程序。 - 请使用Digital Photo Professional 4.10.40或更高版本以正确显示使用RF24-240mm F4-6.3 IS USM拍摄的图像。 - 请使用Digital Photo Professional 4.12.60或更高版本以正确显示使用所安装的XTENDER RF1.4x, 2x拍摄的图像。 -为了使用 "RAW短片工具"，需要以下环境。 [推荐的] CPU：Intel Xeon E5-2687W v3 3.1GHz x2或更快 GPU：NVIDIA GeForce RTX 2080 内存：32GB或更多 存储：读取速度为400MB / s或更快 [最低] CPU：Intel Core-i系列或更高 GPU：由NVIDIA制造（EOS-1D X Mark III: VRAM 4GB或更高, EOS R5: VRAM 4GB或更高） 必须安装NVIDIA生产的最新驱动程序。
安装说明
请参阅以下关于如何下载并安装软件的说明。 安装此软件时，请先退出其他所有应用程序。 1. 在下载页面输入印在标签上的相机机身序列号，并下载"dppw4.12.60-installer.zip"。将 "dppw4.12.60-installer.zip" 文件保存到计算机上您选定的文件夹中。 2. 当保存在计算机的 "dppw4.12.60-installer.zip" 文件夹被解压，就会出现 "dppw4.12.60-installer"，双击解压缩文件夹中的 "dppw4.12.60-installer.exe"，将启动Digital Photo Professional的安装程序。 (如果出现用户帐户控制窗口，请按照屏幕上的说明操作。) 3. 按照屏幕上的说明完成安装。 4. 安装完成之后，Digital Photo Professional 安装程序可能会要求重新启动计算机。在这种情况下，请重新启动计算机。如果安装正确完成，则不需要下载的文件和 "dppw4.12.60-installer" 文件。
文件信息
文件名: dppw4.12.60-installer.zip
文件版本: 4.12.60
文件类型 : zip
文件语言 : 德文, 英文, 西班牙文, 法文, 意大利文, 日文, 韩文, 俄文, 土耳其文, 简体中文
文件大小 : 297,322KB
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Diabetes Prevention Program (DPP) - NIDDK
Diabetes Prevention Program (DPP) - NIDDK
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Diabetes Prevention Program (DPP)
The NIDDK-sponsored Diabetes Prevention Program (DPP) and ongoing DPP Outcomes Study (DPPOS) are major studies that changed the way people approach type 2 diabetes prevention worldwide. The DPP showed that people who are at high risk for type 2 diabetes can prevent or delay the disease by losing a modest amount of weight through lifestyle changes (dietary changes and increased physical activity). Taking metformin, a safe and effective generic medicine to treat diabetes, was also found to prevent the disease, though to a lesser degree.
The DPPOS has continued to follow most DPP participants since 2002. To date, the DPPOS has shown that participants who took part in the DPP Lifestyle Change Program or are taking metformin continue to prevent or delay type 2 diabetes for at least 15 years. The DPPOS has also shown that the DPP Lifestyle Change Program is cost effective (costs are justified by the benefits of diabetes prevention, improved health, and fewer health care costs) and metformin is cost-saving (leads to a small savings in health care costs) after 10-years. DPPOS researchers are also continuing to follow other health problems in participants such as cancer, cardiovascular diseases (heart and blood vessel disease), nerve damage, kidney disease, and eye disease. As participants age, researchers are following age-related health problems such as trouble with physical function and difficulties with thinking or memory.
The NIDDK built on the success of the DPP by funding additional research to make modified versions of the DPP Lifestyle Change Program that are more cost-effective and more easily available to the tens of millions of Americans at risk for type 2 diabetes. Several modified group versions of the DPP Lifestyle Change Program have shown great promise. One version tested in YMCAs is now widely available in the United States through a partnership with the CDC’s National Diabetes Prevention Program. Beginning in 2018, Medicare will cover participation in the CDC’s National Diabetes Prevention Program for those who are eligible.
Diabetes Prevention Program (DPP)
DPP Goal
The DPP looked at whether the DPP Lifestyle Change Program or taking metformin would delay or prevent type 2 diabetes.
DPP Results
After about 3 years, the DPP showed that participants in the DPP Lifestyle Change Program lowered their chances of developing type 2 diabetes by 58 percent compared with participants who took a placebo (a pill without medicine). The DPP Lifestyle Change Program was effective for all participating racial and ethnic groups and both men and women. The Program worked particularly well for participants ages 60 and older, lowering their chances of developing type 2 diabetes by 71 percent. About 5 percent of participants in the DPP Lifestyle Change Program developed diabetes each year during the study compared with 11 percent of participants who took a placebo.
Participants who took metformin lowered their chances of developing type 2 diabetes by 31 percent compared with participants who took a placebo. Metformin was effective for all participating racial and ethnic groups and both men and women. Metformin was most effective in women with a history of gestational diabetes, in people between the ages of 25 and 44, and in people with obesity who had a body mass index of 35 or higher.
DPP Study Design
The DPP was a randomized, controlled clinical trial conducted at 27 clinical centers around the United States from 1996 to 2001. The trial enrolled 3,234 participants; 55 percent were Caucasian, and 45 percent were from minority groups at high risk for the disease, including African American, Alaska Native, American Indian, Asian American, Hispanic/Latino, or Pacific Islander. The trial also recruited other groups at high risk for type 2 diabetes, including people ages 60 and older, women with a history of gestational diabetes, and people with a parent, brother, sister, or child who had type 2 diabetes.
DPP participants were randomly assigned to one of the following groups:
Lifestyle Change Group – Group participants joined a DPP Lifestyle Change Program that provided intensive training. Participants tried to lose 7 percent of their body weight and maintain that weight loss by eating less fat and fewer calories and exercising 150 minutes per week. Researchers met with participants individually at least 16 times in the first 24 weeks, and then every 2 months with at least 1 phone call between visits.
Metformin Group – Group participants took 850 mg of metformin twice a day and were provided standard advice about diet and physical activity.
Placebo Group – Group participants took a placebo twice a day instead of metformin and were provided standard advice about diet and physical activity.
DPP participants who developed diabetes remained in the study and received additional care from their own physicians if good blood glucose control could not be maintained.
After DPP ended all participants were provided a modified group version of the DPP’s Lifestyle Change program.
Diabetes Prevention Program Outcomes Study (DPPOS)
DPPOS Goal
The DPPOS is following DPP participants to see if participants who took part in the DPP Lifestyle Change Program or who are continuing to take metformin have a delay in the development of type 2 diabetes over time and if they experience fewer health problems such as cancer, cardiovascular diseases, nerve damage, kidney disease, eye disease, and age-related health problems such as trouble with physical function and difficulties with thinking or memory.
DPPOS Results
10-Year Findings
At the 10-year follow-up
participants who took part in the DPP Lifestyle Change Program continued to have a delay in the development of diabetes by 34 percent—and developed diabetes about 4 years later—compared with participants who took a placebo. Participants from the DPP Lifestyle Change Program ages 60 and older had a delay in the development of diabetes by 49 percent.
participants who continued to take metformin had a delay in the development of diabetes by 18 percent—and developed diabetes about 2 years later—compared with participants who took a placebo.
participants from the DPP Lifestyle Change Program and participants who continued to take metformin or took a placebo all improved their risk factors for cardiovascular diseases, such as high blood pressure and cholesterol. However, the participants from the DPP Lifestyle Change Program achieved these results with fewer blood pressure and cholesterol-lowering medications.
the DPP Lifestyle Change Program was shown to be cost-effective and metformin was shown to be cost-saving.
15-Year Findings
At the 15-year follow-up
participants from the DPP Lifestyle Change Program continued to have a delay in the development of diabetes by 27 percent compared with participants who took a placebo.
participants who continued to take metformin had a delay in the development of diabetes by 18 percent compared with participants who took a placebo.
about half (55 percent) of participants from the DPP Lifestyle Change Program and 56 percent of participants who continued to take metformin developed diabetes compared with 62 percent of participants who took a placebo.
there were no overall differences in small blood vessel problems such as those found in eyes, nerves, and kidneys between participants from the DPP Lifestyle Change Program and participants who continued to take metformin or took a placebo. However, women from the DPP Lifestyle Change Program developed fewer small blood vessel problems than participants who continued to take metformin or took a placebo. Participants who did not develop diabetes had a 28 percent lower rate of small blood vessel problems compared with participants who developed diabetes.
Current Focus
In early 2016 the NIDDK, in partnership with the National Heart Lung and Blood Institute (NHLBI) and National Cancer Institute (NCI), began funding a third phase of DPPOS—proposed to last 10 years—to find out if people who are at high risk for type 2 diabetes and take metformin have lower rates of cardiovascular diseases and cancer, as suggested by several earlier small-scale studies.
DPPOS Study Design
The DPPOS follow-up study started in 2002. All 3,149 surviving participants of DPP groups were eligible for the DPPOS, including those with and without diabetes. Of the 3,149 surviving participants, 2,776 (88 percent) joined the DPPOS. Similar proportions of each DPP group joined the DPPOS and remained in their original groups. There were some changes to the treatments each group received:
Lifestyle Change Group –Group participants received quarterly group lifestyle change classes throughout the study and two group classes yearly to reinforce self-management behaviors for weight loss.
Metformin Group – Group participants received quarterly group lifestyle change classes throughout the study. Participants continued to take metformin and were told that they were taking metformin.
Placebo Group – Group participants received quarterly group lifestyle change classes throughout the study. Participants did not take a placebo pill.
DPPOS participants who developed diabetes remained in the study and received additional care from their own physicians if good blood glucose control could not be maintained.
Related Health Information
CDC’s National Diabetes Prevention Program – The CDC’s National Diabetes Prevention Program uses key components of the DPP—lifestyle changes such as physical activity and weight loss—to prevent or delay the start of type 2 diabetes.
Health Information on Diabetes – The NIDDK offers information on many diabetes-related topics.
Related Studies
Scalable modified versions of the DPP Lifestyle Change Program– Researchers are making modified group versions of the DPP Lifestyle Change Program—such as the YMCA’s Diabetes Prevention Program—that are more cost-effective and more easily available to Americans at risk for type 2 diabetes.
Action for Health in Diabetes (Look AHEAD) Study – Look AHEAD used an intensive lifestyle change program modeled on the DPP Lifestyle Change Program to study how diet and physical activity affect heart attack, stroke, and cardiovascular disease-related death in people who already had type 2 diabetes.
Vitamin D and Type 2 Diabetes (D2d) – This ongoing study is examining whether vitamin D supplements can reduce or delay development of type 2 diabetes in people at high risk for the disease.
Studies on lifestyle change – Researchers are looking at cost-effective ways to teach people about lifestyle change and weight loss, such as in group settings and over the internet.
Ancillary studies of DPP and DPPOS data – Researchers continue to study DPP and DPPOS data. One study found that DPP participants carrying two copies of a gene mutation were at a higher risk of developing diabetes but benefited from lifestyle changes as much as, or more than, those without the gene mutation. Another study found that weight loss was the main way to predict whether a participant in the DPP Lifestyle Change Program would have a lower risk of developing diabetes. Researchers said that risk-reduction efforts should focus on weight loss, which is helped by increased physical activity.
News Releases and Reports
Diabetes Prevention Program Outcomes Study launches new phase to study CVD, cancer outcomes
Diabetes Prevention Program Outcomes Study commemorates 20 years of landmark research
NIH study finds interventions to prevent type 2 diabetes provide good return on investment
Scientific Publications and Resources
DPPOS website
DPP on ClinicalTrials.gov
DPPOS on ClinicalTrials.gov
DPP documents and materials from the NIDDK Central Repository
DPPOS documents and materials from the NIDDK Central Repository
DPP grant award information from dkNET
DPPOS grant award information from dkNET
Type 2 Diabetes Knowledge Portal
Diabetes Prevention Program (DPP) Research Group. The Diabetes Prevention Program (DPP): description of lifestyle intervention. Diabetes Care 2002;25(12):2165‒2171.
Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. The New England Journal of Medicine. 2002;346(6):393–403.
Diabetes Prevention Program Research Group, Knowler WC, Fowler SE, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374(9702):1677–1686.
Diabetes Prevention Program Research Group. The 10-year cost-effectiveness of lifestyle intervention or metformin for diabetes prevention: an intent-to-treat analysis of the DPP/DPPOS. Diabetes Care 2012; 35(4):723–730.
Diabetes Prevention Program Research Group, Orchard TJ, Temprosa M, et al. Long-term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: a report from the DPP Outcomes Study. Diabetic Medicine. 2013;30(1):46–55.
Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. The Lancet Diabetes & Endocrinology 2015;3(11):866–875.
Last Reviewed May 2023
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李焱教授：“西”力不凡，笃行不怠——再话DPP-4i在血糖管理中的应用价值与要点_腾讯新闻
李焱教授：“西”力不凡，笃行不怠——再话DPP-4i在血糖管理中的应用价值与要点_腾讯新闻
李焱教授：“西”力不凡，笃行不怠——再话DPP-4i在血糖管理中的应用价值与要点
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国家药监局临床指导意见及药品评审专家
近年来尽管糖尿病治疗领域的药物不断推陈出新， DPP-4i仍是重要的降糖方案之一，您如何看待DPP-4i在T2DM患者中的应用价值？
李焱教授：DPP-4i是一种比较新的降糖药，主要通过抑制DPP-4而减少GLP-1在体内的失活，使内源性GLP-1水平升高，进而通过多种机制影响血糖控制（促进胰岛素分泌，抑制胰高血糖素分泌，抑制食欲中枢、减慢胃排空等）1。自问世以来，DPP-4i凭借着确切的降糖疗效和良好的安全性，在降糖药领域一直占据重要地位。研究发现，DPP-4i单药治疗使糖化血红蛋白（HbA1c）下降0.5%～1%，与二甲双胍、α糖苷酶抑制剂、磺脲类、噻唑烷二酮类或SGLT2i联合可进一步改善血糖控制1。DPP-4i总体安全性良好，临床中不良反应较为少见，具有低血糖风险小、不增加体重、无明显胃肠道反应、心血管安全性整体表现良好等优势2。
基于上述优势，DPP-4i在国内外权威指南中逐步得到充分认可。《中国2型糖尿病防治指南（2020年版）》已将DPP-4i列为与二甲双胍联合使用的主要药物之一3。《中国老年糖尿病诊疗指南（2021年版）》推荐DPP-4i为老年糖尿病患者一线治疗方案之一4。2023版AACE共识中，对于超重/肥胖或有低血糖风险患者，两药联合治疗方案中二甲双胍联合DPP-4i治疗推荐程度高于联合磺脲类药物或α-糖苷酶抑制剂5。
对于目前国内已上市的DPP-4i，您如何评价它们在降糖疗效和安全性方面的表现？
李焱教授：目前，临床常用的DPP-4i有5种，分别为西格列汀、维格列汀、沙格列汀、利格列汀和阿格列汀。其中西格列汀是国内最早上市（2009年）的DPP-4i，积累了大量的临床应用经验和循证证据，并且已经纳入国家医保和基药目录。
降糖疗效：DPP-4i之间尚缺乏直接的头对头比较试验。一项纳入83项RCT的荟萃分析显示，相较于安慰剂，DPP-4i单药治疗显著降低HbA1c，五种DPP-4i的降糖疗效无显著差异6。
图1：五种DPP-4i的降糖疗效
安全性：DPP-4i整体安全性良好。需要注意的是，DPP-4i对心衰（HF）的影响略有差异。有研究发现基线无HF史的患者使用沙格列汀及阿格列汀增加HF住院风险；因此，对于合并HF的T2DM患者，不建议使用沙格列汀及阿格列汀；对于有HF危险因素的患者，使用沙格列汀或阿格列汀时，如出现HF症状应立即停用7。药物相互作用也是需要特别关注的安全性指标。DPP-4抑制剂并非CYP酶诱导剂或抑制剂，与他汀类等多种常用药物同时服用时，通常不会发生药物相互作用，但DPP-4i会不同程度地被CYP酶代谢，可能会与其他药物相互竞争代谢酶，使药物浓度产生波动2。研究显示，西格列汀不会对CYP同工酶CYP3A4、2C8或2C9产生抑制作用，也不会抑制CYP2D6、1A2、2C19或2B6，不会诱导CYP3A4109；提示西格列汀极少发生药物相互作用。CYP3A4或P-gp的诱导剂（例如利福平）会使利格列汀的暴露水平降低到亚治疗水平，很可能会降至无效的浓度。对于需要使用这类药物的患者，强烈建议替换利格列汀10。
对于肾功能不全的T2DM患者，使用DPP-4i时需要注意哪些问题？
李焱教授：T2DM患者在DPP-4i治疗前和治疗期间通常都需要评估肾功能，以便及时调整药物剂量。需要强调的是，DPP-4i本身对肾功能没有影响，调整DPP-4i剂量是由于大部分DPP-4i会经肾脏排泄，对于肾功能不全的T2DM患者，肾功能降低会导致药物的清除率减弱，进而增加药物血浆AUC，为了达到与正常肾功能患者相似的血浆浓度，患者通常需要依据说明书调整药物剂量。以西格列汀为例，西格列汀说明书建议其在eGFR
值得一提的是，国内二甲双胍说明书建议eGFR
即在可以使用二甲双胍的肾功能不全患者中（eGFR≥45 ml·min-1/1.73m2），加用西格列汀时无需调整剂量，十分方便；而在二甲双胍禁用的肾功能不全患者中，西格列汀仍然可以使用，只需调整剂量即可（表1）。
表1：西格列汀和二甲双胍在肾功能不全患者中的使用情况
据您所知，DPP-4i除了降糖以外，还具有哪些额外获益？
李焱教授：近年来越来越多的研究提示，DPP-4i降糖之外还具有额外获益，如改善β细胞功能、减轻炎症反应、促进伤口愈合、改善非酒精性脂肪肝（NAFLD）、改善认知功能障碍、减少骨折风险等13-23。以改善NAFLD和减少骨折风险为例。T2DM和NAFLD存在共同的发病机制16。研究发现，西格列汀可显著降低新诊断T2DM合并NAFLD患者的空腹血糖水平，并改善NAFLD的肝功能指标（AST、ALT和GGT水平均降低）17。国内一项Meta分析探讨了肠促胰素与骨折的关系。结果显示，100 mg西格列汀(OR 0.495，95%CI 0.304～0.806)可以减少骨折发生风险23。此外，研究发现DPP-4i可降低糖尿病合并SARS-CoV-2患者发展为重症肺炎的几率23。DPP-4i的潜在作用尚需大规模的循证医学证据来加以证实。期待未来，DPP-4i的潜在作用及相关机制能得到进一步探索。
参考文献：
1.卡西夫·穆尼尔，等.DPP-4抑制剂类药物在2型糖尿病管理中的应用比较与选择[J].药品评价，2018，15(13):8-10.
2.陈丽.DPP-4抑制剂的差异与选择策略——对《DPP-4抑制剂类药物在2型糖尿病管理中的应用比较与选择》的点评[J].药品评价，2018，15(13):11-12.
3.中华糖尿病杂志.2021.13(4):315-409.
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7.余学锋，等.基层医疗机构二肽基肽酶4抑制剂临床应用常见问题专家指导建议[J].中国糖尿病杂志，2022，30(02):81-85.
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10.利格列汀片说明书（2023年7月检索结果）
11.Bergman aj， et al. clin ther. 2006;28(1)55-72.
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14.厉艳萍，等.DPP-4抑制剂辅助治疗2型糖尿病（T2DM）患者的效果及对其氧化应激及炎症反应的影响[J].实用糖尿病杂志，2021，17(01):67.
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4个月4款申报上市！“Follow”的DPP-4抑制剂将迎爆发
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全球范围内上市了多款DPP-4抑制剂，进入国内市场的有DPP-4抑制剂有利格列汀、曲格列汀、提格列汀、沙格列汀、维格列汀、西格列汀等。除了曲格列汀，其余DPP-4抑制剂均被纳入国家医保目录。
2023年4月26日，石药集团开发的1类新药普卢格列汀片（DBPR108片）递交的上市申请获得国家药品监督管理局正式受理，用于治疗2型糖尿病。关于普卢格列汀片普卢格列汀片是一种新型口服二肽基肽酶-IV(DPP-4)抑制剂，对DPP-4具有高选择性和强抑制性。通过抑制DPP-4，使内源性活性胰高血糖素样肽-1(GLP-1)水平升高从而增强β细胞和α细胞对葡萄糖的敏感性，增加葡萄糖刺激的胰岛素分泌并增强葡萄糖对胰高血糖素分泌的抑制作用，进而降低血糖水平且不诱发低血糖和增加体重。关键性3期临床研究此次申报是基于在中国开展的两项关键3期研究，即普卢格列汀片单药3期试验（CTR20191987）、普卢格列汀片联合二甲双胍3期试验（CTR20192506），这两项研究共纳入约1000例2型糖尿病受试者。2022年8月，石药集团公布了该研究的主要结果，这两项3期试验结果均达到预设终点。结果显示：单药试验 结果 显示，治疗24周后，普卢格列汀片治疗组HbA1c水平变化显著优于安慰剂组，同时非劣于阳性药磷酸西格列汀片组。 与二甲双胍的联合试验 结果显示，治疗第24周后，普卢格列汀片治疗组HbA1c水平变化显著优于安慰剂组。 此外，普卢格列汀片组的安全性数据显示安全性与西格列汀组和安慰剂组相似。 来源：CDE官网 中国糖尿病市场持续扩容2型糖尿病是一种慢性代谢疾病，近些年糖尿病患病率持续上升，已经成为全球重大公共卫生问题之一。根据国际糖尿病联盟（IDF）统计，2021年中国成人糖尿病患者有1.41亿人，患病率高达11.6%，其中90%以上为2型糖尿病。根据公开数据，2021年中国糖尿病药物市场规模为454亿元人民币，同比增长12.8%，2016年至2021年复合增长率为8.6%，预计2021年至2026年复合增长率为11%。 2021年中国医院终端糖尿病销售额为343亿元人民币，占比75.5%，同比增长8.2%，2016年至2021年复合增长率为8.3%。 中国糖尿病药物市场规模（2016年至2021年）国内DPP-4抑制剂研究情况DPP-4抑制剂是治疗糖尿病主要药物之一，它通过抑制体内胰高血糖素样肽-1(GLP-1)分解代谢而发挥作用。DPP-4抑制剂能提高内源性GLP-1和GIP的水平，促进胰岛β细胞释放胰岛素，抑制胰岛α细胞分泌胰高血糖素，从而提高胰岛素水平，降低血糖，且不易诱发低血糖和增加体重。DPP-4抑制剂是一种新型的糖尿病口服药物，具有很多优点，如：一天服用一次，餐前餐后均可服用；不增加低血糖风险，胃肠道副作用少；不增加心血管事件的发生率，安全性及耐受性高等诸多优势。因此，DPP-4抑制剂是各大药企眼中的香饽饽，国内市场火热。 根据公开数据，国内DPP-4抑制剂市场规模持续增长，中国DPP-4靶点药物的年销售额呈持续增长趋势，同比增长率在2018年为最高。2021年，DPP-4抑制剂销售额近30亿。 迄今为止，全球范围内上市了多款DPP-4抑制剂，进入国内市场的有DPP-4抑制剂有利格列汀、曲格列汀、提格列汀、沙格列汀、维格列汀、西格列汀等。除了曲格列汀，其余DPP-4抑制剂均被纳入国家医保目录。 国内获批DPP-4抑制剂 凯莱英药闻整理，截止2023年4月 全球范围内临床在研的DPP-4抑制剂约有28款，第一梯队临床3期的有4款，临床2期的有15款，临床1期的有9款。 目前国内约有12款临床在研的DPP-4药物，涉及的企业有海思科、轩竹生物、苑东生物等。申报上市的产品多达5款，虽然还没有上市的国产DPP-4抑制剂创新药，但该类药物研发竞争格局已十分激烈。 2023年2月，信立泰的1类新药苯甲酸复格列汀片（信复清）申报上市申请获得国家药监局受理。苯甲酸复格列汀片为DPP-4抑制剂，具有口服吸收迅速，半衰期长，作用持久等特点，目标适应症为2型糖尿病。 恒瑞医药布局了瑞格列汀二甲双胍片，已于今年1月13日提交上市申请。 2023年1月，海思科的DPP-4 超长效抑制剂
HSK7653片的上市申请获得CDE受理，用于治疗2型糖尿病。该药最大的特色是双周降糖药，有望成为全球首个DPP-4双周制剂。 苑东生物自主研发的1类小分子优格列汀正在开展3期研究，是一款周制剂。目前国内尚无DPP-4周制剂口服降糖药上市。 由华东理工大学研究团队研发的马来酸博格列汀同样为DPP-4周制剂，该研发项目已与山东百极地长制药达成合作协议，目前处于临床1/2期阶段。 正大天晴布局了2款DPP-4抑制剂1类新药，分别为TQ-F3083胶囊、TQ05510胶囊，足见公司对该类药物的重视。 国内在研DPP-4抑制剂 凯莱英药闻整理，截止2023年4月GLP-1受体激动剂与DPP-4抑制剂的对比GLP-1受体激动剂作为近几年非常火热的降糖药，占据了很大的市场空间。那么，DPP-4抑制剂与之相比，有哪些优势呢？梳理二者的相关信息，我们发现，GLP-1受体激动剂与DPP-4抑制剂有相同的作用机制，即增强胰岛素分泌，一直胰高血糖素分泌；不良反应的表现上也相似，均是胃肠道反应；低血糖风险上也基本一致。 不同点具体表现在以下几个方面。 给药途径 ： GLP-1受体激动剂目前主要是皮下注射，DPP-4抑制剂是口服给药。 作用方式 ：GLP-1受体激动剂可以抵抗DPP-4降解，半衰期更长；而DPP-4抑制剂有效GLP-1的失活，使内源性GLP-1在体内蓄积，在生理范围内增加有活性的GLP-1水平。 心血管作用 ：GLP-1受体激动剂具有心血管获益；DPP-4抑制剂不增加心血管病变风险。 对体重的影响 ：GLP-1受体激动剂能延缓胃排空，降低食欲，显著降低体重；DPP-4抑制剂在胃排空、抑制食欲等方面的作用较弱。
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关键词:
抑制剂,糖尿病,激动剂,低血糖,胰岛素,心血管
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北大姜长涛/乔杰/雷晓光团队《Science》揭示DPP4作为抗糖尿病新靶点
北大姜长涛/乔杰/雷晓光团队《Science》揭示DPP4作为抗糖尿病新靶点
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北大姜长涛/乔杰/雷晓光团队《Science》揭示DPP4作为抗糖尿病新靶点
日期：2023年08月24日
来源：北京大学
作者：
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2023年8月4日，北京大学医学部基础医学院教授、第三医院特聘教授姜长涛团队，北京大学第三医院乔杰院士团队，北京大学化学与分子工程学院雷晓光教授团队与合作者，在Science上共同发表了题为《肠道菌源宿主同工酶分析揭示菌源DPP4作为抗糖尿病新靶点》（“Microbial-host-isozyme analyses reveal microbial DPP4 as a potential antidiabetic target”）的重要研究成果，揭示了肠道菌群如何影响西格列汀临床响应性、肠道菌源宿主同工酶跨物种调控代谢性疾病的新机制，为解开西格列汀临床响应性之谜提供了答案。
论文发表截图
肠道微生物作为连接人体内外环境的桥梁，已被证实在多种人类代谢性疾病中发挥了关键的角色。尽管当前的肠道微生物研究主要关注其产生的小分子代谢物对机体的影响，但对其他功能分子如蛋白质的研究相对缺乏。肠道共生菌的多种酶在代谢物的生成和代谢过程中具有重要的作用。此外，这些菌源酶不仅具有多种与代谢物无关的功能，其在代谢性疾病中的作用仍然尚不清晰。
乔杰院士与合作者团队首次提出了肠道菌源宿主同工酶（Microbial-host-isozyme，MHI）这一新的科学概念，并发现这种菌源宿主同工酶在肠道中广泛存在，能够有效模拟宿主酶的功能，并在疾病的发生和发展中发挥关键作用。
研究人员发现菌源二肽基肽酶4（DPP4）可以通过分泌进入宿主体内并分解活性胰高血糖素样肽-1（GLP-1），进而诱导糖耐量异常。同时，他们发现宿主DPP4抑制剂西格列汀无法有效抑制菌源DPP4的活性。如果患者体内菌源DPP4富集，将会降低西格列汀的临床治疗效果。这一发现揭示了西格列汀临床响应性的个体差异的机制，并找到了关键的作用靶点。
研究人员进一步通过高通量筛选十万种化合物，发现Daurisoline-d4（Dau-d4）能通过特异性抑制菌源DPP4，增加活性GLP-1水平，从而降低血糖。这为后续的基础研究和临床治疗提供了新的研究思路和方向。
这一研究构建了从靶点发现到机制验证，再到药物筛选和疗效验证的全链条研究体系，为理解代谢性疾病的发生机制，提高代谢性疾病药物治疗效果，甚至发现新的治疗方法提供了可能。
肠道菌源宿主同工酶跨物种调控宿主代谢性疾病
北京大学医学部博士后汪锴、北京大学医学部基础医学院博士生张志威、北京大学第三医院副研究员杭婧、首都医科大学附属朝阳医院教授刘佳、北京大学化学与分子工程学院博士生郭富生为共同第一作者；姜长涛、乔杰、雷晓光、美国国立卫生研究院研究员Frank Gonzalez、首都医科大学附属朝阳医院教授王广为共同通讯作者。
本研究得到女性生育力促进全国重点实验室、血管稳态与重构全国重点实验室的大力支持，并得到了国家自然科学基金基础科学中心、重点项目、杰出青年科学基金以及国家重点研发计划基金等资助。
共同第一作者
杭婧
北医三院生殖医学科
副研究员、助理教授、博士生导师
北京市科技新星
主要研究方向：生殖和妊娠障碍的结构机制与代谢调控研究
共同通讯作者
乔杰
中国工程院院士
北京大学常务副校长
北京大学医学部主任
北医三院医学创新研究院院长
北医三院生殖医学科
主任医师、教授、博士生导师
主要研究方向：女性生育力促进
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利格列汀新适应证获批：适应证最全的 DPP-4 抑制剂 - 丁香园
利格列汀新适应证获批：适应证最全的 DPP-4 抑制剂 - 丁香园
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利格列汀新适应证获批：适应证最全的 DPP-4 抑制剂
2015-09-09 17:15
来源：丁香园
作者：
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2015 年 8 月 26 日，由勃林格殷格翰——礼来制药糖尿病联盟共同推出的利格列汀（欧唐宁®）一线单药及二线双联适应证获得国家食品药品监督管理总局（CFDA）批准上市，成为我国目前唯一适应证最全的 DPP-4 抑制剂（单药/与二甲双胍联合/与二甲双胍和磺脲类药物联合使用），为广大糖尿病患者提供了一种强效、安全及简便的治疗方案。糖尿病诊疗复杂 临床呼吁「简化治疗」 我国 2 型糖尿病领域呈现「三高一低」现状，即老年人糖尿病患病率高、肝肾功能受损患者比例高、合并多种疾病及联合用药比例较高，血糖控制达标率低，这些特点导致我国糖尿病的临床治疗需求复杂。在选择糖尿病治疗药物时，除关注降糖疗效外，还要重视药物的低血糖风险、药物相互作用、肝肾安全性及用药依从性等问题。 一方面是 2 型糖尿病患者复杂的医疗需求，另一方面是医疗资源的不足。据丁香园最新的《糖尿病医患沟通调查报告》显示，医生诊治 1 位门诊患者平均时间为 10 分钟/次，住院患者 15 分钟/天。另有调查显示，中国医生门诊时间有限，平均门诊诊疗时间不足 6 分 30 秒 。 「由于沟通时间有限，但要求医生在最短时间内根据患者的个体化需求处方安全有效的药物。」第二军医大学附属长海医院邹大进教授指出：「中国糖尿病管理面临着复杂性的挑战，目前迫切需要探索一种简化的治疗方式，在简化血糖控制流程的同时，又要保证疗效与安全，从而实现医生与患者对糖尿病的轻松管理。」第二军医大学附属长海医院邹大进教授治疗早期就应关注肝肾功能 我国糖尿病患者合并肝肾功能损伤的比例较高，理想的糖尿病治疗兼顾血糖和多种安全因素, 包括肝肾安全。目前包括口服降糖药物在内的大部分药物，都通过肝脏代谢及肾脏清除。肝肾功能受损后，药物相互作用及低血糖等药物不良反应发生风险都会相应增加。糖尿病管理要有长期风险控制的意识，如早期就重视预防肾功能受损，尽量选择不经肝肾代谢的药物。 利格列汀具有独特的药理学特征，是唯一极少通过肾脏排出的 DPP-4 抑制剂（经肾排泄的比例<5%），主要以原形由胆汁和肠道排出体外，无论普通患者及肝肾不全患者均可应用，应用时无需调整剂量和额外监测肝肾功能。 据悉，利格列汀是经过中国 CFDA、美国 FDA 和欧盟 EMA 批准，唯一在 2 型糖尿病患者中无需根据肝肾功能进行剂量调整的 DPP-4 抑制剂；也是唯一获得《中国 2 型糖尿病防治指南》推荐用于不同肝肾功能状态患者无需调整剂量的 DPP-4 抑制剂。DPP-4 抑制剂的良好前景 随着糖尿病治疗的持续进步以及临床研究的不断问世，以利格列汀为代表的新型降糖药物 DPP-4 抑制剂的临床疗效已得到普遍认可，在相关指南中的推荐级别也在近年迅速提升。2013 美国临床内分泌医师学会指南将其列为 2 型糖尿病的一线用药；《中国 2 型糖尿病防治指南（2013 版）》中也将其从二线备选更改为二线并列用药。 作为一种强效、高选择性 DPP-4 抑制剂，德国勃林格殷格翰公司心血管代谢疾病研究副总裁 Michael Mark 博士对利格列汀的临床前景非常有信心。 德国勃林格殷格翰公司心血管代谢疾病研究副总裁 Michael Mark 博士 「目前有 3 个关于利格列汀的临床试验正在进行，这些试验最终都会给患者和医生带来最新的科研成果」，他简单介绍了这几项研究内容，「第一个是 MARLINA 研究，这项研究针对糖尿病肾病的标准治疗方案应用于伴有白蛋白尿、尿白蛋白与肌酐比率（UACR）为 30-3000 mg/g 的 2 型糖尿病患者，对其降糖疗效和安全性进行评估；」 「第二个是 CARMELINA 研究，评估利格列汀应用于伴有心血管和肾脏事件风险的 2 型糖尿病成年患者后，对心血管和肾脏微血管结果的影响的预后临床试验；」 「第三项的 CAROLINA 研究是一项非常特别的试验，它将利格列汀和格列美脲进行应用于 2 型糖尿病患者的心血管结果比较，而不是与安慰剂进行比较。这项研究最早在 2016 年，最迟会在 2018 年得出成果。」强效、安全、简便——理想的糖尿病治疗新标准 「在大多数临床案例和学术指南中，二甲双胍都是 2 型糖尿病一线用药。但有时单独使用二甲双胍还不足以让患者的血糖达到目标水平」。Michael Mark 博士在谈及 2 型糖尿病治疗现状时说道，「这时就需要与其他药物联用，比如以利格列汀为代表的 DPP-4 抑制剂，与二甲双胍和磺脲类药物联用情况不同，利格列汀与二甲双胍联用不仅不会增加低血糖风险，也不会增加患者体重。」 5 mg 利格列汀可单独使用或联合其他糖尿病药物，中国食品和药物监督局批准使用于单药、联合二甲双胍、联合二甲双胍和磺脲类药物，有效改善 HbA1c。 利格列汀的降糖作用强效持久，2012 年《柳叶刀》发布的研究结果显示：利格列汀疗效与常用磺脲类药物格列美脲相当，76% 服用利格列汀的患者达到 HbA1c ≤ 7% 的治疗目标，降糖可维持达 104 周。相对于格列美脲，利格列汀不增加心血管风险、低血糖风险小、降低体重更多，安全性更优。 华中科技大学同济医学院附属协和医院陈璐璐教授介绍：「现代糖尿病治疗理念主张全程管理，早期进行医患沟通，全程关注患者的低血糖风险，体重控制，心血管及肝肾功能的改善，以及服药的依从性和便利等问题。中国医生接诊患者量大、分配给每个患者时间有限，采用有效简单的治疗方案可以减少用药失误的风险，更有利于轻松应对糖尿病的全程管理。」 华中科技大学同济医学院附属协和医院陈璐璐教授 利格列汀适用于不同年龄、不同病程、不同 BMI、不同肝功能和不同肾功能的 2 型糖尿病患者，服用方便，疗效稳定持久，无需根据患者肝肾功能而调整剂量。这种强效、安全及简便的治疗方案让糖尿病的「简化治疗」变成现实。
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Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus | Nature Reviews Endocrinology
Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus | Nature Reviews Endocrinology
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nature
nature reviews endocrinology
review articles
article
Review Article
Published: 14 September 2020
Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus
Carolyn F. Deacon
ORCID: orcid.org/0000-0003-2611-56421
Nature Reviews Endocrinology
volume 16, pages 642–653 (2020)Cite this article
6261 Accesses
152 Citations
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Subjects
Drug therapyType 2 diabetes
AbstractDipeptidyl peptidase 4 inhibitors (DPP4i) have been available for treating type 2 diabetes mellitus since 2006. Although they are a diverse group, DPP4i are all small, orally available molecules that interact with the catalytic site of DPP4 without disturbing any of its other known functions, including its effects on the immune system. DPP4i have no intrinsic glucose-lowering activity, so their efficacy as anti-diabetic agents is related directly to their ability to inhibit DPP4 activity and is mediated through the effects of the substrates they protect. Of these, the incretin hormone, glucagon-like peptide 1, is probably the most important. As the effects of glucagon-like peptide 1 are glucose-dependent, the risk of hypoglycaemia with DPP4i is low. Class effects, which are directly related to the mechanism of action, are common to all DPP4i; these include their overall good safety profile and tolerability, as well as their efficacy in improving glycaemic control, but also, potentially, a small increased risk of acute pancreatitis. Compound-specific effects are those related to their differing chemistries and/or pharmacokinetic profiles. These compound-specific effects could affect the way in which individual DPP4i are used therapeutically and potentially explain off-target adverse effects, such as hospitalization for heart failure, which is seen only with one DPP4i. Overall, DPP4i have a favourable therapeutic profile and are safe and effective in the majority of patients with type 2 diabetes mellitus.Key points
Dipeptidyl peptidase 4 inhibitors (DPP4i) were rationally designed based on the prior knowledge of the physiology of glucagon-like peptide 1 and an understanding of the role of DPP4 in its metabolism.
DPP4i are all small molecules that inhibit the catalytic activity of the enzyme without affecting any of the other known functions of the DPP4 protein.
The DPP4i class comprises a heterogeneous group of unrelated compounds with differing pharmacokinetic profiles.
Potential risks and benefits of DPP4i can be divided into class effects, occurring directly as a consequence of the inhibition of DPP4 activity, and compound-specific effects, related to the individual chemical entities.
DPP4i have a favourable therapeutic profile and are proven not to increase cardiovascular risk; they are safe and effective in the majority of patients with type 2 diabetes mellitus.
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Fig. 1: Anti-diabetic actions of GLP1.Fig. 2: Mechanism of action of DPP4i.
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Download referencesAuthor informationAuthors and AffiliationsDepartment of Biomedical Sciences, University of Copenhagen, Copenhagen, DenmarkCarolyn F. DeaconAuthorsCarolyn F. DeaconView author publicationsYou can also search for this author in
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Carolyn F. Deacon.Ethics declarations
Competing interests
No writing assistance or financial support was used in the preparation of this article. C.F.D. has received consultancy and/or lecture fees from companies with an interest in developing and marketing incretin-based therapies for treatment of type 2 diabetes mellitus (Boehringer Ingelheim, Lilly, Merck/MSD and Novo Nordisk). C.F.D.’s spouse is employed by, and holds stock in, Merck/MSD.
Additional informationPeer review informationNature Reviews Endocrinology thanks G. Mingrone, who co-reviewed with L. Gissey, P. Flatt and K. Kaku, for their contribution to the peer review of this work.Publisher’s noteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Rights and permissionsReprints and permissionsAbout this articleCite this articleDeacon, C.F. Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus.
Nat Rev Endocrinol 16, 642–653 (2020). https://doi.org/10.1038/s41574-020-0399-8Download citationAccepted: 22 July 2020Published: 14 September 2020Issue Date: November 2020DOI: https://doi.org/10.1038/s41574-020-0399-8Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard
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