Relook at DPP-4 inhibitors in the era of SGLT-2 inhibitors

SGLT-2 inhibitors(SGLT-2Is)have significantly improved cardio-renal outcomes and are preferred agents in people with cardiovascular diseases,heart failure,and diabetic kidney disease.Similarly,GLP-1 receptor agonists(GLP-1RAs)have significantly improved atherosclerotic cardiovascular outcomes.To this end,DPP-4 inhibitors(DPP-4Is)are cardiac-neutral drugs.While long-acting GLP-1RAs have shown a favorable HbA1c lowering compared to DPP-4Is,there is no clinically meaningful HbA1c lowering difference between SGLT-2Is vs DPP-4Is.Moreover,the glucose-lowering potential of SGLT-2Is gets compromised with a progressive decline in renal functions,unlike DPP-4Is.Furthermore,the HbA1c lowering potential of DPP-4Is is favorable in people with T2DM having a modest baseline HbA1c(8.0%-8.5%)compared with SGLT-2Is which lowers HbA1c larger in a background of higher baseline HbA1c(>8.5%-9.0%).These findings suggest that the role of DPP-4Is in the management of type 2 diabetes mellitus cannot be completely ignored even in the era of SGLT-2Is.

SGLT-2抑制剂与DPP-4抑制剂联用二甲双胍治疗2型糖尿病的疗效与安全性对比研究

目的:比较钠-葡萄糖协同转运蛋白-2(SGLT-2)抑制剂+二甲双胍和二肽基肽酶-4(DPP-4)抑制剂+二甲双胍治疗2型糖尿病的疗效和安全性。方法:计算机搜索Embase,Pubmed,Cochrane Library数据库,纳入比较SGLT-2抑制剂+二甲双胍和DPP-4抑制剂+二甲双胍治疗2型糖尿病疗效和安全性的随机对照试验(RCT),检索时间截至2021年10月。由2位研究人员依据纳入排除标准对文献进行筛选、资料提取以及质量评价,采用Rev-Man 5.3.5软件进行数据分析。结果:共纳入9篇RCT。Meta分析结果显示:在降低糖化血红蛋白[MD=-0.08,95%CI(-0.15,-0.02),P=0.008],降低空腹血糖[MD=-0.65,95%CI(-0.78,-0.53),P<0.0011]以及减轻体重[MD=-2.46,95%CI(-2.75,-2.17),P<0.00001]方面SGLT-2抑制剂+二甲双胍比DPP-4抑制剂+二甲双胍效果更好,差异有显著意义;在不良反应发生率[RR=1.03,95%CI(0.98,1.09),P=0.27],低血糖反应发生率[RR=1.21,95%CI(0.84,1.73),P=0.31]以及泌尿系感染发生率[RR=1.10,95%CI(0.84,1.44),P=0.48]方面两组并无差别;DPP-4抑制剂+二甲双胍生殖器感染发生率更低[RR=4.84,95%CI(2.74,8.56),P<0.001],差异有显著意义。结论:SGLT-2抑制剂+二甲双胍在降低2型糖尿病患者的糖化血红蛋白,空腹血糖以及体重控制方面效果更好,DPP-4抑制剂+二甲双胍生殖器感染发生率更低,在不良反应以及泌尿系感染发生率方面两者相当。

Design and synthesis of DPP-4 inhibitor for the treatment of type 2 diabetes

An efficient stereoselective synthesis of the rigid aza-bicyclo[3.2.0]heptane scaffold has been developed to provide 2-cyano-pyrrolidine alpha-amino amide 1 as DPP-4 inhibitor.

SGLT-2抑制剂与DPP-4抑制剂联用二甲双胍治疗2型糖尿病的疗效分析

目的研究钠-葡萄糖协同转运蛋白2(sodium-dependent glucose transporters 2,SGLT-2)抑制剂与二肽基肽酶4(dipeptidyl peptidase 4,DPP-4)抑制剂联合二甲双胍治疗2型糖尿病的疗效与安全性。方法选取2019年6月—2020年6月凉山彝族自治州第二人民医院收治的100例2型糖尿病患者进行研究,并运用随机数表法将其分为对照组(n=50)和研究组(n=50)。对照组采用DPP-4抑制剂+二甲双胍治疗,研究组采用SGLT-2抑制剂+DPP-4抑制剂+二甲双胍治疗。对比治疗前后两组血糖指标、体质指数(BMI)变化情况、不良反应发生情况。结果治疗前,两组患者血糖指标、BMI比较,差异无统计学意义(P>0.05)。治疗后,研究组空腹血糖、餐后2 h血糖、糖化血红蛋白水平及BMI低于对照组,差异有统计学意义(P<0.05)。两组患者不良反应发生率比较,差异无统计学意义(P>0.05)。结论采用SGLT-2抑制剂+DPP-4抑制剂+二甲双胍进行治疗,可以改善2型糖尿病患者血糖水平,控制患者体质量,总体疗效良好。

Effects of DPP-4 inhibitor combined with metformin on blood glucose control, oxidative stress and inflammatory response in patients with type 2 diabetes mellitus

Objective: To investigate the effects of DPP-4 inhibitor combined with metformin on blood glucose control, oxidative stress and inflammatory response in patients with type 2 diabetes mellitus (T2DM). Methods: A total of 138 patients with newly diagnosed T2DM who were treated in the hospital between March 2016 and April 2017 were divided into routine group (n=69) and combined treatment group (n=69) by random number table method. Routine group were treated with metformin alone and combined treatment group received DPP-4 inhibitor combined with metformin therapy. The differences in blood glucose control as well as oxidative stress-related indicator and inflammatory factor contents were compared between the two groups before and after treatment. Results: Before treatment, the differences in blood glucose index levels in peripheral blood as well as the oxidative stress index and inflammatory mediator contents in serum were not statistically significant between the two groups. After 4 weeks of treatment, blood glucose indexes FBG and HOMA-IR levels in peripheral blood of combined treatment group were lower than those of routine group;oxidative stress indexes MDA and LHP contents in serum were lower than those of routine group whereas GSH-Px and T-AOC contents were higher than those of routine group;inflammatory mediators hs-CRP, IL-1 and IL-6 contents in serum were lower than those of routine group. Conclusion: DPP-4 inhibitor combined with metformin therapy can effectively control the blood glucose and suppress the systemic oxidative stress and inflammatory response in T2DM paients.

Effect of DPP-4 inhibitor combined with metformin on glucose and lipid metabolism and micro-inflammatory state in patients with type 2 diabetes mellitus complicated by metabolic syndrome

Objective: To study the effect of DPP-4 inhibitor combined with metformin on glucose and lipid metabolism and micro-inflammatory state in patients with type 2 diabetes mellitus complicated by metabolic syndrome. Methods: A total of 60 patients with type 2 diabetes mellitus complicated by metabolic syndrome who were treated in the hospital between February 2015 and December 2016 were divided into control group (n=30) and observation group (n=30) according to the random number table method. Control group received metformin therapy alone, observation group received DPP-4 inhibitor combined with metformin therapy, and the differences in levels of glucose and lipid metabolism indexes and inflammatory factors were compared between the two groups of patients before and after treatment. Results: Before treatment, the differences in glucose and lipid metabolism index levels in peripheral blood as well as inflammatory factor contents in serum were not statistically significant between the two groups. After treatment, the levels of glucose metabolism indexes FPG, FPI and HOMA-IR as well as lipid metabolism indexes TG and TC in peripheral blood of observation group were lower than those of control group while HDL-C level was higher than that of control group;the contents of inflammatory factors IL-6, CRP and TNF-α in serum were lower than those of control group. Conclusion: DPP-4 inhibitor combined with metformin therapy is more effective in controlling the glucose and lipid metabolism process and inhibiting the micro-inflammatory state in patients with type 2 diabetes mellitus complicated by metabolic syndrome.

Effect of metformin combined with DPP-4 inhibitor on the micro-inflammatory status and insulin sensitivity of T2DM patients with metabolic syndrome

Objective: To investigate the effect of metformin combined with DPP-4 inhibitor on the micro-inflammatory status and insulin sensitivity of T2DM patients with metabolic syndrome. Methods: A total of 78 T2DM patients with metabolic syndrome who were treated in the hospital were retrospectively analyzed and divided into the control group (n=41) who received metformin therapy and the combined group (n=37) who received metformin combined with DPP-4 inhibitor therapy, and both groups were treated for 12 weeks. The differences in micro-inflammatory state and insulin sensitivity were compared between the two groups before and after treatment. Results: There was no statistically significant difference in serum inflammatory factor contents and peripheral blood insulin sensitivity-related index levels between the two groups before treatment. After 12 weeks of treatment, serum inflammatory factors IL-1, hs-CRP and TNF-α contents of combined group were lower than those of control group;insulin sensitivity indexes FGP, FINS, ISI and HOMA-IR levels were lower than those of control group. Conclusion: metformin combined with DPP-4 inhibitor Sitagliptin can more effectively inhibit the micro-inflammatory state and improve the insulin sensitivity in T2DM patients with metabolic syndrome.

基于BiRNN模型的DPP-4和SGLT-2双靶点抑制剂设计

目的 设计DPP-4和SGLT-2双靶点抑制剂。方法 根据现有的DPP-4和SGLT-2活性化合物训练BiRNN模型,使其生成具有潜在活性的双靶点新分子,并使用已经报道的活性化合物构建HipHop药效团模型,通过药效团模型对新分子进行初筛,然后使用分子对接、分子动力学模拟以及结合自由能计算等方法对初筛小分子进行进一步筛选最终得到候选化合物。结果 BiRNN模型生成7 494个新分子,经过虚拟筛选发现化合物NM186、NM21、NM249、NM107是相对理想的DPP-4和SGLT-2双靶点抑制剂。结论 NM186、NM21、NM249、NM107可能是一种具有新型结构的DPP-4/SGLT-2双靶点抑制剂,这一研究丰富了DPP-4和SGLT-2双靶点抑制剂的多样性,为其开发提供新的设计思路。

新型口服降糖药物在2型糖尿病治疗中的地位

在新型口服降糖药物上市之前,我国2型糖尿病患者的整体达标率低,其主要原因是传统降糖药物常无法实现血糖控制与安全耐受性及血管获益的平衡.因此,开发用药方便、针对新靶点、降糖疗效强、不良反应少、与现有的传统降糖药无拮抗作用、最好是有协同作用、具备心血管和肾脏保护作用的新型糖尿病药物越来越紧迫.新型降糖药物二肽基肽酶-4(dipeptidyl peptidase-4,DPP-4)抑制剂和钠-葡萄糖协同转运蛋白-2(sodium-glucose co-transporter 2,SGLT2)抑制剂已经在全球大范围上市,众多临床研究证实了其疗效、安全性及带来的其他多方面获益,对2型糖尿病患者的病情可起到综合改善的作用.多项权威指南肯定了它们的临床地位,并进行了相关用药推荐.

Vildagliptin-insulin combination improves glycemic control in Asians with type 2 diabetes

AIM: To assess the efficacy and safety of vildagliptin 50 mg bid as add-on therapy to insulin in Asian patients with type 2 diabetes mellitus(T2DM).METHODS: This was a post hoc analysis of a subgroup of Asian patients from a multicenter,randomized,double-blind,placebo-controlled,parallel-group study in T2DM patients inadequately controlled by stable insulin therapy,with or without metformin.A total of 173 patients were randomized 1:1 to receive treatment with vildagliptin 50 mg bid(n = 87) or placebo(n = 86) for 24 wk.Changes in HbA1c and fasting plasma glucose(FPG),from baseline to study endpoint,were analyzed using an analysis of covariance model.Change from baseline to endpoint in body weight was summarized by treatment.Safety and tolerability of vildagliptin was also evaluated.RESULTS: After 24 wk,the difference in adjusted mean change in HbA1c between vildagliptin and placebo was 0.82%(8.96 mmol/mol;P < 0.001) in Asian subgroup,0.85%(9.29 mmol/mol;P < 0.001) in patients also receiving metformin,and 0.73%(7.98 mmol/mol;P < 0.001) in patients without metformin,all in favor of vildagliptin.There was no significant difference in the change in FPG between treatments.Weight was stable in both treatment groups(+0.3 kg and-0.2 kg,for vildagliptin and placebo,respectively).Overall,vildagliptin was safe and well tolerated with similarly low incidences of hypoglycemia(8.0% vs 8.1%) and no severe hypoglycemic events were experienced in either group.CONCLUSION: In Asian patients inadequately controlled with insulin(with or without concomitant metformin),insulin-vildagliptin combination treatment significantly reduced HbA1c compared with placebo,without an increase in risk of hypoglycemia or weight gain.

基于循证和专家共识:谋求2型糖尿病口服降糖联合治疗新思路

2型糖尿病是一种多基因遗传性慢性代谢疾病,是威胁全球健康的主要疾病之一.因其复杂的病理机制和多样的影响因素使其在临床诊疗中效果差异较大.本文在现有研究的基础上分析了不同治疗方案的差异,比较了常规的单药治疗和序贯治疗存在的差异,而以二肽基肽酶-4(dipeptidyl peptidase-4,DPP-4)抑制剂和钠-葡萄糖协同转运蛋白-2(sodium-glucose co-transporter 2,SGLT2)抑制剂为代表的新型口服降糖药在早期联合治疗中表现出了较为明显的优势,为2型糖尿病治疗提供了新思路,并具有一定的临床参考价值.

Clinical Characteristics of Japanese Type 2 Diabetic Patients Responsive to Sitagliptin

Japanese type 2 diabetic patients were treated with sitagliptin to evaluate the efficacy of this agent, and also to investigate the clinical characteristics of those who responded to sitagliptin. In total, 1001 diabetic patients, inadequately controlled (HbA1c ≥ 6.5%) with oral hypoglycemic agents (OHA) other than DPP-4 inhibitors or with diet and exercise only, were enrolled. We added 50mg of sitagliptin to the therapeutic regimens of 410 patients including 68 OHA naive patients, while the other 591 patients were switched from a single OHA to 50 mg of sitagliptin. After 6 months, glycemic control was significantly improved due to both reduced insulin resistance, as demonstrated by a significant HOMA-R reduction, and recovery of pancreatic β cell function, as assessed by HOMA-β and the proinsulin/insulin (PI/I) ratio. In the bivariable analysis, a good response, defined as an HbA1c reduction during the 6 months of at least 0.9%, was associated with high HbA1c and PI/I at baseline and combination treatments with sulfonylurea, biguanide and α-glucosidase inhibitors, but not with obesity. On the other hand, in the multivariable regression analysis, only high baseline HbA1c and combination treatment with anα-glucosidase inhibitor were significantly associated with a good response to sitagliptin. In patients with type 2 diabetes, the addition of sitagliptin or switching from another OHA to this agent achieved an HbA1c reduction without overloading β cells. In particular, we suggest that a good response to sitagliptin can be expected when this agent is combined with an α-glucosidase inhibitor (UMIN No. #000014157).

SGLT-2抑制剂、二甲双胍以及DPP-4抑制剂联合治疗对老年2型糖尿病患者治疗效果的分析

探究分析老年2型糖尿病患者采取SGLT-2抑制剂联合二甲双胍与DPP-4抑制剂治疗的效果。方法 加入到此次研究的对象为本院在2020年5月-2021年5月期间收治的53例老年2型糖尿病患者。对上述患者分别采取传统三联治疗(二甲双胍+阿卡波糖+瑞格列奈)以及新三联治疗(SGLT-2抑制剂+二甲双胍+DPP-4抑制剂)。从两组的临床疗效,血糖指标,胰岛功能指标,不良反应评价两种治疗方案的效果。结果 新三联治疗的有效率96.23%高于传统三联治疗的有效率81.13%(P<0.05)。新三联治疗后患者的血糖指标低于传统三联治疗(P<0.05)。新三联治疗后患者的胰岛功能指标高于传统三联治疗(P<0.05)。新三联治疗后的不良反应发生率略低于传统三联治疗,但差异不满足统计学意义(P>0.05)。结论 在老年2型糖尿病患者治疗中施行SGLT-2抑制剂联合二甲双胍与DPP-4抑制剂治疗可起到较好的治疗效果,能够实现患者血糖及胰岛功能的有效改善,同时该方案的治疗安全性较高。此种治疗方法可在临床上推广应用。

Hyperglycemia in acute ischemic stroke: physiopathological and therapeutic complexity

Diabetes mellitus and associated chronic hyperglycemia enhance the risk of acute ischemic stroke and lead to worsened clinical outcome and increased mortality. However, post-stroke hyperglycemia is also present in a number of non-diabetic patients after acute ischemic stroke, presumably as a stress response. The aim of this review is to summarize the main effects of hyperglycemia when associated to ischemic injury in acute stroke patients, highlighting the clinical and neurological outcomes in these conditions and after the administration of the currently approved pharmacological treatment, i.e. insulin. The disappointing results of the clinical trials on insulin(including the hypoglycemic events) demand a change of strategy based on more focused therapies. Starting from the comprehensive evaluation of the physiopathological alterations occurring in the ischemic brain during hyperglycemic conditions, the effects of various classes of glucose-lowering drugs are reviewed, such as glucose-like peptide-1 receptor agonists, DPP-4 inhibitors and sodium glucose cotransporter 2 inhibitors, in the perspective of overcoming the up-to-date limitations and of evaluating the effectiveness of new potential therapeutic strategies.

糖尿病药物临床治疗中外新进展

目前,我国糖尿病患者的患病率和死亡率迅速增加,约占全球的1/4,糖尿病药物临床治疗显得尤为重要。文章对近几年的中外治疗指南、文献报道进行了归纳总结,从药物的种类、作用机制、降糖作用、适应症、不良反应等方面对市场上降糖药进行阐述,尤其对近几年降糖新药的研究进展做了详细阐述,作为目前临床医师指导糖尿病用药的参考。

Synthesis of Vildagliptin-β-<i>O</i>-Glucuronide

A linear 7-step synthesis of vildagliptin-β-O-glucuronide (2) starting from commercially available D-glucurono-6, 3-lactone (3) was herein achieved with 11.3% overall yield. Efficient preparation of compound 6 in pure α form was obtained, which was proved critical to achieve high anomeric selectivity in β-O-glycosylation later. The direct β-O-glycosylation of vildagliptin (1) containing both a tertiary alcohol and a secondary amine was studied and achieved in good yield. The deprotection step to afford product was delicately executed to avoid hydrolysis of nitrile group. The target compound 2 was obtained after purification by reversed-phase C18 chromatography.

Efficacy and safety of saxagliptin in patients with type 2 diabetes mellitus:a meta-analysis of randomized controlled trials

As a new oral hypoglycemic agent, saxagliptin belongs to the class of dipeptidyl peptidase-4 （DPP-4） inhibitors. However, it remains inconclusive whether saxagliptin is associated with increased risk of adverse events （AE） and efficacy as add-on treatment. Therefore, we performed an up-to-date meta-analysis to compare the efficacy and safety of saxagliptin with placebo and other oral hypoglycemic agents in adult patients with type 2 diabetes mellitus （T2DM）. Randomized clinical trials （RCTs） comparing saxagliptin with comparators were retrieved by selecting articles from Pubmed, Embase, Cochrane Library and Clinical Trials Registry Platform up to Oct. 2013. Weighted mean difference （WMD） was used to analyze the effect of hypoglycemic agents on HbAlc, weight and fasting plasma glucose （FPG）. While the patients who achieved HbAlc〈7.0% and had AE were analyzed as relative risks （RR）. A total of 18 articles from 16 RCTs and one clinic trial from the WHO International Clinical Trials Registry Platform met the included criterion. Clinically significant decrease from baseline HbAlc compared with placebo was certified for 2.5 mg/day saxagliptin （WMD = -0.45%, 95% CI, -0.48% to -0.42%） and 5 mg/d saxagliptin （WMD = -0.52%, 95% CI, -0.60% to -0.44%）. Saxagliptin as add-on therapy was superior to thiazolidinediones, up-titrated glyburide, up-titrated metformin or metformin monotherapy in achieving HbA1c〈7.0%. Treatment with saxagliptin had negligible effect on weight, and it was considered weight neutral. Saxagliptin treatment did not increase the risk of hypoglycemia （RR = 1.28, 95% CI 0.72 to 2.27, P = 0.40） and serious adverse experiences （RR = 1.25, 95% CI 0.94 to 1.66, P = 0.13）. No statistically significant differences were observed between saxagliptin and comparators in terms of the risk of infections. The present study showed that saxagliptin was effective in improving glycaemic control in T2DM with a low risk of hypoglycaemia and incidence of infections in either monotherapy or add-on treatment. This founding should be further certified by large-sample size and good-designed RCT.

Opportunities and challenges of incretin-based hypoglycemic agents treating type 2 diabetes mellitus from the perspective of physiological disposition

The treatment of patients with diabetes mellitus, which is characterized by defective insulin secretion and/or the inability of tissues to respond to insulin, has been studied for decades. Many studies have focused on the use of incretin-based hypoglycemic agents in treating type 2 diabetes mellitus(T2DM). These drugs are classified as GLP-1 receptor agonists, which mimic the function of GLP-1,and DPP-4 inhibitors, which avoid GLP-1 degradation. Many incretin-based hypoglycemic agents have been approved and are widely used, and their physiological disposition and structural characteristics are crucial in the discovery of more effective drugs and provide guidance for clinical treatment of T2DM.Here, we summarize the functional mechanisms and other information of the drugs that are currently approved or under research for T2DM treatment. In addition, their physiological disposition, including metabolism, excretion, and potential drug drug interactions, is thoroughly reviewed. We also discuss similarities and differences in metabolism and excretion between GLP-1 receptor agonists and DPP-4 inhibitors. This review may facilitate clinical decision making based on patients' physical conditions and the avoidance of drug drug interactions. Moreover, the identification and development of novel drugs with appropriate physiological dispositions might be inspired.

新型降糖药物的降压作用

高血压和糖尿病是引起心脑血管事件的主要危险因素,对于血压处于130~139/80~89 mmHg(1 mmHg=0.133 kPa)的糖尿病患者,根据指南血压应控制在130/80 mmHg以下,但直接处方降压药物尚缺乏指南支持。三类新型降糖药中,SGLT-2抑制剂降压作用较明显,平均24 h动态收缩压/舒张压降低为3.8/1.8 mmHg;GLP-1受体激动剂仅降低收缩压,24 h动态收缩压下降范围在1.1~2.8 mmHg;DPP-4抑制剂降压作用研究结果不一致。三类新型降糖药对血压的影响,临床医生在治疗糖尿病患者时应酌情考虑。

1型糖尿病的非胰岛素辅助降糖治疗

1型糖尿病(T1DM)是一种自身免疫介导的以胰岛素分泌减少或胰岛素绝对缺乏为特征的疾病,胰岛素治疗是其主要的治疗方式。胰岛素治疗存在着增加体重和低血糖风险的缺点。与此同时,胰岛素治疗不能延缓或阻止胰岛功能的进行性破坏,因此T1DM患者病程中晚期多出现脆性糖尿病。文章总结了近些年有关T1DM非胰岛素辅助治疗的最新研究进展,详细阐述了口服降糖药、注射类药物、免疫治疗等作为胰岛素的辅助治疗带来的新作用,为改善T1DM患者生活质量带来新思路与新展望。