改善心血管和肾脏结局的新型抗高血糖药物临床应用中国专家建议

动脉粥样硬化性心血管病(ASCVD)和(或)慢性肾脏病(CKD)不但是2型糖尿病(T2DM)常见合并疾病,也是T2DM患者致残和致死的首要原因。近年来一系列临床研究证据表明,新型抗高血糖药物胰高糖素样肽-1受体激动剂(GLP-1 RA)和钠-葡萄糖共转运蛋白2抑制剂(SGLT2i)类药物能显著改善心血管和肾脏结局的临床获益,且安全性良好。为促使T2DM的治疗模式从单纯控制血糖转移到改善心血管和肾脏临床结局,中国心血管病学、内分泌学、肾脏病学和神经病学专家组成的专家组梳理了GLP-1 RA或SGLT2i的心血管保护的临床证据、可能机制和常见不良反应,提出了对这两类药物在临床实践中的合理定位、应用建议和注意事项,鼓励临床医师在临床实践中对T2DM患者及早启动并长期维持能够改善心血管和肾脏结局的新型抗高血糖药物治疗。     

葡萄糖协同转运蛋白2抑制剂防治心力衰竭的研究进展

心力衰竭是合并动脉粥样硬化性心血管疾病(ASCVD)和ASCVD高危因素2型糖尿病(T2DM)患者最常见的并发症之一。临床试验显示葡萄糖协同转运蛋白2抑制剂(SGLT2i)可有效预防心力衰竭住院的发生。新的证据表明SGLT2i治疗确诊的合并和不合并T2DM的心力衰竭患者明显获益,更多的循证医学依据正在积累中。虽然SGLT2i耐受性良好,但应对严重不良作用进行监测。本文主要介绍SGLT2i防治心力衰竭的获益、不良作用和可能机制。     

胰高糖素样肽-1受体激动剂在2型糖尿病合并动脉粥样硬化性心血管疾病或高危风险人群中的可能机制及循证证据

动脉粥样硬化性心血管疾病(ASCVD)是2型糖尿病(T2DM)患者重要的伴发疾病, 也是其致死和致残的主要原因。近年来, 随着心血管结局研究(CVOT)证据的不断积累, 胰高糖素样肽-1受体激动剂(GLP-1RA)在各大指南中的地位不断提升。大量研究表明, GLP-1RA可以通过多种途径发挥心脑血管保护作用。笔者对GLP-1RA心血管获益的可能机制及其循证证据进行了系统梳理分析, 旨在深入理解GLP-1RA在T2DM患者高血糖管理和ASCVD防治中的作用。     

SGLT2抑制剂和GLP-1受体激动剂对2型糖尿病患者心血管保护作用研究进展

大量研究表明钠-葡萄糖共转运体2(SGLT2)抑制剂和胰高血糖素样肽1(GLP-1)受体激动剂(GLP-1RA)在降低2型糖尿病(T2DM)患者的死亡率和心血管风险方面显示出积极的效果。本文综述了SGLT2抑制剂和GLP-1RA对T2DM患者心血管获益有关的临床研究。以期针对T2DM合并心血管疾病患者的不同临床受益情况，提供个体化用药选择思路。     

新型降糖药在糖尿病合并心力衰竭患者中的应用现状及进展

我国糖尿病(DM)与充血性心力衰竭(CHF)的发病率居高不下。DM和心力衰竭(HF)之间关系密切,互为因果,DM患者罹患HF的风险显著高于非DM患者,而HF合并DM患者也大多存在胰岛β细胞生理功能缺陷、胰岛素抵抗等问题。因此,HF是DM患者所不能忽视的一项重大问题。近年来,降糖药物的心血管获益性及风险性备受各学界关注。目前,传统降糖药物二甲双胍已被证实具有抗动脉粥样硬化以及减少HF发作风险的心血管益处。与此同时,新近涌现的一些新型降糖药物,钠-葡萄糖协同转运蛋白-2抑制剂(SGLT-2i)、胰高血糖素样肽-1受体激动剂(GLP-1 RAs)以及二肽基肽酶-4抑制剂(DPP-4i)也先后被多项临床研究证实同样兼具一定的心血管益处。本文现就SGLT-2i、GLP-1 RAs以及DPP-4i在DM合并HF患者中的研究现状与进展作一综述。     

二肽基肽酶Ⅳ抑制剂治疗2型糖尿病合并慢性肾脏病患者的心肾结局

慢性肾脏病(CKD)是2型糖尿病(T2DM)患者最常见的合并症,也是心血管疾病的独立危险因素。大多数口服降糖药及其代谢产物由肾脏排泄,肾功能不全时半衰期延长,造成药物在体内蓄积,增加低血糖及其他相关不良反应风险。合并CKD的T2DM患者在选择降糖药时,应充分考虑肾功能情况,优选具有肾脏获益证据、经肾脏排泄少、低血糖风险低的药物。二肽基肽酶Ⅳ抑制剂(DPP-4i)作用机制独特,降糖疗效确切,不增加体重和低血糖风险,且使用简便,临床应用越来越广泛。4种DPP-4i开展的大型心血管结局研究(CVOT)在不同肾功能状态的T2DM患者中,评估了药物的疗效和安全性。不同DPP-4i虽降糖疗效相似,但药物特点及心肾结局存在一定差异。本综述基于CVOT,归纳比较了不同肾功能状态患者使用DPP-4i的心血管安全性和肾脏相关结局,并对DPP-4i的潜在肾脏获益及机制进行探讨,以期为合并CKD的T2DM患者的治疗提供循证参考。     

钠-葡萄糖共转运蛋白2抑制剂抗氧化应激防治糖尿病肾脏疾病的研究进展

DKD是终末期肾病的首要原因。钠-葡萄糖共转运蛋白2抑制剂(SGLT2i)除有效降糖外,还可使合并慢性肾脏疾病、心脑血管疾病及心力衰竭的T2DM患者获益。SGLT2i通过肾脏排糖、排钠延缓DKD进展。SGLT2i可通过降低BP、UA、减轻体重、改善肾脏血流动力、减轻内质网应激及激活缺氧诱导因子通路等实现肾脏保护作用。氧化应激在DKD发生发展中起重要作用。本文对SGLT2i通过抗氧化应激防治DKD的研究进展进行综述。     

不同胰升血糖素样肽1受体激动剂类药物心血管结局研究差异及其在临床治疗中的指导意义

动脉粥样硬化性心血管疾病(ASCVD)是T2DM患者重要的伴发疾病和主要死因。在DM新药研发规则的影响下,新型DM药物的心血管结局研究(CVOT)数据不断涌现。7项针对胰升血糖素样肽1受体激动剂(GLP-1 RA)类药物的CVOT,因研究目的不同,采用不同的研究设计来验证不同的科学假设,全面证明GLP-1 RA类药物心血管安全性的同时,显示出某些药物的心血管保护作用。GLP-1 RA类药物临床证据使其在DM管理中的地位上升,为DM患者高血糖管理和心血管疾病防治提供新的解决方案。     

三种新型降糖药治疗老年2型糖尿病患者发生心力衰竭相关住院风险的比较

目的 比较使用胰高血糖素样肽-1受体激动剂(GLP-1 RA)、钠-葡萄糖共转运蛋白2抑制剂(SGLT2i)和二肽基肽酶-4抑制剂(DPP-4i)治疗老年2型糖尿病(T2DM)患者随访3年发生心力衰竭相关住院(HHF)风险，并分析发生HHF的危险因素。方法 前瞻性队列研究。纳入2017年1月至2019年12月入住海安市人民医院的老年T2DM患者。采用倾向评分匹配法，按照1∶1∶1∶1比例，根据降糖用药情况将患者分为4组：对照组(常规降糖治疗，230例)、GLP-1 RA组(常规降糖治疗+GLP-1 RA,230例)、SGLT2i组(常规降糖治疗+SGLT2i, 230例)和DPP-4i组(常规降糖治疗+DPP-4i, 230例)。比较各组的基线临床资料情况和随访3年的发生HHF风险，Cox回归分析发生HHF的危险因素。结果 920例老年T2DM患者中，女性403例(43.8%),年龄60～80岁，平均为(71.7±8.4)岁。四组的基线临床资料相似，差异均无统计学意义(均为P>0.05)。中位随访34个月(29～40个月),失访91例(9.9%),156例(17.0%)患者发生H...     

国外指南和卫生技术评估报告中钠-葡萄糖共转运蛋白2抑制剂的推荐意见

近年来的研究发现,钠-葡萄糖共转运蛋白2(SGLT2)抑制剂在2型糖尿病(T2DM)患者中具有良好的有效性和安全性,同时在心血管和肾脏疾病方面可带来临床获益。本文在梳理药品基本信息的基础上,对国外主要临床诊疗指南和卫生技术评估报告中的相关推荐意见和信息进行梳理与分析。整体来看,SGLT2抑制剂已被推荐作为合并心血管疾病和/或肾脏疾病的T2DM患者的一线治疗选择(或之一),其单药和/或联合治疗也逐渐被各国推荐纳入医保给付范围中。但是,由于临床证据不尽相同,不同SGLT2抑制剂的推荐级别、具体患者人群和用药地位等也有一定的差别,建议应根据说明书批准的适应证、高级别循证医学证据和指南推荐意见等综合选择适宜的药品品种。     

Cardiorenal disease management in type 2 diabetes: An expert consensus

Background and aimThe interplay between cardiovascular disease (CVD), chronic kidney disease (CKD) and type 2 diabetes (T2D) is well established. We aim at providing an evidence-based expert opinion regarding the prevention and treatment of both heart failure (HF) and renal complications in people with T2D.Methodology: The consensus recommendations were developed by subject experts in endocrinology, cardiology, and nephrology. The criteria for consensus were set to statements with ≥80% of agreement among clinicians specialized in endocrinology, cardiology, and nephrology. Key expert opinions were formulated based on scientific evidence and clinical judgment.ResultsAssessing the risk factors of CVD or CKD in people with diabetes and taking measures to prevent HF or kidney disease are essential. Known CVD or CKD among people with diabetes confers a very high risk for recurrent CVD. Metformin plus lifestyle modification should be the first-line therapy (unless contraindicated) for the management of T2D. Glucagon-like peptide 1 (GLP-1) agonists can be preferred in people with atherosclerotic cardiovascular disease (ASCVD) or with high-risk indicators, along with sodium–glucose cotransporter-2 inhibitors (SGLT2i), whereas SGLT2i are the first choice in HF and CKD. The GLP-1 agonists can be used in people with CKD if SGLT2i are not tolerated.ConclusionCurrent evidence suggests SGLT2i as preferred agents among people with T2D and HF, and for those with T2D and ASCVD. SGLT2i and GLP-1RA also lower CV outcomes in those with diabetes and ASCVD, and the treatment choice should depend on the patient profile.     

Cardiovascular prevention with glucose-lowering drugs in type 2 diabetes: An evidence-based approach to the categories of primary and secondary prevention

Aims

Whether to recommend specifically the glucose-lowering therapies with cardiovascular benefit only in secondary prevention, or also in patients with multiple risk factors (MRF) but without established atherosclerotic cardiovascular disease (ASCVD), is controversial across the guidelines for diabetes.

Materials and Methods

We performed a meta-analysis of clinical trials with major adverse cardiovascular events (MACE) as an outcome.

Results

The definitions of ASCVD and MRF were heterogeneous across trials; nevertheless, the incidence of MACE was 2.8-fold higher in people with ASCVD in trials with sodium-glucose cotransporter 2 inhibitors (SGLT2is), and 3.9-fold in trials with glucagon-like peptide-1 receptor agonists (GLP-1 RA). Both SGLT2i and GLP-1 RA were associated with a significant reduction in the incidence of MACE in people with previous ASCVD [inverse variance-odds ratio 0.91, 95% confidence interval (0.86: 0.97) for SGLT2i, Mantel-Haenszel odds ratio 0.85, 95% confidence interval (0.81: 0.90) for GLP-1 RA], whereas no significant reduction was detected in those without; on the other hand, no significant difference in effect was found between the two groups as well. The sample of patients without ASCVD enrolled in clinical trials is insufficient to draw reliable conclusions in this population; however, even assuming the same benefit detected in people with ASCVD also in those with MRF, the number needed to treat would differ (35 for secondary, 99 for primary prevention of a MACE with a SGLT2i; 21 for secondary, 82 for primary prevention with a GLP-1 RA, respectively), given the difference in absolute cardiovascular risk at baseline.

Conclusion

The distinction between patients with ASCVD and those without ASCVD and MRF appears therefore justified by available evidence.     

All-cause mortality and cardiovascular outcomes with sodium-glucose Co-transporter 2 inhibitors,glucagon-like peptide-1 receptor agonists and with combination therapy in people with type 2 diabetes

Aim

To assess the relationship of sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor analogues (GLP-1RA) and their combination (SGLT2i + GLP-1RA) with 5-year risk of all-cause mortality, hospitalization and cardiovascular/macrovascular disease in people with type 2 diabetes.

Materials and Methods

Retrospective cohort analysis of 2.2 million people with type 2 diabetes receiving insulin across 85 health care organizations using a global federated health research network. Three intervention cohorts (SGLT2i, GLP-1RA and SGLT2i + GLP-1RA) were compared against a control cohort (no SGLT2i/GLP-1RA). Propensity score matching for age, ischaemic heart disease, sex, hypertension, chronic kidney disease, heart failure and glycated haemoglobin was used to balance cohorts 1:1 (SGLT2i, n = 143 600; GLP-1RA, n = 186 841; SGLT-2i + GLP-1RA, n = 108 504). A sub-analysis comparing combination and monotherapy cohorts was also performed.

Results

The intervention cohorts showed a reduced hazard ratio (HR, 95% confidence interval) over 5 years compared with the control cohort for all-cause mortality (SGLT2i 0.49, 0.48-0.50; GLP-1RA 0.47, 0.46-0.48; combination 0.25, 0.24-0.26), hospitalization (0.73, 0.72-0.74; 0.69, 0.68-0.69; 0.60, 0.59-0.61) and acute myocardial infarct (0.75, 0.72-0.78; 0.70, 0.68-0.73; 0.63, 0.60-0.66), respectively. All other outcomes showed a significant risk reduction in favour of the intervention cohorts. The sub-analysis showed a significant risk reduction in all-cause mortality for combination therapy versus SGLT2i (0.53, 0.50-0.55) and GLP-1RA (0.56, 0.54-0.59).

Conclusions

SGLT2i, GLP-1RAs or combination therapy confers mortality and cardiovascular protection in people with type 2 diabetes over 5 years. Combination therapy was associated with the greatest risk reduction in all-cause mortality versus a propensity matched control cohort. In addition, combination therapy offers a reduction in 5-year all-cause mortality when compared directly against either monotherapy.     

Metabolic and cardiovascular benefits with combination therapy of SGLT-2 inhibitors and GLP-1 receptor agonists in type 2 diabetes

Both GLP-1 receptor agonists (GLP-1RA) and SGLT-2 inhibitors (SGLT-2I) are newer classes of anti-diabetic agents that lower HbA1c moderately and decrease body weight and systolic blood pressure (SBP) modestly. Combination therapy with GLP-1RA plus SGLT-2I have shown a greater reduction in HbA1c, body weight, and SBP compared to either agent alone without any significant increase in hypoglycemia or other side effects. Since several agents from each class of these drugs have shown an improvement in cardiovascular (CV) and renal outcomes in their respective cardiovascular outcome trials (CVOT), combination therapy is theoretically expected to have additional CV and renal benefits. In this comprehensive opinion review, we found HbA1c lowering with GLP-1RA plus SGLT-2I to be less than additive compared to the sum of HbA1c lowering with either agent alone, although body weight lowering was nearly additive and the SBP lowering was more than additive. Our additional meta-analysis of CV outcomes with GLP-1RA plus SGLT-2I combination therapy from the pooled data of five CVOT found a similar reduction in three-point major adverse cardiovascular events compared to GLP-1RA or SGLT-2I alone, against placebo. Interestingly, a greater benefit in reduction of heart failure hospitalization with GLP-1RA plus SGLT-2I combination therapy was noted in the pooled meta-analysis of two randomized controlled trials. Future adequately powered trials can confirm whether additional CV or renal benefit is truly exerted by GLP-1RA plus SGLT-2I combination therapy.     

Combination therapy with GLP‐1 receptor agonist and SGLT2 inhibitor

The SGLT2 inhibitors (SGLTi) and glucagon‐like‐1 receptor agonists (GLP‐1 RAs) effectively reduce HbA1c, but via very different mechanisms, making them an effective duet for combination therapy. Recently, drugs in both of these antidiabetic classes have been shown to reduce cardiovascular events, most probably by different mechanisms. SGLT2i appear to exert their CV protective actions by haemodynamic effects, while GLP‐1 RAs work via anti‐atherogenic/anti‐inflammatory mechanisms, raising the possibility that combined therapy with these 2 classes may produce additive CV benefits. The SGLT2i and GLP‐1 RAs also reduced macroalbuminuria, decreased the time for doubling of serum creatinine, and slowed the time to end‐stage renal disease. In this perspective, we review the potential benefit of combination SGLT2i/GLP‐1 RA therapy on metabolic‐cardiovascular‐renal disease in patients with type 2 diabetes mellitus.     

Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the prior position statements, published in 2012 and 2015, on the management of type 2 diabetes in adults. A systematic evaluation of the literature since 2014 informed new recommendations. These include additional focus on lifestyle management and diabetes self-management education and support. For those with obesity, efforts targeting weight loss, including lifestyle, medication and surgical interventions, are recommended. With regards to medication management, for patients with clinical cardiovascular disease, a sodium–glucose cotransporter-2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) receptor agonist with proven cardiovascular benefit is recommended. For patients with chronic kidney disease or clinical heart failure and atherosclerotic cardiovascular disease, an SGLT2 inhibitor with proven benefit is recommended. GLP-1 receptor agonists are generally recommended as the first injectable medication.     

The Effectiveness of Sodium-Glucose Cotransporter 2 Inhibitors and Glucagon-like Peptide-1 Receptor Agonists on Cardiorenal Outcomes: Systematic Review and Meta-analysis

BackgroundEvidence for the cardiorenal risk reduction properties of antihyperglycemic medications originally prescribed for type 2 diabetes, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) is rapidly emerging. We completed a meta-analysis of recent literature to provide evidence-based estimates of benefit across various populations and outcomes.MethodsWe searched Medline and Cochrane databases from 2015 to September 2021 for randomized controlled trials of SGLT2i and GLP-1RA with placebo control. Reviewers screened citations, extracted data, and assessed the risk of bias and certainty of evidence. We assessed statistical and methodological heterogeneity and performed a meta-analysis of studies with similar interventions and components.ResultsA total of 137,621 adults (51% male) from 19 studies were included; 14 studies with unclear risk of bias and 5 with low risk of bias. Compared with standard of care, use of SGLT2i showed significant reductions for the outcome of cardiovascular (CV) mortality (14%), any-cause mortality (13%), major adverse CV events (MACE) (12%), heart failure (HF) hospitalization (31%), CV death or HF hospitalization (24%), nonfatal myocardial infarction (10%), and kidney composite outcome (36%). Treatment with GLP-1RA was associated with significant reductions for the outcome of CV mortality (13%), any-cause mortality (12%), MACE (14%), CV death or HF hospitalization (11%), nonfatal stroke (16%), and kidney composite outcome (22%).ConclusionsThe use of GLP-1RA and SGLT2i leads to a statistically significant benefit across most cardiorenal outcomes in the populations studied. This review shows a role for SGLT2i and GLP-1RA in cardiorenal protection in adults, independent of type 2 diabetes status.     

Navigating the “MACE” in Cardiovascular Outcomes Trials and decoding the relevance of Atherosclerotic Cardiovascular Disease benefits versus Heart Failure benefits

The publication of results from recent cardiovascular outcome trials (CVOTs) has transformed the landscape of diabetes treatment. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium glucose co-transporter-2 (SGLT2) inhibitors have demonstrated CV benefits in large, well-conducted, randomized studies. Today, empagliflozin, canagliflozin and liraglutide are US Food and Drug Administration-approved not only for glucose-lowering, but also to reduce the risk of cardiovascular (CV) events/CV mortality in people with type 2 diabetes (T2DM) and established CV disease (CVD)/high CVD risk. Although the CVOTs were primarily powered for CV safety (non-inferiority), they also demonstrated CV efficacy (superiority). This initially surprised many in the diabetes community, but the replication of the CV benefits with different compounds in the same class alleviated concerns about the CV benefits being chance findings. However, many questions remain. While the heterogeneity in the CV benefits in the various CVOTs can be attributed to the variability in CV risk in the different studies, the reason(s) for the differences in the CV benefits between the GLP-1RA class and the SGLT2 inhibitor class appear to be more complex. An analysis of major adverse cardiovascular events (MACE) in the CVOTs shows that the CV benefits of GLP-1RAs are predominantly specific to atherosclerotic CV events (non-fatal myocardial infarction [MI], non-fatal stroke and CV death). By contrast, the SGLT2 inhibitors do not have any significant effects on atherosclerotic CV events (non-fatal MI/stroke). Their benefits are predominantly on hospitalization for heart failure (HF), suggesting effects primarily on myocardial function (“the pump”), and not on the “pipes” (coronary arteries). In the present review, we discuss the rationale for the conduct of CVOTs, highlight the inability of the classic three-point MACE to capture the entire spectrum of atherosclerotic and non-atherosclerotic CVD morbidity, especially HF in T2DM, and discuss the results of the CVOTs with a focus on the clinical significance of atherosclerotic CVD (ASCVD) versus HF, which develops in a sizeable proportion of people with diabetes and without prior ASCVD.     

Prevalence of SGLT2i and GLP1RA use among US adults with type 2 diabetes

AimsTo determine national prevalence of sodium-glucose contransporter-2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP1RA) use among adults with type 2 diabetes mellitus (T2DM).MethodsWe studied adults with T2DM and eGFR ≥ 30 mL/min/1.73 m² who participated in the cross-sectional National Health and Nutrition Examination Survey (NHANES), focusing on the 2017–2020 examination cycle, a key time period prior to widespread dissemination of pivotal trial results and corresponding clinical practice guidelines. We tested prevalence of SGLT2i and GLP1RA use among subgroups based on demographic variables and relevant comorbidities, including chronic kidney disease (CKD), congestive heart failure (CHF), and atherosclerotic cardiovascular disease (ASCVD). We compared use of SGLT2i and GLP1RA to other glucose-lowering medications and assessed trends from prior NHANES cycles.ResultsAmong 1375 participants studied in 2017–2020, mean age was 60 years, 46% were women, 13% self-identified as non-Hispanic Black, 10% self-identified as Mexican American, 37% had CKD, 8.5% had CHF, and 23% had ASCVD. The prevalence of SGLT2i and GLP1RA use was 5.8% and 4.4%, respectively. Among adults with CKD, CHF, or ASCVD, SGLT2i were used by 7.7% and GLP1RA were used by 3.5%. Differences in SGLT2i or GLP1RA use were observed by age, race, ethnicity, health insurance status, body mass index, and by whether a single healthcare provider was identified as responsible for diabetes management. Biguanides, sulfonylureas, DPP-4 inhibitors, and insulin were used more frequently than SGLT2i or GLP1RA. Prevalence of SGLT2i but not GLP1RA use increased significantly from 2013–2014 to 2017–2020.ConclusionsSGLT2i and GLP1RA use is low among adults with T2DM, including among those with strong indications. Enhanced implementation of these agents is crucial to improving kidney and cardiovascular outcomes and mitigating health disparities in T2DM.