溯谈2型糖尿病高血糖治疗路径北大核心CSCD

优化2型糖尿病(T2DM)患者的高血糖治疗路径是有效控制血糖、延缓并发症发生发展并改善临床结局的重要策略。循证医学证据的积累推动着糖尿病治疗理念及高血糖管理路径的更新。近年来的研究表明,钠-葡萄糖共转运蛋白2抑制剂(SGLT2i)和胰高糖素样肽-1受体激动剂(GLP-1RA)显著改善糖尿病患者的心肾结局,推动T2DM高血糖管理从以控制血糖为目标的治疗路径转变为以改善心肾结局为目标的治疗策略。     

溯谈2型糖尿病高血糖治疗路径

优化2型糖尿病（T2DM）患者的高血糖治疗路径是有效控制血糖、延缓并发症发生发展并改善临床结局的重要策略。循证医学证据的积累推动着糖尿病治疗理念及高血糖管理路径的更新。近年来的研究表明,钠-葡萄糖共转运蛋白2抑制剂（SGLT2i）和胰高糖素样肽-1受体激动剂（GLP-1RA）显著改善糖尿病患者的心肾结局,推动T2DM高血糖管理从以控制血糖为目标的治疗路径转变为以改善心肾结局为目标的治疗策略。     

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。     

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。     

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。     

钠-葡萄糖共转运蛋白2抑制剂联合胰岛素治疗2型糖尿病中国专家共识(2023版)

口服降糖药(OAD)联合胰岛素治疗是2型糖尿病(T2DM)患者血糖控制达标的重要方法之一。新型OAD钠-葡萄糖共转运蛋白2抑制剂(SGLT2i)在有效降糖的同时还可发挥心肾保护作用。近年来, SGLT2i在T2DM患者中广泛使用, 如何将这一类新型OAD与胰岛素安全、有效地联合应用, 成为T2DM临床管理中需要关注的问题。本共识针对SGLT2i联合胰岛素的使用原则、患者人群选择、联合用药启动流程、治疗优势、联合治疗的安全性和注意事项等问题方面进行证据梳理, 并结合我国的临床实际用药经验, 提出13条推荐意见。旨在指导广大临床医师规范、合理用药, 从而改善我国T2DM患者的临床结局。     

从药理学角度看胰高糖素样肽-1受体激动剂的心血管保护作用机制

2型糖尿病(T2DM)患者具有更高的心血管风险。近年来多项研究显示胰高糖素样肽-1受体激动剂(GLP-1RA)不仅可以降低T2DM患者的血糖和体重, 更重要的是此类制剂的心血管结局试验(CVOT)结果表明, 部分GLP-1RA可以降低T2DM患者主要不良心血管事件的发生率。但GLP-1RA的心血管保护机制却始终未被完全阐明。胰高糖素样肽-1受体在心脏和血管中处于低表达水平, 这提示了胰高糖素样肽-1可能对心血管系统产生直接和间接作用。而多个CVOT数据表明, GLP-1RA的药物分子结构也与心血管获益密切相关。因此, 深入了解GLP-1RA的心血管保护分子机制, 不仅可以更好地在临床中应用该类药物, 还可以为未来基于胰高糖素样肽-1的全新药物开发提供重要思路。     

钠-葡萄糖共转运蛋白2抑制剂的临床应用:始于降糖超越降糖北大核心CSCD

钠-葡萄糖共转运蛋白2抑制剂(SGLT2i)是一类近年来受高度重视的新型口服降糖药,以肾脏近曲小管SGLT2为作用靶点,降低肾糖阈,促进尿糖排出,从而实现降糖作用。SGLT2i不仅具有不依赖胰岛素的独特降糖作用,还有超越降糖外的获益,如减轻体重、降低血压、调节血脂、降低尿酸、改善代谢相关脂肪性肝病(MAFLD)。更重要的是,SGLT2i能显著减少2型糖尿病(T2DM)患者心血管疾病终点事件,对伴或不伴T2DM的患者心衰和慢性肾脏病均具有保护作用,在T2DM的综合管理中发挥重要作用。     

中国成人2型糖尿病患者糖化血红蛋白控制目标及达标策略专家共识

糖化血红蛋白(HbA1C)控制目标应遵循患者为中心的个体化原则,即根据患者的年龄、病程、健康状况、药物不良反应风险等因素实施分层管理。本共识建议一般成人2型糖尿病(T2DM)患者的HbA1C控制目标为<7.0%,并对其他情况下的HbA1C目标值作出推荐。本共识建议将二甲双胍作为T2DM患者单药治疗的首选,α-糖苷酶抑制剂(AGI)或胰岛素促泌剂作为单药治疗的备选。进行联合治疗时,建议根据患者是否合并动脉粥样硬化性心血管疾病(ASCVD)、心力衰竭(HF)或慢性肾脏疾病(CKD)进行分层。如患者合并ASCVD,建议在具备条件的情况下联合有心血管获益证据的胰升糖素样肽-1受体激动剂(GLP-1RA)或钠-葡萄糖共转运蛋白2抑制剂(SGLT2i)。如患者合并CKD,建议联合用药时在条件允许的情况下首选有肾脏获益证据的SGLT2i,在患者不能使用SGLT2i时可选择有肾脏获益证据的GLP-1RA。如患者合并HF,建议在条件允许时选择SGLT2i。如患者未合并ASCVD、HF或CKD时,可根据基线HbA1C水平、低血糖风险、体重、经济状况、药物可及性等因素选择联合的药物。     

新型降糖药物对心肾保护机制及安全性的研究进展

新型降糖药物能改善心血管和肾脏结局的临床获益,且具有良好的安全性,但确切的心肾保护机制和安全性还有待进一步探索。综述胰高血糖素样肽-1受体激动剂(GLP-1RA)、二肽基肽酶-4抑制剂(DPP-4i)和钠-葡萄糖共转运蛋白-2抑制剂(SGLT-2i)3种新型降糖药的降糖机制、心肾保护作用的可能机制、研究进展及用药安全性,为3种新型降糖药的临床应用提供参考。     

Effects of glucose-lowering agents on surrogate endpoints and hard clinical renal outcomes in patients with type 2 diabetes

Diabetic kidney disease (DKD) represents an enormous burden in patients with type 2 diabetes mellitus (T2DM). Preclinical studies using most glucose-lowering agents have suggested renal-protective effects, but the proposed mechanisms of renoprotection have yet to be defined, and the promising results from experimental studies remain to be translated into human clinical findings to improve the prognosis of patients at risk of DKD. Also, it is important to distinguish effects on surrogate endpoints, such as decreases in albuminuria and estimated glomerular filtration rate (eGFR), and hard clinical endpoints, such as progression to end-stage renal disease (ESRD) and death from renal causes. Data regarding insulin therapy are surprisingly scarce, and it is nearly impossible to separate the effects of better glucose control from those of insulin per se, whereas favourable preclinical data with metformin, thiazolidinediones and dipeptidyl peptidase (DPP)-4 inhibitors are plentiful, and positive effects have been observed in clinical studies, at least for surrogate endpoints. The most favourable renal results have been reported with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium–glucose cotransporter type-2 inhibitors (SGLT2is). Significant reductions in both albuminuria and eGFR decline have been reported with these classes of glucose-lowering medications compared with placebo and other glucose-lowering agents. Moreover, in large prospective cardiovascular outcome trials using composite renal outcomes as secondary endpoints, both GLP-1RAs and SGLT2is added to standard care reduced renal outcomes combining persistent macro-albuminuria, doubling of serum creatinine, progression to ESRD and kidney-related death; however, to date, only SGLT2is have been clearly shown to reduce such hard clinical outcomes. Yet, as the renoprotective effects of SGLT2is and GLP-1RAs appear to be independent of glucose-lowering activity, the underlying mechanisms are still a matter of debate. For this reason, further studies with renal outcomes as primary endpoints are now awaited in T2DM patients at high risk of DKD, including trials evaluating the potential add-on benefits of combined GLP-1RA–SGLT2i therapies.     

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.     

Management of heart failure and type 2 diabetes mellitus: Maximizing complementary drug therapy

Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease and occurs in ~25% of patients with heart failure (HF). Patients with co-morbid HF and T2DM are at elevated risk of adverse outcomes, making optimization of complementary drug therapies essential. While research is ongoing, recent advances in drug therapy, including the introduction of sacubitril/valsartan for HF with reduced ejection fraction and the finding of positive cardiovascular effects of glucose-lowering agents (particularly sodium-glucose co-transporter-2 [SGLT2] inhibitors) have the potential to transform pharmacologic management of co-morbid HF and T2DM. In this review, we provide a comprehensive overview of cardiovascular clinical trials of therapies for HF and diabetes mellitus to date and identify areas requiring further investigation. We also discuss the pathophysiologic overlap of the two diseases and explore the complementary therapeutic effects of HF and T2DM drugs, with a particular focus on sacubitril/valsartan and SGLT2 inhibitors.     

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.     

Cardiovascular effectiveness of glucagon-like peptide 1 receptor agonists versus dipeptidyl peptidase-4 inhibitors in type 2 diabetes: A meta-analysis based on propensity score-matched studies

Glucagon-like peptide 1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) are two novel classes of hypoglycemic agents. The relative cardiovascular effectiveness between these two drug classes in patients with type 2 diabetes (T2D) is unestablished due to the absence of large cardiovascular outcome trials directly comparing DPP-4i with GLP-1RA. We aimed to incorporate large propensity score-matched cohort studies to conduct a meta-analysis, to determine the relative effectiveness of GLP-1RA versus DPP-4i on cardiovascular endpoints in T2D patients. Compared to DPP-4i, GLP-1RA was associated with the significantly lower risks of major adverse cardiovascular events [MACE] (HR 0.76, 95% CI 0.63?0.92), cardiovascular mortality (HR 0.59, 95% CI 0.37?0.95), myocardial infarction (HR 0.89, 95% CI 0.80?0.98), stroke (HR 0.86, 95% CI 0.76?0.96), and all-cause mortality (HR 0.63, 95% CI 0.42?0.96) in T2D patients; whereas these two drug classes had the similar risk of hospitalization for heart failure [HHF] (HR 0.95, 95% CI 0.77–1.16). Meta-regression analyses showed that six factors (i.e., mean age, female proportion, cardiovascular disease proportion, heart failure proportion, and the proportions of receiving metformin and insulin at baseline) did not significantly affect the effects of GLP-1RA on MACE and HHF (P ≥ 0.076). This meta-analysis provides the direct evidence regarding the relative cardiovascular effectiveness of GLP-1RA versus DPP-4i from real-world studies, and its findings suggest that among T2D patients GLP-1RA should be considered in preference to DPP-4i as for preventing atherosclerotic cardiovascular events and death in clinical practice.     

Cardiovascular protection with sodium-glucose co-transporter-2 inhibitors in type 2 diabetes: Does it apply to all patients?

Patients with type 2 diabetes (T2D) are at an increased risk of cardiovascular disease (CVD). Cardiovascular risk in these patients should be considered as a continuum, and comprehensive treatment strategies should aim to target multiple disease risk factors. Large-scale clinical trials of sodium-glucose co-transporter-2 (SGLT2) inhibitors have shown an impact on cardiovascular outcomes, including heart failure hospitalization and cardiovascular death, which appears to be independent of their glucose-lowering efficacy. Reductions in major cardiovascular events appear to be greatest in patients with established CVD, particularly those with prior myocardial infarction, but are independent of heart failure or renal risk. Most large-scale trials of SGLT2 inhibitors predominantly include patients with T2D with pre-existing CVD and high cardiovascular risk at baseline, limiting their applicability to patients typically observed in clinical practice. Real-world evidence from observational studies suggests that there might also be beneficial effects of SGLT2 inhibitors on heart failure hospitalization and all-cause mortality in various cohorts of lower risk patients. The most common adverse events reported in clinical and observational studies are genital infections; however, the overall risk of these events appears to be low and easily managed. Similar safety profiles have been reported for elderly and younger patients. There is still some debate regarding the safety of canagliflozin in patients at high risk of fracture and amputation. Outstanding questions include specific patterns of cardiovascular protection according to baseline risk.     

European Society of Cardiology/Heart Failure Association position paper on the role and safety of new glucose‐lowering drugs in patients with heart failure

Type 2 diabetes mellitus (T2DM) is common in patients with heart failure (HF) and associated with considerable morbidity and mortality. Significant advances have recently occurred in the treatment of T2DM, with evidence of several new glucose‐lowering medications showing either neutral or beneficial cardiovascular effects. However, some of these agents have safety characteristics with strong practical implications in HF [i.e. dipeptidyl peptidase‐4 (DPP‐4) inhibitors, glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA), and sodium–glucose co‐transporter type 2 (SGLT‐2) inhibitors]. Regarding safety of DPP‐4 inhibitors, saxagliptin is not recommended in HF because of a greater risk of HF hospitalisation. There is no compelling evidence of excess HF risk with the other DPP‐4 inhibitors. GLP‐1 RAs have an overall neutral effect on HF outcomes. However, a signal of harm suggested in two small trials of liraglutide in patients with reduced ejection fraction indicates that their role remains to be defined in established HF. SGLT‐2 inhibitors (empagliflozin, canagliflozin and dapagliflozin) have shown a consistent reduction in the risk of HF hospitalisation regardless of baseline cardiovascular risk or history of HF. Accordingly, SGLT‐2 inhibitors could be recommended to prevent HF hospitalisation in patients with T2DM and established cardiovascular disease or with multiple risk factors. The recently completed trial with dapagliflozin has shown a significant reduction in cardiovascular mortality and HF events in patients with HF and reduced ejection fraction, with or without T2DM. Several ongoing trials will assess whether the results observed with dapagliflozin could be extended to other SGLT‐2 inhibitors in the treatment of HF, with either preserved or reduced ejection fraction, regardless of the presence of T2DM. This position paper aims to summarise relevant clinical trial evidence concerning the role and safety of new glucose‐lowering therapies in patients with HF.