Cardiologists' approach to managing cardiovascular risk in patients with type 2 diabetes

In patients with type 2 diabetes (T2D), cardiovascular disease (CVD) has long been the leading cause of morbidity and mortality.1 Historically, the mainstay of cardiovascular risk reduction in patients with T2D has been controlling CVD risk factors such as hypertension and hypercholesterolemia; this remains strongly indicated in current United States T2D guidelines.2 Although metformin is safe and effective for glucose lowering, its effect on macrovascular outcomes is modest at best.3 In fact, tight glycemic control has not been shown to reduce CVD events in patients withT2D4 and A1C is not an ideal surrogate marker of CVD risk. Other anti-hyperglycemic agents (AHAs), such as sulfonylureas and thiazolidinediones, have raised cardiovascular safety concerns, which led the US Food and Drug Administration (FDA) in 2008 to require that all new T2D drugs demonstrate cardiovascular safety.5 However, until recently, no specific AHAs had proven CVD outcome benefits. This era has ended, because selected glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RA) and sodium-glucose cotransporter 2 (SGLT2) inhibitors have now been demonstrated to reduce CVD events and mortality (Table 1). In light of these emerging data, the paradigm of CVD risk reduction in patients with T2D, specifically those with prevalent atherosclerotic CVD, must now evolve beyond simple risk factor control to include expanded use of these new agents proven to improve CVD outcomes, and cardiologists are now called on to take a greater role in the care of patients with T2D, partnering with endocrinologists and primary care physicians.

1 GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS

The currently approved GLP-1RAs are injectable compounds that mimic the action of the incretin hormone GLP-1, delaying gastric emptying, decreasing glucagon release, and increasing insulin secretion in response to an oral glucose load. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial9 recruited patients with T2D either at high risk for or with established CVD. Liraglutide use was associated with a significant reduction in the primary three-point composite outcome of major adverse cardiovascular events (MACE), defined as cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke (hazard ratio [HR] 0.87; 95% confidence interval [CI] 0.78-0.97). Liraglutide has been approved by the FDA for reducing MACE and cardiovascular death in patients with T2D and established CVD (https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022341s027lbl.pdf).

Semaglutide, a once weekly GLP-1RA, was evaluated in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) trial.10 That trial showed a 26% reduction in MACE for semaglutide vs placebo (HR 0.74; 95% CI 0.58-0.95). The efficacy of an oral formulation of semaglutide is now being assessed in the Trial investigating the Cardiovascular Safety of Oral Semaglutide in Subjects with Type 2 Diabetes (PIONEER-6).14 The Albiglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Cardiovascular Disease (HARMONY OUTCOMES) trial11 showed analogous results of superiority vs placebo for MACE (HR 0.78; 95% CI 0.68-0.90). The Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial assessed the efficacy of dulaglutide, another once weekly formulation of GLP-1RA. A company press release announced REWIND has met its primary efficacy endpoint of superiority for three-point MACE; detailed results are expected to be published soon. The improvements in MACE seen in LEADER, SUSTAIN-6, and HARMONY OUTCOMES appear to represent a primarily atherosclerotic benefit. Two liraglutide trials in patients with heart failure with reduced ejection fraction showed a non-significant numerical imbalance unfavorable for liraglutide, raising concern for potential harm in these patients.15, 16

Two additional GLP-1RAs have been shown to be non-inferior to placebo in cardiovascular outcome trials, namely lixisenatide (Evaluation of Lixisenatide in Acute Coronary Syndrome: ELIXA trial12) and exenatide (Exenatide Study of Cardiovascular Event Lowering Trial: EXSCEL trial13). Lixisenatide was studied against placebo in post-ACS patients with T2D and demonstrated non-inferiority, but not statistical superiority, with regard to the primary composite outcome of MACE or hospitalization for heart failure (HR 1.02; 95% CI 0.89-1.17).17 Although it failed to demonstrate statistical superiority, the point estimate for the primary composite outcome of MACE for exenatide compared with placebo (HR 0.91; 95% CI 0.83-1.00; P < 0.001) was qualitatively in line with the other cardiovascular beneficial GLP-1RA. All GLP-1RAs studied to date have demonstrated cardiovascular safety, but there appears to be clinically significant heterogeneity of cardiovascular effect across the trials. This may be explained by differences in the populations studied (e.g., ELIXA recruited exclusively post-ACS patients), variations in drug pharmacokinetics (e.g., shorter versus longer acting), potency, or adherence.9, 10, 12, 13 Therefore, until further information is available, clinicians should focus on the proven agents within the class.

2 SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS

Several SGLT2 inhibitors have also demonstrated cardiovascular benefit. These oral agents block SGLT2 located in the proximal tubule of the kidneys, leading to both natriuresis and glucosuria. This effect restores the tubuloglomerular feedback system and lessens hyperfiltration, the main driver of diabetic kidney disease.18

The EMPA-REG OUTCOME trial19 was the first cardiovascular outcome trial to demonstrate superiority compared with placebo, showing a 14% relative risk reduction in MACE with empagliflozin (HR 0.86; 95% CI 0.74-0.99) and a 35% reduction in the risk of heart failure hospitalization (HR 0.65; 95% CI 0.5-0.85). This heart failure benefit was consistent across different levels of kidney function;18-20 the EMPA-REG OUTCOME kidney outcomes have been published as a prespecified secondary analysis.6 Empagliflozin was associated with a 46% reduction in the composite renal outcome of doubling of serum creatinine with estimated glomerular filtration rate (eGFR) <45 mL/min per 1.73 m², initiation of renal-replacement therapy, or death from renal disease (HR 0.54; 95% CI 0.40-0.75).6

The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program7 combined data from two trials, CANVAS and CANVAS-R, randomizing 10 142 participants to canagliflozin versus placebo. The CANVAS Program showed a 14% reduction in MACE (HR 0.86; 95% CI 0.75-0.97) for canagliflozin versus placebo, along with a reduction in hospitalization for heart failure and an improvement in kidney outcomes.7 A significantly higher risk of lower extremity amputations, particularly in participants with prior amputations, peripheral arterial disease, neuropathy, or diabetic foot ulcers, was an unexpected safety signal with canagliflozin, leading to an FDA boxed warning. The significance of this concern in other SGLT2i remains unclear, but post hoc analysis of EMPA-REG OUTCOME did not show an amputation signal.7, 19

The dapagliflozin effect on cardiovascular events (DECLARE-TIMI 58)8 trial is the largest cardiovascular outcome trial conducted with patients with T2D to date. The DECLARE-TIMI 58 trial randomized 17 160 patients (10 186 without atherosclerotic CVD) to dapagliflozin versus placebo. Dapagliflozin did not demonstrate statistically significantly lower rates of MACE (HR 0.93; 95% CI 0.84-1.03), but did lower the composite of cardiovascular death or heart failure hospitalization (HR 0.83; 95% CI 0.73-0.95).8 Whether variation between DECLARE-TIMI 58, EMPA-REG OUTCOME, and the CANVAS trials is due to different inclusion criteria versus chance alone is unclear.

Targeting the high-risk population with T2D and chronic kidney disease (CKD), the Phase 3 Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in participants with Diabetic Nephropathy (CREDENCE) trial, enrolled 4401 patients with advanced CKD, is the first trial of SGLT2 inhibitors with a dedicated renal primary outcome. Canagliflozin showed a 30% reduction in the primary composite outcome of end-stage renal disease, doubling of serum creatinine or cardiovascular death (HR 0.70; 95% CI 0.59-0.82) and was consistent with the CANVAS results for MACE and HF hospitalization.17 Several large observational studies, such as Comparative Effectiveness of Cardiovascular Outcomes in new users of SGLT-2 inhibitors (CVD-REAL)21 and CVD-REAL 222, have been consistent with the cardiovascular outcomes benefit shown in trials, although the results of observational studies should be interpreted with caution due to the high potential for residual confounding compared with randomized trial data.

The ease of use of SGLT2 inhibitors, coupled with impressive cardiovascular outcome trial results and the beneficial effect on renal disease progression seen in CREDENCE, make these drugs broadly appealing, particularly in patients at risk of heart failure. All three published cardiovascular outcome trials with SGLT2 inhibitors have shown improvement in heart failure outcomes.7, 8, 19, 23 It is important to highlight that in EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58, only approximately 10% of patients had heart failure at baseline. The ongoing empagliflozin trials EMPEROR REDUCED and PRESERVED,24, 25 as well as the dapagliflozin trial Dapa-HF,26 are currently assessing the safety and efficacy of SGLT2 inhibitors in the established heart failure population. Interestingly, the EMPEROR trials are also recruiting patients without T2D. It is likely that these ongoing trials will confirm and extend our understanding of the kidney outcome benefits of SGLT2i.

3 CONCLUSIONS

Contemporary T2D antihyperglycemic treatment in patients with CVD has shifted its primary focus from glycemic control to directly improving cardiovascular outcomes. It is becoming increasingly clear that the choice of therapies should give preference to evidence-based medicines that lower cardiovascular risk. Ongoing trials may expand SGLT2 inhibitor use to patients without atherosclerotic cardiovascular disease but with heart failure or CKD. This is an exciting time in cardiovascular medicine, as the CVD specialist transitions to a more prominent role as part of a multidisciplinary approach to the care of patients with T2D.

在2型糖尿病(T2D)患者中，心血管疾病(CVD)一直都居于高发病率与高死亡率的并发症之首¹。在历史上，降低T2D患者心血管风险的主要手段是控制CVD危险因素(如高血压与高胆固醇血症)；在当前的美国T2D指南中仍然很强调这一点²。虽然使用二甲双胍降糖治疗非常安全并且有效，但是充其量它对大血管结果也只有适度的影响³。事实上，严格控制血糖并沒有显示能够减少T2D患者的CVD事件⁴，而A1C也并非是一个理想的CVD风险替代指标。其他降糖药物(AHAs)如磺脲类与噻唑烷二酮类，已经引起,了对心血管安全的担忧，这导致美国食品药品监督管理局(FDA)在2008年要求所有新的T2D治疗药物都要证明心血管安全性才能上市⁵。然而，直到最近，还没有一个明确的AHAs被证实可使得CVD获益的结局。目前这一时代已经结束，因为被选择的几种胰高血糖素样肽-1(GLP-1)受体激动剂(GLP-1RA)与钠-葡萄糖共转运体2(SGLT2)抑制剂已经证明可减少CVD事件与死亡率(表1)。这些新的数据表明，要减少T2D患者CVD风险的典范，特别是对已经有明显动脉粥样硬化性CVD的患者,，现在除了要控制简单的危险因素，还必须要扩大范围使用这些已经被证实能够改善CVD结果的新型药物，现在还要求心脏病学家要与内分泌学家以及初级保健医师一起合作，在T2D患者的治疗中发挥更大的作用。

1 胰高血糖素样肽-1受体激动剂

目前批准上市的GLP-1RAs都是注射制剂，它们都是模拟肠促胰岛素GLP-1作用的化合物，可以延缓胃排空，减少胰高血糖素的释放，并且口服葡萄糖负荷后还可以增加胰岛素的分泌。利拉鲁肽在糖尿病患者中的疗效与作用:评估心血管预后结果(Cardiovascular Outcomes in New Users of SGLT-2-Inhibitors: Evaluation of Cardiovascular Outcome Results，LEADER)试验⁹招募了高CVD风险或者已经明确诊断CVD的T2D患者。使用利拉鲁肽治疗后可导致主要不良心血管事件(MACE)中的主要3点复合终点显著减少，包括心血管死亡、非致命性心肌梗死(MI)与非致命性中风(风险比[HR]为0.87；95%置信区间[CI]为0.78-0.97)。利拉鲁肽已经被FDA批准用于合并明确CVD的T2D患者以减少MACE与心血管死亡(https://www.accessdata.fda.gov/ drugsatfda_docs /label/2017/022341s027lbl.pdf)。

索马鲁肽是一种每周使用一次的GLP-1RA，在2型糖尿病受试者使用索马鲁肽治疗评估心血管与其他长期结果的试验(Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes，SUSTAIN-6)¹⁰中对其进行了评估。该试验结果表明，索马鲁肽组与安慰剂组相比MACE减少了26%(HR为0.74；95% CI为0.58-0.95)。目前正在2型糖尿病受试者中评估口服索马鲁肽治疗后心血管安全性(Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes，PIONEER-6)，分析一种索马鲁肽口服剂型的疗效¹⁴。合并心血管疾病的2型糖尿病患者使用阿必鲁肽治疗后心血管结果(The Albiglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Cardiovascular Disease，HARMONY OUTCOMES)试验¹¹的结果也证实了治疗组具有类似的优于安慰剂组的MACE结果(HR为0.78；95% CI为0.68-0.90)。度拉糖肽是另一种每周注射一次的GLP-1RA制剂，在研究每周一次肠促胰岛素治疗后心血管事件(The Researching Cardiovascular Events with a Weekly Incretin in Diabetes，REWIND)的试验中评估了度拉糖肽的疗效。公司新闻稿宣布，在REWIND试验中达到了主要疗效终点，治疗组的3点MACE结果更优；期待不久就能公布具体结果。在LEADER、SUSTAIN-6以及HARMONY OUTCOMES试验中我们看到了MACE结果都有所改善，这似乎意味着主要益处就是可以改善动脉粥样硬化。在两项射血分数下降的心力衰竭患者中使用利拉鲁肽治疗的试验里，结果显示利拉鲁肽组在数值上出现了非显著性不利的失衡，这使得人们要更关注这些患者是否会受到潜在的伤害^15,16。

目前发现另外两种GLP-1RAs治疗组的心血管结果非劣于安慰剂组，即利西那肽(评估利西那肽在急性冠状动脉综合征中的作用:ELIXA试验¹²)与艾塞那肽(艾塞那肽减少心血管事件试验研究:EXSCEL试验¹³)。在ACS后的T2D患者使用利西那肽治疗与使用安慰剂治疗的对照研究中证实了非劣性，但是没有发现治疗组的主要MACE复合结果或者心衰住院具有统计学意义的优越性(HR为1.02；95% CI为0.89-1.17)¹⁷。虽然不能证实治疗组具有统计学意义的优越性，但是在艾塞那肽与安慰剂的对照试验中发现，治疗组主要MACE复合结果的点估计值(HR为0.91；95% CI为0.83-1.00；P<0.001)在性质上与其他GLP-1RA的心血管获益相一致。迄今为止所有的GLP-1RAs研究都证实了心血管安全性，但是在所有的试验中发现临床上心血管效应似乎存在显著的异质性。这可以通过研究人群(例如ELIXA试验招募的受试者排除了ACS后的患者)、药物药代动力学变化(例如短效与长效)、效力或者依从性的差异来解释^9,10,12,13。因此，在获得进一步的信息之前，临床医生应该选择在同类中已被证实能够获益的药物。

2 钠-葡萄糖共转运体2抑制剂

目前有几种SGLT2抑制剂也被证实具有心血管益处。这些口服药物可以抑制位于肾脏近端小管的SGLT2，导致尿钠与尿糖增多。这种效应可以恢复管球反馈系统减轻超滤过，而这正是糖尿病肾病的主要驱动因素¹⁸。

EMPA-REG OUTCOME试验¹⁹是第一个证实治疗组优于安慰剂组的心血管结果试验，结果表明恩格列净组MACE相对风险下降了14%(HR为0.86；95% CI为0.74-0.99)，心衰住院风险下降了35%(HR为0.65；95% CI为0.5-0.85)。无论肾功能处于何种不同水平，这种心衰获益都是一致的^18–20；因为预先已经指定要进行二次分析，目前EMPA-REG OUTCOME试验的肾脏结果已经发表了⁶。使用恩格列净治疗后复合肾脏终点(血清肌酐倍增并且预估的肾小球滤过率[eGFR]< 45毫升/分钟/每1.73 m²、开始肾脏透析疗法或者死于肾脏疾病)减少了46%(HR为0.54；95% CI为0.40-0.75)⁶。

卡格列净心血管评估研究(The Canagliflozin Cardiovascular Assessment Study，CANVAS)项目⁷将两项试验(CANVAS与CANVAS-R)的数据进行了汇总，共10142名参与者被随机分配到卡格列净治疗组或者安慰剂组。CANVAS项目结果表明，卡格列净治疗组与安慰剂组相比MACE减少了14%(HR为0.86；95% CI为0.75-0.97)，与此同时心衰住院明显减少并且肾脏结果也有所改善⁷。坎格列净治疗组出现了一个意外的安全性问题，那就是下肢截肢的风险显著升高，尤其是在既往有截肢、外周动脉疾病、神经病变或者糖尿病足溃疡的参与者中，这导致了FDA的黑框警告。在其他SGLT2i中是否存在这个重要的问题目前尚未明确，但是EMPA-REG OUTCOME试验的事后分析并没有发现截肢增多的问题^7,19。

达格列净对心血管事件影响(DECLARE-TIMI 58)⁸试验是一项在T2D患者中进行的迄今为止最大型的心血管结果试验。在DECLARE-TIMI 58试验中将17160名患者(其中10186名没有动脉粥样硬化性CVD)随机分配到达格列净治疗组或者安慰剂组。结果并没有证实达格列净可以显著降低MACE发生率(HR为0.93；95% CI为0.84-1.03)，但是可以减少心血管死亡或者心衰住院的复合终点(HR为0.83；95% CI为0.73-0.95)⁸。在DECLARE-TIMI 58、EMPAREG OUTCOME与CANVAS试验之间存在的差异究竟是因为入选标准的不同还是因为单纯的偶然性原因目前还尚未明确。

针对T2D合并慢性肾病(CKD)的高危人群，在糖尿病肾病参与者中评估卡格列净对肾脏以及心血管结果影响(Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in participants with Diabetic Nephropathy，CREDENCE)的3期试验中，纳入了4401名晚期CKD患者，这是SGLT2抑制剂首次专门针对肾脏主要结果的试验。结果表明卡格列净可以减少30%的主要复合结果(包括终末期肾病、血清肌酐倍增或者心血管死亡，HR为0.70；95% CI为0.59-0.82)，这与CANVAS试验中的MACE以及HF住院结果相一致¹⁷。有几项大型的观察性研究，例如在初次使用SGLT-2抑制剂治疗的患者中对比评估对心血管结果影响(Comparative Effectiveness of Cardiovascular Outcomes in new users of SGLT-2 inhibitors，CVD-REAL)²¹试验与CVD-REAL 2²²试验，得出的结果与随机试验中显示的心血管结果获益相一致，尽管我们应该谨慎地解释观察性研究的结果，因为与随机试验数据相比，观察性研究很可能还残留有混杂因素。

SGLT2抑制剂使用方便，再加卓越的心血管预后试验结果，并且在CREDENCE试验中还看到了对肾脏疾病的进展具有有益的效应，这些优点使得这类药物具有广泛的吸引力，尤其适合于具有心力衰竭风险的患者。3个已经发表的SGLT2抑制剂相关的心血管结果试验全部都证实了可以改善心衰结果^7,8,19,23。需要强调的一点是，在EMPA-REG OUTCOME、CANVAS以及DECLARE-TIMI 58试验中，基线时大约只有10%的患者合并心衰。当前正在进行的使用恩格列净治疗的EMPEROR REDUCED与PRESERVED试验^24,25，以及使用达格列净治疗的Dapa-HF试验²⁶，目前正在评估SGLT2抑制剂在明确合并心衰人群中的安全性与有效性。令人感兴趣的是，EMPEROR试验还招募了没有合并T2D的患者。这些正在进行的试验将很有可能证实SGLT2i有益于改善肾脏结果并且扩大我们对它们的了解。

3 结论

目前，对于合并CVD的T2D患者来说，降糖治疗的主要目标已经从控制血糖转向直接改善心血管结果。目前已经越来越明确的是，在我们选择治疗药物的时候应该优先选择具有循证医学证据能够减少心血管风险的药物。正在进行的试验有可能会将SGLT2抑制剂的适应人群扩展到没有动脉粥样硬化性心血管疾病但却合并心衰或者CKD的患者。对于心血管医学来说这是一个激动人心的时刻，CVD专家正在转变角色成为更重要的多学科治疗T2D患者专家组的一员。

DISCLOSURE

None declared.