SGLT2 inhibitors for primary prevention of cardiovascular events

Sodium glucose cotransporter 2 (SGLT2) inhibitors have been approved for the treatment of type 2 diabetes mellitus since 2012. Early clinical trials with these agents demonstrated their capacity not only for lowering glucose but also for reducing weight and blood pressure, thus addressing several important components of the metabolic syndrome.1

The EMPA-REG study, the cardiovascular outcome study of empagliflozin, revolutionized our view of the drug and class while demonstrating robust reduction in major adverse cardiovascular events (MACE; hazard ratio [HR] [95% confidence interval (CI)] 0.86 [0.74, 0.99]), hospitalization for heart failure (HHF; HR [95% CI] 0.65 [0.50, 0.85])2 as well as marked improvement in renal outcomes (HR [95% CI] 0.61 [0.53, 0.70]).3 All patients included in the study had established atherosclerotic cardiovascular disease (ASCVD); thus, the effect of these agents on the primary prevention of cardiovascular events in patients with diabetes remained unknown.

The CANVAS program, which was published thereafter, included a mixed patient population with and without ASCVD, although the majority had established ASCVD. MACE was reduced with canagliflozin vs placebo (HR [95% CI]) 0.86 [0.75, 0.97]) and there was a trend to a greater effect in those with previous ASCVD (HR [95%CI] 0.82 [0.72, 0.95]) vs those without (HR [95% CI] 0.98 [0.74, 1.3]), interaction P value 0.18.4 HHF and renal outcomes showed robust reduction regardless of risk category.5

The majority of patients included in the cardiovascular outcome study of dapagliflozin — the DECLARE trial — had only risk factors but not established ASCVD. This trial thus presented a unique opportunity to assess the benefit of an SGLT2 inhibitor on the primary prevention of cardiovascular events.6 Dapagliflozin demonstrated a reduction in the co-primary composite endpoint of hospitalization for heart failure/cardiovascular death (HHF/CVD; HR [95% CI] 0.83 [0.73, 0.95]) yet did not achieve statistically significant superiority with respect to the second co-primary outcome of MACE (HR [95% CI] 0.93 [0.84, 1.03]).7 The renal benefits of dapagliflozin were of similar magnitude to those observed with empagliflozin and canagliflozin and were observed irrespective of risk status.5

A meta-analysis study assessed the cardiorenal outcomes of the three SGLT2 inhibitors with respect to their impact on primary vs secondary prevention of cardiovascular outcomes.5 The effect of the agents on MACE was dependent upon risk status — whereas benefit was shown in those with established ASCVD (HR [95% CI] 0.86 [0.80, 0.93]) yet not in primary prevention cohorts (HR [95% CI] 1.00 [0.87, 1.16]), interaction P value 0.05. Contrariwise, the robust reduction of HHF was independent of preexisting ASCVD (interaction P value 0.38), or history of heart failure (interaction P value 0.76). Similarly, the renal benefit was observed in patients with and without established ASCVD (interaction P value 0.71), although it was more pronounced in those with preserved renal function (interaction P value 0.026).5

According to these data, one may simply state that SGLT2 inhibitors carry no benefit in the primary prevention of cardiovascular events. However, this statement, although an accurate recap of the cardiovascular outcome trials data, does not cover the entire scope of the problem.

Cardiovascular disease is markedly increased in patients with diabetes.8 This increase is not annulled by glycemic control alone, although it is mitigated with improved control of glycemia and of concomitant metabolic derangements.9 Long-term control of glycemia as well as of blood pressure and lipids had been shown to markedly reduce cardiovascular morbidity and mortality following >7 years of follow-up.10 Multifactorial intervention, particularly when implemented in the early stages of diabetes, has thus been shown to reduce risk of complications and modify the natural history of disease.

Besides control of the “standard” cardiovascular risk factors (smoking, hypertension, dyslipidemia, dysglycemia) the clinical relevance of the cardio-renal axis is becoming increasing apparent. The presence of reduced estimated glomerular filtration rate markedly increases risk of cardiovascular disease and albuminuria is a marker of cardiovascular disease as well, with the combination of both leading to marked increase in risk.11, 12

SGLT2 inhibitors have consistently demonstrated striking improvements in renal outcomes. This includes both reversal of preexisting albuminuria, as well as reduced conversion from normo- to micro- or macro-albuminuria. Moreover, SGLT2 inhibitors have been shown to slow the decline in estimated glomerular filtration rate and lead to a significant reduction in end-stage renal disease.13-17 These benefits have been observed both in those with and without baseline chronic kidney disease and regardless of established ASCVD.5 It is therefore plausible that long-term therapy with SGLT2 inhibitors will eventually reduce cardiovascular morbidity and mortality by long-term preservation of renal function.

Additional cardiac benefits have been observed with SGLT2 inhibitors - the predominant being reduction in hospitalization for heart failure. Notably, this had been observed regardless of preexisting ASCVD, renal disease, or known heart failure.5 Most recently, this effect has been similarly observed in diabetic and nondiabetic individuals.18 This suggests that the beneficial effect of the drugs is not mediated by improved cardiac function secondary to mitigation of hyperglycemia. The hypothetical mechanisms leading to reduced HHF with SGLT2 inhibitors include hemodynamic effects, reduced arhythmogenicity of the myocardium secondary to shifting to a ketogenic metabolism, reduced sodium in the cardiac myocytes, or other mechanisms.19

Although a short-term effect on primary prevention of cardiovascular morbidity and mortality was not observed with SGLT2 inhibitors, it is possible that the robust improvement in renal outcomes alongside improvement in additional components of the metabolic syndrome seen with these agents will also improve outcomes in primary prevention populations in the long run.

DISCLOSURE

IR discloses the following: advisory board — AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk, Inc, Sanofi; Consultant: AstraZeneca, Insuline Medical, Medial EarlySign Ltd, CamerEyes Ltd, Exscopia, Orgenesis Ltd, BOL, Glucome Ltd, DarioHealth, Diabot; speaker's bureau — AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk, Inc., Sanofi; stock/shareholder — Glucome Ltd, Orgenesis Ltd, DarioHealth, CamerEyes Ltd, Diabot, BOL.

AC reports grants and personal fees from AstraZeneca and Novo Nordisk and personal fees from Eli Lilly, Medial EarlySign, Abbott, Gefen Medical, Sanofi, Boehringer Ingelheim, Merck Sharp & Dohme, and GlucoMe.

SC received payment for lectures from AstraZeneca, Boehringer Ingelheim, Berlin-Chemie Menarini, Eli Lilly, MSD, Novo Nordisk, Sanofi, and Servier Pharma; for clinical trial steering committee meetings as National Lead Investigator for DECLARE-TIMI58 from TIMI Study Group; consultant fees for advisory board from AstraZeneca; and support for travel to meetings from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Sanofi, MSD, Novo Nordisk, and Worwag Pharma.

钠-葡萄糖协调转运蛋白2(sodium glucose cotransporter 2, SGLT2)抑制剂自2012年起获批用于治疗2型糖尿病。这类药物的早期临床试验表明, 其不仅具有降低血糖的疗效, 而且还能够减轻体重和降低血压, 从而同时解决了代谢综合征的几个重要组成部分。

EMPA-REG研究(即恩格列净的心血管结局研究)的结果证实了恩格列净可以显著减少主要心血管不良事件(MACE；风险比[HR][95%置信区间(CI):0.86[0.74, 0.99])和心力衰竭住院(HHF；HR[95% CI]:0.65[0.50, 0.85]), 并显著改善肾脏结局(HR[95% CI]:0.61[0.53, 0.70]), 这彻底改变了我们对这种药物以及这类药物的看法。纳入这项研究的所有患者均有明确的动脉粥样硬化性心血管疾病(atherosclerotic cardiovascular disease, ASCVD)；因此, 目前尚未明确这些药物对糖尿病患者心血管事件一级预防的作用如何。

随后发表的CANVAS项目研究纳入了伴和不伴有ASCVD的混合患者人群, 尽管大部分患者已确诊为ASCVD。与安慰剂相比, 卡格列净治疗后可以减少MACE(HR[95% CI]:0.86[0.75, 0.97]), 并且与未合并ASCVD的患者相比(HR[95% CI]为0.98[0.74, 1.3]), 既往合并ASCVD的患者具有更大的获益趋势(HR[95%CI]为0.82 [0.72, 0.95]), P_相互作用为0.18。无论哪种风险类别的患者, HHF与肾脏结局均有显著改善。

大多数参与达格列净心血管结局研究(即DECLARE试验)的患者只有ASCVD的危险因素但未明确合并ASCVD。因此, 这项试验为评估SGLT2抑制剂对心血管事件的一级预防效果提供了一个独特的机会。达格列净可以减少心力衰竭住院/心血管死亡的共同主要复合终点(HHF/CVD；HR[95% CI]:0.83[0.73, 0.95]), 但在MACE次要共同主要结局方面未达到有显著统计学意义的优势(HR[95% CI]:0.93[0.84, 1.03])。不论患者的风险状况如何, 达格列净治疗后的肾脏获益程度与在恩格列净和卡格列净研究中观察到的获益相似。

一项meta分析评估了三种SGLT2抑制剂在心血管疾病一级预防及二级预防中对心肾结局的影响。这些药物对MACE的影响取决于患者的风险状况——尽管在已确诊ASCVD的患者中显示出获益(HR[95% CI]为0.86 [0.80, 0.93]), 但在一级预防队列中未显示获益(HR[95% CI]:1.00[0.87, 1.16]), P_相互作用为0.05。相反, 显著减少HHF的疗效不依赖于既往合并ASCVD(P_相互作用为0.38)或者心力衰竭病史(P_相互作用为0.76)。同样, 在已确诊和未确诊ASCVD的患者中均观察到肾脏获益(P_相互作用为0.71), 但在保留肾功能的患者中更明显(P_相互作用为0.026)。

根据这些数据, 人们可能很简单地认为, SGLT2抑制剂在心血管事件的一级预防中没有益处。这种说法虽然准确地概括了心血管结局试验的数据, 但并没有涵盖问题的全部。

糖尿病患者的心血管疾病明显增加。虽然改善血糖控制与纠正伴随的代谢紊乱可以减少风险, 但是这种增加的风险并不是单靠控制血糖就能够完全消除的。已经证实长期控制血糖、血压与血脂在随访7年以后可以显著降低心血管疾病的发病率与死亡率。因此, 多因素干预, 特别是在糖尿病的早期阶段实施干预, 已被证实可以降低并发症的风险, 并且还会改变疾病的自然病程。

除了要控制“标准”心血管危险因素(吸烟、高血压、血脂异常、血糖异常)以外, 心-肾轴的临床相关性也越来越明显。肾小球滤过率降低可显著增加心血管疾病的风险, 并且蛋白尿也是心血管疾病的一个标志物, 两者同时存在可导致风险进一步显著增加。

SGLT2抑制剂一致显示出对肾脏结局的显著改善。这些改善作用包括逆转先前存在的蛋白尿, 以及减少从正常到微量白蛋白尿或者大量白蛋白尿的转化。此外, SGLT2抑制剂已被证实可以延缓肾小球滤过率的下降, 并显著减少终末期肾病。这些获益在有或无基线慢性肾脏病的患者当中均可观察到, 并且与是否存在明确的ASCVD无关。因此, 长期使用SGLT2抑制剂治疗可能会通过长期保护肾功能而最终降低心血管疾病的发病率与死亡率。

目前已经观察到的SGLT2抑制剂对心脏的其他益处, 主要是减少心力衰竭住院(HHF)。值得注意的是, 无论患者既往是否存在ASCVD、肾脏疾病或已知的心力衰竭, 均能够观察到这种获益。最近, 在糖尿病患者与非糖尿病患者中也观察到类似的效应。这意味着这些药物并不是通过降低高血糖来改善心功能的。SGLT2抑制剂导致HHF减少的可能机制包括血流动力学效应, 以及因生酮代谢的转换而降低的心肌节律性、心肌细胞中钠水平的降低或其他机制导致的致心律失常心肌病的减少。

尽管未观察到SGLT2抑制剂对心血管发病率和死亡率一级预防的短期影响, 但是从长远来看, 这些药物在一级预防人群中除了显著改善肾脏结局, 还可以改善代谢综合征的其他组分, 因此将有可能会改善心血管结局。