The kidney and cardiovascular outcome trials

Chronic kidney disease (CKD) affects a substantial minority of people with type 2 diabetes (T2D). Analysis of US National Health and Nutrition Examination Survey (NHANES) datasets from 2007 through 2012 showed Stage 3 or worse disease (estimated glomerular filtration rate [eGFR] <60 mL/min per 1.73 m²) in nearly one in five patients, with increasing age, blood pressure, obesity, and levels of glycemia all associated with higher likelihood of Stage 3 or worse CKD,1 comparable to findings from surveys from many other areas, which also show micro- or macroalbuminuria to be present in one-sixth to one-third of diabetic people.2 Improvement in albuminuria has been shown in clinical trials of glycemic interventions, including the Action to Control Cardiovascular Disease in Diabetes (ACCORD) trial,3 the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial, in which the nephroprotective effect of blood pressure lowering was also demonstrated,4 and the UK Prospective Diabetes Study (UKPDS).5 However, over the past decade a host of cardiovascular outcome trials (CVOTs) have been performed with newer T2D therapeutic agents, and many of these have included intriguing information pertaining to renal disease and renal outcomes not necessarily related to changes in glycemia. It is of interest to review some of these findings.

Glucagon-like peptide-1 (GLP-1) has been reported to increase glomerular filtration rate (GFR), renal blood flow, and the fractional excretion both of sodium and potassium, with renal GLP-1 receptors present in afferent arteriolar vascular smooth muscle cells, glomerular endothelial cells and macrophages, juxtaglomerular cells, and the proximal tubule,6 perhaps mediating the greater natriuresis seen after oral than intravenous sodium.7 In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, the significant 13% reduction in the primary composite outcome of cardiovascular death, myocardial infarction, and stroke was found on subgroup analysis to particularly occur among participants with Stage 3 CKD, having eGFR 30–59 mL/min per 1.73 m².8 No significant effect on eGFR was found with liraglutide, although both those receiving and not receiving the drug showed a decline in eGFR from approximately 75 to 65 mL/min per 1.73 m² over the 48-month period of observation.8 Liraglutide administration was associated with a significant reduction in albuminuria, with nearly a 25% lower likelihood of development of macroalbuminuria, and with the albumin:  creatinine ratio (ACR) approximately 20% lower among treated people, regardless of the baseline level of eGFR.8 Similarly, in the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial, a 34% increase in the urine ACR was reported among people receiving placebo, but the increase was 24% among those receiving lixisenatide,9 and in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6),10 persistent macroalbuminuria developed among 2.7% of those receiving semaglutide, but among 4.9% of those receiving placebo.

The enzyme dipeptidyl peptidase (DPP)-4 is, like the GLP-1 receptor, present in multiple renal membrane-bound locations, including afferent arteriolar vascular smooth muscle cells, mesangial cells, podocytes, and proximal tubular cells,6 and DPP-4 inhibitors appear to have salutary effects on albuminuria similar to those of the GLP-1 agents. In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)–Thrombolysis in Myocardial Infarction (TIMI) 53 trial, saxagliptin was associated with significantly less worsening and more improvement in microalbumin levels at 1 year, at 2 years, and by end-of-treatment.11 The reduction in microalbumin levels was similar in patients with and without renal impairment.12 Interestingly, there was no relationship between improvement in albuminuria and improvement in HbA1c.13 The other DPP4i CVOTs have not reported effects of these agents on renal function or albuminuria, but studies of sitagliptin14 and linagliptin15 suggest that these agents may also reduce albuminuria.

Sodium–glucose cotransporter (SGLT) 2 inhibitors affect multiple sites, with the potential to affect renal function.16 The Canagliflozin Cardiovascular Assessment Study (CANVAS) showed a 27% reduction in progression of albuminuria, with a 40% reduction in eGFR, need for renal-replacement therapy, or death from renal causes associated with the use of canagliflozin.17 After a fall in mean eGFR with canagliflozin from 76 to 73 mL/min per 1.73 m² at 3 months, eGFR remained stable through 6 years while gradually declining during the period of observation with placebo.18 Evidence of dual effects of SGLT2 inhibition on both albuminuria and GFR was even more strongly shown in the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME); in that CVOT, although there was an initial decline in eGFR with empagliflozin, from 94 mL/min per 1.73 m² through 192 weeks, eGFR was consistently higher with empagliflozin, although this was less clear in trial participants with baseline eGFR <60 mL/min per 1.73 m².19 Empagliflozin also reduced the development of acute renal failure.19 Further analysis showed empagliflozin to be associated with a reduction in albuminuria, regardless of the baseline urine albumin level.20

The CVOTs have offered the possibility that diabetes treatment may move beyond surrogate endpoints to actual cardiovascular outcome benefits.21 It appears that these drugs will also lead to a reduction in adverse renal outcomes. We should look with optimism at this potential approach to a major complication of diabetes.

有不少一部分的2型糖尿病(T2D)患者合并慢性肾脏疾病(chronic kidney disease,  CKD)。分析2007至2012年间的美国国家健康与营养调查(National Health and Nutrition Examination Survey,  NHANES)数据后发现,  每5名患者中将近有1名合并第3期或更差分期的CKD(每1.73m²体表面积下估算的肾小球滤过率[eGFR]< 60 mL/min),  并且随着年龄、血压、肥胖以及血糖水平的升高,  患者出现第3期或者更差分期CKD的可能性也随之升高¹,  这与许多来自其他地区的调查结果相似,  在那些调查中也发现有六分之一至三分之一的糖尿病患者都存在微量或者大量白蛋白尿²。许许多干预血糖的临床试验都已经证实可以减低尿白蛋白,  包括控制糖尿病患者心血管疾病行动(Action to Control Cardiovascular Disease in Diabetes,  ACCORD)试验³,  糖尿病治疗与血管疾病保护作用:百普乐与达美康缓释片对照评估(Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation,  ADVANCE)试验,  在这些试验中也证实了降压治疗具有肾脏保护作用⁴,  以及英国前瞻性糖尿病研究(UK Prospective Diabetes Study,  UKPDS)⁵。然而,  在过去的10年中有许多新型的T2D治疗药物在上市前都进行了一系列的心血管结局试验(cardiovascular outcome trials,  CVOTs),  这些试验中有许多都包含了一些令人感兴趣的信息,  那就是肾脏疾病以及肾脏终点并不一定与血糖的变化有关。回顾这些研究结果非常有意义。

既往已有研究报告胰高血糖素样肽-1(Glucagon-like peptide-1,  GLP-1)可以增加肾小球滤过率(glomerular filtration rate,  GFR)、肾血流量以及钠与钾的排泄分数,  发现在入球小动脉血管平滑肌细胞、肾小球内皮细胞与巨噬细胞以及球旁细胞与近曲小管中都存在GLP-1受体⁶,  并且可能导致了口服氯化钠后与静脉注射氯化钠相比更多的尿钠排泄。在利拉鲁肽对糖尿病患者的影响与益处:心血管结局结果评估(Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results,  LEADER)试验中,  对存在3期CKD的参与者(每1.73 m²体表面积eGFR为30-59 mL/min)特别进行亚组分析后发现,  心血管死亡、心肌梗死与卒中的主要复合终点显著减少了13%⁸。经过48个月的观察期后,  利拉鲁肽对eGFR没有显著影响,  虽然接受或没有接受利拉鲁肽治疗的患者每1.73 m²体表面积的eGFR都大约从75 mL/min降到了65 mL/min⁸。使用利拉鲁肽治疗后都可以明显减低尿白蛋白,  治疗组人群进展为大量白蛋白尿的可能性下降了近25%,  并且尿白蛋白:肌酐的比值(albumin: creatinine ratio,  ACR)大约降低了20%⁸。相似地,  在评估利西那肽对急性冠状动脉综合征的影响(Evaluation of Lixisenatide in Acute Coronary Syndrome,  ELIXA)研究中,  接受安慰剂治疗的患者报告的尿ACR增加了34%,  但是接受利西那肽治疗的患者报告的ACR只增加了24%⁹,  并且在评估索马鲁肽对2型糖尿病受试者的心血管以及其他长期结局影响(Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes,  SUSTAIN-6)的研究中¹⁰,  发现接受索马鲁肽治疗的患者有2.7%进展为持续性大量白蛋白尿,  但是在接受安慰剂治疗的患者中这个比例却达到了4.9%。

就像GLP-1受体一样,  多种肾细胞膜上的结合位置都存在二肽基肽酶(dipeptidyl peptidase,  DPP)-4,  包括入球小动脉血管平滑肌细胞、系膜细胞、足细胞以及近端肾小管上皮细胞⁶,  并且DPP-4抑制剂也具有与GLP-1类似物相似的对白蛋白尿的有益作用。在评估糖尿病患者使用沙格列汀治疗后的血管疾病结局记录(Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus,  SAVOR)——心肌梗死溶栓(Thrombolysis in Myocardial Infarction,  TIMI)53试验中,  在第1年、第2年以及治疗终点时发现沙格列汀治疗可显著减缓患者的病情恶化并且微量白蛋白尿水平的改善也更明显¹¹。无论患者是否合并肾功能受损,  微量白蛋白尿水平下降情况都相似¹²。有趣的是,  白蛋白尿的改善与HbA1c的改善之间没有相关性¹³。其他的DPP4i CVOTs都没有报告这类药物对肾功能或白蛋白尿有何影响,  但是与西格列汀¹⁴或者利格列汀¹⁵相关的研究提示这些药物也能够减少尿白蛋白。

钠-葡萄糖共转运体2(Sodium–glucose cotransporter,  SGLT 2)抑制剂能够作用于多个部位,  也可能会影响肾功能¹⁶。评估坎格列净的心血管影响研究(The Canagliflozin Cardiovascular Assessment Study,  CANVAS)结果表明,  使用坎格列净治疗后患者的白蛋白尿进展减少了27%,  eGFR、肾脏替代治疗需求率以及肾源性死亡都下降了40%¹⁷。患者使用坎格列净治疗3个月后每1.73 m²体表面积的平均eGFR从76 mL/min降到了73 mL/min,  随后eGFR都一直保持稳定,  而使用安慰剂治疗的患者在为期6年的观察期间eGFR逐渐下降¹⁸。SGLT 2抑制后对白蛋白尿与GFR具有双重影响,  甚至在评估2型糖尿病患者使用恩格列净治疗后心血管结局事件(Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients,  EMPAREG OUTCOME)的试验中还可以看到更强的证据;在那项CVOT中,  患者使用恩格列净治疗后虽然开始时eGFR(每1.73 m²体表面积为94 mL/min)有所下降,  但是在整个为期192周的治疗期间恩格列净治疗组的eGFR始终都比安慰剂组高,  虽然在基线时每1.73 m²体表面积eGFR < 60 mL/min的参与者中这种现象还不是很明确¹⁹。患者使用恩格列净治疗后还可以减少急性肾功能衰竭的发生¹⁹。进一步分析后发现,  无论基线时尿白蛋白水平如何,  恩格列净治疗后都可以减少尿白蛋白²⁰。

CVOTs结果已经表明,  我们在治疗糖尿病的时候可能需要超越替代终点,  要将目标放在实际心血管结局获益上²¹。目前看来这些药物还能够减少不良肾脏结局事件。我们应该乐观地看待这种潜在的可以改善糖尿病主要并发症的治疗方法。