Sodium-glucose cotransporter 2 inhibitors as the first universal treatment of chronic kidney disease

In the last five years, the medical community was astonishingly surprised by the sequential large outcome trials that displayed the renal effects of sodium glucose co-transporter inhibitors (SGLT2Is) in type 2 diabetes mellitus (T2DM) patients with or without chronic kidney disease (CKD). This favorable effect was later disclosed in non-diabetic CKD patients. The EMPA-REG OUTCOME trial was the first trial that showed a reduction for the need for dialysis in patients suffering diabetic kidney disease (DKD) by 55%. This figure is double the score achieved by the angiotensin receptor blocker, Losartan, in RENAAL trial. The need for dialysis in DAPA-CKD trial was reduced in diabetic and non-diabetic CKD patients by 33%. The renal-specific composite outcome was reduced by 39% in EMPA-REG trial, 40% in CANVAS study, 47% in DECLARE-TIMI 58 study, 34% in CREDENCE trial, and 44% in DAPA-CKD trial. The greater surprise is the significant favorable effect of SGLT2Is on overall mortality in CKD patients with or without T2DM. Similar survival benefit was not previously encountered with any of the medications used in CKD patients with or without diabetes. In this review, we disclose the results of the DAPA-CKD trial, the CREDENCE trial and those of several cardiovascular outcome trials (CVOT) that used different SGLT2Is and showed that patients with lower eGFR levels may have greater benefit with respect to cardiovascular morbidity than patients with normal kidney function. In addition, we discuss the different mechanisms of action that explain the renal beneficial effects of SGLT2Is.     

Multimodal efforts to slow the progression of chronic kidney disease in patients with type 2 diabetes mellitus

In patients with chronic kidney disease (CKD) associated with type 2 diabetes mellitus (T2DM), slowing kidney disease progression is an important therapeutic goal. Many patients with T2DM and CKD also have cardiovascular (CV) comorbidities. Renin-angiotensin-aldosterone system inhibitors (RAASis), which include angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), are drugs with known antihypertensive effects as well as CV and kidney protective effects in patients with CKD. Studies have shown that adding a sodium-glucose cotransporter-2 (SGLT2) inhibitor to ACEI or ARB therapy has additive benefits in terms of kidney and CV protection in patients with CKD (with/without T2DM). For patients with CKD associated with T2DM who have persistent albuminuria despite taking the maximum tolerated dose of a RAASi, adding a nonsteroidal mineralocorticoid receptor antagonist (finerenone) has demonstrated CV and kidney benefits in clinical trials. In this article, we review the use of ACEIs and ARBs for their kidney and CV protective effects when used alone or in combination with a drug with a different mechanism of action. From reviewing the available evidence, it seems clear that a multimodal drug effort is needed to achieve maximum kidney and CV protective effects for patients with CKD associated with T2DM.     

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。     

Dedicated kidney disease-focused outcome trials with sodium-glucose cotransporter-2 inhibitors: Lessons from CREDENCE and expectations from DAPA-HF,DAPA-CKD,and EMPA-KIDNEY

In the past decade, many cardiovascular outcome trials (CVOT) on the efficacy and safety of glucose-lowering agents have been completed. Amongst newer agents available for treatment of type 2 diabetes mellitus (T2DM), sodium-glucose cotransporter-2 (SGLT2) inhibitors have garnered much attention in contemporary clinical practice due to observed benefits on cardiovascular and kidney outcomes among patients with T2DM, as reported in large randomized controlled trials (RCT). These findings are reflected in the updated clinical guidelines of several major professional societies. Herein, we briefly review the mechanism of action of SGLT2 inhibitors and their pleiotropic effects, summarize key findings and limitations of initial CVOTs, then discuss three major kidney disease-focused outcome trials, including the Canagliflozin and Renal Events in Diabetes and Established Nephropathy Clinical Evaluation (CREDENCE) trial as well as two ongoing RCTs: Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure-chronic kidney disease and EMPA-KIDNEY.     

Chronic kidney disease in Japan

Chronic kidney disease (CKD) is defined as either kidney damage with urine, imaging, and histologic abnormalities, or a low estimated glomerular filtration rate (GFR) for more than 3 months. The GFR is calculated using either the Modification of Diet in Renal Disease (MDRD) Study equation or the Cockcroft-Gault formula. CKD is a risk factor for end-stage renal disease (ESRD) and cardiovascular disease. In Japan, the prevalence of ESRD is increasing and is currently more than 2,000 per million population. More than 40% of incident ESRD is due to diabetes mellitus (DM). The prevalence of a low GFR (< 60 ml/min/1.73 m(2)) is estimated to be 20% of the adult population. Studies based on several community-based screening programs suggest that Japan has a higher prevalence of CKD than any other country. Early detection and treatment of CKD are necessary to decrease the incidence of ESRD and cardiovascular disease.     

亚临床甲状腺功能减退与2型糖尿病慢性并发症的关系

目的 探讨亚临床甲状腺功能减退 （SCH）与T2DM慢性并发症的关系。 方法 将1294例T2DM患者分为SCH组和甲状腺功能正常组,比较两组间慢性并发症患病率及患者的甲状腺功能,采用Logistic多元回归分析SCH与糖尿病慢性并发症的关系。 结果18.8%的T2DM患者合并SCH。SCH组糖尿病慢性肾脏疾病（CKD）、DR、糖尿病周围神经病变（DPN）和糖尿病足病（DF）患病率均高于甲状腺功能正常组（P〈0.05）;CKD、DR和DPN患者FT3下降,促甲状腺激素（TSH）升高（P〈0.05）。Logistic多元回归分析显示,SCH为CKD的独立危险因素（OR=3.39,P=0.012）。 结论 T2DM合并SCH 患者CKD、DR、DPN和DF患病率升高。SCH是CKD的独立危险因素。     

Impact of chronic kidney disease definition on assessment of its incidence and risk factors in patients with newly diagnosed type 1 and type 2 diabetes in the UK: A cohort study using primary care data from the United Kingdom

AimTo estimate the incidence and risk factors of chronic kidney disease (CKD) in patients with newly-diagnosed diabetes using different CKD definitions.MethodsUsing UK primary care data, patients with diabetes (type 1, 4691; type 2, 109,365) and no CKD were followed to identify newly-diagnosed CKD, classified by a broad and narrow CKD definition (to capture diabetes-induced CKD, termed diabetic kidney disease, DKD). Adjusted incidence rates of CKD/DKD were calculated, and risk factors identified using Cox regression.ResultsThere were 404 CKD cases and 147 DKD cases among patients with type 1 diabetes (T1D), and 29,104 CKD cases, 9284 DKD cases among patients with type 2 diabetes (T2D). Adjusted incidence rates of CKD per 100 years were 5.4 (T1D) and 5.5 (T2D); for DKD they were 1.9 and 1.5, respectively. Risk factors for CKD/DKD were older age, high social deprivation, obesity, cardiovascular disease, hypertension and smoking. Poor glycaemic control in the year after diabetes diagnosis was a strong predictor of CKD/DKD occurrence beyond this first year, and a risk factor for CKD/DKD in T2D.ConclusionsCKD and DKD remain common in diabetics in the decade after diagnosis. Early prevention of T2D and aggressive treatment of risk factors is urgent.     

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。     

Chronic kidney disease prevalence and cardiovascular risk in a cohort of patients with type 2 diabetes followed for 10 years in Badajoz (Spain). An observational study

AimsTo estimate the prevalence of chronic kidney disease (CKD), their risk factors the incidence of cardiovascular and coronary events and total and cardiovascular mortality in a cohort of type 2 diabetes (T2DM) patients observed for 10 years in primary care practices in Badajoz, Spain.MethodsObservational, longitudinal study. A total of 643 patients with T2DM (mean age 64.0 years, 55.7% women), without evidence of cardiovascular disease, were studied. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m² at the beginning of the study, by applying the simplified Modification of Diet in Renal Disease (MDRD) Study formula.ResultsThe prevalence rate of CKD was 24.3%. Patients with CKD had higher percentages of coronary, cerebrovascular and cardiovascular events and higher rates of cardiovascular mortality (18.6 vs. 6.0%, p < 0.001) and total mortality (42.3 vs. 23.4%, p < 0.01), compared to patients without CKD. The Cox proportional hazards model, adjusted for age, systolic blood pressure levels, glycated haemoglobin, total cholesterol, obesity and smoking, revealed that patients with CKD had an increased risk of coronary events (HR:2.18; 95% CI:1.13?4.22, p < 0.05).ConclusionsOur study confirms a high prevalence of CKD in patients with T2DM and its relationship with the presence of cardiovascular disease.     

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.     

Effects of sodium-glucose cotransporter-2 inhibitors on the cardiovascular and renal complications of type 2 diabetes

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have been shown to mitigate the risks of cardiovascular (CV) and renal complications in patients with type 2 diabetes (T2D) and CV risk factors or CV disease (CVD). In CV outcomes trials (CVOTs) of patients with T2D and established CVD or multiple CV risk factors, empagliflozin and canagliflozin were associated with significant reductions in the risks of major adverse CV events (MACE), hospitalization for heart failure (HF) and kidney disease progression. In the DECLARE–TIMI 58 study, in which the majority of patients did not have established CVD, dapagliflozin was associated with significant reductions in the composite end point of CV death or hospitalization for HF and was noninferior to placebo with regard to MACE; although patients had relatively good renal function, dapagliflozin also showed renal benefits similar to those seen with empagliflozin and canagliflozin. This article reviews the increased risk of CVD and renal disease in patients with T2D and discusses the potential mechanisms of the cardioprotective and renoprotective effects of SGLT-2i therapy. The observed improvements in CV and renal outcomes with SGLT-2is in CVOTs suggest a class effect in this patient population and have influenced treatment guidelines for the way add-on therapy to metformin is initiated in patients with T2D and high CV risk. The overall cardioprotective and renoprotective effects of SGLT-2is in patients with T2D and high CV risk are most likely attributable to multiple mechanisms, including cardiac, haemodynamic, metabolic, anti-inflammatory and renal effects.     

Review of glucagon‐like peptide‐1 receptor agonists for the treatment of type 2 diabetes mellitus in patients with chronic kidney disease and their renal effects

Type 2 diabetes mellitus (T2DM) is the most common cause of chronic kidney disease (CKD), and when it causes CKD it is collectively referred to as diabetic kidney disease. One of the newer therapies for managing hyperglycemia is the glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) drug class. This review summarizes the effects of GLP‐1RAs in patients with T2DM with CKD and evidence for renoprotection with GLP‐1RAs using data from observational studies, prospective clinical trials, post hoc analyses, and meta‐analyses. Evidence from some preclinical studies was also reviewed. Taken together, subgroup analyses of patients with varying degrees of renal function demonstrated that glycemic control with GLP‐1RAs was not markedly less effective in patients with mild or moderate renal impairment vs that in patients with normal function. GLP‐1RAs were associated with improvements in some cardiorenal risk factors, including systolic blood pressure and body weight. Furthermore, several large cardiovascular outcome studies showed reduced risks of composite renal outcomes, mostly driven by a reduction in macroalbuminuria, suggesting potential renoprotective effects of GLP‐1RAs. In conclusion, GLP‐1RAs effectively reduced hyperglycemia in patients with mild or moderately impaired kidney function in the limited number of studies to date. GLP‐1RAs may be considered in combination with other glucose‐lowering medications because of their ability to lower glucose in a glucose‐dependent manner, lowering their risk for hypoglycemia, while improving some cardiorenal risk factors. Potential renoprotective effects of GLP‐1RAs, and their renal mechanisms of action, warrant further investigation.     

Sodium-glucose linked transporter-2 inhibitor renal outcome modification in type 2 diabetes: Evidence from studies in patients with high or low renal risk

Data from three completed cardiovascular outcome trials (CVOTs), EMPA-REG OUTCOME, CANVAS Program and DECLARE-TIMI 58, add to the evidence supporting the potential renoprotective effects of sodium-glucose linked transporter-2 (SGLT2) inhibitors in patients with type 2 diabetes. Despite recommendations in recent guidelines, it is difficult to support a view that definitive evidence for renoprotection exists from these SGLT2 inhibitor CVOT results. To date, the only dedicated trial to report definitive data on the renal impact of SGLT2 inhibition is CREDENCE. Notably, the total number of patient-relevant renal endpoint events (dialysis, transplant or renal death) observed in CREDENCE was significantly higher than the total for all three CVOTs collectively (183 events/4401 patients vs. 69 events/34 322 patients, respectively), which shows the increased statistical power of CREDENCE for these renal endpoints. Treatment with canagliflozin was associated with a 30% relative risk reduction (RRR) in the primary composite endpoint of end-stage kidney disease, doubling of serum creatinine, or death from renal or cardiovascular causes and a 34% RRR for the renal-specific elements of this primary endpoint (P <0.001). Canagliflozin has therefore become the first US-approved SGLT2 inhibitor to include an indication for RRR, in addition to type 2 diabetes glycaemic control and cardiovascular risk reduction. While confirmatory of the exploratory data from CVOTs, CREDENCE provides the first robust data on the effects of canagliflozin on patient-relevant renal endpoints. Extrapolation to a conclusion of a SGLT2 inhibitor class effect cannot be made until additional renal trials with other SGLT2 inhibitors are reported.     

Heart failure and diabetes: Clinical significance and epidemiology of this two-way association

People with type 2 diabetes (T2DM) and those with prediabetes have an increased risk of heart failure (HF). Longer duration of T2DM correlates with a greater risk of HF, but HF is also seen in patients with recent-onset diabetes. Insulin resistance is more likely to be present in patients with HF. The risk of HF persists even in the face of standard-of-care preventive treatments for atherosclerotic cardiovascular (CV) disease. HF is commonly the presenting symptom of CV disease in people with diabetes and is the most expensive complication of diabetes because of the high cost of hospitalizations. Recently hospitalization for HF has been included in CV outcome trials (CVOTs), including for medications that are used to treat T2DM, which has led to new therapies for all HF patients. In addition, these CVOTs have shown that many drugs used in the therapy of diabetes are either neutral or detrimental in the HF patient and should be used with caution in patients with existing HF or those at high risk of HF. Most recently, sodium-glucose cotransporter-2 receptor blockers have shown efficacy in both HF with reduced ejection fraction (EF) and HF with preserved EF. The only other oral or injectable diabetes agent shown to improve outcomes in both is metformin.     

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。     

老年2型糖尿病患者肌少症与早期肾功能减退的关系

目的:探讨老年2型糖尿病患者肌少症与早期肾功能减退的关系。方法:回顾性病例对照研究,选取2018年7月至2019年7月在北京医院老年医学科就诊的60岁及以上2型糖尿病患者198例,根据CKD-EPI Cr-Cys公式计算的估计肾小球滤过率分为肾功能正常组(CKD 1期)63例和轻度肾功能减退组(CKD 2-...     

Impact of Glucagon-like peptide 1 receptor agonists on peripheral arterial disease in people with diabetes mellitus: A narrative review

Peripheral arterial disease (PAD) is a common macrovascular complication of diabetes mellitus (DM). Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) are among the latest class of antidiabetic medications that stimulate insulin synthesis and secretion and have been used for the management of type 2 DM. Apart from the effect on glycaemic control, GLP-1RAs also have a robust impact on weight reduction and have shown favorable effects on cardiovascular morbidity and mortality in cardiovascular outcome trials (CVOTs). The aim of this review was to examine the impact of GLP1-RAs on PAD among people with DM based on CVOTs, randomized controlled trials, observational studies as well as systematic reviews and meta-analyses. Data from retrospective studies and meta-analyses have shown superiority of these agents in comparison with other antidiabetic medications such as sodium-glucose cotransporter type 2 inhibitors and dipeptidyl peptidase-4 inhibitors in terms of PAD-related events. Nevertheless, data from CVOTs regarding the impact of GLP-1RAs on PAD are scarce and hence, safe conclusions regarding their effects cannot be drawn. Further prospective studies are needed to examine the impact of GLP-1RAs on PAD-related incidents including major adverse limb events, lower limb amputations and revascularization procedures.     

Prevalence and incidence of cardiovascular and renal diseases in type 1 compared with type 2 diabetes: A nationwide French observational study of hospitalized patients

BackgroundType 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) increase risks of cardiovascular (CV) and renal disease compared with diabetes-free populations. There are only a few studies comparing T1DM and T2DM for the relative risk of these clinical events.MethodsAll adult patients hospitalized in French hospitals in 2013 with at least 5 years of follow-up were identified and categorized by their diabetes status. A total of 50,623 patients with T1DM (age 61.4 ± 18.6, 53% male) and 425,207 patients with T2DM (age 68.6 ± 14.3, 55% male) were followed over a median period of 5.3 years (interquartile range: 2.8 - 5.8 years). Prevalence and event rates of myocardial infarction (MI), heart failure (HF), ischemic stroke, chronic kidney disease (CKD), all-cause death and CV death were assessed with age stratification of 10-year intervals. For clinical events during follow-up, we report hazard ratios (HRs) in T1DM relative to T2DM.ResultsThe age and sex-adjusted prevalence of CV diseases was higher in T2DM for ages above 40 years whereas the prevalence of CKD was more common in T1DM between ages 18 and 70 years. During 2,033,239 person-years of follow-up, age and sex-adjusted HR event rates comparing T1DM, versus T2DM as reference, showed that MI and HF relative risks were increased above 60 years (1.2 and 1.4 -fold). HR of ischemic stroke did not markedly differ between T1DM and T2DM. Risk of incident CKD was 2.4-fold higher in T1DM above 60 years. All-cause death HR risk was 1.1-fold higher in T1DM after 60 years and the CV death risk was 1.15-fold higher in T1DM between 60 and 69 years compared to T2DM.ConclusionsAlthough the crude prevalent burden of CV diseases may be lower in T1DM than in T2DM, patients with T1DM may have a higher risk of incident MI, HF, all-cause death and CV death above 60 years of age, highlighting the need for improved prevention in this population.     

Should metformin still be the first-line of treatment in type 2 diabetes mellitus? A comprehensive review and suggested algorithm

For more than a century, the high occurrences of coronary and peripheral artery diseases in diabetes mellitus patients has been well recognised; despite that, the ability to improve CV event rates by optimizing glycaemic control has remained elusive. Nevertheless, the last decade has seen several cardiovascular outcome clinical trials (CVOTs) of many antihyperglycemic agents that reported promising results for cardiovascular and renal outcomes. This leads to a hot debate on the ideal drug choice for first-line treatment in T2DM. The purpose of this paper is to review the evidence supporting the use of metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors and incretin-based therapies for the management of individuals with T2DM and, discuss the rationale for selection.     

Chronic kidney disease and cardiovascular risk

Chronic kidney disease (CKD) is a global public health concern, and there is emerging a strong relationship between CKD and increased cardiovascular disease (CVD) risk. CKD in the presence of other co-morbidities such as type 2 diabetes mellitus (T2DM) and hypertension (HTN) can lead to early progression to end-stage renal disease (ESRD/stage V CKD) and confer a greater risk for CVD morbidity and mortality. CVD events are the leading cause of premature death in patients with CKD, even before their progression to ESRD, with the rate of CVD progression being twice as common compared with the general population. The higher mortality from CVD persists even after adjusting for most of the traditional risk factors, suggesting the possible contributions of uremia-related, nontraditional risk factors. This has led to the current understanding that the pathophysiology of CVD in CKD involves a complex interplay of both the traditional as well as nontraditional, uremia-related risk factors. This review will elaborate on the pathophysiology of CVD in CKD and will discuss the role of microalbuminuria (MAU)-proteinuria as a potential diagnostic and prognostic tool for CVD in CKD risk assessment.