CE / CME
Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit
Nurses: 1.00 Nursing contact hour
Physicians: maximum of 1.00 AMA PRA Category 1 Credit™
Released: July 22, 2024
Expiration: July 21, 2025
Chronic Kidney Disease Is Common Among US Adults
Although cardiovascular disease (CVD) remains the leading cause of death globally and in the United States, CKD is also a common condition. Approximately 1 in 7 US adults have CKD with women and racial and ethnic minorities having a higher prevalence. Approximately 33% of adults aged 65 years or older have CKD. However, CKD remains largely underrecognized, with 1 in 3 adults being unaware that they have severe CKD. Given the strong relationship that CKD has to diabetes and high blood pressure, it is crucial to address these comorbid conditions concommittantly.1,2
CKD: A “Risk-Enhancing” Condition for CVD
Listen to this clip to hear faculty insights on CKD as a CV risk–enhancing condition.
CKD is a risk-enhancing disease that also occurs more frequently in patients with diabetes, as diabetes is a leading cause of CKD. It is estimated that 30% to 40% of people with T2D have CKD.3 Pathophysiologic changes from CKD contribute to CVD while T2D mechanisms also independently contribute to CVD risk.2 The overlap of CKD and T2D increases the risk of CVD morbidity and mortality.2,4 Data from the Third National Health and Nutrition Examination Survey (NHANES III) implicate the presence of CKD in patients with T2D for an increased all-cause mortality risk. For CVD mortality alone, the adjusted difference in cumulative incidence is approximately 16% for those with both conditions, as compared to roughly 3% for T2D alone or 6% for CKD alone.4
Substantial Overlap in Cardio-Renal-Metabolic Conditions
There is unfortunately a substantial overlap in the conditions that comprise cardiorenal metabolic syndrome. In 2023, the American Heart Association (AHA) released a new scientific advisory about cardiovascular-kidney-metabolic (CKM) spectrum, which affects a significant portion of the US adult population.5
High CV and Mortality Risk Associated with CKD With or Without Diabetes
It is important to assess for CKD in patients with diabetes by using estimated glomerular filtration rate (eGFR) and urinary albumin excretion, because both predict risk for CVD and mortality. Results from this meta-analysis indicate that lower eGFR is associated with higher all-cause and CV mortality, regardless of the presence of diabetes, as shown in the graphs to the left. On the right, a linear relationship emerges for both all-cause and CV mortality as the urine albumin-to-creatinine ratio (uACR) increases, again regardless of the presence of diabetes.6 This highlights the potential need to monitor eGFR and ACR in all patients with and without diabetes who have risk factors such as hypertension and other CVD factors to identify future morbidity.
Assessing Risk in CKD by GFR and Albuminuria Category
To assess kidney function and the risk of CKD progression, categories of both GFR and albuminuria can be combined for a composite picture. The Kidney Disease – Improving Global Outcomes (KDIGO) 2024 clinical practice guidelines provide color-coded risk levels. As severity levels of GFR increases, so does risk. The same is true of albuminuria categories. Thus, a patient with moderate or severe GFR levels can have a high or very high progression risk even with normal albuminuria. Similarly, a severe albuminuria category indicates high risk, even with normal or mildly decreased GFR.7 These CKD progression risk levels also portray a similar risk for CVD.
Guideline Recommended Pillars of CKD Management
Listen to this clip to hear about pillars of CKD management.
There are many medications proven to be cardio- and renoprotective. As with the pillars of therapy outlined for heart failure, the American Diabetes Association (ADA) and KDIGO have issued joint practice guidelines that formed the basis for treatment pillars in the management of CKD.8 The goals of these pillars are to slow CKD progression, prevent kidney failure or end-stage kidney disease, and reduce the burden of associated CVD risks.9
The Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial, and the Irbesartan Diabetic Nephropathy Trial (IDNT) established the value of renin-angiotensin system (RAS) blockade in slowing CKD progression.9,10 CREEDENCE, DAPA-CKD, and EMPA-CKD proved the cardiorenal protective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with elevated albuminuria with or without the presence of diabetes.10,11 Trials of a new class of medications, the nonsteroidal mineralocorticoid receptor antagonists (ns-MRAs), particularly those evaluating finerenone in the FIDELITY program, found significant reductions in CVD sequelae and CKD progression. Multiple trials suggest the CKD risk-lowering potential of the last therapy pillar, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and the FLOW study, which we will examine later, studied kidney and cardiac outcomes for patients with diabetic CKD and albuminuria.9 Evidence shows a reduction in myocardial infarction (MI) with GLP-1 RAs.10
All 4 pillars rest on the foundation of lifestyle modification, including smoking cession, glycemic control, blood pressure control, lipid management, weight maintenance, healthy diet, and regular physical activity. The benefits of combining all therapeutic pillars continues to be explored.10
Despite Decreased ASCVD With Statin Monotherapy, Substantial CV Risk Remains
Listen to this clip to hear faculty insights about residual risk despite LDL lowering.
Patients with CKD are at increased CV risk and statins are recommended first-line therapy to reduce CVD risk as both primary and secondary prevention.12 The trials outlined depict the CVD risk reduction by statin treatment compared to placebo for key secondary and primary prevention lipid trials. Across all of the studies shown, events are reduced but not completely eliminated with statin therapy and we call this residual risk.13-19
Residual risk is possibly due to residual lipid factors such as remnant lipoproteins, lipoprotein(a) and triglyceride-rich lipoproteins, and persistent inflammation20 There is also residual risk unrelated to lipids due to suboptimal control in blood pressure, diabetes, and smoking, which is residual risk as it relates to inflammation that we will discuss further in this module.
Even at LDLC <20, ASCVD Risk Remains Substantial
The FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition With Elevated Risk) trial evaluated the effect of evolocumab with a statin compared to placebo in patients with stable ASCVD. The open-label extension (FOURIER-OLE) further examined the relationship of LDL-C levels to CVD incidents and safety in 6559 patients with available follow-up data nearly 5 years after original enrollment. When categorized by levels of LDL-C achieved with treatment, you can see that cumulative incident rates trend lower as the LDL-C (in mg/dL) decreases. However, even at the lowest range of <20 mg/dL as shown by the bottom red line, there remains some incidence of CVD events that increase over time. Events are reduced, but still not eliminated.21 There remains a gap in residual risk that must be addressed.
The Multiple Facets of Residual Risk
There are many facets of residual risk. Cholesterol risks may remain for those who have not achieved those intensive LDL-C targets. Triglycerides may be elevated. Lipoprotein(a) levels are a consideration. Residual thrombotic risk and residual cardiometabolic risk related to obesity, suboptimal glucose control, and antithrombotic therapy may remain.
Inflammatory risk is an important consideration now being addressed with targeted therapies already available and more in the pipeline undergoing investigation.22
Inflammation Plays a Key Role in All Phases of Atherosclerosis
Watch this animated video reviewing the pathophysiologic role of inflammation in ASCVD and CKD.
While inflammation is an important mechanism in host defenses and tissue repair, continuous unregulated inflammatory cascades promote injury and decreased cellular survival. Rheumatologic diseases and atherosclerosis development are examples of the damage invoked by chronic inflammation. This figure illustrates how inflammatory processes participate in every step of atherogenesis, from endothelial dysfunction, foam cell formation, plaque formation, and then plaque destabilization and rupture.
Subintimal cholesterol triggers endothelial dysfunction through upregulation of adhesion molecules that attract monocytes and T-helper cells into this early plaque formation site. Infiltrating monocytes become macrophages that take up lipids and become foam cells, simultaneously activating the Nod-like receptor 3 (NLRP3) inflammasome. The NLRP3 inflammasome activates caspase-1, which initiates release of the proinflammatory cytokines interleukin (IL)-1 beta and IL-18, further propagating the inflammatory cycle through C-reactive protein production triggered by IL-6 signaling.
Inflammation also influences the stability of plaque by thinning the fibrous cap, leading to rupture and the formation of a thrombus that can instigate myocardial ischemia or acute coronary syndromes.23
Inflammation and Kidney Disease
In addition to atherogenesis, there is mounting evidence that chronic inflammatory insult to the kidney may also underlie structural and functional changes in CKD. The activation of cytokines, chemokines, innate immune cells, and adhesion molecules can mediate the progression of CKD. Various inflammatory mediators are currently under study, as diagnostic and prognostic markers, and potentially as therapeutic targets.24
Risk Factors and Mediators of Inflammation
Multiple risk factors activate proinflammatory cytokines. Many traditional modifiable triggers include smoking, visceral fat, dyslipidemia, hypertension, poor dentition, dysglycemia, and infection.
Other factors help to modulate the inflammatory cascade, including favorable lifestyle choices such as regular exercise and a diet rich in fruits, vegetables, nuts, and oily fish which may mitigate the formation of atherothrombosis.25
Nonstandard Risk Factors Implicated in Inciting Inflammation in Atherothrombosis
Several factors may not be as well-known including the triglyceride-rich lipoproteins. We have been focusing on LDL as a primary target, but these triglyceride-rich lipoproteins are actually more atherogenic per particle than LDL. We know that adipose tissue can release a number of inflammatory cytokines and indeed, therapies that are targeted at weight management and reducing dysfunctional adipose tissue can also decrease inflammation. There is also investigation of clonal hematopoiesis (CHIP) of undetermined potential. This is a nonmalignant condition that increases the risk of CVD. CHIP is caused by age-related DNA mutations in these hemopoietic stem cells, which can lead to the production of proinflammatory immune cells that can worsen ASCVD. There is also some question about chronic infection exposures and the role of the gut microbiome.
Risk Factors and Mediators of Inflammation
What can trigger or contribute to inflammasome activity? Some evidence indicates the role of genetic polymorphisms, but there are many lifestyle factors—some of which are modifiable—that contribute proinflammatory risk. Depicted here are various mechanisms by which some risk factors mediate the inflammatory response.23
Inflammatory Conditions That Are “Risk Enhancers”
Due to the growing recognition of the role inflammation plays in CVD risk, the European Society of Cardiology (ESC) newly added a recommendation for the inclusion of chronic inflammatory conditions as part of CVD risk assessment in their 2021 guidelines.12 Conditions such as systemic lupus erythematosus, rheumatoid arthritis, psoriasis, HIV infection, or an elevated hsCRP are linked to higher risk of atherosclerosis.23 The table on the right denotes the ESC class of recommendation and the grade of the evidence to support the presence of inflammatory diseases as a part of risk estimation along with anti-inflammatory treatment in very–high-risk patients.12
hsCRP Predicts Risk for CV Events Across all Baseline TG and LDL-C Levels
Many biomarkers of inflammation have been proposed as possible indicators of CVD risk, and a large prospective study analyzed the relative association of 12 such markers to determine their relationship to CVD events in postmenopausal women. Although many of the markers studied demonstrated significant associations, hsCRP was found to be the strongest independent predictor of risk regardless of cholesterol level.26 Later analyses solidified that increasing CRP levels were associated with increased CVD risk as LDL-C levels increased.27
JUPITER: Elevated hsCRP Is a Marker of ASCVD Risk Even Among Statin-Treated Patients With LDL-C <70 mg/dL
Published in 2009, JUPITER (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) was a landmark multinational, prospective, randomized clinical trial that enrolled patients with no known CVD, LDL-C levels of <130mg/dL, and hsCRP levels ≥2 mg/L. Participants were randomized to either rosuvastatin 20 mg daily or placebo. Overall, the trial showed reductions in both major adverse cardiovascular events (MACE) and all-cause mortality. This demonstrated that CRP elevation can identify patients who would benefit from more intensive primary prevention and from statin therapy. However, as statins are known to lower LDL and inflammation, it wasn’t quite clear from these data that the pathway to reducing events was via a reduction in systemic inflammation.
A post-hoc analysis of the data parsed the clinical endpoint results by those achieving LDL-C levels <70 mg/dL, hsCRP <2 mg/L, or both. The responder analysis shown in this graph supports the concept that lowering LDL-C and hsCRP is beneficial in primary prevention. Patients treated with rosuvastatin who achieved an on-treatment LDL <70 mg/dL and an on-treatment hsCRP <2 mg/L had the lowest event rate (HR: 0.35; 95% CI: 0.23-0.54; P <.0001 vs placebo). Those achieving only LDL-C targets (HR: 0.55; 95% CI: 0.39-0.77) or hsCRP targets (HR: 0.54; 95% CI: 0.27-1.10) did better than the placebo-treated groups. Composite data for those receiving rosuvastatin who reached one or both targets show an improved compared favorably (HR: 0.64; 95% CI: 0.49-0.84) to those who did not achieve both targets (HR: 0.35; 95% CI: 0.23-0.54), suggesting that these may be independent risk factors. Addressing residual inflammatory risk has the potential to improve outcomes.28
Inflammation and Cholesterol as Predictors of CV Events Among Patients Receiving Statin Therapy
A recent pooled analysis from over 30,000 participants receiving statin therapy in the PROMINENT (Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes), REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) and STRENGTH (Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia) was conducted to test the theory of residual inflammation vs LDL-C in secondary prevention. All patients had, or were at high risk for CVD and enrolled in studies administering intensive guideline-based treatments; as such hsCRP and LDL-C levels represent this specific risk population.
The bar chart on the left shows the risk of CVD death for each quartile of lingering hsCRP (blue bars) and LDL-C (red bars) while receiving therapy. There was a progressive increase across quartiles such that statin-treated individuals who were in the highest quartile of hsCRP had an approximately 2.7-fold increased risk of CV death (P <.0001) as compared to only a 1.3-fold increase for residual LDL-C (P <.01).
On the right, when broken down by LDL-C < or ≥70 mg/dL and hsCRP < or ≥2 mg/L, the risk of CVD death is significantly increased when hsCRP is ≥2 mg/L, regardless of LDL-C category (as shown in dark red bars; all P <.0001).29
In Statin-Intolerant Patients, hsCRP Predicted CV Risk and Death More Strongly Than LDL-C
For patients with CVD or at high CV risk who were statin intolerant, the CLEAR-Outcomes trial (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen Outcomes Trial) examined the effect of bempedoic acid vs placebo on MACE, CVD death, and all-cause mortality along with baseline biomarkers. Analyses of the combined impact of hsCRP (< or ≥2 mg/L) and LD-C (< or ≥130 mg/dL) demonstrate that, while some risk is conferred by high LDL-C with low hsCRP in MACE, the adjusted hazard ratios did not reach significance across outcomes. On the contrary, across all 3 outcomes, hsCRP ≥2 mg/L imparts significant risk.30
It is important to point out that these data from PROMINENT, REDUCE-IT, STRENGTH, and CLEAR trials should not be interpreted to mean that LDL-C bears no role in CVD risk, as multiple studies over many years have proven that it does. Rather, the key takeaway is that lowering LDL-C alone does not eliminate atherosclerotic risk. Anti-inflammatory pathways remain a relatively untapped potential to further reduce fatal and nonfatal CVD events.
Inflammation, Kidney Disease, and Risks of CV and All-cause Mortality
Returning to the overlap of CVD and kidney disease, we find that circulating proinflammatory cytokines, such as IL-1β, IL-1RA, IL-6, TNF-α, TGFβ, fibrinogen, serum albumin, and hsCRP are commonly associated with CKD, and observational data from the CRIC (Chronic Renal Insufficiency Cohort) were extracted from participants with no history of CVD upon enrollment to determine what relationship each may have to future CVD outcomes. Multivariate hazard models, as shown on the right side of the table, point to significant influence (P, .001) of IL-6, TNF-α, hsCRP, and fibrinogen on future events. When a composite inflammation score (CIS) is computed using IL-6, TNF-α, fibrinogen, and serum albumin is coded by quintile, the results displayed in the Kaplan-Meier curve reveal that as adjusted hazard ratios for each quintile increase, the probability of atherosclerotic vascular disease survival decreases. Thus, both hsCRP and the IL-6 are potential predictive CVD markers of inflammation in the setting of CKD.31
In Persons With CVD, CKD, or T2D, Systemic Inflammation Is Common Regardless of Weight
Elevated hsCRP is now identified across 2 high-risk patient groups, and a recent analysis presented at the 2023 European Society of Cardiology congress sought to determine the commonality of this inflammatory marker. Across 3 major CV studies that enrolled patients with known CVD, kidney disease, or both, investigators found approximately half of those with CVD and CKD stage 3-5 had baseline hsCRP ≥2 mg/L. The SELECT trial recruited patients with a body mass index (BMI) above 27kg/m2, while SOUL enrolled patients with established CVD and/or kidney disease, and the FLOW trial included patients with diabetes and CKD. What we see is that despite the standard of care treatment, nearly 50% of these patients have a baseline CRP above 2 mg/L, indicating a high prevalence of systemic inflammation.32
Listen to this audio clip summarizing the role of hsCRP and IL-6 as predictors of ASCVD.
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