 highlights the widespread prevalence of cardiovascular-kidney-metabolic (CKM) syndrome among US adults. Findings also show that adults aged 65 years and older, men, and Black adults face an increased risk of advanced stages.

Between 2011 and 2020, almost 90% of US adults met the criteria for stage 1 or higher of 

 and 15% met the criteria for advanced stages (stages 3 or 4), however, there was no improvement in these prevalence rates over the study period.

“The lack of progress, in part, may reflect concomitant improvement and worsening of different risk factors over time,” researchers from Brigham and Women’s Hospital and Harvard Medical School wrote.

In recent years, there has been a shift in the medical and scientific communities’ appreciation for the connections among CKM diseases and for their combined impact on cardiovascular mortality. In 2023, the 

 the framework for CKM syndrome which included staging and corresponding screening approaches. The stages are based on risk factors and established disease and range from 0 (no risk factors) to 4 (established cardiovascular disease [CVD]), according to the study.

Citing a lack of studies on the stages of CKM syndrome in the US population, investigators conducted a nationally representative study to examine “the prevalence and temporal evolution of CKM syndrome stages,” they wrote.

Investigators used the National Health and Nutrition Examination Survey (NHANES; 2011 to March 2020) to identify adults aged 20 years and older who underwent physical examination and fasting laboratory measurements.

A total of 10 762 adults (mean age, 47.3 years; 51.8% women) were categorized into the following CKM syndrome stages:

Stage 0: No CKM risk factors (eg, hypertension)

Stage 1: Excess or dysfunctional adiposity

Stage 2: Additional metabolic risk factors or moderate- or high-risk chronic kidney disease (CKD)

Stage 3: Very high-risk CKD or high-predicted 10-year CVD risk

Stage 4: Established CVD (eg, coronary artery disease)

“Advanced CKM syndrome stages were defined as stages 3 or 4 because these identify individuals with or at high risk of CVD,” first author Rahul Aggarwal, MD, clinical fellow in medicine, Brigham and Women’s Hospital, and colleagues noted.

Temporal trends between 2011-2012 and 2017-March 2020 were assessed by CKM stage and for advanced stages using linear regression. Prevalence of advanced stages was compared among subgroups (age, sex, race, and ethnicity) using log-binomial regression.

Among the cohort, 64.4% were White, 15.3% were Hispanic, 11.5% were Black, 5.6% were Asian American, and 3.3% were other races and ethnicities.

Between 2011 and 2020, 10.6% of US adults met criteria for stage 0, 25.9% for stage 1, 49.0% for stage 2, 5.4% for stage 3, and 9.2% for stage 4. Aggarwal and colleagues added that the prevalence of each stage did not significantly change during the study period (

Advanced stages of CKM syndrome occurred in 14.6% of participants and did not significantly change over the study period, according to the study.

When investigators analyzed the prevalence of CKM syndrome among the subgroups, they observed that adults aged 65 years and older were more likely to have advanced stages than were those aged 45 to 64 years (55.3% vs 10.7%; 

 < .001) and those aged 20 to 44 years (55.3% vs 2.1%; 

 < .001). Also, 18.2% of adults aged 20 to 44 years had stage 0.

In addition, men were more likely than women to have advanced stages of CKM syndrome (16.9% vs 12.4%; adjusted prevalence ratio [PR] 1.36, 95% CI 1.24-1.49; 

 < .001). Black adults were significantly more likely to have advanced stages compared to White adults (18.9% vs 13.8%; adjusted PR 1.38, 95% CI 1.24-1.55; 

“Poor CKM health is widespread in the US population, especially among Black adults. Equitable health care approaches prioritizing CKM health are urgently needed,” Aggarwal et al.

For interviews with Chiadi Ndumele, MD, PhD, MHS, chair of the writing committee for the AHA’s scientific statement on prevention and management of CKM syndrome and associate professor of medicine and director of obesity and cardiometabolic research in the division of cardiology at Johns Hopkins University, please see:

"CKM Syndrome" Defines a Very Wide Target and Medicine is Ready, Says Chiadi Ndumele, MD, PhD, MHS

The 4 Stages of CKM Syndrome Offer Opportunities to Stop Progression, Promote Regression

Primary Care is the Quarterback in Effective Care for Cardiovascular-Kidney-Metabolic Syndrome

How to Build Assessment for Cardiovascular-Kidney-Metabolic Syndrome into Primary CVD Prevention

Aggarwal R, Ostrominski JW, Vaduganathan M. 

Prevalence of cardiovascular-kidney-metabolic syndrome stages in US adults, 2011-2020.

. Published online May 8, 2024. doi:10.1001/jama.2024.6892

Articles

Results also showed that older adults, men, and Black adults face an increased risk of advanced stages of CKM syndrome. 

Poor Cardiovascular-Kidney-Metabolic Health “Widespread” among US Adults, According to New Study

 (CKD) may affect up to 1 in 6 individuals across 8 major industrialized nations by 2032, ranging from 11.7% in Australia to 16.5% in the US, a new model predicts. The rise in advanced stage disease (stages 3-5) will be the most dramatic over the 8-year period, at nearly 60% (59.3%). In 4 countries, including China, the increase in prevalence of advanced stage CKD will increase by at least 30% over this time.

The data come from a modeling analysis developed in collaboration with AstraZeneca (AZ) presented at the 2024 World Congress of Nephrology in Buenos Aires, Argentina. The IMPACT-CKD study is the first to forecast the multidimensional impact of 

 over a 10-year horizon, projecting trends in the US, Brazil, the UK, Spain, Germany, the Netherlands, China, and Australia, according to an AZ press statement.

The analysis goes beyond estimating the burden of illness, the international group of authors wrote in the study abstract.

By offering a comprehensive assessment of a CKD patient’s journey, our aim is to provide insights and recommendations to effectively reduce the clinical, economic, societal, and environmental burdens associated with CKD.”

Estimates are that by 2040, CKD will be the fifth leading cause of death worldwide, with the demands of treatment straining health care systems and national economies, researchers stressed.

 The national health care budget allocation for CKD is projected to reach an average of 7.3% by then, with some countries distributing more than one-quarter (25.7%) of their health care resources to CKD management, they wrote. In its early stages CKD is asymptomatic which accounts for the findings that up to 90% of individuals are unaware of it until the disease reaches an advanced stage.

 Greater awareness of CKD among potential patients and health care professionals alike would support early recognition and treatment that could prevent disease progression to stages that require tremendous health care and social resources.

For the study, researchers used patient level simulation to create one-million individual patients based on country population size, according to the study abstract. The model maps national and regional CKD treatment pathways, covering the full course of disease from primary care to end-of-life care.

The analysis projects that nearly 125 million people across the 8 countries will have stage 3-5 kidney disease by 2023, which is an increase of 25% since the model began in 2022, stated researchers. The increased number of patients who will require advanced treatment services will increase dialysis requirements by more than 75% across the 8 countries. When the resources required for dialysis and transplant are combined, the cost is estimated at $186 billion. Costs associated with other renal replacement therapies will escalate by 77% or more and, in at least 7 of the countries, there will be a 23% rise in CKD-related emergency and inpatient hospital costs, according to the study findings.

The impact on economic productivity will be significant as well, with combined patient and caregiver absenteeism responsible for a total of more than 3 billion missed workdays across the cohort, a loss equivalent to $37 billion US. Further, the model projects an environmental impact associated with CKD management that will make a carbon footprint equivalent to annual water usage of approximately 2.7 million households, power for ~149. 7 million lightbulbs, and CO2 emissions equivalent to that of ~17.3 million cars.

“Our modelling emphasizes the enormous impact CKD could have on patients, economies, and the environment,” Ruud Dobber, head of the biopharma business unit at AZ, said in the announcement.

“But this future is not inevitable,” added Dobber. “We are committed to working with global policy makers to reduce the worldwide impact of end-stage CKD and drive earlier diagnosis and treatment to slow or halt progression of the disease.”

AZ recently launched the Accelerating Change Together (ACT) for CKD, encompassing a series of studies and initiatives designed to improve understanding and outcomes of CKD worldwide.

Other elements of the program include the 

 study, looking at the extent of underdiagnosis and the clinical impact of an early diagnosis, and the 

 analysis modelling future prevalence, disease burden, and healthcare use and costs, and the benefits of screening.

1. Multidimensional burden of chronic kidney disease in eight countries: insights from the IMPACT-CKD study. Abstract presented at 2024 ISN World Congress of Nephrology 20204; April 13-16, Buenos Aires, Argentina. Accessed April 15, 2024. https://www.kireports.org/article/S2468-0249(24)00629-6/pdf 2. New modelling reveals the escalating toll of chronic kidney disease on patients, planet and economies. News release. AstraZeneca. April 15, 2024. Accessed April 15, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/new-modelling-reveals-the-escalating-toll-of-chronic-kidney-disease-on-patients-planet-and-economies.html
3. Chronic Kidney Disease Initiative. Chronic kidney disease in the United States, 2023. Centers for Disease Control and Prevention. Last reviewed May 30, 2023. Accessed April 15, 2024.  https://www.cdc.gov/kidneydisease/publications-resources/ckd-national-facts.html

The overall CKD population will reach 125 million by 2032 across 8 industrialized nations, with significant clinical, social, economic, and environmental costs. 

Advanced-Stage CKD Prevalence Rising Rapidly Worldwide: Multidimensional Modeling Study 

Data from an interim analysis of the phase 2 proof-of-concept LEGEND trial (NCT05232071) demonstrated that the investigational small molecule lanifibranor significantly lowered hemoglobin A1C (HbA1C) level when given alone and in combination with empagliflozin compared with placebo in adults with metabolic dysfunction–associated steatohepatitis (MASH) and poorly controlled type 2 diabetes (T2D).

Study results also showed statistically significant reductions in several markers of liver injury and glucose and lipid metabolism as well as improvement in hepatic steatosis. The findings were announced in a press statement by Inventiva.

Lanifibranor is a peroxisome proliferator­–activated receptor (PPAR) agonist designed to target the 3 PPAR isoforms. The orally available small molecule induces antifibrotic, anti-inflammatory, and beneficial vascular and metabolic changes. There are other PPAR agonists that target 1 or 2 PPAR isoforms for activation, according to Inventiva; however, lanifibranor is the only pan-PPAR agonist in clinical development for the treatment of MASH/nonalcoholic SH (NASH). The FDA granted lanifibranor both breakthrough therapy and fast-track designations for the treatment of MASH/NASH in 2020.

“These LEGEND results provide valuable insights on the complementary mechanisms of action of an SGLT2 inhibitor and the pan-PPAR agonist, lanifibranor. MASH is a multifaceted disease that we believe will benefit from combination therapies in order to properly address the full cardiometabolic spectrum of the disease,” trial coprincipal investigator Michelle Lai, MD, associate professor of medicine at Harvard Medical School in Boston, Massachusetts, said in the announcement.

LEGEND is a multicenter, randomized, 24-week, placebo-controlled trial designed to assess the safety and efficacy of lanifibranor in combination with the SGLT2 inhibitor empagliflozin for the treatment of patients with noncirrhotic MASH/NASH and T2D. Investigators are using a double-blind design for the lanifibranor 800 mg daily vs placebo arm and an open-label format for the combination of lanifibranor 800 mg and empagliflozin 10 mg daily arm.

The interim analysis, planned per protocol, was performed once half the 63 randomly assigned patients with MASH completed the 24-week treatment period or prematurely discontinued treatment, according to the press release.

 The study’s primary efficacy end point was achieved, with an absolute reduction in HbA1C level at week 24 among participants treated with lanifibranor alone or in combination with empagliflozin. Participants experienced decreases of 1.14% and 1.59%, respectively, vs a 0.26% increase in the placebo arm.

 LEGEND researchers also reported statistically significant reductions in hepatic steatosis in participants treated with both lanifibranor and lanifibranor/empagliflozin (–47% and –38%, respectively) as measured by MRI proton density fat fraction compared with placebo (0%). Furthermore, 83% of participants who received lanifibranor alone and 67% treated with the SGLT2 inhibitor/pan-PPAR agonist combination reached a 30% or greater reduction in hepatic steatosis compared with 0% in the placebo arm.

 Lai and colleagues also reported statistically significant effects for several secondary and exploratory end points, including alanine aminotransferase level, aspartate aminotransferase level, and insulin resistance. Importantly, the research team assessed markers of liver inflammation and fibrosis for the first time with lanifibranor and found significant effects with lanifibranor alone and in combination with empagliflozin.

 Although moderate, metabolically healthy weight gain has been observed in individuals treated with lanifibranor monotherapy, study participants treated with lanifibranor in combination with empagliflozin maintained a stable weight throughout the 24-week study. In addition, the visceral and subcutaneous adipose tissue ratio was significantly reduced in both the lanifibranor alone (–5%) and combination with empagliflozin (–17%) groups whereas an increase in the ratio of 11% was reported in participants assigned to placebo.

“The study was designed as a proof of concept, and these results are significant and strengthen confidence in the potential of lanifibranor to address the specific metabolic imbalance in patients with T2D while also addressing steatosis and fibrosis, a hepatic consequence of insulin resistance,” Onno Holleboom, MD, PhD, associate professor at Amsterdam University Medical Center in the Netherlands and coprincipal investigator of the trial, concluded.

1. Inventiva announces positive results from the phase II, LEGEND, proof-of-concept study combining lanifibranor with empagliflozin in patients with MASH/NASH and T2D. News release. Inventiva. March 18, 2024. Accessed March 20, 2024. https://inventivapharma.com/wp-content/uploads/2024/03/Inventiva-PR-Results-LEGEND-EN-03-18-2024.pdf 
2. Inventiva receives FDA breakthrough therapy designation for lead drug candidate lanifibranor in NASH. News release. Inventiva. October 12, 2020. Accessed March 20, 2024. https://inventivapharma.com/inventiva-receives-fda-breakthrough-therapy-designation-for-lead-drug-candidate-lanifibranor-in-nash/

LEGEND phase 2 interim analysis findings include significant decreases in HbA1c in poorly controlled T2D and positive effects on several markers of liver injury. 

Lanifibranor Plus Empagliflozin Effective in T2D, MASH: Proof-of-Concept Ph2 Findings 

Digital Edition for Patient Care Online for June, 2024

Patient Care Online June 2024 | Patient Care Digital Edition

Poor Cardiovascular-Kidney-Metabolic Health “Widespread” among US Adults, According to New Study

Advanced-Stage CKD Prevalence Rising Rapidly Worldwide: Multidimensional Modeling Study

Lanifibranor Plus Empagliflozin Effective in T2D, MASH: Proof-of-Concept Ph2 Findings