Lifestyle Interventions in Cardiovascular-Kidney-Metabolic Syndrome JACC: Advances Expert Panel

Abstract

Cardiovascular-kidney-metabolic (CKM) syndrome impacts nearly all organ systems, with progressive dysfunction leading to morbidity and mortality. The high burden of CKM syndrome requires accessible, scalable, and low-cost interventions to prevent downstream complications. Nonpharmacologic interventions targeting lifestyle factors, such as diet, physical activity, and behavioral modification, represent the cornerstone of CKM syndrome management to prevent a progressive disease and associated adverse outcomes. Lifestyle interventions play a key role not only in primordial and primary prevention in the earlier stages of CKM syndrome (stages 0-2) but also in subclinical cardiovascular disease (stage 3) as well as prevalent cardiovascular disease (stage 4). The purpose of the present review is to describe the evidence from randomized clinical trials for specific lifestyle interventions across CKM syndrome stages. This review will explore the impact of lifestyle interventions in each CKM syndrome stage and how they impact interrelated systems.

Central Illustration

Cardiovascular-kidney-metabolic (CKM) syndrome represents the interrelationships and interconnected dysfunction of multiple organ systems and contributes to increased morbidity and mortality.^1,2 Recently defined by the American Heart Association, the progressive nature of this multisystem disorder is reflected by the continuous framework that ranges from CKM syndrome stage 0 (healthy) to stage 4 (established cardiovascular disease [CVD]).¹ Epidemiologic data highlight the burden of CKM syndrome in the United States, with nearly 90% of the adult population in the United States meeting the criteria for CKM stage 1 or higher.³ The growing obesity epidemic and aging population suggest that the burden of CKM syndrome will likely increase, necessitating proactive prevention and management strategies.

Despite the availability of pharmacologic treatments targeting metabolic, renal, and cardiovascular components of CKM syndrome, particularly in the advanced stages, the burden of CKM syndrome demands cost-effective and sustainable therapies that are widely accessible. Lifestyle interventions, which include diet, exercise, and behavioral modification, offer potential effective approaches to prevention and treatment across the stages of CKM syndrome. These interventions address individual risk factors and contribute to overall health improvements that can slow disease progression and improve overall quality of life. Lifestyle modification is the foundation of CKM syndrome prevention and management, with evidence supporting its role in obesity, hypertension, diabetes, and other interrelated conditions.⁴

However, there remain important knowledge gaps regarding the implementation of lifestyle interventions, including across the various stages of CKM syndrome. Guidelines acknowledge the importance of nonpharmacologic interventions, but recommendations for specific lifestyle therapies across CKM syndrome stages are lacking.⁴ Recommendations for select lifestyle interventions across CKM syndrome stages may guide clinicians to implement personalized interventions. The current CKM syndrome framework provides an opportunity to integrate evidence-based lifestyle interventions into each stage of the CKM syndrome, which can guide targeted interventions. In this JACC: Advances Expert Panel, we sought to describe the role of lifestyle interventions in CKM syndrome management, focusing on evidence derived exclusively from randomized clinical trials (RCTs). By structuring the review according to CKM syndrome stages, we aim to provide actionable insights for clinicians to implement lifestyle interventions in CKM syndrome across specific stages.

CKM syndrome stage-specific management

CKM syndrome stage 0: prevention of metabolic risk factors

Stage 0 of the CKM syndrome represents a healthy profile free of CKM risk factors.¹ Individuals are free of excess adiposity as assessed by normal body mass index (BMI) and waist circumference levels and also have euglycemia, normotension, a normal lipid profile, and no evidence of kidney disease or subclinical or prevalent CVD. The goal for individuals at this stage is to maintain these optimal health parameters, also considered primordial prevention, and to minimize the risk of progression to CKM syndrome stage 1 and beyond. The American Heart Association's Life's Essential 8 framework provides a comprehensive approach to maintaining cardiovascular health.⁵

Atherosclerosis is a progressive disease that begins in early life and worsens over time as exposure to traditional and nontraditional risk factors accumulates.^6,7 Individuals who develop premature atherosclerotic CVD commonly have modifiable risk factors that present long before the onset of the clinical disease.⁸ Of the risk factors with major clinical impact, obesity serves as a principal driver of metabolic risk factors such as type 2 diabetes (T2D), hypertension, and hypertriglyceridemia.9, 10, 11 From 1975 to 2016, there has been an 8-fold increase in the prevalence of obesity among children and adolescents 5 to 19 years of age.¹² Implementing lifestyle interventions in early life to reduce long-term exposure to risk factors has the potential for substantial long-term benefits.^8,9

Most RCTs in CKM syndrome stage 0 have included children and adolescents due in part to the fact that CKM risk factors are most likely to be absent within this younger population. Intervention trials have primarily targeted diet with or without a physical activity component to prevent excess adiposity. A 2024 Cochrane meta-analysis of 172 RCTs, including 189,707 children aged 5 to 11 years, suggested that physical activity and dietary interventions led to a modest reduction in BMI at short- (12 weeks to <9 months) and intermediate-term (9 months to <15 months) follow-up (mean difference of −0.11 kg/m²) (Table 1).¹³ The beneficial effects on BMI appear to be largely related to physical activity interventions, as dietary interventions alone had no significant effect on BMI. RCTs focused only on overweight or obesity management were excluded from this meta-analysis, leading to its discussion in CKM syndrome stage 0. However, RCTs included in this meta-analysis could have enrolled children who were overweight and obese and may also provide insights into management of CKM syndrome stage 1. Most studies evaluating lifestyle interventions included children from the United States or Europe. In the DECIDE (Diet, Exercise and Cardiovascular Health)–Children study, 24 schools in China were randomly assigned to a physical activity and dietary intervention vs usual practice. DECIDE-Children demonstrated a modest reduction in BMI with the lifestyle intervention.¹⁴ Taken together, diet and physical activity interventions may both be needed to reduce BMI and prevent obesity among adolescents with CKM stage 0 rather than solely focusing on diet modification.

Table 1.

Characteristics and Outcomes of Key Studies Evaluating Lifestyle Interventions in Cardiovascular-Kidney-Metabolic Syndrome Stage 0

First Author/Study Name	Study Population	Intervention	Control	N	Outcome
Spiga et al13,a	•Children aged 5 to <12 y •General population at-risk groups (eg, parental obesity) •Specific settings with high obesity risk •Assumed no baseline CVD or CKD given childhood age of participants. Baseline weight not defined.	•Interventions aimed at modifying diet, physical activity, sedentary behavior, sleep, play, or structured exercise	•Nonintervention control group (no intervention or usual care) or another eligible intervention (head-to-head comparison).	189,707	Dietary and activity interventions vs control: • Short-term follow-up: ○ BMI: MD −0.11 (95% CI −0.21 to −0.01); 27 studies, 16,066 participants ○ zBMI: MD −0.03 (95% CI −0.06 to 0.00); 26 studies, 12,784 participants (low-certainty evidence) • Mid-term follow-up: ○ BMI: MD −0.11 (95% CI −0.21 to 0.00); 21 studies, 17,547 participants ○ zBMI: MD −0.05 (95% CI −0.07 to −0.02); 24 studies, 20,998 participants (moderate-certainty evidence) • Long-term follow-up: ○ BMI: MD 0.03 (95% CI −0.11 to 0.16); 16 studies, 22,098 participants ○ zBMI: MD −0.02 (95% CI −0.06 to 0.01); 22 studies, 23,594 participants (low-certainty evidence)
DECIDE-Children14	•Children aged 8-10 y from grade 4 classes •No medical history of serious diseases •Ability to participate in sports •Normal baseline BMI in all participants and no other risk factors documented	•A multifaceted program targeting both children (health education, physical activity reinforcement, BMI monitoring) and their environment (school and family engagement). •A smartphone app was used to enhance family involvement in supporting behavioral changes.	•Schools continued with usual health education and physical education lessons without a specific focus on obesity prevention.	1,392	•BMI change: Mean BMI decreased in the intervention group and increased in the control group (mean difference: −0.46 [95% CI −0.67 to −0.25]; P < 0.001). •Obesity prevalence: 27.0% relative decrease in obesity in the intervention group vs 5.6% in the control group (OR: 0.34 [95% CI 0.18-0.64]). •Adiposity outcomes: Improved BMI z-score (MD −0.17 [95% CI −0.25 to −0.09]), body fat percentage (MD −1.05 [95% CI −1.83 to −0.28]), and waist circumference (MD −1.63 cm [95% CI −2.82 to −0.43]). •Behavioral changes: Improved dietary habits, sedentary behavior, physical activity levels, and obesity-related knowledge, but no significant change in moderate-to-vigorous physical activity, physical fitness, or blood pressure
Santos-Beneit et al15	•Children aged 6-12 y in Madrid, Spain •Attending public schools with a cafeteria in the South Madrid Education Area. •Assumed baseline normal BMI. Baseline CVH assessed, participants had baseline intermediate CVH scores indicating no evidence of CVD or CKD	•SI! Program, a multidimensional school-based educational program designed to promote healthy behaviors through diet, physical activity, and behavioral strategies over 4 or 2 school years.	•Standard curriculum	1,326	3-Y follow-up (intervention vs control): •BMI z-score increase: Lower in the intervention group (MD −0.09 [95% CI −0.16 to −0.03]; P = 0.003) •Waist-to-height ratio (zWHtR) and waist circumference (zWC) increase: Lower in the intervention group (MD −0.19 [95% CI −0.28 to −0.10]; P < 0.001) 6-Y follow-up: • Sustained benefits in zWC and zWHtR: ○ zWC: Control vs E1-6 (MD −0.19 [95% CI −0.36 to −0.03]; P = 0.020), Control vs E1-3 (MD −0.22 [95% CI −0.38 to −0.06]; P = 0.009) ○ zWHtR: Control vs E1-6 (MD −0.24 [95% CI −0.41 to −0.06]; P = 0.009), Control vs E1-3 (MD −0.29 [95% CI −0.47 to −0.11]; P = 0.001)
MOVE-IT16	•Adults aged 40-74 y •≥20% 10-y CVD risk (QRisk2 score) •Fluent in English •Permanent residents of the UK •Exclusion criteria of baseline CVD or CKD and morbid obesity.	•Enhanced motivational interviewing based on social cognitive theory and the theory of planned behavior.	•Usual care	1,742	Physical activity: •Group intervention vs usual care: MD 70.05 steps (95% CI −288.00 to 147.90) •Individual intervention vs usual care: MD 7.24 steps (95% CI −224.01 to 238.50) Weight change: •Group intervention vs usual care: MD −0.03 kg (95% CI −0.49 to 0.44) •Individual intervention vs usual care: MD −0.42 kg (95% CI −0.93 to 0.09)
Ashton et al17,a	•Adults aged ≥18 y •Enrolled in a RET program lasting ≥2 wk •Participants are defined as “nonathletic” but baseline BMI, CVD, and CKD status is not specified	•RET using methods such as elastic resistance bands, weight machines, or isometric RET with whole-body vibration, regardless of intensity or frequency.	•Nonexercising control group or usual care	6,169	Systolic blood pressure: •Medium term: MD −4.02 mm Hg (95% CI −5.92 to −2.11; P < 0.0001) •Long term: MD −5.08 mm Hg (95% CI −10.04 to −0.13; P = 0.04) Diastolic blood pressure: •Medium-term: MD −1.73 mm Hg (95% CI −2.88 to −0.57; P = 0.003) •Long term: MD −4.93 mm Hg (95% CI −8.58 to −1.28; P = 0.008) Metabolic outcomes: •Fasted insulin (medium term): MD −0.59 μU/mL (95% CI −0.97 to −0.21; P = 0.002) •Insulin resistance (medium term): MD −1.22 μU/mL (95% CI −2.29 to −0.15; P = 0.02)

BMI = body mass index; CKD = chronic kidney disease; CVD = cardiovascular disease; CVH = Cardiovascular health; MD = mean difference; RET = resistance exercise training; zBMI = z-score body mass index (refers to age- and sex-standardized BMI).

^aMeta-analysis of RCTs.

Promoting healthy habits in CKM syndrome stage 0 is a potentially scalable nonpharmacologic intervention. Health-promotion initiatives can extend lessons from RCTs beyond a healthy diet and increased physical activity. The Si! Program evaluated a multicomponent health-promotion initiative in schools.¹⁵ The intervention was an educational program that promoted healthy behaviors to children, families, and teachers. It focused on diet, physical activity, and emotional management, targeting strategies to avoid substance abuse. The school-based health-promotion intervention, compared with standard curriculum, significantly decreased abdominal adiposity markers such as BMI, waist-to-height ratio, and waist circumference. Despite the resulting changes in adiposity measures, there were no differences in knowledge-attitudes-habits scores across randomized treatment groups. Future studies of health-promotion initiatives among school-aged children may need to investigate the acceptance of the intervention to understand the sustainability of such healthy practices better.¹⁸

Approximately 10% of the adult population in the United States has CKM syndrome stage 0, suggesting a relatively smaller population to select from for enrollment in RCTs investigating lifestyle interventions; hence, data are scarcer. Unlike the health-promotion initiatives in the Si! Program in children, motivational interviewing in group and individual formats had no impact on weight changes among adults who were free of CVD and kidney disease (although limited data are available to assess CKM syndrome stage 0).¹⁶ Among adults, resistance exercise training is an effective nonpharmacologic therapy for primordial prevention of CKM syndrome. A meta-analysis of RCTs, most of which included healthy adults likely in CKM syndrome stage 0 (although data for precise classification were limited), demonstrated that resistance exercise training had favorable effects on several cardiometabolic parameters, including reductions in systolic and diastolic blood pressure, decrease in triglycerides and fasting glucose, and an increase in high-density lipoprotein cholesterol.¹⁷

CKM syndrome stage 1: addressing obesity and CKM risk

CKM syndrome stage 1 is characterized by excessive or dysfunctional adiposity, manifesting as overweight or obesity, abdominal obesity, or impaired glucose tolerance, without additional metabolic risk factors or chronic kidney disease.¹ Diagnostic criteria for CKM stage 1 include a BMI ≥25 kg/m² (or ≥23 kg/m² for individuals of Asian ancestry), waist circumference ≥88 cm in women and ≥102 cm in men (with lower thresholds of ≥80 cm and ≥90 cm, respectively, for Asian individuals), fasting blood glucose level 100 to 124 mg/dL, or hemoglobin A1c (HbA1c) 5.7% to 6.4%.¹

In the realm of lifestyle interventions, the initial management strategy for excess adiposity relies on calorie restriction and improvement in diet quality.¹⁹ The effectiveness of diet modification, particularly calorie restriction in creating an energy deficit and inducing weight loss, is related to individual adherence and duration of the dietary intervention being followed.²⁰ Since the 1960s, behavioral modification has been considered integral to obesity management, enhancing the effects of pharmacologic weight loss therapies. RCTs of moderate caloric restriction include ∼1,200 to 1,500 kcal/day from diet combined with behavioral modification resulting in ∼8.5 kg weight loss over 20 weeks.²¹ A very-low-calorie diet (<800-1,000 kcal/day) combined with behavioral modification for short-term weight loss (<3 months) can result in weight reductions of ∼20 kg in 12 to 16 weeks.²² However, most diet interventions lead to modest weight loss of <5% over 1 year of follow-up.²³ Furthermore, RCTs have revealed mixed results on the effect of diet composition on weight loss. Among individuals with CKM syndrome stage 1 with obesity and no history of T2D, Foster et al²⁴ demonstrated that a low-carbohydrate, high-protein, high-fat diet led to ∼4% greater absolute decrease in weight than a high-carbohydrate, low-fat diet at 6 months (Table 2). However, after 12 months, there was no significant difference in weight change between the low-carbohydrate and low-fat diets.²⁴ Among individuals with a mean BMI of 28 kg/m² enrolled in the CALERIE trial, a low-carbohydrate diet led to similar 1-year weight loss compared with a conventional diet composed of a higher percentage of calories from carbohydrates.²⁵ Taken together, weight loss over long-term follow-up is similar across diets with a similar degree of calorie deficit, irrespective of macronutrient composition.^23,28

Table 2.

Characteristics and Outcomes of Key Studies Evaluating Lifestyle Interventions in Cardiovascular-Kidney-Metabolic Syndrome Stage 1

First Author/Study Name	Study Population	Intervention	Control	N	Outcome
Sacks et al23	•Ages 30 to 70 y •40% men •Exclusion of patients with diabetes or cardiovascular disease •BMI between 25 and 40 kg/m2	•Low-fat, high-carb: 20% fat, 15% protein, 65% carbs •Low-fat, high-protein: 20% fat, 25% protein, 55% carbs •High-fat, average protein: 40% fat, 15% protein, 45% carbs •High-fat, high-protein: 40% fat, 25% protein, 35% carbs	•Participants were assigned to different dietary interventions for comparison	811	•At 6 mo: Participants lost an average of 6 kg (∼7% of initial weight) across all diet groups •At 12 mo: Weight regain began in all groups •At 2 y: • Weight loss remained similar across macronutrient compositions: ○ Low vs high protein: 3.0 kg vs 3.6 kg ○ Low vs high fat: 3.3 kg for both groups ○ Low vs high carbohydrate: 2.9 kg vs 3.4 kg
Foster et al24	•BMI ≥30 kg/m2 •Excluded patients with diabetes, those taking lipid lowering medications	•Low-carbohydrate, high-protein, high-fat diet (Atkins diet) •Low-calorie, high-carbohydrate, low-fat (conventional) diet	•Participants on the conventional low-calorie, high-carbohydrate, low-fat diet	63	Weight loss: •At 3 mo: Greater weight loss in low-carb diet group (−6.8% vs −2.7% of body weight; P = 0.001) •At 6 mo: Greater weight loss in low-carb diet group (−7.0% vs −3.2% of body weight; P = 0.02) •12 mo: No significant difference between groups (−4.4% vs −2.5% of body weight; P = 0.26) Cardiovascular risk factors: •No significant difference in total or LDL cholesterol after 3 mo •Greater increase in HDL cholesterol in the low-carb group •Greater decrease in triglycerides in the low-carb group
CALERIE25	•Otherwise healthy, overweight (BMI 25-30 kg/m2) •Mean age of 35 ± 6 y and body mass index (kg/m2) of 27.6 ± 1.4	Randomized to one of 2 calorie-restricted (CR) diets with 30% calorie reduction: •High glycemic load (HG) diet •Low glycemic load (LG) diet	•Not applicable (only HG vs LG diet groups were analyzed)	34	Weight and fat loss: •At 12 mo: ○HG group: −8.04% ± 4.1% weight change ○LG group: −7.81% ± 5.0% weight change •No significant difference between the groups
Diabetes Prevention Program26	•Adults who are overweight BMI ≥25 kg/m2, who were 40-65 y old with impaired glucose tolerance •Fasting plasma glucose: 95-125 mg/dL (5.3-6.9 mmol/L) •Postload glucose (2-hour OGTT): 140-199 mg/dL (7.8-11.0 mmol/L)	•Lifestyle intervention—targeted ≥7% weight loss and ≥150 min/wk physical activity. •Metformin group—850 mg twice daily plus standard lifestyle recommendations. •Placebo group—placebo twice daily plus standard lifestyle recommendations.	•Standard lifestyle recommendations without additional intervention.	522	Outcomes (mean follow-up: 2.8 y): • Diabetes incidence: ○ Lifestyle group: 4.8 cases per 100 person-years (58% reduction, 95% CI 48%-66%). ○ Metformin group: 7.8 cases per 100 person-years (31% reduction, 95% CI 17%-43%). ○ Placebo group: 11.0 cases per 100 person-years. • Number needed to treat (NNT, 3 y): ○ Lifestyle intervention: 6.9 persons to prevent one case of diabetes. ○ Metformin: 13.9 persons to prevent one case of diabetes. •Lifestyle intervention was significantly more effective than metformin.
TOHP27	•Age 30-54 y •Not on antihypertensive medication •Systolic BP < 140 mm Hg, Diastolic BP 83-89 mm Hg •BMI 110%-165% of desirable body weight	•Weight loss counseling (targeting desired weight or ≥4.5 kg reduction), dietary sodium reduction (targeting ≤80 mmol/d), or both combined	•Usual care	2,382	Weight change: •At 6 mo: −4.3 to −4.5 kg in the weight loss and combined groups (P < 0.001) •At 36 mo: −2 kg in the weight loss and combined groups (P < 0.001) Blood pressure reduction: • At 6 mo: ○ Weight loss group: −3.7/−2.7 mm Hg (P < 0.001) ○ Sodium reduction group: −2.9/−1.6 mm Hg (P < 0.001) ○ Combined group: −4.0/−2.8 mm Hg (P < 0.001) • At 36 mo: ○ Weight loss group: −1.3/−0.9 mm Hg (P < 0.001) ○ Sodium reduction group: −1.2/−0.7 mm Hg (P < 0.001, significant for systolic BP). ○ Combined group: −1.1/−0.6 mm Hg (P < 0.001) Hypertension incidence (48 mo): •Significantly lower in all active intervention groups vs usual care (RR 0.78-0.82)

BMI = body mass index; LDL = low-density lipoprotein; HDL = high-density lipoprotein; RR = risk ratio; OGTT = oral glucose tolerance test.

RCTs have examined the long-term effects of lifestyle interventions, combining low-fat diets with physical activity, in CKM syndrome stage 1, specifically among individuals with prediabetes enrolled in diabetes-prevention trials. The Diabetes Prevention Study enrolled adults who are overweight or obese and with impaired glucose tolerance from Finland and evaluated the effect of a lifestyle intervention on the incidence of T2D.²⁶ The lifestyle intervention consisted of individualized counseling with a goal of at least 5% weight loss and a low-fat diet plus regular exercise and resulted in 58% reduction in T2D incidence. A similar reduction in the incidence of T2D was observed with the lifestyle intervention in the Diabetes Prevention Program in the United States.²⁹ In the Da Qing IGT and Diabetes Study, a low-fat diet alone and in combination with exercise reduced the incidence of T2D among Chinese adults with impaired glucose tolerance over a 6-year follow-up despite a very modest change in BMI.³⁰ More long-term data on the effects of low-fat dietary interventions for other CKM outcomes are needed.

Similarly, weight loss has been evaluated as a strategy to prevent the development of hypertension in CKM syndrome stage 1. In the Trial of Hypertension Prevention Phase II, individuals who are overweight or obese and have high-normal blood pressure (defined in the study as <140/90 mm Hg) were randomized to a weight loss intervention and sodium reduction, a combination of both, or usual care.²⁷ The active intervention groups included counseling sessions that focused on knowledge and behavioral skills to achieve weight loss and sodium intake goals. Compared with usual care, the active interventions modestly reduced weight at 6 months (1-4.5 kg) with attenuation over 3 years of follow-up. Weight loss and sodium reduction each reduced systolic blood pressure. Incident hypertension was also reduced by the weight loss intervention with and without the sodium reduction intervention, highlighting the importance of weight loss in CKM syndrome stage 1.

Reducing dietary sodium is an effective strategy to reduce blood pressure among individuals without hypertension.³¹ However, modifying a single nutrient can be challenging. Adopting a healthy dietary intake pattern, such as a diet emphasizing fruits, vegetables, and low-fat dairy products, may be more practical. This combination dietary pattern reduced blood pressure compared with a control diet among 459 adults enrolled in the DASH (Dietary Approaches to Stop Hypertension) trial.³² In the subgroup of the DASH trial without hypertension (n = 326), the combination dietary pattern reduced systolic and diastolic blood pressure. In the DASH-Sodium trial, investigators demonstrated that reducing sodium intake in addition to a DASH diet rich in fruits, vegetables, and low-fat dairy products can further lower blood pressure among individuals without hypertension.³³

CKM syndrome stage 2: addressing metabolic risk factors and chronic kidney disease

CKM syndrome stage 2 involves individuals presenting with metabolic risk factors such as hypertriglyceridemia (triglyceride levels ≥135 mg/dL), hypertension, metabolic syndrome, T2D, or chronic kidney disease.¹ Lifestyle modification is particularly critical in managing CKM syndrome stage 2, especially hypertension and T2D.

The blood pressure-lowering effects of a dietary pattern emphasizing fruits, vegetables, and low-fat dairy products (DASH diet) and sodium restriction were observed across the spectrum of baseline blood pressures and extended to individuals with prevalent hypertension in the DASH and DASH-Sodium trials (Table 3).^32,33 These findings established the DASH diet and sodium restriction as critical components for the management of hypertension. In addition, weight loss, increased physical activity, and moderation of alcohol intake have also been recommended as lifestyle interventions for blood pressure management. The blood pressure effects of these established recommendations focused on weight, sodium intake, physical activity, and alcohol consumption with and without DASH diet were evaluated among 810 adults with above-optimal blood pressure and not taking antihypertensive medication in the PREMIER trial.³⁴ The behavioral interventions included regular group and individual counseling sessions. The control group received advice only through a single session discussing factors impacting blood pressure and printed educational information. After 6 months, systolic blood pressure decreased in the behavioral intervention groups compared with the advice-only group. However, the systolic blood pressure reduction observed with the addition of DASH to established recommendations was modest and not statistically significant. The blood pressure-lowering effects of a similar, nonpharmacologic intervention were extended to individuals with high blood pressure taking one antihypertensive medication in the DEW-IT (Diet, Exercise, and Weight Loss Intervention Trial).³⁵ Lifestyle changes can meaningfully reduce blood pressure with and without dietary modification.

Table 3.

Characteristics and Outcomes of Key Studies Evaluating Lifestyle Interventions in Cardiovascular-Kidney-Metabolic Syndrome Stage 2

Study Name/First Author	Study Population	Intervention	Control	Total Participants	Outcome
DASH32	•Adults aged ≥22 y with systolic BP <160 mm Hg and diastolic BP 80-95 mm Hg •Not taking antihypertensive medication at enrollment •Exclusion of patients with poorly controlled diabetes, cardiovascular event in past 6 mo, pregnant, BMI >35, renal insufficiency, alcohol intake >14 drinks per week	•Fruits-and-vegetables diet—increased potassium, magnesium, fiber, and more fruits/vegetables but otherwise similar to control •Combination diet—rich in fruits, vegetables, low-fat dairy, with reduced saturated fat, total fat, and cholesterol	•Control diet that was low in fruits, vegetables, and dairy products, with a fat content typical of the average diet in the United States	459	Outcomes (BP reduction compared to control diet): • Overall population: ○ Combination diet: SBP −5.5 mm Hg, DBP −3.0 mm Hg (P < 0.001) ○ Fruits-and-vegetables diet: SBP −2.8 mm Hg (P < 0.001), DBP −1.1 mm Hg (P = 0.07) • Hypertensive participants (N = 133): ○ Combination diet: SBP −11.4 mm Hg, DBP −5.5 mm Hg (P < 0.001) • Nonhypertensive participants (N = 326): ○ Combination diet: SBP −3.5 mm Hg (P < 0.001), DBP −2.1 mm Hg (P = 0.003)
DASH-Sodium33	•Adults aged ≥22 y with systolic BP 120-159 mm Hg and diastolic BP 80-95 mm Hg (mean of 3 screening visits) including stage 1 hypertension	•DASH diet—rich in fruits, vegetables, and low-fat dairy	•Control diet typical of intake in the United States	412	Outcomes (BP reduction): • Sodium reduction effects: ○ Control diet: SBP −2.1 mm Hg (P < 0.001), then −4.6 mm Hg (P < 0.001) ○ DASH diet: SBP −1.3 mm Hg (P = 0.03), then −1.7 mm Hg (P < 0.01) • DASH diet effects at each sodium level: ○ Greater BP reduction at high sodium levels than at low sodium levels ○ Compared to high-sodium control diet, the low-sodium DASH diet resulted in: • SBP −7.1 mm Hg in nonhypertensive participants • SBP −11.5 mm Hg in hypertensive participants
PREMIER34	•Healthy adults aged ≥25 y with above optimal BP (SBP 120-159 mm Hg, DBP 80-95 mm Hg) •Included individuals with stage 1 hypertension (140-159/90-95 mm Hg) eligible for nonpharmacologic therapy •BMI 18.5-45.0 kg/m2, not on antihypertensive medication, and at risk of hypertension or CVD due to elevated BP	•“Established” intervention—Behavioral intervention implementing established BP-lowering recommendations (weight loss, sodium reduction, physical activity, limited alcohol) •“Established plus DASH” intervention—Same as the established group, but with DASH diet integration (increased fruit, vegetable, and dairy intake)	•Control group “advise-only” comparison group	810	BP reduction: •Established group: SBP −3.7 mm Hg (P < 0.001) •Established plus DASH group: SBP −4.3 mm Hg (P < 0.001) •No significant difference between intervention groups (P = 0.43) Hypertension prevalence: •Advice only: 26% •Established intervention: 17% (P = 0.01 vs advice only) •Established plus DASH: 12% (P < 0.001 vs advice only; P = 0.12 vs established) Optimal BP (<120/80 mm Hg) prevalence: •Advice only: 19% •Established intervention: 30% (P = 0.005 vs advice only) Established plus DASH: 35% (P < 0.001 vs advice only; P = 0.24 vs established)
DEW-IT35	•Hypertensive, overweight adults on a single antihypertensive medication	•Comprehensive lifestyle intervention •Diet: Hypocaloric version of the DASH diet providing 100 mmol/d of sodium •Exercise: Supervised, moderate-intensity aerobic exercise 3 times per week	•Control group received no intervention	44	Weight loss (net of control): −4.9 kg Ambulatory blood pressure reductions (net of control): •24-hour SBP: −9.5 mm Hg (P < 0.001) •24-hour DBP: −5.3 mm Hg (P = 0.002) •Daytime SBP: −12.1 mm Hg (P < 0.001) •Daytime DBP: −6.6 mm Hg (P < 0.001) Lipid profile changes (net of control): •Total cholesterol: −25 mg/dL (P < 0.001) •LDL cholesterol: −18 mg/dL (P = 0.005) •HDL cholesterol: −5 mg/dL (P < 0.001)
OmniHeart36	•Healthy adults aged ≥30 y •Systolic BP 120-159 mm Hg or diastolic BP 80-99 mm Hg •Included individuals with prehypertension and stage 1 hypertension	•Protein-rich diet (half from plant sources) •Unsaturated fat-rich diet (predominantly monounsaturated fat)	•Carbohydrate-rich diet	164	Compared to the carbohydrate diet: • Protein diet: ○ ↓ Systolic BP by 1.4 mm Hg overall (3.5 mm Hg in hypertensive participants, P = 0.006) ○ ↓ LDL cholesterol by 3.3 mg/dL (P = 0.01) ○ ↓ Triglycerides by 15.7 mg/dL (P < 0.001) ○ ↓ HDL cholesterol by 1.3 mg/dL (P = 0.02) • Unsaturated fat diet: ○ ↓ SBP by 1.3 mm Hg overall (2.9 mm Hg in hypertensive participants, P = 0.02) ○ No significant effect on LDL cholesterol ○ ↑ HDL cholesterol by 1.1 mg/dL (P = 0.03) ○ ↓ Triglycerides by 9.6 mg/dL (P = 0.02) Both the protein and unsaturated fat diets lowered estimated 10-y CHD risk
Samaha et al37	•Participants with high BMI, average BMI of 43, and high prevalence of diabetes (39%) or metabolic syndrome (43%)	•Carbohydrate-restricted (low-carbohydrate) diet	•Calorie and fat restricted (low-fat) diet	132	Weight loss: •Low-carbohydrate diet: −5.8 ± 8.6 kg •Low-fat diet: −1.9 ± 4.2 kg •Between-group difference: P = 0.002 Triglyceride reduction: •Low-carbohydrate diet: −20% ± 43% •Low-fat diet: −4% ± 31% •Between-group difference: P = 0.001 Insulin sensitivity (in participants without diabetes): •Low-carbohydrate diet: +6% ± 9% •Low-fat diet: −3% ± 8% •Between-group difference: P = 0.01
LookAHEAD38	•Adults aged 45-75 y with self-reported type 2 diabetes •BMI ≥25 kg/m2 (≥27 if taking insulin) •Glycated hemoglobin ≤11% •Systolic BP <160 mm Hg, diastolic BP <100 mm Hg •Triglyceride level <600 mg/dL (6.77 mmol/L) •Ability to complete a valid maximal exercise test •T2DM 100% • Systolic blood pressure (mm Hg): • Control group: 129 ± 17 • Intervention group: 128 ± 17 • Diastolic blood pressure (mm Hg): • Control group: 70.4 ± 9.6 • Intervention group: 69.9 ± 9.5	•Intensive lifestyle intervention promoting weight loss through decreased caloric intake and increased physical activity •Participants received behavioral counseling, dietary modifications, and structured exercise plans	•Diabetes support and education	5,145	Greater weight loss in intervention group: •8.6% vs 0.7% at 1 y •6.0% vs 3.5% at study end Greater reductions in glycated hemoglobin, fitness, and CVD risk factors (except LDL cholesterol) Primary outcome (CV events): •403 events (1.83 per 100 person-years) in intervention group •418 events (1.92 per 100 person-years) in control group •HR: 0.95 (95% CI 0.83-1.09, P = 0.51) → No significant reduction in CV events
HART-D39	•Seedentary adults with type 2 diabetes mellitus (HbA1C >6.5%) •Systolic (mm Hg): 126.2 (13.1) •Diastolic (mm Hg): 75.6 (8.5)	•Aerobic training: 3 d/wk, expending 12 kcal/kg per week •Resistance training: 3 d/wk •Combination group: Aerobic training (10 kcal/kg per week) + resistance training (2 d/wk)	•No exercise control group	262	HbA1c reduction: •Combination training: −0.34% (95% CI −0.64% to −0.03%; P = 0.03) (significant reduction) •Aerobic training: −0.24% (95% CI −0.55% to 0.07%; P = 0.14) (not significant) •Resistance training: −0.16% (95% CI −0.46% to 0.15%; P = 0.32) (not significant) Waist circumference reduction: −1.9 to −2.8 cm in all exercise groups Fat mass reduction: •Resistance training group: −1.4 kg (95% CI −2.0 to −0.7 kg; P < 0.05) •Combination training group: −1.7 kg (95% CI −2.3 to −1.1 kg; P < 0.05)
PREDIMED40	•Men aged 55-80 y or women aged 60-80 y •No cardiovascular disease at enrollment • Must have had type 2 diabetes or ≥3 major cardiovascular risk factors, including: ○ Smoking ○ Hypertension ○ Elevated LDL cholesterol ○ Low HDL cholesterol ○ Overweight/obesity ○ Family history of premature coronary heart disease •HTN, 82.7% •T2DM, 48.5%	•Mediterranean diet + extra-virgin olive oil—Participants received 1 L of extra-virgin olive oil per week per household, with recommendations to consume ≥4 tablespoons per day •Mediterranean diet + nuts—Participants received 30 g of mixed nuts per day (15g walnuts, 7.5 g hazelnuts, 7.5 g almonds) at no cost	•Control diet (advised to reduced dietary fat)	7,447	Primary endpoint (major cardiovascular events: MI, stroke, CVD death): •Mediterranean diet + olive oil: 3.8% incidence (96 events) •Mediterranean diet + nuts: 3.4% incidence (83 events) •Control group: 4.4% incidence (109 events) Adjusted HR vs control: •Mediterranean diet + olive oil: HR 0.69 (95% CI 0.53-0.91) •Mediterranean diet + nuts: HR 0.72 (95% CI 0.54-0.95) Reanalysis (excluding 1,588 participants with protocol deviations) yielded similar results

BMI = body mass index; CVD = cardiovascular disease; DASH = Dietary Approaches to Stop Hypertension; DBP = diastolic blood pressure; HDL = high-density lipoprotein; HTN = hypertension; LDL = low-density lipoprotein; MI = myocardial infarction; SBP = systolic blood pressure; T2DM = type 2 diabetes mellitus.

The carbohydrate-rich DASH diet evaluated in the DASH trials reduced blood pressure and low-density lipoprotein cholesterol but also reduced high-density lipoprotein (HDL) cholesterol and had no significant effect on triglycerides, which raised questions regarding the net cardiovascular effect of this dietary approach.⁴¹ The blood pressure and lipid effects of partial replacement of carbohydrates with either protein (half derived from plant sources) or unsaturated fat (mainly monounsaturated fat) were evaluated in the Optimal Macronutrient Intake Trial to Prevent Heart Disease (OmniHeart).³⁶ Participants with hypertension received one of 6 potential sequences of 3 diets that differed based on the primary macronutrient composition of carbohydrate, protein, or unsaturated fat while weight remained constant. Both the protein- and unsaturated fat-rich diets were more effective than the carbohydrate-rich diet (similar to the DASH diet) in reducing systolic and diastolic blood pressure and improving serum lipid profiles.³⁶ Specifically, compared with the carbohydrate-rich diet, the protein- and unsaturated fat-rich diets reduced total and non-HDL cholesterol as well as triglycerides. In contrast, the protein-rich diet reduced LDL and HDL cholesterol, and the unsaturated fat-rich diet increased HDL cholesterol. The OmniHeart study findings suggested that improvements to the DASH diet with the substitution of carbohydrates for either protein or unsaturated (primarily monounsaturated) fat can help improve blood pressure and lipid profiles.

Weight loss through lifestyle modification is recommended for adults with T2D and obesity.⁴² Samaha et al³⁷ demonstrated that a low-carbohydrate, high-protein, high-fat diet reduced body weight at 6 months compared with a more traditional, reduced-fat diet among individuals with T2D (39%) and metabolic syndrome (43%). However, this difference in weight loss across the low-carbohydrate and low-fat diets was no longer significant at 12 months.⁴³ These results are consistent with findings by Foster et al²⁴ discussed earlier in CKM syndrome stage 1. The landmark Look AHEAD (Action for Health in Diabetes) trial incorporated a low-fat, calorie-restricted diet (1,200-1,800 kcal/day with <30% calories from fat and <10% calories from saturated fat) in its intensive lifestyle intervention, similar to that which was evaluated in the Diabetes Prevention Program.³⁸ The intensive lifestyle intervention in Look AHEAD incorporated diet modification plus increased physical activity (≥175 minutes of moderate-intensity physical activity). Although the intensive lifestyle intervention did not significantly reduce the rate of cardiovascular events, participants achieved substantial weight loss and improvements in fitness and glycemic control, but these gains attenuated over time.³⁸ Taken together, dietary modification with and without a physical activity intervention is an effective short-term strategy for weight loss, but its durability appears limited, in line with the now recognized concept of obesity as a chronic relapsing disease.

An additional lifestyle strategy to enhance glycemic control in T2D is exercise training. In the HART-D (Health Benefits of Aerobic and Resistance Training in Type 2 Diabetes) trial, the combination of aerobic and resistance training led to a significant reduction in HbA1c compared to the control group.³⁹ However, aerobic and resistance training alone did not lead to a significant reduction in HbA1c levels. Notably, the combined group also improved cardiorespiratory fitness, fat mass, and waist circumference, emphasizing the additive benefits of integrating both exercise modalities.³⁹

The cardiovascular effects of a dietary intervention were evaluated in CKM syndrome stage 2 in the PREDIMED (Prevención con Dieta Mediterránea) trial. The PREDIMED trial enrolled adults with either T2D or at least 3 traditional cardiovascular risk factors, leading to a population with a high prevalence of metabolic risk factors such as T2D (48.5%), hypertension (82.7%), and obesity (46.8%).⁴⁰ Participants were randomly assigned to Mediterranean diet advice with the provision of extra-virgin olive oil, Mediterranean diet advice with the provision of mixed nuts, or control with advice for a low-fat diet with the provision of small nonfood gifts. After a median follow-up of 4.8 years, the 2 Mediterranean diet groups had 41% of energy intake from fat, while the control group had 37% of energy intake from fat. Compared with participants in the control group, those in the Mediterranean diet advice supplemented with extra-virgin olive oil and nuts groups had lower risk of CVD events.

CKM syndrome stage 3: addressing subclinical cardiovascular disease

CKM Stage 3 is characterized by the presence of subclinical CVD in individuals with excess or dysfunctional adiposity, metabolic risk factors, or chronic kidney disease.¹ Subclinical atherosclerotic CVD is typically identified based on coronary artery calcification but can also be identified by atherosclerotic plaque on CT angiography. Subclinical heart failure (HF) can be identified by echocardiographic parameters and serum cardiac biomarkers, such as elevated levels of natriuretic peptides or cardiac troponins, with a combination of these markers indicating the highest risk of HF.

The Dietary Intervention to Stop Coronary Atherosclerosis in Computed Tomography (DISCO-CT) trial enrolled 97 patients who underwent CT angiography for suspected coronary artery disease and were found to have subclinical atherosclerosis, or nonobstructive coronary artery disease, with <70% stenosis in at least 2 coronary artery segments (Table 4).⁴⁴ Participants were randomly assigned to either the DISCO-CT intervention or control, with both groups receiving optimal medical therapy. Participants in the DISCO-CT intervention received an individualized nutrition plan and 6 counseling sessions, and compliance with the diet and physical activity goals was encouraged. The DISCO-CT intervention reduced noncalcified plaque volume to a greater degree than the control group, which is notable because noncalcified plaque is associated with higher risk of CVD events.⁴⁶ Plaque atheroma volume, fibrous plaque, and dense calcium increased in both randomized groups. Fibrofatty plaque and necrotic core decreased in both groups, with a nonsignificantly greater reduction in the intervention group than in the control group.

Table 4.

Characteristics and Outcomes of Key Studies Evaluating Lifestyle Interventions in Cardiovascular-Kidney-Metabolic Syndrome Stage 3

Study Name/First Author	Study Population	Intervention	Control	N	Outcome
DISCO-CT44	•Patients with nonobstructive atherosclerosis (<70% stenosis) •Coronary artery disease diagnosed via computed tomography angiography •Individuals with diabetes were excluded •4.5% with history of percutaneous coronary angioplasty	•Systematic dietitian follow-up to adhere to the DASH (Dietary Approaches to Stop Hypertension) diet •Optimal medical therapy	•Optimal medical therapy alone	92	Percent atheroma volume (PAV) change: •Control group: increase (+1.1% ± 3.4%; P = 0.033) •Intervention group: no significant change (+1.0% ± 4.2%; P = 0.127) •Intergroup difference: P = 0.851 Reduction in noncalcified plaque: •Intervention group: −51.3 ± 79.5 mm3 (−1.7 ± 2.7%); P < 0.001 •Control group: −21.3 ± 57.7 mm3 (−0.7% ± 1.9%); P = 0.018 •Greater reduction in intervention group: P = 0.045
Hieda et al45	•Left ventricular (LV) hypertrophy (LV septum >11 mm). •Elevated biomarkers with N-terminal pro-B-type natriuretic peptide (NT-proBNP) >40 pg/mL or high-sensitivity troponin T >0.6 pg/mL •Hypertension 69.9% •T2DM 8.7%	•1 y of high-intensity exercise training	•Attention control (routine activity)	46	Exercise training significantly improved maximal oxygen uptake (VO2max): •Exercise group: increased by 21% (from 26.0 ± 5.3-31.3 ± 5.8 mL·min−1 kg−1, P < 0.0001). •Control group: No significant change (from 24.6 ± 3.4-24.2 ± 4.1 mL·min−1 kg−1, P = 0.986). LV myocardial stiffness was reduced in the exercise group (right/downward shift in the end-diastolic pressure-volume relationship) •Baseline: 0.062 ± 0.020 → 1 y later: 0.031 ± 0.009 (P = 0.001) •No significant change in controls (baseline: 0.061 ± 0.033 → 1 y later: 0.066 ± 0.031)

LV = left ventricular; T2DM = type 2 diabetes mellitus.

The cardiovascular benefits observed with exercise training in earlier stages of the CKM syndrome can be extended to stage 3, specifically for individuals with elevated risk of developing HF. Hieda et al⁴⁵ examined the cardiovascular effects of exercise training among individuals with left ventricular hypertrophy, assessed by cardiac magnetic resonance imaging or echocardiography, plus elevated cardiac biomarkers. Of note, the thresholds for elevated N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T used in the trial (≥40 pg/mL and ≥0.6 pg/mL, respectively) were below those recommended for identifying stage B HF or stage 3 of the CKM syndrome (N-terminal pro-B-type natriuretic peptide ≥125 pg/mL; high-sensitivity cardiac troponin T ≥14 pg/mL for women and ≥22 pg/mL for men). Participants randomly assigned to the high-intensity exercise training intervention had individualized training programs, a personal trainer, and a heart rate monitor. Participants in the control group attended group yoga or stretching classes or completed home-based classes. After 1-year follow-up, the exercise training intervention increased fitness and reduced myocardial stiffness compared with the control group. Given the importance of myocardial stiffness in HF, especially HF with preserved ejection fraction (HFpEF), exercise training is an effective strategy to prevent high-risk intermediate phenotypes along the spectrum of HF development.

CKM syndrome stage 4: addressing clinical cardiovascular disease

CKM syndrome stage 4 is characterized by the presence of clinical CVD, including coronary heart disease, stroke, peripheral artery disease (PAD), HF, or atrial fibrillation, among individuals with excess or dysfunctional adiposity, metabolic risk factors, and/or chronic kidney disease.¹

The RCTs of dietary interventions discussed so far in earlier stages of the CKM syndrome mostly examined surrogate endpoints, such as blood pressure or other important risk factors, while RCTs enrolling participants with CKM syndrome stage 4 examined CVD outcomes. The Lyon Heart Study was an RCT that examined the effects of an alpha-linolenic acid-rich Mediterranean diet on CVD events among adults with a history of myocardial infarction in the 6 months prior to enrollment (Table 5).⁶⁰ Participants in the diet intervention (n = 302) received a 1-hour educational session on the Mediterranean-like diet that targeted more vegetables, bread, and fish; at least daily fruit; less red meat; and butter and cream were to be replaced with canola which was similar to olive oil except had more linoleic acid, especially alpha-linoleic acid. The control group of participants (n = 303) received general dietary advice with no specific education. The Mediterranean diet led to a 73% reduction in risk of cardiovascular death or nonfatal acute myocardial infarction after an average follow-up of 27 months.⁶⁰ Larger RCTs of Mediterranean-like diets were performed but either enrolled a primary prevention cohort (PREDIMED) or had concerns (Indo-Mediterranean Diet Heart Study).^40,61 Consistent with the Lyon Heart Study, the CORDIOPREV study demonstrated cardiovascular benefits with the Mediterranean diet compared with a low-fat diet in 1,002 participants with established coronary heart disease over a median of 7 years of follow-up.⁴⁷

Table 5.

Characteristics and Outcomes of Key Studies Evaluating Lifestyle Interventions in Cardiovascular-Kidney-Metabolic Syndrome Stage 4

Study Name/First Author	Study Population	Intervention	Control	TotalParticipants, N	Outcome
CARDIOPREV47	•Ages 20-75 y (mean age 59.5 y) with established coronary heart disease •High prevalence of metabolic syndrome (58%), obesity (56.3%), and dyslipidemia •Baseline eGFR >30 with varying degrees of renal dysfunction	•Mediterranean diet intervention •Diet rich in olive oil, fruits, vegetables, legumes, nuts, and fish •Limited intake of red and processed meats, refined grains, and sweets	•Low-fat diet intervention •Emphasis on reducing total fat intake, mainly from animal sources •Encouraged increased intake of whole grains, fruits, vegetables, and lean proteins	1,002	Primary composite outcome (major cardiovascular events) occurred in 198 participants: •87 events in Mediterranean diet group vs 111 in low-fat diet group •Crude rate per 1,000 person-years: 28.1 (Mediterranean) vs 37.7 (low-fat), P = 0.039 Multivariable-adjusted HR for Mediterranean diet: •0.719 (95% CI 0.541-0.957) to 0.753 (0.568-0.998), favoring Mediterranean diet
SaSS48	•Adults with a history of stroke or aged ≥60 y with poorly controlled blood pressure •Systolic BP ≥140 mm Hg if on BP-lowering medication or ≥160 mm Hg if not	•Salt substitute (75% sodium chloride, 25% potassium chloride)	•Continued using regular salt (100% sodium chloride)	20,995	Primary outcome (stroke incidence) •Lower with salt substitute (29.14 vs 33.65 events per 1,000 person-years, RR = 0.86; 95% CI 0.77-0.96; P = 0.006) Secondary outcomes •Major cardiovascular events: 49.09 vs 56.29 per 1,000 person-years, RR = 0.87; 95% CI 0.80-0.94; P < 0.001 All-cause mortality: 39.28 vs 44.61 per 1,000 person-years, RR = 0.88; 95% CI 0.82-0.95; P < 0.001
EXCITE49	•Patients with stable coronary artery disease at least 1 significant coronary lesion documented as fractional flow reserve ≤0.75 •Mean BMI 29.4 ± 4.8 kg/m2, with additional risk factors including hypertension, hyperlipidemia, and diabetes mellitus.	High-intensity exercise •10 h per week of high-intensity training Moderate-intensity exercise •10 h per week of moderate-intensity training	No structured exercise intervention	60	Change in coronary collateral flow index (CFI) after 4 wk •High-intensity exercise group (A): CFI increased by 39.4% (from 0.142 ± 0.07-0.198 ± 0.09) •Moderate-intensity exercise group (B): CFI increased by 41.3% (from 0.143 ± 0.06-0.202 ± 0.09) •Control group (C): No significant change in CFI (0.7% increase) (from 0.149 ± 0.09-0.150 ± 0.08)
Lane et al50	•Patients with intermittent claudication due to PAD	•Exercise regimens including walking, strength training, pole-striding, upper or lower limb exercises.	•Usual care or placebo Some trials compare exercise with pharmacologic therapy or pneumatic calf compression	1,816	Exercise significantly improved maximum walking time compared to usual care/placebo: •Mean difference (MD): 4.51 minutes (95% CI 3.11-5.92). •Overall improvement in walking ability: ∼50%-200%. Walking distances were also significantly improved: •Pain-free walking distance: MD 82.29 m (95% CI 71.86-92.72). •Maximum walking distance: MD 108.99 m (95% CI 38.20-179.78). Secondary outcomes: •Exercise did not significantly improve ankle-brachial index (ABI): MD 0.05 (95% CI 0.00-0.09).
CLEVER51	•Adults with aortoiliac PAD and claudication •Population with high prevalence of hypertension and diabetes	•OMC +SE: supervised treadmill exercise program OMC + ST: endovascular stent revascularization	•Medical management alone	111	Primary outcome (6 mo): •Peak walking time (graded treadmill test) improved the most in SE group (+5.8 min), followed by ST group (+3.7 min), and least in OMC group (+1.2 min) •SE vs OMC: P < 0.001 •ST vs OMC: P = 0.02 •SE vs ST: P = 0.04 Secondary outcomes: •Walking Impairment Questionnaire & Peripheral Artery Questionnaire: Quality of life improved in both SE and ST, but ST showed greater improvements in some scales •Step activity (free-living movement): Increased the most in ST group (+114 steps/h), followed by SE group (+73 steps/h), and decreased in OMC group (−6 steps/h), but not statistically significant
LITE52	•Lower-extremity PAD with ankle-brachial index (ABI) of 0.90 or less in either leg •BMI and renal function not defined	•Low-intensity walking group •High-intensity walking group	•No structured walking intervention	305	Change in 6-min walk distance at 12 mo: •High-intensity group: +34.5 m (95% CI +20.1 to +48.9; P < 0.001) •Low-intensity group: −6.4 m (95% CI −21.5 to +8.8; P = 0.34) •Nonexercise control: −15.1 m (95% CI −35.8 to +5.7; P = 0.10) •High-intensity vs low-intensity: −40.9 m difference (P < 0.001) •Low-intensity vs nonexercise control: No significant difference (P = 0.44)
HF ACTION53	•Stable HFrEF with left ventricular ejection fraction of 35% or less and NYHA class II to IV symptoms despite optimal heart failure therapy for at least 6 wk •Included participants with comorbid hypertension and diabetes	•Aerobic exercise training	•No structured exercise training	2,331	All-cause mortality or hospitalization •Exercise group vs Control: 65% vs 68% •HR: 0.93 (95% CI 0.84-1.02; P = 0.13) •Nonsignificant reduction in mortality/hospitalization All-cause mortality: •Exercise group vs Control: 16% vs 17% •HR: 0.96 (95% CI 0.79-1.17; P = 0.70) Cardiovascular mortality or hospitalization: •Exercise group vs Control: 55% vs 58% •HR: 0.92 (95% CI 0.83-1.03; P = 0.14) Cardiovascular mortality or heart failure hospitalization: •Exercise group vs Control: 30% vs 34% •HR: 0.87 (95% CI 0.75-1.00; P = 0.06)
SMARTEX54	•HFrEF LVEF ≤35% with NYHA functional class II-IV symptoms, stable, pharmacologically optimally treated for CHF	•High-intensity interval training •Moderate continuous training	•Regular exercise recommendation	261	Change in left ventricular end-diastolic diameter (LVEDD) from baseline to 12 wk •HIIT vs MCT: no significant difference (P = 0.45) •HIIT vs RRE: −2.8 mm change in LVEDD (P = 0.02) •MCT vs RRE: −1.2 mm change in LVEDD (P = 0.34, nonsignificant) Secondary outcomes: • Peak oxygen uptake (V̇O2): ○ No difference between HIIT and MCT (P = 0.70) ○ Both HIIT and MCT superior to RRE • Long-term follow-up (52 wk): ○ No sustained differences in LVEDD or peak V̇O2 in any group
Mueller et al55	•Sedentary patients with history of chronic stable HFpEF •Elderly, predominantly female, with overweight/obesity •Mean age 70, mean BMI 30 kg/m2, 67% women	•High-intensity interval training (HIIT) •Moderate continuous training (MCT)	•Guideline control	180	Change in peak VO2 (mL/kg/min) at 3 mo •HIIT vs guideline control: 1.1 vs −0.6 (difference, 1.5 [95% CI 0.4-2.7]) •MCT vs guideline control: 1.6 vs −0.6 (difference, 2.0 [95% CI 0.9-3.1]) •HIIT vs MCT: 1.1 vs 1.6 (difference, −0.4 [95% CI −1.4 to 0.6])
SECRET56	•Stable HFpEF •Older adults (≥60 y) with obesity (BMI ≥30 kg/m2) •Mean age 67 y, mean BMI 39.3	•Exercise group Supervised aerobic exercise training for 20 wk •Diet group Caloric restriction-based diet for 20 wk •Exercise + Diet group	•Received biweekly telephone calls but no structured intervention	100	Peak oxygen consumption (V̇O2) improvement: •Exercise: +1.2 mL/kg/min (95% CI 0.7-1.7; P < 0.001) •Diet: +1.3 mL/kg/min (95% CI 0.8-1.8; P < 0.001) •Exercise + Diet: +2.5 mL/kg/min (joint effect, additive benefit) Quality of life (MLHF Score Change, lower = better): •Exercise: −1 U (95% CI −8 to 5; P = 0.70) •Diet: −6 U (95% CI −12 to 1; P = 0.08) •No significant difference between groups Weight change (% from baseline): •Exercise: −3% (≈4 kg) •Diet: −7% (≈7 kg) •Exercise + Diet: −10% (≈11 kg) •Control: −1% (≈1 kg)
Abed et al57	•Symptomatic paroxysmal or persistent AF (in sinus rhythm at enrollment) •Body mass index (BMI) > 27 kg/m2 •Waist circumference >100 cm (men) or >90 cm (women) •Aged 21-75 y	Weight reduction and cardiometabolic risk factor management Two-phase program: • Weight loss phase (8 wk): ○ Modified very-low-calorie diet (800-1,200 kcal/d) ○ Meal replacement sachets for 2 meals/d + calorie-controlled third meal ○ Low-intensity exercise (20 min, 3×/wk, increased to 45 min, 3×/wk) Weight maintenance phase (13 mo): ○Gradual transition to low–glycemic index meals ○Exercise intensity up-titration ○Behavioral modification, goal-directed clinic visits every 3 mo ○24-hour email and telephone support ○Diet, activity, and blood pressure diary required	•General lifestyle advice only •Fish oil (3 g/d) prescribed unless on dual antiplatelet or anticoagulants	150	Weight loss: •Intervention group: −14.3 kg •Control group: −3.6 kg (P < 0.001) Atrial fibrillation symptom burden score reduction: •Intervention group: −11.8 points •Control group: −2.6 points (P < 0.001) Symptom severity score reduction: •Intervention group: −8.4 points •Control group: −1.7 points (P < 0.001) Reduction in AF episodes: •Intervention group: −2.5 episodes •Control group: No change (P = 0.01) Cumulative AF duration change: •Intervention group: −692 minutes •Control group: +419 minutes (P = 0.002) Echocardiographic cardiac remodeling: • Interventricular septal thickness reduction: ○ Intervention group: −1.1 mm ○ Control group: −0.6 mm (P = 0.02)
Malmo et al58	•Nonpermanent AF (paroxysmal or persistent) •Mean age 60 y, majority male (80%) •BMI and renal function not defined	•Aerobic interval training (AIT) for 12 wk	•No structured intervention	51	Change in time spent in AF (measured via implanted loop recorder): •Control group: Increased from 10.4% to 14.6% •AIT group: Reduced from 8.1% to 4.8% (P = 0.001 between groups) Secondary outcomes: •Reduction in AF symptom frequency (P = 0.006) and severity (P = 0.009) •Improved peak oxygen uptake (o2peak) •Improved left atrial and ventricular function •Improved quality of life (general health and vitality measures) •Better lipid profile compared to the control group
ACTIVE-AF59	•Adults aged 18-80 y •Symptomatic paroxysmal or persistent atrial AF •Mean BMI was >30 kg/m2 and had additional comorbidities of hypertension and diabetes	•Supervised and home-based aerobic exercise intervention	•Two one-on-one educational sessions on the benefits of exercise for AF •Encouraged to achieve 150 min of moderate physical activity per week •No individualized training plan provided	120	•AF recurrence at 12 mo: 40% of exercise group vs 20% in control (HR: 0.50; 95% CI 0.33-0.78) •AF symptom severity at 6 mo: Lower in exercise group (mean difference −2.3; 95% CI −4.3 to −0.2; P = 0.033) •AF symptom severity at 12 mo: Persistent improvement (mean difference −2.3; 95% CI −4.5 to −0.1; P = 0.041) •Increased peak oxygen consumption in the exercise group at 6 and 12 mo No significant differences in cardiac structure, BMI, or blood pressure between groups

AF = atrial fibrillation; BP = blood pressure; CHF = congestive heart failure; eGFR = estimated glomerular filtration rate; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LVEF = left ventricular ejection fraction; MD = mean difference; MLHF = Minnesota Living with Heart Failure Questionnaire; OMC = optimal medical care; PAD = peripheral artery disease; RR = risk ratio; RRE = recommendation of regular exercise; SE = supervised exercise; ST = stent revascularization.

Furthermore, reduction of dietary sodium was discussed earlier as a strategy to lower blood pressure in CKM syndrome stage 1, and salt substitutes may be a complementary approach to lowering blood pressure with additional cardiovascular benefits. Substituting potassium chloride for sodium chloride, which is found in regular salt, reduces blood pressure and prevents CVD events in CKM syndrome stage 4.^48,62 Specifically, in the Salt Substitute and Stroke Study, among adults with high blood pressure and either history of stroke or age ≥60 years, replacing regular salt with a potassium-enriched salt substitute (75% sodium chloride and 25% potassium chloride) led to a significant 14% reduction in the risk of fatal or nonfatal stroke without an increase in clinical hyperkalemia.

Adults with established coronary heart disease derive several benefits from cardiac rehabilitation, which encompasses exercise training and education. Specifically, cardiac rehabilitation reduces the risk of myocardial infarction and all-cause hospitalizations and improves the quality of life in coronary heart disease.⁶³ Among patients with stable angina and coronary heart disease, exercise training combined with a low-fat diet reduced myocardial ischemia and coronary artery disease progression compared with usual care.⁶⁴ Similar findings were observed in other RCTs of multifactorial interventions incorporating exercise, diet, and other risk factor modification that led to less progression of coronary atherosclerosis and fewer cardiac events.^65,66 The mechanisms by which exercise training improves coronary outcomes are unclear. The proof-of-concept EXCITE trial indicates exercise training increases coronary collateral flow, but the interrelationships with clinical outcomes are less clear.⁴⁹

The classic symptom for patients with PAD is claudication, for which exercise is an effective therapy. Exercise programs reduce pain, improve quality of life, and increase walking distance among patients with claudication.⁵⁰ In the CLEVER (Claudication: Exercise vs Endoluminal Revascularization) trial, among adults with PAD, supervised exercise led to a greater increase in peak walking time than stent revascularization at 6 months, but this difference was no longer significant at 18-month follow-up.⁵¹ The training intensity appears to impact outcomes in PAD such that high-intensity (vs low-intensity) walking exercise led to a greater increase in 6-minute walk distance in the LITE (Low-Intensity Exercise Intervention in PAD) trial.⁵²

A primary concern for patients with HF, including both HF with reduced ejection fraction (HFrEF) and HFpEF, is exercise intolerance. Exercise training significantly improves exercise capacity, commonly assessed as cardiorespiratory fitness, among adults with HFrEF.^53,67 The beneficial effects of exercise training can be observed across the spectrum of left ventricular ejection fraction and extend to individuals with HFpEF.⁶⁸ Tailored exercise training interventions should be examined further in HFpEF and HFrEF.^54,55,69 A complementary strategy to improving exercise capacity in select cases of HFpEF, where obesity and diabetes are primary risk factors, may be weight loss. In the SECRET (Study of the Effects of Caloric Restriction and Exercise Training) trial, among adults with HFpEF and obesity, weight loss through caloric restriction led to similar improvements in exercise capacity compared with aerobic exercise training.⁵⁶ The combination of diet modification plus exercise had an additive beneficial effect on exercise capacity.

Obesity and lack of physical activity appear to be modifiable drivers of atrial fibrillation development and risk. Targeting these factors through lifestyle modification has improved symptoms associated with atrial fibrillation in multiple RCTs. In a single-center, RCT, Abed et al⁵⁷ evaluated the effects of a weight-management intervention among adults with symptomatic paroxysmal or persistent atrial fibrillation and BMI >27 kg/m² (mean BMI ∼33-34 kg/m²). The intervention included a very-low-calorie diet provided to participants plus a written exercise plan, and this diet and exercise intervention reduced atrial fibrillation symptoms and severity compared with a control group. High-intensity exercise training also reduced atrial fibrillation symptoms and burden at 12 weeks among adults with paroxysmal and persistent atrial fibrillation, extending the beneficial effects of exercise to individuals without obesity but are overweight (mean BMI ∼28 kg/m²).⁵⁸ Similar beneficial effects were observed in a longer-term evaluation of effects of exercise training on paroxysmal or persistent atrial fibrillation.⁵⁹

Implications and future directions

Evidence from RCTs indicates several benefits of lifestyle interventions for preventing the adverse consequences of CKM syndrome at each stage (Central Illustration). Lifestyle interventions can be deployed as part of a primordial prevention strategy in CKM syndrome stage 0 which would likely lead to its greatest impact on the population level in a young, healthy group. In addition, these lifestyle interventions were commonly evaluated as therapies for excess adiposity before the development of metabolic risk factors (stage 1) as well as targeted towards common comorbid conditions (stage 2) and demonstrated beneficial effects. Furthermore, individuals with subclinical CVD (stage 3) and clinical CVD (stage 4) also benefit from lifestyle interventions.

Central Illustration.

Lifestyle Interventions to Support Primordial Prevention and Management of CKM Syndrome Stages 1 to 4

A summary of the effects of each lifestyle intervention across CKM syndrome stages are shown in this figure. Created in BioRender. Shahid, I. (2025) https://BioRender.com/0zmy171. 6MWT = 6-minute walk test; AF = atrial fibrillation; BMI = body mass index; BP = blood pressure; CAD = coronary artery disease; CVD = cardiovascular disease; DASH = Dietary Approaches to Stop Hypertension; HbA1c = hemoglobin A1c; HFrEF = heart failure with reduced ejection fraction; MI = myocardial infarction; PAD = peripheral arterial disease; T2DM = type 2 diabetes mellitus.

A key consideration in this review is that the RCTs discussed were designed prior to the development of the CKM syndrome framework, and the study populations do not always clearly align with a single stage. The RCTs were described in the sections related to the CKM syndrome stage predominantly represented in the study population of the trials. In addition, lifestyle interventions were commonly studied across multiple CKM syndrome stages, suggesting those specific therapies may have broader therapeutic relevance. A major advantage of lifestyle interventions includes the positive influence across several organ systems, likely related to modulating pathologic drivers such as insulin resistance or inflammation, which are major determinants of CKM health.

Participants with CKM syndrome stage 3 appeared underrepresented in RCTs of lifestyle interventions compared with other stages. This notable knowledge gap represents an important research opportunity given the elevated risk of progression to prevalent CVD in this population as well as the potential for efficient clinical trial design. Enrolling individuals with a high burden of coronary atherosclerosis assessed by a coronary artery calcium score can lead to prognostic enrichment and include individuals who have high risk of developing a clinical endpoint.⁷⁰ Prognostic enrichment with cardiac biomarkers can lead to clinical trials with a relatively small sample size and short follow-up.⁷¹

Implementing lifestyle interventions remains a challenge for several reasons. The beneficial effects of lifestyle interventions can attenuate over time, a phenomenon that is commonly attributed to factors such as declining adherence, difficulty sustaining behavior change in the absence of ongoing support, multiple compensatory physiologic mechanisms promoting weight regain, and harmful environmental influences.^72,73 This highlights the importance of behavioral change and deploying effective implementation strategies to achieve the sustained benefits of lifestyle interventions.

Future studies are needed in earlier CKM syndrome stages to prevent the progression towards more advanced stages using multifactorial interventions. For example, the PRECAD (Prevent Coronary Artery Disease) trial is an ongoing RCT designed to assess whether aggressive control of cardiovascular risk factors in young adults (ages 20-39) without established CVD can prevent or slow the progression of atherosclerosis.⁷⁴ The trial aims to achieve risk factor control using a stepwise approach that begins with diet and lifestyle modification, followed by pharmacologic interventions as needed. This study builds on growing evidence that even low but sustained exposure to traditional risk factors can contribute to the early development of subclinical atherosclerosis. Lifestyle modification should remain the cornerstone of management across CKM stages, and future work, like the PRECAD trial, is needed to understand the complementary role of pharmacologic and potentially procedural approaches to halt CKM syndrome progression and prevent downstream complications.

Conclusions

CKM syndrome represents a growing public health challenge, with its progression spanning multiple stages from excess and dysfunctional adipose tissue to established CVD. Evidence from numerous RCTs supports the benefits of dietary modification, physical activity, and behavioral interventions in preventing progression of CKM syndrome in the earlier stages as well as managing subclinical and clinical CVD. Lifestyle modification remains the first-line therapy for management of CKM syndrome across the stages due to its accessibility, scalability, and low costs to address the multiple interrelated and dysfunctional organ systems involved. Incorporating evidence-based lifestyle practices should be prioritized early in the management of CKM syndrome to prevent downstream complications.

Funding support and author disclosures

Dr Gulati has been supported by contracts from the National Heart, Lung, and Blood Institutes nos. N01-HV-068161, N01-HV-068162, N01-HV-068163, N01-HV-068164, grants U01 HL064829, U01 HL649141, U01 HL649241, K23 HL105787, K23 HL125941, K23 HL127262, K23HL151867, T32 HL069751, R01 HL090957, R03 AG032631, R01 HL146158, R01 HL146158-04S1, R01 HL124649, R01 HL153500, U54 AG065141, General Clinical Research Center grant MO1-RR00425 from the National Center for Research Resources, the National Center for Advancing Translational Sciences Grant UL1TR000124, Department of Defense grant PR161603 (CDMRP-DoD), and grants from the Gustavus and Louis Pfeiffer Research Foundation, Danville, NJ, The Women’s Guild of Cedars-Sinai Medical Center, Los Angeles, CA, The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA, and QMED, Inc, Laurence Harbor, NJ, the Edythe L. Broad and the Constance Austin Women’s Heart Research Fellowships, Cedars-Sinai Medical Center, Los Angeles, CA, the Barbra Streisand Women’s Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, CA, The Society for Women’s Health Research, Washington, D.C., the Linda Joy Pollin Women’s Heart Health Program, the Erika Glazer Women’s Heart Health Project, the Adelson Family Foundation, Cedars-Sinai Medical Center, Los Angeles, CA, Robert NA. Winn Diversity in Clinical Trials Career Development Award (Winn CDA), and the Anita Dann Friedman Endowment in Women’s Cardiovascular Medicine & Research. This work is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the U.S. Department of Health and Human Services. Consultant Fees/Honoraria: New Amsterdam, Novartis, Medtronic Inc, unrelated to this work. Dr Patel has served as a consultant to Novo Nordisk; has served on the advisory board for Roche Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.