Cardiovascular-kidney-metabolic (CKM) syndrome

SUMMARY

Cardiovascular-kidney-metabolic (CKM) syndrome recognises the connection between metabolic conditions (particularly obesity, diabetes and metabolic dysfunction–associated fatty liver disease), chronic kidney disease and cardiovascular disease.

There is a high and growing prevalence of CKM syndrome. While genetic and epigenetic factors predispose to CKM syndrome, the emergence of disease is heavily influenced by social determinants of health and individual behaviours.

The pathophysiology of CKM syndrome is driven by insulin resistance, inflammation, oxidative stress and vascular dysfunction. Urinary albumin:creatinine ratio is a relatively cheap and accessible biomarker of CKM syndrome, which can be used to identify and monitor disease trajectory.

Primary and secondary prevention is relevant across the life course. Healthy behaviours, including diet, physical activity, sleep and stress management are important. There are established and emerging drugs that are effective across a range of metabolic conditions and that confer reno- and cardio-protective effects. Remission may be achievable.

 

Introduction

The recognition of cardiovascular-kidney-metabolic (CKM) syndrome, proposed by the American Heart Association,¹ represents a paradigm shift in understanding and managing a constellation of interconnected chronic diseases. Cardiac, kidney and metabolic conditions have traditionally been studied largely in isolation; however, it is now understood that they have a dynamic and reciprocal influence on each other.

The CKM syndrome framework recognises the critical role of insulin resistance, inflammation, oxidative stress and vascular dysfunction as shared drivers of cardiovascular disease (CVD), chronic kidney disease (CKD) and a range of metabolic disorders (including prediabetes, type 2 diabetes, obesity, metabolic dysfunction–associated fatty liver disease [MAFLD] and dyslipidaemia). This recognition creates opportunities to develop more effective prevention and early intervention strategies, as well as holistic and integrated models of care, in contrast to traditional single-organ pathology-based and siloed approaches. Public health initiatives, alongside individual behavioural modifications and early detection and intervention, are foundational in preventing and slowing the progression of CKM syndrome.

In addition, new drugs have emerged, particularly sodium-glucose co-transporter 2 (SGLT2) inhibitors, nonsteroidal mineralocorticoid receptor antagonists (e.g. finerenone) and glucagon-like peptide-1 (GLP-1) receptor agonists, that are effective across a range of metabolic conditions and confer reno- and cardio-protective effects.²

 

Drivers of CKM syndrome

While genetic and epigenetic factors predispose to CKM syndrome, environmental and behavioural factors, heavily influenced by social determinants of health, result in dysfunctional visceral (central) adiposity that is the primary source of inflammation and oxidative stress. Air pollution, environmental toxins and behavioural factors, such as diet, level of physical activity and quality of sleep, significantly influence susceptibility to disease.³

 

Epidemiology

CKM syndrome has been divided into 4 stages;¹ stages 1 and 2 provide an opportunity for early intervention and remission, whereas stages 3 and 4 encompass more established disease where slowing progression of kidney disease and optimising cardiac function are the priority:⁴

• Stage 1: Visceral (central) adiposity, insulin resistance, prediabetes, without the presence of other metabolic and CVD risk factors (e.g. hyperlipidaemia, hypertension) or CKD.
• Stage 2: Hypertension, hypertriglyceridaemia, type 2 diabetes (individually or collectively as metabolic syndrome) or CKD in the presence of visceral adiposity.
• Stage 3: Subclinical atherosclerotic CVD or subclinical heart failure in the presence of visceral adiposity, high predicted CVD risk or very high-risk CKD (Stage 4 or 5).
• Stage 4: Clinical CVD (coronary heart disease, heart failure, stroke, peripheral artery disease or atrial fibrillation) in the presence of visceral adiposity or other metabolic risk factors. Stage 4 is further divided into stages 4a (without kidney failure) and 4b (with kidney failure).

In Australia, Stage 1 CKM is common; 63% of men and 72% of women (aged 18 years and above) have central obesity.⁵ This is consistent with a US study that reported 75% of people had evidence of Stage 1 or 2 CKM syndrome⁶ and presents an opportunity for early intervention.

 

Making the diagnosis

The recognition of visceral adiposity and insulin resistance as the basis of CKM syndrome is an essential initial step in clinical assessment. Alerts in the history include features of polycystic ovary syndrome, MAFLD, gout, gestational diabetes and a family history of type 2 diabetes. Features on clinical examination include overweight or obesity, increased waist circumference, the presence of skin tags, acanthosis nigricans (patches of thickened skin with a dark, velvety appearance) and hypertension.

Screening bloods include fasting glucose, glycated haemoglobin (HbA1c), estimated glomerular filtration rate (eGFR), liver function tests, uric acid and a lipid panel including triglycerides and high-density lipoprotein cholesterol. A urine sample for urinary albumin:creatinine ratio (uACR) should also be requested.

Albuminuria – a cross-cutting biomarker

Albuminuria (increased urinary albumin excretion) is a key biomarker in CKM syndrome. Higher levels of albuminuria, defined by an elevated urinary albumin:creatinine ratio (uACR above 2.5 mg/mmol in men and 3.5 mg/mmol in women), are associated with a worse prognosis across the spectrum of CKM syndrome,⁷ including higher mortality among patients with type 2 diabetes, hypertension, CKD or heart failure, and among adults with few cardiovascular risk factors. Albuminuria becomes more likely and severe as MAFLD progresses to cirrhosis;⁸ it also identifies those at higher risk of progressive kidney disease. While uACR is a cheap biomarker of CKM syndrome that should be used for identifying and monitoring disease trajectory, it is underutilised in clinical care.⁹

 

Prevention and management

Prevention and management of CKM syndrome requires behavioural and lifestyle interventions, along with guideline-directed drug therapy.

Bariatric surgery can promote remission of type 2 diabetes;^10,11 however, predicting who will benefit most is still debated.

Supporting healthy behaviours

Healthy behaviours, with attention to diet, physical activity, sleep quality and stress management are the cornerstone of both primary and secondary prevention.

Resistance exercise is a key preventive strategy among adults.¹² Weight management is critical; however, this is complex and impacted by all behavioural and lifestyle pillars. Consumption of ultra-processed (typically high-calorie and low or lower nutritional value) food is a clear driver of obesity,^13,14 accounting for an average of 40% of caloric intake (range 13 to 74%) among Australians.¹³

The multicentre randomised controlled Look AHEAD study evaluated the effect of a 12-year intensive lifestyle intervention (dietary and physical activity advice, and behavioural strategies, including self-monitoring and problem-solving) on remission from type 2 diabetes and the incidence of kidney and cardiac disease in people with overweight or obesity and type 2 diabetes.¹⁵ Compared with usual diabetes support and education about CVD and other chronic health conditions, participants engaging in the lifestyle intervention were more likely to achieve remission. Participants with evidence of remission from type 2 diabetes (12.7%) had a 33% lower rate of kidney disease and a 40% reduction in cardiac disease compared with those who did not. Longer duration of remission conferred greater risk reduction.

Type 2 diabetes remission can be achieved with very low energy diets of processed replacement drinks as shown in the DiRECT¹⁶ and DIADEM-1¹⁷ studies. A low carbohydrate or ketogenic diet approach to type 2 diabetes remission is supported by Australia's Commonwealth Scientific and Industrial Research Organisation (CSIRO) and Diabetes Australia.^10,18

Self-management and healthcare provider resources are available through Diabetes Australia, Kidney Health Australia and the Heart Foundation. Practical education for health professionals is available through the Diabetes Qualified website, the training arm of Diabetes Australia.

The role of pharmacotherapy

Both well-established and new classes of drugs that target common pathophysiological pathways and confer organ protection are recommended early in CKM syndrome and feature in diabetes, kidney and heart guidelines (Table 1).

Table 1 Key drug classes used in cardiovascular-kidney-metabolic (CKM) syndrome

Drug class	Indications [NB1]	Notes and precautions
ACEi or ARB	Chronic kidney disease with or without albuminuria Hypertension Heart failure	Maximise dose, as tolerated by blood pressure Safe at all stages of chronic kidney disease Monitor for hyperkalaemia
SGLT2 inhibitors	Type 2 diabetes with HbA1c greater than 7% on metformin or sulfonylurea Type 2 diabetes (any HbA1c) with high risk of cardiovascular event or established cardiovascular disease Heart failure (either preserved or reduced ejection fraction) Chronic kidney disease, with or without albuminuria or diabetes	Risk of volume depletion; genitourinary infections (particularly candidiasis); and euglycaemic ketoacidosis in people with diabetes
Mineralocorticoid receptor antagonists (MRAs) [NB2]	Type 2 diabetes with albuminuria Heart failure	Choice of MRA depends on stage of CKM syndrome (nonsteroidal MRA for type 2 diabetes with albuminuria; steroidal MRA for heart failure) Monitor for hyperkalaemia
GLP-1 receptor agonists or dual GIP/GLP-1 receptor agonists	Obesity or overweight Type 2 diabetes Cardiovascular disease secondary prevention Obstructive sleep apnoea	Gastrointestinal (including pancreatic) adverse effects are common, as are muscle and bone loss Nutritional deficiencies can occur due to reduced dietary intake Psychiatric and ocular adverse effects have been reported Weight regain and worsened metabolic health can occur if the drug is stopped
NB1: Not all drugs in each class are approved for all indications listed NB2: Also known as aldosterone antagonists ACEi = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; GIP = glucose-dependent insulinotropic polypeptide; GLP-1 = glucagon-like peptide-1; MRA = mineralocorticoid receptor antagonists; SGLT2 = sodium-glucose co-transporter 2

Renin–angiotensin system inhibition

Renin–angiotensin system inhibition (RASi), using angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs), remains the backbone of therapy for CKM syndrome. RASi therapies should be titrated to maximum doses as tolerated to achieve a blood pressure of less than 130/80 mmHg and reduction in albuminuria of at least 30%.¹⁹ They can be safely prescribed at all stages of CKD and should not be ceased as eGFR progressively declines provided the patient does not develop low blood pressure or hyperkalaemia.²⁰

SGLT2 inhibitors

SGLT2 inhibitors should be considered in patients with type 2 diabetes, CKD or heart failure (with preserved or reduced ejection fraction). When starting SGLT2 inhibitors, there should be a review of the patient's other medications and potential rationalisation of hypoglycaemic agents, such as sulphonylureas and insulin, and diuretics.

The risk of euglycaemic diabetic ketoacidosis associated with SGLT2 inhibitor use is negligible in the absence of type 2 diabetes; however, it is increased 2-fold in those with type 2 diabetes.² Sick-day management counselling should be provided; SGLT2 inhibitors should be withheld during illness and stopped 3 days prior to surgery. A sick day action plan template is available through Kidney Health Australia.

Mineralocorticoid receptor antagonists

The use and type of mineralocorticoid receptor antagonists (MRA) depends on the stage of CKM syndrome. In people with diabetes and albuminuric kidney disease (uACR more than 22.6 mg/mmol), finerenone (a nonsteroidal MRA) is indicated. In type 2 diabetes, mineralocorticoid receptor overactivation may contribute to progression of kidney disease, through promoting inflammation and fibrosis. While current Pharmaceutical Benefits Schedule guidelines mandate RASi, SGLT2 inhibitor and finerenone treatment be started in a sequential manner, there is emerging data to suggest an SGLT2 inhibitor and finerenone can be commenced safely together.²¹ Monitoring for hyperkalaemia is important. In people with heart failure with reduced ejection fraction, a steroidal MRA (spironolactone, eplerenone) should be used instead of finerenone.

GLP-1 receptor agonists

GLP-1 agonists (and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists) are well established in weight management and type 2 diabetes, and they can induce remission of diabetes.²² Semaglutide was recently approved in Australia as an adjunctive therapy to reduce the risk of kidney function decline, kidney failure and cardiovascular death in adults with type 2 diabetes and CKD, based on data from the FLOW trial.²³ While GLP-1 agonists reduce the risk of major cardiovascular events in patients with and without type 2 diabetes, additional studies are needed to understand their place in the management of heart failure.^24,25 GLP-1 agonists have adverse effects that limit their use (Table 1),²⁶ and data suggest weight regain and poorer cardiometabolic health if these agents are stopped.²⁷

Practical tips to reduce the risk of muscle and bone loss associated with GLP-1 agonists include consuming protein with every meal (1.2 to 1.6 g/kg body weight, using an obesity-adjusted weight where appropriate) and promoting resistance training in addition to aerobic activity.

Lipid-lowering therapy

The presence of CKM syndrome should prompt the use of the Australian CVD Risk calculator to determine 10-year risk and guide the use of lipid-lowering therapy for atherosclerotic cardiovascular disease prevention.²⁸ Guidelines suggest commencing a statin, with or without ezetimibe, if the atherosclerotic CVD risk is 10% or higher.

The 4 pillars of heart failure treatment

If heart failure with reduced ejection fraction is evident, the 4-pillar heart failure approach, titrated to maximum tolerated dose, is indicated.²⁹ This includes RASi or angiotensin receptor–neprilysin inhibitor (ARNI), beta blocker, SGLT2 inhibitor and MRA.³⁰ Switching from RASi to ARNI therapy requires a 3-day washout period. While the simultaneous initiation of 4 treatments may reduce rehospitalisation, comorbid kidney disease limits the application.^31,32 Support through heart failure clinics including via telehealth can improve medication management and adherence.³³ SGLT2 inhibitor therapy is also indicated in heart failure with preserved ejection fraction.

 

Conclusion

The attribution of CKM syndrome is a significant step forward in the recognition of the interconnectedness of cardiac, kidney and metabolic disease, particularly diabetes and MAFLD, and their upstream drivers (visceral adiposity induced inflammation, oxidative stress, insulin resistance and vascular dysfunction). To genuinely shift the trajectory, early detection, education and management is required. CKM syndrome remission is possible. Person-centred and equitable care that takes a holistic approach, prioritises wellbeing and supports healthy behaviours, and includes guideline-directed medical therapy, is fundamental to effective primary and secondary prevention.

This article was finalised on 23 April 2026.

Conflicts of interest: Karen Dwyer was the Clinical Director of Kidney Health Australia and is currently a member of Kidney Health Australia's Clinical Advisory Committee and PEAK (Primary Education Advisory Committee). She was a member of the working group for the CARI Recommendations for Culturally Safe and Clinical Kidney Care for First Nations Australians and Kidney Health Australia's chronic kidney disease guideline development committee. Karen is chair of the Board of Directors of the Australasian Metabolic Health Society, and a member of the Board of Directors of ePurines. She has received honoraria from AstraZeneca, Boehringer Ingelheim, Bayer and Servier for providing education to primary care professionals, and has participated in advisory boards for GlaxoSmithKline, Boehringer Ingelheim and AstraZeneca and Steering Committees for Novo Nordisk.

Alok Gupta has received honoraria from AstraZeneca, Alexion, Amgen, Bayer, Boehringer Ingelheim and Eli Lilly for providing education.

Katie Oetsch and Penelope Figtree declared no conflicts.

This article is peer reviewed.

 

References

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Further reading

• O'Halloran R, Adams LA, Deed G, Lubel JS. Metabolic dysfunction-associated fatty liver disease: an update. Aust Prescr 2026;49:44-9.
• Yates N, South TL. Injectable drugs for weight management. Aust Prescr 2025;48:197-202.