Preventing cardiovascular–kidney–metabolic syndrome progression: a man with obesity, prediabetes and heart failure

Case presentation

John is a 63-year-old accountant who has attended the practice for 10 years. He was recently discharged from a local tertiary hospital following a non-ST-segment elevation myocardial infarction and diagnosis of heart failure with reduced ejection fraction. During admission, an elevated glycated haemoglobin level of 6.3% (45 mmol/mol) was also identified.

Before John had been admitted to hospital, he had been treated for hypertension with telmisartan 80 mg daily. Over the preceding five years, he had experienced progressive weight gain of 10 kg, reaching a body mass index (BMI) of 33 kg/m² following separation from his wife.

His family history included ischaemic heart disease in his father at the age of 65 years and a haemorrhagic cerebrovascular accident in his mother at the age of 63 years. He stopped smoking five years ago and drinks two standard alcoholic drinks on weekend nights.

During his hospitalisation, John was commenced on aspirin daily, frusemide 40 mg every morning, rosuvastatin 20 mg daily, spironolactone 25 mg every morning, metoprolol succinate 23.75 mg daily and sacubitril/valsartan 48.6  mg/51.4 mg twice daily.

Results from investigations showed:

• fasting blood glucose level, 6.5 mmol/L, repeated two weeks later at 6.3 mmol/L
• glycated haemoglobin level, 6.3% (45 mmol/mol)
• total cholesterol level, 5.5 mmol/L
• HDL-cholesterol level, 1.1 mmol/L
• triglyceride level, 2.6 mmol/L
• LDL-cholesterol level, 2.5 mmol/L
• liver function tests (alanine aminotransferase and aspartate aminotransferase), about twice the upper limit of normal
• estimated glomerular filtration rate, 65 mL/min/1.73 m²
• haemoglobin level, 137 g/L (normal range = 135–175 g/L)
• platelet count, 225 × 10⁹/L  (normal range = 150−450 × 10⁹/L)
• normal white cell count.

On examination at the clinic, his blood pressure was 130/75 mmHg, waist circumference 110 cm, jugular venous pressure was not elevated, and there was no peripheral oedema.

John has two questions:

• How could his health crisis potentially have been prevented, and what should his children know about their own future health risks?
• How can we help keep him healthy moving forward?

Commentary

Cardiovascular disease (CVD) and heart failure often represent the culmination of multiple intersecting risks present many years before a major clinical event, as occurred in John. These risks are now broadly classified under the term cardiovascular–kidney–metabolic (CKM) syndrome.¹

The CKM concept was proposed to support a more focused paradigm highlighting the multidirectional impact of clinically identifiable risk factors, particularly visceral obesity, and opportunities for both early preventive and later interventional strategies.¹ The focus is on addressing the multiorgan dysfunction that may eventuate from prediabetes and type 2 diabetes mellitus through to CVD, chronic kidney disease (CKD) and metabolic dysfunction-associated fatty liver disease (MAFLD) as an interconnected clinical framework.

The pathophysiology of CKM syndrome includes progressive systemic inflammation related to visceral obesity, insulin resistance, oxidative stress and advancing inflammation from glycation end products, dysfunctional neurohormonal signalling (e.g. sympathetic overactivity and renin–angiotensin–aldosterone system activation) and abnormal haemodynamic effects.^2,3

Modifiable clinical risk factors include visceral obesity, hypertension, smoking, physical inactivity, unhealthy dietary patterns, excess alcohol intake, sleep dysfunction (e.g. sleep apnoea) and serious mental illness.

Metabolic syndrome, defined in Table 1Table 1., has traditionally been used to cluster many of these modifiable risk factors.⁴ However, it does not adequately incorporate risks associated with CKD and MAFLD. Historically, clinical guideline pathways have often focused on single diseases such as CVD, CKD, obesity and diabetes, potentially underemphasising the importance of a broader multisystem approach. Furthermore, metabolic measures such as the BMI may inadequately reflect risk in diverse populations, including non-Caucasian ethnic groups, First Nations peoples and those affected by social disadvantage.^5-7

CKM stages

The stages of CKM syndrome are summarised as:¹

• stage 0: normal weight, normal blood glucose levels, normal blood pressure and normal lipid levels
• stage 1: excess or dysfunctional adiposity (BMI >25 kg/m²), prediabetes
• stage 2: established risk factors, including hypertension, diabetes, dyslipidaemia, obesity and CKD
• stage 3: subclinical CVD with CKM risk factors; very high-risk CKD
• stage 4: clinical CVD (heart failure, coronary disease, peripheral artery disease, atrial fibrillation or cerebrovascular disease) and CKM risk factors.

Australian data demonstrate an increasing prevalence of CKM conditions in primary care since 2011. By 2020, 21.8% of patients attending primary care had at least one CKM condition, 8.3% had two CKM conditions and 1.9% had all three CKM risk conditions.⁸

Contemporary CKM frameworks therefore emphasise early identification and prevention, while supporting individualised therapy for progressively increasing multiorgan dysfunction. They also highlight the importance of multidisciplinary care and multisystem interventions rather than single disease-focused approaches.

On reflection, John’s progression through the CKM stages may have been identified earlier, potentially creating opportunities for prevention before the development of stage 4 disease, particularly in relation to cardiovascular risk and weight gain.

Primary care plays a crucial role in early CKM identification and prevention strategies in stages 1 to 3, before the emergence of advanced disease such as that seen in John, with the aim of reducing morbidity and mortality through improved standards of care.

Clinical tools for CKM prevention and intervention

Addressing John’s questions about prevention and support for his children, if risks are identified, includes facilitating access to evidence-based community programs focused on risk reduction.

Use of a broad range of CKM tools and biomarker assessments (lipids, proteinuria and glycaemia) can help translate current clinical risks into supportive pathways aimed at reducing future complications – so-called ‘productive clinical care’ (Box 1Box 1.).⁹ Chronic condition management programs supported through Medicare item numbers may also assist by aligning SMART (specific, measurable, achievable, relevant and timely) goals with appropriate individualised support services such as accredited practicing dietitians, exercise physiologists and psychologists.¹⁰

Healthy lifestyle: diet, activity and weight management across the CKM spectrum

Although John has stopped smoking, relapse prevention remains important and cessation support should be available across multiple domains of the healthcare system from community pharmacy to primary care.

Visceral adiposity remains a core driver of CKM risk.¹ Healthy dietary management is fundamental in reducing childhood weight gain and preventing adolescent- and adult-emergent CKM risk. Community programs and resources supporting healthy lifestyle engagement are outlined in Box 2Box 2. and Box 3Box 3..

There is no universally agreed ideal diet for adults with CKM risk; however, important principles include improved fibre intake, reduced kilojoule consumption, moderation of carbohydrate quantity and quality, and reduced salt and alcohol intake. Dietary approaches consistent with these principles include the Mediterranean diet, PREDIMED and the Dietary Approaches to Stop Hypertension (DASH) diet.^11,12 However, dietary support should remain individualised, culturally sensitive and sustainable, ideally with input from an accredited practising dietitian.

Physical activity goals should be negotiated collaboratively rather than imposed in ways that conflict with individual abilities or preferences. Evidence supports combined aerobic and resistance training, including high-intensity exercise, in stages 1 and 2 CKM.¹³

In more advanced disease, such as in John’s case, enrolment and adherence to cardiac rehabilitation, interval aerobic exercise, resistance training and home-based walking programs should be encouraged. Lifestyle intervention trials have demonstrated benefit in preventing progression from prediabetes to diabetes. Guidelines also support the benefit of similar programs in MAFLD.¹⁴

Specific interventions targeting multiple metabolic targets in CKM

Recent therapeutic developments have created opportunities for therapies that can address the spectrum of CKM organ dysfunction when risks emerge. However, the evidence of benefit may vary according to CKM stage and across different populations, including those with or without diabetes and obesity. PBS  subsidisation also varies according to indication and should be reviewed before prescribing. Therapeutic approaches across CKM stages are summarised in Table 2Table 2..^15-32

Returning to John: practical management priorities

Practical management priorities for John require an organised primary care approach to include the following:

• a focus on John’s goals and values and vigilance for psychological care needs
• implementation of Australian evidence-based guidelines for heart failure management³³
• titration of sacubitril/valsartan, beta blockers and mineralocorticoid receptor antagonist therapy, if required
• addition of an SGLT-2 inhibitor, consistent with guideline recommendations, and consideration of the use of semaglutide
• optimisation of lipid-lowering therapy to achieve an LDL-cholesterol target below 1.4 mmol/L
• further investigation of abnormal liver function tests. John has a fibrosis-4 (FIB-4) score of 2.1, which supports further assessment for liver fibrosis, including liver ultrasound and elastography
• assessment of iron studies in the setting of heart failure, with consideration of intravenous iron therapy where appropriate. In patients with ferritin below 100 mg/L, or transferrin saturation below 20% with ferritin between 100 and 299 mg/L, intravenous iron has demonstrated reductions in heart failure hospitalisation³⁴
• consideration of obstructive sleep apnoea assessment
• development of a chronic condition management plan to support access to multidisciplinary care, including practice nurses, dietitians, exercise physiologists and psychologists
• encouragement of cardiac rehabilitation and transition to ongoing tailored physical activity programs.

Clear communication with his cardiologist, heart failure nurses and rehabilitation team is essential.

John remains at heightened CKM risk. Structured recall and review systems may support timely reassessment for progression of dysglycaemia, MAFLD, fibrosis and CKD. He should also be encouraged to discuss shared familial risk factors with his children and access preventive support programs where appropriate.

Summary

CKM syndrome places general practice at the centre of co-ordinated, proactive and patient-directed care for individuals with interconnected cardiometabolic disease.

Integrating lifestyle intervention, physical activity and targeted multimodal therapies provide opportunities for earlier intervention and reduction in long-term disease burden. Heart failure should be recognised as a signifier of broader CKM risk requiring comprehensive assessment.

The burden of CKM disease may be reduced through proactive primary care, structured chronic disease management and optimisation of clinical systems. Central to this approach is connecting a person’s values and knowledge with clear communication of risk, co-ordinated multidisciplinary care and agreed clinical goals.  MT

COMPETING INTERESTS: Dr Deed provides education and advisory board advice to Abbott, AstraZeneca, Boehringer Ingelheim, Dexcom, Eli Lilly, MSD, Novartis, Novo Nordisk and Sanofi; has received payment for expert testimony and support for attending meetings and/or travel from the Royal Australian College of General Practitioners (RACGP); has participated in a Flash Glucose Monitoring (FlashGM) trial advisory board; and is a member of the RACGP Diabetes Specific Interest Group and the Australian Diabetes Society (ADS) Clinical Standards/Guideline Committee.

References