Metabolic comorbidities are common in patients with cardiorenal disease and may lead to atherosclerotic cardiovascular disease (ASCVD), accelerate disease progression and adversely affect prognosis. Common comorbidities include type 2 diabetes mellitus (T2DM), obesity/overweight, chronic kidney disease (CKD), and chronic liver disease. The cardiovascular system, kidneys, and liver are associated with many of the same risk factors, and common metabolic and functional abnormalities contribute to damage to these organs through overlapping pathophysiological pathways.
The coronavirus pandemic has further complicated the management of cardiometabolic diseases. Obesity, T2DM, CKD, and liver disease are associated with an increased risk of adverse outcomes from COVID-19 infection. Conversely, COVID-19 may cause existing atherosclerotic disease to worsen. The high incidence of these comorbidities underscores the need to improve awareness and treatment of ASCVD in patients with obesity, insulin resistance or T2DM, chronic liver disease, and CKD. Similarly, in patients with ASCVD, there is a need to improve awareness and treatment of these comorbidities.
Center Diagram
Prevalence and impact of cardiovascular disease (CVD) and metabolic disease
The most common cardiometabolic comorbidities include CVD, T2DM, obesity/overweight, renal disease, and liver disease. In 2019, there were 438 million epidemic cases worldwide and 1.5 million deaths from T2DM. Globally, an estimated 50% of patients with T2DM die from CVD. Diabetes is associated with an increased risk of all-cause mortality, CVD, stroke, CKD, chronic liver disease, and cancer. The risk of CVD in adult patients with T2DM is 2~4 times that of non-diabetic patients.
Obesity is a common risk factor for hypertension, CVD, CKD, and T2DM. The prevalence of overweight (30%~40%) and obesity (26%~27%) in developed and developing countries is high and continues to increase. Obesity promotes inflammation, high blood pressure, insulin resistance, impaired heart and blood vessel function, and is associated with an increased risk of cardiometabolic disease and mortality. Globally, high body mass index (BMI) is responsible for 5 million deaths and 160 million disability-adjusted life years (DALYs), more than half of which are attributable to CVD (2019).
In 2019, cirrhosis and other chronic liver diseases caused by nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) were responsible for 1.24 billion morbidities, 134 000 deaths and 3.62 million DALYs worldwide. NAFLD was associated with a high prevalence of metabolic comorbidities, including obesity (51%), T2DM (23%), hyperlipidemia (69%), hypertension (39%), and metabolic disease syndrome (43%). As the stage of liver fibrosis increases, the risk of obesity, hypertension, and T2DM increases.
At least half of all patients with T2DM worldwide have CKD. The 10-year cumulative all-cause mortality was 31% in patients with T2DM and CKD, compared with 12% in patients with T2DM alone. In high-income countries, diabetes alone reduces life expectancy by about 6 years on average, while the presence of CKD may reduce life expectancy by 16 years. Renal impairment is also associated with an increased risk of hospitalization for heart failure. Obesity is associated with the development and progression of CKD. Compared to normal-weight people, the relative risk of developing kidney disease is almost double that of obese patients and 1.4 times that of overweight patients.
About half of people with heart failure have chronic kidney disease. CKD was associated with a 50% increased risk of death in heart failure with reduced ejection fraction (HFrEF) and mildly reduced ejection fraction (HFmrEF), and a 30% increased risk of death in heart failure with preserved ejection fraction (HFpEF).
Impact of COVID-19
1. Cardiometabolic diseases affect COVID-19 infection
Obesity, T2DM, CKD, and liver disease were significantly associated with an increased risk of severe COVID-19, including death. Multiple cardiovascular risk factors are associated with an increased risk of severe COVID-19 infection, including hypertension, obesity, and T2DM. In one study, T2DM was associated with a 6.3-fold increase in the risk of death, which was significantly higher than the increased risk associated with CVD (1.2~1.4).
The underlying mechanism of the interaction between metabolic diseases (i.e., obesity and T2DM) and COVID-19 infection may be related to the inherently cardiovascular, respiratory, metabolic, and thrombotic impairment of obesity and excess ectopic fat. These ectopic fat-related disorders may reduce the patient's ability to cope with COVID-19 infection and secondary immune response (Table 1).
Table 1 Parallel and cross-cutting pathologies of diabetes mellitus and acute COVID-19 infection
In people with COVID-19 infection, CVD is also associated with a worse prognosis, including a higher risk of death and a risk of secondary cardiovascular or renal events. The risk of death in patients hospitalized with heart failure due to COVID-19 infection is approximately 2 times higher than in patients without a history of heart failure and 10 times higher than in patients without hospitalization for COVID-19 due to acute heart failure.
2. COVID-19 affects cardiometabolic diseases
People with severe COVID-19 infection often die from lung disease. However, the virus can damage many other organs, including the heart and blood vessels, and can promote thrombosis, myocardial infarction, and heart inflammation. The relative risk of myocardial infarction and stroke within 14 days of confirmed COVID-19 is 13-fold and six-fold, respectively, compared with before or 14 days after COVID-19 diagnosis.
There is evidence that COVID-19 infection is associated with an increased risk of myocarditis, but to a lesser extent. One systematic review suggests that COVID-19 survivors have a five-fold increased risk of myocarditis compared to people who have not been infected with COVID-19, an absolute increase of about 1 in 10,000. An increased risk of myocarditis is also associated with vaccines, especially in young men, but this risk is much lower than that of COVID-19 infection.
In addition to the direct impact of viral infections, disruptions to health care services during the COVID-19 pandemic have had a severe impact on cardiometabolic diseases. During the pandemic, there was a significant reduction in the number of hospitalizations for CVD, as did the number of ventricular arrhythmias requiring instrumental intervention.
The outbreak has also had a significant impact on the management of T2DM, including missed or delayed diagnosis, inadequate monitoring of HbA1c levels, and delayed follow-up care. A national study on cardiovascular drug prescriptions during the pandemic found that antihypertensive and lipid-lowering drug prescriptions were significantly reduced (much higher than glucose-lowering drugs) and an increased risk of myocardial infarction and stroke was expected in the future.
3. Management strategies for COVID-19 patients
Patients with pre-existing or post-COVID-19 CVD should be treated according to current guidelines (guidelines for acute coronary syndromes, heart failure, or hypertension). Renin-angiotensin-aldosterone system (RAAS) inhibitors may be continued in patients with stable CVD. In patients with T2DM, a systematic registry study in Sweden found that patients treated with sodium-glucose cotransporter 2 (SGLT-2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors (but not glucagon-like peptide-1 receptor agonists [GLP-1 RA]) were at slightly higher risk of severe COVID-19 infection (≤11%). However, the trial of dapagliflozin in respiratory failure in COVID-19 patients found no significant effect of SGLT-2 inhibitors on organ dysfunction or mortality risk, but the drug was well tolerated.
Management of cardiometabolic diseases
1. Social and individual-level interventions targeting common risk factors
One of the key social strategies to combat obesity and cardiometabolic diseases is education and programmes that encourage healthy eating and physical activity. An unhealthy diet, such as frequent visits to fast food restaurants, is associated with an increased risk of obesity. Increased consumption of fresh fruits and vegetables and reduced consumption of sugary foods and beverages should be promoted (Table 2).
Table 2 Summary of UK Chief Medical Officer's strategy for childhood obesity in 2019
In addition to social-level interventions, individual-level interventions have also shown that even light physical activity can reduce obesity and improve blood pressure and lipid levels (Figure 1). A meta-analysis of six prospective observational studies found that individuals who spent more time on light activity had a lower risk of all-cause mortality.
Fig.1 A brief pathway for screening and managing patients with cardiometabolic abnormalities
Based on numerous lifestyle studies, the U.S. Preventive Services Task Force recommends behavioral counseling interventions to improve diet and increase physical activity in patients with cardiometabolic risk factors to prevent long-term cardiovascular events (Figure 1).
Lifestyle modification programmes should also encourage physical activity and provide education on cardiometabolic risks and the benefits of a healthy lifestyle (Figure 2).
Figure 2 Public health initiatives
2. Patient experience
Patient participants agreed on the urgent need for education, prevention, and screening. Chronic diseases such as T2DM and CVD require close doctor-patient collaboration more than any other disease to effectively manage risk factors and diseases. Health professionals must understand the details of the life experiences of patients with CVD and comorbidities.
3. Screening for comorbidities
The high rate of comorbidities suggests that we need to improve the recognition and treatment of CVD in patients with obesity, T2DM, chronic liver disease, and CKD, as well as metabolic and renal diseases in outpatients with heart disease (Figure 1). Guidelines for screening patients with cardiometabolic disease are recommended in Table 3.
Table 3 Guideline screening recommendations in Europe and the United States
A 2022 statement from the American Diabetes Association recommended the use of B-type natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), or highly sensitive cardiac troponin for biomarker screening to detect heart failure in patients with T2DM.
4. Drug treatment for multiple pathologies of cardiometabolic diseases
Many treatment options may offer a mechanism-based approach, the most important of which are lifestyle changes (including diet and physical activity), pharmacotherapy (including statins, SGLT-2 inhibitors, GLP-1RA, salviamarinate synthase gene [SmRAS]), and bariatric surgery (Figure 1).
➤ Statins are one of the important drug therapies for reducing cardiovascular risk and have been shown to reduce the risk of major vascular events (myocardial infarction, death from coronary artery disease, any stroke or coronary revascularization) and overall mortality.
➤ Multiple T2DM management therapies have been shown to target the hemodynamic and metabolic mechanisms involved in the development of CKD (Figure 3). The data suggest that GLP-1 RA (tirzepatide) treatment may be effective, but more data are needed to validate it.
Fig. 3 Treatment options for multiple drivers of T2DM and CKD
➤ GLP-1 RA and DPP-4 inhibitors reduce ectopic fat accumulation but do not reduce inflammation. Statins, metformin, SGLT-2 inhibitors, and SmRAS may reduce the accumulation and inflammation of ectopic fat, as well as the secretion of adipokines.
➤SGLT-2 is expressed in epicardial adipose tissue, and in vitro studies have shown that SGLT-2 inhibitors increase glucose uptake, reduce secretion of pro-inflammatory chemokines, and promote coronary endothelial cell healing.
➤ Some of the cardiovascular benefits of GLP 1-RA may be attributed to the direct effects of GLP-1 on the myocardium. GLP-1 infusion has been shown to improve left ventricular function in patients with acute myocardial infarction and heart failure after successful reperfusion.
5. Surgical and non-surgical weight-loss strategies for multiple pathologies of cardiometabolic diseases
Non-surgical and surgical weight-loss strategies have been shown to reduce weight and improve cardiometabolic derangements in many obese individuals, particularly in slowing the progression of prediabetes to T2DM and treating hypertension. In a meta-analysis of observational studies of obese patients, surgical treatment was associated with a 45%~50% reduction in the risk of death compared to individuals who did not undergo surgical treatment. However, the long-term benefits of surgical treatment have not been established.
Non-surgical weight loss and surgical weight loss may also reduce the progression of CKD. A meta-analysis of 13 studies of people with CKD found that non-surgical interventions (diet, exercise, medications) reduced BMI, proteinuria, and systolic blood pressure (SBP). In obese patients, surgical intervention reduces BMI, normalizes glomerular filtration rate (GFR), and reduces microalbuminuria and SBP.
The ESC and the European Association for the Study of Diabetes (EAA) guidelines for T2DM and CVD recommend the prevention of T2DM and cardiovascular events through weight control and physical activity (Table 4).
Table 4 Guideline recommendations for the prevention of CVD with lifestyle modifications
Summary and call to action
We need to take steps to address the challenges and barriers to early identification, prevention, and treatment of cardiometabolic comorbidities, adopt strategies that include education, screening, and diagnosis, and optimize the use of existing treatments (Figure 1 and Table 5).
Table 5 Strategies to address challenges and barriers in the prevention, identification, and treatment of cardiometabolic comorbidities
参考文献：Francesco Cosentino 1, Subodh Verma, et al. Cardiometabolic risk management: insights from a European Society of Cardiology Cardiovascular Round Table. Eur Heart J. 2023 Oct 14; 44(39):4141-4156.
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