The term ‘cardiometabolic disease’ (CMD) appears to have been initially used by the exercise physiologist, Pescatello and VanHeest , and refers to a combination or clustering of metabolic abnormalities that increases the risk of cardiovascular disease (CVD) and type 2 diabetes mellitus . These metabolic abnormalities include increased insulin resistance, hyperglycaemia, visceral obesity, nonalcoholic fatty liver, dyslipidaemia and hypertension [1,2]. The term may be used as a platform for examining how new pharmacological interventions can be employed to enhance clinical outcomes and improve survival in those with CMD.
The prevalence of CVD increases with age. In the US, the prevalence of CVD is around 54% for those aged 40–59 years, 78% for those aged 60–79 years and 90% for those aged >80 years . The high prevalence of CVD in these age groups is linked to age-related factors such as increased oxidative stress, inflammation, apoptosis and overall myocardial deterioration and degeneration . Frailty and sarcopenia are emerging new factors that promote a state of cardiometabolic abnormalities that increases the risk of CVD. Other age-related unhealthy behaviours such as inactivity, malnutrition and poor sleeping pattern are also factors linked to CVD . This review will evaluate the risk factors that predict cardiometabolic disease in older people and explore ways of prevention. The review will also indicate that the separate specialities of cardiology and diabetes may not be able individually to address all the emerging and often overlapping complex metabolic disturbances requiring treatment, and that a new subspeciality is needed.
The impact of traditional risk factors that predict CVD may change with increasing age. Also, there is emergence of new age-related cardiovascular risk factors such as frailty and sarcopenia.
Risk factors change and reverse metabolism
Longitudinal data have shown that with advancing age the predictive values of BMI and systolic blood pressure decline in relation to myocardial infarction and ischaemic stroke or heart failure, respectively. However, other risk factors such as LDL-cholesterol for myocardial infarction and BMI and fasting blood glucose regarding heart failure remained significantly predictable for incident CVD in old age . A small observational study of 331 older adults, mean age 85 (7.0), has shown that low BMI, low diastolic blood pressure, low total and HDL cholesterol and high insulin sensitivity predicted total mortality indicating a reverse metabolism that is probably attributable to malnutrition with or without other chronic conditions. These inverse associations limit the relevance of conventional cardiovascular risk factors and suggest that future studies are needed to determine whether prevention and treatment of malnutrition would prevent cardiovascular events 
Role of frailty and sarcopenia
Frailty (a state of increased vulnerability to poor resolution of homeostasis after a stressor event) and sarcopaenia are now recognized as high impact complications association with diabetes . Frailty and CVD appear to have a bidirectional relationship . Frailty predicts CVD while CVD is associated with an increased risk of incident frailty and the coexistence of both frailty and CVD is associated with poor outcomes independent of age and comorbidities . However, it is still not clear whether frailty is an independent risk factor for CVD and whether interventions to prevent frailty would prevent the development or slowdown the progression of CVD. Prefrailty has also been shown to independently increase the risk of CVD and those who were prefrail had an increased prevalence of cardiometabolic abnormalities such as insulin resistance, central obesity and increased inflammatory markers suggesting that frailty may promote an adverse cardiometabolic state that mediates the development of CVD . Some obese individuals may have a lower muscle mass (sarcopenia) or lower muscle to fat ratio, a condition known as sarcopenic obesity. The combination of both obesity and sarcopenia may have a synergistic effect on the risk of CMD. A reduced muscle mass is associated with the accumulation of visceral fat including nonalcoholic fatty liver. Accumulated visceral fat induces chronic inflammation which contributes to the development and progression of loss of muscle mass. Therefore, a vicious cycle develops between the loss of muscle and the accumulation of visceral fat which leads to increased risk of atherosclerosis via a complex interplay of factors including increased insulin resistance, proinflammatory cytokines, increased dietary energy, reduced physical activity, increased oxidative stress and mitochondrial dysfunction . (Fig. 1) Obesity is associated with increased accumulation of proinflammatory adipokines secreted by adipocytes. Serum adipokines are positively associated with visceral fat and negatively associated with muscle mass. The presence of sarcopenic obesity is independently associated with increased serum levels of adipokines suggesting that low grade inflammation mediated by adipokines is the main mechanism of the vicious circle between sarcopenic obesity and CMD . On the other hand, skeletal muscles secrete beneficial myokines that increase glucose uptake and fatty acid b-oxidation in muscle, stimulate hepatic gluconeogenesis and induce lipolysis in adipose tissue. Thus, taken together, the vicious circle between muscle loss and fat gain might lead to more severe sarcopenia or obesity via changes in body composition and increases in the risk factors for CMD, which in turn increase the risk of CVD-related events . Reduced muscle strength or dynapenia may also play a role in CMD risk. Subjects with sarcopenic obesity defined as reduced muscle strength in the Cardiovascular Health Study had an increased risk of CVD than those with sarcopenic obesity that was defined as low muscle mass. This may suggest that dynapenia is an important factor for CMD risk than the absolute or relative low muscle mass alone . Also, dynapenic abdominal obesity has been recently shown to be independently associated with high prevalence of cardiometabolic risk factors .
Current risk calculators have not been validated in older people making them inadequate for use in this population . Because of the emergence of new cardiovascular risk factors in this age group, novel predictive tools are required. Relative hand grip strength (hand grip strength divided by BMI) has been shown to be significantly associated with favourable cardiometabolic risk factors such as blood pressure, lipid profile, triglyceride, fasting glucose, HbA1c, log high-sensitivity C-reactive protein (hs-CRP) and metabolic syndrome . Hand grip strength, normalized to body mass, has also been shown to be robustly associated with cardiometabolic risk parameters in the US and the Chinese ageing adults . These results suggest that hand grip strength can be used as a screening noninvasive diagnostic tool in identifying those at risk for future cardiometabolic impairment. Low gait speed also appears to be a useful predictor of future CVD . Activin A is a growth factor that has multiple functions including regulating wound repair, apoptosis and cell differentiation. It has been shown that there is a dose-dependent association between serum activin A levels and frailty, cognitive impairment, malnutrition, metabolic syndrome, uric acid and hs-CRP. Therefore, activin A status may represent a novel biomarker of overall cardiometabolic risk in older people . In view of the increased visceral obesity and reduced height caused by osteoporotic vertebral fractures and thinning of the intervertebral cartilage in older people, waist circumference may have a better predictive value than BMI in this age group .
The prevention of CMD and its progression to CVD should involve maintenance of a healthy metabolic profile and control of the traditional cardiovascular risk factors.
Maintenance of a healthy metabolic profile
The disturbance of fat–muscle ratio caused by the development of sarcopenia and frailty leads to a reduced muscle mass and power (with associated decline in the protective myokines) and increased visceral fat (with associated increase in the harmful adipokines) causes a state of metabolic abnormalities that increases the risk of CMD and its progression to CVD. Therefore, the maintenance of healthy metabolic profile primarily includes the maintenance of muscle mass and power and the prevention of visceral fat accumulation. This is likely to be achieved through the combination of improved diet and regular exercise training.
It has been shown that older people with low Mediterranean diet (Med-Diet) adherence had higher BMI (P = 0.029), higher prevalence of arterial hypertension (P < 0.001), previous coronary (P = 0.002) and cerebrovascular events (P = 0.011), diabetes (P < 0.001) and dyslipidaemia (P = 0.001) compared with those with high adherence suggesting that improved Med-Diet adherence might potentially delay the onset of CMD . Meta-analysis of observational studies have shown overall protective effects of Med-Diet on the risk of CVD . Supplementing Med-Diet with more olive oil or nuts showed 30% reduction in major cardiovascular events in older people (55–80 years old) . A prospective study of 2622 older people, mean (SD) age 74.4 (4.8), showed that higher levels of omega 3 polyunsaturated fatty acids from sea food source was associated with a lower risk of unhealthy ageing and suggests that dietary consumption of fish should be increased . Vitamin D deficiency was found to be associated with higher cardiometabolic risk factors in older people although the clinical impact of this association is still not very clear . High protein intake (35 g) after resistance training 3 days per week for a total of 12 weeks was associated with significant improvement in parameters of cardiometabolic profile compared with low protein intake (35 g placebo) in preconditioned older women .
In the cardiovascular health study which included 4207 subjects, mean (SD) age 72.5 (5.5) years, greater physical activity was inversely associated with ischaemic heart disease, stroke and total CVD even in those ≥75 years. Walking pace, distance, and overall walking score, leisure-time activity and exercise intensity were each associated with lower risk. The findings for walking distance and pace are especially important given that walking is the most common type of physical activity in older people . In a Finnish study of 2456 subjects aged 65–74 years, leisure-time physical activity reduced the risk of total and CVD mortality regardless of their baseline risk factors and the beneficial effect was dose dependent . It has been shown that engagement in light intensity physical activity was independently associated with favourable HDL and total cholesterol profiles in older people with multiple chronic conditions . High intensity interval training (HIIT) appears to have superior effects on cardiometabolic profile than moderate intensity continuous training . Nonweight bearing all extremity HIIT appeared to be feasible and well tolerated in older people which may be an option for those with musculoskeletal and balance problems . Even light physical activity may have a favourable cardiovascular benefit. Among 5861 older women, mean (SD) age 78.5 (6.7) years, the highest quartile of light physical activity, compared with the lowest quartile, was associated with a 42% reduction in the risk of myocardial infarction or coronary death . Similarly, it was observed that modest levels of physical, but not necessarily vigorous, activity confer benefits in terms of CVD risk, compared with being completely inactive in older people above the age of 65 years . Whole body electromyostimulation application has shown a favourable effect on the metabolic profile in community-dwelling women aged ≥70 years with sarcopenic obesity which may be considered an effective and well tolerated novel technology to prevent cardiometabolic risk in those who are unable or unwilling to exercise conventionally .
Control of traditional cardiovascular risk factors
Smoking cessation is beneficial even for those who quit later in life and should be part of multidimensional approach to risk factor modification in older adults with diabetes .
Hypertension is not only a risk factor for CVD but also increases the risk of cognitive impairment, renal failure and mortality. Reducing blood pressure to a target of 150/80 mmHg in the Hypertension in the Very Elderly Trial was beneficial in older people ≥80 years old regardless of the frailty status . The Systolic Blood Pressure Intervention Trial (SPRINT) has shown that further reduction of systolic blood pressure to ≤120 mmHg is more beneficial than systolic of ≤140 mmHg, but this aggressive reduction has resulted in an increased number of side effects such as orthostatic hypotension, electrolyte abnormalities and acute kidney injury. Furthermore, this study had excluded patients with a history of diabetes, heart failure, dementia, stroke, weight loss of >10% and nursing home residence making it difficult to generalize its findings to the general population of older people . There is also a concern for a J-shaped relationship with increased cardiovascular events for both low and elevated blood pressure . Therefore, a target blood pressure of 140/90 mmHg should be considered in most older patients and a lower target of <140 mmHg systolic for those with a high cardiovascular risk and able to tolerate antihypertensive medications without side effects. A more relaxed target of 150 mmHg systolic is reasonable in patients who are frail, residents in care homes or have limited life expectancy.
In a French study of 7284 subjects, median age 80 years followed up for a median of 4.7 years, the use of statins was associated with a lower risk of outcomes in the primary prevention group that has modifiable risk factors [HR 0.93 per year of use; 95% confidence interval (CI), 0.89–0.96, P < 0.01] and in the secondary prevention group (0.75, 0.63–0.90, P < 0.01) but not in the primary prevention group that does not have modifiable risk factors (1.01, 0.86–1.18, P = 0.92) . Similar results were confirmed in a recent meta-analysis of 28 randomized studies that showed that statin therapy was associated with 21% [relative risk (RR) 0.79, 95% CI, 0.77–0.81] risk reduction in major vascular events per 1.0 mmol/L reduction in LDL cholesterol. The beneficial effect of statins was similar, irrespective of age, among patients with pre-existing vascular disease (P = 0.2), but appeared smaller among older (>75 years) than among younger (≤55 years) individuals not known to have vascular disease (P = 0.05). This suggests that, in older people (>75 years), there is good evidence to support statin therapy in the secondary but not in the primary prevention of vascular events .
Hyperglycaemia is a risk factor for CVD and also increases the risk of geriatric syndromes such as cognitive impairment, frailty and falls in older people . However, tight glycaemic control (HbA1c < 6%) does not provide cardiovascular protection and appears to be harmful in this group of patients . Therefore, glycaemic control should be individualized with a target of 7.5% in healthy older patients, 8% for those with comorbidities and 8.5% for those who are frail or with limited life expectancy.
Data on the benefits of aspirin in primary prevention in older people ≥70 years old are mixed, but recently, it has been shown that the use of aspirin as a primary prevention derives no benefits and is harmful to healthy community-dwelling older people .
With increasing age, there is a decline in the impact of the traditional cardiovascular risk factors on the risk of CVD. Instead, frailty and sarcopenia emerge as new factors that promote a state of cardiometabolic abnormalities such as increased insulin resistance and chronic inflammation that increases the risk of CVD. Assessment of frailty has been advocated as part of standard care for all healthcare sectors including cardiology specialist services  and as older adults with frailty have nearly a five-fold increase in major cardiac events , it is now time to integrate this assessment into cardiometabolic disease management. Further details of these assessment processes are available in our cited references [7,42], and emphasize the characteristics of the frailty and sarcopaenia phenotypes and how they can be measured in a straightforward and practical office-based manner.
Maintenance of a healthy metabolic profile through maintaining of muscle mass and reducing visceral fat by adequate diet and regular exercise combined with control of traditional cardiovascular risk factors may help reduce the progression into CVD.
Although it appears that frailty and sarcopenia play a crucial role in the mechanism of the CMD and in turn its progression to CVD in older people, the pathogenesis still needs further understanding. It is also not clear whether interventions to prevent sarcopenia and frailty would reduce the incidence of CVD. Future predictive tools that measure the muscle–fat ratio as well as the introduction of novel therapeutic interventions are still required.
What is becoming evident is that the overlap between cardiology and diabetes is increasing and that it is unclear which speciality can manage all these various metabolic issues effectively without the need for more integration of therapeutic approaches. A call for developing a subspeciality of cardiometabolic medicine is sensible and overdue .
Conflicts of interest
There are no conflicts of interest.
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