Overview of cardiovascular risk in older people with diabetes: Basic pathophysiology, risk factors and management

Ageing is associated with progressive decline in many physiological processes that affect health status and contribute to inflammatory changes and oxidative stress that contribute to diabetes, CVD and other complications. Atherosclerosis causes 80% of deaths in people with diabetes and 75% of hospital admissions are related to CVD (Huxley et al, 2006). CVD-related mortality is 3–10-fold higher in type 1 diabetes, and 2-fold higher in men and 4-fold higher in women with diabetes than those who do not have diabetes. Significantly, women have a 50% higher CVD risk than men and CVD develops 7–10 years later in women than men (Huxley et al, 2006; Maas and Appelman, 2010).

As older people are highly individual, management needs to be individualised to be effective. Generally, older age refers to people older than age 60 but chronological age is not a good indicator of health status or functional capacity (International Diabetes Federation [IDF], 2013; Dunning et al, 2014). Therefore, it is important to consider functional status when planning care for older people. The IDF functional categories are outlined in Box 1. These functional categories can be used with a CVD risk screen and thorough assessment.

This article gives an overview of the basic changes in cardiac physiology associated with diabetes, the risk factors for CVD and outlines management strategies.

Overview of age-related changes in the cardiovascular system
A healthy cardiovascular system is important to transport oxygenated blood, nutrients and often medicines to tissues and to remove waste products (North and Sinclair, 2012). Age-related changes in cardiovascular tissues include cardiac hypertrophy, changed left ventricular (LV) function and LV reserve, arterial stiffness and impaired endothelial function, which compromises the transport system. There may be few or no changes in overall resting cardiac function up to age 80; however, unstable age-associated changes are usually present in specific aspects of heart function and structure, and these changes can be exacerbated by “lifestyle factors” (North and Sinclair, 2012).

Arterial stiffness often induces myocardial compensatory mechanisms, such as LV hypertrophy and fibroblast proliferation, reduced cardiac output and increased fibrosis. These changes slow the electrical impulses within the heart, and reduce heart rate, variability and capacity to respond to beta-adrenergic receptor activation. This compromises cardiac function in the long term.

Clinically, these changes manifest as increased systolic blood pressure, which is a significant risk factor for hypertension, atherosclerosis, stroke and atrial fibrillation (Lakatta and Levy, 2003). Tissue perfusion is compromised, leading to cardiac ischaemia, which compromises the capacity of endothelial cells to proliferate and migrate after tissues are injured. The endothelium becomes porous, allowing vascular smooth muscle cells to migrate into the sub-endothelial spaces and deposit extracellular matrix proteins that cause intimal thickening. This contributes to major CVD events such as myocardial infarction (MI) and stroke. The risk of recurrent MI, stroke and death is high, occurring 12–36 months after the initial event. Older age and multiple risk factors are strong predictors of adverse outcomes (Jernberg et al, 2015).

Six main causal mechanisms are proposed that might all be driven by a single process – overproduction of superoxide in the mitochondria electron transport channels (Giacco and Brownlee, 2010):

1. Glucose and other sugars enter the polyol pathway and lead to sorbitol accumulation.
2. Increased production of advanced glycated end products (AGE).
3. Increased expression of AGE receptors and activating ligands.
4. Activation of protein kinase C (PKC) isoforms.
5. Overactive hexamine pathway.
6. Inactivation of two critical antiatherosclerotic enzymes (endothelial nitric oxide synthase and prostacyclin synthase).

Although reactive oxygen species contribute to CVD, the role of antioxidants, such as vitamin E, is unclear. A healthy balanced diet and regular exercise are important to prevent or manage obesity, maintain heart health and reduce the risk of diabetes and CVD. They are key aspects of primary prevention as well as essential management strategies. Recent research suggests high-calorie diets and little exercise might suppress the “longevity genes” that promote cellular defence mechanisms against ageing and age-related disease, including CVD (Sinclair, 2005).

Risk factors for CVD
Table 1 outlines the key CVD risk factors and management considerations for older people. CVD risk can be calculated using one of several recommended CVD-risk calculators available on the Internet. Most modern risk calculators recommend calculating absolute risk to decide management goals and an individualised care plan (Jenkins et al, 2015).

Gender-specific risk factors should also be considered, such as pre-menopausal hormonal dysfunction, hypertension and/or pre-eclampsia and gestational diabetes during pregnancy in women. The role that polycystic ovarian disease plays in CVD risk is unclear (Maas and Appelman, 2010).

Significantly, diabetes is an equivalent risk factor to previous MI among men aged 60–79 with early onset diabetes (Giacco and Brownlee, 2010). Over 30% of people admitted to hospital with acute MI have diabetes and 35% have impaired glucose tolerance (Giacco and Brownlee, 2010). Interestingly, the relative glucose-related risk of CVD appears to decrease with age; however, the overall absolute risk increases with age and is closely associated with congestive heart failure (Avery et al, 2012).

In addition, age-related risks include:

• Reduced insulin sensitivity and insulin resistance.
• Central obesity.
• Mitochondrial dysfunction.
• Reduced protein synthesis and protein quality, which compromises muscle quality and strength, especially in the presence of oxidative stress and DNA damage. Regular exercise helps reduce insulin resistance and maintains muscle strength and is important to preventing falls in older people (Ruas et al, 2012).
• Declining beta-cell function and beta-cell mass is evident before diabetes is diagnosed and is progressive, which suggests insulin might be required over time. Older people who are not obese can adapt to these changes but metabolic stress exacerbates deficits in glucose regulation and overwhelms adaptive mechanisms (Taichi et al, 2012).

In addition, some commonly used medicines such as corticosteroids, antihypertensive agents, thiazide diuretics and some antipsychotic agents are associated with disrupted glucose homeostasis and increased risk of diabetes and its most significant complication, CVD.

Managing cardiovascular risk
Most countries have guidelines for managing diabetes, CVD and CVD risk factors such as dyslipidaemia, hypertension and hyperglycaemia (NICE 2010; Scottish Intercollegiate Guideline Network, 2014; American Diabetes Association, 2015). Strategies to manage key CVD risk factors are outlined in Table 2. A number of overarching considerations and clinical challenges influence management decisions. These include:

• Functional status, and the relative risks and benefits of guideline recommendations for individual older people in light of their absolute cardiovascular risk, life expectancy, care goals and preferences.
• Chronological age is not an appropriate indicator of health, function or self-care capacity.
• The importance of managing CVD-related symptoms such as dyspnoea, breathlessness, exertion angina, exercise tolerance, tiredness, depression and peripheral oedema. Thus, a palliative approach to managing symptoms to promote comfort and quality of life can be integrated into usual care.
• The potential influence of the legacy effect (metabolic memory). The legacy effect highlights the benefit of controlling hyperglycaemia and its associated metabolic derangements before the person becomes old, and the importance of identifying CVD and diabetes risk early in life.
• Managing CVD risk might be more important and relevant than focusing on optimal blood glucose control. The Veterans trial showed intensive blood glucose control in people with mean age 60.5 did not significantly reduce CVD risk (Hayward et al, 2015).
• Cognitive changes and the effects on self-care, the ability to problem-solve, make decisions and recognise symptoms.
• The presence of comorbidities, such as hyperthyroidism, which can be subclinical and lead to atrial fibrillation (AF). AF can be due to transient conditions, such as infection.
• Many older people have peripheral and/or autonomic neuropathy. The former is associated with risk of foot complications, such as ulcers and infections. The latter, combined with CVD, compromises sexual function. It also affects sensation and a person’s ability to recognise important life-threatening events such as MI and hypoglycaemia (Knopman et al, 2001). The latter can trigger MI in older people and is associated with dementia (Knopman et al, 2001).
• The need to manage surgical risk and risks associated with investigations (Pearse et al, 2006). Knowing the person’s absolute CVD risk can be useful when emergencies, such as acute MI and foot problems that require surgical intervention, occur. Absolute risk can also be used to initiate conversations about documenting end-of-life care preferences.
• Accepting that health professionals’ recommended care is likely to differ from the individual’s goals and preferences and that of their families.
• The way older people learn and process information changes over time. Therefore, education strategies, written and other types of information, must be suitable to the individual older person. Significantly, the individual and their carers need education about how to recognise and act on atypical signs and symptoms of MI, and the importance of seeking advice early.
• The need for pharmacovigilance (Dunning and Sinclair, 2014), see Table 2.

Summary
Older people are at high risk of CVD. Identifying and managing CVD needs to occur as early as possible for prevention to be successful. This is before metabolic abnormalities and age-related factors lead to irreversible tissue damage. Changed pathophysiology and complications are often present approximately 10 years before CVD and diabetes manifest. A proactive comprehensive, individualised and person-centred approach to care, based on absolute cardiovascular risk, is essential.

This article made the following key points: CVD is common in older people with types 1 and 2 diabetes and is responsible for >50% of diabetes-related deaths. Older people are likely to have several concomitant CVD risk factors; however, it is important to determine the individual’s absolute risk to guide care planning. Important management and prescribing issues were also presented.