19.4 Cardiovascular risk assessment in diabetes and pre-diabetes

Patients with diabetes exhibit an increased propensity to develop cardiovascular disease with an increased mortality. Early risk assessment, especially for coronary artery disease, is important to initiate therapeutic strategies to reduce cardiovascular risk. This chapter reviews the current literature on risk scores in patients with type 1 and type 2 diabetes and summarizes the role of risk assessment based on biomarkers and different imaging strategies. Current guidelines recommend that patients with diabetes are characterized as high-risk or very high-risk patients. In the presence of target organ damage or other risk factors such as smoking, marked hypercholesterolaemia, or hypertension, patients with diabetes are classified as very high-risk patients while most other people with diabetes are categorized as high-risk patients.

Current European and American guidelines for the prevention of cardiovascular disease recommend the assessment of cardiovascular risk, since therapeutic approaches to prevent cardiovascular disease should be individualized based on the individual risk profile. It is recommended that cardiovascular risk should be assessed in a systematic way in individuals at increased cardiovascular risk, for example, those with a history of premature cardiovascular disease, familial hyperlipidaemia, major risk factors (smoking, high blood pressure, diabetes, or dyslipidaemia) or co-morbidities associated with an increased severe risk.

European guidelines for cardiovascular prevention published in 2016 suggest that total risk estimation should use risk estimation systems such as Systematic COronary Risk Evaluation: High & Low cardiovascular Risk Charts (SCORE risk charts) to define patients being at risk or very high risk for cardiovascular disease.¹ Various risk scores have previously been developed such as the Framingham Score, Prospective Cardiovascular Münster Study (PROCAM), and others. However, none of these risk calculators has been established in a dysglycaemic population, thus making it difficult to apply these risk scores in patients with pre-diabetes or diabetes. In addition, data from applying these scores in subjects with diabetes suggest that risk is usually underestimated.

These limitations have led to the development of risk scores that are more specific for subjects with diabetes.

The UK Prospective Diabetes Study (UKPDS) risk score is based on the UKPDS, but the good sensitivity achieved in patients from the UK is different to that achieved in subjects from other areas.^2,3 Depending on the region examined, the UKPDS risk score overestimated the risk of coronary artery disease with suboptimal discrimination (see also Chapter 31.17).⁴ Most importantly, the risk score was developed more than two decades ago, not considering recent therapeutic advances such as statin therapy, angiotensin-converting enzyme inhibitors, and others. The Swedish National Diabetes Register (NDR) was applied in a homogeneous Swedish population and reported a good calibration with observed and predicted cardiovascular disease rate of 0.96–0.99.⁵ The Hong Kong Diabetes Registry for Coronary Artery Disease predicts cardiovascular risk in a Chinese population with a sensitivity of 64% and a specificity of 68%, respectively.⁶

Various risk engines have been developed to determine cardiovascular risk in patients with type 1 diabetes. The Swedish NDR study developed a model based on 3661 type 1 diabetes patients and included diabetes duration, systolic blood pressure, lipids, glycated haemoglobin, macroalbuminuria, as well as smoking as contributors to the model. In this model, more than 90% of patients had no history of cardiovascular disease and it predicted the incidents of non-fatal myocardial infarction, unstable angina, percutaneous coronary intervention, and/or coronary bypass grafting whereas stroke was defined as fatal or non-fatal.⁷

Recently, the Steno Risk Engine has been published, including parameters such as age, sex, diabetes duration, glycated haemoglobin, systolic blood pressure, low-density lipoprotein cholesterol, albuminuria, estimated glomerular filtration rate, smoking, and exercise. This risk score—developed as a primary prevention model for a first fatal or non-fatal cardiovascular event—included ischaemic heart disease, ischaemic stroke heart failure, and peripheral arterial disease from 4306 patients with type 1 diabetes.⁸ This risk score showed a higher prediction of cardiovascular events than the Swedish NDR study. However, the Steno Risk Engine has several limitations including the fact that very few type 1 diabetes patients with a diagnosis in early childhood were included.

Given the paucity of data on score-based risk assessment in asymptomatic subjects with diabetes, the European guidelines for cardiovascular prevention categorize patients with diabetes as very high-risk or high-risk patients. Patients with diabetes are considered very high-risk patients in the presence of target organ damage such as proteinuria or with a major risk factor such as smoking or marked hypercholesterolaemia or marked hypertension. Most other people with diabetes (with the exception of young people with type 1 diabetes and without major risk factors that may be at low or moderate risk) are categorized as high-risk patients. In addition, the guidelines state that individuals automatically at high to very high cardiovascular risk do not need the use of a risk score and require immediate attention to risk factors.⁹

Currently, there is no clear evidence that in patients with diabetes the use of biomarkers such as high-sensitive C-reactive protein provides additional benefit with respect to risk stratification. Still, it is indicated to estimate the urinary albumin excretion rate but mainly to detect changes in kidney function and to guide blood pressure lowering towards target values of less than 130/80 mmHg.⁹

In asymptomatic patients with diabetes, exercise stress testing helps to identify patients with silent ischaemia as shown in the ‘Does coronary Atherosclerosis Deserve to be Diagnosed and treated early in Diabetics?’ (DADDY-D) trial but fails to shown a significant benefit with respect to cardiac events reduction.¹⁰ Thus, the role of exercise stress testing in risk assessment is very limited.

Various non-invasive imaging modalities have been tested for risk assessment in asymptomatic patients with diabetes. Among them, carotid intima–media thickness and detection of carotid plaques were not prognostically useful in screening studies. Similarly, coronary computed tomography angiography (see Chapter 12.3) does not provide prognostic benefit and no prognostic data on screening of asymptomatic subjects with diabetes is available for echocardiography, as reviewed by Budoff and colleagues.¹¹

Different studies suggest that the presence of coronary artery calcium (CAC; see Chapter 12.2) is associated with myocardial ischaemia and the short-term outcome.^{12,13,14,15,16,17,18,19,20} The absence of CAC predicted a low short-term risk of death in subjects with diabetes with about 1% mortality in 5 years and an increase in each CAC score category increased the mortality risk.²¹ Myocardial perfusion imaging is able to detect silent ischaemia in 6–50% of all asymptomatic patients with diabetes depending on the pre-test risk, but has not been shown to improve the prognosis in various studies.¹¹ Still, CAC and myocardial perfusion scintigraphy findings were synergistic for the prediction of short-term cardiovascular events leading to a proposed algorithm in the 2010 American College of Cardiology Foundation/American Heart Association guideline for assessment of cardiovascular risk in asymptomatic adults suggesting that asymptomatic subjects with diabetes over 40 years of age should undergo stress imaging if the CAC score is greater than 400.²² However, there is no evidence that this approach can improve prognostic outcome.

Overall, there are many gaps in knowledge on the prognostic value of the different risk assessment tools. Based on the available information, the European Society of Cardiology Guidelines⁹ give the recommendations shown in Table 19.4.1