routinely for all patients with diabetes. On the contrary, perhaps the clinical approach should vary depending on a more nuanced assessment of an individual patient’s risk, with more intensive intervention reserved for those at higher personal risk.
Variability in Risk Associated with Diabetes
Despite diabetes being a strong independent risk factor for cardiovascular disease, the degree of risk inferred by the presence of diabetes is not the same in all groups. Interestingly, the relative risk associated with diabetes is greater in groups with lower absolute cardiovascular risk, including among women, younger age groups, non-smokers and those with lower-than-average blood pressure [4]. A meta-analysis of 64 cohorts, including more than 850,000 individuals found that the effect of diabetes on the risk of incident coronary heart disease was 44% greater in women than in men, though the absolute risk remains higher in men [25]. This difference in the risk posed by diabetes may in part relate to the inequitable management of cardiometabolic disease in women. There is evidence that women are less likely than men to be treated sufficiently to meet target risk factor levels [26]. Nevertheless, in more recent studies, where treatment was felt to be equitable, there is still evidence of a disparity in the relative risk of cardiovascular disease inferred by diabetes [25]. At the time of diagnosis of diabetes, women tend to have greater adiposity and less favourable levels of other cardiovascular risk factors. It is thought that women may tend to have a greater deterioration in their overall cardiometabolic health prior to having sufficient hyperglycaemia to be diagnosed as having diabetes. Along with treatment inequalities, these physiological differences may also contribute to the observed differences in relative risk of cardiovascular disease between men and women with diabetes. It may also be that the relative effect of diabetes (or any other single cardiovascular risk factor) is greater in low-risk groups than high-risk groups (as noted above), and that this simply reflects that many risk factors have overlapping mechanistic pathways. Thus, adding the first or second risk factor to low-risk groups will have more of an effect than adding the fourth or fifth risk factor to high-risk groups.
Predicting Risk in Individuals
Increasingly, international guidelines are recommending treatment decisions be based on an individual patient’s overall cardiovascular risk rather than solely targeting particular risk factor levels [27, 28]. There is also a growing focus on tailoring treatment targets, including glycaemic targets, for individuals according to a personalised risk-benefit assessment. Therefore, clinicians need to be equipped with strategies to interpret and apply epidemiological evidence in their provision of care to individual patients. Such strategies should be rigorously investigated in interventional trials. Determining an individual’s absolute risk of cardiovascular disease and knowing at what threshold of risk to intervene and with what therapy are not straightforward. Hence, existing guidelines have varying suggested approaches.
Intensive pharmacological risk factor modification for patients with established cardiovascular disease (i.e., “secondary prevention”) is an accepted standard of care with a robust evidence base. Clinical risk assessment and management for patients with diabetes but without known cardiovascular disease is more complicated, with guidelines suggesting various potential approaches. Essentially, the goal is to translate available evidence into day-to-day clinical care, to maximise benefits to individuals, while minimising treatment-related harm and economic costs. Individual patients and healthcare settings will have unique factors that influence treatment decisions that may not always align with published guidelines. Nevertheless, guidelines provide a valuable framework for standardisation of care.
Figure 6 provides a conceptual overview of different approaches to considering cardiovascular risk in patients with diabetes. One potential approach in primary prevention is to treat specific risk factors in all patients when they are outside of the normal range. For example, to commence an antihypertensive agent if the systolic blood pressure remains above 140 mm Hg or a statin if the LDL level is 3.5 mmol/L (135 mg/dL) or higher.
Fig. 6. Various approaches used to assess the need for pharmacological therapy to modify cardiovascular risk factors in patients with diabetes.
An alternate approach is to determine initiation of pharmacotherapy on the basis of an individual’s overall cardiovascular risk. Some guidelines essentially recommend treating all patients with diabetes as being at high risk. For example, the 2013 European Society of Cardiology and European Association for the Study of Diabetes guidelines consider all patients with type 2 diabetes at “high risk” and recommend statin therapy with a target LDL of <2.5 mmol/L (97 mg/dL) [27]. Patients with type 2 diabetes and an additional risk factor are recommended statin therapy with a target LDL of less than 1.8 mmol/L (80 mg/dL). Similarly, the 2018 American Diabetes Association guidelines recommend moderate intensity statin therapy to all patients with diabetes aged 40 years and above [28].
A more nuanced risk assessment option is to calculate an estimated absolute cardiovascular risk for a patient using a validated risk score and then initiate treatment in patients who score above a specified threshold. For example, the 2014 National Institute for Health and Care Excellence guidelines recommend commencement of statin therapy in patients with type 2 diabetes and a 10% or greater 10-year risk of developing cardiovascular disease on the QRISK2 assessment tool [29].
Cardiovascular Disease Risk Scores
As early as the late 1970s, the first widely used cardiovascular risk score was developed, which is the Framingham Risk Score [30]. Over recent decades, more than 45 additional scores applicable to patients with diabetes have been published [31]. Some have been developed in populations with diabetes and others in general populations but include diabetes status as a variable. Most cardiovascular risk scores that have been assessed in diabetes populations include similar parameters such as age, sex, smoking status, systolic blood pressure, lipids and, for those scores that are not diabetes-specific, diabetes status. Some scores include additional factors such as HbA1c; weight or body mass index; chronic kidney disease stage, estimated glomerular filtration rate (eGFR), or presence of albuminuria; presence of retinopathy; ethnicity; family history; and markers of social deprivation. Risk scores are now being incorporated into diabetes guidelines and increasingly used in clinical practice, mostly being available as charts or as web-based calculators. The statistical models underlying these scores use a patient’s personal risk factor values and the average cardiovascular disease risk of the population to predict the individual’s risk of a cardiovascular event within a specified time frame, often 10-years. Establishing a clinical risk score should involve 3 key stages [31]:
1. development and internal validation
2. external validation
3. model impact studies
Risk
