Dysglycaemia, dyslipidaemia and hypertension: risk factors primarily focused on the disease or risk estimates primarily focused on the patient?
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A diagnosis of diabetes independently increases the future risk of serious cardiovascular outcomes by up to threefold in women and twofold in men . This relationship has been demonstrated in scores of prospective studies [2, 3, 4, 5, 6] and in administrative databases. For example, in one database comprising all residents of the province of Ontario, Canada, the 6 year incidence of death in middle-aged and older men with a history of diabetes did not differ from that of middle-aged and older men with a recent myocardial infarction . Reasons for this strong relationship remain unclear and many hypotheses continue to be considered. However, as diabetes is defined on the basis of an elevated glucose level, much attention has focused on glucose or glycation of various molecules. Indeed, many prospective studies have noted a strong relationship between elevated glucose or HbA1c levels and incident cardiovascular outcomes that is independent of history of diabetes. Indeed, this relationship extends well below the glycaemic thresholds used to diagnose diabetes  and into the normal range for the general population [2, 9, 10, 11]. Thus, elevated fasting glucose, post-load glucose or HbA1c levels (i.e. dysglycaemia) are related to cardiovascular outcomes  in a manner that is similar to the relationship between dyslipidaemia or elevated blood pressure and cardiovascular outcomes [13, 14, 15]. Whether this means that cardiovascular outcomes are caused by an elevated glucose level, insufficient metabolic action of insulin (which allows the glucose to rise) or other associated biological abnormalities cannot be discerned from these data and, indeed, remains unclear .
Knowing that a particular risk factor such as HbA1c, lipid level or blood pressure is related to future cardiovascular outcomes clearly expands our understanding of cardiovascular disease and leads to future research hypotheses. A risk factor for a disease (or outcome) is therefore primarily focused on the disease, and the associated relative risk or relative hazard can be viewed as a ‘disease-centred’ metric. This metric provides little information on the risk of cardiovascular outcomes in a particular patient with this risk factor. Such information is best conveyed by the absolute risk or incidence of the outcome, which can be viewed as a ‘patient-centred’ metric. Moreover, patients typically have many risk factors for cardiovascular outcomes, which together confer a very different personal risk of disease than could be predicted on the basis of any one risk factor alone. Recognition of this fact has led to the development of various risk scores [17, 18, 19]. These patient-centred scores integrate age and other easily measured risk factors to generate a personalised estimate of absolute risk or incidence for an individual patient. These scores clearly only incorporate a fraction of the more than 100 statistically independent risk factors that have been identified for cardiovascular outcomes . However, they show that for clinical care, knowledge of several risk factors provides more information about a particular patient’s chance of suffering a cardiovascular event than knowledge of the level of any one risk factor alone.
The difference between disease-centred risk factors and patient-centred risk estimates is beautifully illustrated in the most recent analysis of data from the EPIC-Norfolk prospective study by Chamnan et al. in this issue of Diabetologia . The authors studied 10,144 people (of whom 44% were men and 4.8% had diabetes) with a mean age of 57 years who were free of cardiovascular disease. Participants had baseline measurements of HbA1c, blood pressure, cholesterol, HDL-cholesterol and other risk factors, and were followed for a mean of 10 years with prospective ascertainment of cardiovascular outcomes. Consistent with many other studies, the authors clearly demonstrated that the risk of incident cardiovascular events progressively rose with age, smoking, age-adjusted HbA1c levels ≥5.5%, systolic blood pressure levels ≥130 mmHg, total cholesterol:HDL ratios ≥4 and progressively lower HDL-cholesterol levels below 1.5 mmol/l. These data once again confirm that these are important risk factors for cardiovascular outcomes.
The authors then took this information to the (virtual) bedside to show how information about several risk factors is more relevant to an individual patient’s risk than information on one isolated risk factor. They compared the clinical usefulness of information based on the HbA1c alone (classified as either <5.5%, 5.5–5.9% or 6.0–6.4%) as a single risk factor with the usefulness of cumulative information based on age, sex, smoking, lipids and blood pressure. They found that people in the highest HbA1c group who were females and non-smokers, and in the lowest category of age, lipids and blood pressure, had a lower incidence of cardiovascular outcomes than people in the lowest HbA1c group who were male, smokers, and in the highest category of age, lipids and blood pressure. They also found that once these factors were taken into account, knowledge of the HbA1c level provided little additional information on the incidence of cardiovascular outcomes. Exactly the same approach was then applied to: (1) the cholesterol:HDL ratio; and (2) systolic blood pressure. Thus people in the highest cholesterol:HDL group who were females, non-smokers, and in the lowest category of age, systolic blood pressure and HbA1c had a lower incidence of cardiovascular outcomes than people in the lowest cholesterol:HDL group who were males, smokers, and in the highest category of age, systolic blood pressure and HbA1c. Similarly, people in the highest systolic blood pressure group who were females, non-smokers, and in the lowest category of age, cholesterol:HDL and HbA1c had a lower incidence of cardiovascular outcomes than people in the lowest systolic blood pressure group who were males, smokers, and in the highest category of age, cholesterol:HDL and HbA1c.
These analyses show that the HbA1c level behaves like other established risk factors for cardiovascular disease and that the best estimate of the future incidence of a cardiovascular outcome requires the integration of many risk factors and should not be based on the measurement of any one risk factor alone, be it dysglycaemia, dyslipidaemia, hypertension, inflammation, abdominal obesity or others.
What conclusions can be drawn from this and other papers on this topic? First, there is a clear difference between identification and characterisation of a risk factor, and using one or more risk factors to estimate the incidence or absolute risk of a disease. The information provided by risk factors (and relative risks or hazards) is focused on the disease and can thus best inform further research and insights into pathophysiology. Risk estimates (and absolute risks or risk scores), on the other hand, provide information that is focused on the patient and can therefore best inform clinical management of that patient. Second, patients do not present with one abnormality and should not be characterised or treated on the basis of any one abnormality. Rather, the totality of available information, based on setting, history, physical examination and clinical investigations, should be integrated to generate an estimate of individual risk. This estimate can then help to identify the most appropriate management. Third, dysglycaemia, dyslipidaemia and hypertension all behave similarly as risk factors for cardiovascular outcomes and provide much more information on the incidence of cardiovascular outcomes when they are combined than when considered separately. Indeed, it is very likely that most other identified independent cardiovascular risk factors would behave in a similar way. Fourth, assessment of a patient’s risk of suffering an outcome based on knowledge of several risk factors can certainly identify people with the greatest need for risk-reduction therapies, but provides little information regarding the best interventions to mitigate that risk. These interventions can only be reliably identified from randomised clinical trials of thousands of participants, which generally require several years of follow-up. For cardiovascular outcomes in people with diabetes, such trials have already demonstrated the efficacy of blood pressure lowering , ACE inhibitors , statins [24, 25] and bypass surgery , but have generated mixed results on glucose lowering [27, 28].
In summary, (1) detecting risk factors for disease, (2) using several risk factors to estimate a particular patient’s risk, (3) identifying the menu of appropriate therapies from those proven in reliable clinical trials, and then (4) integrating this information into the patient’s overall clinical presentation to determine optimal management will clearly optimise the clinician’s ability to truly provide the best evidence-based care.
HC Gerstein holds the Population Health Research Institute Chair in Diabetes, which is endowed by a grant from Sanofi-Aventis to McMaster University.
Duality of interest
The author declares that there is no duality of interest associated with this manuscript.
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