Summary: HbA1c in Cardiovascular Disease
January 2018 - Source, lecture held by prof Naveed Sattar, University of Glasgow, United Kingdom
HbA1c is a measure used in diagnosis and management of diabetes. HbA1c is glycated hemoglobin, which refers to hemoglobin bound to glucose. Measurement of HbA1c levels reflects the average glucose level of the last 2-3 months, since red blood cells survive for 8 to 12 weeks before they are renewed.
HbA1c to diagnose diabetes
To diagnose diabetes, three measurements can be performed: fasting plasma glucose (FPG), HbA1c and oral glucose tolerance test (OGTT) (6). In the past decade, new HbA1c assays with better quality control and international standardization (to intra-assay coefficients of variation of typically less than 5%) have become available.
An HbA1c assay is performed by collecting blood in EDTA, which remains stable during transportation for up to seven days. Day-to-day intra-individual variation in HbA1c is very low, making it a robust test. HbA1c can be measured anytime during the day, and fasting is not necessary. Moreover, unlike glucose testing, HbA1c is accurate after a recent event and can be done for example in the coronary care unit, when the patient is typically not fasted. As a consequence, some authorities now recommend measuring HbA1c to diagnose diabetes (7, 8). Some concerns remain regarding the sensitivity of HbA1c tests in predicting DM, especially when HbA1c is <6.5% (9).
Diagnostic criteria now use a cut-off value of HbA1c of ≥6.5% (≥48 mmol/mol) for diagnosis of diabetes. If a patient meets this criterion, the HbA1c measurement should be repeated to confirm the finding, unless the patient has clear symptoms and FPG >11.1 mmol/L. FPG is also recommended as a first line diagnostic test. If HbA1c testing is not possible, for instance if the patient has hemoglobinopathy or abnormal red blood cell turnover (e.g in advanced renal disease or severe anemia), FPG is recommended.
Patients are considered at high-risk for DM if their HbA1c is between 6.0% and 6.4% in the UK, and between 5.7% and 6.4% in the USA. At these values, patients should be informed about it and they should be given advice or guided to make lifestyle changes to prevent the onset of diabetes, irrespective of whether they have existing CVD.
HbA1c and micro and macrovascular complications
In a curve displaying the prevalence of retinopathy at varying levels of FPG, the point of inflection above which retinopathy starts to develop, is at 6.5-7% (10), while the cut-off point in the diagnostic criteria is 7%. In a similar curve for HbA1c levels, the inflection point is around 6.5%, which concurs with the diagnostic criteria. 2-Hour glucose levels do not show a clear inflection point (5). These data show that HbA1c is a good demarcator for the risk of developing retinopathy, which defines the diagnostic criteria for diabetes, as it reflects end-organ damage. A post-hoc analysis of the ADVANCE study has shown that microvascular event risk begins above HbA1c of 6.5% (11), again concurring with diagnostic criteria.
For macrovascular event risk, inflection of the curve was seen at around 7%, and the risk increased at higher HbA1c levels (11). In patients without known diabetes, post-load glucose is considered the best method to predict CHD. A meta-analysis has, however, shown that per 1 mmol/L higher FPG the risk ratio is 1.05, as for 1 mmol/L higher post-load glucose, while the risk ratio was 1.20 for 1% higher HbA1c (12).
The evidence presented above has been implemented in the guidelines of the European Society of Cardiology (ESC) on diabetes, pre-diabetes, and CVD (6). These guidelines recommend that the diagnosis of diabetes is based on HbA1c and FPG combined or on an OGTT if still in doubt (class I, level B recommendation). In most clinical scenarios, HbA1c is likely to be tested, as patients have not been fasting.
Effects of lowering HbA1c
Once a patient has been diagnosed with T2DM, HbA1c can be used as a measure of diabetes control. Lowering HbA1c decreases the risk of microvascular disease such as kidney and eye disease, and nerve disease, although this takes several years, and a modest effect is seen on macrovascular risk.
Newer drugs that lower HbA1c can lower CVD beyond the effects of glycemia reduction. Mechanisms that may be involved include hemodynamic effects, effects on the vasculature, weight reduction and BP reduction. An added advantage may be that patients stop taking drugs that carry a risk of causing hypoglycemia, thereby contributing to avoiding its occurrence.
The modest CV effect that can be achieved with lowering HbA1c, becomes clear when comparing observations in a study of 200 T2DM patients treated for 5 years that lowering HbA1c by 0.9% with glucose-lowering drugs prevented about 2.9 events, while lowering LDL-c by 1 mmol/L prevented about 8.2 events, and each 4 mmHg lower systolic BP prevented 12.5 CV events (5). Thus, statins and BP-lowering medication have a greater effect on macrovascular CV events than does glucose-lowering per se.
Glycemic targets and CVD risk
An HbA1c target of <7.0% or <53 mmol/mol is associated with a decreased frequency and severity of microvascular disease. For macrovascular disease, a specific target is less compelling, but hyperglycemia is positively associated with increased CVD risk. HbA1c of <7.0% or <53 mmol/mol may be targeted in the majority of patients, acknowledging the individual needs of the patients. When a patient has just been diagnosed and is free from significant CVD and has a long life expectancy and no other concerns, one should aim for 6.0-6.5% or 42-48 mmol/mol. By contrast, in an elderly patient with long-standing and/or complicated disease, relaxing the target to 7.5-8.0% or 58-64 mmol/mol may be wiser, given that the benefits in terms of life expectancy are less relevant.
All targets should be achieved without inducing hypoglycemia or other adverse effects (6). Glycemic control should be individualized in each patient, considering its effects on quality of life, adverse effects on polypharmacy and the possible inconvenience of intensified control. In each patient, the best individual compromise between glucose control and vascular risk should be searched for. Patients should be informed on the risks and benefits of intensified treatment.
In addition to hypoglycemia, which increases the risk of severe CVD events (read more in chapter 5), one should be aware of chronic kidney disease. This is common in people with diabetes, and some medications require dose adjustment or termination.