6.2.1 Acute coronary syndrome and disturbances of glucose metabolism
In Study I, approximately 66% of the patients were identified with diabetes or prediabetes following an OGTT and in Study II, an OGTT classified 83% of the study population as having dysglycaemia, while a single HbA1c classified 62%. The results are in line with previously published studies (5, 135, 136).
A similar outcome could be found in study III, where patients with no previous history of diabetes underwent a CABG operation and where approximately 66% of the patients were diagnosed with newly discovered disturbances of glucose metabolism. Previous studies have reported comparable results in patients undergoing CABG (137, 138).
By screening patients with ACS for disturbances of glucose metabolism, hyperglycaemia can be detected, and pharmacological treatment and lifestyle modifications can be initiated earlier.
Patients with diabetes and prediabetes in combination with CVD have a poorer outcome
compared to patients with NGT (65, 66). Several studies have tried to evaluate different risk factor modifications and pharmaceutical treatments to minimize the poorer outcome (87-89).
So far, treatment with metformin has been shown to improve the outcome in patients with prediabetes (91). Recently it was shown that SGLT-2 inhibitors reduce the risk of mortality and cardiovascular events in patients with T2DM and is now a recommended treatment in T2DM patients with high cardiovascular risk (92, 93).
6.2.2 Diagnostic methods to identify disturbances of glucose metabolism in patients with ACS
Disturbances of glucose metabolism can be diagnosed by measuring FPG, OGTT, HbA1c or random blood glucose according to the definition by ADA (37) and the WHO (9). These methods identify different patients with hyperglycaemia and the best method to identify patients for a higher risk of CVD is not decided.
Methods used in study I-IV
In study I-II, HbA1c and/or OGTT were used to identify patients with disturbances of glucose metabolism who were followed for mortality and cardiovascular events. Patients with previously unknown diabetes underwent an OGTT at 4-5 days after their ACS to explore their glycaemic status. HbA1c was measured at the time as their ACS and if this wasn’t done, an HbA1c within 3 months of the ACS was accepted. In study III, OGTT was performed to identify disturbances of glucose metabolism within 3 months of CABG operation. In study IV, random plasma glucose was measured in the ED. However, an elevated, random blood glucose measurement cannot be used as diagnostic criteria for diabetes without knowing if the patients had any symptoms. But it is an indicator for disturbances of the glucose metabolism and potential underlying diabetes or prediabetes.
Which diagnostic method is preferred, HbA1c vs OGTT?
ESC and the European Diabetes Society recommend OGTT in patients with CVD when HbA1c or fasting blood glucose are still in doubt (13). According to several studies, an OGTT in patients with ACS seems to identify more patients with disturbances of glucose metabolism than FPG or HbA1c alone (110, 111, 139-142). However, it has not been clarified if the screening by OGTT in patients with ACS will affect outcomes regarding mortality and longevity or whether it is sufficient to screen these patients with only Hb1Ac. One study showed that known or newly diagnosed T2DM in patients with CVD was associated with a higher risk for coronary artery disease. However, IGT could not be identified as a risk marker for mortality during the follow-up time of one year (8). Another study demonstrated that OGTT was a better prognostic test regarding cardiovascular events in patients with CAD during the follow-up time of 2 years (143). A third study showed that a pathological OGTT is an indicator for a poorer prognosis. This study did not compare OGTT with HbA1c, nor did it investigate the outcome in cardiovascular patients specifically (144). It has also been shown that 2h-PG, but not FPG is a predictor for all-cause mortality or reinfarction, but without a comparison to HbA1c (145). These studies (8, 143-145) could also verify that patients with diabetes have a poorer outcome.
Study II revealed that HbA1c is a better predictor for future cardiovascular events than OGTT.
841 patients and compared HbA1c to OGTT specifically. In study II it was also shown that patients categorized as being prediabetic by HbA1c had a higher incidence of MI, hospitalization for heart failure, ischaemic stroke and mortality than patients diagnosed with diabetes. A similar result could not be found in patients diagnosed with hyperglycaemia by an OGTT.
One reason for the poorer outcome in patients with prediabetes diagnosed by HbA1c could be that HbA1c cannot diagnose impaired glucose tolerance, which only OGTT can do. The poorer outcome in patients diagnosed with prediabetes could also be explained by patients with newly discovered diabetes receiving better information about their hyperglycaemia and a better follow-up. With confirmed diabetes, patients are recommended lifestyle changes, medication and are referred to outpatient clinics for a follow-up, thus improving secondary prevention as compared to patients with prediabetes. The superiority of HbA1c could also be explained by an unbalance in the choice of methods. HbA1c was not routinely introduced in Sweden until 2014 even though it was recommended by ADA in 2009 (104) and by the WHO in 2011 (9).
In study II the inclusion time was 2006-2013 and the physicians were more accustomed to using OGTT as diagnostic criteria. Therefore, HbA1c could have been used less frequently which might have affected the outcome.
Screening with a random plasma glucose
In study IV a random blood glucose value ≥ 11.1 mmol/l was used to define hyperglycaemia.
Since the correct terminology for diabetes diagnosed by random blood glucose, according to the definition of diabetes according to ADA, i.e. a value ≥11.1 mmol/l and symptoms of diabetes were not met, the word hyperglycaemia was used instead (107).
Study IV showed that a random plasma glucose value > 11.1 mmol/L detected in the ED, identified patients with a significantly increased risk of both short-term and long-term mortality as well as a higher risk of CVD. The elevated risk started at blood glucose ≥ 7.8 mmol/L with more than a 2-fold risk of all-cause mortality and a higher risk of MI, stroke and heart failure in comparison to patients with normal glucose tolerance.
Previous smaller studies have found that elevated random blood glucose in patients admitted to the hospital for an acute illness is associated with a poorer outcome in regards to 28-30 - day mortality, readmission rates, length of hospital stay and a higher rate of in-hospital mortality (113, 116, 121). In study IV all patients without known diabetes, who were attending the ED, were included no matter the diagnosis for visiting the ED. Patients with elevated random blood glucose displayed a comparable risk of higher mortality and cardiovascular events as the previous studies in terms of short-term follow-up (113, 116, 121). In addition to previous studies, Study IV demonstrated a higher risk of mortality and cardiovascular events, to the best of our knowledge which has not been shown before. In comparison to all other studies, study IV has the largest study population of similar studies (622 018 patients) and the longest follow-up time (3.9 years) and have included a general population regardless of their index diagnosis which makes this study quite unique.
A Random plasma glucose is often overlooked when it comes to diabetes diagnosis and OGTT, FPG and HbA1c are more favoured. Study IV shows the importance of random plasma glucose measurement which is a quick and easy method and does not involve fasting, glucose intake or a more advanced analysis and it can be carried out as soon as the patient enters the hospital.
6.2.3 Prediabetes and the risk of mortality and cardiovascular disease
The importance of prediabetes in patients with CVD has been debated (8, 10, 146). Recent research has shown an association between prediabetes and an increased risk of mortality and CVD (147).
In line with recent research (148), study I could show that patients with prediabetes had a significantly higher risk of heart failure and reinfarction compared to patients with newly discovered diabetes diagnosed by an OGTT. Ten years after patients with ACS were diagnosed with prediabetes, they had a significantly higher rate of heart failure and reinfarction as compared to patients with newly diagnosed diabetes 10 years earlier. Study II displayed similar results in patients diagnosed with prediabetes by an HbA1c. Similarly, these patients had a higher rate of MI, heart failure, ischaemic stroke and mortality than patients diagnosed with diabetes; this can be explained by inferior secondary prevention. As of today, the recommended treatment option for patients with prediabetes is only lifestyle changes according to ESC guidelines (13) without a professional follow-up.
In contrast to study I-II, study IV, where a random plasma glucose test was used as a definition of hyperglycaemia, the patients in study IV with newly discovered diabetes had the highest risk of mortality and cardiovascular events. This difference may be explained by the different methods used to define hyperglycaemia, a general study population and not only patients with CVD were included and that the true definition of diabetes diagnosed by using a random plasma glucose test according to ADA is not met in study IV (107).
6.2.4 Prospects of treating prediabetes
Several studies have attempted to establish the best regime to treat ACS patients that have disturbances of the glucose metabolism to improve their outcome. Today we know that patients with heart failure benefit from SGLT2 inhibitors no matter what their glucose status is and that SGLT2 inhibitors are a recommended treatment by the ESC for patients with heart failure (149, 150). Possibly, patients with prediabetes and CVD in study I-II had a reduced ejection fraction and could have benefitted from treatment with SGLT2 inhibitors.
Attempts to conduct more intense treatment with insulin in patients with ACS and diabetes was associated with higher long-term mortality after coronary angiography (151). It was also associated with a higher rate of MI and stroke in patients with ACS whereas treatment with metformin was more protective (152). An explanation could be that insulin causes a higher BMI, higher blood pressure and a higher level of triglycerides which are all risk factors for CVD.
In 2019 the ESC presented new guidelines for diabetes, prediabetes and CVD. The ESC pointed out gaps in evidence regarding the adherence and effects of lifestyle measures and clinical outcomes in patients with CVD and prediabetes. Furthermore, the new guidelines stated that the optimal strategy for multifactorial treatment in primary and secondary intervention has not been established. (153) Study I-II and IV support a gap in evidence by showing a higher risk of mortality and cardiovascular events in patients with prediabetes, diabetes and hyperglycaemia. They highlight the question as to whether patients with prediabetes and ASC would benefit from earlier and/or more intense glycaemic treatment or better risk factor modifications to prevent a poorer outcome after a cardiovascular event.
6.2.5 CABG and disturbances of glucose metabolism
Several studies have investigated the importance of unknown disturbances of glucose metabolism before CABG and the short and/or long-term prognosis. Thus far the results of these studies are inconclusive. One study including 244 patients, showed that the risk of early mortality after CABG in patients with known diabetes was similar to the mortality in patients with prediabetes and newly discovered diabetes (154). Another study indicated a strong association between the severity of disturbed glucose metabolism and cardiovascular events after CABG with the follow-up of only 6 months to 3 years (155). Holzmann et al demonstrated that patients with T2DM had a similar risk and that patients with T1DM had a two-fold risk of mortality (156).
Study III, which included 497 patients and a follow-up time of 10 years, showed that patients with prediabetes or newly discovered diabetes prior to CABG had similar long-term mortality compared to patients with normal glucose tolerance (85). These results are in line with the result from Holzman et al (156).
So far, research has shown that patients with ACS and diabetes have higher mortality and a poorer outcome compared to patients with normal glucose tolerance (3). However, this is contradicted by the result of study III which displayed no significant difference in mortality after CABG in patients with newly discovered hyperglycaemia vs normal glucose levels. This may be explained by the fact that CABG involves open-chest surgery, which is a major life event with more pain, discomfort, a longer rehabilitation period in comparison to PCI. By undergoing cardiac surgery patients might become more motivated to follow up treatment and compliance with recommendations when it comes to medication and lifestyle changes.
Furthermore, the diagnosis of diabetes and prediabetes before surgery may have had an impact on behaviour.
6.3 METHODOLOGICAL CONSIDERATIONS