Diabetes and glucose abnormalities in cardiovascular disease : studies on prevalence and prognosis in myocardial infarction and atrial fibrillation

Sammanfattning: Background: Cardiovascular disease and diabetes are both common chronic conditions associated with a high disease and economic burden globally. Diabetes increases the risk of cardiovascular disease and leads to a worse prognosis after a cardiovascular event. In order to prevent complications, the early detection and treatment of risk factors is important. Many patients with established cardiovascular disease have undiagnosed glucose abnormalities, both diabetes and prediabetes, which can negatively influence the prognosis. The proposed criteria for diagnosing prediabetes from the American Diabetes Association (ADA) and the World Health Organisation (WHO) differ, with the ADA adopting lower cut-offs for fasting plasma glucose and HbA1c for the diagnosis of prediabetes. There is a need for improved knowledge of the impact of the early detection of glucose abnormalities in high-risk populations with cardiovascular disease and of the prognosis and complication burden in patients with established diabetes and atrial fibrillation. In this thesis the term glucose abnormalities includes both newly diagnosed diabetes and prediabetes. Aims: The overall aim of this thesis was to study the prognostic significance of glucose abnormalities and diabetes in patients with cardiovascular disease. The specific aims were: 1. To investigate the baseline characteristics and prognostic differences between patients with and without diabetes in a contemporary cohort with an ST-elevation myocardial infarction (Study I) 2. To investigate the association of glucose abnormalitites and long-term prognosis after acute myocardial infarction and to compare the predictive importance of the Oral Glucose Tolerance Test (OGTT, i.e. fasting plasma glucose and two-hour postload plasma glucose) and HbA1c (Study II) 3. To investigate the prevalence of diabetes and its prognostic importance for cardiovascular events and mortality in a nationwide cohort with atrial fibrillation (Study III) 4. To investigate, in a nationwide cohort with atrial fibrillation, the prognostic differences between type 1 and type 2 diabetes, using patients without diabetes as a reference group, and the impact of severe hypoglycaemia on mortality, cardiovascular events and dementia. (Study IV) 5. To investigate the prevalence of undetected glucose abnormalities in a selected cohort with atrial fibrillation and compare the differences in prevalence when using the criteria for diagnosis of diabetes and prediabetes from the American Diabetes Association compared to the criteria from the World Health Organisation (WHO) (Study V). Methods and results: In Study I, participants in the register-based, randomised Thrombus Aspiration in ST-segment Elevation Myocardial Infarction in Scandinavia (TASTE) trial (n=7,244) were included between 2010- 2013, of whom 13.9% had diabetes. The main finding was that diabetes mellitus was associated with an increase in one-year mortality after STEMI (HR 1.57; 95% CI 1.23-2.00). This risk was higher in insulin-treated patients, who also displayed a higher risk of recurrent myocardial infarction. This risk was not explained by an increased thrombus burden in the coronary vessels or by a more extensive coronary artery disease. In Study II, 841 patients with an acute myocardial infarction at Danderyd University Hospital, Stockholm, Sweden, without known diabetes, were screened for glucose abnormalities before discharge in 2006 to 2013 and were followed for mortality and future cardiovascular events (mean follow-up 4.8 years). Values for both the OGTT and HbA1c were available. When using the ADA cut-offs for diagnosis of diabetes and prediabetes, 754 of 841 patients (89.7%) had previously unknown glucose abnormalities. The OGTT and HbA1c identified different at-risk populations. The combination of fasting plasma glucose and HbA1c identified 626 of the 754 (83%) patients with previously unknown glucose abnormalities. In our population, only prediabetes identified by HbA1c according to ADA criteria (39-47 mmol/mol) was associated with an increased risk of the combined event of first of mortality, myocardial infarction, ischaemic stroke or hospitalisation for heart failure (HR 1.31; 95% CI 1.05–1.63) compared with patients with normoglycaemia. However, individuals with glucose abnormalities according to OGTT results were referred for follow-up and risk factor optimisation, which could have affected our results. In Study III, all patients hospitalised with atrial fibrillation in Sweden (n=326,832) were included between 2006-2012, of whom 17.7% had diabetes. Information regarding comorbidities, pharmacological therapies and outcomes was collected from national health data registers. The combination of atrial fibrillation and diabetes was associated, after adjustments, with a higher risk of heart failure (HR 1.19; 95% CI 1.15-1.24), myocardial infarction (HR 1.25; 95% CI 1.18-1.33), ischaemic stroke (HR 1.11; 95% CI 1.05-1.17) and all-cause mortality (HR 1.28; 95% CI 1.25-1.31) compared with those without diabetes. The combination of diabetes and atrial fibrillation doubled the standardised mortality ratio (2.06; 95% CI 2.00-2.12) compared with the general population, while the standardised mortality ratio in those with atrial fibrillation but without diabetes was only slightly increased (1.33; 95% CI 1.31-1.35). In Study IV, using data from Swedish national registers, we included 309,611 patients with atrial fibrillation between 2013-2014, of whom 19.5% had diabetes (n=60,294). Of patients with diabetes, 96.3% were classified as diabetes mellitus type 2 and 3.7% had type 1 diabetes. Diabetes, regardless of type, was associated with increased risks of premature death, heart failure, myocardial infarction, stroke and dementia, compared with patients without diabetes. Patients with type 1 diabetes compared with those with type 2 diabetes had a somewhat higher risk of all-cause mortality (Type 1 vs. Type 2 respectively; HR 1.87; 95% CI 1.73-2.02 vs. HR 1.51; 95% CI 1.47-1.55) and myocardial infarction (HR 2.49; 95% CI 2.17-2.85 vs. HR 1.70; 95% CI 1.59-1.81), when both groups were compared with the group without diabetes (HR=1). A history of severe hypoglycaemia was associated with an increased risk of mortality and dementia, although this did not reach statistical significance in type 1 diabetes. In an interim analysis (Study V) of the ongoing EDGA-AF study, which started inclusion in 2019, 119 patients with AF were screened for glucose abnormalities four weeks after cardioversion. Using the ADA criteria for a diagnosis of diabetes and prediabetes, 92 (77.3%) patients were identified with newly detected glucose abnormalities by either the OGTT or the HbA1c, most of them with prediabetes. The WHO criteria identified 54 patients (45.3%) with glucose abnormalities. Individuals with undiagnosed glucose abnormalities identified by the OGTT had features of the metabolic syndrome, such as a larger waist circumference. Conclusion: This thesis confirms that established diabetes and newly detected glucose abnormalities are common in patients with a myocardial infarction but also in patients with atrial fibrillation and are associated with an increased risk of mortality and cardiovascular events, especially in insulintreated individuals with diabetes. Among patients with atrial fibrillation, type 1 diabetes confers risks of adverse events similar to those in type 2 diabetes and an even higher risk than type 2 diabetes for the events of premature death and myocardial infarction. The available screening methods for glucose abnormalities, fasting plasma glucose, two-hour postload plasma glucose and HbA1c, identify different at-risk populations. In our studies, the combination of fasting plasma glucose and HbA1c identified more than 80% of patients with undiagnosed glucose abnormalities. The best screening method to predict cardiovascular prognosis needs to be further explored.