Epidemiological studies of fructosamine in relation to diabetes, cardiovascular disease and mortality

BACKGROUND: Diabetes is associated with an increased risk of micro- and macrovascular disease and mortality. Two main methods for diagnosis and control of type 2 diabetes are the measurements of blood glucose and glycosylated hemoglobin (HbA1c). These methods have some limitations where other techniques may complement. Hence, there is a need for other methods to be scientifically investigated and documented. Fructosamine is a biochemical marker of the amount of glycated proteins in the extracellular compartment of the blood and can serve as a complement to established blood markers of glycemic exposure. This thesis aims to evaluate fructosamine in relation to serum glucose and HbA1c and as a risk factor for type 2 diabetes (T2D), coronary heart disease (CHD) and death.

METHODS AND RESULTS: For all studies in this thesis, subpopulations of the AMORIS cohort (n=812,073) were used. Study I. In 871 subjects with a documented diagnosis of type 2 diabetes (T2D), the mean fasting fructosamine was 2.7 mmol/L and the mean value for fasting glucose and HbA1c respectively was 9.6 mmol/L and 7.2%. The linear correlation of fructosamine and HbA1c was high (r=0.75). Across three repeated measurements within one year, fructosamine and HbA1c followed the changes of fasting glucose over time. At a fructosamine level of 2.5 mmol/L, the sensitivity for the diagnostic criteria for diabetes was 61% and the specificity 97%. Study II. In 338,443 subjects, we observed an increased incidence of myocardial infarction or death from coronary heart disease (CHD) in subjects with higher levels of fructosamine. A fructosamine level of ≥ 2.7 mmol/L was associated with an increased hazard compared to a reference group of normoglycemic individuals (Adjusted HR=2.1 (2.0-2.2). Comparable risk increases of CHD events and all-cause mortality were seen in groups of hyperglycemia defined by HbA1c. Study III. We investigated the risk of all-cause mortality based on fasting fructosamine levels over a study period of 27 years and included 215,011 subjects without diabetes at baseline. We observed a U-shaped mortality in relation to levels of fructosamine. The lowest decile of fructosamine was associated with an increased mortality (HR=1.20; 95% CI: 1.16-1.24) vs. a reference group (decile 2 to 9). The HR was decreased when we adjusted for haptoglobin. Analyses of cause-specific mortality showed increased risk ranging over several causes of death including an adjusted 42% increased mortality in lung cancer/COPD at low fructosamine levels. Study IV. We followed 296,436 subjects for diagnoses of T2D over a total study period of 27 years. We described trajectories of several metabolic risk factors. More than 20 years before a diagnosis of T2D, BMI and fasting glucose as well as triglycerides were increased compared to a matched control population. The average 20-year risk of T2D was 8.1% in this population. This risk was considerably increased with higher values of these factors.

CONCLUSIONS: The results from this thesis suggest that fructosamine levels are strongly associated with serum glucose and HbA1c and may be used as a complementary marker of glucose metabolism. High levels of fructosamine are associated with an increased incidence of myocardial infarction and death after adjustment for major cardiovascular risk factors. Several metabolic factors including BMI, fasting glucose, triglycerides and inflammatory blood markers, were increased in cases compared to matched controls more than two decades before a diagnosis of T2D. This suggests an early progression of the pathophysiology of T2D.

List of scientific papers

I. Malmström H, Walldius G, Grill V, Jungner I, Gudbjörnsdottir S, Hammar N. Fructosamine is a useful indicator of hyperglycaemia and glucose control in clinical and epidemiological studies - cross-sectional and longitudinal experience from the AMORIS cohort. PLOS ONE. 2014;9(10):e111463.
https://doi.org/10.1371/journal.pone.0111463

II. Malmström H, Walldius G, Grill V, Jungner I, Hammar N. Fructosamine is a risk factor for myocardial infarction and all-cause mortality - Longitudinal experience from the AMORIS cohort. Nutrition, Metabolism and Cardiovascular Diseases. (2015), Vol. 25, Issue 10, p943–950.
https://doi.org/10.1016/j.numecd.2015.07.002

III. Malmström H, Wändell PE, Holzmann MJ, Ärnlöv J, Jungner I, Hammar N, Walldius G, Carlsson AC. Low fructosamine and mortality – a long term follow-up of 215,011 non-diabetic subjects in the Swedish AMORIS study. Nutrition, Metabolism and Cardiovascular Diseases. (2016), Vol. 26, Issue 12, p1120–1128.
https://doi.org/10.1016/j.numecd.2016.08.006

IV. Malmström H, Walldius G, Carlsson S, Grill V, Jungner I, Gudbjörnsdottir S, Kosiborod M, Hammar N. Elevations of metabolic risk factors 20 years or more before diagnosis of type 2 diabetes – experience from the AMORIS study. [Manuscript]