Fibrinogen and diabetes mellitus: is it time for intervention trials?

Ceriello, Antonio

doi:10.1007/s001250050741

Cited by 46 publications

(30 citation statements)

References 42 publications

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“…Fibrinogen is considered to be an indicator of inflammation, which is now widely accepted as a contributory factor in the development of atherosclerosis. Alternatively, fibrinogen may be directly involved in atherosclerosis and thrombosis, since hyperfibrinogenaemia leads to enhanced coagulant activity and is associated with increased blood viscosity [33]. Our findings suggest that in diabetic subjects, this relatively inexpensive test may be useful in the identification of high-risk subjects.…”

Section: Discussionmentioning

confidence: 83%

“…In diabetic subjects with plasma fibrinogen levels >4.1 g/l and macroalbuminuria, the risk of cardiovascular mortality is almost four times higher than that in normoalbuminuric subjects with plasma fibrinogen levels <3.0 g/l. Lifestyle modifications [34] and drugs, such as bezafibrate [33], have been found to reduce fibrinogen levels, though not selectively, which prevents assessment of the effect of its reduction in intervention trials.…”

Section: Discussionmentioning

confidence: 99%

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Fibrinogen and AER are major independent predictors of 11-year cardiovascular mortality in type 2 diabetes: the Casale Monferrato Study

et al. 2005

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Aims/hypothesis: Fibrinogen and elevated AER increase cardiovascular mortality, but few data are available in the type 2 diabetic population. We have conducted an 11-year follow-up study of the Casale Monferrato cohort to assess: (1) the long-term predictive role of AER independently of conventional risk factors; (2) the shape of its relationship with cardiovascular mortality; and (3) whether fibrinogen has a predictive effect independent of the increased cardiovascular risk associated with nephropathy. Methods: During the follow-up period (1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001) a population-based cohort of 1,565 patients was regularly examined, and measurements of HbA 1 c were centralised. Multivariate Cox proportional hazards modelling was employed to assess the role of fibrinogen and AER as predictors of all-cause and cardiovascular mortality, independently of baseline variables and individual cumulative average values of HbA 1 c during follow-up. Results: In 10,890.2 person-years of observations, 685 deaths were identified, giving an all-cause mortality rate of 63.4 per 1,000 person-years (95% CI 58.8-68.3). In Cox regression analyses, the strongest predictor of cardiovascular mortality was macroalbuminuria (relative risk 2.18, 95% CI 1.62-2.94), which was mainly associated with a high risk of shortterm mortality. No increased risk was evident until the upper microalbuminuric range of AER values. Plasma fibrinogen was also a major independent predictor, and its role was not modified by AER, or by the exclusion of subjects developing chronic renal failure or diabetic nephropathy during followup. Conclusions/interpretation: The results indicate that: (1) AER is the main independent predictor of 11-year cardiovascular mortality; (2) this effect is mainly evident in the upper range of microalbuminuria and in macroalbuminuria; and (3) fibrinogen has an independent effect on cardiovasvascular mortality, but no synergistic effect with AER, suggesting that both endothelial dysfunction and chronic inflammation are involved in the excess cardiovascular mortality of type 2 diabetic patients.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Fibrinogen and AER are major independent predictors of 11-year cardiovascular mortality in type 2 diabetes: the Casale Monferrato Study

et al. 2005

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“…Several studies have shown that high plasma fibrinogen levels represent an independent marker for cardiovascular morbidity in both non-diabetic [5] and diabetic [6] subjects. Diabetic subjects have higher fibrinogen levels than the general population [7], but the data on subjects with IGT are contradictory [8,9].…”

Section: Introductionmentioning

confidence: 99%

Improved fibrinolysis by an intensive lifestyle intervention in subjects with impaired glucose tolerance. The Finnish Diabetes Prevention Study

et al. 2005

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Aims/hypothesis: The aim of this study was to investigate the effects of lifestyle intervention on the levels of plasminogen activator inhibitor (PAI-1) and fibrinogen in subjects participating in the Finnish Diabetes Prevention Study (DPS). Methods: In five DPS centres, 321 subjects with impaired glucose tolerance (intervention group, n= 163; control group, n=158) had their PAI-1 and fibrinogen levels measured at baseline and at the 1-year follow-up. Additional 3-year follow-up assessments were carried out in a sample of 97 subjects in one of the DPS centres (Turku). The intervention programme included an intensive lifestyle intervention aiming at weight reduction, healthy diet and increased physical activity. Results: During the first intervention year, PAI-1 decreased by 31% in the intervention group but showed no change in the control group (p<0.0001). In the Turku subgroup, the decrease in PAI-1 persisted throughout the 3-year follow-up. Changes in PAI-1 were associated with the number of lifestyle changes made during the first year (p=0.008). Weight reduction was the most important factor explaining the decrease in PAI-1. Changes in fibrinogen levels did not differ between the groups. Conclusions/interpretation: In addition to the previously reported reduction in the risk of type 2 diabetes in DPS participants with impaired glucose tolerance, the intensive dietary and exercise intervention had beneficial long-term effects on fibrinolysis as indicated by the reduced levels of PAI-1. These results suggest that elevated PAI-1 levels in obese subjects with impaired glucose tolerance are mostly reversible by lifestyle changes, especially those geared to weight reduction.

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“…This hypothesis is supported by studies which found an increased ratio between fibrinogen and antithrombin III, due to a decrease in antithrombin III, in the aorta of diabetic rats [32] and the observation of increased levels of markers of thrombin activation in diabetic patients [33]. As recently suggested, this last condition may produce an increase in fibrinogen [34], a well recognized cardiovascular risk factor also in diabetes [35]. The fall in endothelial cell HS contents might also influence local fibrinolysis.…”

Section: Gags Microalbuminuria Diabetic Nephropathy and Cardiovascumentioning

confidence: 66%

“…An increasing number of studies are showing that the administration of GAGs lowers fibrinogen levels, the relevance of which as a cardiovascular risk factor in diabetes has already been stressed [35]. In particular, the fibrinogen reducing activity of sulodexide was demonstrated in hyperlipidaemic subjects [38] and in pilot studies in diabetic patients [25,39].…”

Section: Perspectivesmentioning

confidence: 99%

Glycosaminoglycan therapy for long-term diabetic complications?

1998

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Long-term complications are the most important cause of mortality of diabetic patiens in western countries and diabetic nephropathy has emerged as a major determinant of end-stage renal failure [1]. Moreover, patients with diabetes mellitus have a high probability of developing acute cardiovascular disease, in particular myocardial infarction and cerebrovascular stroke which are the cause of death in nearly 80 % of this population [2]. Although data from the Diabetes Control and Complications Trial establish that hyperglycaemia has a central role in diabetic complications, strict metabolic control can be difficult to achieve. The search for new and ancillary approaches to diabetic complications is therefore warranted and understanding the distal pathway of glucose toxicity assumes clinical and therapeutical significance. Thus, evidence has been provided [3,4] that the alterations of the glycosaminoglycan (GAG) structure and metabolism may be of major importance for the development of diabetic complications. The aim of this article is to stress the hypothesis that GAGs might play an important role in the pathogenesis of late diabetic complications and that their treatment may be useful in several of these complications. GAG structure and functionGAGs are highly glycosylated and sulphated glycoproteins, consisting of dimeric repeated units containing an uronic acid (iduronic or glucuronic acid) and an aminosugar (glucosamine or galattosamine) [5]. These molecules are widely distributed in the body and prominent in extracellular matrices [5].Three major classes of GAGs have been described: a predominant large chondroitin sulphate, a small dermatan sulphate and a polydisperse heparan sulphate (HS) [5]. GAGs are vital in maintaining the structural integrity of the tissue and studies have shown that basement membranes contain HS in the form of a proteoglycan unique to that tissue [5]. HS forms anionic sites in this matrix and are thought to restrict the passage of proteins through the basement membrane [5]. GAG metabolism and diabetes mellitusIn diabetic patients, the increased macromolecular permeability within the glomeruli that precedes the onset of established renal lesions and the increased vascular permeability to albumin seem to be related to structural alterations in the macromolecular pathway, i. e. the extracellular matrix, between the endothelial cells [4]. The nature of this alteration may be related to the loss of negatively charged molecules of extracellular matrix and of the endothelium, among which HS is highly represented. A number of reports indicate that HS metabolism is impaired in diabetes and this is responsible for the extracellular matrix negative charge loss [4]. HS is a strongly negatively charged molecule that is structurally similar to heparin but its base polymer has a lower degree of processing (sulphation, epimerization) (Fig. 1). The HS chain imparts a negative charge to the basement membrane and determines the molecular charge permselectivity of the glomerular basement membrane [4]. Th...

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Fibrinogen and diabetes mellitus: is it time for intervention trials?

Abstract: During the past decade, the potential role of haemostatic factors, particularly fibrinogen, in atherosclerosis and its complications has gained considerable interest.

Cited by 46 publications

References 42 publications

Fibrinogen and AER are major independent predictors of 11-year cardiovascular mortality in type 2 diabetes: the Casale Monferrato Study

Fibrinogen and AER are major independent predictors of 11-year cardiovascular mortality in type 2 diabetes: the Casale Monferrato Study

Improved fibrinolysis by an intensive lifestyle intervention in subjects with impaired glucose tolerance. The Finnish Diabetes Prevention Study

Glycosaminoglycan therapy for long-term diabetic complications?

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