Glycemic Control

Future cohort studies and clinical trials should focus on studying the relation between glycated hemoglobin exposure and the risk of macrovascular complications, particularly among individuals with type 1 diabetes. In addition, more studies are needed that examine the relation between glycated hemoglobin and the risks of stroke and CHF, as there are little data on these outcomes in individuals with type 1 or type 2 diabetes. There are much fewer data on these outcomes than there are on microvascular outcomes. This has important implications for the role of glycemic control in the prevention of the cardiovascular sequelae in individuals with type 1 and type 2 diabetes. In addition, more studies are needed to evaluate the presence of a threshold effect of glycated hemoglobin on the risk of macrovascular complications.

Among the microvascular complications, there are fewer data on the risk relationship between glycated hemoglobin and peripheral neuropathy in individuals with type 2 diabetes compared to those with type 1 diabetes and there are very little data on the relationship of glycated hemoglobin to autonomic neuropathy in either type 1 or type 2 diabetes. More studies are also needed to determine whether there is a threshold effect of glycated hemoglobin on the risk of neuropathy outcomes.

The majority of the studies reviewed for this report were conducted in homogeneous populations that did not report the race of the cohort. Because many of these studies were conducted in Europe, we assume the race to be Caucasian. Future studies should examine the risk relation between glycated hemoglobin and risk of complications in ethnic minority populations (i.e. African-Americans, Hispanic-Americans) who have a disproportionately high incidence of type 2 diabetes. Knowing which complications are more common in which ethnic groups and the role of glycemic control in the development of these complications can help to target areas of interventions for these groups.

There is great heterogeneity in the literature on the reporting of glycated hemoglobin (i.e. HbA1c, HbA1, total GHb) in relation to microvascular and macrovascular complications, and in the biochemical measurement methods used. Future cohort studies and clinical trials should aim to use NGSP certified methods of measuring glycated hemoglobin and report results as percent HbA1c or percent HbA1c equivalents to allow risk comparisons across studies.

Finally, this report focused on the risk relation between glycated hemoglobin and the risk of microvascular and macrovascular outcomes among individuals with diabetes; however, there is emerging evidence suggesting that more subtle forms of glucose dysregulation that predate the onset of diabetes may contribute to vascular disease (de Vegt, et al. 1999 [92182]; Park, et al. 1996 [92183]; Khaw, et al. 2001 [92184]; Singer, et al. 1992 [92185]; Vitelli, et al. 1997 [92186]). Future studies are needed to examine the relation between glycated hemoglobin and risk of complications, particularly macrovascular complications, in individuals without diabetes.

Urine Albumin

There is great need for future research which seeks to define the optimal and most feasible tests for standardized measurement of microalbuminuria. Our review revealed that published definitions of microalbuminuria (as determined by reported lower and upper limits for this designation), were similar but quite varied. Consistent adherence to accepted guidelines for the definition of microalbuminuria will help with ascertaining more precisely the magnitude of risk of renal and cardiovascular risk afforded by microalbuminuria.

Similarly, there is great need for studies which assess the relation between urinary albumin excretion and progression of renal disease in a standard fashion. Particularly important is the standardized ascertainment of renal disease progression, which we found to be summarized in several manners. Use of standardized definitions for progression of renal disease will help with the ascertainment of the magnitude of risk of renal disease progression afforded by the presence of microalbuminuria at baseline.

While our review identifies what appears to be a graded relation between urinary albumin excretion at baseline and renal, cardiovascular outcomes, and death at follow up, it is not known whether levels of detectable urinary albumin excretion which are lower than currently accepted definitions for microalbuminuria might improve prediction of these outcomes. Future research is needed to characterize the nature of the relation between microalbuminuria and these outcomes and to assess whether lower levels of detectable urinary albumin excretion should be used to help predict progression toward important clinical outcomes in persons with types 1 and 2 diabetes. Such research should seek to identify whether a threshold level of urinary albumin excretion exists at which detection of urinary albumin might yield optimal prediction of renal and cardiovascular outcomes, or whether the relation between urinary albumin excretion and development of outcomes is purely linear, indicating that use of more sensitive tests for microalbuminuria early in disease might provide more optimal prediction of future outcomes. Further, it is not known whether current testing is accurate enough to reliably detect low levels of urinary albumin excretion which are associated with poor outcomes at follow up. This is particularly important now that many experts favor spot urine collections for more reliable ascertainment of urinary albumin excretion versus timed urine collections, which are often deemed difficult to collect from patients in a standardized manner. (National Kidney Foundation 2002 [3]), (American Diabetes Association 2002 [2])) Future work is needed to understand which testing strategies most reliably and efficiently predict the risk of future outcomes early in the disease process. Research to determine the optimal test for microalbuminuria will need to take into account how the results might be used to guide clinical decisions and the effects of specific interventions to prevent outcomes associated with microalbuminuria.

Finally, while this review focuses on albuminuria among persons with known diabetes, very little is known about the prognostic significance of albuminuria in persons with lower, albeit still abnormally high, levels of serum glucose (e.g. persons with glucose intolerance). Future work is needed to determine whether urinary albumin excretion in persons with lower levels of serum glucose remains an independent predictor of renal, cardiovascular and mortality outcomes. Improvement in all of the aforementioned areas will likely have important implications for the future development of guidelines for screening practices among persons with types 1 and 2 diabetes.