Treating Postprandial Hyperglycemia Does Not Delay Progression of Early Type 2 D

Factors other than postprandial hyperglycemia may be greater determinants of progression of diabetes. Postprandial hyperglycemia characterizes early type 2 diabetes. We investigated whether ameliorating postprandial hyperglycemia with acarbose would prevent or delay progression of diabetes, defined as progression to frank fasting hyperglycemia, in subjects with early diabetes (fasting plasma glucose [FPG] <140 mg/dl and 2-h plasma glucose 200 mg/dl).
Two hundred nineteen subjects with early diabetes were randomly assigned to 100 mg acarbose t.i.d. or identical placebo and followed for 5 years or until they reached the primary outcome (two consecutive quarterly FPG measurements of 140 mg/dl). Secondary outcomes included measures of glycemia (meal tolerance tests, HbA1c, annual oral glucose tolerance tests [OGTTs]), measures of insulin resistance (homeostasis model assessment [HOMA] of insulin resistance and insulin sensitivity index from hyperglycemic clamps), and secondary measures of ß-cell function (HOMA-ß, early- and late-phase insulin secretion, and proinsulin-to-insulin ratio).

The results showed that Acarbose significantly reduced postprandial hyperglycemia. However, there was no difference in the cumulative rate of frank fasting hyperglycemia (29% with acarbose and 34% with placebo; P = 0.65 for survival analysis). There were no significant differences between groups in OGTT values, measures of insulin resistance, or secondary measures of ß-cell function. In a post hoc analysis of subjects with initial FPG <126 mg/dl, acarbose reduced the rate of development of FPG 126 mg/dl (27 vs. 50%; P = 0.04).

It is possible that the dietary suggestions provided to both groups were potent and overwhelmed any effects of acarbose on ß-cell function. However, postprandial glucose was significantly lower in the acarbose group, and acarbose lowered A1C slightly but significantly over the first several years, suggesting that the drug itself had a superior effect on glycemia.
Another possible explanation is that our subjects, like those in the UKPDS and in clinical practice, were "too far gone" along the path of ß-cell failure for the intervention to affect progression. This would require us to believe that early diabetes is quite different from IGT, a condition in which controlling postprandial hyperglycemia seems to preserve ß-cell function or at least delay onset of diabetes. Our post hoc analysis of subjects who entered with FPG <126 mg/dl (presumably with even earlier diabetes) suggested that the rate of progression to FPG 126 mg/dl may have been reduced by acarbose. This would support the argument that once FPG exceeds 126 mg/dl, it may be too late to significantly affect ß-cell function.

It is also possible that EDIP truly disproved our hypothesis and that postprandial hyperglycemia is not the primary driver of ß-cell failure. Other factors such as genetics, lifestyle factors, or postprandial free fatty acids (lipotoxicity) may be more important. Our results lend further support to efforts to prevent diabetes. It is unlikely that diabetes could be easily diagnosed in stages earlier than that of our subjects, a group in whom treating postprandial hyperglycemia did not seem to delay ß-cell failure. Subjects at high risk for diabetes should be offered interventions known to delay the onset of early diabetes, such as acarbose, metformin, or intensive lifestyle interventions

From the results it was concluded that ameliorating postprandial hyperglycemia did not appear to delay progression of early type 2 diabetes. Factors other than postprandial hyperglycemia may be greater determinants of progression of diabetes. Alternatively, once FPG exceeds 126 mg/dl, ß-cell failure may no longer be remediable.
Diabetes Care 29:2095-2101, 2006

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