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-0.60 HbA1c initial (6.1-10.4%)

Abbreviation: NA, not available. Source: From Refs. 48 and 73.

Abbreviation: NA, not available. Source: From Refs. 48 and 73.

treatment. Recently, early combinations of oral antidiabetics with AGIs, to achieve perfect control of the glucotriad with lower dosage of the single drug and fewer side effects, have been discussed. Coadministration of AGIs to patients treated with metformin has an effect complementary to the major action of metformin, reducing hepatic gluconeogenesis and improving peripheral glucose disposal. There is now evidence from long-term studies that the add-on therapy with acarbose (54) or miglitol (55) to metformin results in an average decrease of HbA1c of 0.8% to 0.9% in placebo-controlled long-term trials. The addition of metformin to patients on acarbose was particularly useful in fasting hyperglycemia (56).

Titration of metformin therapy should be started with a bedtime tablet, to optimize the effect on gluconeogenesis after midnight. Long-acting sulfonylureas, such as glibenclamide and glimepiride, are still in widespread use as first-line drugs. Addition of AGIs in subjects insufficiently treated with these insulin secretagogues has a synergistic effect to better control postprandial hyperglycemia. As consistently shown in controlled trials (52,56), an average reduction in HbA1c of 0.8% to 0.9% can be achieved with this combination. Long-term data so far available suggest that add-on therapy with AGIs may delay the chronic progression of beta-cell failure, by protecting them from postprandial glucose spikes (25,26). Information comparing combination treatment of sulfonylurea plus metformin with the combination of either drugs with AGIs is scarce. An additive effect of acarbose on postprandial glucose excursions in type 2 patients treated by prandial insulin secretagogue repaglinide has been shown (57). Less favorable results are available on the combination of AGIs with insulin treatment in type 2 diabetes (58). The only moderately successful option in this trial was the combination of daytime AGI with bedtime injection of a long-acting insulin.


AGIs have been used as adjunct in type 1 diabetic patients whose postprandial glucose excursions cannot be adequately controlled with an insulin regimen (59). They reduce rapid rise in the early postprandial phase, and prevent spikes and troughs in the premeal phase (60). This smoothing effect is beneficial to avoid hypoglycemic episodes and acute hunger attacks before meals, due to delayed gastric emptying. A reduction of 0.5% in HbA1c, by addition of acarbose, was shown in a 24-week placebo-controlled study, but no significant impact on frequency of hypoglycemic episodes was shown. In another study (59), nocturnal hypoglycemia was shown to be prevented when acarbose was given before dinner (60). Insulin dosage remained unchanged in the majority of cases. AGIs may therefore be helpful in brittle diabetes if best efforts to control postprandial glucose spikes by insulin regimen adjustment do not give an adequate control of postprandial glucose excursions. The same applies for excessive premeal hunger and nocturnal hypoglycemia.

Cardiovascular Effects

As already described AGIs have beneficial effects on a broad spectrum of cardiovascular risk factors inclusive low-grade inflammation and blood coagulation (61). In animal experiments increased platelet activation in Zucker rats with IGT was corrected by acarbose (62). Cardiac ischemia injury could be prevented by reducing postprandial hyperglycemia with AGI acarbose (63). In patients with IGT control of postprandial hyperglycemia with acarbose was associated with a significant improvement in flow-mediated vasodilation (64). Impressive cardiovascular preventive effects have been reported from the STOP-NIDDM trial where cardiovascular events were a secondary objective. In this study with IGT patients an overall reduction of cardiovascular events by 49% was observed inclusive 12:1 newly registered myocardial infarctions (65). In a substudy of STOP-NIDDM, which measured intima media thickness (IMT) as surrogate parameter of atherosclerosis progression IMT was reduced by ~50% comparable to people with normal glucose tolerance.

In a meta-analysis with seven controlled studies comprising 2180 patients with type 2 diabetes with a follow-up time of > 1 year treatment with acarbose was associated with a 65% lower incidence of myocardial infarction and 35% less overall cardiovascular events. Thus these data suggest that AGIs, with preliminary evidence so far only for acarbose, have vasoprotective potentials. Two prospective studies with cardiovascular events as primary objective are under way to confirm these beneficial results.

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