AGIs are the safest oral antidiabetics, but are associated with a rather high frequency of gastrointestinal side effects because they inhibit digestion of carbohydrates. With > 1 million patients having taken acarbose for > 1 year, no serious adverse event has been reported. As antihyperglycemic agents they carry no risk of causing hypoglycemia. When given in combination with oral insulin secretagogues, the frequency of hypoglycemic episodes was reduced (52) and there was no increase in hypoglycemias observed in insulin-treated patients (54). A minor weight loss is observed in monotherapy with AGIs, and the weight gain caused by sulfonylureas is reduced if AGIs are added to this treatment regimen (52).
Gastrointestinal side effects frequently noted by patients are meteorism, flatulence, diarrhea (Table 4) or simple "abdominal discomfort (7)." Gastrointestinal complaints exhibit strong interindividual and regional differences, depending on nutrition habits, diet compliance, and advice from medical staff. During the first weeks of treatment, and within the first 3 months, the enzyme content of the lower part of the small intestine increases and most of the carbohydrates reaching this part of the bowel can be digested here. This is indicated by a decrease in gastrointestinal side effects to < 10% in long-term follow-up studies (26). No malabsorption of carbohydrates is observed, together with fermentative digestion of carbohydrates in the colon. Thus, weight remains nearly unchanged, with a maximal weight loss of 0.7 to 0.9 kg in long-term follow-up studies (26,40). Gastrointestinal side effects diminish after 4 to 6 weeks (Fig. 4) (48), as has been consistently shown in controlled studies. In the UKPDS follow-up of a dosage of 100 mg of acarbose three times a day, 49% (diet alone), 43% (with sulfonylureas), and 39% (with metformin combinations) still took the drug at 3 years, compared with 70%, 60%, and 58%, respectively taking the placebo (40). On the other hand, in a large 2-year follow-up clinical trial with 1907 patients, 7.5% reported gastrointestinal side effects and the dropout rate resulting from gastrointestinal adverse events was only 2.5% (66). In a follow-up after 5 years, the incidence of acarbose-associated side effects was 4.7% (26).
The good compliance rate in motivated subjects and physicians was confirmed in the STOP-NIDDM study, a primary prevention trial in 1429 subjects with IGT. In the placebo arm, 2.5% of patients stopped taking the "drug" during 3.4 years follow-up because of adverse gastrointestinal events, versus 13.0% in the acarbose arm (25). In combination treatment, no increase in gastrointestinal side effects and drug interaction was observed if combined with sulfonylurea or insulin (52,54). The incidence of gastrointestinal side effects with metformin plus acarbose (54) and metformin plus miglitol (55) was not significantly different from that observed for monotherapy with either AGIs or metformin, although the rate of discontinuations was higher for the combination with metformin—as observed in the UKPDS. Flatulence (30% vs. 12%) and diarrhea (16% vs. 8%) were the major reasons for noncompliance with acarbose treatment in the UKPDS (40). In a face-to-face comparison, miglitol intake was
TABLE 4 Gastrointestinal and Other Side Effects, Extrapolation from Controlled and Surveillance Studies
Spasm and abdominal discomfort 3-4
Constipation < 1
Nausea and vomiting ^5
associated with a lower frequency of gastrointestinal symptoms (49). On the other hand, elderly patients, particularly women with constipation, may benefit from the soft stools and report fewer problems with constipation.
AGIs in general have no liver toxic effects. In all controlled studies the incidence of transaminase elevations was at the level of the placebo group (47-49). In a safety review from the United States and Japan, 6/100,000 transient transaminase elevations were reported with AGIs (67). Two cases of severe hepatotoxic reactions during treatment with acarbose have been described recently. Both patients fully recovered and the reaction was interpreted as idiosyncratic (68). Acarbose degradation products may accumulate in cases of renal insufficiency, but no clinical complications have so far been reported. The upper limit for the use of acarbose where there is renal dysfunction was set for a creatinine level of > 3.5 mg/ dL. Hematological studies with AGIs have not shown any changes in blood cells and bleedings. No effect on urine excretion of minerals or blood concentration levels of sodium and potassium has been observed (15).
A slight, clinically nonrelevant, reduction was seen in beta-acetyldigoxin and propranolol after coadministration of miglitol in healthy volunteers (15). Comedication with acarbose resulted in subtherapeutic plasma level of digitoxin in two cases of cardiac failure (69). AGIs do not interfere with the absorption of sulfonylureas, ACE inhibitors, beta-blockers or warfarin. The clinical bioavailability of metformin was marginally reduced by comedication with acarbose (70). In clinical practice this was not relevant for any AGIs.
AGIs can be used as first-line drugs in newly diagnosed type 2 diabetes insufficiently treated with diet and exercise alone (34,73), as well as in combination with all oral antidiabetics and insulin if monotherapy with these drugs fails to achieve the targets for HbA1c and postprandial blood glucose. As first-line drugs, AGIs are particularly useful in newly diagnosed type 2 diabetes with an excessive postprandial hyperglycemia, because of their unique mode of action in controlling the release of glucose from complex carbohydrates and disaccharides. In these cases, they lower postprandial blood glucose level peaks by > 50 mg/ dL, resulting in an average reduction of HbA1c by 0.7% to 1.2%. Table 5 summarizes subgroups of type 2 diabetes that may preferentially benefit from the use of AGIs as first-line treatment. Among them are elderly obese women. High percentages of who exhibit postchallenge hyperglycemia as the dominant abnormality of glucose homeostasis. Since AGIs are very safe and have very few contraindications and drug interactions, they also may be considered in polymorbid patients with beginning renal and hepatic dysfunction. Their weak weight-reducing effect could be an advantage over oral insulin secretagogues for some patients. As antihyperglycemic agents, AGIs have no risk of causing hypoglycemia, they are therefore a rational alternative for patients who experience hypoglycemic episodes with insulin secretagogues. In newly diagnosed type 2 diabetes with high-fasting plasma-glucose and high postprandial glucose, an early combination of either metformin or long-acting insulin secretagogues, such as glibenclamide and glimepiride, should be considered. This approach has the advantage of increasing efficacy and reducing side effects if low doses of either drug is used for the combination.
Many patients on monotherapy with either metformin or sulfonylureas do not reach HbA1c levels < 6.5% to 7%. A further reduction of HbA1c of 0.5% to 1% can be achieved by addon therapy with AGIs (26,36). There is increasing evidence (71,72) that postprandial hyperglycemic excursions add to the risk of progression of type 2 diabetes and its cardiovascular complications. In this context, AGIs are also useful adjuncts if postprandial glucose levels cannot be controlled sufficiently with metformin, sulfonylureas, or insulin. A meta-analysis (36) revealed an additional effect of 0.7% of acarbose given after metformin pretreatment, and 0.85% when added to sulfonylurea treatment. Extrapolation of controlled clinical trials with AGIs as add-on therapy showed an additional reduction in postprandial glucose of > 40 mg/dL. The additional reduction in fasting blood glucose is > 20 mg/dL. Little is known so far about combination therapy with thiazolidinediones and "prandial oral insulin secretagogues," such as nateglinide and repaglinide. Scarce information exists on the clinical use of AGIs in combination with bedtime administered long-acting insulin injections in type 2 diabetes. With AGIs as add-on therapy, a further reduction of HbA1c of 0.4% to 0.54% was obtained. This combination may be useful in avoiding weight gain and to achieve better control of postprandial hyperglycemia.
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