**5. Alpha-glucosidase inhibitors**

The competitive inhibitors of alpha-glucosidase, such as acarbose, miglitol and voglibose, are administered orally and inhibit alpha-glucosidase, which is an enzyme that converts polysac‐ charides (e.g., amylase, maltase and sucrase) into monosaccharides, thus acting as an antago‐ nist enzyme. Therefore, such inhibitors decrease the intestinal absorption of glucose, particularly postprandial absorption that modulates insulin secretion [70]. The slower rise in postprandial blood glucose concentrations is potentially beneficial in both type 1 and type 2 diabetes. In older patients with type 2 diabetes, acarbose may also increase insulin sensitivity [71]. These inhibitor lower the incidence of cardiovascular events, and they have no systemic absorption [72].

In addition, alpha-glucosidase is inhibited competitively, and its availability for oligosacchar‐ ides derived from the diet is reduced. Thus, there is a reduced formation of monosaccharides and less insulin is required for metabolism, which leads to a reduction of glucose (because it is not absorbed) as well as postprandial insulin-induced increases [73]. These effects reflect a significant decrease in glycated hemoglobin, which was observed in a meta-analysis of 41 trials of alpha-glucosidase inhibitor therapy (primarily acarbose trials) in which beneficial effects were observed (compared with placebo) on HbA1c (-0.77 percentage points), fasting, and postload glucose and postload insulin levels. These benefits are more evident in highly hyperglycemic patients. Hyperglycemia in patients with mild or moderate glycemic control is less common than in those using other oral antidiabetic agents. In such cases, competitive inhibitors of alpha-glucosidase can be used in combination with insulin or any other oral hypoglycemic agents [74-76].

The most frequent side effects of alpha-glucosidase inhibitors are observed at the intestinal level and include flatulence, diarrhea, abdominal pain and elevated transaminases [35, 77-79]

The occurrence of hypoglycemia and an increase in body weight are rare because the agent does not stimulate insulin release or hypersecretion. These effects are only observed when miglitol is combined with other therapies, and its use is contraindicated in cases of inflammatory bowel disease, pregnancy, lactation, and hepatic or renal impairment. In one prospective study of 893 patients treated with acarbose, only 16 to 20% were still taking the drug after one year, and half of the patients had stopped the drug during year two because of the side effects [80].

Recently, a mixed-treatment comparison (MTC) meta-analysis showed that there was no significantincrease inhypoglycemia riskorbodyweightwithalpha-glucosidase inhibitors [81].

#### **5.1. Acarbose**

Mitiglinide is rapidly absorbed and eliminated by the body [66] and metabolized in the kidneys and liver and generates metabolites with little of the secretory activity of insulin. The half-life of mitiglinide is 1.48 h [54], and it has been shown to prevent increases in oxidative stress and inflammation markers after meals in patients with diabetes mellitus because of the suppression of postprandial hyperglycemia promoted by this drug [69]. Because of its characteristics, mitiglinide is currently considered an ideal drug for the treatment of T2DM and is widely used

The competitive inhibitors of alpha-glucosidase, such as acarbose, miglitol and voglibose, are administered orally and inhibit alpha-glucosidase, which is an enzyme that converts polysac‐ charides (e.g., amylase, maltase and sucrase) into monosaccharides, thus acting as an antago‐ nist enzyme. Therefore, such inhibitors decrease the intestinal absorption of glucose, particularly postprandial absorption that modulates insulin secretion [70]. The slower rise in postprandial blood glucose concentrations is potentially beneficial in both type 1 and type 2 diabetes. In older patients with type 2 diabetes, acarbose may also increase insulin sensitivity [71]. These inhibitor lower the incidence of cardiovascular events, and they have no systemic

In addition, alpha-glucosidase is inhibited competitively, and its availability for oligosacchar‐ ides derived from the diet is reduced. Thus, there is a reduced formation of monosaccharides and less insulin is required for metabolism, which leads to a reduction of glucose (because it is not absorbed) as well as postprandial insulin-induced increases [73]. These effects reflect a significant decrease in glycated hemoglobin, which was observed in a meta-analysis of 41 trials of alpha-glucosidase inhibitor therapy (primarily acarbose trials) in which beneficial effects were observed (compared with placebo) on HbA1c (-0.77 percentage points), fasting, and postload glucose and postload insulin levels. These benefits are more evident in highly hyperglycemic patients. Hyperglycemia in patients with mild or moderate glycemic control is less common than in those using other oral antidiabetic agents. In such cases, competitive inhibitors of alpha-glucosidase can be used in combination with insulin or any other oral

The most frequent side effects of alpha-glucosidase inhibitors are observed at the intestinal level and include flatulence, diarrhea, abdominal pain and elevated transaminases [35, 77-79]

The occurrence of hypoglycemia and an increase in body weight are rare because the agent does not stimulate insulin release or hypersecretion. These effects are only observed when miglitol is combined with other therapies, and its use is contraindicated in cases of inflammatory bowel disease, pregnancy, lactation, and hepatic or renal impairment. In one prospective study of 893 patients treated with acarbose, only 16 to 20% were still taking the drug after one year, and half of the patients had stopped the drug during year two

in clinical practice [54].

156 Treatment of Type 2 Diabetes

absorption [72].

hypoglycemic agents [74-76].

because of the side effects [80].

**5. Alpha-glucosidase inhibitors**

Acarbose has a microbial origin and is structurally similar to natural oligosaccharides, with an affinity 104-105 times higher than drugs of the same class of alpha-glucosidases. With regard to its pharmacokinetic aspects, acarbose is poorly absorbed in the intestine (less than 2%). The products produced by bacterial enzymes cleave acarbose, yielding intermediate 4-methyl pyrogallol, which is conjugated and excreted as sulfates or glucuronidate [75].

Several trials have demonstrated the efficacy of acarbose in patients with type 2 diabetes [35, 82-85]. In one trial, 96 patients who were inadequately controlled by diet alone were randomly assigned to receive either glyburide or acarbose, and their HbA1c values and fasting blood glucose concentrations fell by a similar amount; the postprandial blood glucose concentrations, however, remained high in the glyburide group but fell in the acarbose group [83]. A second trial evaluated 354 patients treated with diet alone or diet plus a sulfonylurea, metformin or insulin. Compared with the placebo, the addition of acarbose in each of these groups reduced the mean postprandial blood glucose concentration and lowered the HbA1c values [35]. In general, acarbose has resulted in a greater improvement of HbA1c values than in fasting blood glucose concentrations, which is consistent with its predominant effect on postprandial hyperglycemia [85].

In a randomized, double-blind, placebo-controlled trial [82], satisfactory control of fasting and postprandial glucose occurred with acarbose in T2DM. In a multicenter, randomized, doubleblind, placebo-controlled clinical trial [83] conducted for patients with T2DM who were subjected to a specific diet and use of insulin, the patients showed decreased levels of blood glucose and glycated hemoglobin as well as a reduced daily requirement for insulin.

In a systematic review of the literature, it was concluded that acarbose inhibits postprandial hyperglycemia by lowering insulin levels after a glucose overload. However, it presents no advantages with respect to corporal weight or lipid metabolism, and there are no statistically significant effects on mortality, morbidity and quality of life in patients with T2DM. Compared with the placebo, acarbose reduces HbA1c, fasting plasma glucose and postprandial glucose. Compared with sulfonylureas, it reduces glycemic control and has major adverse effects, particularly gastrointestinal effects [76]. Thus, treatment with acarbose might have a favorable effect on endothelial function in type 2 diabetes patients with ischemic heart disease [86-90]

#### **5.2. Voglibose**

Voglibose also has a microbial origin, and only 3-5% of the drug is absorbed at the intestinal level. It is a potent inhibitor of alpha-glucosidase, but it is weaker than acarbose in the inhibition of sucrase and has little effect on pancreatic alpha-amylase [75]. Furthermore, voglibose decreases the level of postprandial glucose with very low risk of hypoglycemia, but it is associated with frequent gastrointestinal side effects [91].

## **5.3. Miglitol**

Miglitol has a synthetic origin and unique pharmacokinetic properties. It is absorbed rapidly through a transport mechanism in the jejunum that is close to the mechanism of glucose, and it is quantitatively excreted unchanged by the kidneys. Miglitol differs from acarbose because it does not inhibit alpha-amylase but rather inhibits intestinal isomaltase [75].

Based on studies in which miglitol was given alone or in combination with insulin or a sulfonylurea, the efficacy was similar to that of a placebo [92-95]. Miglitol is also effective when combined with metformin [96]. Thus, miglitol can be expected to suppress postprandial glucose more strongly than acarbose [97], so it should reduce the incidence of cardiovascular events [98].
