**6. Sulfonylureas**

Another class of drugs used in the treatment of T2DM are the sulfonylureas chlorpropa‐ mide, acetohexamide, tolazamide and tolbutamide (first generation), glibenclamide, glipizide, gliclazide (second generation) and glimepiride (third generation). This class has long been established in the treatment of diabetes, and it was the first oral glucoselowering medication to be introduced into clinical practice in the 1950s and has since been recognized as a first-line therapy as either a monotherapy or in combination [85, 99]. In the United Kingdom, sulfonylureas have been the second-line choice after metformin [100]. Furthermore, sulfonylureas are the drug of choice for type 2 diabetics who do not benefit exclusively from diet and exercise [101, 102].

Sulfonylureas usually lower blood glucose concentrations by approximately 20% and HbA1c by 1 to 2% [103, 104]. Recently, a systematic review of double-blind randomized control trials found that sulfonylurea monotherapy reduced HbA1c by an average of 1.5% (16 mmol/mol) compared with that of placebo groups [99, 105]. These drugs are most effective in patients whose weight is normal or slightly increased. In contrast, insulin should be used in patients (regardless of age) who are underweight, losing weight, or ketotic despite adequate caloric intake. Some of these latter patients may actually have type 1 diabetes, which can be confirmed by the presence of islet cell antibodies [106, 107].

Sulfonylureas act as insulin secretagogues and exert their main action on islet β cells, stimulating insulin secretion and thereby reducing the plasma glucose concentration. The mechanism of action involves binding of the drug to the subunit SUR1 of the ATPsensitive potassium channels in the plasma membranes of β cells; these channels are then closed, which leads to a change in the membrane voltage, calcium influx and exocytosis of insulin granules [108-111]. The ATP-sensitive potassium channels are also present in other tissues but often contain different types of SUR subunits (e.g., SUR1 in β cells, SUR2A in heart cells, SUR2B in smooth muscle cells). The sensitivity of these different types of channels to sulfonylureas is variable [110].

The net effect of sulfonylureas is an increased responsiveness of β cells to both glucose and non-glucose secretagogues (such as amino acids), resulting in more insulin being released at all blood glucose concentrations. Thus, sulfonylureas are useful only in patients with some β cell function. Sulfonylureas may also have extrapancreatic effects, which includes an increased tissue sensitivity to insulin; however, the clinical importance of these effects is minimal [101, 103].

The basal secretion and insulin secretory response to various stimuli are intensified in the early days of treatment with sulfonylureas. With long-term treatment, circulating insulin levels decline to levels that occurred before treatment; however, despite this reduction, the decreased plasma glucose levels are maintained. The mechanism for this response is still unknown but may be associated with reduced plasma glucose, which allows the circulating insulin to have more pronounced effects on their target tissues, as well as the impairment of insulin secretion by chronic hyperglycemia.

Sulfonylureas are well absorbed after oral administration by the gastrointestinal tract. However, the presence of food and hyperglycemia may reduce their absorption. The peak plasma concentrations occur within 2-4 hours, and the duration of the effect varies. All of these drugs bind tightly to plasma albumin and are involved in interactions with other drugs (e.g., salicylates and sulfonamides) such that there is competition for binding sites. All sulfonylureas are metabolized by the liver, and their active metabolites are mostly excreted in the urine; thus, their action is increased in elderly patients or those with renal or hepatic disease.

The choice of sulfonylurea is primarily dependent upon cost and availability because their efficacy is similar. However, because of the relatively high incidence of hypoglycemia in patients taking glyburide or chlorpropamide, shorter acting drugs should be used, especially in elderly patients [112]. In a patient who is not a candidate for metformin or cannot tolerate metformin as initial monotherapy, a shorter-duration sulfonylurea such as glipizide is suggested.

#### **6.1. First-generation sulfonylureas**

**5.3. Miglitol**

158 Treatment of Type 2 Diabetes

events [98].

**6. Sulfonylureas**

exclusively from diet and exercise [101, 102].

by the presence of islet cell antibodies [106, 107].

channels to sulfonylureas is variable [110].

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

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

Another class of drugs used in the treatment of T2DM are the sulfonylureas chlorpropa‐ mide, acetohexamide, tolazamide and tolbutamide (first generation), glibenclamide, glipizide, gliclazide (second generation) and glimepiride (third generation). This class has long been established in the treatment of diabetes, and it was the first oral glucoselowering medication to be introduced into clinical practice in the 1950s and has since been recognized as a first-line therapy as either a monotherapy or in combination [85, 99]. In the United Kingdom, sulfonylureas have been the second-line choice after metformin [100]. Furthermore, sulfonylureas are the drug of choice for type 2 diabetics who do not benefit

Sulfonylureas usually lower blood glucose concentrations by approximately 20% and HbA1c by 1 to 2% [103, 104]. Recently, a systematic review of double-blind randomized control trials found that sulfonylurea monotherapy reduced HbA1c by an average of 1.5% (16 mmol/mol) compared with that of placebo groups [99, 105]. These drugs are most effective in patients whose weight is normal or slightly increased. In contrast, insulin should be used in patients (regardless of age) who are underweight, losing weight, or ketotic despite adequate caloric intake. Some of these latter patients may actually have type 1 diabetes, which can be confirmed

Sulfonylureas act as insulin secretagogues and exert their main action on islet β cells, stimulating insulin secretion and thereby reducing the plasma glucose concentration. The mechanism of action involves binding of the drug to the subunit SUR1 of the ATPsensitive potassium channels in the plasma membranes of β cells; these channels are then closed, which leads to a change in the membrane voltage, calcium influx and exocytosis of insulin granules [108-111]. The ATP-sensitive potassium channels are also present in other tissues but often contain different types of SUR subunits (e.g., SUR1 in β cells, SUR2A in heart cells, SUR2B in smooth muscle cells). The sensitivity of these different types of

The net effect of sulfonylureas is an increased responsiveness of β cells to both glucose and non-glucose secretagogues (such as amino acids), resulting in more insulin being released

it does not inhibit alpha-amylase but rather inhibits intestinal isomaltase [75].

The first-generation sulfonylureas vary considerably in their half-lives and the extent of their metabolism. The acetohexamide half-life is short, but the drug is reduced to an active com‐ pound whose half-life is similar to that of tolazamide and tolbutamide (4 to 7 hours). If required, these drugs can be divided into daily doses. Chlorpropamide has a long half-life (24 to 48 hours) [113]

The action of chlorpropamide, acetohexamide, tolazamide and tolbutamide is long lasting, and there is substantial excretion in the urine. Therefore, these drugs can cause severe hypoglycemia in elderly patients who have experienced a progressive decline in glomerular filtration. These drugs cause flushing after alcohol consumption and exert similar effects to that of the diuretic hormone on the distal nephron, producing hyponatremia and water intoxication [113].

#### **6.2. Second-generation sulfonylureas**

The second-generation sulfonylureas (glibenclamide, glipizide and gliclazide) are more potent, but their hypoglycemic effects are not much improved, and they fail to control blood glucose, which is commonly observed with tolbutamide. All of these drugs contain the sulfonylurea molecule, but different substitutions result in differences in pharmacokinetics and duration of action. Glibenclamide should be avoided in the elderly and patients with mild renal impairment because of the risk of hypoglycemia because several of its metabolites are excreted in the urine and are moderately active [113].

The sulfonylureas cross the placenta and stimulate insulin release by fetal β cells, causing severe hypoglycemia at birth. Consequently, their use is contraindicated during pregnancy, and gestational diabetes is treated by diets supplemented with insulin when required [113].

In general, sulfonylureas are well tolerated. The observed side effects are hematological, including hypoglycemia, leukopenia, agranulocytosis, thrombocytopenia, and hemolytic anemia, gastrointestinal, including nausea, vomiting, and cholestatic jaundice (rare), and allergic reactions. Sulfonylureas may also cause weight gain, and their binding to plasma proteins can be potentiated by other drugs used concomitantly, which may cause hypoglyce‐ mia. This condition is the most problematic adverse event and may be prolonged, which can have severe consequences in elderly patients, patients treated with multiple drugs and those with impaired renal function. Moreover, sulfonylureas stimulate appetite and can occasionally cause allergic rashes and bone marrow injury [113].

Sulfonylureas have structural characteristics that allow them to be given in much lower doses than the first-generation sulfonylureas. Nevertheless, the different sulfonylureas are equally effective in lowering blood glucose concentrations. There are, however, differences in absorp‐ tion, metabolism and effective dose [114], which is partly caused by the formation of active metabolites [115]. These drugs also cause greater suppression of overnight hepatic glucose output, thereby lowering fasting blood glucose concentrations. These benefits may be coun‐ terbalanced by an increased risk of hypoglycemia [112].

### **6.3. Glimepiride**

The US Food and Drug Administration (FDA) approved glimepiride in 1995 for the treatment of T2DM alone and in combination with metformin or insulin. It has prolonged action and lasts over 24 hours. Glimepiride has advantages with respect to its clinical and pharmacological profile, and it has also been shown to cause a low incidence of severe hypoglycemia compared to other representatives of its class [116, 117].

Regarding hypoglycemia, the findings observed in certain studies differ. In a systematic review and meta-analysis [118], glimepiride was found to cause increased hypoglycemia compared to other sulfonylureas and even more than other secretagogues. In other studies, the longacting sulfonylureas, such as chlorpropamide and glibenclamide, were shown to have an increased likelihood of causing hypoglycemia [112, 119]. In a UK survey, the rate of diagnosis of hypoglycemia was higher for glibenclamide compared to other representatives of the same class [120].

With regard to weight gain, in the UK Prospective Diabetes Study [34], the mean weight change after 10 years of follow up ranged from a minimum of 1.7 kg as a result of glibenclamide use to a maximum 2.6 kg with chlorpropamide use. Glimepiride was found to be neutral with respect to body weight, whereas other authors observed weight reduction [121, 122].

Sulfonylureas have different cross reactivities with cardiovascular ATP-dependent potassium channels. The closing of these channels by ischemic preconditioning can lead to cardiovascular mortality [123].

Several compounds increase the hypoglycemic effect of sulfonylureas, and several of these interactions are potentially important from a clinical standpoint. Non-steroidal anti-inflam‐ matory agents (including azapropazone, phenylbutazone and salicylates), coumarin, certain uricosuric agents (e.g., sulfinpyrazone), alcohol, monoamine oxidase inhibitors, certain antibacterials (including sulfonamides, chloramphenicol, and trimethoprim) and certain antifungal agents (including miconazole and possibly fluconazole) produce severe hypogly‐ cemia when administered with sulfonylureas. The probable basis for these interactions is the competition for metabolizing enzymes, but interference in plasma protein binding or excretion may also exert some effect. The agents that reduce the action of sulfonylureas include diuretics (thiazides and loop diuretics) and corticosteroids [113].
