**4. Meglitinides**

Insulin secretagogue agents act by stimulating endogenous insulin secretion via pancreatic β cells, and they include classes of sulfonylureas and meglitinides used in the treatment of T2DM. Meglitinide analogues consist of a relatively new class of oral hypoglycemic, and their clinical use in adult patients with T2DM was approved in 2000. These drugs were developed to promote the rapid increase in insulin secretion from β cells and therefore affect postprandial glucose levels. The mechanism of action of meglitinides is quite similar to that of sulfonylureas; however, meglitinide analogues have the advantage of a reduced risk of hypoglycemia because of their shorter half-life. Meglitinides are secretagogues of short-acting insulin, and they act primarily on postprandial hyperglycemia. Because of their characteristics, the meglitinides are preferable to insulin secretagogues such as sulfonylureas, especially in elderly patients [50-53]. Representatives of the meglitinide class include repaglinide, nateglinide and mitiglinide derived from benzoic acid and the amino acid D-phenylalanine, whose action is initiated approximately 30 minutes after administration because of rapid absorption. The advantages of these drugs are that they have no interactions with other drugs and are not contraindicated in pregnancy, during lactation or in the presence of other pathologies [52, 54].

### **4.1. Repaglinide**

Repaglinide was the first meglitinide analogue approved for use in adults with T2DM; it is the S(+) enantiomer of 2-ethoxy-4-(2-((3-methyl-1-(2-(1-piperidinyl) phenyl)-butyl) amino)-2 oxoethyl) benzoic acid and has a molecular weight of 452.6 Da [50]. Repaglinide stimulates insulin release in a rapid action style, thereby promoting a decrease in blood glucose levels. Because of the rapid action, repaglinide is one of the most commonly used antidiabetic drugs in patients who have high postprandial glycemia [55-57].

The mechanism of action by which the meglitinide analogue stimulates insulin secretion comes from blocking the ATP-dependent potassium channels (KATP) of pancreatic β-cells, which results in membrane depolarization and calcium influx through voltage-dependent calcium channels. This mechanism culminates in an increased influx of calcium into the β cells, which stimulates exocytosis of insulin-containing granules [50, 58].

With regard to pharmacokinetics, repaglinide, whose absorption is independent of concurrent food intake, is rapidly absorbed following oral administration with 63% bioavailability. The maximum concentration is reached approximately 45 minutes after administration (Tmax ~ 45 min), and the half-life of plasma elimination is relatively short (approximately 1 hour); therefore, the drug is eliminated from the body within 6 hours. The drug is metabolized in the liver via cytochrome P450 (CYP3A4), with approximately 90% of the metabolites excreted in the bile and only 8% secreted in the urine. Altogether, 2% of the drug is eliminated in an unchanged form, and because the metabolites are not biologically active, there is no effect on the blood glucose. There is a rapid elimination of repaglinide through the biliary tract and no apparent accumulation in the plasma after multiple doses [50, 59-61].

Hepatic metabolism via cytochrome P450 means that concentrations of repaglinide may be increased by concomitant use of substances that inhibit the CYP3A4 enzyme, such as certain antibiotics and steroids; however, the concomitant intake of CYP3A4-inducing agents, such as barbiturates and carbamazepine, can lead to an increased metabolism of the meglitinide analogue, thus reducing its concentrations [50, 59-61].

### **4.2. Nateglinide**

Another insulin secretagogue agent that also belongs to the class of meglitinides corresponds to nateglinide. Similar to repaglinide, nateglinide ((N-[(trans-4-isopropylcyclohexyl)-carbon‐ yl]-D-phenylalanine A-4166) phenylalanine derivative) acts through the inhibition of KATP and causes the depolarization of the plasma membrane of β cells. This culminates in the influx of calcium ions into the cell and subsequent secretion of insulin [50, 62].

Despite the similar mechanism of action of these two meglitinide analogues, in vitro studies have demonstrated that nateglinide inhibits KATP channels faster and with a shorter duration of action than repaglinide. In addition, the half-life of repaglinide at the receptor of action is approximately 3 minutes, whereas the half-life of nateglinide is 2 seconds. Therefore, the time required for nateglinide to dissociate from the receptor is 90 times faster than that of repagli‐ nide, so nateglinide has a very fast and ephemeral effect on insulin release. In vitro experiments have demonstrated that the action of nateglinide is enhanced in the presence of glucose compared to that glyburide and repaglinide, so that the response of the KATP channel with nateglinide is significantly less in periods of euglycemia than in periods of hyperglycemia. Thus, the minimum total insulin exposure generated by this meglitinide analogue protects the body against hypoglycemic attacks and allows the patient greater flexibility in relation to the intervals between meals. Pharmacodynamic studies have demonstrated that when nateglinide is administered before meals in type 2 diabetic patients, a secretion of early stage insulin occurs that causes a significant dose-dependent reduction in postprandial hyperglycemia [50, 59, 63].

Regarding its pharmacokinetic properties, nateglinide is absorbed rapidly, with peak plasma concentrations reached within 1 hour. This drug is rapidly eliminated from the plasma, with a half-life of 1.8 hour. Because of the short half-life, nateglinide is not accumulated at any administration dose. The drug is metabolized mainly via the cytochrome P450 (CYP2C9 and CYP3A4) and is eliminated via the kidneys, with 10% eliminated unchanged in the urine and 20% eliminated unchanged in the bile [50, 59, 64].

Both repaglinide and nateglinide may be used as a monotherapy or in combination with other agents, such as metformin and glitazones. The meglitinides have similar abilities in reducing fasting blood glucose, postprandial levels of plasma glucose and early insulin secretion, and they improve the insulin sensitivity and function of pancreatic β cells. However, repaglinide was more effective in reducing the glycosylated hemoglobin HbA1c and is also preferred to nateglinide in patients with chronic renal disease because nateglinide has active metabolites that are eliminated by the kidneys [52, 63].

### **4.3. Mitiglinide**

of their shorter half-life. Meglitinides are secretagogues of short-acting insulin, and they act primarily on postprandial hyperglycemia. Because of their characteristics, the meglitinides are preferable to insulin secretagogues such as sulfonylureas, especially in elderly patients [50-53]. Representatives of the meglitinide class include repaglinide, nateglinide and mitiglinide derived from benzoic acid and the amino acid D-phenylalanine, whose action is initiated approximately 30 minutes after administration because of rapid absorption. The advantages of these drugs are that they have no interactions with other drugs and are not contraindicated

Repaglinide was the first meglitinide analogue approved for use in adults with T2DM; it is the S(+) enantiomer of 2-ethoxy-4-(2-((3-methyl-1-(2-(1-piperidinyl) phenyl)-butyl) amino)-2 oxoethyl) benzoic acid and has a molecular weight of 452.6 Da [50]. Repaglinide stimulates insulin release in a rapid action style, thereby promoting a decrease in blood glucose levels. Because of the rapid action, repaglinide is one of the most commonly used antidiabetic drugs

The mechanism of action by which the meglitinide analogue stimulates insulin secretion comes from blocking the ATP-dependent potassium channels (KATP) of pancreatic β-cells, which results in membrane depolarization and calcium influx through voltage-dependent calcium channels. This mechanism culminates in an increased influx of calcium into the β cells, which

With regard to pharmacokinetics, repaglinide, whose absorption is independent of concurrent food intake, is rapidly absorbed following oral administration with 63% bioavailability. The maximum concentration is reached approximately 45 minutes after administration (Tmax ~ 45 min), and the half-life of plasma elimination is relatively short (approximately 1 hour); therefore, the drug is eliminated from the body within 6 hours. The drug is metabolized in the liver via cytochrome P450 (CYP3A4), with approximately 90% of the metabolites excreted in the bile and only 8% secreted in the urine. Altogether, 2% of the drug is eliminated in an unchanged form, and because the metabolites are not biologically active, there is no effect on the blood glucose. There is a rapid elimination of repaglinide through the biliary tract and no apparent

Hepatic metabolism via cytochrome P450 means that concentrations of repaglinide may be increased by concomitant use of substances that inhibit the CYP3A4 enzyme, such as certain antibiotics and steroids; however, the concomitant intake of CYP3A4-inducing agents, such as barbiturates and carbamazepine, can lead to an increased metabolism of the meglitinide

Another insulin secretagogue agent that also belongs to the class of meglitinides corresponds to nateglinide. Similar to repaglinide, nateglinide ((N-[(trans-4-isopropylcyclohexyl)-carbon‐ yl]-D-phenylalanine A-4166) phenylalanine derivative) acts through the inhibition of KATP

in pregnancy, during lactation or in the presence of other pathologies [52, 54].

in patients who have high postprandial glycemia [55-57].

stimulates exocytosis of insulin-containing granules [50, 58].

accumulation in the plasma after multiple doses [50, 59-61].

analogue, thus reducing its concentrations [50, 59-61].

**4.1. Repaglinide**

154 Treatment of Type 2 Diabetes

**4.2. Nateglinide**

Mitiglinide ((-)-2(S)-benzyl-4-(cis-perhydroisoindol-2-yl) butyric acid) is the third meglitinide analogue and corresponds to a benzylsuccinic acid derivative. It presents a similar mechanism of action to the other two meglitinide analogs, and its selective action on KATP channels of pancreatic β cells promotes insulin secretion with few adverse effects on the cardiovascular system [58, 59, 65]. Similar to nateglinide, mitiglinide is often used in early stage diabetes mellitus because it induces a rapid and short duration of postprandial insulin secretion, mimicking the normal insulin secretion and glucose metabolism of healthy individuals and thereby promoting a reduced risk of hypoglycemia [66, 67]. A randomized clinical trial demonstrated a similar efficacy between mitiglinide and nateglinide when used as a mono‐ therapy in patients treated with diet and exercise in the three months leading up to trial [68].

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 in clinical practice [54].
