**3. Thiazolidinediones**

The thiazolidinediones (TZDs) are popularly known as glitazones, and representatives include the drug troglitazone (withdrawn from the market because of liver toxicity), rosiglitazone and pioglitazone (second generation TZDs).

TZDs are widely used in the treatment of type 2 diabetes and increase and sensitize insulin action in the liver, muscles and adipocytes, thereby decreasing peripheral resistance. They activate intracellular nuclear receptors (PPAR-gamma-peroxisome proliferator-activated receptor) that regulate the expression of genes encoding glucose and lipid metabolism and are responsible for glucose uptake mediated by insulin in the peripheral tissues and differentiation of preadipocytes into adipocytes. Additionally, these drugs inhibit peripheral lipolysis in adipocytes and assist in reducing the levels of free fatty acids and visceral adipose tissue, resulting in improved glycemic and metabolic parameters. These drugs show good results in terms of long-term glycemic control compared with other consecrated therapeutic options, such as sulfonylureas and metformin [41-43].

TZDs decrease glucose levels by approximately 20% but do not increase insulin secretion. They inhibit the oxidation of long-chain fatty acids in the liver, decreasing gluconeogenesis and the availability of free fatty acids. Although these drugs reduce triglycerides by 15 to 20% and increase HDL-cholesterol by 5 to 10%, the total cholesterol and LDL-cholesterol levels may not change or may increase from 10 to 15% [33]. When compared to metformin, troglitazone has a greater potentiating effect of peripheral insulin action and little effect on the reduction of hepatic glucose production. The association of thiazolidinedione with metformin is interesting because it produces additive effects [39].

TZDs also increase the expression of glucose transporters (GLUT4) and lipoprotein lipase and reduce the expression of leptin and tumor necrosis factor (TNF-alpha). These results make it one of the most widely prescribed classes for the treatment of T2DM [33, 44].

Side effects occur in less than 5% of patients, and they consist of upper respiratory tract infections, headaches, elevated transaminase levels, edema, weight gain and anemia. Hypo‐ glycemia can occur when its use is concomitant with secretagogues or insulin. The drugs are contraindicated for use in children and pregnant women and in individuals with liver disease and elevated transaminase levels (2-3 times the reference values) [33].

#### **3.1. Troglitazone**

In mice subjected to arterial injury, troglitazone inhibited the growth of vascular smooth muscle cells and intimal hyperplasia, suggesting that TZDs decrease the progression of atherosclerosis. Diabetic patients treated with troglitazone show decreases in platelet adhe‐ sion, activation of plasminogen activator inhibitor (PAI-1) and blood pressure levels. These multiple effects strengthen its indication for the treatment of the metabolic syndrome. However, caution is advised with troglitazone treatment because of possible liver complica‐ tions, including fatal cases. In addition, caution is required when troglitazone is used with cardiac patients because of the possibility of edema [33, 45, 46].

#### **3.2. Pioglitazone**

alcoholics. In patients with proteinuria who are subjected to radiological examination con‐ taining iodine, it is prudent to provide adequate hydration and discontinue the medication a few days prior to such examinations [33]. This drug shows a synergistic effect with cimetidine

The thiazolidinediones (TZDs) are popularly known as glitazones, and representatives include the drug troglitazone (withdrawn from the market because of liver toxicity), rosiglitazone and

TZDs are widely used in the treatment of type 2 diabetes and increase and sensitize insulin action in the liver, muscles and adipocytes, thereby decreasing peripheral resistance. They activate intracellular nuclear receptors (PPAR-gamma-peroxisome proliferator-activated receptor) that regulate the expression of genes encoding glucose and lipid metabolism and are responsible for glucose uptake mediated by insulin in the peripheral tissues and differentiation of preadipocytes into adipocytes. Additionally, these drugs inhibit peripheral lipolysis in adipocytes and assist in reducing the levels of free fatty acids and visceral adipose tissue, resulting in improved glycemic and metabolic parameters. These drugs show good results in terms of long-term glycemic control compared with other consecrated therapeutic options,

TZDs decrease glucose levels by approximately 20% but do not increase insulin secretion. They inhibit the oxidation of long-chain fatty acids in the liver, decreasing gluconeogenesis and the availability of free fatty acids. Although these drugs reduce triglycerides by 15 to 20% and increase HDL-cholesterol by 5 to 10%, the total cholesterol and LDL-cholesterol levels may not change or may increase from 10 to 15% [33]. When compared to metformin, troglitazone has a greater potentiating effect of peripheral insulin action and little effect on the reduction of hepatic glucose production. The association of thiazolidinedione with metformin is interesting

TZDs also increase the expression of glucose transporters (GLUT4) and lipoprotein lipase and reduce the expression of leptin and tumor necrosis factor (TNF-alpha). These results make it

Side effects occur in less than 5% of patients, and they consist of upper respiratory tract infections, headaches, elevated transaminase levels, edema, weight gain and anemia. Hypo‐ glycemia can occur when its use is concomitant with secretagogues or insulin. The drugs are contraindicated for use in children and pregnant women and in individuals with liver disease

In mice subjected to arterial injury, troglitazone inhibited the growth of vascular smooth muscle cells and intimal hyperplasia, suggesting that TZDs decrease the progression of

one of the most widely prescribed classes for the treatment of T2DM [33, 44].

and elevated transaminase levels (2-3 times the reference values) [33].

and may decrease the absorption of vitamin B12 [30].

**3. Thiazolidinediones**

152 Treatment of Type 2 Diabetes

pioglitazone (second generation TZDs).

such as sulfonylureas and metformin [41-43].

because it produces additive effects [39].

**3.1. Troglitazone**

Pioglitazone may be used as a monotherapy or in combination with metformin (increasing the anti-hyperglycemic effect), sulfonylurea, meglitinide, or even insulin, especially in diabetic patients with metabolic syndrome. The dose varies from 15 to 45 mg, which can be adminis‐ tered once a day. Pioglitazone displays a similar mechanism of action and side effects as rosiglitazone and less liver toxicity than troglitazone. However, it can interact with other drugs that are metabolized by P45 enzymes and alter their serum levels. An example is a decrease of approximately 30% of the contraceptive effect of ethinyl estradiol and norethindrone. There‐ fore, the contraceptive dose should be increased in diabetic women who do not wish to become pregnant. Its pharmacokinetics are not altered by mild to moderate renal impairment, so dose modification is required [47].

#### **3.3. Rosiglitazone**

Rosiglitazone is more powerful and has less liver toxicity than troglitazone. Additionally, it does not induce metabolism by cytochrome P450 (CYP) 3A4; thus, there is no interaction with oral contraceptives such as digoxin, ranitidine, nifedipine, etc. The rosiglitazone dose varies from 4 to 8 mg, which can be administered once a day. Similar to pioglitazone, rosiglitazone's pharmacokinetics are not altered by mild to moderate renal impairment, so dose modification is required [48].

Recently published safety data have raised concerns related to a possible association between the chronic use of rosiglitazone and increased risk of cardiovascular events, which is consistent with the use of TZDs in clinical practice. In addition, recently published studies have indicated that there is a loss of bone mass and increased possibility of fracture in patients using these medications [42, 44, 49].
