**2. Biguanides**

Metformin and phenformin are oral antidiabetic drugs of the biguanide class. Metformin is the drug of choice for the treatment of adults with type 2 diabetes because of its lower frequency of side effects. This drug is currently used by nearly one-third of the diabetic patients in Italy and is the most prescribed in the U.S. (> 40 million prescriptions in 2008). Phenformin is no longer marketed in many countries, although it is still available in Italy [26-28].

Both metformin and phenformin increase weight loss in obese non-diabetic patients without substantially reducing blood glucose levels. This weight loss is attributed to the drugs' anorectic effect and a slight reduction in the gastrointestinal absorption of carbohydrates [29]. Phenformin was withdrawn from clinical practice in the 1970s because of a greater tendency to develop severe and fatal adverse events, such as lactic acidosis.

#### **2.1. Metformin**

hypoglycemia. Because of their rapid absorption, the action of these drugs is initiated 30

The thiazolidinedione drugs (pioglitazone and rosiglitazone) are oral hypoglycemic agents capable of increasing the sensitivity of liver, muscle and fat cells to insulin, which results in reduced peripheral resistance. This class is contraindicated in patients with hepatic dysfunc‐ tion and heart conditions and adverse effects include upper respiratory tract infections,

With respect to alpha-glucosidase, competitive inhibitors such as acarbose, miglitol and voglibose act as antagonists of amylase and sucrose, thereby decreasing the intestinal absorp‐ tion of glucose. These drugs are contraindicated in pregnant or lactating patients and in

Another recent class of oral hypoglycemic drug is the DPP-4 inhibitors (sitagliptin, vildagliptin and saxagliptin), which act by increasing the levels of hormones that help to control glucose concentrations. These drugs have few adverse events, and incidences of hypoglycemia and

In addition to these oral medications, subcutaneous administration of exenatide (GLP-1 agonist) can stimulate insulin secretion (secretagogue). In addition to facilitating glycemic control, this medicine also helps in patient weight loss. Possible adverse events include nausea,

For injectable drugs, the application of human insulin analogs (lispro, aspart and glargine) for the treatment of T2DM may be indicated for patients who no longer respond to diet combined with exercise and oral hypoglycemic agents or in more severe hyperglycemia cases. In addition to the different types of administration (including the innovation of inhalable insulin), this

In short, with the emergence of new treatments for diabetes, various individualized treatment options are possible that consider ease of access, cost, mode of administration and patient

Thus, the aim of this chapter is to evaluate the available treatments for T2DM as well as their mechanisms of action and adverse effects and describe the new drugs and therapeutic trends that are available. Such diabetes treatment updates for healthcare professionals and caregivers

Metformin and phenformin are oral antidiabetic drugs of the biguanide class. Metformin is the drug of choice for the treatment of adults with type 2 diabetes because of its lower frequency of side effects. This drug is currently used by nearly one-third of the diabetic patients in Italy and is the most prescribed in the U.S. (> 40 million prescriptions in 2008). Phenformin is no

longer marketed in many countries, although it is still available in Italy [26-28].

hormone may be used in combination with oral hypoglycemics [12, 25].

is essential for proper disease management and health promotion.

minutes after administration [16, 22].

150 Treatment of Type 2 Diabetes

weight gain are low [16, 23].

characteristics.

**2. Biguanides**

vomiting and diarrhea [16, 23, 24]

headaches, weight gain, anemia and edema [12, 16, 23].

diabetic patients with renal or hepatic dysfunction [6, 18].

Metformin is sold in 500 and 850 mg tablets, and the maximum dosage is 2.5 g/day, although there are reports in the literature of dosages up to 3 g, which are always administered after meals to minimize gastrointestinal side effects [30]. It has been reported that this drug increases the number and improves the affinity of insulin receptors both in adipocytes and muscle. In muscle, glucose uptake increases from 15 to 40% and gluconeogenesis is stimulated. In adipocytes, metformin inhibits lipolysis and the availability of free fatty acids (FFA). Further‐ more, metformin improves insulin action in the liver by reducing hepatic glucose production from 10 to 30%, and at the cellular level, it increases the tyrosine kinase activity of the insulin receptor in the muscles, which stimulates GLUT4 translocation and the activity of glycogen synthetase [31].

The use of metformin also improves the lipid profile by decreasing triglyceride levels by 20-25%, LDL-cholesterol by up to 10% and plasminogen activation inhibitor (PAI-1) by 20-30% and increasing HDL-cholesterol by 17%. Insulin secretion to stimuli may remain unchanged or decrease, and its anorectic effect helps in weight loss. In addition to being associated with weight reduction, its effectiveness in glycemic control is similar to that of sulfonylurea [32]. Another advantage is the absence of hypoglycemia because insulin secretion is not stimulated [33].

The isolated use of metformin in type 2 diabetes lowers blood glucose levels by approximately 25%, or 60 to 70 mg/dl, and glycosylated hemoglobin by 1.5 to 2% [31]. Intensive glucose control using metformin significantly decreases the risk of cardiovascular disease and diabetes mellitus-related mortality and is associated with less weight gain and a lack of treatmentinduced hypoglycemia associated with insulin or sulfonylureas [34].

Metformin is absorbed in the intestine, excreted by the kidneys and minimally metabolized by the liver. Metformin has a low affinity for mitochondrial membranes and does not interfere with oxidative phosphorylation, and it is indicated as a monotherapy in obese or even glucose intolerant diabetics. Approximately 5 to 10% of patients each year fail to have an appropriate response to this drug. In these cases, metformin can be used in combination with sulfonylurea, acarbose, thiazolidinediones, repaglinide and/or insulin to achieve satisfactory control [35-40].

The most common side effects of metformin are diarrhea (15%), metallic taste and nausea, which often decrease with continued use of the medication. The occurrence of lactic acidosis is rare (0.03 to 0.4/1000/year) and occurs most often in people who have a contraindication to metformin, such as chronic liver disease (elevated transaminases 2-3 times the normal values) and heart, respiratory, or renal conditions (clearance < 70 ml/min or serum creatinine ≥ 1.5 mg/ dL). The use of metformin is not advisable in people over 80, pregnant women, infants or 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 and may decrease the absorption of vitamin B12 [30].
