**1. Introduction**

Type 2 diabetes mellitus (T2DM) is the most common type of diabetes, which is defined as a chronic metabolic disorder characterized by hyperglycemia. In this disease, the body is able to produce insulin; however, its secretion is irregular and/or the body's cells fail to use and respond appropriately to this hormone (insulin resistance), leading to an accumulation of blood glucose [1, 2].

Although the reasons for the development of T2DM are still unknown, it is a multifactorial disease that involves a genetic predisposition as well as other factors, including a poor diet, sedentary lifestyle, age (45 or older), previous gestational diabetes, and overweight or obese physical conditions, which represent the most common risk factors for the development of insulin resistance [3, 4].

Epidemiologically, the number of individuals with T2DM (representing 85-95% of all cases of diabetes mellitus) in recent decades has increased rapidly worldwide. This disease usually affects adults, especially males, but an increase in the number of cases in children and adolescents has also been observed [5, 6]

The high incidence of T2DM is associated with economic development, aging populations, increasing urbanization, dietary changes, reduced physical activity and changes in lifestyle and other cultural patterns. It is estimated that more than 382 million people suffer from this disease worldwide (8.3% prevalence). In 2013, 5.1 million deaths were reportedly caused by diabetes. If these trends continue, it is estimated that by the year 2035, approximately 592 million people (1 in 10 adults) will be carriers of the disease [7-9].

Therefore, the increasing number of new cases of diabetes per year combined with high prevalence and mortality rates impose high costs socially and economically to the populations of all countries. In 2013, approximately 548 billion dollars were spent worldwide on diabetic patients. Thus, understanding this disease and all the variables involved, including preven‐ tion, diagnosis and treatment must be a priority [8].

The diagnosis of T2DM is based on summarized plasma glucose quantification criteria (either fasting or after a glucose tolerance test). Furthermore, the assessment of the amount of glycated hemoglobin (HbA1c) is included as a diagnostic option for diabetes. However, many individuals with T2DM are asymptomatic in the early stages of this disorder and only discover the disease after the onset of more severe symptoms and other complications. The first symptoms of T2DM may include polyuria, polydipsia, constant hunger, appearance of wounds with delayed healing, visual changes and frequent infections [10, 11].

When undiagnosed or poorly controlled, this disease is a risk factor for the onset of various complications at both the microvascular (nephropathy, retinopathy and neuropathy) and macrovascular (cardiovascular disease) level. Diabetes is one of the major factors that leads to blindness, kidney failure, lower limb amputation and development of cardiovascular disease, the latter being the primary cause of death worldwide [3, 11].

Therefore, simple lifestyle changes, including increased physical activity, diet modification and weight loss are recommended for the management of pre-diabetes and early diabetes. These changes have been shown to be effective in preventing or delaying the progression of T2DM or damage to target organs [4, 12].

The treatment of diabetes mainly targets glycemic control, thus aiming to relieve symptoms, improve the quality of life of patients, prevent further complications and reduce mortality. However, the use of other therapeutic treatments is needed as a strategy for reducing multi‐ factorial risks [3, 13].

The basic strategies for the treatment and control of diabetes mostly consist of a specific balanced diet, physical activity and proper use of medications (oral and/or insulin agents). Patient education coupled with self-care and support from family and physicians are essential procedures for the prevention of acute complications and reduction of long-term complica‐ tions. Additionally, frequent tests (including blood pressure measurement and lipid profile), foot care (avoiding the appearance of lesions), stress control and reduction in the consumption of alcoholic beverages and tobacco are important actions related to disease control [1, 14, 15].

Compared with type 1 diabetes mellitus patients, the majority of type 2 patients typically do not require daily insulin doses. The disease can be treated with oral medications and changes in lifestyle until resistance becomes difficult to control, after which an insulin regimen is usually required [8].

Thus, drug treatment of T2DM is based on the knowledge of patient characteristics together with the severity of the hyperglycemia and availability of therapeutic options. Many oral drugs are used to control diabetes, such as metformin (biguanide), sulfonylureas and thiazolidine‐ diones, which have been used for decades with satisfactory results. These antidiabetic drugs compose the most studied cast of oral pharmacologicals worldwide and play an important role in glycemic control; in addition, they are often recommended as the first option for the treatment of the disease by the American Diabetes Association (ADA) and European Associ‐ ation for the Study of Diabetes (EASD) [10, 15, 16]. Technological advances and new avenues of drug research have enabled the development of new drug therapies for the treatment of T2DM, and approximately 180 new drugs are currently under study [17, 18].

Therefore, the increasing number of new cases of diabetes per year combined with high prevalence and mortality rates impose high costs socially and economically to the populations of all countries. In 2013, approximately 548 billion dollars were spent worldwide on diabetic patients. Thus, understanding this disease and all the variables involved, including preven‐

The diagnosis of T2DM is based on summarized plasma glucose quantification criteria (either fasting or after a glucose tolerance test). Furthermore, the assessment of the amount of glycated hemoglobin (HbA1c) is included as a diagnostic option for diabetes. However, many individuals with T2DM are asymptomatic in the early stages of this disorder and only discover the disease after the onset of more severe symptoms and other complications. The first symptoms of T2DM may include polyuria, polydipsia, constant hunger, appearance of wounds with delayed

When undiagnosed or poorly controlled, this disease is a risk factor for the onset of various complications at both the microvascular (nephropathy, retinopathy and neuropathy) and macrovascular (cardiovascular disease) level. Diabetes is one of the major factors that leads to blindness, kidney failure, lower limb amputation and development of cardiovascular disease,

Therefore, simple lifestyle changes, including increased physical activity, diet modification and weight loss are recommended for the management of pre-diabetes and early diabetes. These changes have been shown to be effective in preventing or delaying the progression of

The treatment of diabetes mainly targets glycemic control, thus aiming to relieve symptoms, improve the quality of life of patients, prevent further complications and reduce mortality. However, the use of other therapeutic treatments is needed as a strategy for reducing multi‐

The basic strategies for the treatment and control of diabetes mostly consist of a specific balanced diet, physical activity and proper use of medications (oral and/or insulin agents). Patient education coupled with self-care and support from family and physicians are essential procedures for the prevention of acute complications and reduction of long-term complica‐ tions. Additionally, frequent tests (including blood pressure measurement and lipid profile), foot care (avoiding the appearance of lesions), stress control and reduction in the consumption of alcoholic beverages and tobacco are important actions related to disease control [1, 14, 15].

Compared with type 1 diabetes mellitus patients, the majority of type 2 patients typically do not require daily insulin doses. The disease can be treated with oral medications and changes in lifestyle until resistance becomes difficult to control, after which an insulin regimen is

Thus, drug treatment of T2DM is based on the knowledge of patient characteristics together with the severity of the hyperglycemia and availability of therapeutic options. Many oral drugs are used to control diabetes, such as metformin (biguanide), sulfonylureas and thiazolidine‐ diones, which have been used for decades with satisfactory results. These antidiabetic drugs

tion, diagnosis and treatment must be a priority [8].

healing, visual changes and frequent infections [10, 11].

the latter being the primary cause of death worldwide [3, 11].

T2DM or damage to target organs [4, 12].

factorial risks [3, 13].

148 Treatment of Type 2 Diabetes

usually required [8].

Typically, various drug classes can be used to control type 2 diabetes, including human insulin analogs, drugs that reduce insulin resistance (biguanides and thiazolidinediones or glita‐ zones), secretagogues and their analogues (sulfonylureas, meglitinides, inhibitors of dipep‐ tidyl peptidase IV (DPP-4) or agonists and analogues of glucagon-like peptide-1 (GLP-1)), and drugs that reduce the rate of carbohydrate degradation (alpha-glucosidase inhibitors). Dapagliflozin is one of the newer medications for glycemic control and was recently approved by the FDA (January 2014). Its mechanism of action inhibits the sodium-glucose cotransporter 2 (SGLT2), a protein responsible for glucose reabsorption in the kidney, which leads to the elimination of excess glucose in the urine [17, 18].

Multiple therapies, or a combination of oral hypoglycemic drugs and/or other drugs, are also an option for the control of diabetes mellitus [11, 19]. However, the therapeutic use of drugs is limited by factors such as their efficacy, adverse events, costs, side-effects, dose management problems, inflexible dosages, weight gain, etc.; therefore, such effects should be critically evaluated for each patient [19].

For example, weight loss is a priority in obese diabetics. If glycemic control is not ach‐ ieved after 4-6 weeks of treatment with drugs that increase sensitivity to insulin action (such as biguanides and thiazolidinediones) medications may be given to control obesity, which include drugs that affect the appetite and induce satiety, such as orlistat. If necessa‐ ry, drugs may also be used that retard the degradation of sugars in the diet (such as acarbose or miglitol) or drugs such as sulfonylureas or meglitinides that increase insulin secretion in the pancreas [20-23].

In terms of therapeutic classes, the action of biguanides, whose main representative is metformin, is related to decreased peripheral insulin sensitivity, reduced hepatic glucose output, and modified lipid metabolism. All of these effects contribute to the control of T2DM. The advantages of these drugs include the absence of hypoglycemia and its anorectic effect, which also aids in patient weight loss. The adverse effects of this class are few but include diarrhea, nausea, metallic taste and intestinal colic, which gradually decreases with continued use [16, 19, 23].

The class of sulfonylureas that act by directly stimulating insulin secretion (secretago‐ gues) includes chlorpropamide, glibenclamide, gliclazide and glimepiride. These drugs have several adverse effects, including nausea and vomiting (gastrointestinal), hypoglycemia (glucose), leukopenia, agranulocytosis, thrombocytopenia and hemolytic anemia (hemato‐ logical) and weight gain. Accordingly, the use of newer insulin secretagogues (glinides class, including mitiglinide, repaglinide and nateglinide) is suggested as an alternative for patients treated with sulfonylureas who have irregular meal times or late postprandial hypoglycemia. Because of their rapid absorption, the action of these drugs is initiated 30 minutes after administration [16, 22].

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

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

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 weight gain are low [16, 23].

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, vomiting and diarrhea [16, 23, 24]

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

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 characteristics.

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 is essential for proper disease management and health promotion.
