**1. Introduction**

T2DM is a chronic progressive metabolic disease characterized by chronic hyperglycemia and increased risk of CVDs that result from defective regulation of the blood glucose and requires continuous medical care with multifactorial riskreduction strategies beyond glycemic control [1].

The magnitude of the problem can be assessed from the report of International Diabetes Federation (IDF) Atlas, where it was estimated that in 2017 there were 451 million people (age 18–99 years) with diabetes mellitus (DM) worldwide and that almost half of all people (49.7%) living with DM are undiagnosed [2]. More alarmingly, the projected figures for the prevalence of DM according to the same IDF report are expected to increase to 693 million by year 2045. In addition, there

was an estimated 374 million people with impaired glucose tolerance (IGT), and in 2017 sadly, approximately 5 million deaths worldwide were attributable to DM. The global healthcare expenditure on people with DM was estimated to be USD 850 billion in 2017 [2]. Therefore, it is obvious that T2DM comes with a huge burden of morbidity and mortality and this is mainly due to the development of diabetesspecific microvascular complications and accelerated atherosclerotic macrovascular disease [3, 4].

T2DM is the seventh leading cause of death in the United States, and the estimate of the World Health Organization that T2DM-related mortality is expected to double in number by year 2030 if not treated properly further raises the alarm [5].

Improving glycemic control in people with DM not only substantially reduces their risk of microvascular complications and CVDs but also ameliorates the metabolic dysfunctions that contribute to the progressive nature and course of the disease. Evidence from United Kingdom Prospective Diabetes Study (UKPDS) showed that 1% reduction in glycosylated hemoglobin (HbA1C) was associated with relative risk reduction of 14% in fatal and nonfatal myocardial infarctions, 12% in fatal and nonfatal stroke, and 16% in heart failure [6].

While intensive glycemic control has been shown to substantially reduce the risk of microvascular complications, its value in reducing macrovascular complications that was previously reported 20 years after the end of UKPDS has recently been put in doubt after the ACCORD and ADVANCE Trials, which either showed increased risk of death or no benefit [7–9].

The UKPDS was the first study to show unequivocally that in patients with newly diagnosed T2DM, lowering blood glucose with intensive therapy to a median HbA1C of 7.0% was associated with 25% reduction in the rate of microvascular complications [7].

Moreover, after 10 years of follow-up post UKPDS, the benefits continued with regard to reduction in microvascular complication, and the reduction in macrovascular events was clearer [10].

Notable are the results of ACCORD, ADVANCE, and the Veterans Affairs Diabetes Trial (VADT) studies in patients with advanced T2DM, and either known CVD or multiple CVD risk factors showed that lowering blood glucose (HbA1C levels 6.4–6.9%) delayed the onset or slowed the progression of microvascular complications, but there was no significant reduction in CVD outcomes [8, 9, 11]. On the other hand, the ACCORD study suggests that less intensive therapy may be more appropriate in patients with T2DM and high risk of CVDs because intensive therapy to target HbA1C levels (6.4–7.5) was associated with a 22% increased risk of all-cause mortality [9].

Based on what we have learned from these studies, the American Diabetes Association and the European Association for the Study of Diabetes guideline suggest reducing HbA1C levels to around 7%, but in younger patients with short duration of diabetes and no significant heart diseases, HbA1C levels can be reduced to less than 6.5%. In older patients and those with advanced CVD and limited life expectancy, less stringent HbA1C levels around 8% may be appropriate [3].

Hypoglycemia, weight gain, and progressive beta-cell failure are the major limiting factors for intensive glycemic control approach and in achieving the proposed HbA1C goals [12].

The efficacy of the available OAHs and their effectiveness in the management of T2DM were reported in 2013 according to which and despite availability of several therapeutic options, 33–49% of patients fail to meet the targets for control of glycemia, blood pressure, or cholesterol and only a minority, around 14%, were able to meet targets for all three measures [13].

**77**

*SGLT2 Inhibitors Therapy in Type 2 Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.84152*

cular outcome trials on all newer OAH agents [15].

sis and has never been explored before.

such as DM and hepatic disorders [16].

**2.1 Handling of glucose in the intestine**

**2. Glucose homeostasis**

increase mortality from CVDs.

Apart from the limited efficacy of some OAHs in reducing CV risk, most of these agents are neutral when it comes to CVD risk reduction and some may even

Therefore, for some time, T2DM unmet needs remained unresolved, and the need for innovation continued. For some experts in the field, it was suggested that newer OAHs should be so unique in their properties, namely, addressing the unmet needs and filling the gaps of the available OAHs such as weight gain, hypoglycemia, and CV safety to pass the test of FDA approval after the rosiglitazone story which was withdrawn from the market in 2008 because of its association with increased risk of CVDs [14]. Following rosiglitazone incident, the FDA mandated cardiovas-

T2DM treatment requires individualized management with consideration of a number of patient factors. These include the degree of HbA1c reduction needed, risk of hypoglycemia, the side effect profile of medications, comorbid medical conditions, and the ability of patients to adhere to the medication regimen along with their preferences. Development of novel drugs with newer and complimentary mechanisms of action is needed to address the unwanted side effects and limitations of most of the old OAH agents, namely, the risk of hypoglycemia, weight gain, durability, and CV safety profile. Availability of newer medications with such profiles will simplify therapy and enhance patient adherence, especially in this era of increasing obesity. Among newer classes of drugs, SGLT2-I hold great promise, and several agents from this group have already been approved by the US FDA and elsewhere for treatment of T2DM. They have a novel therapeutic mechanism of action when compared with other drugs available for T2DM management. The main site of action of SGLT2 inhibitors is in kidneys—a site which plays a major role in glucose homeosta-

Glucose is an essential and principal fuel source for cellular metabolism in the human body and is the main energy resource for the central nervous system, muscles, and fat—and insulin plays a key role in its effective utilization. The glucose homeostasis is rapidly adjusted in response to physiological changes such as food intake, exercise, and acute stress, and its blood level is adjusted by control of absorption of glucose, its metabolism in the liver, its excretion by kidneys, and uptake into muscles and adipose tissue. Functions of various proteins associated with regulation of glucose metabolism and homoeostasis get affected by diseases

After ingestion of carbohydrate-rich diet, blood glucose is regulated in response to the increase in glucose concentration in the intestinal lumen and in response to the increase in blood glucose level. The increase in glucose levels in the lumen of the small intestine provides a signal for the upregulation of intestinal glucose absorption [17] and leads to secretion of gut hormones such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), which increase the glucose-dependent stimulation of insulin secretion from the pancreatic β-cells and also influence appetite [18]. Insulin reduces glucagon secretion by acting on pancreatic alpha cells and also reduces blood glucose level by increasing glucose uptake in

fat and muscle cells and changing glucose metabolism in the liver [1].

*Type 2 Diabetes - From Pathophysiology to Modern Management*

fatal and nonfatal stroke, and 16% in heart failure [6].

risk of death or no benefit [7–9].

cular events was clearer [10].

all-cause mortality [9].

HbA1C goals [12].

to meet targets for all three measures [13].

complications [7].

disease [3, 4].

was an estimated 374 million people with impaired glucose tolerance (IGT), and in 2017 sadly, approximately 5 million deaths worldwide were attributable to DM. The global healthcare expenditure on people with DM was estimated to be USD 850 billion in 2017 [2]. Therefore, it is obvious that T2DM comes with a huge burden of morbidity and mortality and this is mainly due to the development of diabetesspecific microvascular complications and accelerated atherosclerotic macrovascular

T2DM is the seventh leading cause of death in the United States, and the estimate of the World Health Organization that T2DM-related mortality is expected to double in number by year 2030 if not treated properly further raises the alarm [5]. Improving glycemic control in people with DM not only substantially reduces

While intensive glycemic control has been shown to substantially reduce the risk of microvascular complications, its value in reducing macrovascular complications that was previously reported 20 years after the end of UKPDS has recently been put in doubt after the ACCORD and ADVANCE Trials, which either showed increased

The UKPDS was the first study to show unequivocally that in patients with newly diagnosed T2DM, lowering blood glucose with intensive therapy to a median HbA1C of 7.0% was associated with 25% reduction in the rate of microvascular

Moreover, after 10 years of follow-up post UKPDS, the benefits continued with regard to reduction in microvascular complication, and the reduction in macrovas-

Notable are the results of ACCORD, ADVANCE, and the Veterans Affairs Diabetes Trial (VADT) studies in patients with advanced T2DM, and either known CVD or multiple CVD risk factors showed that lowering blood glucose (HbA1C levels 6.4–6.9%) delayed the onset or slowed the progression of microvascular complications, but there was no significant reduction in CVD outcomes [8, 9, 11]. On the other hand, the ACCORD study suggests that less intensive therapy may be more appropriate in patients with T2DM and high risk of CVDs because intensive therapy to target HbA1C levels (6.4–7.5) was associated with a 22% increased risk of

Based on what we have learned from these studies, the American Diabetes Association and the European Association for the Study of Diabetes guideline suggest reducing HbA1C levels to around 7%, but in younger patients with short duration of diabetes and no significant heart diseases, HbA1C levels can be reduced to less than 6.5%. In older patients and those with advanced CVD and limited life expectancy, less stringent HbA1C levels around 8% may be appropriate [3].

Hypoglycemia, weight gain, and progressive beta-cell failure are the major limiting factors for intensive glycemic control approach and in achieving the proposed

The efficacy of the available OAHs and their effectiveness in the management of T2DM were reported in 2013 according to which and despite availability of several therapeutic options, 33–49% of patients fail to meet the targets for control of glycemia, blood pressure, or cholesterol and only a minority, around 14%, were able

their risk of microvascular complications and CVDs but also ameliorates the metabolic dysfunctions that contribute to the progressive nature and course of the disease. Evidence from United Kingdom Prospective Diabetes Study (UKPDS) showed that 1% reduction in glycosylated hemoglobin (HbA1C) was associated with relative risk reduction of 14% in fatal and nonfatal myocardial infarctions, 12% in

**76**

Apart from the limited efficacy of some OAHs in reducing CV risk, most of these agents are neutral when it comes to CVD risk reduction and some may even increase mortality from CVDs.

Therefore, for some time, T2DM unmet needs remained unresolved, and the need for innovation continued. For some experts in the field, it was suggested that newer OAHs should be so unique in their properties, namely, addressing the unmet needs and filling the gaps of the available OAHs such as weight gain, hypoglycemia, and CV safety to pass the test of FDA approval after the rosiglitazone story which was withdrawn from the market in 2008 because of its association with increased risk of CVDs [14]. Following rosiglitazone incident, the FDA mandated cardiovascular outcome trials on all newer OAH agents [15].

T2DM treatment requires individualized management with consideration of a number of patient factors. These include the degree of HbA1c reduction needed, risk of hypoglycemia, the side effect profile of medications, comorbid medical conditions, and the ability of patients to adhere to the medication regimen along with their preferences. Development of novel drugs with newer and complimentary mechanisms of action is needed to address the unwanted side effects and limitations of most of the old OAH agents, namely, the risk of hypoglycemia, weight gain, durability, and CV safety profile. Availability of newer medications with such profiles will simplify therapy and enhance patient adherence, especially in this era of increasing obesity.

Among newer classes of drugs, SGLT2-I hold great promise, and several agents from this group have already been approved by the US FDA and elsewhere for treatment of T2DM. They have a novel therapeutic mechanism of action when compared with other drugs available for T2DM management. The main site of action of SGLT2 inhibitors is in kidneys—a site which plays a major role in glucose homeostasis and has never been explored before.
