**6. Clinical effects of SGLT2 inhibitors in diabetes mellitus**

Currently, there are seven SGLT2 inhibitors approved for clinical use. They are given orally and absorbed by the intestine. Due to higher selectivity for SGLT2 versus SGLT1, inhibition of intestinal SGLT1 can be avoided, though it is still possible at high oral doses. At pharmacological doses, their serum levels achieved are too low to inhibit SGLT1 in other organs (**Table 2**).

Clinical effects observed for different SGLT2-I will be described and discussed together for the sake of clarity.

### **6.1 Effects on diabetes and metabolism**

In T2DM, upregulation of SGLT2 expression increases its Tm by around 20%. SGLT2-I is filtered in glomeruli and inhibits glucose reabsorption in S1 segment of proximal tubule leading to a reduction of 30–50% in Tm of SGLT2 [67].

In the presence of functional SGLT2, less than 10% of glucose is absorbed through SGLT1; therefore, it is expected that SGLT2 inhibitor therapy would lead to around 90% reduction in Tm but the observed decrease of only 30–50% in Tm can be explained by higher amount of SGLT1-mediated glucose reabsorption [70].


#### **Table 2.**

*Preparation strength and SGLT2 versus SGLT1 selectivity of various approved SGLT2 inhibitors.*

During preclinical studies with animal models of diabetes as well as in clinical studies with both T2DM and T1DM patients, it has been demonstrated that prolonged SGLT2-I therapy decreased fasting and prandial plasma glucose levels, reduced HbA1C, and improved oral glucose tolerance. They also exerted nephroprotective effects, reduced blood pressure, and increased utilization of fatty acid substrates; thus, they also conferred metabolic benefits [68–73].

SGLT2-I have insulin-independent mechanism of action. They can be used both as monotherapy as well as in combination with other OAHs [74, 75]. Clinical trials have shown that SGLT2-I are effective when administered in combination with metformin [74, 76–78], metformin plus sulfonylurea [79], insulin [80], DPP4 inhibitors [77], and thiazolidinediones [75].

SGLT2-I do not increase the risk of hypoglycemia like other OAH agents. The filtered renal glucose load is directly correlated with plasma glucose level, and there is compensatory increase in SGLT1-mediated glucose reabsorption when SGLT2 is blocked [81]. The other mechanism preventing hypoglycemia is the glucagon secretion from pancreatic alpha cells due to SGLT2 inhibition [31].

SGLT2-I therapy in patients with T2DM increases both plasma glucagon and endogenous glucose production. Despite such physiological changes, patients on SGLT2-I have lower plasma glucose levels than those receiving placebo, possibly because of increased glycosuria and improved insulin sensitivity [82, 83].

SGLT2-I administration changes body metabolism and shifts it to enhanced usage of fat for metabolic needs; consequently beta-hydroxybutyrate levels in plasma increase [69]. The metabolic inflexibility characteristically seen in patients with T2DM and nondiabetic insulin-resistant subjects is an inability to switch from predominantly fatty acid oxidation during fasting state to predominantly glucose oxidation in fed state [84]. Lack of variability in measured respiratory quotient (RQ ) between fasting and fed states has been observed as an evidence of metabolic inflexibility. SGLT2-I reduce whole body fasting RQ which is indicative of increased oxidation of fatty acids and amino acids, suggesting its partial restoration [85].

As a consequence of improved glucose homoeostasis, SGLT2-I may slow down glucotoxicity-mediated degeneration of beta cells and thus may also slow down the progression of T2DM. Experimental diabetic animal models on SGLT2-I have shown an improvement in both beta cell mass and functions [86]. Improvement in insulin sensitivity is another beneficial aspect [82, 83].

#### **6.2 Effects on blood pressure**

Increased urinary excretion of glucose and sodium leads to mild diuresis coupled with urinary sodium loss. Reduction of extracellular volume occurs which has a favorable effect on blood pressure, and the magnitude of the effect is most apparent in patients with preexisting hypertension [87].

Empagliflozin causes a reduction in systolic blood pressure (SBP) of 4–6 mmHg, whereas diastolic blood pressure (DBP) was similar to placebo with no increase in the heart rate [88]. Similarly, canagliflozin at 300 mg/day resulted in a reduction in SBP of 5.1 mmHg [89].

In analysis of 12 studies with dapagliflozin at 10 mg/day, reduction of 4.4 mmHg and 0.5 mmHg in SBP and DBP, respectively, was seen with no increase in the heart rate compared to placebo [90].

#### **6.3 Effects on body weight**

On SGLT2-I therapy, initial weight loss could result from osmotic diuresis. However, sustained weight loss over the period is a consequence of renal glucose

**85**

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

**6.4 Effects on plasma lipids and plasma uric acid**

cholesterol (HDL) has been observed [76, 78, 94].

*6.5.1 Effects on cardiovascular disease*

all plausible protective mechanisms.

carcinoma and may result in liver cirrhosis also.

required no dose adjustments [98, 99].

*6.5.2 Effects on liver disease*

and high CVD risk [96].

trial [91].

excretion leading to a caloric deficit of about 280 calories/day. This translates into

SGLT2-I therapy has been associated with alteration in serum lipid profile. Small increase in low-density lipoprotein cholesterol (LDL) and high-density lipoprotein

Any increase in serum cholesterol is considered to be a risk factor for the development of heart failure and CVDs. However, it may not be relevant clinically, as empagliflozin has been shown to have a protective effect on MACE in EMPA-REG

They also promote uric acid excretion and reduce uric acid level in the blood [94] which may contribute to their protective effect on the development of diabetic

In EMPA-REG trial, empagliflozin has shown a lower risk for MACE as well as

In CANVAS Program, canagliflozin has been found to reduce the risk of cardiovascular death or hospitalization for heart failure in patient with a history of T2DM

Lately, DECLARE-TIMI 58 trial demonstrated the CV safety of dapagliflozin in patients with T2DM who had or were at risk of CVDs. It was found to reduce hospitalization for heart failure as has been seen with other SGLT2-I [97].

Both empagliflozin and canagliflozin has got FDA approval for cardiovascular risk reduction in T2DM patients who are at high risk for such events. The mechanism of cardiovascular protection exerted by SGLT2-I is unknown and seems to be glucose independent. Apart from improved glycemic control, the pleiotropic effects of SGLT2 inhibitors which include their ability to lower blood pressure, reduction in intraglomerular pressure and albuminuria, and amelioration of volume overload are

T2DM affects metabolism in the liver and may manifest as hepatic steatosis and nonalcoholic steatohepatitis (NASH). NASH increases the risk of hepatocellular

In preclinical studies on rodent models, SGLT2-I have been found to ameliorate nonalcoholic fatty liver disease (NAFLD) and NASH [70–72]. Although SGLT2-I are metabolized by the liver, studies involving patient with mild or moderate

hepatic impairment showed dapagliflozin and empagliflozin were well tolerated and

Canagliflozin has shown improvement in serum aminotransferases and gammaglutamyl transferase levels in patients with T2DM [100]. In humans, ipragliflozin has shown reduction in liver fat in patients with T2DM and NAFLD [101]. Empagliflozin addition to the standard treatment of T2DM and NAFLD signifi-

cantly reduced liver fat, and improved ALT levels were seen [102].

nephropathy observed in the EMPA-REG renal study [73, 80, 95].

for cardiovascular death and has been found to be protective [88].

decrease in body weight by 1–3 kg along with decreased visceral adiposity. In the EMPA-REG trial, empagliflozin resulted in weight loss of about 2 kg [91]. The average weight loss achieved with dapagliflozin and canagliflozin stands

between 1 and 3%, while other studies report a loss more than 5% [92, 93].

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

*Type 2 Diabetes - From Pathophysiology to Modern Management*

[77], and thiazolidinediones [75].

substrates; thus, they also conferred metabolic benefits [68–73].

tion from pancreatic alpha cells due to SGLT2 inhibition [31].

insulin sensitivity is another beneficial aspect [82, 83].

in patients with preexisting hypertension [87].

**6.2 Effects on blood pressure**

SBP of 5.1 mmHg [89].

rate compared to placebo [90].

**6.3 Effects on body weight**

During preclinical studies with animal models of diabetes as well as in clinical studies with both T2DM and T1DM patients, it has been demonstrated that prolonged SGLT2-I therapy decreased fasting and prandial plasma glucose levels, reduced HbA1C, and improved oral glucose tolerance. They also exerted nephroprotective effects, reduced blood pressure, and increased utilization of fatty acid

SGLT2-I have insulin-independent mechanism of action. They can be used both as monotherapy as well as in combination with other OAHs [74, 75]. Clinical trials have shown that SGLT2-I are effective when administered in combination with metformin [74, 76–78], metformin plus sulfonylurea [79], insulin [80], DPP4 inhibitors

SGLT2-I do not increase the risk of hypoglycemia like other OAH agents. The filtered renal glucose load is directly correlated with plasma glucose level, and there is compensatory increase in SGLT1-mediated glucose reabsorption when SGLT2 is blocked [81]. The other mechanism preventing hypoglycemia is the glucagon secre-

SGLT2-I therapy in patients with T2DM increases both plasma glucagon and endogenous glucose production. Despite such physiological changes, patients on SGLT2-I have lower plasma glucose levels than those receiving placebo, possibly because of increased glycosuria and improved insulin sensitivity [82, 83].

SGLT2-I administration changes body metabolism and shifts it to enhanced usage of fat for metabolic needs; consequently beta-hydroxybutyrate levels in plasma increase [69]. The metabolic inflexibility characteristically seen in patients with T2DM and nondiabetic insulin-resistant subjects is an inability to switch from predominantly fatty acid oxidation during fasting state to predominantly glucose oxidation in fed state [84]. Lack of variability in measured respiratory quotient (RQ ) between fasting and fed states has been observed as an evidence of metabolic inflexibility. SGLT2-I reduce whole body fasting RQ which is indicative of increased oxidation of fatty acids and amino acids, suggesting its partial restoration [85]. As a consequence of improved glucose homoeostasis, SGLT2-I may slow down glucotoxicity-mediated degeneration of beta cells and thus may also slow down the progression of T2DM. Experimental diabetic animal models on SGLT2-I have shown an improvement in both beta cell mass and functions [86]. Improvement in

Increased urinary excretion of glucose and sodium leads to mild diuresis coupled

Empagliflozin causes a reduction in systolic blood pressure (SBP) of 4–6 mmHg, whereas diastolic blood pressure (DBP) was similar to placebo with no increase in the heart rate [88]. Similarly, canagliflozin at 300 mg/day resulted in a reduction in

In analysis of 12 studies with dapagliflozin at 10 mg/day, reduction of 4.4 mmHg and 0.5 mmHg in SBP and DBP, respectively, was seen with no increase in the heart

On SGLT2-I therapy, initial weight loss could result from osmotic diuresis. However, sustained weight loss over the period is a consequence of renal glucose

with urinary sodium loss. Reduction of extracellular volume occurs which has a favorable effect on blood pressure, and the magnitude of the effect is most apparent

**84**

excretion leading to a caloric deficit of about 280 calories/day. This translates into decrease in body weight by 1–3 kg along with decreased visceral adiposity.

In the EMPA-REG trial, empagliflozin resulted in weight loss of about 2 kg [91]. The average weight loss achieved with dapagliflozin and canagliflozin stands between 1 and 3%, while other studies report a loss more than 5% [92, 93].

### **6.4 Effects on plasma lipids and plasma uric acid**

SGLT2-I therapy has been associated with alteration in serum lipid profile. Small increase in low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) has been observed [76, 78, 94].

Any increase in serum cholesterol is considered to be a risk factor for the development of heart failure and CVDs. However, it may not be relevant clinically, as empagliflozin has been shown to have a protective effect on MACE in EMPA-REG trial [91].

They also promote uric acid excretion and reduce uric acid level in the blood [94] which may contribute to their protective effect on the development of diabetic nephropathy observed in the EMPA-REG renal study [73, 80, 95].
