*6.5.1 Effects on cardiovascular disease*

In EMPA-REG trial, empagliflozin has shown a lower risk for MACE as well as for cardiovascular death and has been found to be protective [88].

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 and high CVD risk [96].

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 all plausible protective mechanisms.

#### *6.5.2 Effects on liver disease*

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

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 required no dose adjustments [98, 99].

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

### *6.5.3 Effects on kidney disease*

The kidney is the main target of action for SGLT2-I. Findings from animal models suggest it to be protective against development of diabetic nephropathy which exceeds the nephroprotective effect achieved secondary to improved glycemic control. During early stage of nephropathy, empagliflozin has been shown to prevent glomerular hyperfiltration, attenuate diabetes-associated renal growth, improve expression of inflammation markers, and reduce albuminuria in animal models [24].

Progression of nephropathy was slowed by luseogliflozin in T2DN rats, a genetic model of T2DM associated with severe nephropathy. It also prevents GFR decline and attenuates focal glomerulosclerosis, tubular necrosis, tubulointerstitial fibrosis, and progressive proteinuria [103].

Reduction in estimated GFR and nephroprotective effects has been reported with SGLT2-I in patients with DM [73, 80, 104]. Empagliflozin has been found to attenuate glomerular hyperfiltration in humans. It also reduces micro- and macroalbuminuria, and the effects are independent of the improved glycemic effect [105]. In CANVAS trial, canagliflozin has been found to reduce albuminuria and the albumin-to-creatinine ratio when compared with placebo [106].

Results from a recent meta-analysis have indicated that SGLT2 inhibition preserves renal function in patient with or without renal impairment. They slow down the progression of albuminuria and reduce urinary albumin-to-creatinine ratio in addition to reducing the risk of doubling of the serum creatinine level, initiation of kidney transplant, and death from kidney disease in patient with T2DM with or without history of renal impairment [107].

#### **6.6 Risks for adverse drug effects and restrictions of application**

#### *6.6.1 Genital and urinary infections*

Increased risk of GMI and urinary tract infections (UTI) are seen in DM due to hyperglycemia and glucosuria. SGLT2-I therapy has been associated with increased risks for GMIs and UTIs. Women otherwise also are more commonly affected than men, and SGLT2-I therapy further increases the risk in them.

When treated with canagliflozin for 4 months, around 10.4% of women and 4.2% of men developed GMIs compared to 3.2% of women and 0.6% of men treated with placebo [108]. Most of the cases were of mild to moderate severity and could be treated with standard antifungal agents successfully.

Canagliflozin therapy in T2DM has been associated with UTIs in 8.7% of women compared to 7.7% treated with placebo. Figures for men were 1.4% versus 0.6%, respectively [109]. Similar findings were reported from pooled analysis of four studies (n = 2477) using empagliflozin. It was concluded that GMI were more common with empagliflozin than placebo (approximately 4 versus 1%, respectively); however, the frequency of UTI was about 8–9% for each [110].

Safety data from meta-analysis of eight studies using canagliflozin and dapagliflozin found that UTIs were more common with SGLT2-I as compared to other OAH (odds ratio, 1.42 [95% CI 1.06, 1.90]) as were GMI (odds ratio, 5.06 [95% CI 3.44, 7.45]) [111].

These studies suggests that most UTIs were mild to moderate, responded well to standard antimicrobial therapy, and rarely led to SGLT2-I discontinuation [112].

#### *6.6.2 Euglycemic ketoacidosis*

SGLT2-I therapy has been observed to be associated with small number of cases with EKA during treatment of T1DM and insulin-deficient T2DM [113].

**87**

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

occurred among placebo-treated group [97].

should be followed [115].

pared to 10 and 25 mg, respectively [116].

glycemic control in this population [115].

*6.6.3 SGLT2 inhibitors and risk of limb amputations*

the US FDA Adverse Event Reporting System [117].

benefits of SGLT2 inhibitors in clinical practice [117].

ard ratio 1.97) versus placebo as seen in CANVAS trial [114].

involved [31, 69].

In CANVAS study, the incidence rates were 0.5 per 1000 patient years with canagliflozin 100 mg, 0.8 per 1000 patient years with canagliflozin 300 mg, and 0.2 per 1000 patient years with comparator [114]. In the EMPA-REG trial, the incidence rates were 0.5 and 0.2 per 1000 patient years with empagliflozin 10 and 25 mg, respectively, and 1.2 per 1000 patient years in placebo group [88]. In DECLARE-TIMI 58, using dapagliflozin, the corresponding rates were 0.3%, whereas 0.1%

Majority of the cases have been reported from clinical practice rather than trials and have occurred in patients on exogenous insulin. Reduction in insulin dose on starting SGLT2-I has been observed in them. Usually they present with classical diabetic ketoacidosis (DKA) features. However, some cases may present atypically

Almost all cases occurred in patients challenged with metabolically stressful events and common precipitants such as surgery, myocardial infarction, stroke,

Low serum bicarbonate and positive urinary ketones may be suggestive but may be inaccurate; therefore, direct measurement of serum betahydroxybutyrate level to confirm the diagnosis of EKA has been recommended by the AACE. Once the diagnosis of EKA is confirmed, SGLT2-I should be discontinued, and DKA protocol

The increased risk of EKA associated with SGLT2-I therapy may be explained

Most cases of EKA have occurred in patients with T1DM, which is an off-label use of these agents that is not an FDA-approved indication. Because insulin deficiency may be the most important contributing factor, the AACE recommends against stopping insulin or decreasing the dose excessively. The risk of EKA has recently been shown in the EASE Trial to be dose dependent as lower doses of empagliflozin 2.5 mg were shown to be associated with lower rates of DKA, com-

Although not approved for treatment of T1DM and SGLT2-I use is still off-label

Canagliflozin significantly reduced the risk of CV events by 14% but increased the risk of lower limb amputation in patients with T2DM and high CVD risk (haz-

In the EMAP REG trial using empagliflozin, in T2DM patient with established

In a recent report, canagliflozin, but not dapagliflozin or empagliflozin, was associated with a higher risk of amputation in a pharmacovigilance analysis using

Presently the evidence may not be enough to explain a precise causal relationship between canagliflozin and amputation. Neither the underlying mechanisms are currently known, nor do we know whether it is specifically related to canagliflozin. As amputation carries a negative impact on patient's clinical course, understanding predisposing factors and mechanisms of amputation will be crucial to maximize the

Recently in DECLARE-TIMI 58 trial, the rate of amputation was similar between

CVD, the rate of lower limb amputation was similar to placebo group [88].

the dapagliflozin- and placebo-treated patient (hazard ratio 1.09) [97].

in T1DM, the AACE encourages clinical trials due to their promising effect on

by absolute or relative insulin deficiency, increased glucagon secretion, and stimulation of lipolysis and ketogenesis; however, other ketogenic factors are also

with lower-than-expected hyperglycemia, and it can go unrecognized.

extensive exercise, severe infections, and prolonged fasting.

#### *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*

The kidney is the main target of action for SGLT2-I. Findings from animal models suggest it to be protective against development of diabetic nephropathy which exceeds the nephroprotective effect achieved secondary to improved glycemic control. During early stage of nephropathy, empagliflozin has been shown to prevent glomerular hyperfiltration, attenuate diabetes-associated renal growth, improve expression of inflammation markers, and reduce albuminuria in animal models [24]. Progression of nephropathy was slowed by luseogliflozin in T2DN rats, a genetic model of T2DM associated with severe nephropathy. It also prevents GFR decline and attenuates focal glomerulosclerosis, tubular necrosis, tubulointerstitial fibrosis,

Reduction in estimated GFR and nephroprotective effects has been reported with SGLT2-I in patients with DM [73, 80, 104]. Empagliflozin has been found to attenuate glomerular hyperfiltration in humans. It also reduces micro- and macroalbuminuria, and the effects are independent of the improved glycemic effect [105]. In CANVAS trial, canagliflozin has been found to reduce albuminuria and the

Results from a recent meta-analysis have indicated that SGLT2 inhibition preserves renal function in patient with or without renal impairment. They slow down the progression of albuminuria and reduce urinary albumin-to-creatinine ratio in addition to reducing the risk of doubling of the serum creatinine level, initiation of kidney transplant, and death from kidney disease in patient with T2DM with or

Increased risk of GMI and urinary tract infections (UTI) are seen in DM due to hyperglycemia and glucosuria. SGLT2-I therapy has been associated with increased risks for GMIs and UTIs. Women otherwise also are more commonly affected than

When treated with canagliflozin for 4 months, around 10.4% of women and 4.2% of men developed GMIs compared to 3.2% of women and 0.6% of men treated with placebo [108]. Most of the cases were of mild to moderate severity and could

Canagliflozin therapy in T2DM has been associated with UTIs in 8.7% of women compared to 7.7% treated with placebo. Figures for men were 1.4% versus 0.6%, respectively [109]. Similar findings were reported from pooled analysis of four studies (n = 2477) using empagliflozin. It was concluded that GMI were more common with empagliflozin than placebo (approximately 4 versus 1%, respectively);

Safety data from meta-analysis of eight studies using canagliflozin and dapagliflozin found that UTIs were more common with SGLT2-I as compared to other OAH (odds ratio, 1.42 [95% CI 1.06, 1.90]) as were GMI (odds ratio, 5.06 [95% CI 3.44, 7.45]) [111]. These studies suggests that most UTIs were mild to moderate, responded well to standard antimicrobial therapy, and rarely led to SGLT2-I discontinuation [112].

SGLT2-I therapy has been observed to be associated with small number of cases

with EKA during treatment of T1DM and insulin-deficient T2DM [113].

albumin-to-creatinine ratio when compared with placebo [106].

**6.6 Risks for adverse drug effects and restrictions of application**

men, and SGLT2-I therapy further increases the risk in them.

however, the frequency of UTI was about 8–9% for each [110].

be treated with standard antifungal agents successfully.

*6.5.3 Effects on kidney disease*

and progressive proteinuria [103].

without history of renal impairment [107].

*6.6.1 Genital and urinary infections*

*6.6.2 Euglycemic ketoacidosis*

**86**

In CANVAS study, the incidence rates were 0.5 per 1000 patient years with canagliflozin 100 mg, 0.8 per 1000 patient years with canagliflozin 300 mg, and 0.2 per 1000 patient years with comparator [114]. In the EMPA-REG trial, the incidence rates were 0.5 and 0.2 per 1000 patient years with empagliflozin 10 and 25 mg, respectively, and 1.2 per 1000 patient years in placebo group [88]. In DECLARE-TIMI 58, using dapagliflozin, the corresponding rates were 0.3%, whereas 0.1% occurred among placebo-treated group [97].

Majority of the cases have been reported from clinical practice rather than trials and have occurred in patients on exogenous insulin. Reduction in insulin dose on starting SGLT2-I has been observed in them. Usually they present with classical diabetic ketoacidosis (DKA) features. However, some cases may present atypically with lower-than-expected hyperglycemia, and it can go unrecognized.

Almost all cases occurred in patients challenged with metabolically stressful events and common precipitants such as surgery, myocardial infarction, stroke, extensive exercise, severe infections, and prolonged fasting.

Low serum bicarbonate and positive urinary ketones may be suggestive but may be inaccurate; therefore, direct measurement of serum betahydroxybutyrate level to confirm the diagnosis of EKA has been recommended by the AACE. Once the diagnosis of EKA is confirmed, SGLT2-I should be discontinued, and DKA protocol should be followed [115].

The increased risk of EKA associated with SGLT2-I therapy may be explained by absolute or relative insulin deficiency, increased glucagon secretion, and stimulation of lipolysis and ketogenesis; however, other ketogenic factors are also involved [31, 69].

Most cases of EKA have occurred in patients with T1DM, which is an off-label use of these agents that is not an FDA-approved indication. Because insulin deficiency may be the most important contributing factor, the AACE recommends against stopping insulin or decreasing the dose excessively. The risk of EKA has recently been shown in the EASE Trial to be dose dependent as lower doses of empagliflozin 2.5 mg were shown to be associated with lower rates of DKA, compared to 10 and 25 mg, respectively [116].

Although not approved for treatment of T1DM and SGLT2-I use is still off-label in T1DM, the AACE encourages clinical trials due to their promising effect on glycemic control in this population [115].
