**8. SGLT2 inhibitors**

#### **8.1. Dapagliflozin**

Dapagliflozin was the first hypoglycemic agent of the new class of selective reversible inhibitors of sodium-glucose cotransporter 2 (SGLT2) approved in the US (April 2012) and demonstrates a new mechanism of action independent of insulin. This drug is recommended in adults aged 18 years or older with type 2 diabetes, both as a monotherapy and as a combi‐ nation therapy with other hypoglycemic drugs, including insulin when diet and exercise does not provide adequate glycemic control [143-145].

The hypoglycemic effect occurs by reducing the reabsorption of glucose from the renal proximal tubule, which leads to increased urinary excretion of glucose with an associated loss of calories [143, 144]. On average, a daily dose of 10 mg dapagliflozin increases the amount of glucose excreted in the urine of a patient with type 2 diabetes to 50-80 g/day. This effect is observed with the first dose, and with chronic treatment, this increased excretion of glucose can be maintained for at least two years [146, 147].

In patients with type 2 diabetes, urinary loss of glucose works through a mechanism inde‐ pendent of insulin secretion and action [148-153] and has the potential to improve glycemic control, including control of HbA1c, fasting plasma glucose and postprandial glucose.

The selectivity of dapagliflozin for SGLT2 is 1000-3000 times greater than for SGLT1 [154].

Dapagliflozin is rapidly and extensively absorbed following oral administration. The oral bioavailability of a 10 mg dose is ≥ 75% and may be administered with or without food. It is extensively metabolized to inactive conjugates, predominantly dapagliflozin 3-*O*-glucuronide, which is then eliminated via the kidneys [146, 154].

Dapagliflozin's effectiveness is dependent on renal function and therefore should not be used by patients with moderate to severe renal impairment; dose adjustment is necessary for patients with mild renal failure or moderate hepatic impairment. Moreover, dapagliflozin should not be used in patients with severe hepatic impairment because exposure to dapagli‐ flozin can be increased.

Interactions between dapagliflozin and other agents routinely used in the control of diabetes mellitus, including sulfonylureas, statins, warfarin and digoxin, were observed [154].

Dapagliflozin was generally well tolerated in clinical trials lasting 1 or 2 years and in studies lasting approximately 2 years [146]. Polyuria, nocturia and thirst may be experienced by some patients, and the increased excretion of glucose causes osmotic diuresis, which is similar to what is observed in patients with uncontrolled diabetes. The additional fluid loss of 300-400 ml/day is well tolerated by most patients [149, 155].

Genital infections are common in patients receiving dapagliflozin because glycosuria provides a favorable environment for the growth of microorganisms [146, 149, 155].

Dapagliflozin is recommended for patients with T2DM in the following situations [154]:


fenfluramine and dexfenfluramine (sympathomimetic amines that promote appetite suppres‐ sion) were withdrawn from the market because of the risk of heart damage. The European Medicines Agency (EMA) suggested the withdrawal of various anti-obesity drugs, such as diethylpropion (amfepramone), mazindol and phentermine (also sympathomimetic amines inhibiting appetite), in the 2000s because of the high risk of adverse events. In 2006, rimonabant (first selective blocker of endocannabinoid receptor subtype 1-CB1) became available in 56 countries; however, because of its adverse psychiatric events, this drug was never approved by the FDA and was withdrawn from the European market in 2009. Additionally, after clinical trials assessing the safety and tolerability of sibutramine (an appetite suppressant that acts as a selective inhibitor of the reuptake of norepinephrine and serotonin), the FDA considered the option to restrict access to this substance or withdraw it from the market, causing the suspen‐

From the drugs approved before 2012, several sympathomimetic amines are available. These include phentermine, diethylpropion, benzphetamine and phendimetrazine, which are approved for short-term weight management (≤ 12 weeks), and orlistat (a potent reversible inhibitor of gastric and pancreatic lipase capable of preventing the absorption of up to 30% of dietary fat), which is the only anti-obesity drug for long-term use [130, 134, 135]. In 2012, the FDA approved two new drugs for obesity control: lorcaserin (agonist of the serotonin receptor 5-HT2C) and extended release phentermine-topiramate (association between a sympathomi‐ metic amine appetite suppressant and an anticonvulsant). The mechanism responsible for weight loss when using extended release phentermine-topiramate is believed to be the subsequent increase in activity of the neurotransmitter gamma-aminobutyric acid (GABA), although the exact association mechanism remains unclear. Both drugs were approved for

Depression is a common side effect observed in patients with type 2 diabetes, which may be associated with a lack of glycemic control, increased risk of complications, lack of adherence to treatment and even the presence of obesity or overweightness [137, 138]. A meta-analysis in 2001 by Anderson et al. showed that the prevalence of depression was twice as high in individuals with T2DM than in those without this health condition. Thus, reducing the incidence of depression and improving the quality of life of diabetic patients, especially those who are also obese, are highly relevant clinical objectives [139-141]. The treatment of depres‐ sion in diabetics is usually accomplished by the use of serotonin reuptake inhibitors, such as fluoxetine and sertraline. These drugs not only act on depression but also promote weight loss,

Dapagliflozin was the first hypoglycemic agent of the new class of selective reversible inhibitors of sodium-glucose cotransporter 2 (SGLT2) approved in the US (April 2012) and demonstrates a new mechanism of action independent of insulin. This drug is recommended

which is highly desired in obese or overweight diabetics [68, 142].

sion of marketing authorization in 2010 [130, 133].

long-term use [131, 136, 137].

162 Treatment of Type 2 Diabetes

**8. SGLT2 inhibitors**

**8.1. Dapagliflozin**

**3.** with metformin, diet and exercise, to improve glycemic control in patients when these measures alone do not achieve adequate glycemic control and there is little prospect of therapeutic response to metformin (e.g., high HbA1c levels);


A number of other SGLT2 inhibitors are under investigation, including empagliflozin, canagliflozin and ipragliflozin. In addition, a non-selective SGLT inhibitor (LX4211) is under development. It is likely that these and other agents that share similar pharmacodynamic properties may become available in the coming years [146].
