Due to considerable glycemic and non-glycemic benefits, the FDA approved several selective SGLT-2 inhibitors for T2DM treatment ^[1][35]. Currently, all available gliflozins as drugs commercialized in pharmacies (Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin, and Bexagliflozin) have T2DM as a main common indication. Heart failure (HF) is mentioned for Dapagliflozin and Empagliflozin, and chronic kidney disease (CKD) only for Dapagliflozin.

Sotagliflozin, a dual SGLT-1/2 inhibitor, is the only representative officially indicated in T1DM.

Other new similar compounds (Ipragliflozin, Luseogliflozin, Tofogliflozin, and Remogliflozin) are investigated in clinical studies. The most recent SGLT inhibitors are investigated using pharmacokinetic and pharmacodynamic analyses (Remoglicoflozin ^[2][3][4][5][36,37,38,39], Henaglicoflozin ^[6][7][8][9][40,41,42,43], and Licoglicoflozin ^{[10][11][12][13]}[44,45,46,47]).

All data are summarized in Table 1.

Globally, SGLT-2 inhibitors are approximately the most prescribed oral antidiabetic drugs. Their beneficial effects beyond glycemic control include weight loss, protection against major cardiovascular events, blood pressure reduction, and delaying the progression of chronic kidney disease (CKD).

SGLT-2i directly reduces body weight by removing glucose through urine, thus increasing calorie loss. Glycosuria due to the SGLT-2 inhibitors leads to lower plasma glucose and insulin levels, followed by increased fasting and post-meal glucagon concentration. While blood glucose concentration is diminished, lipid storage is mobilized to be used as an energy substrate. The persistent excretion of glucose in urine induces increasing gluconeogenesis, suppresses tissue glucose disposal and glucose oxidation, accelerates lipolysis and fat oxidation, and enhances ketogenesis. The overall result of these metabolic changes resembles a fasting state, which will cause the loss of fat mass and weight in the long run ^[62][96]. Another study shows the concomitance of weight loss and Hemoglobin A1c level diminution during the therapy with SGLT-2is ^[63][97]. Thus, sodium-glucose cotransporter inhibitors could be called mimic-fasting medication to prevent cardiovascular complications ^[64][65][98,99]. SGLT-2 inhibitors reduce body weight by around 2–4 kg; this average is constant for all representatives and persists for up to 4 years ^[62][96].

Renal function improvement and preservation through hemodynamic and nonhemodynamic mechanisms are essential for SGLT-2 inhibitors in heart protection ^[66][100]. It is necessary to know the interactions between all biochemical processes, the chronology of all changes, and their correlation with the cardiovascular benefits of gliflozin therapy ^[67][101]. The potential mechanisms ^[68][31] are diuresis and natriuresis, changes in myocardial energetics, increased erythropoietin (EPO) production and erythropoiesis, changes in reno-cardiac signaling, inhibition of the sympathetic nervous system, inhibition of the Na⁺/H⁺ Exchanger-1 (NHE1), inhibition of the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome, potential vascular effects, and reducing uric acid levels in serum ^[69][102].

The highlight of SGLT-2i kidney protection led to significant interest in gliflozins’ broader applications in CKD therapy ^[70][103]. The potential mechanisms of their protective effects could be glucosuria, inducing natriuresis and osmotic diuresis and leading to reduced plasma volume and lower blood pressure, reducing proteinuria, and delaying CKD progression in patients with albuminuria ^[71][104], hemodynamic changes at the systemic and glomerular levels, metabolic pathway, and decreasing oxidative stress and inflammation.

The SGLT-2is induces glucose and sodium overexcretion, conducting osmotic diuresis. It may lead to hyperosmolarity and dehydration, increasing the risk of AKI ^[72][105]. Recent studies rigorously demonstrate that SGLT-2 inhibitors are safe for the kidneys and do not predispose to AKI ^[73][106].

Significant glucosuria and natriuria induced by SGLT-2is lead to polyuria due to osmotic diuresis.

Production of ketone bodies may show a dual face. The heart and brain can rapidly use them as energetic substrates, avoiding the accumulation of fatty acid or glucose metabolites. Normal ketone levels are <0.6 mmol/L. Most patients treated with SGLT-2is concomitantly have ketosis (ketone levels are slightly increased 0.6–1.5 mmol/L), and they do not develop ketoacidosis. Thus, the tendency toward ketosis can be augmented by a low-carb intake in patients who are trying to lose weight. Ketone bodies are produced by the oxidation of fatty acids in the liver as a source of alternative energy, generally occurring in glucose-limiting conditions. Elevated blood levels of acetoacetate (AA), 3-β-hydroxybutyrate (BHB), and acetone are known as hyperketonemia. BHB serum concentration increases after fasting but should not exceed 0.4 mmol/L. High levels of circulating ketones are linked to oxidative stress and numerous morbid conditions.

The risk of DKA is 1.5–3 mmol/L. DKA manifests when the ketone level is highly increased, over 3 mmol/L. Possible mechanisms ^[72][105] of SGLT-2 inhibitors associated with euglycemic DKA could be noninsulin-dependent glucose clearance, hyperglucagonemia, and volume depletion.

Glycosuria is the main factor implied in these infectious diseases, being a favorable medium for the growth of bacterial and fungal strains. They are more frequent in females and can be easily treated with non-expensive drugs.

Potential mechanisms for fractures ^[74][107] could be volume contraction leading to dizziness and falls, possible effects on calcium, phosphate, and vitamin D homeostasis, and reduction in bone mineral density. The amputation risk ^[75][108] is linked to peripheral vascular disease, neuropathy, history of diabetic foot ulcer, and previous history of amputations. Euglycemic DKA and its potential association with a significant risk for lower-extremity amputation represent sporadic but possible fatal adverse events of SGLT-2is. Some studies reported that SGLT-2 inhibitors in T2DM may cause latent autoimmune DM of adulthood (LADA) ^[76][109].

Despite the common knowledge that DM is associated with most known complications (traditional complications such as stroke, coronary heart disease, and heart failure, peripheral neuropathy, retinopathy, diabetic kidney disease), an increased prevalence of cardiovascular pathology and a group of lesser-studied ones have been reported (cancer, infections, functional and cognitive disability, liver disease and affective disorders) ^[77][110].

The benefits of SGLT-2 inhibitors in DM complications and comorbidities could be explained through the dual redox behavior of gliflozins (Figure 1) because oxidative stress has an essential role in their onset and harmful evolution. High blood glucose levels induce ROS production, leading to overexpression of the SGLT-2 in tubular cells, exacerbating oxidative stress. SGLT-2is has demonstrated clear cardiovascular and renal protection due to its antioxidant properties. Severe systemic comorbidity that involves the whole body, leading to functional decline and harmful outcomes ^[78][79][80][111,112,113] is frailty ^{[81][82][83][84][85][86][87]}[114,115,116,117,118,119,120] or functional disability ^{[88][89][90][91]}[121,122,123,124], and its management is still debated ^[86][87][119,120]. SGLT-2i positively acts on cardiovascular complications, especially on the HF rehospitalization rate ^[92][125], during several potential mechanisms: improving cardiovascular energetics, reducing vascular tone and blood pressure, decreasing systemic inflammation, atheroprotective effects, reduction of vascular damage, and direct neuroprotective mechanisms (acetylcholinesterase inhibition and increase in cerebral levels of brain-derived neurotrophic factor). All benefits could be maintained through rigorous balancing between oxidant and antioxidant processes ^[93][126].

The anticancer potential of gliflozins depends on the blood glucose-lowering capacity ^[95][96][128,129]. SGLT-2 inhibitors induce apoptosis and DNA damage, reducing cancer cell proliferation ^{[97][98][99][100][101][102][103][104]}[130,131,132,133,134,135,136,137] through mitochondrial membrane instability metabolic changes (oxidative phosphorylation, DNA synthesis, glycolysis, ATP and fatty acids level diminution, beta-oxidation, and ketone amount augmentation).

DM is also associated with cancer development through a complex mechanism. Treatment with SGLT-2 inhibitors can diminish the risk of cancer incidence in DM patients ^[105][138] because gliflozins have anticancer activity through various mechanisms, as previously shown ^{[106][107][108][109][110][111][112]}[139,140,141,142,143,144,145]. Moreover, SGLT-2 inhibitors can protect DM patients against the cardiotoxic action of anticancer drugs ^[68][31].

The most common reasons for discontinuing treatment with SGLT-2is are frequent urination, genital infection, improved glycemic control, and renal dysfunction. A recent retrospective study ^[113][146] did not find a correlation between patients’ compliance and DM type, duration, diabetic control, renal function, or DM complications of diabetes in both groups. Only the age was correlated (the adherence negatively correlates with the patient’s age).