Sodium Glucose Cotransporter-2 Inhibitors: Spotlight On Favorable Effects On Clinical Outcomes Beyond Diabetes Ⅱ

3. Decreasing the Body Weight

The first studies testing gliflozins for effectivity and safety usually also reported a loss of body weight [38–41], even if not all of them [42]. Gliflozins stimulate lipolysis, lipid oxidation, and ketogenesis, which helps to reduce body fat [43]. The change in gut microbiota might partly drive the decrease in body weight. This was proven in mice [44], but not in humans [45]. Loss of glucose decreases the calories available to the body. This might lead to hyperphagia to compensate, as reported in Reference [18]. However, not every experiment is in concordance with this. Sawada et al. reported no hyperphagia compared to untreated rats when rats were fed on a high-fat diet. In their experiment, the explanation for the slower gains in body weight was the liver–brain–adipose neural axis. Tofogliflozin decreased fat mass in intact mice, but this effect was attenuated by hepatic vagotomy [46]. SGLT2 inhibition by canagliflozin promoted adipose thermogenesis, mitochondrial biogenesis, and lipolysis via the β-adrenoceptor-cyclic adenosine30 5 0 -monophosphate-protein kinase A pathway [47]. Moreover, SGLT 2 inhibitors induce white adipose tissue lipolysis. This effect is not highly desirable as it might trigger diabetic ketoacidosis [48], but it can prevent fat accumulation driven by insulin. As both American and European guidelines recommend the treatment of obesity in individuals with type 2 diabetes (T2D) [49], lowering body weight might be another pathway to better outcomes in treated patients. 

HOW LONG DOES IT TAKE FOR CISTANCHE TO WORK FOR KIDNEY DISEASE PATIENTS?

4. Blood Pressure Lowering 

SGLT2 inhibitors decrease blood pressure, as was found in earlier studies [40,41] and pooled data [50], and confirmed in recent metanalyses [51,52]. However, the real decrease is only several mmHg compared with usual care. Canagliflozin induced natriuresis, but not urine output, so no osmotic diuresis was seen [53]. However, in acute cardiac failure, osmotic diuresis was found, but fractional sodium excretion was not increased [54]. Dapagliflozin was found to decrease estimated plasma volume by approximately 10%, which might help to decrease blood pressure [55]. Extracellular and plasma volumes were also decreased after empagliflozin [56]. The skin sodium content was decreased after 6 weeks of dapagliflozin [57]. A lower plasma volume and sodium body content are probably the primary mechanisms that decrease blood pressure. In animals, night dipping might also be restored by gliflozins; in humans, the pattern was maintained [58]. This effect is increased in combination with RAAS inhibitors. A benefit was also found in combination with beta-blockers or calcium-channel blockers [59] but was not potentiated by thiazide diuretics or furosemide, probably because gliflozins trigger a substantial increase in plasma renin and aldosterone [29]. However, not every study found a correlation with other antihypertensives [60]. Decreasing the sympathetic activity driven by the kidney might be one of the major mechanisms that lead to decreased incidence of heart failure, as summarized in a recent review [61]. In our opinion, the kidney protection cannot be explained by the blood pressure effect only, as glomerular and interstitial fibrosis and inflammatory infiltrates were attenuated by empagliflozin, without any effect on blood pressure in angiotensin-IIdependent hypertension in rats [62]. Based on the available evidence, clinical guidelines recommend the treatment of hypertension and maintenance of normal blood pressure in both diabetic and non-diabetic populations to prevent cardiovascular and kidney complications [63–66]. The contribution of SGLT2 inhibitors to blood pressure lowering might be another benefit leading to better outcomes. 

5. Vascular Effects and Inflammation 

Cardiovascular outcomes, as well as the kidney outcomes mentioned above, might be driven by vascular, inflammatory, and subcellular changes. Indeed, inflammation, angiogenesis, atherosclerosis, and arterial stiffness were influenced by this medication.

Activation of the NLR family, pyrin-domain-containing 3 (NLRP3) inflammasome, and subsequent interleukin (IL)-1β release induces atherosclerosis and heart failure [67]. Patients with T2D and high cardiovascular risk received SGLT2 inhibitor empagliflozin or sulfonylurea for 30 days, with NLRP3 inflammasome activation analyzed in macrophages. While the SGLT2 inhibitor's glucose-lowering capacity is comparable to sulfonylurea, it showed a greater reduction in IL-1β secretion compared to sulfonylurea, accompanied by increased serum β-hydroxybutyrate and decreased serum insulin [67]. 

Canagliflozin decreased leptin increased adiponectin and decreased proinflammatory IL-6. Some increase in tumor necrosis factor (TNF) alpha was also found in this study; however, the cause and significance of this is unknown [68].

Canagliflozin decreased angiogenesis in diabetic mice [69]. However, this is a double-edged sword. It might decrease the repair after ischemia, as in the cited study. The CANVAS trial reported a higher incidence of amputations in humans as well, even if this was not confirmed in other studies. On the other hand, the inhibition of angiogenesis might lead to a slower progression of diabetic retinopathy [70]. The second study used the same model of diabetic mice but a different drug, tofogliflozin. Both drugs decreased the vascular endothelial growth factor. A pilot trial in humans also suggests beneficial effects in retinopathy [71]. 

Another common pathway leading to better outcomes might be improved mitochondrial function [72,73]. Improved energy production and mitochondrial biogenesis were found in experimental studies [74]. 

No long-term trials with atherosclerosis development as an outcome are available in humans at present. Atherosclerosis risk factors, such as glucose metabolism, uric acid concentrations, blood pressure normalization, and body-weight lowering are all influenced by gliflozins. The lipid profile changes have also been investigated in more detail, as well as parameters of vascular stiffness and endothelial function. Dapagliflozin was proven to decrease atherosclerosis development and endothelial dysfunction in apo-E-deficient diabetic mice [75]. In a different model, empagliflozin accelerated the regression of atherosclerosis [76]. Lowered triglyceride content and an increase in HDL cholesterol were also found in hypertriglyceridemic mice [77]. A recent meta-analysis found that SGLT2 inhibitors increase total cholesterol levels, high-density lipoprotein (HDL)-cholesterol, and low-density lipoprotein (LDL)-cholesterol. Gliflozins also decreased triglyceride concentrations, which is consistent with animal studies [28]. Increased LDL-cholesterol is not a desirable effect. However, a study with dapagliflozin found an increase in the less atherogenic, large buoyant LDL-cholesterol and suppression of atherogenic, small dense LDL-cholesterol [27], which suggests a more favorable profile. Vascular parameters were also studied in humans. Arterial stiffness is an established risk factor for cardiovascular risk. In a post hoc analysis of a phase III study with empagliflozin, the ambulatory arterial stiffness index exhibited a decreasing trend, and pulse pressure and double product (systolic BP * heart rate) were significantly lower [50]. In a pooled analysis of five randomized studies with canagliflozin, the pulse pressure and double product were also decreased [78]. However, the double product is not a very helpful predictor of cardiovascular outcomes [79]. Acute dapagliflozin medication decreased brachial artery-endothelium-dependent and independent vasodilatation and pulse wave velocity [80]. Flow-mediated dilation was also improved in another study [81]. Improved vascular health and less inflammation might be another benefit of SGLT2 inhibitors. However, long-term human studies are still lacking.

6. Other Metabolic and Blood Composition Consequences 

As mentioned previously, gliflozins also have significant effects on parameters that are not directly related to their main antidiabetic role [82,83]. Some of them can add to the beneficial effects of gliflozins. Others can mediate the adverse events associated with this medication. Glycosuria increases the excretion of uric acid [84]. This is most probably not mediated by SGLT2 because SGLT2 does not transport fructose and fructosuria has the same uricosuric effect in mice [85]. The connecting transporter can be glucose transporter type 9 (GLUT9), which transports both hexoses and uric acid in the opposite direction. If there is abundant glucose in the lumen, uric acid excretion increases in both the proximal tubule and the collecting duct, where different isoforms of GLUT 9 are located [86]. However, in a recent study in mice, urate transporter URAT1, rather than GLUT9, was necessary for the uricosuric effect of canagliflozin [87]. Baseline uric acid levels were associated with worse outcomes in a sub-analysis of the EMPA-Reg study and empagliflozin improved these outcomes [88]. In pooled data from four studies with canagliflozin, a 13% reduction in uric acid concentration was found [25]. A recent network meta-analysis [26] confirmed these findings. Uricosuria is a class effect; however, individual compounds were not found equal in this study. A Japanese analysis of three studies with luseogliflozin found both decreased and increased uric acid after 12 weeks, and this effect was dependent on the baseline uric acid concentration, glycosylated hemoglobin, and glomerular filtration [89]. Thus, more research elucidating these differences is necessary.

Magnesium deficiency increases cardiovascular risks and diabetics frequently have hypomagnesemia [90]. Gliflozin treatment increases plasma magnesium [22]. In pooled data from 10 studies, a correction of hypomagnesemia by dapagliflozin was found [23].

Hyperkalemia is frequent in patients with decreased glomerular filtration and diabetes. Drugs that inhibit the renin-angiotensin-aldosterone system substantially increase this risk. On the other hand, hypokalemia is also a risk, mainly in heart failure patients. An increased distal nephron flow increases potassium losses. Post-hoc analysis of the CREDENCE trial showed a lower incidence of hyperkalemia or initiation of potassium binders [20]. According to a review by Fillipatos et al., a very small increase in potassium concentration was reported in some studies, but no significant change was found [21].

SGLT2 inhibitors increase hematocrit, and this effect is slightly dependent on dose [30]. It can be partly attributed to a decrease in plasma volume, as mentioned previously. However, in an analysis of the EMPA-REG study, a transient increase in reticulocytes was also observed, suggesting increased erythrocyte production [91]. Increased erythrocyte production was also found in another study with empagliflozin: transferrin was elevated, while ferritin, total iron, and transferrin saturation decreased. There was some trend toward increased erythropoietin [92]. 

The evidence of bone metabolism changes is somewhat conflicting. Some small studies did not find any changes in the parameters of bone formation or resorption [39,93]. On the other hand, in healthy volunteers, canagliflozin increased phosphate, fibroblast growth factor 23 (FGF-23), and parathormone (PTH), and decreased 1,25-OH vitamin D, in a crossover study, and very similar findings have been demonstrated after dapagliflozin treatment [22,24]. In a post hoc analysis of the IMPROVE trial, dapagliflozin increased serum phosphate, PTH, and FGF- 23 and tended to decrease 1,25-OH vitamin D, without any correlation with the changes in estimated glomerular filtration rate (eGFR) and albuminuria [24]. 

Some changes in laboratory parameters have been associated with better outcomes and some with increased risk of complications, as mentioned above. However, as they might be mixed in individual patients, it is difficult to predict the outcome on this basis only. 

7. Kidney Protection 

As SGLT 2 is found in the kidney, the first positive organ effect should be found there. In fact, hemodynamic, glomerular, and tubulointerstitial mechanisms work in concert and all of them contribute to the beneficial effect, demonstrated as a slower deterioration in glomerular filtration [94], and better renal survival in clinical studies, together with decreased albuminuria [3,95]. Patients without diabetes benefited to the same extent, as patients with decreased renal function [96]. This effect was not attenuated by significantly lower baseline glomerular filtration and the benefits for patients with CKD grade 4 were consistent with other patients in DAPA-CKD [97]. A post hoc analysis of EMPA-REG outcome found a consistent decrease in renal outcome across KDIGO risk categories [98].

Non-diabetic patients with heart failure also exhibited fewer renal outcomes over 16 months of treatment [9].

Glomerular protection is the main pathway to better outcomes. Lower systemic blood pressure and a decrease in hyperfiltration have already been mentioned. However, a drop in glomerular filtration rate appears at the beginning of treatment, which is probably absent in individuals with normal glomerular filtration rate [99] and is not sustained. In moderate renal impairment, there was a decrease in glomerular filtration at the beginning of treatment, but this was found to be reversible after drug withdrawal following 24 weeks of treatment [100]. In the DECLARE-TIMI study, the decrease was larger after one year, the same after 2 years, and lower than in controls after 3 or 4 years [3], showing better renal function preservation after dapagliflozin treatment. Similar findings were found with canagliflozin in the CREDENCE study. This effect was maintained in lower GFR groups [101,102]. 

The decrease in albumin/creatinine ratio in those starting with albuminuria is remarkable and, unlike the decrease in glomerular filtration, it is usually sustained [96,103]. Proproteinuria/albuminuria is a surrogate marker, and its decrease cannot replace hard outcomes. However, in the CREDENCE trial, the decrease in albuminuria caused by canagliflozin was independently associated with a lower risk of primary kidney outcome, major cardiovascular events, and hospitalization for heart failure or cardiovascular death. Residual albuminuria after 26 weeks was an independent risk factor for kidney and cardiovascular events [101]. In non-diabetics, the lowering of albuminuria is reduced compared to in diabetics, but the effect on outcomes is comparable [104].

The decreased absorption of sodium in the proximal tubule increases sodium delivery to macula densa. The tubuloglomerular feedback then increases afferent arteriolar vascular tone and decreases glomerular filtration, abolishing the hyperfiltration that leads to albuminuria and glomerular damage, which was also found in diabetes type 1 (T1D) patients [105]. However, in type 2 diabetics, postglomerular rather than preglomerular vasodilatation was found [106]. 

Tubular cells are also protected under SGLT2 inhibition. Gilbert, in his letter to the editor [107], suggested the underlying mechanism of this: sodium and glucose reabsorption in the proximal tubule is energy- and oxygen-consuming. If this transport is blocked, the decreased workload and oxygen demand decrease tubulointerstitial damage. However, in a human study, no difference was found in cortical or medullary oxygenation. Proximal sodium reabsorption decreased but was restored after 1 month due to the rise in renin and aldosterone [29]. 

In the experiment, podocyte protection by the restoration of autophagy was found after medication with empagliflozin [108]. Autophagy is a cellular recycling process involving self-degradation and the reconstruction of damaged organelles and proteins. This process is vital for podocytes [109]. Dapagliflozin decreased mesangial expansion, tubulointerstitial fibrosis renal collagen, and fibronectin accumulation. It also modulates tubular cells' response to hypoxia in streptozotocin-induced diabetes in rats [110]. 

SGLT2 inhibition decreases the O-linked N-acetylglucosamine-acylation of megalin, leading to accelerated internalization. This ameliorated protein overload of proximal tubular cells, mitochondrial morphological abnormality, renal oxidative stress, and tubulointerstitial fibrosis [111]. In tubules, SGLT2 inhibition reduced apoptosis and lipid droplet deposition in tubular cells [112]. 

There are additional tissue and cellular effects in the kidneys. Li et al. have demonstrated the decreased availability of mitochondrial deacetylase sirtuin 3 in the proximal tubule cells of diabetic mice [113]. This leads to aberrant glucose metabolism and increased endothelial–memenchymal transition in adjacent vessels, which increases the amount of interstitial fibrosis. Empagliflozin, but not insulin, was able to restore these changes, and, at the same time, improved glomerular damage.

In summary, SGLT2 treatment improves kidney functional and structural parameters by multiple mechanisms, which was confirmed in both experiments and humans. Functional changes, mainly the decrease in hyperfiltration and tubular protein overload, occur rapidly and might be the underlying cause of the short-term outcomes. Structural improvements will hopefully show long-term effects on humans in the future. 

8. Heart and Cardiovascular Protection 

Gliflozin treatment reduced the risk of heart failure in diabetic patients, as demonstrated in more clinical trials and confirmed in metanalysis [114]. Patients with established heart failure with reduced ejection fraction also profited from the treatment, as was shown in numerous studies: EMPA-HEART in diabetics [115], Define-HF in the diabetic and non-diabetic population [116], or DAPA-HF [4,117]. The findings were consistent in a large study on real-life patients in registries [6]. The DAPA-HF results show that favorable results are maintained in older age categories [118]. Empagliflozin not only decreased the risk of worsening but was associated with improved cardiorespiratory fitness [119]. There was a significant decrease in left ventricular mass indexed to body surface area in the EMPA-HEART study [115]. However, the REFORM trial, recruiting patients with diabetes and heart failure with reduced ejection fraction (HFrEF), was not able to see any significant remodeling of the left ventricle. However, the study had only 56 patients and most of them had New York Heart Association (NYHA) class I-II, so this was probably an underpowered study. On the contrary, the ATRU-4 study recruited non-diabetic patients with HFrEF NYHA class II-III. After 6 months of follow-up, they were able to demonstrate significant heart remodeling. There wasa  decrease in end-systolic and end-diastolic volumes, a decrease in the intracellular matrix and the amount of epicardial adipose tissue, and decreased arterial stiffness [120]. Remarkable clinical benefits, as well as improved quality of life, were also demonstrated [121]. In a study of 244 patients with 12 weeks of dapagliflozin, there was a reduction in stroke volume cardiac output, and vascular stiffness, together with mean blood pressure. The systemic changes did not correlate with renal hemodynamic changes. [122] 

Single studies reported no change in N-terminal natriuretic propeptide type B (NTproBNP) in patients with heart failure with reduced ejection fraction [116]. However, the clinical endpoints were improved in acute heart failure [123]. The analysis of participants in the CANVAS program, after 1 year and 6 years, showed a consistent reduction in NT-BNP in patients with canagliflozin versus those without canagliflozin [124]. The EMPEROR-REDUCED study also found decreases in cardiac and renal adverse outcomes in non-diabetic individuals [9]. Diastolic, rather than systolic, function was improved in a small study with empagliflozin [125]. However, another study with the same drug also found improvements in systolic function and reductions in left ventricular mass in patients with HFrEF after 6 months of treatment [126]. Empagliflozin reduces extracellular volume in the heart, thus improving the volume of active tissue [127]. Twelve weeks of therapy with dapagliflozin also decreased lung fluid volume [128]. However, myocardial flow reserve was not improved after 13 weeks of empagliflozin [129].

The mechanisms underlying these effects have not been completely explored. Decreased energy requirements and the improved mitochondrial metabolism and utilization of ketone bodies are probably the most plausible explanations for this [130,131]. Dapagliflozin was also found to be protective in ischemia-reperfusion injury in the animal experiments [132]. Luseogliflozin decreases pericardial fat and muscle mass [133]. In conclusion, SGLT2 inhibitors improve the functional and structural characteristics of the heart and energy requirements and utilization. Apart from structural changes, all others can be beneficial in the short term and might explain short-term cardiovascular benefits. 

9. Liver Steatosis 

Improvements in the concentration of liver enzymes are frequently found in studies. According to recent meta-analyses, gliflozins decrease alanine aminotransferase (ALT)and gamma-glutamyl transferase (GGT) concentrations and decrease the content of liver fat [134]. In a different metanalysis, the results were similar, but aspartate aminotransferase (AST) was also significantly lower [135]. This effect probably does not depend on weight loss only [135]. A small study in India found decreased liver fat on magnetic resonance imaging after 20 weeks of empagliflozin [136], and a similar effect was found in the European population [137]. However, there are no clinical studies that would include liver histology; therefore, changes in liver structure are not directly documented.

There is some more evidence from experimental data. Empagliflozin was found to decrease liver steatosis similarly to metformin and change liver transcriptome in a rat model of T2D [138]. Non-alcoholic steatohepatitis (NASH) was also ameliorated, but comparatively with metformin in rodent experiments [139]. A non-obese prediabetic model of hereditary hypertriglyceridemic rats and treatment with empagliflozin was used in another experiment. Hepatokines fibroblast growth factor 21 (FGF21) and fetuin-A decreased in controls and hypertriglyceridemic rats after treatment. Hepatic glycogen was also significantly decreased [140]. As non-alcoholic fatty liver disease (of which NASH is the most severe stage) is a risk factor for cardiovascular outcomes [141], the amelioration of liver function and structure might lead to improved outcomes after SGLT2 inhibition.

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