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

Abstract: Sodium glucose transporter type 2 (SGLT2) molecules are found in proximal tubules of the kidney, and perhaps in the brain or intestine, but rarely in any other tissue. However, their inhibitors, intended to improve diabetes compensation, have many more beneficial effects. They improve kidney and cardiovascular outcomes and decrease mortality. These benefits are not limited to diabetics but were also found in non-diabetic individuals. The pathophysiological pathways underlying the treatment success have been investigated in both clinical and experimental studies. There have been numerous excellent reviews, but these were mostly restricted to limited aspects of the knowledge. This review aims to summarize the known experimental and clinical evidence of SGLT2 inhibitors' effects on individual organs (kidney, heart, liver, etc.), as well as the systemic changes that lead to an improvement in clinical outcomes. 

Keywords: SGLT2; SGLT2 inhibitors; diabetes; chronic kidney disease; heart failure 

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

1. Introduction 

Physicians who trained at the end of the last century were used to evaluate the compensation of diabetes by the presence or absence of glucosuria. They may consider improving compensation by increasing glucose excretion in urine to be considered very controversial. However, sodium-glucose transporter type 2 (SGLT2) inhibitors not only cause glucosuria and improve diabetic compensation, but also decrease the risk of chronic kidney disease (CKD) progression [1–3], decrease the risk of cardiovascular events [3–7], and even lower all-cause mortality in treated patients [2,4,6,8]. The most puzzling information is that they have these effects in non-diabetic individuals as well [4,9], even if the mortality is not decreased, as was shown in a recent meta-analysis [10]. After years of negative studies with other kinds of drugs, this was a very satisfying result.

To some extent, this resembles the impact of angiotensin-converting enzyme inhibitors (ACEI). However, it is known that the renin-angiotensin-aldosterone system (RAAS) or its parts are found throughout the body [11]. It is not difficult to understand that ACEI will have different effects than merely lowering blood pressure. On the other hand, SGLT2 is mainly expressed in the S1 and S2 parts of the proximal renal tubule. There were hardly any other sites where substantial amounts of SGLT2 receptors were found [12], apart from the brain [13], and maybe also the intestinal mucosa [14]. SGLT2 is responsible for the renal reabsorption of 90% of filtered glucose. The rest is transported further downstream by sodium glucose transporter type 1 (SGLT1) [15]. However, blockade or knockout of SGLT2 only decreases glucose reabsorption by 30–50%, and not by 90%, as would be expected. This is probably caused by the upregulation of SGLT1. Mice with double knockout of SGLT1 and SGLT2 excreted three times more glucose than SGLT 2 knockouts alone [16]. Dual SGLT1 and SGLT2 inhibitors, canagliflozin and sotagliflozin, were also found to inhibit intestinal SGLT1 [17,18], but this is not a class effect.

How can the inhibition of a single transporter in a tiny part of the nephron in a small organ of the kidney have such a huge impact on the fate of the whole body? There have been numerous recent reviews on this topic, which cannot be cited here in full; however, they mostly deal with only part of the effects.

Thus, this review aims to summarize the effects to explain the improvement in many renal, cardiovascular, and mortality outcomes. However, it is important to bear in mind that not everything is known at present, and most effects are subject to interconnecting regulatory positive and negative feedback. SGLT2 inhibitors induce systemic changes that might affect individual organs, such as kidneys and heart, secondarily, and specific singleorgan changes that contribute to the overall improvement. The systemic changes include diabetes compensation, a decrease in body weight, blood pressure lowering, and decreased sympathetic tone, as well as the suppression of inflammation and atherosclerosis. Other important metabolic improvements include a lower concentration of uric acid, lower incidence of hyperkalemia, normalization of magnesium concentrations, etc. Blood parameter changes after SGLT2 inhibitors are summarized in Table 1. Improvements in the composition and function of individual organs were found in the kidney, heart, liver, and retina [19].

Table 1. Metabolic effects of gliflozins, apart from decreasing glycemia and glycosylated hemoglobin. LDLcholesterol: low-density lipoprotein cholesterol; HDL-cholesterol: high-density lipoprotein cholesterol. 

2. Diabetes Compensation 

SGLT2 inhibitors are primarily antidiabetic drugs. They were properly tested for efficacy and safety before being approved by respective regulatory authorities. Thus, the studies confirming a glucose-lowering effect and diabetes compensation will not be cited in this paragraph; they will be cited when additional effects are documented. 

A better compensation for diabetes undoubtedly improves outcomes for diabetics [31]. Gliflozins decrease glycosylated hemoglobin (GHbA1c) by approximately one percentage point when used as a monotherapy or as an add-on to other drugs. This is comparable to dipeptidyl-peptidase 4 inhibitors, but lower than sulfonylureas or glucagon-like-peptide-1 (GLP-1) agonists. This decrease cannot fully explain the early improvement in heart, kidney, and survival outcomes (within 1–2 years of follow-up), which are not proportionate to the degree of compensation [32]. SGLT2 inhibitors not only decrease the amount of glucose in the system but also improve insulin sensitivity [33]. Gliflozins improve the survival and regeneration of beta-cells [34]; however, this effect has also been described after other drugs [35]. Again, this does not explain the short-term effect. However, in the long term, it alleviates the burden of diabetic complications.

The beneficial effect might be partly attenuated by increased endogenous glucose production [36,37]. Gliflozins also shift the utilization of substrates from carbohydrates to lipids [37], which might improve the nutrition of the cells. In conclusion, SGLT2 inhibitors improve diabetes compensation by decreasing glucose availability and improving insulin sensitivity and energy utilization.

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 decrease in body weight might be partly driven by the change in gut microbiota. 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.