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

10. Adverse Effects 

SGLT 2 inhibition or absence can also have substantial risks. Mice lacking SGLT2 had better diabetes control than wild-type controls, but they had immensely increased mortality and rate of infection. This was proportionate to gene loss; heterozygotes had a more favorable outcome than homozygotes. There were also increased urinary losses of magnesium and calcium in these sweet pee mice and some trend towards an increased excretion of phosphate [142]. The discrepancy between the outcome of these mice and patients with SGLT2 inhibition is striking; however, these mice have very good outcomes unless they were given streptozotocin to make them diabetic. This condition is not comparable to type 2 diabetes. Homozygous mice excreted an enormous amount of urine and glucose. Such a challenge to homeostasis obviously cannot be sustained for a long time. In humans, there are very few life-threatening side effects, with dehydration [40], diabetic ketoacidosis (often euglycemic), risk of amputation, genitourinary infections, and fractures being the most prominent.

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

SGLT2 increases the concentration of ketone bodies and may lead to euglycemic diabetic ketoacidosis, particularly in patients who lack enough insulin in the system [143]). As this is not the case in non-diabetic patients, no ketoacidosis event has been reported in this population [10]. Apart from the known risks, there is one more, probably underreported, side-effect of ketoacidosis: it might trigger arrhythmias. However, this is probably opposed by the decreased sympathetic activity that results from treatment with gliflozins. A very thorough review on this topic has recently been published [144]. A review of reports to the Food and Drug Administration's adverse event-reporting system revealed fewer atrial fibrillation events in patients on SGLT2 inhibitors compared to other antidiabetic drugs [145].

Genitourinary infections are more frequent in patients treated with SGLT2 inhibitors, which is not surprising [38,41,42,146]. There are few studies that did not report this side effect. They are also significantly more frequent in non-diabetic patients [10]. However, these are usually uncomplicated and mostly single episodes [147,148]. There is also a concern about bone homeostasis. The increased risk of fractures was found to be significant after more classes of antidiabetic drugs, including SGLT2 inhibitors [53]. However, in most large studies, no increase in fractures was reported. Meta-analyses are not completely conclusive. One of them found a significant increase in fractures after canagliflozin [149]; a more recent study did not find any statistical significance compared to placebo [150].

The higher risk of limb amputations reported in the CANVAS study [5] raised concern. However, most large studies did not find an increased risk and a recent meta-analysis confirmed no increase in amputations in a combined cohort of 63,716 patients [151]. This evidence was consistent across different types of SGLT2 inhibitors, baseline populations and lengths of treatment use. In an analysis including the CANVAS program and CREDENCE trials, a history of previous amputation was the strongest predictor of future amputation [152]; thus, the association with treatment was not necessarily causative. On the other hand, impaired recovery from hind limb ischemia was found in experimental diabetic mice treated with canagliflozin [69], so this risk needs ongoing vigilance and more experimental investigation. 

Some interesting and non-intuitive findings were reported when gliflozins were combined with training and other lifestyle modifications. Dapagliflozin blunted the improvement in insulin sensitivity induced by endurance exercise [153]. The effect of dietary counseling was also impeded by the same drug [154]. On the other hand, in another study, intensive exercise + dapagliflozin decreased the trunk fat mass [155]. However, the controls received dapagliflozin treatment only, and there was no control with training without treatment.

The described adverse effects were not numerous and were not severe enough to abolish the beneficial outcomes in the studies cited above.

11. Conclusions

Gliflozins decrease the amount of salt and water in the body, which decreases the workload of the heart. The increased availability of ketone bodies and switch of energy consumption from glucose to other sources improves its nutrition. The kidney workload is also decreased as hyperfiltration is abolished and the reabsorption of sodium and glucose is lower, which leads to lowered energy requirements. Both organs benefit from improved blood flow and a better oxygen supply with increased hematocrit. Better mitochondrial function also contributes to the better energy and oxygen utilization in the cells. Decreased sympathetic activity might be a significant contributor to both kidney and cardiac benefits. These effects are rapid and may partly explain the beneficial effects seen during short-term follow-up.

Improved compensation of diabetes or blood pressure is probably associated with better long-term outcomes after SGLT2 inhibition. In addition, gliflozins might also alleviate the burden of the "thrifty genotype" [156]. Fewer calories and salt are available for the body, even without a change in dietary habits. This effect differs from that of a low-carbohydrate diet because gliflozins help to excrete not only the glucose that was ingested but also glucose that originates from other types of nutrients and gluconeogenesis. The increased lipolysis of white fat has additional benefits for other organs, such as liver. A simplified graphic summary of the beneficial effects of SGLT2 inhibitors is provided in Figure 1. 

Figure 1. Beneficial effects of SGLT2 inhibitors on kidney, cardiovascular system, and liver. 

It is not obvious whether each of the metabolic changes described above contributes to the beneficial effect, and to what extent. Decreased inflammation and atherosclerosis will probably confer even more benefits when long-term follow-up is available. However, the long-term risk of fractures might also increase. As with all new drugs, a thorough and dutiful monitoring of adverse effects is necessary. SGLT2 inhibitors have attracted a huge amount of interest, which is probably at its peak at present. Their many beneficial effects improve our armamentarium against the burden of civilization diseases. If the side effects are carefully checked and controlled, their benefits are immense. As every functioning human kidney filters glucose, people without diabetes can also profit from the effect of this group of drugs, as was repeatedly shown. 

Author Contributions: V. ˇC.C. and O.Z. equally planned the work, extracted information from available evidence, and evaluated them for relevance to the paper. V. ˇC.C. wrote the paper. All authors have read and agreed to the published version of the manuscript. 

Funding: This research received funding from General University Hospital Research Project RVO-VFN64165. 

Conflicts of Interest: The authors declare no conflict of interest pertinent to the content of this paper.