5.1 Adverse events

The adverse events related to SGLT2 inhibitors mainly include genital infection, urinary tract infection (UTI), diabetic ketoacidosis (DKA), acute kidney injury (AKI), hypotension, lower limb amputation, hypoglycemia, cancer risk, Fournier gangrene, skin disorders, and bone fracture.26 Among the adverse events above, genital infection, UTI and DKA are more common and convictive in current studies.

In patients who received SGLT2 inhibitors, genital infection is a common adverse event reported in most RCTs, including the EMPA-REG outcome and DECLARE-TIMI 58.13, 15A meta-analysis including 52 RCTs showed that canagliflozin, dapagliflozin, and empagliflozin involved a higher risk of genital infection than placebo.27 The Association of British Clinical Diabetologists analysed 1049 patients (476 women, 573 men) with type 2 diabetes who were treated with dapagliflozin; the results showed that the incidence of genital fungal infection was higher in women and patients with a previous history of genital fungal infection.28 Some previous studies have also found that women were at a higher risk of genital infection.29, 30 UTI appeared to be more common in patients who received SGLT2 inhibitors; however, no consensus has been reached in recent studies. A higher incidence of UTI was not observed in popular, large-scale RCTs, such as the DECLARE-TIMI 58, EMPA-REG outcome, and CREDENCE. A meta-analysis on 110 studies reported the incidence of UTI related to SGLT2 inhibitors therapy and found that patients with dapagliflozin were at a higher risk of UTI than those with placebo; however, such risk was not observed in patients with the empagliflozin, canagliflozin, ipragliflozin, or non-marketed SGLT2 inhibitors.31 Thus, more attention with respect to UTI should be paid in patients with dapagliflozin, although the mechanism of action remains unclear.

DKA occurred in patients with SGLT2 inhibitors and was generally euglycemic or slightly elevated, termed as euglycemic diabetic ketoacidosis. The large-scale RCTs, such as DECLARE-TIMI 58, EMPA-REG Outcome, and CREDENCE, showed that the risk of DKA was higher in the SGLT2 inhibitors group than in the placebo group. Moreover, the US FDA and the EMA had issued a warning that SGLT2 inhibitors may lead to euglycemic diabetic ketoacidosis. Data from the FDA Adverse Event Reporting System also shows that a higher risk of DKA is related to SGLT2 inhibitors therapy as compared to that with GLP1 receptor agonists.32 As infection is a trigger for DKA, in order to reduce the occurrence of DKA during the COVID-19 pandemic, clinicians should pay more attention to COVID-19 patients on SGLT2 inhibitors. Some case reports have warned that SGLT2 inhibitors may increase the incidence of DKA in COVID-19 patients.33, 34

Except for the adverse reaction mentioned previously, prevalence of other adverse reactions, such as AKI, hypotension, hypoglycemia, bone fracture, and lower limb amputation seemed to be conflicting. It was reassuring that no increased risk of amputation was found in the large RCTs, such as EMPA-REG Outcome,13 DECLARE-TIMI 58,15 and CREDENCE.16 Both the register-based cohort study in Sweden and Denmark and the propensity-matched analysis in US showed that SGLT2 inhibitors do no increase the risk of AKI more than GLP1 receptor agonists or nonusers.35, 36 It is noteworthy that Fournier gangrene, as a life-threatening necrotizing fasciitis, attracted increasing attention because of the Drug Safety Communication published by the US FDA. However，data from DECLARE-TIMI 58 showed that the incidence of Fournier gangrene was surprisingly higher in the placebo group, rather than in the dapagliflozin group.15

5.2 Obstacles on paediatric use

Thus far, most studies on SGLT2 inhibitors in adults are researches on the benefits in patients with diabetes, especially type 2 diabetes. Based on the experiences of studies on adults, study of SGLT2 inhibitors in children with diabetes seems to be more promising. As such, the phase-III RCTs on paediatric patients that are still in the recruiting stage are also focused on children with diabetes. However, it is important to remember that paediatric diabetes and renal disease patients have a different pathophysiology than adult patients. Although previous pharmacokinetic and pharmacodynamic studies have shown that the effects of SGLT2 inhibitors observed in adults with type 2 diabetes are also found in paediatric patients, several research questions remain unanswered.

The epidemiology of diabetes is different for children and adults. For the latter, type 2 diabetes is the primary disease; however, this is not true for paediatric patients. Although the prevalence of obesity has increased among adolescents and school-age children, the number of teenagers with type 2 diabetes is relatively small. Worse, patients interested in research are fewer, which make it difficult to recruit eligible subjects. In addition, safety is another challenge. Different from that in adults, more attention should be paid with regard to hypotension, DKA, and hypoglycemia in addition to genital infection and UTI during the treatment of SGLT2 inhibitors in paediatric patients, owing to their higher sensitivity to effective blood volume and blood glucose. In contrast, the risk of lower limb amputation may be low in children with diabetes, at least in youth.37 Liver function and kidney function are not fully developed in children; therefore, monitoring should be more frequent and careful in paediatric users of SGLT2 inhibitors. Furthermore, the participants of the pharmacokinetics and pharmacodynamics studies mentioned above could represent only few paediatric patients with type 2 diabetes because their weights were closer to those of adults. Thus, it is necessary that pharmacokinetics and pharmacodynamics studies or phase-III paediatric studies of SGLT2 inhibitors include children with normal body weight.

Considering the adverse impact on children's studies caused by the frequent visits by researchers for data collection, many parents are unwilling to enrol their children in studies on SGLT2 inhibitors. In addition, some parents have instinctive fears about clinic trials that may treat their children as “mice” in addition to demanding a lot of working time. For clinicians, the processes of recruiting and monitor the subjects is very taxing, specially without sufficient compensation and sponsorship. Moreover, the strict exclusion criteria may further discourage studies on new drugs, such as SGLT2 inhibitors.

An anonymous online survey that aimed to explore the obstruction of studies on new therapeutic drugs in paediatric patients with type 2 diabetes found that the most important negative factors were (1) too many study visits, (2) limitations of ongoing treatment, (3) overstrict inclusion/exclusion criteria, (4) absence of interested subjects, and (5) lack of adequate financial support.38