Key findings
We conducted a pilot case–control study in ICU patients with type 2 diabetes treated according to a liberal glucose control protocol to assess the relationship between empagliflozin therapy and renal, glycemic, metabolic, infectious, and exploratory clinical outcomes. We observed increasing blood sodium and chloride levels after empagliflozin initiation but no association with acid–base status. In keeping with such observations, the overall urinary output and diuretic response to furosemide appeared greater in the empagliflozin group. A numerically lower proportion of patients treated with empagliflozin developed worsening kidney function. In contrast, a positive urine culture was numerically more common after empagliflozin initiation. We observed no apparent relationship between empagliflozin treatment and hypoglycemia or ketoacidosis. Hospital mortality was approximately 20% in both groups.
Relationship with previous studies
To the best of our knowledge, our study is the first to assess early physiological, biochemical, and microbiological responses to SGLT2 inhibitors in critically ill patients with type 2 diabetes. We observed a gradual increase in blood sodium levels after empagliflozin initiation. This is likely explained by free water loss from glucosuria-induced osmotic diuresis. Indeed, in a recent study, empagliflozin increased plasma sodium levels by 10 mmol/l on average after four days in patients with the syndrome of inappropriate antidiuresis [
16]. A similar absolute increase was observed in our study. In addition, we observed an almost parallel increase in blood chloride levels and negligible differences in aSID, pH, and base excess trajectories compared to our matched control group. A lack of effect on acid–base status confirms data from previous animal experiments [
17].
Monotherapy with SGLT2 inhibitors is not associated with increased risk of hypoglycemia compared with placebo [
18]. In combination with insulin, this risk is significantly increased [
19]. Despite a combination of insulin and empagliflozin therapy in the treatment group, we observed similar hypoglycemia occurrence (6%) in the two study groups. Our liberal glucose control protocol likely contributed to this low rate of hypoglycemia [
14].
Ketosis is common in critically ill patients with type 2 diabetes on admission to the ICU but typically resolves within 24–48 h [
15]. In the present study, empagliflozin treatment was not associated with greater ketotic burden and no patients developed ketoacidosis. Similarly, the occurrence of ketoacidosis was low (0.3%) among hospitalized COVID-19 patients randomized to dapagliflozin [
7]. However, our limited sample size and the fact that most patients in the treatment group received insulin should be acknowledged. Additionally, the elimination half-life of β-hydroxybutyrate in healthy volunteers is only 1–3 h [
20]. As we only measured β-hydroxybutyrate once daily around the time of empagliflozin administration, it is possible that we somewhat underestimated the prevalence of mild to marked ketosis. However, with accumulating doses, ketosis would likely be detected even with this infrequent sampling strategy.
Despite robust data on nephroprotective effects of long-term treatment with SGLT2 inhibitors, there are concerns that such therapy may lead to acute kidney injury due to reduced plasma volume, an early decline in glomerular pressure and GFR via tubulo-glomerular feedback activation, and hypoxia in the renal medulla [
21‐
23]. However, recent studies refute these concerns. For example, in a meta-analysis of placebo-controlled trials, allocation to an SGLT2 inhibitor reduced the risk of AKI (defined by its specific Medical Dictionary for Regulatory Activities Preferred Term) by 23% (95% CI 19–26%) [
1]. In a propensity score matched cohort study of elderly patients (mean age 72 years) with type 2 diabetes, initiation of an SGLT2 inhibitor was associated with reduced risk of hospitalization for AKI (discharge diagnosis) compared with dipeptidyl peptidase 4 inhibitors or glucagon-like peptide 1 receptor agonists [
24]. In a Scandinavian cohort, new use of SGLT2 inhibitors, compared with dipeptidyl peptidase-4 inhibitors, was associated with reduced risk of serious renal events (RRT, death from renal causes, or hospitalization for renal events) (adjusted HR 0.42, 95% CI 0.34–0.53) [
25]. In 1250 acutely ill patients with COVID-19, dapagliflozin, compared with placebo, resulted in numerically fewer events of worsening kidney function (doubling of serum creatinine or initiation of RRT) within 30 days (HR 0.65, 95% CI 0.38–1.10) [
7]. In line with the above observations, our data suggest that treatment with empagliflozin is not associated with an early decline in kidney function in critically ill patients.
Evidence regarding risk of severe urinary tract infections with SGLT2 inhibitors are conflicting but most reports conclude that such events are rare [
4]. Most ICU patients have an indwelling urinary catheter, which predisposes to asymptomatic bacteriuria. We observed a numerically higher rate of positive urine cultures in our empagliflozin treated patients but a similar rate of Candida albicans isolation. The clinical significance of this finding, however, is uncertain.
Study implications
We have provided preliminary evidence of the effects and possible side effects of empagliflozin therapy in critically ill patients with type 2 diabetes exposed to permissive hyperglycemia. Our findings imply that empagliflozin likely increases free water clearance and increases loop-diuretic responsiveness. The clinical significance of the observed increase in sodium and chloride remains uncertain. If they increase in similar proportions, which appears to be the case, there would be no effect on acid base status. This is confirmed by our additional analysis of strong ion difference, base excess, and pH trajectories. Observational data suggest that hyperchloremia is associated with acute kidney injury development [
26]. This is not supported by our data, which showed a numerically lower incidence of worsening kidney function in the treatment group. Yet, clinicians should be aware of the effect of empagliflozin on free water clearance and corresponding changes in sodium and chloride and should consider minimizing the content of these solutes in administered fluids. Within the limitations of small numbers, our findings also imply that empagliflozin therapy in the ICU might reduce insulin requirements without inducing ketoacidosis. The majority (> 80%) of treatment group patients received insulin at the time of empagliflozin initiation. As insulin suppresses lipolysis and ketogenesis, early ketoacidosis was not expected in this group. However, our data implies that continuing empagliflozin therapy may not lead to delayed ketoacidosis despite gradual weaning from insulin therapy. At least during exposure to permissive hyperglycemia, the combination of empagliflozin and insulin does not appear to increase the risk of hypoglycemia. Furthermore, our results do not support the view that SGLT2 inhibitors result in acutely decreased kidney function. Finally, our data support further cautious assessment of the safety and efficacy of SGLT2 inhibitors in the ICU setting in randomized controlled trials.
Strengths and limitations
Our study has limitations. It is not a randomized controlled trial. Furthermore, the treating staff was unblinded to β-hydroxybutyrate levels and empagliflozin treatment. This could potentially have biased insulin dosing decisions. Although cases and controls were matched on age, HbA1c, and ICU length of stay, they differed significantly with respect to other baseline characteristics. For example, treatment group patients were less likely to be admitted from the operating room and more likely to be admitted from the emergency department, representing subgroups with different risk of ketoacidosis development. The limited sample size prevented adjustment of potential confounders in the analyses. However, our exploratory analysis is an important first step to inform and justify the cautious step-by-step conduct and design of future trials. Patients were exposed to a liberal glucose control strategy. Our findings should, therefore, not be generalized to ICU patients managed according to more strict blood glucose control protocols.