SGLT‐2 inhibitors and the risk of hospitalization for community‐acquired pneumonia: A population‐based cohort study

Abstract

Purpose: Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) have been associatedwith an increased risk of genitourinary tract infections. Through similar biological mechanisms, they may also increase the risk of community-acquired pneumonia. Our objective was to compare the rate of hospitalization for community-acquired pneumonia (HCAP) with SGLT-2i compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) among patients with type 2 diabetes.Methods: We used the United Kingdom's Clinical Practice Research Datalink Gold, linked to hospitalization data, to construct a cohort of patients with type 2 diabetes.Using a time-dependent Cox proportional hazards model, we estimated the adjusted hazard ratio (HR) for HCAP with current use of SGLT-2i versus DPP-4i.Results: Among 29 896 patients, 705 HCAPs occurred over a mean follow-up of 1.7 years (SD: 1.2). Incidence rates for SGLT-2i and DPP-4i users were 6.2 (95% confidence interval [CI]: 3.7, 10.2) and 17.8 (95% CI: 15.3, 20.7) per 1000 person-years, respectively. Current use of SGLT-2i was associated with a decreased risk of HCAP compared to current use of DPP-4i (adjusted HR: 0.48, 95% CI: 0.28, 0.82). However, a comparison of SGLT-2i versus glucagon-like peptide-1 receptor agonists (GLP-1 RA) found no difference in risk of HCAP (adjusted HR: 0.94, 95% CI: 0.44, 1.89).Conclusions: SGLT-2i are associated with a decreased rate of HCAP compared to DPP-4i, but not when compared to GLP-1 RA, among patients with type 2 diabetes.Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) are a novel class of glucose-lowering drugs used for the treatment of type 2 diabetes. 1In addition to their glucose lowering effects, SGLT-2i also improve cardiovascular outcomes, 2-4 which has made them increasingly prescribed in recent years. 5 However, the United States Food and Drug Administration has issued a safety warning for an increased risk of genital and urinary tract infections, 6 possibly due to increased bacterial proliferation resulting from glycosuria. Some SGLT-2i also have affinities for SGLT-1 receptors found in the lungs and intestines. 7 Inhibition of SGLT-1 receptors in rat alveolar cells leads to increased airway surface liquid glucose concentration, which translates directly to increased proliferation of pathogenic bacteria, 8 which may lead to lung infections such as community-acquired pneumonia (CAP). This mechanism may be analogous to the increased risk of

Novel antihyperglycaemic drugs and prevention of chronic obstructive pulmonary disease exacerbations among patients with type 2 diabetes: population based cohort study

“…In a meta-analysis of nine randomised controlled trials, SGLT-2 inhibitors were associated with a trend towards a reduced risk of new onset of chronic obstructive pulmonary disease (risk ratio 0.79, 0.61 to 1.02). 51 Furthermore, large observational studies and a meta-analysis of cardiovascular outcome trials have associated SGLT-2 inhibitors with a decreased risk of pneumonia, 10 11 52 a condition that often leads to chronic obstructive pulmonary disease exacerbations. The mechanisms behind heterogeneous findings of SGLT-2 inhibitors preventing severe but not moderate chronic obstructive pulmonary disease exacerbations are unclear and should be explored further.…”

“… 8 Finally, although SGLT-2 receptors are not expressed in the lungs, these drugs may exert beneficial effects by reducing carbon dioxide retention by inducing glucosuria and by reducing the risk of pneumonia, a major precipitator of chronic obstructive pulmonary disease exacerbations. 9 10 11 12 To date, observational studies investigating the effects of these novel antihyperglycaemic drugs on respiratory disease exacerbations have been limited. 13 14 In one study, DPP-4 inhibitors were not associated with a decreased risk of severe exacerbation of chronic obstructive pulmonary disease.…”

Safety and efficacy of the SGLT2 inhibitor dapagliflozin in patients with systemic lupus erythematosus: a phase I/II trial

“…A population-based cohort study provided reassuring evidence that SGLT2is were associated with a decreased rate of community-acquired pneumonia among patients with type 2 diabetes. 33 In this study, the mean baseline SLEDAI score of 4 suggested that these participants had only low-grade disease activity. No clinically meaningful changes in the SLEDAI score over time were observed.…”

The Cardiovascular Benefits and Infections Risk of SGLT2i versus Metformin in Type 2 Diabetes: A Systemic Review and Meta-Analysis

“…With the exception of the most common genitourinary tract infections, sporadic studies have reported that SGLT2i was associated with skin and pulmonary infections [ 61 , 62 , 63 ]. Urticaria, pruritus, photosensitivity, and various rashes caused by SGLT2i may be driven by a potential skin toxicity [ 61 , 62 ].…”

“…Urticaria, pruritus, photosensitivity, and various rashes caused by SGLT2i may be driven by a potential skin toxicity [ 61 , 62 ]. In addition, SGLT2i also led to an increased liquid glucose concentration of the airway surface, which translated directly to an increased proliferation of pathogenic bacteria and induced the occurrence of lung infections, for some SGLT2i bound with the SGLT-1 receptors in the lungs, such as canagliflozin and ipragliflozin [ 63 , 64 ]. Hence, we conducted further research to determine whether SGLT2i increased the risk of a potential extra-urogenital infection.…”