HK data: SGLT2 inhibitors cut risks of respiratory and renal diseases in T2DM

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risks of respiratory and renal diseases vs dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes mellitus (T2DM), researchers from the University of Hong Kong (HKU) have reported.

SGLT2 inhibitors have gained increasing attention in recent years for their beneficial effects on the cardiovascular and renal systems, and possibly the respiratory system. However, head-to-head comparison of SGLT2 inhibitors’ and DPP-4 inhibitors’ renal and respiratory benefits has been scarce. The HKU researchers therefore conducted three territory-wide retrospective cohort studies (all n>28,000) to compare these two classes of medications in T2DM patients using data from the Clinical Data Analysis and Reporting System (CDARS). [JAMA Netw Open 2023;6:e2251177; J Clin Endocrinol Metab 2022;107:e2962-e2970; J Clin Endocrinol Metab 2022;107:e1719-e1726]

Respiratory outcomes

“Patients with diabetes are at higher risk of pneumonia and pneumonia mortality, but the association of SGLT2 inhibitors with pneumonia remains largely unclear,” wrote the researchers. After a mean follow-up of 3.8 years, SGLT2 inhibitors were found to significantly reduce the risks of pneumonia (rate ratio [RR], 0.71; 95 percent confidence interval [CI], 0.62–0.81; p<0.001) and pneumonia mortality (hazard ratio [HR], 0.57; 95 percent CI, 0.42–0.77; p<0.001) vs DPP-4 inhibitors.

“Given the interrelated nature of obstructive airway disease [OAD] and diabetes, it is of clinical importance to investigate the effects of antidiabetic medications on OAD,” noted the researchers. Results revealed that SGLT2 inhibitors significantly decreased the risks of OAD (HR, 0.65; 95 percent CI, 0.54–0.79; p<0.001) and OAD exacerbations (RR, 0.54; 95 percent CI, 0.36–0.83; p=0.01) vs DPP-4 inhibitors, after a median follow-up of 2.2 years. The associations were consistent in sex subgroup analysis.

“SGLT2 inhibitors may alleviate OAD symptoms through inhibition of lung NLRP3 inflammasome activation, which has been implicated in both asthmatic airway inflammation and chronic obstructive pulmonary disease exacerbations in some animal studies,” explained the researchers.

Renal outcomes

“Although the renoprotective effects of SGLT2 inhibitors have been demonstrated in several clinical trials, inconsistent results were observed for the composite endpoint of renal disease progression, end-stage renal disease [ESRD] and acute kidney injury in recent real-world studies,” noted the researchers.

The current HKU study showed that SGLT2 inhibitors were associated with significantly lower risks of ESRD (HR, 0.51; 95 percent CI, 0.42–0.62; p<0.001) and acute renal failure (ARF; HR, 0.59; 95 percent CI, 0.48–0.73; p<0.001), as well as a slower decline in estimated glomerular filtration rate (eGFR) (-0.060 mL/min/1.73m² per year vs -0.625 mL/min/1.73m² per year; p_interaction<0.001), vs DPP-4 inhibitors. “Importantly, the associations remained statistically significant among patients with or without rapid eGFR decline and patients who added or switched to SGLT2 inhibitors from DPP-4 inhibitors,” highlighted the researchers.

Extraglycaemic effects

“These [local] studies provided novel real-world evidence that SGLT2 inhibitors could confer extraglycaemic protection [ie, protection against OAD, pneumonia, ESRD and ARF, and slowing of eGFR decline] to T2DM patients, and are potentially better alternatives to DPP-4 inhibitors,” summarized the researchers.