Examining the extra-glycaemic properties of SGLT2 inhibitors among type 2 diabetes patients using real-world clinical data

Abstract

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a new class of glucose-lowering drugs. Multiple placebo-controlled cardiorenal outcomes trials and multinational observational studies have been conducted to study the extra-glycaemic properties of SGLT2i. SGLT2i were found to confer cardiovascular and renal benefits in patients with type 2 diabetes. Despite initial efforts, there is still much to learn about the comparative effectiveness of SGLT2i against other classes of glucose-lowering drugs in terms of cardiorenal benefits. Dipeptidyl peptidase 4 inhibitors (DPP4i) are of particular interest. Like SGLT2i, DPP4i are a recent class of glucose-lowering drugs that have been widely used as second or third-line antidiabetic medication. Regarding the comparative renal benefits of SGLT2i and DPP4i, besides composite renal outcomes, there have not been many large studies investigating specific renal endpoints, such as albuminuria and acute renal failure (ARF), and existing results were not consistent.

Interestingly, outside cardiorenal benefits, recent adverse events analyses and network meta-analysis of previous cardiorenal trials suggested additional benefits to the respiratory system. Although these studies were hypothesis-generating in nature, they started to attract interest in the real-world effectiveness of the observed respiratory benefits.

This thesis studied the associations of SGLT2i with renal and respiratory outcomes, using DPP4i as active comparator. Renal outcomes included end-stage renal disease (ESRD), albuminuria, ARF, and the change in estimated glomerular filtration rate (eGFR) decline, while respiratory outcomes included the incidence and mortality of pneumonia, and the incidence and exacerbations of obstructive airway disease (OAD). These are population-based retrospective cohort studies which collected electronic health data of patients with type 2 diabetes from the Hong Kong CDARS electronic health database. Since DPP4i are an older class of drugs than SGLT2i, many patients using SGLT2i in Hong Kong are previous or ongoing DPP4i users. Unlike previous studies, to account for the potential bias due to previous exposure to an active comparator, this thesis adopted the recent “prevalent new-user” design. A propensity score matching method was also adopted to balance the baseline characteristics of the study groups.

In this thesis, compared to DPP4i, for renal outcomes, SGLT2i were found to associate with a 81% reduced risk of ESRD, a 70% reduced risk of ARF, a 50% reduced risk of albuminuria, as well as a slower decline in eGFR. For respiratory outcomes, SGLT2i were found to associate with a 41% reduced risk of pneumonia, as well as a 35% reduced risk of incident OAD and a 46% reduced rate of OAD exacerbations.

These studies provided real-world evidence on the comparative benefits of SGLT2i over DPP4i, and filled the potential research gaps regarding extra renal and respiratory effects of SGLT2i. These results would have clinical significance in changing the use of SGLT2i among patients with type 2 diabetes. However, due to the observational nature of these studies, they are prone to residual or unmeasured confounding. Further pooled analyses of similar studies from different populations and subgroups are warranted.