SGLT2i and GLP-1 RA therapy in type 1 diabetes and reno-vascular outcomes: a real-world study

Abstract

Aims/hypothesis Insulin is the primary treatment for type 1 diabetes. However, alternative glucose-lowering therapies are used adjunctively, but importantly are off-label in type 1 diabetes. Little work has previously been undertaken to evaluate safety with long-term efficacy and cardio-renal benefits of such therapies. We sought to investigate the real-world impact of sodium–glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy in individuals with type 1 diabetes in relation to effect on blood glucose levels, adverse events and cardio-renal outcomes. Methods We performed a retrospective cohort study of all patients aged 18 or over with type 1 diabetes on the TriNetX platform, a global collaborative network providing access to real-time, anonymised medical records. We included patients who had been treated with an SGLT2i or GLP-1 RA for at least 6 months and analysed the efficacy, safety and cardio-renal outcomes 5 years after initiation of therapy. Results We identified 196,691 individuals with type 1 diabetes, 13% of whom were treated with adjunctive glucose-lowering therapy in addition to insulin. Included in the core analysis were 1822 patients treated with a GLP-1 RA and 992 individuals treated with an SGLT2i. Both agents provided clinically meaningful reductions in HbA1c (−2.6 mmol/mol [−0.2%] with SGLT2i and −5.4 mmol/mol [−0.5%] with GLP-1 RA). The SGLT2i treated cohort showed preservation of eGFR over a 5-year period compared with the GLP-1 RA treated cohort (+3.5 ml/min per 1.73 m2 vs −7.2 ml/min per 1.73 m2, respectively), including patients with established chronic kidney disease (CKD). The SGLT2i treated cohort experienced higher rates of diabetic ketoacidosis (DKA) (RR 2.08 [95% CI 1.05, 4.12] p=0.0309) and urinary tract infection/pyelonephritis (RR 2.27 [95% CI 1.12, 4.55] p=0.019) compared with the GLP-1 RA treated cohort. However, the SGLT2i treated cohort were less likely to develop heart failure (RR 0.44 [95% CI 0.23, 0.83] p=0.0092), CKD (RR 0.49 [95% CI 0.28, 0.86] p=0.0118) and be hospitalised for any cause (RR 0.59 [95% CI 0.46, 0.76] p≤0.0001) when compared with the GLP-1 RA treated cohort. Conclusions/interpretation Both SGLT2is and GLP-1 RAs have potential benefits as adjunctive agents in type 1 diabetes. SGLT2is provide cardio-renal benefits, despite an increase in the risk of DKA and urinary tract infection compared with GLP-1 RA therapy. Long-term evaluation of the efficacy and safety of these adjunctive therapies is required to guide their use in individuals with type 1 diabetes. Graphical Abstract

Balancing Risks and Benefits: Sodium-Glucose Cotransporter 2 Inhibitors and the Risk of Diabetic Ketoacidosis

“…The SGLT2i-treated cohort showed the preservation of the estimated glomerular filtration rate (eGFR) over a 5-year period compared with the GLP-1 RA-treated cohort (+3.5 vs. −7.2 mL/min/1.73 m 2 ), including patients with established chronic kidney disease (CKD). Moreover, patients treated with SGLT2is were less likely to develop heart failure (relative risk of 0.44) and CKD (relative risk 0.49) when compared to GLP-1RA-treated patients [ 15 ]. A post hoc analysis of the DEPICT trials, two randomised controlled trials investigating the use of dapagliflozin in type 1 diabetes, showed a significant reduction in albuminuria after 1 year of dapagliflozin treatment compared to placebo.…”

Cardio‐renal‐metabolic disease in primary care setting

“…Both SGLT2is and GLP-1 RAs have potential benefits as adjunctive agents in T1DM. SGLT2is provide cardio-renal benefits, despite an increase in the risk of DKA, 163 however more studies on T1DM are needed. 164,165 Technologies are T A B L E 5 Cardiovascular-renal outcome trials evaluating novel cardio-renal-metabolic drugs: Overview in relation to haemoglobin A1c (HbA1c) and weight changes.…”

“…Both SGLT2is and GLP‐1 RAs have potential benefits as adjunctive agents in T1DM. SGLT2is provide cardio‐renal benefits, despite an increase in the risk of DKA, 163 however more studies on T1DM are needed 164,165 . Technologies are being developed for T1DM by combining risk factors into probability models to predict 10‐year risk for microvascular and macrovascular complications.…”

“…Technologies are being developed for T1DM by combining risk factors into probability models to predict 10‐year risk for microvascular and macrovascular complications. However, continued work on these models is needed 158–165 …”

Can Unmet Needs Be Addressed by Adjunctive Therapies? Findings from a Patient Perspectives Survey in Adults with Type 1 Diabetes

“… 6 A real-world, global study found 13% of individuals with T1D have taken a non-insulin adjunct for glycemic management, and just 1.7% were prescribed a GLP-1RA off-label. 9 Potential benefits for individuals with T1D include decreased HbA1c, improved glycemic stability, weight reduction, and improved insulin sensitivity and cardiovascular health. 10 , 11 …”