SGLT2 Inhibitor Therapy Could Confer CardioRenal Benefits in Type 1 Diabetes

Uazam Alam, MBChB, PhD
Credit: Weill Cornell Medicine

The largest study of its kind to date is providing care providers and patients with new insight into the effects of off-label SGLT2 inhibitor or GLP-1 receptor agonist use in people with type 1 diabetes.

Results of the analysis, which suggest about 2.5% of people with type 1 diabetes had used at least one of the medications, suggest use of SGLT2 inhibitors and GLP-1 receptor agonists conferred cardiorenal benefit in people with type 1 diabetes despite the increased potential for diabetic keto acidosis and urinary tract infection.¹

“We have conducted the largest real-world retrospective cohort study to date investigating the safety and outcomes of individuals with type 1 diabetes using SGLT2 inhibitors and GLP-1 receptor agonist therapy, and the first to report cardio-renal benefits. We demonstrate that both therapies offer clinically significant reductions in HbA1c with no difference in 5-year all-cause mortality,” investigators wrote.¹

The ascent of both the SGLT2 inhibitor and GLP-1 receptor agonist classes into the spotlight has been historic. Driven by demonstrated benefits on cardiorenal outcomes and weight loss, respectively, emerging data from the classes have headlined dozens of international meetings in the last half decade.^2,3

Acknowledging real-world, off-label use of these agents occurs among people with type 1 diabetes, Uazam Alam, MBChB, PhD, a senior clinical lecturer and honorary consultant physician of Cardiovascular and Metabolic Medicine at the University of Liverpool, and a team of investigators launched the current study to explore the real-world impact of SGLT2 inhibitor and GLP-1 receptor agonist therapy in adults with type 1 diabetes as it pertains to blood glucose levels, adverse events, and cardiorenal outcomes.¹

To do so, investigators designed their study as Ana analysis of data from all patients aged 18 years or older with type 1 diabetes from the TriNetX platform, which provided electronic medical record data from 196,691 people with type 1 diabetes. For the purpose of analysis, investigators limited their analysis to who had been treated with an SGLT2 inhibitor or GLP-1 receptor agonist for at least 6 months. The primary endpoints of interest for the analyses were efficacy, safety, and cardiorenal outcomes at 5 years.¹

Of the 196,691 people with type 1 diabetes identified from the TriNetX platform, 13% were using an adjunctive glucose-lowering therapy in addition to insulin. The most common among these was metformin, which accounted for 43% of this group, but 1822 patients treated with a GLP-1 receptor agonist and 992 patients treated with a SGLT2 inhibitor were identified by investigators.¹

Among the GLP-1 receptor agonist cohort, 37% used liraglutide, 25% used semaglutide, 24% used dulaglutide, and 13% with exenatide. Among the SGLT2 inhibitor cohort, 47% used empagliflozin, 27% used dapagliflozin, and 25% used canagliflozin. Investigators pointed out propensity score-matching was performed and reduced the cohorts to 933 individuals each.¹

Results of the investigators’ analysis indicated use of GLP-1 receptor agonists (-0.5%) and SGLT2 inhibitors (-0.2%) were associated with clinically meaningful reductions in HbA1c. Further analysis suggested those using SGLT2 inhibitors experienced a greater preservation of eGFR relative to GLP-1 receptor agonists (3.5 ml/min/1.73 m2 vs −7.2 ml/min/1.73m2, respectively), with this trend consistent among patients with or without established chronic kidney disease.¹

Additional analysis revealed those using SGLT2 inhibitors were less likely to develop heart failure (Risk ratio [RR], 0.44; 95% CI, 0.23 to 0.83; P = .0092), chronic kidney disease (RR, 0.49; 95% CI, 0.28 to 0.86; P = .0118) and be hospitalized for any cause (RR, 0.59; 95% CI 0.46 to 0.76; P ≤.0001). Investigators cautioned an apparent increase in rates of diabetic ketoacidosis (RR, 2.08; 95% CI, 1.05 to 4.12; P = .0309) and urinary tract infection/pyelonephritis (RR, 2.27; 95% CI, 1.12 to 4.55; P = .019) relative to GLP-1 receptor agonists.¹

Investigators noted multiple limitations to consider prior to overinterpretation of the results of their study. These included inherent limitations with reliance on coding of medical data, potential underreporting of minor adverse reactions, and inherent limitations of real-world data.¹

“Careful and targeted patient selection are required, alongside robust education and novel technologies to monitor glucose and ketone levels to mitigate the risks and enhance the beneficial effects of SGLT2 inhibitor and GLP-1 receptor agonist therapy,” investigators wrote.¹ “Dedicated long-term trials investigating the benefits of such therapies on hospitalisation, major cardiovascular adverse events and all-cause mortality are required.”

References:

1. ^{Anson M, Zhao SS, Austin P, Ibarburu GH, Malik RA, Alam U. SGLT2i and GLP-1 RA therapy in type 1 diabetes and reno-vascular outcomes: a real-world study [published online ahead of print, 2023 Jul 28]. Diabetologia. 2023;10.1007/s00125-023-05975-8. doi:10.1007/s00125-023-05975-8}
2. ^{Campbell P, Iapoce C. 10 years of SGLT2 inhibitors: A Decade of Redefining Cardiometabolic Care. HCPLive. March 29, 2023. Accessed August 3, 2023. https://www.hcplive.com/view/10-years-of-sglt2-inhibitors-a-decade-of-redefining-cardiometabolic-care.}
3. ^{Campbell P, Iapoce C. 10 years of obesity: A Decade of Advancement and challenges. HCP Live. June 23, 2023. Accessed August 3, 2023. https://www.hcplive.com/view/10-years-of-obesity-a-decade-of-advancement-and-challenges.}