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Glucose-Lowering Therapies for Type 1 Diabetes and Renovascular Outcomes
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This study investigated the real-world impact of SGLT2 inhibitor (SGLT2i) and GLP-1 receptor agonist (GLP-1 RA) therapy on individuals with type 1 diabetes in relation to efficacy, safety, and cardiorenal outcomes. The authors analyzed data from the TriNetX platform, a global collaborative network with access to real-time electronic medical records. A total of 196,691 individuals with type 1 diabetes were identified, of whom 1822 were treated with a GLP-1 RA and 992 were treated with an SGLT2i. The study found that, 5 years after therapy initiation, there were improvements in glycemic control with both medications (−0.2% for SGLT2is and −0.5% for GLP-1 RAs). SGLT2i use was associated with higher rates of DKA (RR, 2.08) and urinary tract infections (RR, 2.27) and lower risk of heart failure (RR, 0.44), CKD (RR, 0.49), and hospitalizations (RR, 0.59) than GLP-1 RA use.
- SGLT2is and GLP-1 RAs can improve glycemic control and cardiometabolic outcomes in people with type 1 diabetes. Given that SGLT2i use increases the risk of DKA and urinary tract infections, the risks and benefits should be carefully weighed when considering the use of this medication in this patient population.
abstract
This abstract is available on the publisher's site.
Access this abstract nowAIMS/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.
Additional Info
SGLT2i and GLP-1 RA therapy in type 1 diabetes and reno-vascular outcomes: a real-world study
Diabetologia 2023 Oct 01;66(10)1869-1881, M Anson, SS Zhao, P Austin, GH Ibarburu, RA Malik, U AlamFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Although numerous large-scale clinical trials have demonstrated the cardiorenal benefits of SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1 RA) in patients with type 2 diabetes, these agents are not currently approved by the FDA as an adjunctive therapy to insulin in patients with type 1 diabetes. This real-world study by Anson et al, the largest available to date, attempts to better characterize some potential benefits, risks, and long-term cardiorenal outcomes of using these agents in patients with type 1 diabetes.
Using a large database of real-time medical records, the authors compared the 5-year efficacy and safety outcomes of 1822 participants who were on a GLP-1 RA and 992 participants on a SGLT2i. For methodological reasons, the authors could not compare these groups with a cohort that was treated with insulin alone.
The authors found that use of GLP-1 RA led to a greater reduction in HbA1c levels when compared with HbA1c levels in the SGLT2i group (−0.5% vs −0.2%, respectively). Interestingly, they found that weight loss was not sustained over 5 years in the GLP-1 RA group (+1.5 kg) and was actually less than what was observed in those using SGLT2i (−2.4 kg). Of note, a significant percentage of patients were on older and potentially less effective formulations of GLP-1 RA during this study period.
With regard to the cardiorenal outcomes over 5 years, eGFR improved in those in the SGLT2i cohort while it declined in the GLP-1 RA cohort, irrespective of CKD status. Those in the SGLT2i cohort were less likely to develop CKD (RR, 0.49; P = .0118) and heart failure (RR, 0.44; P = .0092) compared with those in the GLP-1 RA group.
In terms of safety outcomes, there were higher rates of DKA (RR, 2.08; P = .0309) and urinary tract infection/pyelonephritis (RR, 2.27; P = .019) in the SGLT2i cohort when compared with the GLP-1 RA group. Despite this, risk of hospitalization for any cause was still lower in the SGLT2i group (RR, 0.59; P ≤ .0001) than in the GLP-1 RA cohort. There were no differences in rates of hypoglycemia, pancreatitis, or gastrointestinal upset and no difference in all-cause mortality between the two cohorts.
Overall, this study demonstrated that SGLT2i use in patients with type 1 diabetes may lead to clinically significant reductions in HbA1c levels and weight while also providing some important long-term cardiorenal benefits. Reassuringly, although risks of DKA and gastrointestinal infections did increase with use of SGLT2i, the rates of hospitalizations and mortality did not. The benefits of GLP-1 RA in type 1 diabetes are more difficult to ascertain from this study largely due to the use of older formulations, and the absence of an insulin-only comparator arm. It is clear that there are many unmet needs in the treatment of type 1 diabetes, and studies such as these contribute to our understanding of whether these agents may have a role to play in improving the outcomes of those with type 1 diabetes.