SGLT2 inhibitors in comparison with (or in addition to) GLP1 agonists - cardiovascular and renal benefits

A study has evaluated sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk (1).

A network analysis was undertaken involving:

• randomised controlled trials comparing SGLT-2 inhibitors or GLP-1 receptor agonists with placebo, standard care, or other glucose-lowering treatment in adults with type 2 diabetes with follow-up of 24 weeks or longer
• 764 trials including 421346 patients proved eligible. All results refer to the addition of SGLT-2 inhibitors and GLP-1 receptor agonists to existing diabetes treatment
  • both classes of drugs lowered all-cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence)
  • differences noted by the study authors included:
    • SGLT-2 inhibitors reduced mortality and admission to hospital for heart failure more than GLP-1 receptor agonists
    • GLP-1 receptor agonists reduced non-fatal stroke more than SGLT-2 inhibitors (which appeared to have no effect)
    • SGLT-2 inhibitors caused genital infection (high certainty),
    • GLP-1 receptor agonists might cause severe gastrointestinal events (low certainty)
    • SGLT-2 inhibitors and GLP-1 receptor agonists might lower body weight (low certainty for both)
    • absolute benefits of these drugs vary substantially across patients from low to very high risk of cardiovascular and renal outcomes (eg, SGLT-2 inhibitors resulted in 5 to 48 fewer deaths in 1000 patients over five years)
  • study authors concluded that for patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with notable differences in benefits and harms. Absolute benefits are determined by the individual risk profiles of patients

Combination of GLP-1 receptor agonist and SGLT-2 inhibitors

• there is evidence of synergy with the use of GLP-1 receptor agonists and SGLT-2 inhibitors in terms of reducing cardiovascular risk and risk of renal disease (2):
  • a study (15,638) found that compared to either drug class alone, GLP-1RA+SGLT-2i combination was linked to a lower risk of major adverse CV events (7.0 vs 10.3 events/1000 person-years; HR 0.70, 95% CI 0.49-0.99) and serious renal events (2.0 vs 4.6 events/1000 person-years; HR 0.43, 95% CI 0.23-0.80)
    • results of this population-based cohort study, designed to emulate a randomised controlled trial, suggest that the combined use of GLP-1 receptor agonists and SGLT-2 inhibitors is associated with a reduced risk of major adverse cardiovascular events and serious renal events, compared with using either drug class alone
    • addition of an SGLT-2 inhibitor to existing GLP-1 receptor agonist use was also associated with a reduced risk of cardiovascular mortality and heart failure compared with GLP-1 receptor agonists alone

An emulation study of a target trial found that SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in lowering mean HbA_1c, BMI, and systolic blood pressure and in reducing the hazards of hospital admission for heart failure (vs DPP-4 inhibitors) and kidney disease progression (vs sulfonylureas), with no evidence of differences in other clinical endpoint (3):

• SGLT-2 inhibitors were found to be more effective than sulfonylureas or DPP-4 inhibitors in lowering mean haemoglobin A1c levels, body mass index, and systolic blood pressure for a broad population of people with T2DM
• SGLT-2 inhibitors were found to be more effective than sulfonylureas or DPP-4 inhibitors in reducing the hazards of hospital admission for heart failure (vs DPP-4 inhibitors) and kidney disease progression (vs sulfonylureas) for a broad population of people with T2DM

References:

1. Palmer SC et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ 2021;372:m4573http://dx.doi.org/10.1136/bmj.m4573s
2. Simms-Williams N, Treves N, Yin H, Lu S, Yu O, Pradhan R et al. Effect of combination treatment with glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors on incidence of cardiovascular and serious renal events: population based cohort studyBMJ 2024; 385 :e078242
3. Bidulka P et al. Comparative effectiveness of second line oral antidiabetic treatments among people with type 2 diabetes mellitus: emulation of a target trial using routinely collected health data BMJ 2024; 385 :e077097 doi:10.1136/bmj-2023-077097