All‐cause mortality and cardiovascular outcomes with sodium‐glucose Co‐transporter 2 inhibitors, glucagon‐like peptide‐1 receptor agonists and with combination therapy in people with type 2 diabetes

Abstract

AimTo assess the relationship of sodium‐glucose cotransporter‐2 inhibitors (SGLT2i), glucagon‐like peptide‐1 receptor analogues (GLP‐1RA) and their combination (SGLT2i + GLP‐1RA) with 5‐year risk of all‐cause mortality, hospitalization and cardiovascular/macrovascular disease in people with type 2 diabetes.Materials and MethodsRetrospective cohort analysis of 2.2 million people with type 2 diabetes receiving insulin across 85 health care organizations using a global federated health research network. Three intervention cohorts (SGLT2i, GLP‐1RA and SGLT2i + GLP‐1RA) were compared against a control cohort (no SGLT2i/GLP‐1RA). Propensity score matching for age, ischaemic heart disease, sex, hypertension, chronic kidney disease, heart failure and glycated haemoglobin was used to balance cohorts 1:1 (SGLT2i, n = 143 600; GLP‐1RA, n = 186 841; SGLT‐2i + GLP‐1RA, n = 108 504). A sub‐analysis comparing combination and monotherapy cohorts was also performed.ResultsThe intervention cohorts showed a reduced hazard ratio (HR, 95% confidence interval) over 5 years compared with the control cohort for all‐cause mortality (SGLT2i 0.49, 0.48‐0.50; GLP‐1RA 0.47, 0.46‐0.48; combination 0.25, 0.24‐0.26), hospitalization (0.73, 0.72‐0.74; 0.69, 0.68‐0.69; 0.60, 0.59‐0.61) and acute myocardial infarct (0.75, 0.72‐0.78; 0.70, 0.68‐0.73; 0.63, 0.60‐0.66), respectively. All other outcomes showed a significant risk reduction in favour of the intervention cohorts. The sub‐analysis showed a significant risk reduction in all‐cause mortality for combination therapy versus SGLT2i (0.53, 0.50‐0.55) and GLP‐1RA (0.56, 0.54‐0.59).ConclusionsSGLT2i, GLP‐1RAs or combination therapy confers mortality and cardiovascular protection in people with type 2 diabetes over 5 years. Combination therapy was associated with the greatest risk reduction in all‐cause mortality versus a propensity matched control cohort. In addition, combination therapy offers a reduction in 5‐year all‐cause mortality when compared directly against either monotherapy.

Effectiveness and safety of the combination of sodium–glucose transport protein 2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of observational studies

“…2 . Quantitative meta-analysis was performed using 8 studies [ 23 , 26 – 31 , 33 ]. The remaining 5 studies were considered to be ineligible for inclusion in this meta-analysis as mean values were not available (n = 1), follow-up duration was less than 6 months (n = 2), and only differences in outcomes were provided instead of absolute values (n = 2) (Additional file 1 : Table S3).…”

Treating Type 2 Diabetes With Early, Intensive, Multimodal Pharmacotherapy: Real‐World Evidence From an International Collaborative Database

“…Importantly, our study demonstrated benefit in a cohort without preexisting cardiorenal disease. Our previous real-world data study has demonstrated that combination therapy with SGLT2i and GLP-1 RA conferred mortality and cardiovascular protection in T2D over 5 years, particularly in all-cause mortality [ 21 ]. Current joint ADA (American Diabetes Association) and EASD (European Association for the Study of Diabetes) guidelines [ 9 ] suggest initiating GLP-1 RA or SGLT2i instead of metformin as first-line therapy only in individuals with high ASCVD risk factors.…”

Guideline for the Management of Diabetes Mellitus in the Elderly in China (2024 Edition)

“…A meta‐analysis has suggested that, compared with single drug treatment, the combination of two classes of drugs confers more benefits regarding blood glucose, blood pressure, and blood lipid 104 . A retrospective cohort study has found that, compared with single drug treatment, combined therapy with SGLT2 inhibitors and GLP‐1RAs achieves better all‐cause mortality and cardiovascular benefits 105 . However, little high‐quality evidence to date has demonstrated the clinical benefits of combined therapy with these two drugs in the older population.…”

“… 104 A retrospective cohort study has found that, compared with single drug treatment, combined therapy with SGLT2 inhibitors and GLP‐1RAs achieves better all‐cause mortality and cardiovascular benefits. 105 However, little high‐quality evidence to date has demonstrated the clinical benefits of combined therapy with these two drugs in the older population.…”