Add-on therapy in metformin-treated patients with type 2 diabetes at moderate cardiovascular risk: a nationwide study

Abstract

Background: In randomised clinical trials, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors reduced cardiovascular events in patients with type 2 diabetes (T2D) at high cardiovascular risk, as compared to standard care. However, data comparing these agents in patients with T2D who are at moderate risk is sparse.

Methods: From Danish national registries, we included patients with T2D previously on metformin monotherapy, who started an additional glucose-lowering agent [GLP-1 RA, SGLT-2 inhibitor, dipeptidyl peptidase-4 (DPP-4) inhibitor, sulfonylurea (SU), or insulin] in the period 2010-2016. Patients with a history of cardiovascular events [heart failure (HF), myocardial infarction (MI) or stroke] were excluded. Patients were followed for up to 2 years. Cause-specific adjusted Cox regression models were used to compare the risk of hospitalisation for HF, a composite endpoint of major adverse cardiovascular events (MACE) (MI, stroke or cardiovascular death), and all-cause mortality for each add-on therapy. Patients who initiated DPP-4 inhibitors were used as reference.

Results: The study included 46,986 T2D patients with a median age of 61 years and of which 59% were male. The median duration of metformin monotherapy prior to study inclusion was 5.3 years. Add-on therapy was distributed as follows: 13,148 (28%) GLP-1 RAs, 2343 (5%) SGLT-2 inhibitors, 15,426 (33%) DPP-4 inhibitors, 8917 (19%) SUs, and 7152 (15%) insulin. During follow-up, 623 (1.3%, range 0.8-2.1%) patients were hospitalised for HF-hazard ratios (HR) were 1.11 (95% CI 0.89-1.39) for GLP-1 RA, 0.84 (0.52-1.36) for SGLT-2 inhibitors, 0.98 (0.77-1.26) for SU and 1.54 (1.25-1.91) for insulin. The composite MACE endpoint occurred in 1196 (2.5%, range 1.5-3.6%) patients, yielding HRs of 0.82 (0.69-0.97) for GLP-1 RAs, 0.79 (0.56-1.12) for SGLT-2 inhibitors, 1.22 (1.03-1.49) for SU and 1.23 (1.07-1.47) for insulin. 1865 (3.9%, range 1.9-9.0%) died from any cause during follow-up. HRs for all-cause mortality were 0.91 (0.78-1.05) for GLP-1 RAs, 0.79 (0.58-1.07) for SGLT-2 inhibitors, 1.13 (0.99-1.31) for SU and 2.33 (2.08-2.61) for insulin.

Conclusion: In a nationwide cohort of metformin-treated T2D patients and no history of cardiovascular events, the addition of either GLP-1 RA or SGLT-2 inhibitor to metformin treatment was associated with a similar risk of hospitalisation for HF and death, and a lower risk of MACE for GLP-1 RA when compared with add-on DPP-4 inhibitors. By contrast, initiation of treatment with SU and insulin were associated with a higher risk of MACE. Additionally, insulin was associated with an increased risk of all-cause mortality and hospitalisation for HF.

Keywords: Heart failure; Myocardial infarction; Prognosis; Treatment; Type 2 diabetes.

Fig. 1

Graphical representation of the criteria for add-on therapy

Fig. 2

Consort Diagram for the inclusion and exclusion of patients in the study—GLP-1 glucagon like peptide-1 analogues, SGLT-2 sodium–glucose transporter 2 inhibitor, DPP-4 dipeptidyl peptidase inhibitor. Add-on therapy is the introduction of a new glucose-lowering drug in addition to on-going metformin treatment

Fig. 3

Crude cumulative incidence plot for the events of hospitalisation for heart failure, composite MACE endpoint (myocardial infarction, stroke, or cardiovascular death), and all-cause mortality. GLP-1 glucagon like peptide-1 receptor agonist, SGLT Sodium–glucose transporter 2 inhibitor, DPP-4 dipeptidyl peptidase 4 inhibitor

Fig. 4

Forrest plot of risk of adverse outcomes according to add-on therapy. Hospitalisation for heart failure, composite MACE endpoint of MI, stroke, or cardiovascular (CV) death, and all-cause mortality according to second-line add-on treatment. GLP-1 RA glucagon like peptide-1 receptor agonist, SGLT-2 sodium–glucose cotransporter 2 inhibitor, DPP-4 dipeptidyl peptidase inhibitor. The results visualised in the Forest plot is adjusted for age, comorbidities time in metformin monotherapy, year of inclusion, use of statin, CV risk profile, and sex. DPP-4 inhibitors were used as reference