Cardiovascular morbidity and mortality in patients with type 2 diabetes using novel antidiabetic medicines as add-on therapy: an observational real-world study

Abstract

ObjectiveTo evaluate the effect of sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA), compared with dipeptidyl peptidase-4 inhibitors (DPP-4i) as add-on therapy on cardiovascular (CV) morbidity and mortality in patients with type 2 diabetes (T2D).Design and settingA nationwide cohort study using three linked healthcare databases from Slovenia (outpatient prescription claims data, hospitalisation claims data and death registry data).ParticipantsPatients with T2D with newly introduced DPP-4i (n=3817), GLP-1RA (n=855) or SGLT2i (n=2851) add-on therapy between June 2014 and June 2018.Primary and secondary outcome measuresThe primary outcome was a major adverse CV event (MACE), while the secondary outcomes were CV death and heart failure (HF). The effects of the antidiabetic medicine group on the risk of each outcome were estimated with Cox proportional hazards regression. Intention-to-treat and on-treatment approaches were used.ResultsIn the intention-to-treat analysis, SGLT2i as add-on therapy, when compared with DPP-4i, was associated with lower risk of MACE (HR=0.66; 95% CI 0.50 to 0.85; p=0.002) and CV death (HR=0.46; 95% CI 0.30 to 0.73; p=0.001). On-treatment analysis revealed lower HF risk in patients initiating SGLT2i (HR=0.54; 95% CI 0.30 to 0.99; p=0.047). In the intention-to-treat analysis, GLP-1RA add-on therapy was associated with a lower MACE risk when compared with DPP-4i (HR=0.64; 95% CI 0.43 to 0.97; p=0.034), but it had a non-significant effect on CV death (HR=0.62; 95% CI 0.34 to 1.14; p=0.128) and HF (HR=1.39; 95% CI 0.88 to 2.21; p=0.157). The results of on-treatment analyses were in agreement with the results of intention-to-treat analyses.ConclusionsSGLT2i and GLP-1RA improved CV morbidity and mortality in patients with T2D when compared with DPP-4i as an add-on therapy. The results of this study may serve as a basis for the selection of an optimal add-on antidiabetic medicine to reduce CV morbidity and mortality in patients with T2D in clinical practice.Trial registration numberEUPAS32558.

Cardiovascular and Renal Effectiveness of GLP-1 Receptor Agonists vs. Other Glucose-Lowering Drugs in Type 2 Diabetes: A Systematic Review and Meta-Analysis of Real-World Studies

“…Overall, GLP-1RA significantly reduced the composite cardiovascular outcome by 18% (HR 0.82, 95% CI 0.73-0.91, I 2 = 4%) and MACE by 30% (HR 0.70, 95% CI 0.58-0.84, I 2 = 72%) (Figure 2A,B). All-cause mortality was found to be also reduced to an even greater extent with GLP-1RA use in all considered studies regardless of the comparator [21][22][23][24][25][26] (HR 0.61, 95% CI 0.52-0.73, I 2 = 88%) (Figure 2C). Only some studies investigated cardiovascular death, suggesting a significant benefit on this particular outcome (HR 0.66, 95% CI 0.49-0.88, I 2 = 63%) (Figure 2G).…”

“…Pineda et al found that GLP-1RA initiation significantly reduced the risk of the composite cardiovascular outcome by 29% [17], while Yang et al and O'Brien et al demonstrated a 27% [18] and 22% [19] risk reduction vs. DPP-4i users, respectively; in contrast, Patorno et al observed no significant difference between treatment groups [20]. GLP-1RA produced a significant reduction in MACE risk, ranging from 10 to 45% when compared to DPP-4i [18,[21][22][23][24]. We carried out a meta-analysis of the cardiovascular effects of GLP-1RA vs. other glucose-lowering drugs as observed in real-world studies.…”

“…The meta-analysis of five studies addressing the risk of heart failure-related outcomes as a secondary endpoint [17,19,21,22,25] showed an overall 12% reduction in initiators of GLP-1RA vs. other glucose-lowering drugs (HR 0.88, 95% CI 0.81-0.95, I 2 = 16%) (Figure 2D). However, in none of the individual meta-analyzed studies, was there a significant difference between GLP-1RA and other glucose-lowering drugs new users [17,19,[21][22][23][24][25]. Accordingly, another previously published meta-analysis of ten observational studies reporting heart failure-related outcomes in type 2 diabetic patients treated with GLP-1RA found conflicting results: in three cohort studies GLP-1RA use was associated with heart failure prevention, in three cohort and three nested case-control studies no differences with comparators emerged, while in one study GLP-1RA use was inferior vs. comparator [28].…”

Risk of lower extremity amputations in patients with type 2 diabetes using sodium-glucose co-transporter 2 inhibitors

“…Moreover, the beneficial effects of SGLT2i on cardiovascular and renal outcomes also should be considered when prescribing SGLT2i. The beneficial effect of SGLT2i on cardiovascular morbidity and mortality was also shown in another study that evaluated cardiovascular outcomes of Slovenian patients with type 2 diabetes [ 15 ].…”

“…We used three National Institute of Public Health (NIJZ) databases from Slovenia (Outpatient Prescription Medicines Database, National Hospital Health Care Statistics Database, and Causes of Death Registry) for the period 2009 to 2019. The databases, respectively, contain information on outpatient prescription claims, hospitalisation claims, and patient death for the entire Slovenian population (a detailed description of the databases is provided elsewhere [ 15 ]). The study protocol was registered at the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (registration number: EUPAS32558).…”