Sodium glucose cotransporter 2 inhibitors and risk of major adverse cardiovascular events: multi-database retrospective cohort study

Abstract

Objective To compare the risk of cardiovascular events between sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors among people with type 2 diabetes in a real world context of clinical practice. Design Multi-database retrospective cohort study using a prevalent new user design with subsequent meta-analysis. Setting Canadian Network for Observational Drug Effect Studies (CNODES), with administrative healthcare databases from seven Canadian provinces and the United Kingdom, 2013-18. Population 209 867 new users of a SGLT2 inhibitor matched to 209 867 users of a DPP-4 inhibitor on time conditional propensity score and followed for a mean of 0.9 years. Main outcome measures The primary outcome was major adverse cardiovascular events (MACE, a composite of myocardial infarction, ischaemic stroke, or cardiovascular death). Secondary outcomes were the individual components of MACE, heart failure, and all cause mortality. Cox proportional hazards models were used to estimate site specific adjusted hazards ratios and 95% confidence intervals, comparing use of SGLT2 inhibitors with use of DPP-4 inhibitors in an as treated approach. Site specific results were pooled using random effects meta-analysis. Results Compared with DPP-4 inhibitors, SGLT2 inhibitors were associated with decreased risks of MACE (incidence rate per 1000 person years: 11.4 v 16.5; hazard ratio 0.76, 95% confidence interval 0.69 to 0.84), myocardial infarction (5.1 v 6.4; 0.82, 0.70 to 0.96), cardiovascular death (3.9 v 7.7; 0.60, 0.54 to 0.67), heart failure (3.1 v 7.7; 0.43, 0.37 to 0.51), and all cause mortality (8.7 v 17.3; 0.60, 0.54 to 0.67). SGLT2 inhibitors had more modest benefits for ischaemic stroke (2.6 v 3.5; 0.85, 0.72 to 1.01). Similar benefits for MACE were observed with canagliflozin (0.79, 0.66 to 0.94), dapagliflozin (0.73, 0.63 to 0.85), and empagliflozin (0.77, 0.68 to 0.87). Conclusions In this large observational study conducted in a real world clinical practice context, the short term use of SGLT2 inhibitors was associated with a decreased risk of cardiovascular events compared with the use of DPP-4 inhibitors. Trial registration ClinicalTrials.gov NCT03939624 .

Cardiovascular safety of evogliptin in patients with type 2 diabetes: A nationwide cohort study

“…Although a prior history of cardiovascular disease in patients with T2D is acknowledged to be strongly associated with an increased risk of recurrent cardiovascular events, reducing the long‐term risks with adequate glycaemic control is the major goal of T2D treatment 41 . Thus, the investigation of the risk of cardiovascular events, regardless of whether incident or recurrent, is important, as patients with T2D, both with or without a history of cardiovascular disease, may benefit from continuous antidiabetic treatment, especially in real‐world clinical practice 19,42,43 . Moreover, there were no imbalances present in the medical history of cardiovascular disease (AP, MI, HF, TIA and cerebrovascular diseases) between DPP‐4i and glimepiride users (Table 1), whereas the results of the sensitivity analysis excluding patients with a history of cardiovascular disease were consistent with our main findings.…”

Diabetes and stroke: An important complication

“…However, the Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT2 Inhibitors (CVD‐REAL) propensity score–matched follow‐up of 205 160 persons treated with SGLT2i vs other agents showed stroke event rates of 0.42 vs 0.58 per 100 person‐years, yielding a significant 20% event reduction 57 . In the Canadian Network for Observational Drug Effect Studies (CNODES), administrative health care databases from seven Canadian provinces and the United Kingdom during the period of 2013 to 2018 showed a significant 22% lower ischemic stroke rate with SGLT2i than with DPP‐IVi, although adjustment for age, sex, diabetes duration, and propensity score led to a hazard rate of 0.85, failing to achieve statistical significance 58 …”

“…57 In the Canadian Network for Observational Drug Effect Studies (CNODES), administrative health care databases from seven Canadian provinces and the United Kingdom during the period of 2013 to 2018 showed a significant 22% lower ischemic stroke rate with SGLT2i than with DPP-IVi, although adjustment for age, sex, diabetes duration, and propensity score led to a hazard rate of 0.85, failing to achieve statistical significance. 58…”

Various and sundry recent publications

“…In a propensity score‐matched analysis of 105 130 persons not having diagnosed cardiovascular disease (CVD) or CKD receiving SGLT2i and the same number treated with a DPP‐4i, the former agents were associated with 29% lower likelihood of heart failure (HF), 56% lower likelihood of CKD, and 33% and 39% lower likelihood of all‐cause and CV death; but no differences in stroke or myocardial infarction (MI) 8 . In another real‐world comparative study, however, a propensity score‐matched cohort of 209 867 new users of a SGLT2i vs the same number of users of a DPP‐4i followed for a mean of 0.9 years had 5.1 vs 6.4 MI, 3.9 vs 7.7 CV deaths, and 2.6 vs 3.5 ischemic strokes, the composite of major adverse CV events occurring significantly less often at rates of 11.4 vs 16.5 per 1000 person‐years; furthermore, there were 3.1 vs 7.7 HF events per 1000 person‐years 9 . Using the same dataset to match 208 757 new users of SGLT2i with the same number of users of a DPP‐4i, ketoacidosis occurred at rates of 2.03 vs 0.75 per 1000 person‐years, with overlapping 95% confidence ranges for dapagliflozin, empagliflozin, and canagliflozin; persons treated with insulin had lower risk, suggesting that, although infrequent, ketoacidosis might be particularly likely to occur in persons requiring insulin but not begun on this treatment 10 …”

“…8 In another real-world comparative study, however, a propensity score-matched cohort of 209 867 new users of a SGLT2i vs the same number of users of a DPP-4i followed for a mean of 0.9 years had 5.1 vs 6.4 MI, 3.9 vs 7.7 CV deaths, and 2.6 vs 3.5 ischemic strokes, the composite of major adverse CV events occurring significantly less often at rates of 11.4 vs 16.5 per 1000 person-years; furthermore, there were 3.1 vs 7.7 HF events per 1000 person-years. 9 Using the same dataset to match 208 757 new users of SGLT2i with the same number of users of a DPP-4i, ketoacidosis occurred at rates of 2.03 vs 0.75 per 1000 person-years, with overlapping 95% confidence ranges for dapagliflozin, empagliflozin, and canagliflozin; persons treated with insulin had lower risk, suggesting that, although infrequent, ketoacidosis might be particularly likely to occur in persons requiring insulin but not begun on this treatment. 10 While there is impressive and growing evidence of CV outcome benefit of treatment with GLP-1RA, clinicians should as well use these agents because of the glycemic and weight loss benefits of the class.…”