Use of sodium glucose cotransporter 2 inhibitors and risk of major cardiovascular events and heart failure: Scandinavian register based cohort study

Abstract

Objective To investigate the cardiovascular effectiveness of sodium glucose cotransporter 2 (SGLT2) inhibitors in routine clinical practice. Design Cohort study using data from nationwide registers and an active-comparator new-user design. Setting Denmark, Norway, and Sweden, from April 2013 to December 2016. Participants 20 983 new users of SGLT2 inhibitors and 20 983 new users of dipeptidyl peptidase 4 (DPP4) inhibitors, aged 35-84, matched by age, sex, history of major cardiovascular disease, and propensity score. Main outcome measures Primary outcomes were major cardiovascular events (composite of myocardial infarction, stroke, and cardiovascular death) and heart failure (hospital admission for heart failure or death due to heart failure). Secondary outcomes were the individual components of the cardiovascular composite and any cause death. In the primary analyses, patients were defined as exposed from treatment start throughout follow-up (analogous to intention to treat); additional analyses were conducted with an as-treated exposure definition. Cox regression was used to estimate hazard ratios. Results Mean age of the study cohort was 61 years, 60% were men, and 19% had a history of major cardiovascular disease. Of the total 27 416 person years of follow-up in the SGLT2 inhibitor group, 22 627 (83%) was among patients who initiated dapagliflozin, 4521 (16%) among those who initiated empagliflozin, and 268 (1%) among those who initiated canagliflozin. During follow-up, 467 SGLT2 inhibitor users (incidence rate 17.0 events per 1000 person years) and 662 DPP4 inhibitor users (18.0) had a major cardiovascular event, whereas 130 (4.7) and 265 (7.1) had a heart failure event, respectively. Hazard ratios were 0.94 (95% confidence interval 0.84 to 1.06) for major cardiovascular events and 0.66 (0.53 to 0.81) for heart failure. Hazard ratios were consistent among subgroups of patients with and without history of major cardiovascular disease and with and without history of heart failure. Hazard ratios for secondary outcomes, comparing SGLT2 inhibitors with DPP4 inhibitors, were 0.99 (0.85 to 1.17) for myocardial infarction, 0.94 (0.77 to 1.15) for stroke, 0.84 (0.65 to 1.08) for cardiovascular death, and 0.80 (0.69 to 0.92) for any cause death. In the as-treated analyses, hazard ratios were 0.84 (0.72 to 0.98) for major cardiovascular events, 0.55 (0.42 to 0.73) for heart failure, 0.93 (0.76 to 1.14) for myocardial infarction, 0.83 (0.64 to 1.07) for stroke, 0.67 (0.49 to 0.93) for cardiovascular death, and 0.75 (0.61 to 0.91) for any cause death. Conclusions In this large Scandinavian cohort, SGLT2 inhibitor use compared with DPP4 inhibitor use was associated with reduced risk of heart failure and any cause death, but not with major cardiovascular events in the primary intention-to-treat analysis. In the additional as-treated analyses, the magnitude of the association with heart failure and any cause death became larger, and a reduced risk of major cardiovascular events that was largely driven by the cardiovascular death component was observed. These data help inform patients, practitioners, and authorities regarding the cardiovascular effectiveness of SGLT2 inhibitors in routine clinical practice.

Reappraisal on pharmacological and mechanical treatments of heart failure

“…The initiation of SGLT-2is, underscoring the potential benefit and risks [107], was related to a lower risk of cardiovascular events, including HHF and death in the cardiovascular disease population [108,109]. In a cohort, SGLT-2i use compared with dipeptidyl peptidase-4 inhibitor (DPP4i) use was associated with a reduced risk of HF [110]. The promising results of SGLT-2is may be related to the upregulation of the renin-angiotensinaldosterone system [111].…”

Cardiovascular outcomes associated with SGLT-2 inhibitors versus other glucose-lowering drugs in patients with type 2 diabetes: A real-world systematic review and meta-analysis

“…The literature screening process was shown in figure 1. A total of 2209 studies were initially retrieved, and fourteen studies [17][18][19][20][21][22][23][24][25][26][27][28][29][30] were finally included after excluding those that did not meet the inclusion criteria.…”

“…Fourteen [17][18][19][20][21][22][23][24][25][26][27][28][29][30] observational studies or cohort studies met the inclusion criteria, A total of 20 cohort (3,157 The quality of the studies was assessed using the Newcastle-Ottawa Scale. Studies given greater than 4 stars were recognized as being moderate to high quality.…”

“…ACM was reported in 15 trials [17][18][19][20][21][22][24][25][26][27][28]30] . For the outcome of ACM, the pooled results from the random-effects model showed that compared with oGLD, SGLT-2i had significantly lowered the risk of ACM (OR, 0.53; 95% CI 0.49,0.57; P< 0.001; Figure 3).…”

“…Toulis KA [18] and Cavender MA [25] have divided people into low-risk and high-risk subset based on their cardiovascular risk. We performed a subgroup analysis based on the incidence of CVD, and they were divided into four groups: low-risk population, high risk population, population with incidence of CVD < 15% [23,24] and population with incidence of CVD (20-30) % [17,20,21,27,30] . Table 3 showed the results of stratified analysis.…”