Effects of canagliflozin on myocardial infarction:a post hoc analysis of the CANVAS Program and CREDENCE trial

AIMS: Given the benefits of sodium glucose co-transporter 2 inhibition (SGLT2i) in protecting against heart failure in diabetic patients, we sought to explore the potential impact of SGLT2i on the clinical features of patients presenting with myocardial infarction (MI) through a post-hoc analysis of CANVAS Program and CREDENCE trial.METHODS AND RESULTS: Individuals with type 2 diabetes and history or high risk of cardiovascular disease (CANVAS Program) or type 2 diabetes and chronic kidney disease (CREDENCE) were included. The intervention was Canagliflozin 100 or 300 mg (combined in the analysis) or placebo. MI events were adjudicated as ST-elevation myocardial infarction (STEMI), non-STEMI as well as type 1 MI or type 2 MI. 421 first MI events in the CANVAS Program and 178 first MI events in the CREDENCE trial were recorded (83 fatal, 128 STEMI, 431 non-STEMI, and 40 unknown). No benefit of canagliflozin compared with placebo on time to first MI event was observed (HR 0.89; 95% CI 0.75, 1.05). Canagliflozin was associated with lower risk for non-STEMI (HR 0.78; 95% CI 0.65, 0.95) but suggested a possible increase in STEMI (HR 1.55; 95% CI 1.06, 2.27), with no difference in risk of type 1 or type 2 MI. There was no change in fatal MI (HR 1.22, 95% CI 0.78, 1.93).CONCLUSIONS: Canagliflozin was not associated with a reduction in overall MI in the pooled CANVAS Program and CREDENCE trial population. The possible differential effect on STEMI and Non-STEMI observed in the CANVAS cohort warrants further investigation.</p

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Effects of canagliflozin on myocardial infarction: a post hoc analysis of the CANVAS Program and CREDENCE trial

AIMS: Given the benefits of sodium glucose co-transporter 2 inhibition (SGLT2i) in protecting against heart failure in diabetic patients, we sought to explore the potential impact of SGLT2i on the clinical features of patients presenting with myocardial infarction (MI) through a post-hoc analysis of CANVAS Program and CREDENCE trial. METHODS AND RESULTS: Individuals with type 2 diabetes and history or high risk of cardiovascular disease (CANVAS Program) or type 2 diabetes and chronic kidney disease (CREDENCE) were included. The intervention was Canagliflozin 100 or 300 mg (combined in the analysis) or placebo. MI events were adjudicated as ST-elevation myocardial infarction (STEMI), non-STEMI as well as type 1 MI or type 2 MI. 421 first MI events in the CANVAS Program and 178 first MI events in the CREDENCE trial were recorded (83 fatal, 128 STEMI, 431 non-STEMI, and 40 unknown). No benefit of canagliflozin compared with placebo on time to first MI event was observed (HR 0.89; 95% CI 0.75, 1.05). Canagliflozin was associated with lower risk for non-STEMI (HR 0.78; 95% CI 0.65, 0.95) but suggested a possible increase in STEMI (HR 1.55; 95% CI 1.06, 2.27), with no difference in risk of type 1 or type 2 MI. There was no change in fatal MI (HR 1.22, 95% CI 0.78, 1.93). CONCLUSIONS: Canagliflozin was not associated with a reduction in overall MI in the pooled CANVAS Program and CREDENCE trial population. The possible differential effect on STEMI and Non-STEMI observed in the CANVAS cohort warrants further investigation