•GLP-1 RAs reduced MACE regardless of metformin use at baseline.•Background metformin did not affect the favorable effect of GLP-1 RAs on mortality.•GLP-1 RAs had a neutral effect on stroke, ...myocardial infarction and heart failure hospitalization.
To explore the effect of background treatment with metformin on the efficacy of GLP-1 receptor agonists (GLP-1 RAs) on cardiovascular outcomes in type 2 diabetes.
We searched MEDLINE and EMBASE through May 5, 2021 for randomized, placebo-controlled, cardiovascular outcomes trials of GLP-1 RAs in patients with type 2 diabetes that reported cardiovascular or mortality outcomes by baseline metformin use. Main outcome was incidence of major adverse cardiovascular events (MACE). Other outcomes included the individual components of the primary composite outcome (myocardial infarction, stroke, cardiovascular death), all-cause mortality and hospitalization for heart failure. We pooled hazard ratios (HRs) with 95% confidence intervals (CIs) stratified by baseline use of metformin using random-effects meta-analysis.
We included 4 trials (43,456 patients) assessing albiglutide, dulaglutide, exenatide once weekly and liraglutide. GLP-1 RAs reduced MACE by 13% (HR 0.87, 95% CI 0.82–0.93), an effect which was consistent in both subgroups (HR 0.91, 95% CI 0.85–0.97 and HR 0.80, 95% CI 0.72–0.90 with and without metformin, respectively). Presence of metformin at baseline did not affect the overall favorable effect of GLP-1 RAs both on cardiovascular and all-cause mortality. Finally, subgroup meta-analyses suggested that GLP-1 RAs had a neutral effect on stroke, myocardial infarction and hospitalization for heart failure, irrespective of metformin use at baseline.
Subgroup analyses suggested that treatment with GLP-1 RAs has a beneficial effect on cardiovascular outcomes irrespective of baseline use of metformin. However, given the exploratory nature of subgroup analyses, these findings should be treated as hypothesis-generating rather than conclusive evidence.
Supranormal ejection fraction by echocardiography in clinically referred patient populations has been associated with an increased risk of cardiovascular disease (CVD). The prognostic implication of ...supranormal left ventricular ejection fraction (LVEF)—assessed by cardiac magnetic resonance (CMR)—in healthy, community-dwelling individuals is unknown.
The purpose of this study is to investigate the prognostic implication of supranormal LVEF as assessed by CMR and its inter-relationship with stroke volume among community-dwelling adults without CVD.
Participants from the MESA (Multi-Ethnic Study of Atherosclerosis) and DHS (Dallas Heart Study) cohorts free of CVD who underwent CMR with LVEF above the normal CMR cutoff (≥57%) were included. The association between cohort-specific LVEF categories and risk of clinically adjudicated major adverse cardiovascular events (MACE) was assessed using adjusted Cox models. Subgroup analysis was also performed to evaluate the association of LVEF and risk of MACE among individuals stratified by left ventricular stroke volume index.
The study included 4,703 participants from MESA and 2,287 from DHS with 727 and 151 MACE events, respectively. In adjusted Cox models, the risk of MACE was highest among individuals in LVEF Q4 (vs Q1) in both cohorts after accounting for potential confounders (MESA: HR = 1.27 95% CI: 1.01-1.60, P = 0.04; DHS: HR = 1.72 95% CI: 1.05-2.79, P = 0.03). A significant interaction was found between the continuous measures of LVEF and left ventricular stroke volume index (P interaction = 0.02) such that higher LVEF was significantly associated with an increased risk of MACE among individuals with low but not high stroke volume.
Among community-dwelling adults without CVD, LVEF in the supranormal range is associated with a higher risk of adverse cardiovascular outcomes, particularly in those with lower stroke volume.
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Cardiovascular outcomes trials of sodium-glucose co-transporter-2 (SGLT2) inhibitors have demonstrated consistent signals of benefit in terms of both prevention and treatment of heart failure (HF), ...in patients with and without type 2 diabetes (T2D). In response to growing evidence of the benefits of SGLT2 inhibitors, including increased survival, reduced hospitalizations and improved patient-reported symptoms, functional status, and quality of life, the treatment landscape for HF has evolved. Importantly, these agents have also demonstrated safety and tolerability in individuals with HF across the spectrum of left ventricular ejection fraction, with improvements in clinical and patient-reported outcomes occurring as early as days to weeks after treatment initiation. For patients with heart failure with reduced ejection fraction (HFrEF), SGLT2 inhibitors are now increasingly recognized as foundational disease-modifying therapy. An updated joint guideline from the American College of Cardiology and American Heart Association now recommends including SGLT2 inhibitors for patients with HF across the spectrum of ejection fraction, irrespective of the presence of diabetes, and regardless of background therapy (Class 1 recommendation for HFrEF, Class 2a recommendation for HF with mildly reduced ejection fraction HFmrEF and HF with preserved ejection fraction HFpEF). The European Society of Cardiology also include a Class I recommendation to use SGLT2 inhibitors for patients with HFrEF to reduce the risk of hospitalization for HF and CV death, irrespective of T2D status. This chapter reviews published clinical trial data about the efficacy and safety of SGLT2 inhibitors among patients with HFrEF, HFpEF, and patients hospitalized for HF.
Heart failure (HF) is common and associated with a poor prognosis, despite advances in treatment. Over the last decade cardiovascular outcome trials with sodium–glucose co‐transporter 2 (SGLT2) ...inhibitors in patients with type 2 diabetes mellitus have demonstrated beneficial effects for three SGLT2 inhibitors (empagliflozin, canagliflozin and dapagliflozin) in reducing hospitalisations for HF. More recently, dapagliflozin reduced the risk of worsening HF or death from cardiovascular causes in patients with chronic HF with reduced left ventricular ejection fraction, with or without type 2 diabetes mellitus. A number of additional trials in HF patients with reduced and/or preserved left ventricular ejection fraction are ongoing and/or about to be reported. The present position paper summarises recent clinical trial evidence and discusses the role of SGLT2 inhibitors in the treatment of HF, pending the results of ongoing trials in different populations of patients with HF.
Abstract
Aims
The ongoing Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction OCEAN(a)-Outcomes trial is evaluating whether Lp(a) lowering can reduce the incidence of ...cardiovascular events among patients with prior myocardial infarction (MI) or percutaneous coronary intervention (PCI) and elevated Lp(a) (≥200 nmol/L). The purpose of this study is to evaluate the association of elevated Lp(a) with cardiovascular outcomes in an observational cohort resembling the OCEAN(a)-Outcomes trial main enrolment criteria.
Methods and results
This study included patients aged 18–85 years with Lp(a) measured as part of their clinical care between 2000 and 2019. While patients were required to have a history of MI, or PCI, those with severe kidney dysfunction or a malignant neoplasm were excluded. Elevated Lp(a) was defined as ≥200 nmol/L consistent with the OCEAN(a)-Outcomes trial. The primary outcome was a composite of coronary heart disease death, MI, or coronary revascularization. Natural language processing algorithms, billing and ICD codes, and laboratory data were employed to identify outcomes and covariates. A total of 3142 patients met the eligibility criteria, the median age was 61 (IQR: 52–73) years, 28.6% were women, and 12.3% had elevated Lp(a). Over a median follow-up of 12.2 years (IQR: 6.2–14.3), the primary composite outcome occurred more frequently in patients with versus without elevated Lp(a) 46.0 vs. 38.0%, unadjHR = 1.30 (95% CI: 1.09–1.53), P = 0.003. Following adjustment for measured confounders, elevated Lp(a) remained independently associated with the primary outcome adjHR = 1.33 (95% CI: 1.12–1.58), P = 0.001.
Conclusion
In an observational cohort resembling the main OCEAN(a)-Outcomes Trial enrolment criteria, patients with an Lp(a) ≥200 nmol/L had a higher risk of cardiovascular outcomes.
Statins reduce low-density lipoprotein cholesterol (LDL-C) and are efficacious in the prevention of atherosclerotic cardiovascular disease (ASCVD). Dose-response to statins varies among patients and ...can be modeled using 3 distinct pharmacological properties: 1) E0 (baseline LDL-C), 2) ED50 (potency: median dose achieving 50% reduction in LDL-C); and 3) Emax (efficacy: maximum LDL-C reduction). However, individualized dose-response and its association with ASCVD events remains unknown.
The authors analyzed the relationship between ED50 and Emax with real-world cardiovascular disease outcomes.
We leveraged deidentified electronic health record data to identify individuals exposed to multiple doses of the 3 most commonly prescribed statins (atorvastatin, simvastatin, or rosuvastatin) within the context of their longitudinal health care. We derived ED50 and Emax to quantify the relationship with a composite primary endpoint of ASCVD events (ischemic heart disease, cerebrovascular disease, peripheral vascular disease, coronary artery revascularization procedure) and all-cause mortality.
We estimated ED50 and Emax for 3,033 unique individuals (atorvastatin: 1,632, simvastatin: 1,089, and rosuvastatin: 312) using a nonlinear, mixed effects dose-response model. Time-to-event analyses revealed that ED50 and Emax are independently associated with the primary endpoint. Hazard ratios were 0.85 (P < 0.01), 0.83 (P < 0.01), and 0.87 (P = 0.10) for ED50 and 1.13 (P < 0.001), 1.06 (P < 0.001), and 1.15 (P = 0.009) for Emax in the atorvastatin, simvastatin, and rosuvastatin cohorts, respectively.
The class-wide association of ED50 and Emax with clinical outcomes indicates that these measures influence the risk for ASCVD events in patients on statins.
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Background: Timing drug administration to endogenous circadian rhythms may enhance treatment efficacy. In the Chronotype sub-study of the Treatment in Morning versus Evening (TIME) clinical trial we ...examined whether timing of usual antihypertensive medications according to patient chronotype (a behavioural marker of personal circadian rhythm) may influence clinical cardiovascular outcomes. Methods: This was a cohort sub-study of TIME, a prospective, randomised, open-label, blinded-endpoint, UK clinical trial of morning versus evening dosing of usual antihypertensive medications and cardiovascular outcomes. On August 3rd, 2020, all active TIME participants were invited to complete a validated chronotype questionnaire. Chronotype was quantitatively assessed as the mid sleep time on free days corrected for sleep debt on workdays (MSFsc). We analysed associations between chronotype and antihypertensive dosing time and explored their combined effect on cardiovascular outcomes (a composite endpoint of hospitalisation for non-fatal myocardial infarction (MI) or non-fatal stroke, and single components) using proportional hazard time-to-event models adjusted for baseline covariates. These were used to specifically test for interactions between dosing time and chronotype. Findings: Between August 3, 2020, and March 31, 2021, 5358 TIME participants completed the online questionnaire. 2778 were previously randomised to morning dosing and 2580 to evening dosing of their usual antihypertensives. Chronotype was symmetrically distributed around a median MSFsc of 3:07 am. The composite endpoint increased for later MSFsc (later chronotype) dosed in the morning but not in those dosed in the evening (hazard ratios 1.46 95% CI 1.14–1.86 and 0.96 95% CI 0.70–1.30 per hour of MSFsc, respectively; interaction p = 0.036). Later chronotype was associated with increased risk of hospitalisation for non-fatal MI in the morning dosing group, and reduced risk in the evening dosing group (hazard ratios 1.62 95% CI 1.18–2.22 and 0.66 95% CI 0.44–1.00 per hour of MSFsc, respectively; interaction p < 0.001). No interaction between chronotype and antihypertensive dosing time was observed for stroke events. Interpretation: Alignment of dosing time of usual antihypertensives with personal chronotype could lower the incidence of non-fatal MI compared to a ‘misaligned’ dosing time regimen. Future studies are warranted to establish whether synchronizing administration time of antihypertensive therapy with individual chronotype reduces risk of MI. Funding: The TIME study was funded by the British Heart Foundation (CS/14/1/30659) with support from the British and Irish Hypertension Society.
•Alirocumab improves cardiovascular outcomes after ACS irrespective of sex.•Reduction of total cardiovascular events was greater at higher baseline Lp(a).
The ODYSSEY OUTCOMES trial (NCT01663402) ...compared the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo on major adverse cardiovascular events (MACE) in patients with recent acute coronary syndrome (ACS).
We assessed efficacy and safety of alirocumab versus placebo according to sex and lipoprotein(a) level.
This prespecified analysis compared the effects of alirocumab versus placebo on lipoproteins, MACE (coronary heart disease death, non-fatal myocardial infarction, fatal/non-fatal ischemic stroke, unstable angina requiring hospitalization), death, total cardiovascular events, and adverse events in 4762 women and 14,162 men followed for a median of 2.8 years. In post-hoc analysis, we evaluated total cardiovascular events according to sex, baseline lipoprotein(a), and treatment.
Women were older, had higher baseline LDL-C levels (89.6 vs 85.3 mg/dL) and lipoprotein(a) (28.0 vs 19.3 mg/dL) and had more co-morbidities than men. At 4 months, alirocumab lowered LDL-C by 49.4 mg/dL in women and 54.0 mg/dL in men and lipoprotein(a) by 9.7 and 8.1 mg/dL, respectively (both p < 0.0001). Alirocumab reduced MACE, death, and total cardiovascular events similarly in both sexes. In the placebo group, lipoprotein(a) was a risk factor for total cardiovascular events in women and men. In both sexes, reduction of total cardiovascular events was greater at higher baseline lipoprotein(a), but this effect was more evident in women than men (pinteraction=0.08). Medication adherence and adverse event rates were similar in both sexes.
Alirocumab improves cardiovascular outcomes after ACS irrespective of sex. Reduction of total cardiovascular events was greater at higher baseline lipoprotein(a).
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