Effects of sodium-glucose co-transporter-2 inhibitors by background cardiovascular medications: A systematic review and meta-analysis

Aim

To explore whether the beneficial cardiovascular (CV) effect of sodium-glucose co-transporter-2 (SGLT-2) inhibitors is consistent with or without concurrent use of CV medications in patients with type 2 diabetes, heart failure (HF) or chronic kidney disease.

Methods

We searched Medline and Embase up to September 2022 for CV outcomes trials. The primary endpoint was the composite of cardiovascular (CV) death or hospitalization for HF. Secondary outcomes included the individual components of CV death, hospitalization for HF, death from any cause, major adverse CV events or renal events, volume depletion and hyperkalaemia. We pooled hazard ratios (HRs) and risk ratios alongside 95% confidence intervals (CIs).

Results

We included 12 trials comprising 83 804 patients. SGLT-2 inhibitors reduced the risk of CV death or hospitalization for HF regardless of background use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), b-blockers, diuretics, mineralocorticoid receptor antagonists (MRAs), or triple combination therapy of either an ACEI/ARB plus b-blocker plus MRA, or an ARNI plus b-blocker plus MRA (HRs ranged from 0.61 to 0.83; P > .1 for each subgroup interaction). Similarly, no subgroup differences were evident for most analyses for the secondary outcomes of CV death, hospitalization for HF, all-cause mortality, major adverse CV or renal events, hyperkalaemia and volume depletion rate.

Conclusions

The benefit of SGLT-2 inhibitors seems to be additive to background use of CV medications in a broad population of patients. These findings should be interpreted as hypothesis generating because most of the subgroups analysed were not prespecified.     

Cardiovascular Outcomes with SGLT-2 inhibitors in patients with heart failure with or without type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials

Background and aimsWe conducted a systematic review and meta-analysis of all the randomized controlled trials (RCTs) with SGLT-2 inhibitors (SGLT-2i) in patients with known heart failure (HF) with or without type 2 diabetes (T2DM), that have studied the outcomes of cardiovascular (CV) death, hospitalization due to HF (HHF), and composite of CV death or HHF.MethodsA systematic search in PubMed, Embase and Cochrane Library database were made up till November 20, 2020 using specific keywords. RCTs that qualified underwent a meta-analysis by applying the inverse variance-weighted averages of pooled logarithmic hazard ratio (HR) using both random- and fixed-effects model.ResultsThis meta-analysis of 9 RCTs (N = 19,741) have found a significant 26% relative risk reduction in composite of CV death or HHF (HR 0.74; 95% CI, 0.69–0.79; p < 0.001) with SGLT-2i in patients with HF. The meta-analysis of 8 RCTs (N = 16,460) also showed a significant reduction in CV death (HR 0.86; 95% CI, 0.78–0.95; p = 0.003) and HHF (HR 0.68; 95% CI, 0.62–0.74; p < 0.001) outcomes with SGLT-2i in patients with HF. Subgroup analysis stratified on baseline ejection fraction (EF) showed a similar benefit in the composite of CV death or HHF in patients with HF with reduced EF (HFrEF) or preserved EF (HFpEF).ConclusionsSGLT-2i significantly reduces the composite of CV death or HHF, CV death, and HHF in patients with HF. Although subgroup analysis suggested an insignificant P_heterogenity for these outcomes irrespective of the types of HF, however, reduction in both CV death and HHF were more pronounced in patients with HFrEF.     

Effects of sodium glucose cotransporter type 2 inhibitors on heart failure

Heart failure (HF) is emerging as one of the most common cardiovascular (CV) events in patients with type 2 diabetes (T2D), and the one associated with the worst prognosis. T2D and insulin resistance are strong predictors of incident HF, especially HF with preserved ejection fraction (HFpEF). Recent data suggest that even when all traditional risk factors for ASCVD are well controlled, patients with T2D continue to have a substantially greater risk of developing HF—indicating that traditional risk factor control is insufficient from a HF prevention standpoint, and highlighting the need for novel, more effective strategies for both prevention and treatment of heart failure in patients with T2D. Until recently, medications developed for glucose-lowering had, at best, neutral effect on heart failure outcomes in patients with T2D, while several classes of T2D medications had little data in regards to HF risk, and others actually increased the risk of HF hospitalization. Sodium glucose cotransporter type 2 inhibitors (SGLT-2i) have a novel and unique mechanism of action. By inhibiting sodium and glucose reabsorption in the proximal tubule, SGLT-2i result in a number of downstream effects, including glucosuria, weight loss, osmotic diuresis and natriuresis, which should theoretically be beneficial in HF. Three CVOTs of various SGLT-2i (EMPA-REG OUTCOME, CANVAS and DECLARE-TIMI 58) enrolled markedly different patient populations in terms of ASCVD risk, but have demonstrated robust and consistent benefits in reduction of hospitalization for HF. In a meta-analysis of the three outcomes trials, SGLT-2i significantly reduced the risk of cardiovascular death or hospitalization for HF by 23% and hospitalization for HF by 31%. Although the declines in HF hospitalization with SGLT-2is are impressive, only a small proportion of patients with established HF were enrolled in these trials, and these benefits, therefore, represent primarily a HF prevention signal. Whether this prevention of HF benefit will translate to better outcomes for those patients with established HF (with or without diabetes), and whether it will extend across the spectrum of HF phenotypes (HFrEF and HFpEF) is yet to be determined, and is being actively investigated in several large ongoing trials.     

Effects of sodium-glucose cotransporter-2 inhibitors on the cardiovascular and renal complications of type 2 diabetes

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have been shown to mitigate the risks of cardiovascular (CV) and renal complications in patients with type 2 diabetes (T2D) and CV risk factors or CV disease (CVD). In CV outcomes trials (CVOTs) of patients with T2D and established CVD or multiple CV risk factors, empagliflozin and canagliflozin were associated with significant reductions in the risks of major adverse CV events (MACE), hospitalization for heart failure (HF) and kidney disease progression. In the DECLARE–TIMI 58 study, in which the majority of patients did not have established CVD, dapagliflozin was associated with significant reductions in the composite end point of CV death or hospitalization for HF and was noninferior to placebo with regard to MACE; although patients had relatively good renal function, dapagliflozin also showed renal benefits similar to those seen with empagliflozin and canagliflozin. This article reviews the increased risk of CVD and renal disease in patients with T2D and discusses the potential mechanisms of the cardioprotective and renoprotective effects of SGLT-2i therapy. The observed improvements in CV and renal outcomes with SGLT-2is in CVOTs suggest a class effect in this patient population and have influenced treatment guidelines for the way add-on therapy to metformin is initiated in patients with T2D and high CV risk. The overall cardioprotective and renoprotective effects of SGLT-2is in patients with T2D and high CV risk are most likely attributable to multiple mechanisms, including cardiac, haemodynamic, metabolic, anti-inflammatory and renal effects.     

Impact of SGLT2 inhibitors on major clinical events and safety outcomes in heart failure patients: a meta-analysis of randomized clinical trials

BACKGROUNDSodium-glucose co-transporter-2 inhibitors (SGLT2i) significantly reduce the risk of cardiovascular (CV) and renal adverse events in patients with diabetes mellitus, heart failure (HF) and/or chronic kidney disease. We performed a meta-analysis to explore the impact of several different SGLT2i on all-cause mortality, CV mortality, HF hospitalizations and the combined outcome CV death/HF hospitalization in HF patients across the spectrum of left ventricular ejection fraction (LVEF) phenotypes.METHODSA systematic search in MEDLINE database and Cochrane library through March 2021 was performed without limitations. Randomized clinical trials that provided data about the impact of SGLT2i on all-cause mortality, CV mortality, HF hospitalizations or the combined outcome of CV death/HF hospitalization in HF patients were included. A random effects model was used for calculating the effect estimates.RESULTSNine studies (n = 16,723 patients, mean age: 65.9 years, males: 70.7%) were included in the quantitative synthesis. Compared to placebo, SGLT2i use was associated with 14% lower risk of all-cause mortality [hazard ratio (HR) = 0.86, 95% CI: 0.78−0.94,I² = 0, P = 0.0008], 32% lower risk of HF hospitalizations (HR = 0.68, 95% CI: 0.62−0.74,I² = 0, P < 0.001), 14% lower risk of CV mortality (HR = 0.86, 95% CI: 0.77−0.95, I² = 0, P = 0.003) and 26% lower risk of CV death/HF hospitalization (HR = 0.74, 95% CI: 0.68−0.80,I² = 0, P < 0.001). Regarding the safety outcomes, our data revealed no significant differences between SGLT2i and placebo groups in drug related discontinuations, amputations, severe hypoglycemia, hypotension, volume depletion, ketoacidosis and genital infections. By contrast, a protective role of SGLT2i against placebo was found for serious adverse events and acute kidney injury. CONCLUSIONSIn patients with HF, regardless of LVEF phenotype, all SGLT2i had an excellent safety profile and significantly reduced the risk of all-cause mortality, CV mortality, HF hospitalizations and CV deaths/HF hospitalizations compared to placebo.

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) is an antidiabetic class category that acts by blocking glucose resorption in the proximal tubule of the kidney promoting glucosuria.^[1] Randomized clinical trials have shown the beneficial role of SGLT2i in cardiovascular (CV) and renal outcomes in patients with or without diabetes mellitus (DM), including patients with heart failure (HF) and/or chronic kidney disease (CKD).^[2–8] According to current guidelines, empagliflozin, canagliflozin and dapagliflozin are recommended in patients with type 2 DM (T2DM) and CV disease, or at very high/high CV risk to reduce CV events, while empagliflozin is also recommended in patients with T2DM and CV disease to reduce the risk of death.^[9] The protective role of SGLT2i on CV events is mainly driven by the reduction in HF hospitalizations.^[4] For that reason, SGLT2i (empagliflozin, canagliflozin and dapagliflozin) are also recommended to lower risk of HF hospitalization in patients with DM.^[9] Recent studies and meta-analyses have shown that empagliflozin and dapagliflozin can further improve CV and renal outcomes in HF patients with reduced left ventricular ejection fraction [LVEF, especially HF with reduced ejection fraction (HFrEF)], regardless of the presence of DM.^[8,10,11] In addition, the American College of Cardiology has already recommended SGLT2i for the treatment of HFrEF.^[12] However, there are still unanswered questions as to whether the observed favorable outcomes in efficacy and safety constitute a class effect of SGLT2i or an effect confined to specific agents and whether the benefit also extends to HF with preserved LVEF [especially HF with preserved ejection fraction (HFpEF)]. The aim of this meta-analysis is to shed some light on these open issues by pooling data from randomized controlled trials (RCTs) on all clinically available SGLT2i, while examining the effects of SGLT2i across the spectrum of LVEF phenotypes.     

Effect of SGLT-2 inhibitors on cardiovascular outcomes in heart failure patients: A meta-analysis of randomized controlled trials

BackgroundTo investigate the overall effect of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on cardiovascular outcomes in a broad spectrum of heart failure (HF) patients, and further stratified by status of ejection fraction and diabetes mellitus.MethodsElectronic databases were searched to identify randomized controlled trials that compared SGLT-2i with placebo in patients with HF. Efficacy outcomes included the composite of cardiovascular death (CVD) or hospitalization for heart failure (HHF), individual CVD, individual HHF, and all-cause mortality (ACM).ResultsA total of 8 large trials comprising 16,460 HF patients were enrolled. Pooled data demonstrated that SGLT-2i significantly reduced the risk for primary composite outcome (CVD or HHF) by 23% (HR: 0.77, 95% CI: 0.72–0.82) in HF patients. Use of SGLT-2i was associated with a statistically significant 32% reduction in HHF (HR: 0.68, 95% CI: 0.62–0.75), a 15% reduction in CVD (HR: 0.85, 95% CI: 0.76–0.94) and a 16% reduction in ACM (HR: 0.84, 95% CI: 0.77–0.92). Sensitivity analyses using Mantel-Haenszel method displayed consistent results. Subgroup analyses demonstrated that SGLT-2i were robustly effective in HFrEF subgroup as well as in HF with absence/presence of T2DM, and displayed a strong trend to be effective in HFpEF. Safety analysis demonstrated SGLT-2i group had a lower proportion of serious adverse events than placebo group (RR 0.89, 95% CI: 0.86–0.93).ConclusionsCompared with placebo, SGLT-2 inhibitors have remarkable cardiovascular benefits in a broad range of HF patients. Beneficial effects were robust in HF patients regardless of T2DM status, and a strong trend to be effective in HFpEF.     

Heart failure and diabetes: Clinical significance and epidemiology of this two-way association

People with type 2 diabetes (T2DM) and those with prediabetes have an increased risk of heart failure (HF). Longer duration of T2DM correlates with a greater risk of HF, but HF is also seen in patients with recent-onset diabetes. Insulin resistance is more likely to be present in patients with HF. The risk of HF persists even in the face of standard-of-care preventive treatments for atherosclerotic cardiovascular (CV) disease. HF is commonly the presenting symptom of CV disease in people with diabetes and is the most expensive complication of diabetes because of the high cost of hospitalizations. Recently hospitalization for HF has been included in CV outcome trials (CVOTs), including for medications that are used to treat T2DM, which has led to new therapies for all HF patients. In addition, these CVOTs have shown that many drugs used in the therapy of diabetes are either neutral or detrimental in the HF patient and should be used with caution in patients with existing HF or those at high risk of HF. Most recently, sodium-glucose cotransporter-2 receptor blockers have shown efficacy in both HF with reduced ejection fraction (EF) and HF with preserved EF. The only other oral or injectable diabetes agent shown to improve outcomes in both is metformin.     

Iron deficiency in heart failure: screening,prevalence, incidence and outcome data from the Swedish Heart Failure Registry and the Stockholm CREAtinine Measurements collaborative project

Aims

Iron deficiency (ID) is common in heart failure (HF) and linked with poor prognosis regardless of anaemia. We assessed temporal trends in ID testing, ID prevalence, ID incidence, iron need, and outcomes associated with ID in HF across the ejection fraction (EF) spectrum.

Methods and results

From the Swedish HF registry, we enrolled 15 197 patients from Region Stockholm with available EF and collected laboratory tests from routine practice. Iron screening improved since 2016 but remained <25% as of 2018. In 1486 patients with iron biomarkers at baseline, the prevalence of ID was 55% (HF with reduced EF 54%; mildly reduced EF 51%; preserved EF 61%). Iron need was ≥1500 mg in 72% of patients. ID was independently associated with higher risk for HF rehospitalizations (incidence rate ratio [IRR] 1.62, 95% confidence interval [CI] 1.13–2.31) and with cardiovascular (CV) death or repeated HF hospitalizations (IRR 1.63, 95% CI 1.15–2.30) regardless of EF (p-interaction 0.21 and 0.26, respectively), but not with all-cause death, CV death, or first HF hospitalization. Among 96 patients without ID at baseline and with follow-up iron biomarkers, 21% developed ID within 6 months.

Conclusions

Iron deficiency screening improved over time but is still limitedly implemented, despite being highly prevalent and incident, and independently associated with CV death or HF rehospitalizations regardless of EF. Most patients with ID had an iron need necessitating either repeated administrations of intravenous iron or a preparation permitting >1000 mg doses. These data highlight the need for improved screening for ID in HF.     

Association of Coronary Microvascular Dysfunction With Heart Failure Hospitalizations and Mortality in Heart Failure With Preserved Ejection Fraction: A Follow-up in the PROMIS-HFpEF Study

BackgroundCoronary microvascular dysfunction (CMD) is common in heart failure with preserved ejection fraction (HFpEF). We assessed the association of CMD with hospitalization and mortality in HFpEF.Methods and ResultsWe assessed the 1-year outcomes in patients from the PROMIS-HFpEF study, a prospective observational study of patients with chronic stable HFpEF undergoing coronary flow reserve measurements. Outcomes were (1) time to cardiovascular (CV) death/first HF hospitalization, (2) CV death/recurrent HF hospitalizations, (3) all-cause death/first HF hospitalization, and (4) first and (5) recurrent all-cause hospitalizations. CMD was defined as coronary flow reserve of <2.5. Time to CV death/first hospitalization was compared by log-rank test and recurrent HF and all-cause hospitalizations by Poisson test. Of 263 patients enrolled, 257 were evaluable at 1 year. Where the coronary flow reserve was interpretable (n = 201), CMD was present in 150 (75%). The median follow-up was 388 days (Q1, Q3 365, 418). The outcome of CV death/first HF hospitalization occurred in 15 patients (4 CV deaths). The incidence rate was in CMD 96 per 1000 person-years, 95% confidence interval 54–159, vs non-CMD 0 per1000 person-years, 95% confidence interval 0–68, P = .023, and remained significant after accounting for selected clinical variables. In patients with CMD, the incidence rates were significantly higher also for CV death/recurrent HF hospitalizations, all-cause death/first HF, and recurrent but not first all-cause hospitalization.ConclusionsIn this exploratory assessment of the prognostic role of CMD in HFpEF, CMD was independently associated with primarily CV- and HF-specific events. The high prevalence of CMD and its CV and HF specific prognostic role suggest CMD may be a potential treatment target in HFpEF.     

2022 Canadian Cardiovascular Society Guideline for Use of GLP-1 Receptor Agonists and SGLT2 Inhibitors for Cardiorenal Risk Reduction in Adults

This guideline synthesizes clinical trial data supporting the role of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors (SGLT2i) for treatment of heart failure (HF), chronic kidney disease, and for optimizing prevention of cardiorenal morbidity and mortality in patients with type 2 diabetes. It is on the basis of a companion systematic review and meta-analysis guided by a focused set of population, intervention, control, and outcomes (PICO) questions that address priority cardiorenal end points. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system and a modified Delphi process were used. We encourage comprehensive assessment of cardiovascular (CV) patients with routine measurement of estimated glomerular filtration rate, urinary albumin-creatinine ratio, glycosylated hemoglobin (A1c), and documentation of left ventricular ejection fraction (LVEF) when evaluating symptoms of HF. For patients with HF, we recommend integration of SGLT2i with other guideline-directed pharmacotherapy for the reduction of hospitalization for HF when LVEF is > 40% and for the reduction of all-cause and CV mortality, hospitalization for HF, and renal protection when LVEF is ≤ 40%. In patients with albuminuric chronic kidney disease, we recommend integration of SGLT2i with other guideline-directed pharmacotherapy to reduce all-cause and CV mortality, nonfatal myocardial infarction, and hospitalization for HF. We provide recommendations and algorithms for the selection of glucagon-like peptide-1 receptor agonists and SGLT2i for patients with type 2 diabetes and either established atherosclerotic CV disease or risk factors for atherosclerotic CV disease to reduce all-cause and CV mortality, nonfatal stroke, and for the prevention of hospitalization for HF and decline in renal function. We offer practical advice for safe use of these diabetes-associated agents with profound cardiorenal benefits.     

Do SGLT-2 inhibitors exhibit similar cardiovascular benefit in patients having reduced ejection fraction heart failure with type 2 diabetes,prediabetes and normoglycemia?

Background and aimsWe aimed to know whether SGLT-2 inhibitors (SGLT-2I) exhibit similar cardiovascular (CV) benefit in patients having reduced ejection fraction heart failure (HFrEF) with varying degree of glycemia.MethodWe meta-analyzed the trial-level hazard ratio and 95% confidence interval of randomized trials that reported the CV outcomes stratified in to three subgroups of normoglycemia, prediabetes and diabetes.ResultsThis meta-analysis found a significant and similar CV risk reduction in patients with HFrEF without any significant interaction between three subgroups (P_Intercation = 0.98).ConclusionsSGLT-2I exhibit similar CV risk reduction in HFrEF, regardless of baseline glycemic status. However, this finding is limited to pooled data from only 2 studies in people without T2DM.     

The effects of canagliflozin on heart failure and cardiovascular death by baseline participant characteristics: Analysis of the CREDENCE trial

Heart failure is prevalent in those with type 2 diabetes and chronic kidney disease, and is associated with significant mortality and morbidity. In the CREDENCE trial, canagliflozin reduced the risk of hospitalization for heart failure (HHF) or cardiovascular (CV) death by 31%. In the current analysis we sought to determine whether the effect of canagliflozin on HHF/CV death differed in subgroups defined by key baseline participant characteristics. Cox regression models were used to estimate hazard ratios and 95% confidence intervals. Canagliflozin was associated with a reduction in the relative risk of HHF/CV death regardless of age, sex, history of heart failure or CV disease, and the use of loop diuretics or glucagon-like peptide-1 receptor agonists (all p_interaction > .114). The absolute benefit of canagliflozin was greater in those at highest baseline risk, such as those with CV disease (50 fewer events/1000 patients treated over 2.5 years vs. 20 fewer events in those without CV disease) or advanced kidney disease (estimated glomerular filtration rate [eGFR] 30–45 mL/min/1.73m²: 61 events prevented/1000 patients treated over 2.5 years vs. 23 events in eGFR 60–90 mL/min/1.73m²). Canagliflozin consistently reduces the proportional risk of HHF/CV death across a broad range of subgroups with greater absolute benefits in those at highest baseline risk.     

Prognostic Impact of Cardiovascular Versus Noncardiovascular Hospitalizations in Heart Failure With Preserved Ejection Fraction: Insights From TOPCAT

BackgroundPatients with heart failure (HF) with preserved ejection fraction are commonly admitted to the hospital for both cardiovascular (CV) and noncardiovascular (non-CV) reasons. The prognostic implications of non-CV hospitalizations in this population are not well understood. In this study, we aimed to examine the prognostic implications of hospitalizations owing to CV and non-CV reasons in a HF with preserved ejection fraction population.Methods and ResultsThe Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT) randomized 3445 stable outpatients with chronic HF with a left ventricular ejection fraction of 45% or greater and either prior hospitalization for HF or elevated natriuretic peptides to treatment with spironolactone or placebo. Hospitalizations for any cause were reported by investigators during study follow-up and characterized according to prespecified category causes. This analysis focused on the subset of TOPCAT participants enrolled in the Americas (n = 1767), in which 2973 hospitalizations were observed in 1062 subjects (60%) over a mean follow-up of 3.3 years of study follow-up, of which 1474 (49%) were ascribed to CV causes. Among 1056 first hospitalizations, 478 (45%) were for CV reasons and 578 (55%) for non-CV reasons. Mortality rates were lowest for participants not hospitalized during the trial (3.2 per 100 patient-years [PY]), but similarly elevated after first hospitalization for CV and non-CV reasons (11.0 per 100 PY vs 12.6 per 100 PY, respectively; P = .24). Among those hospitalized for CV reasons, mortality rates were similar after hospitalization for HF and non-CV related reasons (15.2 per 100 PY vs 12.6 per 100 PY; P = .23). Recurrent hospitalization, whether owing to CV or non-CV causes, was associated with a heightened risk for subsequent mortality, with similar death rates after hospitalization twice for CV reasons (18.5 per 100 PY), twice for non-CV reasons (21.6 per 100 PY), or once each for CV and non-CV reasons (18.4 per 100 PY).ConclusionsAmong patients with HF with preserved ejection fraction, hospitalization for any cause is associated with a heightened risk for postdischarge mortality, with an even higher risk associated with recurrent hospitalization. Given the high burden of non-CV hospitalizations in this population, the targeted management of comorbid medical illness may be critical to decreasing morbidity and mortality.     

Network meta-analysis of nine large cardiovascular outcome trials of new antidiabetic drugs

The aim of this network meta-analysis (NMA) was to indirectly compare the cardiovascular (CV) safety of new antidiabetic medications in patients with type 2 diabetes mellitus (T2DM).Data synthesisA search of the Embase and MEDLINE databases was conducted systematically to identify cardiovascular outcome trials (CVOTs) of new antidiabetic medications (DPP-4 inhibitors, GLP-1 agonists and SGLT-2 inhibitors) in patients with T2DM. The primary outcomes were the composite endpoint of CV death, nonfatal MI, and nonfatal stroke (MACE), death from CV causes, nonfatal MI, nonfatal stroke and death from any cause. Hospitalization for HF and unstable angina were evaluated as secondary endpoints. A total of 9 trials, including 87,162 patients, met the eligibility criteria and were retained for the analysis.The NMA results showed no significant differences among the DPP-4 inhibitors (sitagliptin, alogliptin, and saxagliptin) in any of the CV endpoints. Similarly, no significant changes were seen in the NMA among the GLP-1 receptor agonists nor the SGLT-2 inhibitors. The pairwise meta-analysis showed that DPP-4 inhibitors have a CV safety profiled comparable to placebo. GLP-1 agonists on the other hand, showed significant reduction in MACE (RR 0.92; 95% CI 0.87–0.97), death from CV causes (RR = 0.88; 95% CI 0.80–0.97), and death from any cause (RR = 0.89; 95% CI 0.82–0.96). SGLT-2 inhibitors showed significant reduction in hospitalization for heart failure events (RR 0.72; 95% CI 0.6–0.86) compared to placebo.ConclusionThis meta-analysis has shown that new antidiabetic medications do not impose any additional CV risk. The indirect comparison among the medications of each class resulted in no significant changes regarding CV endpoints and death from any cause.     

CCS/CHFS Heart Failure Guidelines: Clinical Trial Update on Functional Mitral Regurgitation,SGLT2 Inhibitors,ARNI in HFpEF,and Tafamidis in Amyloidosis

In this update, we focus on selected topics of high clinical relevance for health care providers who treat patients with heart failure (HF), on the basis of clinical trials published after 2017. Our objective was to review the evidence, and provide recommendations and practical tips regarding the management of candidates for the following HF therapies: (1) transcatheter mitral valve repair in HF with reduced ejection fraction; (2) a novel treatment for transthyretin amyloidosis or transthyretin cardiac amyloidosis; (3) angiotensin receptor-neprilysin inhibition in patients with HF and preserved ejection fraction (HFpEF); and (4) sodium glucose cotransport inhibitors for the prevention and treatment of HF in patients with and without type 2 diabetes. We emphasize the roles of optimal guideline-directed medical therapy and of multidisciplinary teams when considering transcatheter mitral valve repair, to ensure excellent evaluation and care of those patients. In the presence of suggestive clinical indices, health care providers should consider the possibility of cardiac amyloidosis and proceed with proper investigation. Tafamidis is the first agent shown in a prospective study to alter outcomes in patients with transthyretin cardiac amyloidosis. Patient subgroups with HFpEF might benefit from use of sacubitril/valsartan, however, further data are needed to clarify the effect of this therapy in patients with HFpEF. Sodium glucose cotransport inhibitors reduce the risk of incident HF, HF-related hospitalizations, and cardiovascular death in patients with type 2 diabetes and cardiovascular disease. A large clinical trial recently showed that dapagliflozin provides significant outcome benefits in well treated patients with HF with reduced ejection fraction (left ventricular ejection fraction ≤ 40%), with or without type 2 diabetes.     

Comparison of Clinical characteristics and long-term outcomes of patients with ischemic cardiomyopathy with versus without angina pectoris (from the Duke Databank for Cardiovascular Disease)

Myocardial ischemic origin is a significant independent predictor of mortality in patients with heart failure (HF). The implications of angina pectoris (AP) in HF are less well characterized. The aim of this study was to compare the clinical characteristics and outcomes of patients with and without AP in a cohort of patients with reduced ejection fractions and ischemic cardiomyopathy (iCM). Patients who underwent coronary angiography at Duke University Medical Center from January 2000 to September 2009 with ejection fractions <40% and diagnoses of iCM with AP in the previous 6 weeks were compared to similar patients without AP. Time to event was examined using Kaplan-Meier methods for 5 end points: death; death or nonfatal myocardial infarction (MI); death, MI, or revascularization; death or hospitalization; and cardiovascular (CV) death or CV hospitalization. Of 2,376 patients with iCM, 1,412 (59%) had AP. They had more co-morbidities and more previous revascularization than patients without AP. After multivariate adjustment, those with and without AP had similar risks for death (p = 0.32), death or MI (p = 0.15), and death or hospitalization (p = 0.37) (5-year event rates 41% vs 41%, 46% vs 47%, and 87% vs 85%, respectively), but those with AP had lower rates of death, MI, or revascularization (p = 0.01) and higher rates of CV death or CV hospitalization (p = 0.03) (5-year event rates 85% vs 87% and 77% vs 73%, respectively). In conclusion, AP is common in patients with iCM despite medical therapy and previous revascularization and is associated with increased CV death or CV rehospitalization.     

Sodium–glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction: A protocol for meta-analysis

Background:Nearly half of patients with heart failure (HF) have preserved ejection fraction (EF) and the mortality and morbidity of patients with HF with preserved EF (HFpEF) are high. Patients with HFpEF are often elderly and their primary chronic symptom is severe exercise intolerance that results in a reduced quality of life. Thus, improvement of exercise capacity presents another important clinical outcome in HFpEF patients. Recent randomized controlled trials (RCTs) and meta-analyses of RCTs reported that sodium–glucose cotransporter 2 (SGLT-2) inhibitors improved cardiovascular outcomes in patients with HF with reduced EF. Although the effects of SGLT-2 inhibitors in HFpEF patients have been examined in multiple RCTs, the results are inconsistent due partly to limited power. The purpose of this meta-analysis is to evaluate the efficacy and safety of SGLT-2 inhibitors in HFpEF patients.Methods:This meta-analysis will include RCTs examining the effects of SGLT-2 inhibitors on HF severity and health-related quality of life in HFpEF patients. Information of studies will be collected from electronic databases. The primary outcome will be HF severity (plasma B-type natriuretic peptide levels and exercise capacity assessed as 6-minute walk distance). The secondary outcome will be health-related quality of life. The safety outcomes will be all-cause death, HF hospitalization, hypotension, acute renal failure, diabetic ketoacidosis, and urinary tract infection.Discussion:This meta-analysis will evaluate the efficacy and safety of SGLT-2 inhibitors in HFpEF patients, providing evidence to the clinical use of SGLT-2 inhibitors in these patients.Systematic review registration:INPLASY2021120033     

Empagliflozin in heart failure with preserved ejection fraction with and without atrial fibrillation

Aims

Atrial fibrillation/flutter (AF) is common in heart failure (HF) with preserved left ventricular ejection fraction (LVEF) and associated with worse outcomes. Empagliflozin reduces cardiovascular death or HF hospitalizations and slows estimated glomerular filtration rate (eGFR) decline in patients with HF and LVEF >40%. We aimed to assess the efficacy and safety of empagliflozin in improving outcomes in patients with HF and LVEF >40% with and without AF.

Methods and results

In this pre-defined secondary analysis of EMPEROR-Preserved, we compared the effects of empagliflozin versus placebo on the primary and secondary endpoints and safety outcomes, stratified by baseline AF, defined as AF reported in any electrocardiogram before empagliflozin initiation or in medical history. Among 5988 patients randomized, 3135 (52%) had baseline AF; these patients were older, with worse functional class, more previous HF hospitalizations and higher natriuretic peptides compared to those without AF (all p < 0.001). After a median of 26 months, empagliflozin reduced cardiovascular death or HF hospitalization compared to placebo to a similar extent in patients with and without AF (hazard ratio [HR] 0.78 [95% confidence interval 0.66–0.93] vs. 0.78 [0.64–0.95], interaction p = 0.96). Empagliflozin also reduced total HF hospitalizations (HR 0.73 [0.57–0.94] vs. 0.72 [0.54–0.95], interaction p = 0.94) and annual eGFR decline (difference = 1.368 vs. 1.372 ml/min/1.73 m²/year, interaction p = 0.99) consistently in patients with and without AF. There was no increase in serious adverse events with empagliflozin versus placebo in patients with and without AF.

Conclusions

In patients with HF and ejection fraction >40%, empagliflozin reduced the risk of serious HF events and slowed the eGFR decline regardless of baseline AF.     

The Effectiveness of Sodium-Glucose Cotransporter 2 Inhibitors and Glucagon-like Peptide-1 Receptor Agonists on Cardiorenal Outcomes: Systematic Review and Meta-analysis

BackgroundEvidence for the cardiorenal risk reduction properties of antihyperglycemic medications originally prescribed for type 2 diabetes, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) is rapidly emerging. We completed a meta-analysis of recent literature to provide evidence-based estimates of benefit across various populations and outcomes.MethodsWe searched Medline and Cochrane databases from 2015 to September 2021 for randomized controlled trials of SGLT2i and GLP-1RA with placebo control. Reviewers screened citations, extracted data, and assessed the risk of bias and certainty of evidence. We assessed statistical and methodological heterogeneity and performed a meta-analysis of studies with similar interventions and components.ResultsA total of 137,621 adults (51% male) from 19 studies were included; 14 studies with unclear risk of bias and 5 with low risk of bias. Compared with standard of care, use of SGLT2i showed significant reductions for the outcome of cardiovascular (CV) mortality (14%), any-cause mortality (13%), major adverse CV events (MACE) (12%), heart failure (HF) hospitalization (31%), CV death or HF hospitalization (24%), nonfatal myocardial infarction (10%), and kidney composite outcome (36%). Treatment with GLP-1RA was associated with significant reductions for the outcome of CV mortality (13%), any-cause mortality (12%), MACE (14%), CV death or HF hospitalization (11%), nonfatal stroke (16%), and kidney composite outcome (22%).ConclusionsThe use of GLP-1RA and SGLT2i leads to a statistically significant benefit across most cardiorenal outcomes in the populations studied. This review shows a role for SGLT2i and GLP-1RA in cardiorenal protection in adults, independent of type 2 diabetes status.     

Surrogate cardiovascular outcomes with sodium-glucose co-transporter-2 inhibitors in women: An updated meta-analysis

The burden of cardiovascular disease morbidity and mortality among women with type 2 diabetes mellitus remains high, despite the improvement in therapeutic management over the recent years. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors have revolutionized treatment of cardiovascular disease in subjects with diabetes. However, previous meta-analyses of cardiovascular outcome trials failed to prove a significant effect on surrogate cardiovascular outcomes among female participants. Therefore, we sought to update these results, by incorporating data from the most recently published trials. We pooled available data from all available trials (EMPA-REG OUTCOME, DECLARE-TIMI 58, VERTIS CV, DAPA-HF, EMPEROR-Reduced), except for the CANVAS trial. In the present updated meta-analysis we document that SGLT-2 inhibitors do not confer a significant decrease in the risk for major adverse cardiovascular events among women; however, they provide significant results in terms of reduction in the risk for cardiovascular death or hospitalization for heart failure, primarily driven by the results observed in the heart failure with reduced ejection fraction population. Better representation of women in future trials will provide further insights into the question whether there are true gender differences in the cardiovascular efficacy with this drug class.