Cardiovascular Outcome Trials Research Articles

Inclisiran and cardiovascular events: a patient-level analysis of phase III trials.

Inclisiran, an siRNA administered twice-yearly, significantly reduced LDL cholesterol (LDL-C) in Phase III trials. Whether lowering LDL-C with inclisiran translates into a lower risk of cardiovascular (CV) events is not yet established. Patient-level, pooled analysis of ORION-9, -10 and -11, included patients with heterozygous familial hypercholesterolaemia, atherosclerotic CV disease (ASCVD), or ASCVD risk equivalent on maximally tolerated statin-therapy, randomized 1:1 to receive 284 mg inclisiran or placebo on Days 1, 90, and 6-monthly thereafter for 18 months. Prespecified exploratory endpoint of major cardiovascular events (MACEs) included non-adjudicated CV death, cardiac arrest, non-fatal myocardial infarction (MI), and fatal and non-fatal stroke, evaluated as part of safety assessments using a standard Medical Dictionary for Regulatory Activities basket. Although not prespecified, total fatal and non-fatal MI, and stroke were also evaluated. Mean LDL-C at baseline was 2.88 mmol/L. At Day 90, the placebo-corrected percentage reduction in LDL-C with inclisiran was 50.6%, corresponding to an absolute reduction of 1.37 mmol/L (both P < 0.0001). Among 3655 patients over 18 months, 303 (8.3%) experienced MACE, including 74 (2.0%) fatal and non-fatal MIs, and 28 (0.8%) fatal and non-fatal strokes. Inclisiran significantly reduced composite MACE [OR (95% CI): 0.74 (0.58-0.94)], but not fatal and non-fatal MIs [OR (95% CI): 0.80 (0.50-1.27)] or fatal and non-fatal stroke [OR (95% CI): 0.86 (0.41-1.81)]. This analysis offers early insights into the potential CV benefits of lowering LDL-C with inclisiran and suggests potential benefits for MACE reduction. These findings await confirmation in the larger CV outcomes trials of longer duration.

LBSUN162 Cumulative Probability Of Heart Failure Hospitalization Among Non-Hispanic Black Compared To Non-Hispanic White Individuals With Type 2 Diabetes On Empagliflozin (EMPA-AA): Real-world Data

Abstract The results from the SGLT-2 inhibitors cardiovascular outcome trials were generalized to all, despite that non-Hispanic Black (hereafter, "Black") participants were underrepresented. Our goal was to evaluate, among patients with type 2 diabetes, the risk of heart failure hospitalizations among black vs non-Hispanic White (hereafter "White") patients initially prescribed empagliflozin. | We performed a multicenter retrospective study using clinical data derived from Electronic Medical Records (EMR's) from adults with type 2 diabetes cared for at 4 healthcare systems (UNC Health, Duke Health, MUSC, and ECU Health) who were prescribed empagliflozin between August 2014 and December 2019. Our primary outcome was time to first heart failure hospitalization. We wanted to understand if the outcomes were different in Black vs White patients with previous hospitalizations for heart failure that occurred prior to an empagliflozin prescription. Cumulative probability of heart failure hospitalization by race was estimated using the cumulative incidence function. The association of race with risk of heart failure hospitalization was evaluated using multivariable Cox hazards models. Hazard ratio (HR) and 95% confidence interval (CI) are provided as measures of strength of association and precision, respectively. | A total of 704 patients with previous heart failure hospitalizations were eligible. Mean age by race category (Black/White) was 60.2 vs 64.3 years (p &amp;lt; 0. 0001); 42.8% vs 61. 0% were males (p &amp;lt; 0. 0001) and 81.2% vs 73.2% had a history of hypertension respectively. Black patients were significantly younger and predominantly female. Cumulative probability of heart failure hospitalization at 2-years post-initiation of empagliflozin was 71.7% (95% CI = 61.6%, 79.6%) vs. 70.9% (95% CI = 64. 0%, 76.7%) for Black vs White, respectively. When adjusting for age, gender, and baseline comorbidities, there was no statistically significant difference in the risk of hospitalizations for heart failure between Black vs White patients (HR = 1. 03; 95% CI = 0.85, 1.25, p = 0.79). | In patients with type 2 diabetes with a documented previous hospitalization for heart failure prior to a prescription for empagliflozin, we found no significant difference in the cumulative probability of heart failure hospitalization in Black vs White patients. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

RF16 | PSUN155 Empagliflozin and the risk of nephrolithiasis

Abstract Aims Nephrolithiasis is a common disease, estimated to affect 10% of the US population. In addition to pain, often severe, it can lead to urinary tract infections and acute kidney injury, while contributing to health care costs from emergency room visits and follow-up interventions necessary to relieve stone burden. Type 2 diabetes (T2D) is a well-known risk factor for nephrolithiasis. Recently in an observational study of patients with T2D, use of sodium-glucose transport protein 2 (SGLT2) inhibitors as glucose lowering agents was associated with a 49% lower risk of nephrolithiasis when compared with use of glucagon like peptide 1 (GLP-1) receptor agonists. We examined, prospectively, the association between renal stone disease and the use of the SGLT2 inhibitor empagliflozin, using existing data from randomized clinical trials. Methods Pooled data from 15,081 patients with T2D treated with empagliflozin (10,177) or placebo (4,904) from 20 phase I-IV randomized, placebo-controlled trials including the large cardiovascular outcome trial, EMPA-REG OUTCOME, were included in this analysis. Incident urinary tract stone events were captured using a pre-defined collection of MedDRA terms: nephrolithiasis, renal colic, ureterolithiasis, calculus bladder, calculus urinary, calculus urethral, and nephrocalcinosis (MedDRA version 22.1). A sensitivity analysis used a narrower definition by excluding the terms renal colic and nephrocalcinosis. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were calculated using the relative risk estimate stratified by study. Results The median exposure to study drug was 543 (placebo) and 549 (empagliflozin 10 or 25 mg) days We found that a total of 183 patients experienced an incident urolithiasis during follow-up (79 in placebo, 104 in pooled empagliflozin) yielding annual incidence rates of 1.01 versus 0.63 events per 100 patient years in placebo and empagliflozin, respectively. All but one event occurred in patients with no prior history of urinary tract stones. The IRR was 0.64 (95% CI 0.48, 0.86), in favor of empagliflozin. In the sensitivity analysis, now restricted to nephrolithiasis, ureterolithiasis, calculus bladder, calculus urinary, and calculus urethral, the results were similar (IRR, empagliflozin vs. placebo, 0.62 [95% CI 0.45, 0.85]). Conclusion As compared to placebo, use of empagliflozin was associated with an approximate 40% reduction in the risk of urolithiasis in patients with T2D. Alterations in lithogenic profile of the urine (including dilutional effects) of potential stone formers after SGLT2 inhibition may explain this finding. Based on these initial observations, mechanistic studies to elucidate the mediator(s) of this seemingly protective effect and dedicated randomized prospective clinical trials appear warranted in patients with renal stone disease. As with follow-up SGLT2 inhibitor investigations conducted in patients with heart failure and chronic kidney disease, such trials should include individuals who do not have T2D. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 1:12 p.m. - 1:17 p.m.

Uno scompenso per due, col terzo incomodo

The importance of differentiating between primary cardiovascular prevention and secondary prevention in diabetes will be discussed in light of the results obtained by the cardiovascular outcome trials (CVOTs). In patients with diabetes, the distinction between primary and secondary cardiovascular prevention could be artificial. The main criteria for enrollment in cardiovascular outcome trials that define the so-called patient in secondary prevention are, typically: i) the history of heart attack or unstable angina; ii) the history of ischemic or hemorrhagic stroke, iii) subclinical conditions, i.e., multivessel coronary ar¬tery disease, occlusive peripheral vascular disease with stenosis greater than 50%, or with a Winsor index less than 0.9. However, in patients with diabetes, a significant coronary atherosclerotic disease can be asymptomatic: this has important clinical implications, i.e., i. patients with diabetes are frequently undertreated, ii: it is unclear whether all asymptomatic patients should be screened for coronary artery disease for implementing optimal medical therapy. The conclusion is that placing the outpatient in the so-called primary or secondary prevention without a clinical event is impossible.

Age, sex, race, BMI, and duration of diabetes differences in cardiovascular outcomes with glucose lowering drugs in type 2 diabetes: A systematic review and meta-analysis.

SummaryBackgroundSummarized data of cardiovascular outcomes trials (CVOTs) of sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have shown a reduction in major adverse cardiovascular event (MACE), whether these benefits are extended in certain risk groups (elderly or obese patients or those with a longer duration of diabetes) or certain minorities (Black participants) are not clearly established. We aimed to provide overall hazard ratios (HRs) estimates for MACE of SGLT2i and GLP-1 RAs stratified by age (< 65 years vs. ≥ 65 years and < 75 years vs. ≥ 75 years), sex (male vs. female), race (Black vs. White, Black vs. Asian, and White vs. Asian), body mass index (BMI: < 30 kg/m2 vs. ≥ 30 kg/m2), and duration of diabetes (< 10 years vs. ≥ 10 years).MethodsWe performed a MEDLINE database search from inception up to July 31, 2022 to identify all placebo-controlled phase 3 CVOTs that evaluated the efficacy of SGLT2i and GLP-1 RAs on vascular events at least 1-year after randomisation in participants with type 2 diabetes, and we selected those reporting hazard ratios (HRs) for the specific risk groups for MACE. Differences on MACE in risk groups were examined using a random-effect meta-analysis. The study protocol was registered on PROSPERO (CRD42022347901).FindingsA total of 11 studies fulfilled the prespecified criteria, comprising 96,580 patients with T2D were included. Of these patients, 61,975 (64.2%) were male, 34,605 (35.8%) were female, and race groups included 74,982 (77.6%) White, 7760 (8.0%) Asian, and 4023 (4.2%) Black. In two SGLT2i trials, the HR (95% CI) for long-term diabetes duration more than10 years versus short duration was 0.84 (0.77–0.93) vs. 1.02 (0.89–1.16), respectively (Pinteraction = 0.03). In four SGLT2i trials, the MACE benefit was similar by sex (Pinteraction = 0.13), age (Pinteraction = 0.36), BMI (Pinteraction = 0.69), and race groups (Pinteraction = 0.86 between Black and White, Pinteraction = 0.98 between Black and Asian, and Pinteraction = 0.69 between White and Asian). For GLP-1 RAs, the MACE benefit from the seven trials tended to be greater for Asian (0.71, [0.58–0.87]) than for White (0.87, [0.81–0.94]), (Pinteraction = 0.07). In two GLP-1 RAs trials, the MACE outcome was reduced by 22% (0.78, 0.63–0.95) in elderly patients (≥ 75 years) while no difference was observed in those < 75 years (0.87; 0.75–1.01), (Pinteraction = 0.37). In the remaining risk groups, the MACE benefit was similar by sex (Pinteraction = 0.37), age < 65 years (Pinteraction = 0.80), duration of diabetes (Pinteraction = 0.70), and race (Pinteraction = 0.57 between Black and White, and Pinteraction = 0.15 between Black and Asian), BMI (Pinteraction = 0.78). Risk of bias was lower, and overall heterogeneity was high for sex with SGLT2i, and moderate to low for the remaining comparisons, with a I2 values ranging from 0% to 54%.InterpretationIn patients with type 2 diabetes at highest risk of cardiovascular disease or established cardiovascular disease, a greater benefit on MACE was found for elderly patients and for Asian individuals compared with White individuals with GLP-1 RAs, and those with a long duration of diabetes with SGLT2i. These findings could help in providing guidance for treatment prescription and facilitate selection and stratification of patients for future CVOTs. Furthermore, pooled individual patient-level data are urgently needed to support our conclusions, and to derive definitive evidence.FundingNone.

Absolute treatment effects for the primary outcome and all-cause mortality in the cardiovascular outcome trials in type 2 diabetes: a meta-analysis of individual patient data

Abstract Background and purpose Treatment effects from the large cardiovascular outcome trials (CVOTs) in diabetes are almost exclusively communicated as hazard ratios, although reporting guidelines recommend to report treatment effects also on an absolute scale, e.g. as numbers needed to treat (NNT). We aimed to analyze NNT in CVOTs of novel oral antidiabetic drugs comparing dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, or sodium-glucose cotransporter-2 (SGLT2) inhibitors to placebo. Methods and results We extracted individual time-to-event information for the primary outcome and all-cause mortality from 19 CVOTs that compared DPP-4 inhibitors, GLP-1 receptor agonists, or SGLT2 inhibitors to placebo. We estimated Weibull models for each trial and outcome and derived monthly NNTs. NNTs were summarized across all trials and within drug-classes by random effects meta-analysis methods. Treatment effects in the CVOTs appear smaller if they are reported as NNTs: Overall, 60 (95%-CI: 40–124) patients have to be treated for 29 months (the median follow-up time across all trials) to avoid a single event of the primary outcome, and 101 (95%-CI: 69–191) patients have to be treated for 39 months to avoid a single death. Conclusion We found that the respective treatment effects of novel oral antidiabetic drugs look less impressive when communicated on an absolute scale, as numbers needed to treat. For a valid overall picture of the benefit of these drugs, trial authors should thus also report treatment effects on an absolute scale. Funding Acknowledgement Type of funding sources: None.

Baseline cardiovascular risk in subjects with type 2 diabetes and chronic kidney disease from the FLOW trial

Abstract Background Patients with chronic kidney disease and type 2 diabetes (T2D) have a high risk of progression to kidney failure as well as cardiovascular (CV) events. It is established that glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and reduce body weight. Some CV outcomes trials have shown that GLP-1RAs reduce CV risk in people with T2D at high CV risk; for example, the SUSTAIN 6 trial demonstrated that the GLP-1RA semaglutide significantly lowered the rate of major CV events (CV death, non-fatal myocardial infarction and non-fatal stroke) versus placebo. Some trials have also indicated that GLP-1RAs reduce albuminuria and estimated glomerular filtration rate (eGFR) decline. Based on these previous results indicating potential kidney-protective effects, the FLOW trial (NCT03819153) is evaluating once-weekly, subcutaneous semaglutide 1.0 mg versus placebo on kidney- and CV-related outcomes in participants with T2D. We describe the baseline characteristics and the calculated CV risk of this patient population using the atherosclerotic CV disease (ASCVD) and second manifestations of arterial disease (SMART) risk calculators. Methods FLOW is an ongoing, multicentre, randomised, double-blind, parallel-group, event-driven, phase 3b trial, with participants randomised 1:1 to semaglutide or placebo, each in addition to standard of care. Recruitment is complete and 3,535 participants with T2D, an eGFR ≥25–≤75 mL/min/1.73 m2, and urine albumin-to-creatinine ratio ≥100–≤5,000 mg/g have been enrolled. The primary endpoint is time to first occurrence of a kidney composite that includes ≥50% persistent eGFR reduction, kidney failure (persistent eGFR &amp;lt;15 mL/min/1.73 m2 or initiation of chronic dialysis or kidney transplantation), and kidney-related death, or CV death. Key secondary outcomes include time to first occurrence of CV death, myocardial infarction or stroke. Results The baseline clinical characteristics and demographics are shown (Table 1). Median age was 68 years, 30% were female, mean diabetes duration was 17 years, and 98% had a history of hypertension. Overall, 52% of participants had a previous CV event. The calculated 10-year risk for ASCVD events in those without prior ASCVD was 31% in males and 18% in females, and in those with previous CV events was 37–56% in males and 35–53% in females depending on the type of CV disease reported in the calculator (Table 2). Conclusions The FLOW trial has completed enrolment. Based on the ASCVD and SMART risk calculators, the enrolled population has a substantial risk for adverse CV outcomes. Event ascertainment is ongoing, and the FLOW trial will provide evidence for the potential of semaglutide to improve kidney and CV outcomes in the T2D population. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novo Nordisk

Causes of death in patients with chronic kidney disease: insights from the ASCEND-D and ASCEND-ND cardiovascular outcomes trials

Abstract Background There are limited contemporary data available regarding adjudicated causes of death in patients with chronic kidney disease (CKD). Prior studies have indicated that cardiovascular (CV) events are one of the most common causes of death among patients with CKD, with previous reports stating approximately 30% of patients died from CV causes [1]. Here, we report the adjudicated causes of death in two recently completed large-scale randomised controlled trials (RCTs) with ∼14,200 person years of follow-up: ASCEND-D [2] (median follow-up: 2.5 years; NCT02879305) and ASCEND-ND [3] (median follow-up: 1.9 years; NCT02876835). These trials investigated the safety and efficacy of daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), in correcting anaemia in patients with CKD. Purpose This study assessed the causes of death in patients with CKD in the ASCEND-D and ASCEND-ND trials. Methods ASCEND-D and ASCEND-ND were global, randomised, open-label, CV outcome trials in adult patients with CKD-related anaemia undergoing maintenance dialysis (ASCEND-D) or with pre-dialysis CKD (ASCEND-ND) who received daily oral daprodustat or conventional erythropoiesis-stimulating agents (ESAs). Cause of death was systematically and centrally adjudicated in a blinded fashion to the study treatment assignment by an independent committee. Results In ASCEND-D and ASCEND-ND, respectively, 2964 and 3872 patients were randomised, of which 92% and 97% completed the study. Baseline characteristics were well-balanced across treatment groups within each trial. Adjudicated causes of death for the ASCEND-D and -ND trials are shown in the Table. All-cause mortality was similar in patients treated with daprodustat as compared with those treated with conventional ESA in both the ASCEND-D and -ND trials. Overall mortality in the ASCEND-D and -ND trials was 20.0% and 15.5%, respectively, and CV causes accounted for approximately 30–40% of all deaths and infection accounted for 25–30% of all deaths in both trials. Conclusion Although CV events were the most common cause of death in the ASCEND-D and ASCEND-ND trials (30–40% of cases), the risk of death due to infection was also high, accounting for approximately 25–30% of all deaths across all study arms. Sudden death accounted for most CV deaths, particularly in the ASCEND-D trial. Infection as a cause of death was more frequent than previously reported in other RCTs or disease registries. Causes of death did not differ significantly between ASCEND-D and ASCEND-ND, or between treatments. However, as this is a selected population for a CV trial, it may not be representative of a real-life CKD population. Our results provide important data to inform the design of future studies in this population. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This study was funded by GlaxoSmithKline. Medical writing support was provided Natasha Tracey, PhD (Ashfield MedComms, Macclesfield, UK) and was funded by GlaxoSmithKline.

Absolute treatment effects of novel oral antidiabetic drugs on cardiovascular mortality and hospitalization for heart failure: a meta-analysis of digitalized individual patient outcomes

Abstract Background and purpose Absolute treatment effects of novel oral antidiabetic drugs for cardiovascular outcomes have thus far not been comprehensively evaluated. We thus aimed to perform a meta-analysis of digitalized individual patient data. Methods and results Individual patient outcomes from Cardiovascular Outcome Trials (CVOTs) evaluating dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium glucose transporter 2 (SGLT2) inhibitors against placebo with time-to-event information for cardiovascular mortality (CM) and/or hospitalization for heart failure (HHF) endpoints were digitalized from Kaplan-Meier plots; Weibull regression models with random-effects meta-analysis were used to estimate numbers-needed-to-treat (NNT) and Meta-NNT with 95% confidence intervals (CI). Sixteen CVOTs reported time-to-event information (14 in primary diabetes, two in primary heart failure populations). Thirteen studies including 96,860 patients were meta-analyzed for CM: at the median follow-up of 30 months, Meta-NNTs were 178 (64 to ∞ to −223) for DPP-4 inhibitors, 261 (158 to 745) for GLP-1 receptor agonists and 118 (68 to 435) for SGLT2 inhibitors. Ten studies including 96,128 patients were meta-analyzed for HHF: at the median follow-up of 29 months, estimated Meta-NNTs were −644 (229 to ∞ to −134) for DPP-4 inhibitors, 441 (184 to ∞ to −1100) for GLP-1 receptor agonists and 126 (91 to 208) for SGLT2 inhibitors. SGLT2 inhibitors were especially effective for HHF in primary heart failure populations (Meta-NNT 25 (19 to 39)) vs. primary diabetes populations (Meta-NNT 233 (167 to 385)) at 16 months of follow-up. Conclusion We found modest treatment benefits of GLP-1 receptor agonists and SGLT2 inhibitors for CM and HHF in primary T2DM populations. In primary heart failure populations, however, SGLT2 inhibitor benefits were substantial and comparable to established heart failure medication. Funding Acknowledgement Type of funding sources: None.

Pharmacological selectivity of SGLT2 inhibitors and cardiovascular outcomes in patients with type 2 diabetes: a meta-analysis

Abstract Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus. However, SGLT2 inhibitors show great variance in pharmacological selectivity to SGLT2 over SGLT1. Reduced functional capacity of SGLT1 is associated with lower risk of heart failure development and mortality in humans. Yet, the clinical relevance of additional pharmacological SGLT1 inhibition is unclear. Purpose To assess whether additional pharmacological SGLT1 blockade adds further benefits to SGLT2 inhibition. Methods In this preregistered meta-analysis, we included randomized placebo-controlled cardiovascular outcome trials (CVOTs) of SGLT2 inhibitors assessing MACE (composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in patients with type 2 diabetes. Hazard ratios (HRs) and 95% confidence intervals (CIs) of prespecified clinical endpoints were pooled using a random-effects model. Interactions were assessed according to low versus high pharmacological SGLT2 selectivity of the given medication. Mixed-effects meta-regression analysis was performed to quantify correlation between pharmacological SGLT2:SGLT1 selectivity ratio and clinical outcomes. Results A total of 6 independent CVOTs comprising 57553 type 2 diabetic patients (mean age 64.6±7.9 years; 36769 [63.9%] men) were included. Overall, SGLT2 inhibitors significantly reduced risk of adverse cardiovascular and renal outcomes, but had no significant impact on the risk of fatal and nonfatal stroke compared with placebo (HR, 0.92; 95% CI, 0.77–1.10; p=0.36; I2=63%). Agents with clinically relevant SGLT1 inhibitory effect (sotagliflozin, canagliflozin) significantly reduced the risk of stroke (HR, 0.78; 95% CI, 0.64–0.94) compared with placebo, whereas those with high SGLT2 selectivity did not (HR, 1.06; 95% CI, 0.92–1.22), yielding a significant interaction (p=0.018). The difference was also significant in patients with estimated glomerular filtration rate (eGFR) lower than 60 mL/min/1.73 m2 (p=0.047). Meta-regression indicated that lower SGLT2:SGLT1 pharmacological selectivity ratio was associated with lower risk of stroke (pseudo-R2=78%; p=0.011), which was evident even after adjusting for baseline eGFR values (p=0.047). Pharmacological selectivity of SGLT2 inhibitors had no significant impact on any other assessed clinical outcomes, including hospitalization for heart failure and all-cause death. Conclusion These hypothesis-generating results indicate that targeting SGLT1 in addition to SGLT2 inhibition might constitute a new avenue for stroke risk reduction in patients with type 2 diabetes. Further confirmatory studies are needed. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This project was supported by grants from the National Research, Development and Innovation Office (NKFIH) of Hungary (K134939 to T.R.), and by the New National Excellence Program of the Ministry of Human Capacities of Hungary (ÚNKP-21-3-II-SE-45 to A.A.S.).

The effect of ziltivekimab on the neutrophil-lymphocyte ratio: analysis from RESCUE

Abstract Background The neutrophil-lymphocyte ratio (NLR), derived from the complete blood count, independently predicts atherosclerotic events and is a potential biomarker for residual inflammatory risk. A previous study showed that interleukin (IL)-1β inhibition reduces the NLR, but whether inhibition with IL-6, a cytokine downstream of IL-1, also lowers the NLR is unknown. Purpose To evaluate whether ziltivekimab, a monoclonal antibody targeting the IL-6 ligand, dose-dependently lowers the NLR compared to placebo. Methods The phase II RESCUE trial randomized 264 patients with moderate to severe chronic kidney disease (CKD) and high-sensitivity CRP (hsCRP) &amp;gt;2mg/L in a 1:1:1:1 ratio to placebo or ziltivekimab 7.5 mg, 15 mg, and 30 mg subcutaneously once every four weeks. As previously reported, the trial met its primary endpoint as demonstrated by hsCRP reductions of 4% in the placebo group as compared to 77%, 88%, and 92% at 12 weeks in the ziltivekimab 7.5, 15, and 30 mg groups, respectively. Using RESCUE trial data, we further evaluated the percent change from baseline in the NLR at 12 weeks and sought evidence of correlation between any observed changes in the NLR with changes in other measured biomarkers. Results Ziltivekimab dose-dependently reduced the NLR starting at week one and sustained through week 12 (Table). The median change in the NLR at 12 weeks, the primary pre-specified endpoint, was −13.5% in the 7.5 mg group, −14.3% in the 15 mg group, and −22.4% in the 30 mg group compared to 1.56% in the placebo group. The estimated treatment difference was −14.6% (p=0.004), −15.3% (p=0.004), and −23.6% (p&amp;lt;0.0001) in the ziltivekimab 7.5, 15, and 30 mg groups respectively. These changes were driven largely by reductions in the absolute neutrophil count with minimal change in lymphocyte count. The change in NLR with ziltivekimab correlated modestly with the changes in hsCRP (R=0.26, p=0.0006), fibrinogen (R=0.18, p=0.02), and haptoglobin (R=0.17, p=0.03), but not serum amyloid A, ApoA1, ApoB, ApoB/ApoA ratio, or traditional risk markers. Conclusions IL-6 inhibition with ziltivekimab lowers the NLR. The ongoing ZEUS cardiovascular (CV) outcomes trial will assess whether ziltivekimab can reduce CV event rates among individuals with stage 3 to 4 CKD, known atherosclerotic disease, and elevated hsCRP. If ziltivekimab reduces CV risk, it would provide further evidence for critical inter-relationships between bone marrow function and atherothrombosis. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novo Nordisk

Cost-effectiveness of cholesterol-lowering drugs for secondary cardiovascular prevention in the UK: ezetimibe, evolocumab, and alirocumab

Abstract Background Despite statin treatment, patients with elevated low-density lipoprotein cholesterol (LDL-C) levels remain at high risk for acute cardiovascular events. Ezetimibe, evolocumab, and alirocumab were consequently developed to reduce the risk of recurrent ischemic events in patients with established cardiovascular diseases by 6%, 15%, and 15%, respectively. However, these novel treatments must demonstrate both clinical efficacy and cost-effectiveness to promote long-term adoption by patients, physicians, and insurers. Objective To assess the cost-effectiveness of statins in combination with ezetimibe, evolocumab, and alirocumab for secondary cardiovascular prevention from the perspective of England's National Health Service (NHS). Methods The incidence of major adverse cardiovascular events, including, myocardial infarction, stroke, angina, and coronary revascularization, was simulated with a Markov cohort model. The model was populated with transition probabilities and hazard ratios derived from cardiovascular outcome trials for statin combinations with ezetimibe (IMPROVE-IT), evolocumab (FOURIER), and alirocumab (ODYSSEY). Costs and utilities were retrieved from previous literature. Principle outcomes of interest were the incremental cost-effectiveness ratios (ICER) per quality-adjusted life year (QALY) gained in 2021 Great Britain Pounds (£). Univariate, scenario, willingness-to-pay, and probabilistic sensitivity analyses were conducted to assess the robustness of results. Results For secondary cardiovascular prevention, ezetimibe in combination with statins increased QALYs gained by 0.60 at cost reductions of −£2,529 (ICER: −4,231 £/QALY) per patients compared to statin monotherapy. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors provided incremental QALYs of 0.53 and 0.86 at costs of £45,279 and £46,375 for evolocumab (ICER: 75,283 £/QALY) and alirocumab (ICER: 40,708 £/QALY), respectively. At the NHS' willingness-to-pay threshold of 30,000 £/QALY, there is 100% probability for ezetimibe and 0% probability for PCSK9 inhibitors to be cost-effective in secondary prevention. Results remained robust under univariate, scenario, and probabilistic sensitivity analyses. Conclusions Ezetimibe is cost-effective for secondary cardiovascular prevention at an annual price of £346 in the UK. For PCSK9 inhibitors, discounts of −37% to −53% on alirocumab's (£4,412) and evolocumab's (£4,467) prices are necessary to achieve cost-effectiveness. Funding Acknowledgement Type of funding sources: None.

Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).

The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the previous consensus statements on the management of hyperglycemia in type 2 diabetes in adults, published since 2006 and last updated in 2019. The target audience is the full spectrum of the professional health care team providing diabetes care in the U.S. and Europe. A systematic examination of publications since 2018 informed new recommendations. These include additional focus on social determinants of health, the health care system, and physical activity behaviors, including sleep. There is a greater emphasis on weight management as part of the holistic approach to diabetes management. The results of cardiovascular and kidney outcomes trials involving sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists, including assessment of subgroups, inform broader recommendations for cardiorenal protection in people with diabetes at high risk of cardiorenal disease. After a summary listing of consensus recommendations, practical tips for implementation are provided.

Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).

The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the previous consensus statements on the management of hyperglycaemia in type 2 diabetes in adults, published since 2006 and last updated in 2019. The target audience is the full spectrum of the professional healthcare team providing diabetes care in the USA and Europe. A systematic examination of publications since 2018 informed new recommendations. These include additional focus on social determinants of health, the healthcare system and physical activity behaviours including sleep. There is a greater emphasis on weight management as part of the holistic approach to diabetes management. The results of cardiovascular and kidney outcomes trials involving sodium–glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, including assessment of subgroups, inform broader recommendations for cardiorenal protection in people with diabetes at high risk of cardiorenal disease. After a summary listing of consensus recommendations, practical tips for implementation are provided.Graphical abstract Supplementary InformationThe online version of this article (10.1007/s00125-022-05787-2) contains peer-reviewed but unedited supplementary material.

Evaluating the impact of glucokinase activation on risk of cardiovascular disease: a Mendelian randomisation analysis

BackgroundGlucokinase activators (GKAs) are an emerging class of glucose lowering drugs that activate the glucose-sensing enzyme glucokinase (GK). Pending formal cardiovascular outcome trials, we applied two-sample Mendelian randomisation (MR) to investigate the impact of GK activation on risk of cardiovascular diseases.MethodsWe used independent genetic variants in or around the glucokinase gene meanwhile associated with HbA1c at genome-wide significance (P < 5 × 10−8) in the Meta-Analyses of Glucose and Insulin-related traits Consortium study (N = 146,806; European ancestry) as instrumental variables (IVs) to mimic the effects of GK activation. We assessed the association between genetically proxied GK activation and the risk of coronary artery disease (CAD; 122,733 cases and 424,528 controls), peripheral arterial disease (PAD; 7098 cases and 206,541 controls), stroke (40,585 cases and 406,111 controls) and heart failure (HF; 47,309 cases and 930,014 controls), using genome-wide association study summary statistics of these outcomes in Europeans. We compared the effect estimates of genetically proxied GK activation with estimates of genetically proxied lower HbA1c on the same outcomes. We repeated our MR analyses in East Asians as validation.ResultsGenetically proxied GK activation was associated with reduced risk of CAD (OR 0.38 per 1% lower HbA1c, 95% CI 0.29–0.51, P = 8.77 × 10−11) and HF (OR 0.54 per 1% lower HbA1c, 95% CI 0.41–0.73, P = 3.55 × 10−5). The genetically proxied protective effects of GKA on CAD and HF exceeded those due to non-targeted HbA1c lowering. There was no causal relationship between genetically proxied GK activation and risk of PAD or stroke. The estimates in sensitivity analyses and in East Asians were generally consistent.ConclusionsGKAs may protect against CAD and HF which needs confirmation by long-term clinical trials.

Retrieved-Dropout-Based multiple imputation for time-to-event data in cardiovascular outcome trials

ABSTRACT Recently, retrieved-dropout-based multiple imputation has been used in some therapeutic areas to address the treatment policy estimand, mostly for continuous endpoints. In this approach, data from subjects who discontinued study treatment but remained in study were used to construct a model for multiple imputation for the missing data of subjects in the same treatment arm who discontinued study. We extend this approach to time-to-event endpoints and provide a practical guide for its implementation. We use a cardiovascular outcome trial dataset to illustrate the method and compare the results with those from Cox proportional hazard and reference-based multiple imputation methods.

Fragility of cardiovascular outcome trials (CVOTs) examining nutrition interventions among patients with diabetes mellitus: a systematic review of randomized controlled trials

PurposeThere is controversy regarding the optimal statistical method to interpret how robust is a statistically significant result. The fragility index (FI) and the reverse fragility index (RFI) are quantitative measures that can facilitate the appraisal of a clinical trial’s robustness. This study was performed to evaluate the FI and RFI of randomized controlled trials (RCTs) examining nutritional interventions in patients with diabetes mellitus, focusing on cardiovascular outcomes.MethodsA systematic search was conducted and relevant RCTs were identified in three databases. RCTs examining nutritional interventions (supplements or dietary patterns) in patients with DM with dichotomous primary endpoints involving cardiovascular outcomes were eligible. Data were extracted to compose 2 × 2 event tables and the FI and RFI were calculated for each comparison, using Fisher’s exact test. Risk of bias (RoB) of the included RCTs was assessed with the Cochrane RoB 2.0 tool.ResultsA total of 14,315 records were screened and 10 RCTs were included in the analyses. The median FI of the paired comparisons was 3 (IQR: 2–4) and the median RFI was 8 (IQR: 4.5–17). RoB and heterogeneity were low.ConclusionsRCTs examining nutritional interventions and cardiovascular outcomes among patients with diabetes mellitus appear to be statistically fragile. Τhe FI and the RFI can be reported and interpreted as an additional perspective of a trial’s robustness.Highlights• In the evidence-healthcare era, assessing how robust statistically significant results are remains a matter of controversy.• Recently, the fragility index (FI) and reverse fragility index (RFI) were proposed to assess the robustness of randomized controlled trials (RCTs) with 2 × 2 comparisons.• When applying the FI and RFI, RCTs examining nutritional interventions and cardiovascular outcomes among patients with diabetes mellitus (DM) appear to be statistically fragile.• Τhe FI and the RFI can be reported and interpreted as an additional perspective of a trial’s robustness.• RCTs implementing nutrition interventions among patients with DM can improve their methodology.

The potential of glucagon-like peptide-1 receptor agonists in heart failure.

Heart failure (HF) remains one of the cardiovascular diseases (CVDs) associated with a high unmet medical need due to high morbidity and mortality rates and lack of efficacious interventions. HF is closely related to cardiometabolic diseases such as diabetes, obesity and chronic kidney disease, and strategies that address most or all these intertwined conditions are desirable. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are approved for type 2 diabetes (T2D), and some are also indicated for reduction of the risk of atherosclerotic CVD in T2D and for weight management. As we summarise in this concise review, preliminary evidence suggests that the cardioprotective benefits of GLP-1 RAs may also extend to HF. The most robust clinical evidence arguably originates from the large cardiovascular outcomes trials (CVOTs) completed for most GLP-1 RAs, of which the latest showed a significant relative risk reduction (RRR) of 39% (HR) with once-weekly efpeglenatide on HF requiring hospitalisation, corroborating a meta-analysis which found a significant RRR across eight GLP-1 RA CVOTs of 11%. Further, although incompletely described, multiple studies are available to provide insights into the mechanistic underpinnings, which appear to be associated mostly with indirect cardioprotective benefits owing to the ability of GLP-1 RAs to address hyperglycaemia, and reduce body weight, and, amongst others, inflammation. In sum, current evidence positions GLP-1 RAs as a potential cardioprotective strategy in HF, with HF with preserved ejection fraction emerging as the clinically most relevant phenotype for the drug class, especially when occurring in people with obesity with and without diabetes.

Empagliflozin and Decreased Risk of Nephrolithiasis: A Potential New Role for SGLT2 Inhibition?

Diabetes mellitus is a risk factor for nephrolithiasis. A recent observational study found that in patients with type 2 diabetes (T2D), SGLT2 inhibitor use was associated with a 49% lower risk of nephrolithiasis compared with GLP-1 receptor agonists.&#x0D; Aim: we examined the association between nephrolithiasis and the SGLT2 inhibitor empagliflozin, using existing data from randomized clinical trials.&#x0D; Methods: we pooled data from 15 081 T2D patients randomized to empagliflozin (n = 10 177) or placebo (n = 4904) from 20 phase I-IV trials, including the large cardiovascular outcome trial, EMPA-REG OUTCOME. Incident urinary tract stone events were captured using a predefined collection of MedRA terms. A sensitivity analysis using a narrower definition was also performed. Incidence rate ratios (IRR) and 95% CIs were calculated using the relative risk estimate, stratified by study.&#x0D; Results: the median exposures to study drug were 543 days (placebo) and 549 days (empagliflozin); 183 patients experienced an incident urolithiasis during follow-up (placebo, 79; empagliflozin, 104), yielding annual incidence rates of 1.01 vs 0.63 events/100 patient-years in the 2 respective groups. The IRR was 0.64 (95% CI, 0.48-0.86), in favor of empagliflozin. In the sensitivity analysis, the results were similar (IRR, 0.62 [95% CI, 0.45-0.85]).&#x0D; Conclusion: compared with placebo, empagliflozin therapy was associated with an approximate 40% reduced risk of urinary tract stone events in T2D patients. The underlying mechanisms are unknown but may involve altered lithogenic profile of the urine. Dedicated randomized prospective clinical trials are warranted to confirm these initial observations in patients with and without T2D.

Prevention is still the key to success.

In this issue of the journal, we publish a survey of cardiovascular disease (CVD) risk factors in patients with rheumatoid arthritis (RA) in 14 503 patients from 19 countries during 2014–2019. Dr Semb and co-workers report considerable geographical differences in estimated CVD risk and preventive treatment. Low goal attainment for lipid lowering treatment was observed, and only half of the patients obtained blood pressure goal. The authors conclude that despite a high focus on the increased CVD risk in RA patients over the last decade,1 there is still substantial potential for improvement in CVD preventive measures. In recent years, numerous cardiovascular (CV) outcomes trials have demonstrated not only CV safety but reductions in CV outcomes with two new classes of glucose lowering drugs, namely glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter-2 inhibitors (SGLT-2i) in patients with type II DM.2–6 In a Danish study, Dr Nørgaard and co-workers examined CV outcomes associated with the initiation of GLP-1RA vs. SGLT-2i treatment in a real-world setting among patients with type 2 diabetes. They used a Danish nationwide registry-based cohort study included patients with type 2 diabetes with a first-ever prescription of either GLP-1RA or SGLT-2i from 2013 through 2015, with follow-up until the end of 2018. The authors concluded that in this nationwide study of patients with type 2 diabetes, initiating GLP-1RA vs. SGLT-2i was not found to be associated with significant differences in CV risk.