Epidemiology and Burden of Peripheral Artery Disease in People With Type 2 Diabetes: A Systematic Literature Review.

Type 2 diabetes (T2D) and lower-extremity peripheral artery disease (PAD) are growing global health problems associated with considerable cardiovascular (CV) and limb-related morbidity and mortality, poor quality of life and high healthcare resource use and costs. Diabetes is a well-known risk factor for PAD, and the occurrence of PAD in people with T2D further increases the risk of long-term complications. As the available evidence is primarily focused on the overall PAD population, we undertook a systematic review to describe the burden of comorbid PAD in people with T2D. The MEDLINE, Embase and Cochrane Library databases were searched for studies including people with T2D and comorbid PAD published from 2012 to November 2021, with no restriction on PAD definition, study design or country. Hand searching of conference proceedings, reference lists of included publications and relevant identified reviews and global burden of disease reports complemented the searches. We identified 86 eligible studies, mostly observational and conducted in Asia and Europe, presenting data on the epidemiology (n = 62) and on the clinical (n = 29), humanistic (n = 12) and economic burden (n = 12) of PAD in people with T2D. The most common definition of PAD relied on ankle-brachial index values ≤ 0.9 (alone or with other parameters). Incidence and prevalence varied substantially across studies; nonetheless, four large multinational randomised controlled trials found that 12.5%-22% of people with T2D had comorbid PAD. The presence of PAD in people with T2D was a major cause of lower-limb and CV complications and of all-cause and CV mortality. Overall, PAD was associated with poor quality of life, and with substantial healthcare resource use and costs. To our knowledge, this systematic review provides the most comprehensive overview of the evidence on the burden of PAD in people with T2D to date. In this population, there is an urgent unmet need for disease-modifying agents to improve outcomes.

DCRM 2.0: Multispecialty practice recommendations for the management of diabetes, cardiorenal, and metabolic diseases.

The spectrum of cardiorenal and metabolic diseases comprises many disorders, including obesity, type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), dyslipidemias, hypertension, and associated comorbidities such as pulmonary diseases and metabolism dysfunction-associated steatotic liver disease and metabolism dysfunction-associated steatohepatitis (MASLD and MASH, respectively, formerly known as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis [NAFLD and NASH]). Because cardiorenal and metabolic diseases share pathophysiologic pathways, two or more are often present in the same individual. Findings from recent outcome trials have demonstrated benefits of various treatments across a range of conditions, suggesting a need for practice recommendations that will guide clinicians to better manage complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. To meet this need, we formed an international volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM 2.0 Practice Recommendations, an updated and expanded revision of a previously published multispecialty consensus on the comprehensive management of persons living with DCRM. The recommendations are presented as 22 separate graphics covering the essentials of management to improve general health, control cardiorenal risk factors, and manage cardiorenal and metabolic comorbidities, leading to improved patient outcomes.

Inclisiran in individuals with diabetes or obesity: Post hoc pooled analyses of the ORION-9, ORION-10 and ORION-11 Phase 3 randomized trials.

AIMS: To conduct a pooled analysis of Phase 3 trials investigating the efficacy and safety of inclisiran across glycaemic and body mass index (BMI) strata. MATERIALS AND METHODS: Participants were randomized 1:1 to receive 300 mg inclisiran sodium or placebo twice yearly, after initial and 3-month doses up to 18 months, with background oral lipid-lowering therapy. Analyses were stratified by glycaemic status (normoglycaemia, prediabetes, and diabetes) or BMI (<25, ≥25 to <30, ≥30 to <35, and ≥35 kg/m2). Co-primary endpoints were percentage and time-adjusted percentage change in low-density lipoprotein (LDL) cholesterol from baseline. Safety was also assessed. RESULTS: Baseline characteristics were balanced between treatment arms and across strata. Percent LDL cholesterol change (placebo-corrected) with inclisiran from baseline to Day 510 ranged from -47.6% to -51.9% and from -48.8% to -54.4% across glycaemic/BMI strata, respectively. Similarly, time-adjusted percentage changes after Day 90 and up to Day 540 ranged from -46.8% to -52.0% and from -48.6% to -53.3% across glycaemic/BMI strata, respectively. Inclisiran led to significant reductions in proprotein convertase subtilisin/kexin type 9 and other atherogenic lipids and lipoproteins versus placebo across the glycaemic/BMI strata. The proportions of individuals achieving LDL cholesterol thresholds of <1.8 mmol/L and <1.4 mmol/L with inclisiran increased with increasing glycaemic and BMI strata. Across the glycaemic/BMI strata, a higher proportion of individuals had mild/moderate treatment-emergent adverse events (TEAEs) at the injection site with inclisiran (2.8%-7.7%) versus placebo (0.2%-2.1%). CONCLUSION: Inclisiran provided substantial and sustained LDL cholesterol lowering across glycaemic/BMI strata, with a modest excess of transient mild-to-moderate TEAEs at the injection site.

Weight management using meal replacements and cardiometabolic risk reduction in individuals with pre-diabetes and features of metabolic syndrome: A systematic review and meta-analysis of randomized controlled trials.

This review synthesized the evidence from randomized controlled trials comparing the effect of meal replacements (MRs) as part of a weight loss intervention with conventional food-based weight loss diets on cardiometabolic risk in individuals with pre-diabetes and features of metabolic syndrome. MEDLINE, EMBASE, and Cochrane Library were searched through January 16, 2024. Data were pooled using the generic inverse variance method and expressed as mean difference [95% confidence intervals]. The overall certainty of the evidence was assessed using GRADE. Ten trials (n = 1254) met the eligibility criteria. MRs led to greater reductions in body weight (-1.38 kg [-1.81, -0.95]), body mass index (BMI, -0.56 kg/m2 [-0.78, -0.34]), waist circumference (-1.17 cm [-1.93, -0.41]), HbA1c (-0.11% [-0.22, 0.00]), LDL-c (-0.18 mmol/L [-0.28, -0.08]), non-HDL-c (-0.17 mmol/L [-0.33, -0.01]), and systolic blood pressure (-2.22 mmHg [-4.20, -0.23]). The overall certainty of the evidence was low to moderate owing to imprecision and/or inconsistency. The available evidence suggests that incorporating MRs into a weight loss intervention leads to small important reductions in body weight, BMI, LDL-c, non-HDL-c, and systolic blood pressure, and trivial reductions in waist circumference and HbA1c, beyond that seen with conventional food-based weight loss diets.

Inclisiran administration potently and durably lowers LDL-C over an extended-term follow-up: the ORION-8 trial.

BACKGROUND AND AIMS: Data describing the long-term efficacy, safety, and tolerability of inclisiran are limited. This was explored in ORION-8, an open-label extension study of preceding Phase 2 and Phase 3 placebo-controlled and open-label extension trials. METHODS: Adults with ASCVD, ASCVD risk equivalent, or HeFH received open-label inclisiran every 180 days (after completion of the parent trial) until Day 990, followed by an end-of-study (EOS) visit at Day 1080 or ≥90 days after last dose. Study endpoints included proportion of patients achieving pre-specified LDL-C goals (ASCVD: <1.8 mmol/L [<70 mg/dL]; ASCVD risk equivalent: <2.6 mmol/L [<100 mg/dL]), percentage and absolute changes in LDL-C at EOS, and safety of inclisiran. RESULTS: Of 3274 patients included in the analysis, 2446 (74.7%) were followed until EOS. Mean age was 64.9±9.9 years, 82.7% (n=2709) had ASCVD, and mean baseline LDL-C was 2.9±1.2 mmol/L. Mean cumulative exposure to inclisiran (including parent trials) was 3.7 years; maximum exposure was 6.8 years. With inclisiran, 78.4% (95% CI: 76.8, 80.0) of patients achieved pre-specified LDL-C goals and mean percentage LDL-C reduction was -49.4% (95% CI: -50.4, -48.3). No attenuation of LDL-C lowering over time was observed. Treatment-emergent adverse events at the injection site (all mild or moderate) occurred in 5.9% of inclisiran-treated patients. Inclisiran-associated anti-drug antibodies were infrequent (5.5%) and had no impact on the efficacy or safety of inclisiran. No new safety signals were identified. CONCLUSIONS: In the largest and longest follow-up to date, inclisiran demonstrated sustained and substantial LDL-C lowering with a favourable long-term safety and tolerability profile. ClinicalTrials.gov identifier: NCT03814187.

Limb Outcomes With Ticagrelor Plus Aspirin in Patients With Diabetes Mellitus and Atherosclerosis.

BACKGROUND: Ticagrelor reduced major adverse cardiovascular events (MACE) and increased bleeding in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease. Limb events including revascularization, acute limb ischemia (ALI), and amputation are major morbidities in patients with T2DM and atherosclerosis. OBJECTIVES: This study sought to determine the effect of ticagrelor on limb events. METHODS: Patients were randomized to ticagrelor or placebo on top of aspirin and followed for a median of 3 years. MACE (cardiovascular death, myocardial infarction, or stroke), limb events (ALI, amputation, revascularization), and bleeding were adjudicated by an independent and blinded clinical events committee. The presence of peripheral artery disease (PAD) was reported at baseline. RESULTS: Of 19,220 patients randomized, 1,687 (8.8%) had PAD at baseline. In patients receiving placebo, PAD was associated with higher MACE (10.7% vs 7.3%; HR: 1.48; P < 0.001) and limb (9.5% vs 0.8%; HR: 10.67; P < 0.001) risk. Ticagrelor reduced limb events (1.6% vs 1.3%; HR: 0.77; 95% CI: 0.61-0.96; P = 0.022) with significant reductions for revascularization (HR: 0.79; 95% CI: 0.62-0.99; P = 0.044) and ALI (HR: 0.24; 95% CI: 0.08-0.70; P = 0.009). The benefit was consistent with or without PAD (HR: 0.80; 95% CI: 0.58-1.11; and HR: 0.76; 95% CI: 0.55-1.05, respectively; Pinteraction = 0.81). There was no effect modification of ticagrelor vs placebo based on PAD for MACE (Pinteraction = 0.40) or TIMI major bleeding (Pinteraction = 0.3239). CONCLUSIONS: Patients with T2DM and atherosclerosis are at high risk of limb events. Ticagrelor decreased this risk, but increased bleeding. Future trials evaluating the combination of ticagrelor and aspirin would further elucidate the benefit/risk of such therapy in patients with PAD, including those without coronary artery disease. (A Study Comparing Cardiovascular Effects of Ticagrelor Versus Placebo in Patients With Type 2 Diabetes Mellitus [THEMIS]: NCT01991795).

Estimating potential cardiovascular health benefits of improved population level control of LDL cholesterol through a twice-yearly siRNA-based approach: A simulation study of a health-system level intervention.

BACKGROUND AND AIMS: Inclisiran, an siRNA therapy, consistently reduces low-density lipoprotein cholesterol (LDL-C) with twice-yearly dosing. Potential cardiovascular benefits of implementing inclisiran at a population level, added to statins, were evaluated through simulation. METHODS: For each participant in the ORION-10 and ORION-11 trials comparing inclisiran with placebo, baseline 10-year cardiovascular risk was estimated using the SMART equation. The time-adjusted LDL-C difference from baseline observed 90-540 days after baseline was assumed to persist and used to estimate potential reduction in 10-year cardiovascular risk. Impact on 500,000 ORION-like individuals was simulated with Monte-Carlo. RESULTS: Mean baseline LDL-C and predicted 10-year major vascular risk among patients randomized to inclisiran (n = 1288) versus placebo (n = 1264) were 2.66 mmol/L versus 2.60 mmol/L and 24.9% versus 24.6%, respectively. Placebo-corrected time-adjusted absolute reduction in LDL-C with inclisiran was -1.32 mmol/L (95% CI -1.37 to -1.26; p < 0.001), which predicted a 10-year cardiovascular risk of 18.1% with inclisiran versus 24.7% with placebo (absolute difference [95% CI], -6.99% [-7.33 to -6.66]; p < 0.001) NNT 15. Extrapolating to 500,000 inclisiran-treated individuals, the model predicted large population shifts towards lower quintiles of risk with fewer remaining in high-risk categories; 3350 to 471 (≥80% risk), 11,793 to 3332 (60-<80% risk), 52,142 to 22,665 (40-<60% risk), 197,752 to 141,014 (20-<40% risk), and more moving into the lowest risk category (<20%) from 234,963 to 332,518. CONCLUSIONS: Meaningful gains in population health might be achieved over 10 years by implementing at-scale approaches capable of providing substantial and sustained reductions in LDL-C beyond those achievable with statins.

Icosapent ethyl modulates circulating vascular regenerative cell content: The IPE-PREVENTION CardioLink-14 trial.

BACKGROUND: REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) showed that icosapent ethyl (IPE) reduced major adverse cardiovascular events by 25%. Since the underlying mechanisms for these benefits are not fully understood, the IPE-PREVENTION CardioLink-14 trial (ClinicalTrials.gov: NCT04562467) sought to determine if IPE regulates vascular regenerative (VR) cell content in people with mild to moderate hypertriglyceridemia. METHODS: Seventy statin-treated individuals with triglycerides ≥1.50 and <5.6 mmol/L and either atherosclerotic cardiovascular disease or type 2 diabetes with additional cardiovascular risk factors were randomized to IPE (4 g/day) or usual care. VR cells with high aldehyde dehydrogenase activity (ALDHhi) were isolated from blood collected at the baseline and 3-month visits and characterized with lineage-specific cell surface markers. The primary endpoint was the change in frequency of pro-vascular ALDHhiside scatter (SSC)lowCD133+ progenitor cells. Change in frequencies of ALDHhiSSCmid monocyte and ALDHhiSSChi granulocyte precursor subsets, reactive oxygen species production, serum biomarkers, and omega-3 levels were also evaluated. FINDINGS: Baseline characteristics, cardiovascular risk factors, and medications were balanced between the groups. Compared to usual care, IPE increased the mean frequency of ALDHhiSSClowCD133+ cells (-1.00% ± 2.45% vs. +7.79% ± 1.70%; p = 0.02), despite decreasing overall ALDHhiSSClow cell frequency. IPE assignment also reduced oxidative stress in ALDHhiSSClow progenitors and increased ALDHhiSSChi granulocyte precursor cell content. CONCLUSIONS: IPE-PREVENTION CardioLink-14 provides the first translational evidence that IPE can modulate VR cell content and suggests a novel mechanism that may underlie the cardioprotective effects observed with IPE in REDUCE-IT. FUNDING: HLS Therapeutics provided the IPE in kind and had no role in the study design, conduct, analyses, or interpretation.

Effect of albiglutide on cardiovascular outcomes in older adults: A post hoc analysis of a randomized controlled trial.

AIM: To analyse the effects of albiglutide, a glucagon-like peptide 1 receptor agonist, on cardiovascular outcomes in older adults aged ≥65 years with type 2 diabetes and cardiovascular disease who participated in the Harmony Outcomes trial (NCT02465515). MATERIALS AND METHODS: We conducted a post hoc analysis of the primary endpoint of the Harmony Outcomes trial-time to first occurrence of a major adverse cardiovascular event-in subgroups of participants aged <65 and ≥65 years and <75 and ≥75 years at baseline. Hazard ratios and 95% confidence intervals (CIs) were generated using Cox proportional hazards regression. RESULTS: The analysis population included 9462 Harmony Outcomes participants, including 4748 patients ≥65 and 1140 patients ≥75 years at baseline. Hazard ratios for the prevention of major adverse cardiovascular events were 0.66 (95% CI, 0.53-0.82) in persons <65 and 0.86 (95% CI, 0.71-1.04) in those ≥65 years (age interaction p = .07), and 0.78 (95% CI, 0.67-0.91) in <75 and 0.70 (95% CI, 0.48-1.01) in ≥75 year age groups (interaction p = .6). When analysed as a continuous variable, age did not modify the effect of albiglutide on the primary endpoint. CONCLUSIONS: This post hoc analysis adds to the body of literature showing that glucagon-like peptide 1 receptor agonists added to standard type 2 diabetes therapy safely reduce the incidence of cardiovascular events in older adults with established cardiovascular disease. In this analysis, the risk-benefit profile was similar between younger and older age groups treated with albiglutide.

Effects of albiglutide on myocardial infarction and ischaemic heart disease outcomes in patients with type 2 diabetes and cardiovascular disease in the Harmony Outcomes trial.

AIMS: Large outcome trials have demonstrated cardiovascular benefits of selected glucagon-like peptide-1 (GLP-1) receptor agonists. We examined coronary disease outcomes in the Harmony Outcomes trial of the GLP-1 receptor agonist albiglutide. METHODS AND RESULTS: Harmony Outcomes was an event-driven, multicenter, double-blind, and placebo-controlled trial involving 9463 patients >40 years of age with type-2 diabetes and established atherosclerotic cardiovascular disease. It tested the effects of albiglutide on the occurrence of a composite primary endpoint, consisting of cardiovascular death, myocardial infarction (MI), or stroke. Within this post-hoc analysis, the effects of albiglutide on MI subtypes and other ischaemic endpoints were analysed.During the median-follow up of 1.6 years, a total of 421 patients (4.5%) experienced at least one MI, with 72 patients having more than one event. Treatment with albiglutide reduced both first events [hazard ratio (HR) 0.75 (0.62-0.91)] and overall events [HR 0.75 (0.61-0.91)] as well as first type 1 [HR 0.73 (0.57-0.92)] and type 2 myocardial infarctions [HR 0.65 (0.46-0.92)]. The effect of albiglutide treatment was consistent for ST-segment elevation [HR 0.69 (0.38-1.26)] and non-ST elevation (HR 0.86 (0.66-1.2) MI. CONCLUSION: Treatment with the GLP-1 receptor agonist albiglutide resulted in a 25% relative risk reduction in MI that was consistent for type of infarction and presence or absence of ST elevation. Our findings add novel information about the effects of GLP-1 receptor agonists on ischaemic events in patients with type 2 diabetes.

Real-World Risk of Recurrent Cardiovascular Events in Atherosclerotic Cardiovascular Disease Patients with LDL-C Above Guideline-Recommended Threshold: A Retrospective Observational Study.

INTRODUCTION: The 2021 Canadian Cardiovascular Society (CCS) guidelines recommend intensive low-density lipoprotein cholesterol (LDL-C) reduction for patients with atherosclerotic cardiovascular disease (ASCVD). For patients above LDL-C threshold on maximally tolerated statins, adding ezetimibe and/or a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) is recommended. This population-based, real-world study examined cardiovascular (CV) events in patients with ASCVD who are on statins and above current guideline threshold LDL-C levels. METHODS: Using administrative health data in Alberta, Canada, we identified patients with myocardial infarction (MI), ischemic stroke (IS), or peripheral artery disease with LDL-C > 1.8 mmol/L on statins between April 1, 2010 and March 31, 2016. Exploratory subgroups included very high-risk patients with ASCVD shown to derive the most benefit from PCSK9i intensification as identified by the CCS guidelines, including those with acute coronary syndrome (ACS) or recent MI. Frequencies and rates of individual and composite CV events (primary outcome: MI, IS, hospitalization for unstable angina, coronary revascularization, cardiovascular death; secondary outcome: MI, IS, CV death) were calculated over follow-up. RESULTS: The study included 32,984 patients with a mean (standard deviation) follow-up of 40.8 (21.0) months. Overall, 17.7% and 15.6% experienced a primary and secondary outcome, respectively, with rates of 5.58 and 4.83 per 100 patient-years, respectively. CV death and MI were the most common events. Subgroups with recurrent MI and comorbid diabetes exhibited higher CV event rates (23.6% and 22.2% had a primary outcome, respectively). Rates of CV events were notably high in patients with ACS or recent MI (49.4% and 54.0% had a primary outcome, respectively). CONCLUSION: This real-world study confirms that statin-treated high-risk patients with ASCVD and above-threshold LDL-C levels have substantial incidence of recurrent CV events. These findings reinforce the opportunity for lipid-lowering therapy intensification in high-risk patients to levels below guideline-recommended threshold in order to reduce CV risk.

Rationale and design of the effect of evolocumab in patients at high cardiovascular risk without prior myocardial infarction or stroke (VESALIUS-CV) trial.

BACKGROUND: The reduction of low-density lipoprotein cholesterol (LDL-C) with evolocumab, a fully human monoclonal antibody inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9i), reduces the risk of major adverse cardiovascular events in patients with established atherosclerotic cardiovascular disease (ASCVD) with a prior MI, prior stroke, or symptomatic peripheral artery disease, with no offsetting safety concerns. The effect of evolocumab on CV outcomes in lower risk patients without a history of MI or stroke has not been explored. STUDY DESIGN: VESALIUS-CV is a randomized, double-blind, placebo-controlled, global clinical trial designed to evaluate the effect of evolocumab on the risk of major cardiovascular events in patients at high cardiovascular risk but without a prior ischemic event. The study population consists of 12,301 patients with atherosclerosis or high-risk diabetes mellitus without a prior MI or stroke; an LDL-C ≥ 90 mg/dL, or non-high-density lipoprotein cholesterol (non-HDL-C) ≥ 120 mg/dL, or apolipoprotein B ≥ 80 mg/dL; and treated with optimized lipid-lowering therapy. Patients were randomized in a 1:1 ratio to evolocumab 140 mg subcutaneously every 2 weeks or matching placebo. The primary efficacy objective is to assess whether evolocumab reduces the risk of the dual primary composite endpoints of coronary heart disease (CHD) death, myocardial infarction (MI), or ischemic stroke (triple primary endpoint) and of CHD death, MI, ischemic stroke, or ischemia-driven arterial revascularization (quadruple primary endpoint). Recruitment began in June 2019 and completed in November 2021. The trial is planned to continue until at least 751 patients experience an adjudicated triple endpoint, at least 1254 experience an adjudicated quadruple endpoint, and the median follow-up is ≥4.5 years. CONCLUSION: VESALIUS-CV will determine whether the addition of evolocumab to optimized lipid-lowering therapy reduces cardiovascular events in patients at high cardiovascular risk without a prior MI or stroke. TRIAL REGISTRATION: NCT03872401.

Natriuretic peptides, body mass index and heart failure risk: Pooled analyses of SAVOR-TIMI 53, DECLARE-TIMI 58 and CAMELLIA-TIMI 61.

AIM: N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations are lower in patients with obesity. The interaction between body mass index (BMI) and NT-proBNP with respect to heart failure risk remains incompletely defined. METHODS AND RESULTS: Data were pooled across three randomized clinical trials enrolling predominantly patients who were overweight or obese with established cardiometabolic disease: SAVOR-TIMI 53, DECLARE-TIMI 58 and CAMELLIA-TIMI 61. Hospitalization for heart failure (HHF) was examined across strata of baseline BMI and NT-proBNP. The effect of dapagliflozin versus placebo was assessed for a treatment interaction across BMI categories in patients with or without an elevated baseline NT-proBNP (≥125 pg/ml). Among 24 455 patients, the median NT-proBNP was 96 (interquartile range [IQR]: 43-225) pg/ml and the median BMI was 33 (IQR 29-37) kg/m2, with 68% of patients having a BMI ≥30 kg/m2. There was a significant inverse association between NT-proBNP and BMI which persisted after adjustment for all clinical variables (p < 0.001). Within any range of NT-proBNP, those at higher BMI had higher risk of HHF at 2 years (comparing BMI <30 vs. ≥40 kg/m2 for NT-proBNP ranges of <125, 125-<450 and ≥450 pg/ml: 0.0% vs. 0.6%, 1.3% vs. 4.0%, and 8.1% vs. 13.8%, respectively), which persisted after multivariable adjustment (adjusted hazard ratio [HRadj] 7.47, 95% confidence interval [CI] 3.16-17.66, HRadj 3.22 [95% CI 2.13-4.86], and HRadj 1.87 [95% CI 1.35-2.60], respectively). In DECLARE-TIMI 58, dapagliflozin versus placebo consistently reduced HHF across BMI categories in those with an elevated NT-proBNP (p-trend for HR across BMI = 0.60), with a pattern of greater absolute risk reduction (ARR) at higher BMI (ARR for BMI <30 to ≥40 kg/m2: 2.2% to 4.7%; p-trend = 0.059). CONCLUSIONS: The risk of HHF varies across BMI categories for any given range of circulating NT-proBNP. These findings showcase the importance of considering BMI when applying NT-proBNP for heart failure risk stratification, particularly for patients with low-level elevations in NT-proBNP (125-<450 pg/ml) where there appears to be a clinically meaningful absolute and relative risk gradient.

Safety and Tolerability of Inclisiran for Treatment of Hypercholesterolemia in 7 Clinical Trials.

BACKGROUND: Inclisiran is a small interfering RNA agent to lower low-density lipoprotein cholesterol. OBJECTIVES: The purpose of this study was to provide reliable evidence to date on the long-term safety profile of inclisiran. METHODS: This post hoc analysis comprised patients treated with 300 mg inclisiran sodium or placebo in the completed (ORION-1, -3, -5, -9, -10, and -11) and ongoing (ORION-8) trials. Exposure-adjusted incidence rates and Kaplan-Meier estimates of cumulative incidence of reported treatment-emergent adverse events (TEAE), abnormal laboratory measurements, and incidence of antidrug antibodies were analyzed. RESULTS: This analysis included 3,576 patients treated with inclisiran for up to 6 years and 1,968 patients treated with placebo for up to 1.5 years, with 9,982.1 and 2,647.7 patient-years of exposure, respectively. Baseline characteristics were balanced between groups. Kaplan-Meier analyses showed that TEAEs that were serious or led to discontinuation; hepatic, muscle, and kidney events; incident diabetes; and elevations of creatine kinase or creatinine accrued at a comparable rate between groups for up to 1.5 years, with similar trends continuing for inclisiran beyond this period. Numerically fewer major cardiovascular events reported as TEAEs occurred with inclisiran during this period. Treatment-induced antidrug antibodies were uncommon with inclisiran (4.6%), with few of these persistent (1.4%) and not associated with greater incidence of TEAEs leading to study drug discontinuation or serious TEAEs. CONCLUSIONS: Long-term treatment with inclisiran was well tolerated in a diverse population, without new safety signals, supporting the safety of inclisiran in patients with dyslipidemia.

Inclisiran in patients with prior myocardial infarction: A post hoc pooled analysis of the ORION-10 and ORION-11 Phase 3 randomised trials.

BACKGROUND AND AIMS: Among patients with prior myocardial infarction (MI), the risk of future ischaemic cardiovascular events is increased, and intensive lipid-lowering therapy (LLT) is indicated to achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals. Here, the efficacy and safety of inclisiran, a small interfering ribonucleic acid, were evaluated in patients with or without prior MI from the pooled ORION-10 and ORION-11 Phase 3 trials. METHODS: Patients (n = 2636) were randomised 1:1 to receive 284 mg inclisiran (300 mg inclisiran sodium) or placebo on Day 1, Day 90, and 6-monthly thereafter over 18 months, along with background oral LLT, including statins. Of these, 1643 (62.3%) patients had an MI prior to randomisation, stratified as recent (>3 months to <1 year) or remote (≥1 year), and 993 (37.7%) patients were without a prior MI. The percentage change in LDL-C from baseline and safety were assessed. RESULTS: Baseline characteristics were well balanced across the treatment arms and MI strata. The mean (95% confidence interval) placebo-corrected LDL-C reductions from baseline to Day 510 with inclisiran were 52.6% (40.1, 65.1), 50.4% (47.0, 53.8), and 51.6% (47.4, 55.9) for recent, remote, and no prior MI, respectively. Corresponding time-adjusted LDL-C reductions were 50.0% (41.4, 58.7), 52.2% (49.8, 54.7), and 51.2% (48.1, 54.2). In each MI stratum, treatment-emergent adverse events (TEAEs) at the injection site (all mild to moderate) were observed more in inclisiran-treated patients than placebo, without an excess of other TEAEs. CONCLUSIONS: Inclisiran provided effective and consistent LDL-C lowering, irrespective of MI status.

GLP-1 Receptor Agonist Therapy With and Without SGLT2 Inhibitors in Patients With Type 2 Diabetes.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors and GLP-1 receptor agonists (GLP-1 RAs) reduce adverse cardiovascular outcomes in type 2 diabetes (T2D). However, the efficacy of combination therapy is unclear. OBJECTIVES: The aim of this study was to evaluate the effects of GLP-1 RAs on cardiovascular outcomes in patients with T2D treated with or without SGLT2 inhibitors. METHODS: Post hoc analysis of Harmony Outcomes (Albiglutide and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Cardiovascular Disease) evaluating the effect of albiglutide in T2D with cardiovascular disease by background SGLT2 inhibitor use. Additionally, a trial-level meta-analysis of Harmony Outcomes and AMPLITUDE-O (Effect of Efpeglenatide on Cardiovascular Outcomes), which evaluated T2D with cardiovascular or renal disease, was performed, combining the treatment effect estimates according to SGLT2 inhibitor use. RESULTS: Of the 9,462 participants in Harmony Outcomes, 575 (6.1%) were treated with SGLT2 inhibitors at baseline. The effect of albiglutide on reducing the composite of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular events) was consistent with or without SGLT2 inhibitors (P interaction = 0.70). The effect of albiglutide on secondary outcomes and adverse events was not modified by SGLT2 inhibitors. A meta-analysis of Harmony Outcomes and AMPLITUDE-O included 13,538 patients, of whom 1,193 (8.8%) used SGLT2 inhibitors. Compared to placebo, GLP1-RAs reduced major adverse cardiovascular events without effect modification by SGLT2 inhibitor use (HR: 0.77; 95% CI: 0.68-0.87 without SGLT2 inhibitors; and HR: 0.78; 95% CI: 0.49-1.24 with SGLT2 inhibitors) (P for interaction = 0.95) and reduced heart failure hospitalization (HR: 0.72; 95% CI: 0.55-0.92 vs HR: 0.34; 95% CI: 0.12-0.96) (P for interaction = 0.18). CONCLUSIONS: In patients with T2D and cardiovascular disease, GLP-1 RAs reduced cardiovascular events independently of SGLT2 inhibitor use. These findings suggest that the combination of GLP-1 RAs with SGLT2 inhibitors may further reduce cardiovascular risk. Clinical trials with combination therapy are needed.

Evaluation of the efficacy and safety of bempedoic acid in women and men: Pooled analyses from phase 3 trials.

BACKGROUND AND AIMS: Sex-specific differences in the response to lipid-lowering therapies have been reported. Here, we assessed the effect of bempedoic acid in women and men using pooled, patient-level data from four phase 3 clinical trials of bempedoic acid. METHODS: Patients were grouped into two pools: 1) atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) "on statins" and 2) "low-dose or no statin". Percent changes from baseline to at least week 12 in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), apolipoprotein B (Apo B), and high-sensitivity C-reactive protein (hsCRP), as well as safety, were analyzed by statin pool and sex. RESULTS: Overall, 3623 patients were included (bempedoic acid, 2425; placebo, 1198). Significant reductions in lipid parameters and hsCRP were observed with bempedoic acid vs. placebo in both sexes in the ASCVD and/or HeFH on statins (n = 3009) and the low-dose or no statin (n = 614) pools (p ≤ 0.002). Compared with men, women had significantly greater placebo-corrected reductions in LDL-C (-21.2% vs. -17.4%; p = 0.044), non-HDL-C (-17.3% vs. -12.1%; p = 0.003), TC (-13.8% vs. -10.5%; p = 0.012), and Apo B (-16.0% vs. -11.3%; p = 0.004) in the ASCVD and/or HeFH on statins pool. Women had similar reductions to men in lipid parameters in the low-dose or no statin pool and hsCRP in both pools. The safety of bempedoic acid was comparable between sexes. CONCLUSIONS: In this pooled analysis, women experienced significant improvements in levels of LDL-C and other lipid parameters with bempedoic acid.

Fructose-containing food sources and blood pressure: A systematic review and meta-analysis of controlled feeding trials.

Whether food source or energy mediates the effect of fructose-containing sugars on blood pressure (BP) is unclear. We conducted a systematic review and meta-analysis of the effect of different food sources of fructose-containing sugars at different levels of energy control on BP. We searched MEDLINE, Embase and the Cochrane Library through June 2021 for controlled trials ≥7-days. We prespecified 4 trial designs: substitution (energy matched substitution of sugars); addition (excess energy from sugars added); subtraction (excess energy from sugars subtracted); and ad libitum (energy from sugars freely replaced). Outcomes were systolic and diastolic BP. Independent reviewers extracted data. GRADE assessed the certainty of evidence. We included 93 reports (147 trial comparisons, N = 5,213) assessing 12 different food sources across 4 energy control levels in adults with and without hypertension or at risk for hypertension. Total fructose-containing sugars had no effect in substitution, subtraction, or ad libitum trials but decreased systolic and diastolic BP in addition trials (P<0.05). There was evidence of interaction/influence by food source: fruit and 100% fruit juice decreased and mixed sources (with sugar-sweetened beverages [SSBs]) increased BP in addition trials and the removal of SSBs (linear dose response gradient) and mixed sources (with SSBs) decreased BP in subtraction trials. The certainty of evidence was generally moderate. Food source and energy control appear to mediate the effect of fructose-containing sugars on BP. The evidence provides a good indication that fruit and 100% fruit juice at low doses (up to or less than the public health threshold of ~10% E) lead to small, but important reductions in BP, while the addition of excess energy of mixed sources (with SSBs) at high doses (up to 23%) leads to moderate increases and their removal or the removal of SSBs alone (up to ~20% E) leads to small, but important decreases in BP in adults with and without hypertension or at risk for hypertension. Trial registration: Clinicaltrials.gov: NCT02716870.