Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials.

BACKGROUND: In the STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials, the GLP-1 receptor agonist semaglutide improved symptoms, physical limitations, bodyweight, and exercise function in people with obesity-related heart failure with preserved ejection fraction. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, we aimed to provide a more definitive assessment of the effects of semaglutide across a range of outcomes and to test whether these effects were consistent across key patient subgroups. METHODS: We conducted a prespecified pooled analysis of individual patient data from STEP-HFpEF and STEP-HFpEF DM, randomised, double-blind, placebo-controlled trials at 129 clinical research sites in 18 countries. In both trials, eligible participants were aged 18 years or older, had heart failure with a left ventricular ejection fraction of at least 45%, a BMI of at least 30 kg/m2, New York Heart Association class II-IV symptoms, and a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; a measure of heart failure-related symptoms and physical limitations) of less than 90 points. In STEP-HFpEF, people with diabetes or glycated haemoglobin A1c concentrations of at least 6·5% were excluded, whereas for inclusion in STEP-HFpEF DM participants had to have been diagnosed with type 2 diabetes at least 90 days before screening and to have an HbA1c of 10% or lower. In both trials, participants were randomly assigned to either 2·4 mg semaglutide once weekly or matched placebo for 52 weeks. The dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and bodyweight in all randomly assigned participants. Confirmatory secondary endpoints included change from baseline to week 52 in 6-min walk distance, a hierarchical composite endpoint (all-cause death, heart failure events, and differences in changes in KCCQ-CSS and 6-min walk distance); and C-reactive protein (CRP) concentrations. Heterogeneity in treatment effects was assessed across subgroups of interest. We assessed safety in all participants who received at least one dose of study drug. FINDINGS: Between March 19, 2021 and March 9, 2022, 529 people were randomly assigned in STEP-HFpEF, and between June 27, 2021 and Sept 2, 2022, 616 were randomly assigned in STEP-HFpEF DM. Overall, 1145 were included in our pooled analysis, 573 in the semaglutide group and 572 in the placebo group. Improvements in KCCQ-CSS and reductions in bodyweight between baseline and week 52 were significantly greater in the semaglutide group than in the placebo group (mean between-group difference for the change from baseline to week 52 in KCCQ-CSS 7·5 points [95% CI 5·3 to 9·8]; p<0·0001; mean between-group difference in bodyweight at week 52 -8·4% [-9·2 to -7·5]; p<0·0001). For the confirmatory secondary endpoints, 6-min walk distance (mean between-group difference at week 52 17·1 metres [9·2 to 25·0]) and the hierarchical composite endpoint (win ratio 1·65 [1·42 to 1·91]) were significantly improved, and CRP concentrations (treatment ratio 0·64 [0·56 to 0·72]) were significantly reduced, in the semaglutide group compared with the placebo group (p<0·0001 for all comparisons). For the dual primary endpoints, the efficacy of semaglutide was largely consistent across multiple subgroups, including those defined by age, race, sex, BMI, systolic blood pressure, baseline CRP, and left ventricular ejection fraction. 161 serious adverse events were reported in the semaglutide group compared with 301 in the placebo group. INTERPRETATION: In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide was superior to placebo in improving heart failure-related symptoms and physical limitations, and reducing bodyweight in participants with obesity-related heart failure with preserved ejection fraction. These effects were largely consistent across patient demographic and clinical characteristics. Semaglutide was well tolerated. FUNDING: Novo Nordisk.

Semaglutide in HFpEF across obesity class and by body weight reduction: a prespecified analysis of the STEP-HFpEF trial.

In the STEP-HFpEF trial, semaglutide improved symptoms, physical limitations and exercise function and reduced body weight in patients with obesity phenotype of heart failure and preserved ejection fraction (HFpEF). This prespecified analysis examined the effects of semaglutide on dual primary endpoints (change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) and body weight) and confirmatory secondary endpoints (change in 6-minute walk distance (6MWD), hierarchical composite (death, HF events, change in KCCQ-CSS and 6MWD) and change in C-reactive protein (CRP)) across obesity classes I-III (body mass index (BMI) 30.0-34.9 kg m-2, 35.0-39.9 kg m-2 and ≥40 kg m-2) and according to body weight reduction with semaglutide after 52 weeks. Semaglutide consistently improved all outcomes across obesity categories (P value for treatment effects × BMI interactions = not significant for all). In semaglutide-treated patients, improvements in KCCQ-CSS, 6MWD and CRP were greater with larger body weight reduction (for example, 6.4-point (95% confidence interval (CI): 4.1, 8.8) and 14.4-m (95% CI: 5.5, 23.3) improvements in KCCQ-CSS and 6MWD for each 10% body weight reduction). In participants with obesity phenotype of HFpEF, semaglutide improved symptoms, physical limitations and exercise function and reduced inflammation and body weight across obesity categories. In semaglutide-treated patients, the magnitude of benefit was directly related to the extent of weight loss. Collectively, these data support semaglutide-mediated weight loss as a key treatment strategy in patients with obesity phenotype of HFpEF. ClinicalTrials.gov identifier: NCT04788511 .

Design and Baseline Characteristics of STEP-HFpEF Program Evaluating Semaglutide in Patients With Obesity HFpEF Phenotype.

BACKGROUND: The majority of patients with heart failure with preserved ejection fraction (HFpEF) have the obesity phenotype, but no therapies specifically targeting obesity in HFpEF exist. OBJECTIVES: The aim of this study was to describe the design and baseline characteristics of 2 trials of semaglutide, a glucagon-like peptide-1 receptor agonist, in patients with the obesity HFpEF phenotype: STEP-HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF; NCT04788511) and STEP-HFpEF DM (Semaglutide Treatment Effect in People with obesity and HFpEF and type 2 diabetes; NCT04916470). METHODS: Both STEP-HFpEF and STEP-HFpEF DM are international multicenter, double-blind, placebo-controlled trials that randomized adults with HFpEF and a body mass index ≥30 kg/m2 to once-weekly semaglutide at a dose of 2.4 mg or placebo. Participants were eligible if they had a left ventricular ejection fraction (LVEF) ≥45%; NYHA functional class II to IV; a Kansas City Cardiomyopathy Questionnaire (KCCQ)-Clinical Summary Score (CSS) <90 points; and ≥1 of the following: elevated filling pressures, elevated natriuretic peptides plus structural echocardiographic abnormalities, recent heart failure hospitalization plus ongoing diuretic use, and/or structural abnormalities. The dual primary endpoints are the 52-week change in the KCCQ-CSS and body weight. RESULTS: In STEP-HFpEF and STEP-HFpEF DM (N = 529 and N = 617, respectively), nearly half were women, and most had severe obesity (median body mass index of 37 kg/m2) with typical features of HFpEF (median LVEF of 57%, frequent comorbidities, and elevated natriuretic peptides). Most participants received diuretic agents and renin-angiotensin blockers at baseline, and approximately one-third were on mineralocorticoid receptor antagonists. Sodium-glucose cotransporter-2 inhibitor use was rare in STEP-HFpEF but not in STEP HFpEF DM (32%). Patients in both trials had marked symptomatic and functional impairments (KCCQ-CSS ∼59 points, 6-minute walking distance ∼300 m). CONCLUSIONS: In total, STEP-HFpEF program randomized 1,146 participants with the obesity phenotype of HFpEF and will determine whether semaglutide improves symptoms, physical limitations, and exercise function in addition to weight loss in this vulnerable group.

Treatment with glucagon-like peptide-1 receptor agonists and incidence of dementia: Data from pooled double-blind randomized controlled trials and nationwide disease and prescription registers.

INTRODUCTION: People with type 2 diabetes have increased risk of dementia. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are among the promising therapies for repurposing as a treatment for Alzheimer's disease; a key unanswered question is whether they reduce dementia incidence in people with type 2 diabetes. METHODS: We assessed exposure to GLP-1 RAs in patients with type 2 diabetes and subsequent diagnosis of dementia in two large data sources with long-term follow-up: pooled data from three randomized double-blind placebo-controlled cardiovascular outcome trials (15,820 patients) and a nationwide Danish registry-based cohort (120,054 patients). RESULTS: Dementia rate was lower both in patients randomized to GLP-1 RAs versus placebo (hazard ratio [HR]: 0.47 (95% confidence interval [CI]: 0.25-0.86) and in the nationwide cohort (HR: 0.89; 95% CI: 0.86-0.93 with yearly increased exposure to GLP-1 RAs). DISCUSSION: Treatment with GLP-1 RAs may provide a new opportunity to reduce the incidence of dementia in patients with type 2 diabetes.

Heart failure with insulin degludec versus glargine U100 in patients with type 2 diabetes at high risk of cardiovascular disease: DEVOTE 14.

BACKGROUND: Heart failure (HF) is a common cardiovascular complication of type 2 diabetes (T2D). This secondary analysis investigated baseline factors and treatment differences associated with risk of hospitalization for HF (hHF), and the possible association between severe hypoglycemia and hHF. METHODS: DEVOTE was a treat-to-target, double-blind cardiovascular outcomes trial in patients (n = 7637) with T2D and high cardiovascular risk randomized to insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100). The main endpoint of this secondary analysis was time to first hHF (standardized MedDRA Query definition). Severe hypoglycemia was adjudicated (American Diabetes Association definition). The main endpoint and the temporal association between severe hypoglycemia and hHF were analyzed with a Cox proportional hazards regression model. Predictors of time to first hHF were identified using baseline variables. RESULTS: Overall, 372 (4.9%) patients experienced hHF (550 events). There was no significant difference in the risk of hHF between treatments (hazard ratio [HR] 0.88 [0.72;1.08]95% CI, p = 0.227). Prior HF (HR 4.89 [3.90;6.14]95% CI, p ≤ 0.0001) was the strongest predictor of future hHF events. The risk of hHF significantly increased after (HR 2.2), and within a week after (HR 11.1), experiencing a severe hypoglycemic episode compared with before an episode. CONCLUSIONS: In patients with T2D and high cardiovascular risk there were no treatment differences in terms of hHF. Prior HF was the strongest predictor of future hHF events, and there was an association between severe hypoglycemia and subsequent hHF. Further research should evaluate whether the risk of hHF can be modified by treatments aimed at reducing hypoglycemia. Trial Registration NCT01959529.

Pharmacokinetic and Pharmacodynamic Characteristics of Dasiglucagon, a Novel Soluble and Stable Glucagon Analog.

OBJECTIVE: Treatment of severe hypoglycemia outside of the hospital setting is limited to glucagon formulations requiring reconstitution before use, which may lead to erroneous or delayed glucagon administration. We compared the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and safety and tolerability of different doses of dasiglucagon, a novel soluble glucagon analog, with approved pediatric and full doses of GlucaGen in insulin-induced hypoglycemia in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: In this single-center, randomized, double-blind trial, 58 patients with type 1 diabetes received single subcutaneous injections of 0.1, 0.3, 0.6, or 1.0 mg dasiglucagon or 0.5 or 1.0 mg GlucaGen in a state of hypoglycemia (blood glucose target 55 mg/dL) induced by an intravenous insulin infusion. RESULTS: Dasiglucagon demonstrated a dose-dependent and rapid increase in plasma concentrations, reaching a maximum at ∼35 min with a half-life of ∼0.5 h. Dasiglucagon rapidly increased plasma glucose (PG) by ≥20 mg/dL (9-14 min) to PG ≥70 mg/dL (within 6-10 min), similar to GlucaGen, but with a longer-lasting and greater effect on PG. All patients on both treatments reached these end points within 30 min (predefined success criteria). Both treatments were well tolerated. Nausea was the most frequent adverse event, occurring at a similar rate (44-56%). CONCLUSIONS: Dasiglucagon was well tolerated and showed an early PD response similar to that of GlucaGen at corresponding doses, suggesting comparable clinical effects of the two glucagon formulations. Dasiglucagon has the potential to become an effective and reliable rescue treatment for severe hypoglycemia in a ready-to-use pen.

Insulin analogues dosing and costs - comparing real-life daily doses of insulin detemir and insulin glargine in type 2 diabetes patients.

BACKGROUND: The uncertainties regarding dose similarities between basal long-acting insulin analogues remain. Recent real-world studies indicate dose similarities between insulin detemir and insulin glargine, but further studies are still warranted.The aim of this study was to compare real-life daily doses of insulin detemir and insulin glargine in type 2 diabetes patients when administered once daily. METHODS: We analysed 536 patient cases from general practice (63%) and endocrinological outpatient clinics (37%). A self-administered questionnaire completed by the treating physician was used to obtain data on patient characteristics (gender, age, weight, height, latest HbA1c-value), daily doses, administration of and number of years treated with insulin detemir and insulin glargine, concomitant insulin use and use of non-insulin anti-diabetic medication. Both bivariate analyses and multivariate regression analyses were applied to examine whether there were differences in the daily doses of insulin detemir and insulin glargine. RESULTS: There was no significant difference in the mean daily doses of insulin detemir (0.414 U/kg) and insulin glargine (0.416 U/kg) (p = 0.4341). In multivariate regression analyses, age and BMI had a significant influence on daily insulin dose with the dose increasing 0.003 U/kg (p = 0.0375) and 0.008 U/kg (p = 0.0003) with every 1 increment in age and BMI, respectively. CONCLUSIONS: Dose similarities between insulin detemir and insulin glargine were seen in type 2 diabetes patients when administered once daily. Thus, the use of insulin detemir and insulin glargine is not associated with different medical costs if the price and treating algorithm are similar.

Mutation analysis of the candidate genes SCN1B-4B, FHL1, and LMNA in patients with arrhythmogenic right ventricular cardiomyopathy.

INTRODUCTION: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart disease characterized by fibrofatty infiltrations in the myocardium, right and/or left ventricular involvement, and ventricular tachyarrhythmias. Although ten genes have been associated with ARVC, only about 40% of the patients have an identifiable disease-causing mutation. In the present study we aimed at investigating the involvement of the genes SCN1B-SCN4B, FHL1, and LMNA in the pathogenesis of ARVC. METHODS: Sixty-five unrelated patients (55 fulfilling ARVC criteria and 10 borderline cases) were screened for variants in SCN1B-4B, FHL1, and LMNA by direct sequencing and LightScanner melting curve analysis. RESULTS: A total of 28 sequence variants were identified: seven in SCN1B, three in SCN2B, two in SCN3B, two in SCN4B, four in FHL1, and ten in LMNA. Three of the variants were novel. One of the variants was non-synonymous. No disease-causing mutations were identified. CONCLUSIONS: In our limited sized cohort the six studied candidate genes were not associated with ARVC.

[Short QT syndrome as an inherited condition]. / Kort QT-syndrom som arvelig sygdom.

Inherited ion-channel disorders can lead to life-threatening cardiac arrhythmias. A recent, rare entity has been discovered and termed short QT syndrome due to its electrocardiac features in conjunction with atrial and ventricular tachyarrhythmias as well as syncope and sudden cardiac death. The basis of the new syndrome is genetic and this review covers the genes responsible for the condition as well as the pathophysiology and diagnostic challenges involved in the syndrome. Furthermore, treatment for this new arrhythmic syndrome is reviewed.

[Another genetic cause of sudden cardiac death]. / Endnu en genetisk årsag til pludselig uventet hjertedød.

Mutations in the Lamin A/C gene (LMNA) are a new part of the spectrum of genes responsible for sudden cardiac death (SCD). Relatives of SCD-cases should receive counselling, clinical assessment and perhaps molecular screening. The consequence of being an LMNA mutation carrier is discussed with regard to counselling and prophylactic measures. Device therapy may be relevant in LMNA-mutation carriers, although the proper time for implantation is uncertain. However, we recommend LMNA genetic screening in SCD cases with dilated cardiomyopathy as well as cases with unexplained SCD.

Heart failure etiology impacts survival of patients with heart failure.

BACKGROUND: The impact of heart failure (HF) etiology on prognosis of HF is not well known. METHODS: 3078 patients (median age 75 years, 61% male) hospitalized with HF were studied. Patients were classified into six etiology groups: hypertension (HTN, 13.9%), ischemic heart disease (IHD, 42.4%), valvular disease (VHD, 9.5%), dilated cardiomyopathy (DCM, 7.9%), other (11.5%), and unknown etiology (14.8%). Patients with normal left ventricular ejection fraction (LVEF) were also included. Follow-up was up to 5 years. RESULTS: In multivariable analysis, with HTN as the reference, VHD showed the highest risk, HR 1.71 (CI: 1.3-2.2, p<0.0001), followed by DCM, HR 1.66 (CI: 1.2-2.3, p=0.002), IHD, HR 1.4 (CI: 1.1-1.7, p=0.001), and unknown etiology, HR 1.4 (CI: 1.1-1.7, p=0.007). For HF of IHD mortality risk was greater for patients with LVEF<30% (HR 2.1, CI: 1.7-2.7, p<0.0001) than for patients with LVEF ≥ 30% (HR 1.3, CI: 1.0-1.5, p=0.03), compared to the reference (p-value for interaction<0.001). CONCLUSION: HF due to VHD, DCM and IHD carry a worse prognosis than that of HTN. For the IHD the risk increases progressively with lower values of LVEF.

Long-term prognostic importance of resting heart rate in patients with left ventricular dysfunction in connection with either heart failure or myocardial infarction: the DIAMOND study.

BACKGROUND: Elevated resting heart rate is associated with increased mortality in a variety of cardiac diseases, but comparisons between different clinical settings are lacking. We investigated the long-term prognostic importance of resting heart rate in patients hospitalized with left ventricular dysfunction in connection with either heart failure (HF) or myocardial infarction (MI). METHODS: In the Danish Investigations and Arrhythmia ON Dofetilide (DIAMOND) study; patients with left ventricular dysfunction were randomized to Dofetilide (class III antiarrhythmic drug) or placebo. One part of the study enrolled 1518 patients with HF and another 1510 patients with MI. Mortality analyses were performed using multivariable adjusted Cox proportional hazard models. RESULTS: During 10 years of follow-up, 1076 (72%) patients with MI and 1336 (89%) patients with HF died. In multivariable adjusted models, every increment in baseline heart rate of 10 bpm was associated with an increase in mortality in both MI-patients (hazard ratio, 1.14; 95%-confidence interval (CI): 1.09-1.19; P<.0001) and HF-patients (hazard ratio, 1.10; CI: 1.06-1.15; P<.0001). The importance of resting heart rate on short-term prognosis was stronger in the MI patients compared to the HF patients (P<.0001 for interaction). There was no interaction between heart rate and beta-blockade, and inclusion of beta-blockade in the model did not change the results. CONCLUSIONS: Resting heart rate was independently associated with increased risk of overall mortality. The prognostic importance of resting heart rate is stronger in patients with MI compared to patients with HF, especially in the short term.

The role of sarcomere gene mutations in patients with idiopathic dilated cardiomyopathy.

We investigated a Danish cohort of 31 unrelated patients with idiopathic dilated cardiomyopathy (IDC), to assess the role that mutations in sarcomere protein genes play in IDC. Patients were genetically screened by capillary electrophoresis single strand conformation polymorphism and subsequently by bidirectional DNA sequencing of conformers in the coding regions of MYH7, MYBPC3, TPM1, ACTC, MYL2, MYL3, TNNT2, CSRP3 and TNNI3. Eight probands carried disease-associated genetic variants (26%). In MYH7, three novel mutations were found; in MYBPC3, one novel variant and two known mutations were found; and in TNNT2, a known mutation was found. One proband was double heterozygous. We find evidence of phenotypic plasticity: three mutations described earlier as HCM causing were found in four cases of IDC, with no history of a hypertrophic phase. Furthermore, one pedigree presented with several cases of classic DCM as well as one case with left ventricular non-compaction. Disease-causing sarcomere gene mutations were found in about one-quarter of IDC patients, and seem to play an important role in the causation of the disease. The genetics is as complex as seen in HCM. Thus, our data suggest that a genetic work-up should include screening of the most prominent sarcomere genes even in the absence of a family history of the disease.

Differential prognostic importance of QRS duration in heart failure and acute myocardial infarction associated with left ventricular dysfunction.

BACKGROUND/AIMS: Studies of the prognostic importance of QRS duration in patients with heart failure (HF) have shown conflicting results and few studies have estimated the importance after myocardial infarction (MI). METHODS: The Danish Investigations and Arrhythmia ON Dofetilide (DIAMOND) study randomised 3028 patients to dofetilide (class III antiarrhythmic) or placebo. The study consisted of two almost identical trials conducted simultaneously. One trial included 1518 patients with chronic HF and the other trial 1510 patients with a recent MI. All patients had left ventricular dysfunction. Dofetilide did not influence mortality in either trial. QRS duration was systematically measured at randomisation and was available in 2972 patients. RESULTS: Over a 10 year observation period 1037 (70%) patients in the MI study and 1324 (87%) in the HF study died. In the MI study, risk of death increased 6% for each 10 ms increase in QRS duration (HR=1.06/10 ms increase in QRS (CI=1.04-1.09), p<0.0001) whereas QRS duration had no influence in the HF study after multivariable adjustment. The difference between HF and MI was significant (p<0.0004 for interaction). CONCLUSION: QRS duration predicts death in patients with left ventricular dysfunction who have suffered MI. In patients with HF QRS duration is not predictive of mortality.