Aims
In heart failure with reduced ejection fraction (HFrEF), there is an ‘obesity paradox’, where survival is better in patients with a higher body mass index (BMI) and weight loss is associated ...with worse outcomes. We examined the effect of a sodium–glucose co‐transporter 2 inhibitor according to baseline BMI in the Dapagliflozin And Prevention of Adverse‐outcomes in Heart Failure trial (DAPA‐HF).
Methods and results
Body mass index was examined using standard categories, i.e. underweight (<18.5 kg/m2); normal weight (18.5–24.9 kg/m2); overweight (25.0–29.9 kg/m2); obesity class I (30.0–34.9 kg/m2); obesity class II (35.0–39.9 kg/m2); and obesity class III (≥40 kg/m2). The primary outcome in DAPA‐HF was the composite of worsening heart failure or cardiovascular death. Overall, 1348 patients (28.4%) were under/normal‐weight, 1722 (36.3%) overweight, 1013 (21.4%) obesity class I and 659 (13.9%) obesity class II/III. The unadjusted hazard ratio (95% confidence interval) for the primary outcome with obesity class 1, the lowest risk group, as reference was: under/normal‐weight 1.41 (1.16–1.71), overweight 1.18 (0.97–1.42), obesity class II/III 1.37 (1.10–1.72). Patients with class I obesity were also at lowest risk of death. The effect of dapagliflozin on the primary outcome and other outcomes did not vary by baseline BMI, e.g. hazard ratio for primary outcome: under/normal‐weight 0.74 (0.58–0.94), overweight 0.81 (0.65–1.02), obesity class I 0.68 (0.50–0.92), obesity class II/III 0.71 (0.51–1.00) (P‐value for interaction = 0.79). The mean decrease in weight at 8 months with dapagliflozin was 0.9 (0.7–1.1) kg (P < 0.001).
Conclusion
We confirmed an ‘obesity survival paradox’ in HFrEF. We showed that dapagliflozin was beneficial across the wide range of BMI studied.
Clinical Trial Registration: ClinicalTrials.gov NCT03036124.
Key findings from the analyses of body mass index in the DAPA‐HF trial. BMI, body mass index; HFrEF, heart failure with reduced ejection fraction.
Kidney transplantation is the treatment of choice for end-stage kidney diseases. Unfortunately, kidney allograft recipients rarely develop tolerance or accommodation and require life-long ...immunosuppression. Among many other regulatory mechanisms, CD5+ B lymphocytes (mainly B-1a) seem to be involved in the process of allograft acceptance. These cells are the major source of natural, low-affinity antibodies, which are polyreactive. Thus, we hypothesized that CD5+ B cells could be referred to as a biomarker in those patients who developed accommodation towards kidney allotransplant. In this study, 52 low-immunized kidney transplant recipients were evaluated for transplant outcome up to 8 y post-transplant. The follow up included anti-HLA antibodies, B cells phenotype and cytokines. We have identified a cohort of recipients who produced alloantibodies (Abs+), which was associated with increased levels of CD5+ B cells, mainly during the first year after transplantation but also later on. Importantly, creatinine levels were comparable between Abs+ and Abs− allorecipients at 2 years after the transplantation and graft survival rate was comparable between these groups even eight years post-transplant. So, it seems that despite the presence of alloantibodies the graft function was sustained when the level of CD5+ B cells was increased. Targeting CD5+ B cells may be a valuable therapeutic option to increase transplant success. The phenotype can be also tried as a biomarker to increase the effectiveness of individualized post-transplant treatments.
ABSTRACT
Aims
Reflecting both increased venous pressure and reduced cardiac output, abnormal liver tests are common in patients with severe heart failure and are associated with adverse clinical ...outcomes. We aimed to investigate the prognostic significance of abnormal liver tests in ambulatory patients with heart failure with reduced ejection fraction (HFrEF), explore any treatment interaction between bilirubin and sodium–glucose cotransporter 2 (SGLT2) inhibitors and examine change in liver tests with SGLT2 inhibitor treatment.
Methods and results
We explored these objectives in the Dapagliflozin And Prevention of Adverse outcomes in Heart Failure (DAPA‐HF) trial, with focus on bilirubin. We calculated the incidence of cardiovascular death or worsening heart failure by bilirubin tertile. Secondary cardiovascular outcomes were examined, along with the change in liver tests at the end‐of‐study visit. Baseline bilirubin was available in 4720 patients (99.5%). Participants in the highest bilirubin tertile (T3) have more severe HFrEF (lower left ventricular ejection fraction, higher N‐terminal pro‐B‐type natriuretic peptide NT‐proBNP and worse New York Heart Association class), had a greater burden of atrial fibrillation but less diabetes. Higher bilirubin (T3 vs. T1) was associated with worse outcomes even after adjustment for other predictive variables, including NT‐proBNP and troponin T (adjusted hazard ratio for the primary outcome 1.73 95% confidence interval 1.37–2.17, p < 0.001; and 1.52 1.12–2.07, p = 0.01 for cardiovascular death). Baseline bilirubin did not modify the benefits of dapagliflozin. During follow‐up, dapagliflozin had no effect on liver tests.
Conclusion
Bilirubin concentration was an independent predictor of worse outcomes but did not modify the benefits of dapagliflozin in HFrEF. Dapagliflozin was not associated with change in liver tests.
Clinical Trial Registration: ClinicalTrials.gov NCT03036124.
Summary of key findings in analysis of liver tests in DAPA‐HF. Using restricted cubic splines to model risk of the primary outcome by baseline bilirubin level as a continuous variable shows an essentially linear relationship, with higher bilirubin associated with increased risk. Forest plot for each outcome demonstrates the benefit of dapagliflozin is not modified by baseline bilirubin tertile. Bilirubin adds incremental information about risk of the primary outcome after adjustment for known prognostic markers (high‐sensitivity troponin T hs‐TnT and N‐terminal pro‐B‐type natriuretic peptide NT‐proBNP). CI, confidence interval; HR, hazard ratio.
The lack of a uniform method for determining unacceptable HLA mismatches (UAMs) for organ transplantation worldwide has resulted in many different algorithms for donor-recipient matching. Here we ...present our proposal for changes to the current algorithm for immune evaluation of potential kidney recipients in Poland based on the experience of various transplantation centers. The most important finding of this article is an algorithm that stratifies the pretransplant immunologic risk based on strict laboratory criteria, enabling harmonization between transplant centers in Poland. This is because of a step-by-step algorithm for alloantibody assessment using solid-phase assays (SPA) and clearly defined technical issues, as well as cutoffs for reporting UAMs. Our novel approach focuses on a laboratory testing extension in the scope of HLA typing; detection and characterization of alloantibodies before transplantation; desensitization; and post-transplant monitoring. The proposed changes will allow for the assessment of clinically relevant anti-HLA antibodies with complement binding properties; the determination of UAMs in the potential donor; the calculation of virtual panel reactive antibodies (vPRA); the calculation of the recipient’s immunologic rejection risk stratification; the assessment of the donor-recipient virtual cross-match (vXM); and the determination of the final recipient’s selection for the biological cross-match testing. Collectively, the optimized algorithm permit for UAM verification is based on laboratory proofed data and will firmly improve organ allocation and transplant outcomes in Poland. We hope that this novel approach also improves the individual patient’s risk stratification and future personalized treatment.
•Current immune algorithm for organ transplantation in Poland needs improvement.•The virtual crossmatch based on a single antigen test leads to the accumulation of sensitized recipients on the kidney transplant list.•The new approach for sensitized recipients transplantation should be set up on an extended HLA matching and virtual crossmatch based on a C1q assessment.•The improved algorithm enables for unacceptable mismatches verification and boosts organ transplantation in Poland.
ObjectiveHere we looked for possible mechanisms regulating the progression of type 1 diabetes mellitus (T1DM). In this disease, autoaggressive T cells (T conventional cells, Tconvs) not properly ...controlled by T regulatory cells (Tregs) destroy pancreatic islets.Research design and methodsWe compared the T-cell compartment of patients with newly diagnosed T1DM (NDT1DM) with long-duration T1DM (LDT1DM) ones. The third group consisted of patients with LDT1DM treated previously with polyclonal Tregs (LDT1DM with Tregs). We have also looked if the differences might be dependent on the antigen specificity of Tregs expanded for clinical use and autologous sentinel Tconvs.ResultsPatients with LDT1DM were characterized by T-cell immunosenescence-like changes and expansion of similar vβ/T-cell receptor (TCR) clones in Tconvs and Tregs. The treatment with Tregs was associated with some inhibition of these effects. Patients with LDT1DM possessed an increased percentage of various proinsulin-specific T cells but not GAD65-specific ones. The percentages of all antigen-specific subsets were higher in the expansion cultures than in the peripheral blood. The proliferation was more intense in proinsulin-specific Tconvs than in specific Tregs but the levels of some proinsulin-specific Tregs were exceptionally high at baseline and remained higher in the expanded clinical product than the levels of respective Tconvs in sentinel cultures.ConclusionsT1DM is associated with immunosenescence-like changes and reduced diversity of T-cell clones. Preferential expansion of the same TCR families in both Tconvs and Tregs suggests a common trigger/autoantigen responsible. Interestingly, the therapy with polyclonal Tregs was associated with some inhibition of these effects. Proinsulin-specific Tregs appeared to be dominant in the immune responses in patients with T1DM and probably associated with better control over respective autoimmune Tconvs.Trial registration numberEudraCT 2014-004319-35.
In DAPA-HF, the SGLT2 inhibitor (i) dapagliflozin (dapa) reduced worsening heart failure (HF) and cardiovascular death in 4744 patients (pts) with HF and reduced ejection fraction (HFrEF.) Only 45% ...had type 2 diabetes (T2D) at baseline. We evaluated whether dapa reduced the incidence of diabetes in the 55% of pts without T2D. Pts were randomized to dapa 10 mg or placebo and followed for a median of 18.2 months. New-onset T2D was defined as A1c ≥6.5% measured at 2 consecutive study visits post-randomization or investigator-reported new T2D (with the initiation of a glucose-lowering agent.) The effect of dapa on incident T2D was assessed using a Cox proportional hazards model and confirmed with a Fine and Gray competing risk model to account for mortality. Of the 2605 non-T2D pts at baseline, 157 developed T2D on trial, 150 (95.5%) of whom had prediabetes (A1c 5.7-6.4%) (136 86.6% using the more restrictive 6.0-6.4% criterion.) Those with incident T2D had a higher mean baseline A1c (6.2 ±0.3 vs. 5.7 ±0.4%; p<0.001), greater BMI (28.5 ±5.9 vs. 27.1 ±5.7 kg/m2; p=0.003), and lower eGFR (61.5 ±17.4 vs. 68.2 ±19.3 ml/min/1.73 m2; p<0.001) than those who remained nondiabetic. Dapa reduced new-onset diabetes by 32%: placebo 93/1307 (7.1%) vs. dapa 64/1298 (4.9%); HR 0.68 (95% CI, 0.50-0.94; p=0.019) (Cox.) Results were virtually identical using the Fine and Gray model. Diabetes prevention may be another benefit of dapagliflozin.
Disclosure
S.E. Inzucchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; Abbott, Merck & Co., Inc., vTv Therapeutics. K. Docherty: Speaker’s Bureau; Self; Eli Lilly and Company. Other Relationship; Self; AstraZeneca. L. Kober: Speaker’s Bureau; Self; AstraZeneca, Novartis AG. Other Relationship; Self; AstraZeneca. M.N. Kosiborod: Consultant; Self; Amarin Corporation, Amgen, Applied Therapeutics, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., Eli Lilly and Company, GlaxoSmithKline plc., Glytec, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi US, Vifor Pharma Group. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. F. Martinez: Board Member; Self; AstraZeneca, Novartis Pharmaceuticals Corporation. P. Ponikowski: None. M.S. Sabatine: Consultant; Self; Amgen, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, DalCor Pharmaceuticals, Dyrnamix Inc., Esperion Therapeutics, Inc., IFM Therapeutics, Intarcia Therapeutics, Ionis Pharmaceuticals, Inc., Medicines Company, MedImmune, Merck & Co., Inc. Research Support; Self; Amgen, AstraZeneca, Bayer U.S., Daiichi Sankyo, Eisai Inc., Intarcia Therapeutics, Janssen Research and Development, Medicines Company, MedImmune, Merck & Co., Inc., Novartis AG, Pfizer Inc., Quark Pharmaceuticals. S. Solomon: Consultant; Self; AstraZeneca, Theracos, Inc. Research Support; Self; AstraZeneca, Theracos, Inc. J. Belohlavek: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH. M. Böhm: Speaker’s Bureau; Self; Abbott, Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb, Medtronic, Novartis Pharmaceuticals Corporation, Servier, Vifor Pharma Group. C. Chiang: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Merck Sharp & Dohme Corp., Novartis AG, Pfizer Inc., Sanofi. R.A. de Boer: Speaker’s Bureau; Self; Abbott, AstraZeneca, Novartis AG, Roche Diagnostics France. M. Diez: Other Relationship; Self; AstraZeneca. A. Dukat: None. C.E.A. Ljungman: Advisory Panel; Self; AstraZeneca, Novartis AG, Pfizer Foundation. Stock/Shareholder; Self; AstraZeneca. Other Relationship; Self; AstraZeneca, Novartis AG. S. Verma: Advisory Panel; Self; Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Other Relationship; Self; AstraZeneca, AstraZeneca, Bayer AG, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Eli Lilly and Company, EOCI Pharmacomm, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Canada Inc., Novo Nordisk A/S, Novo Nordisk A/S, Sanofi, Sanofi, Sun Pharmaceuticals, Toronto Knowledge Translation Working Group. D.L. DeMets: Consultant; Self; Actelion Pharmaceuticals US, Inc., AstraZeneca, Boston Scientific, Bristol-Myers Squibb, DalCor Pharmaceuticals, Intercept Pharmaceuticals, Inc., Medtronic. O. Bengtsson: Employee; Self; AstraZeneca. A. Langkilde: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. M. Sjöstrand: Employee; Self; AstraZeneca. P. Jhund: Advisory Panel; Self; Cytokinetics Inc. Research Support; Self; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; Novartis AG. Other Relationship; Self; AstraZeneca. J.J. McMurray: Other Relationship; Self; AbbVie Inc., Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Bristol-Myers Squibb, Cardurion, GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, Theracos, Inc.
Funding
AstraZeneca
Insulin-like growth factor–binding protein-7 (IGFBP-7) has been proposed as a potential prognostic biomarker in heart failure (HF), but the association between elevation in IGFBP-7 and HF outcomes in ...ambulant patients with heart failure with reduced ejection fraction (HFrEF) is unknown.
The authors addressed this question in a post hoc analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial.
The primary outcome was a composite of cardiovascular death or a worsening HF event. The risk of adverse outcome was compared across tertiles of IGFBP-7 concentration by means of Cox proportional hazard models adjusted for N-terminal pro–B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT). The efficacy of randomized treatment across IGFBP-7 tertiles was assessed. Change in IGFBP-7 at 12 months was compared with the use of geometric means.
A total of 3,158 patients had IGFBP-7 measured at baseline, and 2,493 had a repeated measure at 12 months. Patients in the highest tertile of IGFBP-7 had evidence of more advanced HFrEF. The adjusted HR for the primary endpoint in tertile 3, compared with tertile 1, was 1.48 (95% CI: 1.17-1.88). There was no modification of the benefit of dapagliflozin by baseline IGFBP-7 (P interaction = 0.34). Dapagliflozin did not change IGFBP-7 levels over 1 year (P = 0.34).
Higher IGFBP-7 in patients with HFrEF was associated with worse clinical profile and an increased risk of adverse clinical outcomes. IGFBP-7 provided prognostic information incremental to clinical variables, NT-proBNP, and hsTnT. The benefit of dapagliflozin was not modulated by IGFBP-7 level. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure DAPA-HF; NCT03036124)
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Insulin-like growth factor-binding protein-7 (IGFBP-7) has been proposed as a potential prognostic biomarker in heart failure (HF), but the association between elevation in IGFBP-7 and HF outcomes in ...ambulant patients with heart failure with reduced ejection fraction (HFrEF) is unknown.
The authors addressed this question in a post hoc analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial.
The primary outcome was a composite of cardiovascular death or a worsening HF event. The risk of adverse outcome was compared across tertiles of IGFBP-7 concentration by means of Cox proportional hazard models adjusted for N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT). The efficacy of randomized treatment across IGFBP-7 tertiles was assessed. Change in IGFBP-7 at 12 months was compared with the use of geometric means.
A total of 3,158 patients had IGFBP-7 measured at baseline, and 2,493 had a repeated measure at 12 months. Patients in the highest tertile of IGFBP-7 had evidence of more advanced HFrEF. The adjusted HR for the primary endpoint in tertile 3, compared with tertile 1, was 1.48 (95% CI: 1.17-1.88). There was no modification of the benefit of dapagliflozin by baseline IGFBP-7 (P interaction = 0.34). Dapagliflozin did not change IGFBP-7 levels over 1 year (P = 0.34).
Higher IGFBP-7 in patients with HFrEF was associated with worse clinical profile and an increased risk of adverse clinical outcomes. IGFBP-7 provided prognostic information incremental to clinical variables, NT-proBNP, and hsTnT. The benefit of dapagliflozin was not modulated by IGFBP-7 level. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure DAPA-HF; NCT03036124).
A significant body of evidence suggests that treatment with naturally occurring CD4
+
CD25
+
T regulatory cells (Tregs) is an appropriate therapy for graft-versus-host disease (GvHD). GvHD is a major ...complication of bone marrow transplantation in which the transplanted immune system recognizes recipient tissues as a non-self and destroys them. In many cases, this condition significantly deteriorates the quality of life of the affected patients. It is also one of the most important causes of death after bone marrow transplantation. Tregs constitute a population responsible for dominant tolerance to self-tissues in the immune system. These cells prevent autoimmune and allergic reactions and decrease the risk of rejection of allotransplants. For these reasons, Tregs are considered as a cellular drug in GvHD. The results of the first clinical trials with these cells are already available. In this review we present important experimental facts which led to the clinical use of Tregs. We then critically evaluate specific requirements for Treg therapy in GvHD and therapies with Tregs currently under clinical investigation, including our experience and future perspectives on this kind of cellular treatment.
Abstract Pretransplant identification of allosensitized patients is possible thanks to new technologies, which allow for accurate detection of clinically relevant alloantibodies. Implementation of ...these methods in the screening of patients awaiting transplantation increased their chance for successful donor–recipient matching. Here, 1460 patients reported to the Polish National Waiting List were screened with the Luminex Screen (LS) solid phase test for anti-HLA antibodies. The patients with detected anti-HLA antibodies were assayed with the Luminex Single Antigen (LSA) tests in order to establish defined antigen specificity of the alloantibodies. The results were compared with data on the immunization assessed with the routine complement-dependent-cytotoxicity panel-reactive-antibody assay (PRA CDC). The study showed significantly higher sensitivity of the LS method when compared with PRA CDC. It has been shown that LSA test is a useful technique identifying the specificities of alloantibodies. In particular, LSA allowed to assess donor specific antibodies (DSA) to previous mismatches (MM) and to determine acceptable HLA mismatches of the potential donors. The introduction of solid phase tests in routine pretransplant diagnostics allowed for faster and more accurate assessment of the immunological risk of the recipients and optimal donor–recipient matching. Hence, the presented algorithm of solid phase assays has become a new standard for the identification of allosensitized patients awaiting kidney transplantation in Poland.
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