Showing papers by "Silvio E. Inzucchi published in 2023"

Association of Dapagliflozin Use With Clinical Outcomes and the Introduction of Uric Acid–Lowering Therapy and Colchicine in Patients With Heart Failure With and Without Gout

Abstract: This post hoc analysis of 2 randomized clinical trials analyzes data for patients with heart failure and with and without gout to gauge the effects of dapagliflozin on the risk of clinical outcomes and the new use of uric acid–lowering agents and colchicine.

Heart failure, peripheral artery disease, and dapagliflozin: a patient-level meta-analysis of DAPA-HF and DELIVER

Abstract: Abstract Aims Because an increased risk of amputation with canagliflozin was reported in the CANVAS trials, there has been a concern about the safety of sodium–glucose cotransporter 2 inhibitors in patients with peripheral artery disease (PAD) who are at higher risk of amputation. Methods and results A patient-level pooled analysis of the DAPA-HF and DELIVER trials, which evaluated the efficacy and safety of dapagliflozin in patients with heart failure (HF) with reduced, mildly reduced/preserved ejection fraction, respectively, was conducted. In both trials, the primary outcome was the composite of worsening HF or cardiovascular death, and amputation was a prespecified safety outcome. Peripheral artery disease history was available for 11 005 of the total 11 007 patients. Peripheral artery disease was reported in 809 of the 11 005 patients (7.4%). Median follow-up was 22 months (interquartile range 17–30). The rate of the primary outcome (per 100 person-years) was higher in PAD patients than that in non-PAD patients: 15.1 [95% confidence interval (CI) 13.1–17.3) vs. 10.6 (10.2–11.1]; adjusted hazard ratio 1.23 (95% CI 1.06–1.43). The benefit of dapagliflozin on the primary outcome was consistent in patients with [hazard ratio 0.71 (95% CI 0.54–0.94)] and without PAD [0.80 (95% CI 0.73–0.88)] (Pinteraction = 0.39). Amputations, while more frequent in PAD patients, were not more common with dapagliflozin, compared with placebo, irrespective of PAD status (PAD, placebo 4.2% vs. dapagliflozin 3.7%; no PAD, placebo 0.4% vs. dapagliflozin 0.4%) (Pinteraction = 1.00). Infection rather than ischaemia was the main trigger for amputation, even in patients with PAD. Conclusion The risk of worsening HF or cardiovascular death was higher in patients with PAD, as was the risk of amputation. The benefits of dapagliflozin were consistent in patients with and without PAD, and dapagliflozin did not increase the risk of amputation.

Dapagliflozin and Physical and Social Activity Limitations in Heart Failure With Reduced Ejection Fraction.

Abstract: Heart failure (HF) is associated with impaired physical function and poor quality of life and affects health status more profoundly than many other chronic diseases.The authors examined the effects of dapagliflozin on specific physical and social limitations as reported by patients in the DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) trial.The effect of dapagliflozin on the change from baseline to 8 months in each of the individual physical and social activity limitation questions answered by patients completing the Kansas City Cardiomyopathy Questionnaire (KCCQ), and overall scores, were examined with mixed-effects models and responder analyses.In total, 4,269 (90.0%) and 3,955 (83.4%) patients had complete data for both the physical and social activity limitation scores at baseline and 8 months, respectively. Compared with placebo, dapagliflozin significantly increased (improved) the mean KCCQ physical and social activity limitation scores at 8 months (placebo-corrected mean difference 1.94 [95% CI: 0.73-3.16] and 1.84 [95% CI: 0.43-3.25], respectively). Dapagliflozin also increased each of the individual components that comprise the physical and social activity limitations domains at 8 months, with the largest improvement seen in "hobbies or recreational activities" (placebo-corrected mean difference: 2.76 [95% CI: 1.06-4.46]) and "doing yardwork, housework, or carrying groceries" (placebo-corrected mean difference: 2.59 [95% CI: 0.76-4.42]). The proportion of patients with a 5-point improvement from baseline to 8 months in the KCCQ physical and social activity limitation scores was greater with dapagliflozin than with placebo (ORs: 1.23 [95% CI: 1.09-1.40] and 1.19 [95% CI: 1.05-1.35], respectively).In patients with HFrEF, dapagliflozin, compared with placebo, improved physical and social activity limitations as measured by KCCQ. (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).

Persistence on Novel Cardioprotective Antihyperglycemic Therapies in the United States.

Abstract: Selected glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have cardioprotective effects in patients with type 2 diabetes mellitus (T2D) and elevated cardiovascular risk. Prescription and consistent use of these medications are essential to realizing their benefits. In a nationwide deidentified United States administrative claims database of adults with T2D, the prescription practices of GLP-1RAs and SGLT-2i were evaluated across guideline-directed co-morbidity indications from 2018 to 2020. The monthly fill rates were assessed for 12 months after the initiation of therapy by calculating the proportion of days with consistent medication use. Of 587,657 subjects with T2D, 80,196 (13.6%) were prescribed GLP-1RAs and 68,149 (11.5%) SGLT-2i from 2018 to 2020, representing 12.9% and 11.6% of patients with indications for each medication, respectively. In new initiators, 1-year fill rate was 52.5% for GLP-1RAs and 52.9% for SGLT-2i, which was higher for patients with commercial insurance than those with Medicare Advantage plans for both GLP-1RAs (59.3% vs 51.0%, p <0.001) and SGLT-2i (63.4% vs 50.3%, p <0.001). After adjusting for co-morbidities, there were higher rates of prescription fills for patients with commercial insurance (odds ratio 1.17, 95% confidence interval 1.06 to 1.29 for GLP-1RAs, and 1.59 [1.42 to 1.77] for SGLT-2i); and higher income (odds ratio 1.09 [1.06 to 1.12] for GLP-1RAs, and 1.06 [1.03 to 1.1] for SGLT-2i). From 2018 to 2020, the use of GLP-1RAs and SGLT-2i remained limited to fewer than 1 in 8 patients with T2D and indications, with 1-year fill rates around 50%. The low and inconsistent use of these medications compromises their longitudinal health outcome benefits in a period of expanding indications for their use.

Patient Characteristics, Outcomes, and Effects of Dapagliflozin According to the Duration of Heart Failure: A Prespecified Analysis of the DELIVER Trial

Abstract: Background: How patient characteristics and outcomes vary according to the duration of heart failure (HF) is unknown in individuals with mildly reduced or preserved ejection fraction. We compared these, and the efficacy and safety of dapagliflozin, according to the time from diagnosis of HF in a prespecified analysis of the DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure). Methods: HF duration was categorized as ≤6 months, >6 to 12 months, >1 to 2 years, >2 to 5 years, or >5 years. The primary outcome was the composite of worsening HF or cardiovascular death. The effect of treatment was examined by HF duration category. Results: The number of patients in each category was as follows: 1160 (≤6 months), 842 (>6 to 12 months), 995 (>1 to 2 years), 1569 (>2 to 5 years), and 1692 (>5 years). Patients with longer-duration HF were older and had more comorbidities with worse symptoms. The rate of the primary outcome (per 100 person-years) increased with HF duration: ≤6 months, 7.3 (95% CI, 6.3 to 8.4); >6 to 12 months, 7.1 (6.0 to 8.5); >1 to 2 years, 8.4 (7.2 to 9.7); >2 to 5 years, 8.9 (7.9 to 9.9); and >5 years, 10.6 (9.5 to 11.7). Similar trends were seen for other outcomes. The benefit of dapagliflozin was consistent across HF duration category: the hazard ratio for the primary outcome in the ≤6-month group was 0.67 (95% CI, 0.50 to 0.91); >6 to 12 months, 0.78 (0.55 to 1.12); >1 to 2 years, 0.81 (0.60 to 1.09); >2 to 5 years, 0.97 (0.77 to 1.22); and >5 years, 0.78 (0.64 to 0.96; Pinteraction=0.41). The absolute benefit was greatest in longest-duration HF; the number needed to treat for HF >5 years was 24 versus 32 for ≤6 months. Conclusions: Patients with longer-duration HF were older, had more comorbidities and symptoms, and had higher rates of worsening HF and death. The benefits of dapagliflozin were consistent across HF duration. Even patients with long-standing HF and generally mild symptoms are not stable, and it is not too late for such patients to benefit from a sodium–glucose cotransporter 2 inhibitor. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03619213.

Polysomnographic predictors of incident diabetes and pre-diabetes: an analysis of the DREAM study.

Abstract: STUDY OBJECTIVES We sought to evaluate sleep measures that better predict incident diabetes and pre-diabetes in a large cohort of veterans. METHODS This secondary analysis included 650 patients without baseline diabetes from a multisite observational veterans' cohort. Participants underwent OSA evaluation via laboratory-based polysomnography between 2000-2004 with follow-up through 2012. The primary outcomes were pre-diabetes and diabetes defined by fasting blood glucose, hemoglobin A1c or use of glucose-lowering medication at study initiation. Exposure variables included respiratory event frequency, arousals, and oxygen desaturation. Cox models adjusted for BMI, age, race, sex, change in BMI, and continuous positive airway pressure (CPAP) device utilization. RESULTS The adjusted analysis revealed that time spent with oxygen saturation less than 90 (T90) (HR 1.009, CI 1.001-1.017, p=0.02), respiratory arousals (HR 1.009, CI 1.003-1.015, p=0) and total arousals (HR 1.006 CI 1.001 - 1.011 p = 0.02) were associated with an increased incidence of diabetes. Increases in mean nocturnal oxygen saturation were associated with decreased incidence of diabetes (HR 0.914 CI 0.857-0.975, P<0.01 and pre-diabetes (HR 0.914 CI 0.857-0.975, P<0.01). No significant relationships were demonstrated for AHI, measures related to central apnea, Cheyenne Stokes respiration, periodic limb movements, or Epworth Sleepiness Scale score. CONCLUSIONS There was no significant association of incident pre-diabetes or diabetes with AHI, the gold standard of sleep apnea severity. This study suggests that hypoxia may be a better predictor of glycemic outcomes than AHI in an OSA population and may provide clues to the underlying mechanism(s) that link sleep-disordered breathing and its metabolic consequences.

Renal and Blood Pressure Effects of Dapagliflozin in Recently Hospitalized Patients with Heart Failure with Mildly Reduced or Preserved Ejection Fraction: Insights from the DELIVER Trial.

Abstract: BACKGROUND Patients recently hospitalized for heart failure (HF) often have unstable hemodynamics and experience worsening renal failure, and are at elevated risk for recurrent HF events. In DELIVER, dapagliflozin reduced HF events or cardiovascular death including among patients who were hospitalized or recently hospitalized. METHODS We examined the effects of dapagliflozin vs. placebo on eGFR slope (acute and chronic), 1 month change in systolic blood pressure (SBP), and the occurrence of serious hypovolemic or renal adverse events in patients with and without HF hospitalization within 30 days of randomization. RESULTS The 654 (90 randomized during hospitalization, 147 1-7 days post-discharge and 417 8-30 days post-discharge) recently hospitalized patients had lower baseline eGFR compared with those without recent HF hospitalization median[IQR] of 55 [43,71] vs 60 [47,75] ml/min/1.73m2 ). Dapagliflozin consistently reduced the risk of all-cause (Pinteraction =0.20), cardiac-related (Pinteraction =0.75), and HF-specific (Pinteraction =0.90) hospitalizations, irrespective of recent HF hospitalization. In those recently hospitalized, acute placebo-corrected eGFR reductions with dapagliflozin were modest and similar to patients without recent hospitalization (-2.0 [-4.1,+0.1] vs. -3.4 [-3.9,-2.9] ml/min/1.73m2 , Pinteraction =0.12). Dapagliflozin's effect to slow chronic eGFR decline was similar regardless of recent hospitalization (Pinteraction =0.57). Dapagliflozin had a minimal effect on 1-month SBP and to a similar degree in patients with and without recent hospitalization (-1.3 vs.-1.8 mmHg, Pinteraction =0.64). There was no treatment-related excess in renal or hypovolemic serious AE, irrespective of recent HF hospitalization. CONCLUSION In patients recently hospitalized with HF, initiation of dapagliflozin had minimal effects on BP and did not increase renal or hypovolemic serious AEs, yet afforded long-term cardiovascular and kidney protective effects. These data suggest that the benefit to risk ratio favours initiation of dapagliflozin among stabilized patients hospitalized or recently hospitalized for HF. This article is protected by copyright. All rights reserved.

Association of Dapagliflozin vs Placebo With Individual Kansas City Cardiomyopathy Questionnaire Components in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction

Abstract: Key Points Question What is the association between improvement in individual components of the Kansas City Cardiomyopathy Questionnaire (KCCQ) and treatment with dapagliflozin vs placebo in patients with heart failure with mildly reduced or preserved ejection fraction? Findings In this post hoc exploratory analysis of the DELIVER trial, treatment with dapagliflozin was associated with improvements in almost all individual KCCQ components, with the greatest benefits in domains related to symptom frequency and physical limitations emerging as early as 1 month after treatment initiation. Meaning The findings suggest that dapagliflozin is associated with rapid improvement in a broad range of symptoms, function, and quality of life in patients with heart failure with mildly reduced or preserved ejection fraction.

Cardio-Renal-Metabolic Overlap, Outcomes, and Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction.

Abstract: Cardio-renal-metabolic (CRM) conditions are individually common among patients with heart failure (HF), but the prevalence and influence of overlapping CRM conditions in this population have not been well-studied.This study aims to evaluate the impact of overlapping CRM conditions on clinical outcomes and treatment effects of dapagliflozin in HF.In this post hoc analysis of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), we evaluated the prevalence of comorbid CRM conditions (atherosclerotic cardiovascular disease, chronic kidney disease, and type 2 diabetes), their impact on the primary outcome (cardiovascular death or worsening HF), and treatment effects of dapagliflozin by CRM status.Among 6,263 participants, 1,952 (31%), 2,245 (36%), and 1,236 (20%) had 1, 2, and 3 additional CRM conditions, respectively. HF alone was uncommon (13%). Greater CRM multimorbidity was associated with older age, higher body mass index, longer-duration HF, worse health status, and lower left ventricular ejection fraction. Risk of the primary outcome increased with higher CRM overlap, with 3 CRM conditions independently associated with highest risk of primary events (adjusted HR: 2.16 [95% CI: 1.72-2.72]; P < 0.001) compared with HF alone. Relative benefits of dapagliflozin on the primary outcome were consistent irrespective of the type of CRM overlap (Pinteraction = 0.773) and by the number of CRM conditions (Pinteraction = 0.734), with greatest absolute benefits among those with highest CRM multimorbidity. Estimated 2-year numbers needed to treat with dapagliflozin to prevent 1 primary event were approximately 52, 39, 33, and 24 for participants with 0, 1, 2, and 3 additional CRM conditions at baseline, respectively. Adverse events between treatment arms were similar across the CRM spectrum.CRM multimorbidity was common and associated with adverse outcomes among patients with HF and left ventricular ejection fraction >40% in DELIVER. Dapagliflozin was safe and effective across the CRM spectrum, with greater absolute benefits among those with highest CRM overlap (Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).

Dapagliflozin Improves Heart Failure Symptoms and Physical Limitations Across the Full Range of Ejection Fraction: Pooled Patient-Level Analysis From DEFINE-HF and PRESERVED-HF Trials

Abstract: BACKGROUND: Patients with heart failure (HF) have a high burden of symptoms and physical limitations, regardless of ejection fraction (EF). Whether the benefits of SGLT2 (sodium-glucose cotransporter-2) inhibitors on these outcomes vary across the full range of EF remains unclear. METHODS: Patient-level data were pooled from the DEFINE-HF trial (Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction) of 263 participants with reduced EF (≤40%), and PRESERVED-HF trial (Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With Preserved Ejection Fraction Heart Failure) of 324 participants with preserved EF (≥45%). Both were randomized, double-blind 12-week trials of dapagliflozin versus placebo, recruiting participants with New York Heart Association class II or higher and elevated natriuretic peptides. The effect of dapagliflozin on the change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at 12 weeks was tested with ANCOVA adjusted for sex, baseline KCCQ, EF, atrial fibrillation, estimated glomerular filtration rate, and type 2 diabetes. Interaction of dapagliflozin effects on KCCQ-CSS by EF was assessed using EF both categorically and continuously with restricted cubic spline. Responder analyses, examining proportions of patients with deterioration, and clinically meaningful improvements in KCCQ-CSS were conducted using logistic regression. RESULTS: Of 587 patients randomized (293 dapagliflozin, 294 placebo), EF was ≤40, >40-≤60, and >60% in 262 (45%), 199 (34%), and 126 (21%), respectively. Dapagliflozin improved KCCQ-CSS at 12 weeks (placebo-adjusted difference 5.0 points [95% CI, 2.6–7.5]; P<0.001). This was consistent in participants with EF≤40 (4.6 points [95% CI, 1.0–8.1]; P=0.01), >40 to ≤60 (4.9 points [95% CI, 0.8–9.0]; P=0.02) and >60% (6.8 points [95% CI, 1.5–12.1]; P=0.01; Pinteraction=0.79). Benefits of dapagliflozin on KCCQ-CSS were also consistent when analyzing EF continuously (Pinteraction=0.94). In responder analyses, fewer dapagliflozin-treated patients had deterioration and more had small, moderate, and large KCCQ-CSS improvements versus placebo; these results were also consistent regardless of EF (all Pinteractionvalues nonsignificant). CONCLUSIONS: In patients with HF, dapagliflozin significantly improves symptoms and physical limitations after 12 weeks of treatment, with consistent and clinically meaningful benefits across the full range of EF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02653482 and NCT03030235.

Effect of Dapagliflozin on Total Heart Failure Events in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction

Abstract: Key Points Question Does dapagliflozin reduce the risk of total episodes of worsening heart failure (HF; defined as hospitalization for HF or urgent HF visit requiring intravenous HF therapies) and cardiovascular death in patients with mildly reduced or preserved ejection fraction heart failure? Findings In this prespecified analysis of the DELIVER trial including 6263 patients, dapagliflozin reduced the risk of total HF events and cardiovascular death by 23%, and this was consistent across a range of subgroups, including across the spectrum of ejection fraction. Meaning In this study, dapagliflozin demonstrated no reduction in efficacy in reducing second or subsequent HF events.

Dapagliflozin and diuretic utilization in heart failure with mildly reduced or preserved ejection fraction: the DELIVER trial.

Abstract: AIMS Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure with mildly reduced or preserved ejection fraction. In this study, the safety and efficacy of dapagliflozin according to background diuretic therapy and the influence of dapagliflozin on longitudinal diuretic use were evaluated. METHODS AND RESULTS In this pre-specified analysis of the Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, the effects of dapagliflozin vs. placebo were assessed in the following subgroups: no diuretic, non-loop diuretic, and loop diuretic furosemide equivalent doses of <40, 40, and >40 mg, respectively. Of the 6263 randomized patients, 683 (10.9%) were on no diuretic, 769 (12.3%) were on a non-loop diuretic, and 4811 (76.8%) were on a loop diuretic at baseline. Treatment benefits of dapagliflozin on the primary composite outcome were consistent by diuretic use categories (Pinteraction = 0.64) or loop diuretic dose (Pinteraction = 0.57). Serious adverse events were similar between dapagliflozin and placebo arms, irrespective of diuretic use or dosing. Dapagliflozin reduced new initiation of loop diuretics by 32% [hazard ratio (HR) 0.68; 95% confidence interval (CI): 0.55-0.84, P < 0.001] but did not influence discontinuations/disruptions (HR 0.98; 95% CI: 0.86-1.13, P = 0.83) in follow-up. First sustained loop diuretic dose increases were less frequent, and sustained dose decreases were more frequent in patients treated with dapagliflozin: net difference of -6.5% (95% CI: -9.4 to -3.6; P < 0.001). The mean dose of loop diuretic increased over time in the placebo arm, a longitudinal increase that was significantly attenuated with treatment with dapagliflozin (placebo-corrected treatment effect of -2.5 mg/year; 95% CI: -1.5, -3.7, P < 0.001). CONCLUSION In patients with heart failure with mildly reduced or preserved ejection fraction, the clinical benefits of dapagliflozin relative to placebo were consistent across a wide range of diuretic categories and doses with a similar safety profile. Treatment with dapagliflozin significantly reduced new loop diuretic requirement over time.

Effects of oral semaglutide on cardiovascular outcomes in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease: Design and baseline characteristics of SOUL, a randomized trial

Abstract: To describe the design of the SOUL trial (Semaglutide cardiOvascular oUtcomes triaL) and the baseline clinical data of its participants.

Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction According to Polypharmacy Status.

Abstract: Patients with heart failure (HF) have a high burden of multimorbidity, often necessitating numerous medications. There may be clinical concern about introducing another medication, especially among individuals with polypharmacy.This study examined the efficacy and safety of addition of dapagliflozin according to the number of concomitant medications in HF with mildly reduced or preserved ejection fraction.In this post hoc analysis of the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, 6,263 participants with symptomatic HF with left ventricular ejection fraction >40% were randomized to dapagliflozin or placebo. Baseline medication use (including vitamins and supplements) was collected. Efficacy and safety outcomes were assessed by medication use categories ("nonpolypharmacy": <5 medications; "polypharmacy": 5 to 9 medications; and "hyperpolypharmacy": ≥10 medications) and continuously. The primary outcome was worsening HF or cardiovascular death.Overall, 3,795 (60.6%) patients met polypharmacy and 1,886 (30.1%) met hyperpolypharmacy criteria. Higher numbers of medications were strongly associated with higher comorbidity burden and increased rates of the primary outcome. Compared with placebo, dapagliflozin similarly reduced the risk of the primary outcome irrespective of polypharmacy status (nonpolypharmacy HR: 0.88 [95% CI: 0.58-1.34]; polypharmacy HR: 0.88 [95% CI: 0.75-1.03]; hyperpolypharmacy HR: 0.73 [95% CI: 0.60-0.88]; Pinteraction = 0.30). Similarly, benefits with dapagliflozin were consistent across the spectrum of total medication use (Pinteraction = 0.06). Although adverse events increased with higher number of medications, they were not more frequent with dapagliflozin, regardless of polypharmacy status.In the DELIVER trial, dapagliflozin safely reduced worsening HF or cardiovascular death across a broad range of baseline medication use, including among individuals with polypharmacy (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).

Effect of Dapagliflozin on Health Status and Quality-of-Life Across the Spectrum of Ejection Fraction: Participant-Level Pooled Analysis from the DAPA-HF & DELIVER Trials.

Abstract: INTRODUCTION Patients with heart failure experience a high burden of symptoms, physical limitations, and poor quality-of-life. Dapagliflozin improves heart failure hospitalization and cardiovascular death in patients with reduced, mildly reduced, and preserved ejection fractions. We examined the effects of dapagliflozin on health status, measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), across the full spectrum of left ventricular ejection fraction (LVEF). METHODS Participant-level data were pooled from the DAPA-HF and DELIVER trials. Both trials were randomized, global, double-blind, placebo-controlled trials of patients with symptomatic HF and elevated natriuretic peptides. DAPA-HF and DELIVER included patients with LVEF≤40% and LVEF>40%, respectively. KCCQ was evaluated at randomization and at 8-months post randomization; the effect of dapagliflozin vs. placebo on KCCQ total symptom score (TSS) was a prespecified secondary outcome in both trials. Interaction testing was performed to assess potential heterogeneity in the effects of dapagliflozin vs. placebo on KCCQ TSS, Clinical Summary Score (CSS), Overall Summary Score (OSS), and Physical Limitations Score (PLS), by continuous LVEF using restricted cubic splines. Responder analyses examining the proportion of patients with meaningful deterioration (≥5 point decline) and meaningful improvements (≥5 point increase) in KCCQ-TSS was assessed across LVEF categories. RESULTS Of 11 007 patients randomized, 10 238 (93%) had full data on KCCQ-TSS at randomization. Benefits of dapagliflozin vs. placebo on KCCQ-TSS, -CSS, -OSS, -PLS, at 8 months were consistent across the full range of LVEF (P for interactions = 0.19, 0.10, 0.12, 0.10 respectively). In responder analyses, fewer dapagliflozin- vs. placebo-treated patients had clinically meaningful deteriorations in KCCQ-TSS (Overall: 21% vs. 23%; LVEF≤40%: 21% vs. 29%; LVEF 41%-60%: 21% vs. 26%; LVEF>60%: 22% vs. 27%). A greater proportion of patients randomized to dapagliflozin experienced meaningful improvements in KCCQ-TSS (Overall: 50% vs. 45%; LVEF≤40%: 48% vs. 41%; LVEF 41%-60%: 51% vs. 49%; LVEF>60%: 53% vs. 45%). The effects of dapagliflozin vs. placebo on clinically meaningful deteriorations and improvements in health status by KCCQ-TSS were consistent across the full spectrum of LVEF assessed continuously (p for interaction: 0.20 and 0.64, respectively). Across the LVEF spectrum, the number-needed-to-treat to affect ≥5 point improvement in health status assessed by KCCQ-TSS was 20. Health status declines preceeding a HF hospitalization by approximately 10 points on average were observed in both trials, evident up to 3 months prior to the event. CONCLUSIONS In participant-level pooled analyses of DAPA-HF and DELIVER, dapagliflozin improved all key domains of health status across the full range of LVEF. Clinically meaningful improvements in health status were also observed consistently across the full range of LVEF, including in those with LVEF above 60%. This article is protected by copyright. All rights reserved.

Baseline Cardiovascular Risk Factor Control in Patients With Type 2 Diabetes and Coronary Disease Versus Stroke: Secondary Analysis of Cardiovascular Outcome Trials

Abstract: BACKGROUND: Patients with type 2 diabetes (T2D) and cardiovascular disease are at increased risk for recurrent ischemic events. Cardiovascular risk factor control is vital for secondary prevention, but how this compares among individuals with different T2D macrovascular complications is unknown. We aimed to determine if there might be differences in risk factor control in patients with T2D with previous stroke versus coronary artery disease (CAD). METHODS: Cross-sectional analyses were performed on 12 856 patients with T2D with prior history of stroke with or without CAD from 3 diabetes cardiovascular outcome trials: CARMELINA (The Cardiovascular and Renal Microvascular Outcome Study With Linagliptin), EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), and CAROLINA (The Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Type 2 Diabetes). Risk factors at baseline assessed included dyslipidemia, hypertension, smoking, and current antiplatelet/anticoagulant therapy. Control, respectively, was defined as LDL (low-density lipoprotein)-C <100 mg/dL or statin use, systolic blood pressure <140 and diastolic blood pressure <90 mm Hg, not currently smoking, and use of an antiplatelet/anticoagulant medication. The odds ratio of 3 to 4 (or good) versus 0 to 2 (or suboptimal) risk factors controlled was analyzed by logistic regression models. RESULTS: The odds for good versus suboptimal risk factor control in patients with CAD alone was higher than in those with stroke alone across all 3 trials odds ratios (95% CI): CARMELINA, 2.05 (1.67–2.51), EMPA-REG OUTCOME, 2.50 (2.10–2.99), and CAROLINA, 1.63 (1.21–2.20). The respective odds ratios were lower (and rendered nonsignificant in CAROLINA) when cardiovascular risk factor control in patients with both CAD and stroke were compared with those with stroke alone: CARMELINA, 1.45 (1.13–1.87); EMPA-REG OUTCOME, 1.62 (1.25–2.08); and CAROLINA, 1.16 (0.74–1.83). CONCLUSIONS: In contemporary populations of patients with T2D, there was significant discordance in control of cardiovascular risk factors between patients with stroke versus CAD, with the former having less optimal control. The intermediate results in patients with both CAD and stroke suggest that these differences could be related at least in part to clinician factors. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01243424, NCT01131676, NCT01897532.

The effects of empagliflozin on measured glomerular filtration rate and estimated extracellular and plasma volumes in patients with type 2 diabetes.

Abstract: AIMS To investigate the effects of empagliflozin on measured glomerular filtration rate (mGFR), estimated plasma volume (PV) and estimated extracellular volume (ECV) in a cohort of patients with type 2 diabetes (T2D) and high risk of cardiovascular events. MATERIALS AND METHODS In this prespecified substudy of the randomized, placebo-controlled SIMPLE trial, patients with T2D at high risk of cardiovascular events were allocated to either empagliflozin 25 mg or placebo once daily for 13 weeks. The prespecified outcome was between-group change in mGFR, measured by the 51 Cr-EDTA method after 13 weeks; changes in estimated PV and estimated ECV were included. RESULTS From April 4, 2017 to May 11, 2020, 91 participants were randomized. Of these, 45 patients from the empagliflozin group and 45 patients from the placebo group were included in the intention-to-treat analysis. Treatment with empagliflozin reduced mGFR by -7.9 mL/min (95% confidence interval [CI] -11.1 to -4.7; P < 0.001), estimated ECV by -192.5 mL (95% CI -318.0 to -66.9; P = 0.003) and estimated PV by -128.9 mL (95% CI -218.0 to 39.8; P = 0.005) at Week 13. CONCLUSIONS Treatment with empagliflozin for 13 weeks reduced mGFR, estimated ECV and estimated PV in patients with T2D and high risk of cardiovascular events.

Effects of Dapagliflozin on Heart Failure Hospitalizations According to Severity of Inpatient Course: Insights from DELIVER and DAPA-HF.

Abstract: AIMS Dapagliflozin resulted in significant and sustained reductions in first and recurrent HF hospitalizations among patients with HF across the spectrum of ejection fraction. How treatment with dapagliflozin differentially impacts hospitalization for HF of varying complexity is not well studied. METHODS AND RESULTS In the DELIVER and DAPA-HF trials, we examined the effects of dapagliflozin on adjudicated HF hospitalizations of varying complexity and hospital length of stay (LOS). HF hospitalizations requiring ICU stay, IV vasoactive therapies, invasive/non-invasive ventilation, mechanical fluid removal or MCS were categorized as complicated. The balance were classified as uncomplicated. Of the total 1209 HF hospitalizations reported in DELIVER, 71% (854) were uncomplicated and 29% (355) were complicated. Of the total 799 HF hospitalizations reported in DAPA-HF, 57% (453) were uncomplicated and 43% (346) were complicated. Relative to patients experiencing a first uncomplicated HF hospitalization, those with complicated HF hospitalizations had a significantly higher in-hospital mortality both in DELIVER (16.8% vs. 2.3%, p < 0.001) and DAPA-HF (15.1% vs. 3.8%, p < 0.001). Dapagliflozin similarly reduced total 'uncomplicated' (DELIVER: RR 0.67, 95% CI: 0.55-0.82 and DAPA-HF: RR 0.69, 95% CI: 0.54-0.87) and 'complicated' HF hospitalizations (DELIVER: 0.82, 95% CI: 0.63-1.06 and DAPA-HF: 0.75, 95% CI: 0.58-0.97). Dapagliflozin consistently reduced hospitalizations irrespective of their LOS: <5 days (DELIVER: RR 0.76; 95% CI: 0.58-0.99 and DAPA-HF: 0.58; 95%: 0.42-0.80) or ≥5 days (DELIVER: RR 0.71; 95% CI: 0.58-0.86 and DAPA-HF: 0.77; 95% CI: 0.62-0.94). CONCLUSION A substantial proportion of hospitalizations (~30%-40%) among patients with HF irrespective of ejection fraction required intensification of treatment beyond standard intravenous diuretics. Such patients experienced significantly higher in-hospital mortality. Treatment with dapagliflozin consistently reduced HF hospitalizations regardless of severity of inpatient treatment course or LOS. This article is protected by copyright. All rights reserved.

Improved extremity tissue oxygenation with short-term exposure to textiles embedded with far infrared light emitting thermoactive particles in patients with diabetes mellitus

Abstract: Use of far infrared (FIR) energy may improve peripheral circulation. This study aimed to determine whether FIR delivered through textiles improves peripheral microcirculation as measured by transcutaneous oximetry (TcPO2) in individuals with diabetes mellitus (DM). Methods A single-center, prospective, randomized, placebo-controlled, double-blinded, crossover study of 32 subjects with either type 1 or type 2 DM. An active FIR wrap followed by a placebo wrap (or vice versa) was applied to the arm, calf, ankle, and forefoot for 60 min each with continuous TcPO2 measurements. The treatment effect of the active versus placebo wrap was estimated using a linear mixed effect model adjusted for period, sequence, baseline value, and anatomic site. Results The active FIR wrap increased mean TcPO2 at the arm (2.6 ± 0.8 mmHg, p = .002), calf (1.5 ± 0.7 mmHg, p = .03), and ankle (1.7 ± 0.8 mmHg, p = .04) and composite of all sites (1.4 ± 0.5 mmHg, p = .002) after 60 min. The estimated treatment effect was significant for the active FIR wrap at the calf (1.5 ± 0.7 mmHg, p = .045) and in composite of all sites (1.2 ± 0.5 mmHg, p = .013). Conclusion Short-term exposure to FIR textiles improves peripheral tissue oxygenation in patients with diabetes.

Primary hypothyroidism presenting as neuropsychiatric symptoms and pituitary enlargement in a young woman: illustrative case.

Abstract: BACKGROUND Pituitary adenomas are the most common cause of pituitary enlargement and can potentially warrant surgical intervention. However, there are physiological causes of pituitary enlargement that can be reversed with hormone replacement alone. OBSERVATIONS A 29-year-old female presented with acute onset paranoia to the psychiatry department. A computed tomography scan of the head revealed a 2.3 cm sellar mass with confirmation on magnetic resonance imaging. Testing showed a markedly elevated thyroid-stimulating hormone 1,600 µIU/mL (0.470-4.200 µIU/mL), suggesting pituitary hyperplasia. Treatment with levothyroxine replacement resulted in marked improvement in symptoms and resolution of pituitary hyperplasia on four month follow up. LESSONS This rare presentation of severe primary hypothyroidism highlights the importance of evaluating for physiological causes of pituitary enlargement.

Comparative Effects of Glucose-Lowering Medications on Kidney Outcomes in Type 2 Diabetes: The GRADE Randomized Clinical Trial.

Abstract: Importance Type 2 diabetes (T2D) is the leading cause of kidney disease in the US. It is not known whether glucose-lowering medications differentially affect kidney function. Objective To evaluate kidney outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) trial comparing 4 classes of glucose-lowering medications added to metformin for glycemic management in individuals with T2D. Design, Setting, and Participants A randomized clinical trial was conducted at 36 sites across the US. Participants included adults with T2D for less than 10 years, a hemoglobin A1c level between 6.8% and 8.5%, and estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m2 who were receiving metformin treatment. A total of 5047 participants were enrolled between July 8, 2013, and August 11, 2017, and followed up for a mean of 5.0 years (range, 0-7.6 years). Data were analyzed from February 21, 2022, to March 27, 2023. Interventions Addition of insulin glargine, glimepiride, liraglutide, or sitagliptin to metformin, with the medication combination continued until the HbA1c was greater than 7.5%; thereafter, insulin was added to maintain glycemic control. Main Outcomes and Measures Chronic eGFR slope (change in eGFR between year 1 and trial end) and a composite kidney disease progression outcome (albuminuria, dialysis, transplant, or death due to kidney disease). Secondary outcomes included incident eGFR less than 60 mL/min/1.73 m2, 40% decrease in eGFR to less than 60 mL/min/1.73 m2, doubling of urine albumin-to-creatinine ratio (UACR) to 30 mg/g or greater, and progression of Kidney Disease Improving Global Outcomes stage. Analyses were intention-to-treat. Results Of the 5047 participants, 3210 (63.6%) were men. Baseline characteristics were mean (SD) age 57.2 (10.0) years; HbA1c 7.5% (0.5%); diabetes duration, 4.2 (2.7) years; body mass index, 34.3 (6.8); blood pressure 128.3/77.3 (14.7/9.9) mm Hg; eGFR 94.9 (16.8) mL/min/1.73 m2; and median UACR, 6.4 (IQR 3.1-16.9) mg/g; 2933 (58.1%) were treated with renin-angiotensin-aldosterone inhibitors. Mean chronic eGFR slope was -2.03 (95% CI, -2.20 to -1.86) mL/min/1.73 m2 per year for patients receiving sitagliptin; glimepiride, -1.92 (95% CI, -2.08 to -1.75) mL/min/1.73 m2 per year; liraglutide, -2.08 (95% CI, -2.26 to -1.90) mL/min/1.73 m2 per year; and insulin glargine, -2.02 (95% CI, -2.19 to -1.84) mL/min/1.73 m2 per year (P = .61). Mean composite kidney disease progression occurred in 135 (10.6%) patients receiving sitagliptin; glimepiride, 155 (12.4%); liraglutide, 152 (12.0%); and insulin glargine, 150 (11.9%) (P = .56). Most of the composite outcome was attributable to albuminuria progression (98.4%). There were no significant differences by treatment assignment in secondary outcomes. There were no adverse kidney events attributable to medication assignment. Conclusions and Relevance In this randomized clinical trial, among people with T2D and predominantly free of kidney disease at baseline, no significant differences in kidney outcomes were observed during 5 years of follow-up when a dipeptidyl peptidase 4 inhibitor, sulfonylurea, glucagonlike peptide 1 receptor agonist, or basal insulin was added to metformin for glycemic control. Trial Registration ClinicalTrials.gov Identifier: NCT01794143.