Comparative analysis of hospitalization risk for incident heart failure in non-Hispanic Black versus non-Hispanic White individuals with type 2 diabetes on empagliflozin (Empa-AA): Insights from real-world data.

AIM: There are limited data to evaluate hospitalization for heart failure (hHF) in non-Hispanic Black (hereafter Black) or non-Hispanic White (hereafter White) individuals without previous hHF. Our goal was to evaluate the risk of hHF among Black versus White patients with type 2 diabetes (T2DM) who were initially prescribed empagliflozin using real-world data. METHODS: This multicentre retrospective cohort study included participants aged ≥18 years who had T2DM, were either Black or White, had no previous hHF, and were prescribed empagliflozin between August 2014 and December 2019. Our primary outcome was time to first hHF after the initial prescription of empagliflozin. A propensity-score (PS)-weighted analysis was performed to balance characteristics by race. The inverse probability treatment weighting method based on PS was used to make treatment comparisons. To compare Black with White, a PS-weighted Cox's cause-specific hazards model was used. RESULTS: In total, 8789 participants were eligible for inclusion (Black = 3216 vs. White = 5573). The Black cohort was significantly younger, had a higher proportion of females, and had a higher prevalence of chronic kidney disease, hypertension and diabetic retinopathy, while the White cohort had a higher prevalence of coronary artery disease. After adjustment for confounding factors such as age, gender, coronary artery disease, hypertension and diabetic retinopathy, the hazard ratio for first-time hHF was not significantly different between the two racial groups [hazard ratio (95% confidence interval) = 1.09 (0.84-1.42), p = .52]. CONCLUSION: This study showed no significant difference in incident hHF among Black versus White individuals with T2DM following a prescription for empagliflozin.

Concordance between clinical outcomes in the Systolic Blood Pressure Intervention Trial and in the electronic health record.

BACKGROUND: Randomized trials are the gold standard for generating clinical practice evidence, but follow-up and outcome ascertainment are resource-intensive. Electronic health record (EHR) data from routine care can be a cost-effective means of follow-up, but concordance with trial-ascertained outcomes is less well-studied. METHODS: We linked EHR and trial data for participants of the Systolic Blood Pressure Intervention Trial (SPRINT), a randomized trial comparing intensive and standard blood pressure targets. Among participants with available EHR data concurrent to trial-ascertained outcomes, we calculated sensitivity, specificity, positive predictive value, and negative predictive value for EHR-recorded cardiovascular disease (CVD) events, using the gold standard of SPRINT-adjudicated outcomes (myocardial infarction (MI)/acute coronary syndrome (ACS), heart failure, stroke, and composite CVD events). We additionally compared the incidence of non-CVD adverse events (hyponatremia, hypernatremia, hypokalemia, hyperkalemia, bradycardia, and hypotension) in trial versus EHR data. RESULTS: 2468 SPRINT participants were included (mean age 68 (SD 9) years; 26% female). EHR data demonstrated ≥80% sensitivity and specificity, and ≥ 99% negative predictive value for MI/ACS, heart failure, stroke, and composite CVD events. Positive predictive value ranged from 26% (95% CI; 16%, 38%) for heart failure to 52% (95% CI; 37%, 67%) for MI/ACS. EHR data uniformly identified more non-CVD adverse events and higher incidence rates compared with trial ascertainment. CONCLUSIONS: These results support a role for EHR data collection in clinical trials, particularly for capturing laboratory-based adverse events. EHR data may be an efficient source for CVD outcome ascertainment, though there is clear benefit from adjudication to avoid false positives.

Effect of Intensive versus Standard BP Control on AKI and Subsequent Cardiovascular Outcomes and Mortality: Findings from the SPRINT EHR Study.

Background: Adjudication of inpatient AKI in the Systolic Blood Pressure Intervention Trial (SPRINT) was based on billing codes and admission and discharge notes. The purpose of this study was to evaluate the effect of intensive versus standard BP control on creatinine-based inpatient and outpatient AKI, and whether AKI was associated with cardiovascular disease (CVD) and mortality. Methods: We linked electronic health record (EHR) data from 47 clinic sites with trial data to enable creatinine-based adjudication of AKI. Cox regression was used to evaluate the effect of intensive BP control on the incidence of AKI, and the relationship between incident AKI and CVD and all-cause mortality. Results: A total of 3644 participants had linked EHR data. A greater number of inpatient AKI events were identified using EHR data (187 on intensive versus 155 on standard treatment) as compared with serious adverse event (SAE) adjudication in the trial (95 on intensive versus 61 on standard treatment). Intensive treatment increased risk for SPRINT-adjudicated inpatient AKI (HR, 1.51; 95% CI, 1.09 to 2.08) and for creatinine-based outpatient AKI (HR, 1.40; 95% CI, 1.15 to 1.70), but not for creatinine-based inpatient AKI (HR, 1.20; 95% CI, 0.97 to 1.48). Irrespective of the definition (SAE or creatinine based), AKI was associated with increased risk for all-cause mortality, but only creatinine-based inpatient AKI was associated with increased risk for CVD. Conclusions: Creatinine-based ascertainment of AKI, enabled by EHR data, may be more sensitive and less biased than traditional SAE adjudication. Identifying ways to prevent AKI may reduce mortality further in the setting of intensive BP control.

Diabetes-Related Microvascular Complications - A Practical Approach.

Diabetes-related microvascular complications include diabetic neuropathy (eg, diabetic symmetric polyneuropathy (DSPN), cardiac autonomic neuropathy, gastroparesis, enteropathy, erectile dysfunction, female sexual dysfunction, and hypoglycemia unawareness), diabetic kidney disease (DKD), and diabetes-related eye disease (eg, diabetic retinopathy (DR) and cataract). Both diabetes duration and degree of glycemic control strongly correlate with the development of microvascular complications. The development of diabetes-related microvascular complications interferes with the patient's quality of life and poses higher health system costs. This article will discuss a practical approach to effectively minimize/delay and manage the most common diabetes-related microvascular (DSPN, DKD, and DR).

Cardiovascular benefits of GLP-1RA and SGLT-2i in women with type 2 diabetes.

Given the CV benefit noted in the CVOTs, GLP-1RAs and SGLT-2is are given preference in T2DM guidelines. While guidelines do not report potential gender difference, those differences exist. On restricting the CVOTs results to women with increased CV risk or established ASCVD, GLP-1RAs significantly reduced MACE while SGLT-2is resulted in a non-significant reduction.

The benefit of GLP-1RA in different age groups in the cardiovascular outcome trials.

There may be hesitancy in prescribing GLP-1RA in older adults. On pooling results from the CVOTs comparing GLP-1RA to placebo, there was a significantly lower incidence of MACE favoring GLP-1RA in both younger and older adults. GLP-1RA should be considered in high risk patients regardless of age.

Sodium-glucose co-transporter-2 inhibitors and atrial fibrillation in the cardiovascular and renal outcome trials.

Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT2) inhibitor that has recently been shown to reduce the incidence of reported episodes of atrial fibrillation (AF)/atrial flutter in the DECLARE-TIMI 58 trial. This raises the question regarding whether SGLT2 inhibitors can reduce the incidence of AF in a high-risk population. We searched for trials comparing SGLT2 inhibitors to placebo in high-risk individuals with or without diabetes (ie, cardiovascular and renal outcome trials) and that reported the incidence of AF as a serious adverse event. The EMPA-REG OUTCOME trial, CANVAS, CANVAS-R, the DECLARE-TIMI 58 trial, CREDENCE, DAPA-HF, VERTIS-CV and DAPA-CKD were included. The incidence of AF, reported as a serious adverse event, was 0.9% in individuals who received an SGLT2 inhibitor compared to 1.1% in those who received placebo. Pooled results showed a significantly lower incidence of AF in individuals with and without diabetes (relative risk 0.79, 95% confidence interval 0.67,0.93). This review suggests that there is a significantly lower risk of incident AF for individuals on SGLT2 inhibitors versus placebo. While there was a statistically significant lower incidence of AF, reported as a serious adverse event, more research is needed to evaluate its clinical significance.

Bekenstein's Entropy Bound-Particle Horizon Approach to Avoid the Cosmological Singularity.

The cosmological singularity of infinite density, temperature, and spacetime curvature is the classical limit of Friedmann's general relativity solutions extrapolated to the origin of the standard model of cosmology. Jacob Bekenstein suggests that thermodynamics excludes the possibility of such a singularity in a 1989 paper. We propose a re-examination of his particle horizon approach in the early radiation-dominated universe and verify it as a feasible alternative to the classical inevitability of the singularity. We argue that this minimum-radius particle horizon determined from Bekenstein's entropy bound, necessarily quantum in nature as a quantum particle horizon (QPH), precludes the singularity, just as quantum mechanics provided the solution for singularities in atomic transitions as radius r → 0 . An initial radius of zero can never be attained quantum mechanically. This avoids the spacetime singularity, supporting Bekenstein's assertion that Friedmann models cannot be extrapolated to the very beginning of the universe but only to a boundary that is 'something like a particle horizon'. The universe may have begun in a bright flash and quantum flux of radiation and particles at a minimum, irreducible quantum particle horizon rather than at the classical mathematical limit and unrealizable state of an infinite singularity.

Should Baseline Hemoglobin A1c or Dose of SGLT-2i Guide Treatment With SGLT-2i Versus DPP-4i in People With Type 2 Diabetes? A Meta-Analysis and Systematic Review.

Our aim was to explore whether the baseline hemoglobin A1c or the dose of sodium glucose cotransporter-2 inhibitor (SGLT-2i) chosen better predicted the efficacy of SGLT-2i versus dipeptidyl peptidase-4 inhibitor (DPP-4i) in type 2 diabetes. We searched for randomized trials that compared SGLT-2i with DPP-4i in type 2 diabetes and reported a change in hemoglobin A1c over time. We created 2 separate analyses (one based on baseline hemoglobin A1c and the other according to US Food and Drug Administration [FDA]-approved SGLT-2i dose). Thirteen trials were included. In the analysis according to baseline hemoglobin A1c , there was a significantly greater reduction in hemoglobin A1c when baseline hemoglobin A1c was ≥8.5%, favoring SGLT-2i over DPP-4i but not when baseline hemoglobin A1c was <8.5% (mean difference [95%CI], -0.36% [-0.53% to -0.18%] and 0.04% [-0.09% to 0.17%], respectively). On restricting the analysis to trials stratifying hemoglobin A1c to <8.0% or ≥8.0%, results did not change. In the analysis based on FDA-approved SGLT-2i doses, higher SGLT-2i doses caused a significantly greater hemoglobin A1c reduction at ≤26 and ≥52 weeks compared with the highest DPP-4i doses (mean difference [95%CI], -0.11% [-0.18% to -0.04%] and -0.24% [-0.34% to -0.15%], respectively). Lower SGLT-2i doses caused a significantly greater hemoglobin A1c reduction at ≥52 weeks but not at ≤26 weeks compared with the highest DPP-4i doses (mean difference [95%CI], -0.12% [-0.23% to -0.02%] and 0.01% [-0.05% to 0.07%], respectively). In people with type 2 diabetes and a baseline hemoglobin A1c ≥ 8.0%, SGLT-2i produced significantly greater reductions in hemoglobin A1c compared with DPP-4i and may be preferred. SGLT-2i dose titration to a higher FDA-approved dose is recommended in suitable patients.

Transitioning to non-insulin therapy in a patient receiving high dose insulin.

In people with type 2 diabetes with evidence of obesity-related insulin resistance, use of insulin to treat hyperglycemia has not been shown to reduce macrovascular complications, despite widespread use for many years. However, newer classes of diabetes medications, designed to address the prevalent pathophysiologic defect of type 2 diabetes, have emerged. Consequently, in many patients, reduction of insulin doses or even total elimination is possible after the addition of these newer agents. The authors suggest a cautious approach in which people with type 2 diabetes and established cardiovascular disease who are on high insulin doses (>1.0 unit/kg/day) be treated with diabetes medications that showed evidence of cardiovascular benefit (such as glucagon-like peptide-1 receptor agonists [GLP-1RAs]), on whom close monitoring is crucial because they may be at particular risk for developing hypoglycemia. This approach can be labor intensive and may be challenging for busy primary care providers for who may have limited time to evaluate and follow the patient. The authors present a case report of adding a GLP-1RA to high insulin doses. If the hemoglobin A1c is <8.0% when GLP-1RA is added, insulin doses should be reduced by 20%. Patients should be monitored at least every 4 weeks initially until it is confirmed there is no hypoglycemia risk. If glycemic targets (defined as fasting or preprandial glucose level between 80 and 130 mg/dl) are consistently achieved, providers may consider proactively reducing insulin doses by 10-20% to avoid hypoglycemia. The authors recommend creating appropriate goals and expectation before initiating this process.

Impact of Intensive Blood Pressure Therapy on Concern about Falling: Longitudinal Results from the Systolic Blood Pressure Intervention Trial (SPRINT).

OBJECTIVES: Concern about falling is common among older hypertension patients and could impact decisions to intensify blood pressure therapy. Our aim was to determine whether intensive therapy targeting a systolic blood pressure (SBP) of 120 mm Hg is associated with greater changes in concern about falling when compared with standard therapy targeting an SBP of 140 mm Hg. DESIGN: Subsample analysis of participants randomized to either intensive or standard therapy in the Systolic Blood Pressure Intervention Trial (SPRINT). SETTING: Approximately 100 outpatient sites. PARTICIPANTS: A total of 2313 enrollees in SPRINT; participants were all age 50 or older (mean = 69 y) and diagnosed with hypertension. MEASUREMENTS: Concern about falling was described by the shortened version of the Falls Efficacy Scale International as measured at baseline, 6 months, 1 year, and annually thereafter. RESULTS: Concern about falling showed a small but significant increase over time among all hypertension patients. No differences were noted, however, among those randomized to intensive vs standard therapy (P = .95). Among participants younger than 75 years, no increase in concern about falling over time was noted, but among participants aged 75 years and older, the mean falls self-efficacy score increased by .3 points per year (P < .0001). No differences were observed between the intensive and standard treatment groups when stratified by age (P = .55). CONCLUSION: Intensive blood pressure therapy is not associated with increased concern about falling among older hypertension patients healthy enough to participate in SPRINT. J Am Geriatr Soc 68:614-618, 2020.

Do GLP-1RAs and SGLT-2is reduce cardiovascular events in black patients with type 2 diabetes? A systematic review and meta-analysis.

AIMS: While recent cardiovascular safety trials (CVST) concerning newer diabetes medications included mostly white participants, results are being generalized to all races in recent guidelines. This raises a controversial question regarding the appropriateness of applying CVST data to black patients with type 2 diabetes. MATERIALS AND METHODS: We searched for randomized trials comparing diabetes medications to placebo in type 2 diabetes and investigated three- or four-point major adverse cardiovascular events (MACE). Data concerning black patients were then extracted. As the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) updated their recommendations for patients with established cardiovascular risk based on the CVST showing cardiovascular benefit, we performed a sensitivity analysis by including those trials only. RESULTS: A total of 11 trials were included, investigating a glucagon-like peptide-1 receptor agonist (GLP-1RA) in five, a sodium-glucose co-transporter-2 inhibitor (SGLT-2i) in two and dipeptidyl peptidase-4 inhibitors (DPP-4i) in four. Of the 102 416 participants enrolled in the included trials, only 4601 were black (4.5%). Pooled results showed no significant difference in the incidence of MACE among diabetes medications (GLP-1RA, SGLT-2i or DPP-4i) and placebo in black patients with type 2 diabetes (relative risk [RR] [95% CI], 0.94 [0.77,1.16]). Restricting the analysis to different classes of diabetes medication, the results remained non-significant. Restricting the analysis to CVST with significant outcomes, the results remained non-significant (RR [95% CI], 0.97 [0.68,1.39]). CONCLUSIONS: Given that black patients with type 2 diabetes were not well represented in CVSTs and such trials were underpowered to evaluate racial differences, it remains unclear whether GLP-1RAs or SGLT-2is would reduce cardiovascular risk in such patients, and additional studies targeting black patients are urgently needed.

Low-salt diet adherence in African Americans with hypertension.

AIMS AND OBJECTIVES: To identify health and physiological measures, depressive symptoms and locus of control (LOC) in adherence to a low salt (1,500 mg sodium), diet in African American (AA) adults with hypertension (HTN). BACKGROUND: Adherence determinants to self-management behaviours among AA adults with HTN is essential in prevention of outcomes such as stroke. A low-salt diet is one key factor in the successful management of HTN. DESIGN: A cross-sectional correlational design. METHODS: Systolic blood pressure, co-morbidities, serum creatinine, potassium, education, depression, LOC and social support were examined in relationship to self-reported adherence to a low-salt diet in a sample of AA adults (N = 77) aged 55-84. Demographic and physiologic data were collected in addition to diet adherence on a 100 mm visual analog scale. Standardised tools included Multidimensional Health LOC scale and the Patient Health Question-9 Depression Instrument. RESULTS: Lower adherence to a low-salt diet was more prevalent in females (n = 27; 73%). A moderate negative correlation (r = -0.294; p < 0.01) was found with low-salt diet adherence in the PHQ-9 (r = -0.294; p < 0.01). Both multiple regression, models significantly influenced adherence to low salt diet, with both models explaining 24% of the variance; internal LOC (F = 2.599 [8, 68]; p = 0.02) and external LOC (F = 2.667 [8, 68]; p = 0.013). CONCLUSION: Increasing awareness of factors affecting adherence to a low-salt diet is important for clinicians for effective management of HTN in AA adults. RELEVANCE TO CLINICAL PRACTICE: Nurses are encouraged to adopt a comprehensive assessment of those with HTN to identify psychosocial needs, in particular depressive symptoms, as a potential secondary prevention measure.

Factors associated with physical activity in African Americans with hypertension.

BACKGROUND: Pharmacological management only controls 58% of those with hypertension. Combining pharmacological therapy with physical activity is important in controlling hypertension. AIM: To examine factors associated with physical activity (PA) adherence in African Americans (AAs) with hypertension and antihypertensive medication adherence. METHODS: A cross-sectional descriptive correlational design was used to examine if systolic BP, co-morbidities, serum creatinine and potassium, education, depression, locus of control, and social support explained PA adherence in a convenience sample of AAs (N = 77) aged 55 to 84. All completed: demographic data, PA visual analog scale (VAS-PA); Multidimensional Health Locus of Control Scale; Patient Health Question-9 Depression Instrument. Physiological data and co-morbidities were also collected. RESULTS: A third (n = 26) had systolic BP over 140 mm/Hg. The model explained 26% variance in adherence to PA (F = 3.378 [8, 68]; p = .003) with creatinine (p < .05), depression (p < .01), and social support (p < .05) as significant. Differences in VAS-PA scores between levels of depression were significant (F = 4.707 [269], p = .012; Eta2 = 0.12). Those with no depression had significantly higher PA adherence (M = 88.26, SD = 18.97) compared to mildly depressed (M = 70.24, SD 27.71) and moderately depressed (M = 66.83, SD = 23.31). CONCLUSIONS: Clinicians should promote PA as an adjunct to medications for effective control of hypertension in AAs. Screening and intervening for depression are important when examining adherence to PA in AAs with hypertension.

Integrated Microarray-based Tools for Detection of Genomic DNA Damage and Repair Mechanisms.

The genetic information contained within the DNA molecule is highly susceptible to chemical and physical insult, caused by both endogenous and exogenous sources that can generate in the order of thousands of lesions a day in each of our cells (Lindahl, Nature 362(6422):709-715, 1993). DNA damages interfere with DNA metabolic processes such as transcription and replication and can be potent inhibitors of cell division and gene expression. To combat these regular threats to genome stability, a host of DNA repair mechanisms have evolved. When DNA lesions are left unrepaired due to defects in the repair pathway, mutations can arise that may alter the genetic information of the cell. DNA repair is thus fundamental to genome stability and defects in all the major repair pathways can lead to cancer predisposition. Therefore, the ability to accurately measure DNA damage at a genomic scale and determine the level, position, and rates of removal by DNA repair can contribute greatly to our understanding of how DNA repair in chromatin is organized throughout the genome. For this reason, we developed the 3D-DIP-Chip protocol described in this chapter. Conducting such measurements has potential applications in a variety of other fields, such as genotoxicity testing and cancer treatment using DNA damage inducing chemotherapy. Being able to detect and measure genomic DNA damage and repair patterns in individuals following treatment with chemotherapy could enable personalized medicine by predicting response to therapy.

Clinical Outcomes by Race and Ethnicity in the Systolic Blood Pressure Intervention Trial (SPRINT): A Randomized Clinical Trial.

BACKGROUND: The Systolic Blood Pressure Intervention Trial (SPRINT) showed that targeting a systolic blood pressure (SBP) of ≤ 120 mm Hg (intensive treatment) reduced cardiovascular disease (CVD) events compared to SBP of ≤ 140 mm Hg (standard treatment); however, it is unclear if this effect is similar in all racial/ethnic groups. METHODS: We analyzed SPRINT data within non-Hispanic White (NHW), non-Hispanic Black (NHB), and Hispanic subgroups to address this question. High-risk nondiabetic hypertensive patients (N = 9,361; 30% NHB; 11% Hispanic) 50 years and older were randomly assigned to intensive or standard treatment. Primary outcome was a composite of the first occurrence of a myocardial infarction, acute coronary syndrome, stroke, decompensated heart failure, or CVD death. RESULTS: Average postbaseline SBP was similar among NHW, NHB, and Hispanics in both treatment arms. Hazard ratios (HRs) (95% confidence interval) (intensive vs. standard treatment groups) for primary outcome were 0.70 (0.57-0.86), 0.71 (0.51-0.98), 0.62 (0.33-1.15) (interaction P value = 0.85) in NHW, NHB, and Hispanics. CVD mortality HRs were 0.49 (0.29-0.81), 0.77 (0.37-1.57), and 0.17 (0.01-1.08). All-cause mortality HRs were 0.61 (0.47-0.80), 0.92 (0.63-1.35), and 1.58 (0.73-3.62), respectively. A test for differences among racial/ethnic groups in the effect of treatment assignment on all-cause mortality was not significant (Hommel-adjusted P value = 0.062) after adjustment for multiple comparisons. CONCLUSION: Targeting a SBP goal of ≤ 120 mm Hg compared to ≤ 140 mm Hg led to similar SBP control and was associated with similar benefits and risks among all racial ethnic groups, though NHBs required an average of ~0.3 more medications. CLINICAL TRIALS REGISTRATION: Trial Number NCT01206062, ClinicalTrials.gov Identifier at https://clinicaltrials.gov/ct2/show/NCT01206062.

Hypertension Treatment and Concern About Falling: Baseline Data from the Systolic Blood Pressure Intervention Trial.

OBJECTIVES: To determine the extent of concern about falling in older adults with hypertension, whether lower blood pressure (BP) and greater use of antihypertensive medications are associated with greater concern about falling, and whether lower BP has a greater effect on concern about falling in older and more functionally impaired individuals. DESIGN: Secondary analysis involving cross-sectional study of baseline characteristics of participants enrolled in the Systolic Blood Pressure Intervention Trial (SPRINT). SETTING: Approximately 100 outpatient sites. PARTICIPANTS: SPRINT enrollees aged 50 and older (mean age 69) diagnosed with hypertension (N = 2,299). MEASUREMENTS: Concern about falling was determined using the shortened version of the Falls Efficacy Scale International as measured at the baseline examination. RESULTS: Mild concern about falling was present in 29.3% of participants and moderate to severe concern in 17.9%. Neither low BP (systolic BP<120 mmHg, diastolic BP <70 mmHg) nor orthostatic hypotension was associated with concern about falling (P > .10). Participants with moderate to severe concern about falling were taking significantly more antihypertensive medications than those with mild or no concern. After adjusting for baseline characteristics, no associations were evident between BP, medications, and concern about falling. Results were similar in older and younger participants; interactions between BP and age and functional status were not significantly associated with concern about falling. CONCLUSION: Although concern about falling is common in older adults with hypertension, it was not found to be associated with low BP or use of more antihypertensive medications in baseline data from SPRINT.