Selective β1-Antagonism with Bisoprolol Is Associated with Fewer Postoperative Strokes than Atenolol or Metoprolol

Abstract Background: Perioperative metoprolol increases postoperative stroke. Animal studies indicate that the mechanism may be related to attenuated β2-adrenoreceptor-mediated cerebral vasodilatation. The authors therefore conducted a cohort to study whether the highly β1-specific β-blocker (bisoprolol) was associated with a reduced risk of postoperative stroke compared with less selective β-blockers (metoprolol or atenolol). Methods: The authors conducted a single-center study on 44,092 consecutive patients with age 50 yr or more having noncardiac, nonneurologic surgery. The primary outcome was stroke within 7 days of surgery. The secondary outcome was a composite of all-cause mortality, postoperative myocardial injury, and stroke. A propensity score-matched cohort was created to assess the independent association between bisoprolol and less β1-selective agents metoprolol or atenolol. A secondary analysis using logistic regression, based on previously identified confounders, also compared selective β1-antagonism. Results: Twenty-four percent (10,756) of patients were exposed to in-hospital β-blockers. A total of 88 patients (0.2%) suffered a stroke within 7 days of surgery. The matched cohort consisted of 2,462 patients, and the pairs were well matched for all variables. Bisoprolol was associated with fewer postoperative strokes than the less selective agents (odds ratio = 0.20; 95% CI, 0.04–0.91). Multivariable risk-adjustment in the β-blockers-exposed patients comparing bisoprolol with the less selective agents was associated with a similarly reduced stroke rate. Conclusions: The use of metoprolol and atenolol is associated with increased risks of postoperative stroke, compared with bisoprolol. These findings warrant confirmation in a pragmatic randomized trial.

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Timing of β-Blocker Reintroduction and the Occurrence of Postoperative Atrial Fibrillation after Cardiac Surgery

Anesthesiology ◽

10.1097/aln.0000000000003064 ◽

2020 ◽

Vol 132 (2) ◽

pp. 267-279 ◽

Cited By ~ 4

Author(s):

Camille Couffignal ◽

Julien Amour ◽

Nora Ait-Hamou ◽

Bernard Cholley ◽

Jean-Luc Fellahi ◽

...

Keyword(s):

Atrial Fibrillation ◽

Cardiac Surgery ◽

Odds Ratio ◽

Adjusted Odds Ratio ◽

Postoperative Atrial Fibrillation ◽

Secondary Outcome ◽

Outcome Relationship ◽

History Of ◽

Β Blocker ◽

Β Blockers

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background For cardiac surgery patients under chronic β-blocker therapy, guidelines recommend their early postoperative reintroduction to decrease the incidence of postoperative atrial fibrillation. The authors hypothesized that the timing of β-blocker reintroduction affects their effectiveness on the incidence of postoperative atrial fibrillation. Methods This multicenter prospective French cohort study included patients on β-blockers (more than 30 days before surgery) in sinus rhythm without a pacemaker. The primary outcome, time sequence of β-blocker reintroduction, was analyzed for 192 h after surgery. The secondary outcome, relationship between the occurrence of postoperative atrial fibrillation and timing of β-blocker reintroduction, was analyzed based on pre- and intraoperative predictors (full and selected sets) according to landmark times (patients in whom atrial fibrillation occurred before a given landmark time were not analyzed). Results Of 663 patients, β-blockers were reintroduced for 532 (80%) but for only 261 (39%) patients in the first 48 h after surgery. Median duration before reintroduction was 49.5 h (95% CI, 48 to 51.5 h). Postoperative atrial fibrillation or death (N = 4) occurred in 290 (44%) patients. After performing a landmark analysis to take into account the timing of β-blocker reintroduction, the adjusted odds ratios (95% CI) for predictor full and selected (increased age, history of paroxysmal atrial fibrillation, and duration of aortic cross clamping) sets for the occurrence of postoperative atrial fibrillation were: adjusted odds ratio (full) = 0.87 (0.58 to 1.32; P = 0.517) and adjusted odds ratio (selected) = 0.84 (0.58 to 1.21; P = 0.338) at 48 h; adjusted odds ratio (full) = 0.64 (0.39 to 1.05; P = 0.076) and adjusted odds ratio (selected) = 0.58 (0.38 to 0.89; P = 0.013) at 72 h; adjusted odds ratio (full) = 0.58 (0.31 to 1.07; P = 0.079) and adjusted odds ratio (selected) = 0.53 (0.31 to 0.91; P = 0.021) at 96 h. Conclusions β-Blockers were reintroduced early (after less than 48 h) in fewer than half of the cardiac surgery patients. Reintroduction decreased postoperative atrial fibrillation occurrence only at later time points and only in the predictor selected set model. These results are an incentive to optimize (timing, doses, or titration) β-blocker reintroduction after cardiac surgery.

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Differences in the Microbial Composition of Hemodialysis Patients Treated With and Without β-Blockers

10.21203/rs.3.rs-36588/v1 ◽

2020 ◽

Author(s):

Yi-Ting Lin ◽

Ting-Yun Lin ◽

Szu-Chun Hung ◽

Po-Yu Liu ◽

Wei-Chun Hung ◽

...

Keyword(s):

Gut Microbiota ◽

Hemodialysis Patients ◽

Size Analysis ◽

Matched Cohort ◽

Microbial Composition ◽

Full Cohort ◽

Α Diversity ◽

Β Blocker ◽

Β Blockers ◽

The Impact

Abstract Background: β-blockers are commonly prescribed medications to treat cardiovascular disease and prevent sudden cardiac death during hemodialysis. Beyond the medication effects on the host, no study has investigated the impact of β-blocker on the gut microbiota in hemodialysis patients. Results: The β-blocker users had a higher proportion of diabetes mellitus, hypertension, dyslipidemia, coronary artery disease, heart failure, cerebrovascular disease, and concurrent medications than non-users. After propensity score (PS) matching, there were no differences in comorbidities and concomitant medications. The α-diversity (Simpson index) increased in β-blocker users with a distinct β-diversity (Bray-Curtis Index) compared to non-users in the full cohort and PS-matched cohort. In the linear discriminative analysis effect size analysis and zero-inflated Gaussian fit model, there was a significant enrichment in the genus Flavonifractor in β-blocker users compared to non-users in the full cohort and PS-matched cohort; this was confirmed by random forest analysis. Conclusions: Hemodialysis patients using β-blocker used had a different gut microbiota composition compared to non-users, in particular, the Flavonifractor genus was significantly increased with β-blocker treatment. These findings highlight the significant impact of β-blockers on the gut microbiome in hemodialysis patients. Further research is warranted regarding the mechanisms and their clinical consequences.

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Use of opposing reflex stimuli and heart rate variability to examine the effects of lipophilic and hydrophilic β-blockers on human cardiac vagal control

Clinical Science ◽

10.1042/cs0970585 ◽

1999 ◽

Vol 97 (5) ◽

pp. 585-593 ◽

Cited By ~ 10

Author(s):

Julian C. VAILE ◽

Janine FLETCHER ◽

Muzahim AL-ANI ◽

Hamish F. ROSS ◽

William A. LITTLER ◽

...

Keyword(s):

Heart Rate ◽

Heart Rate Variability ◽

High Frequency ◽

Animal Studies ◽

Vagal Activity ◽

Blocker Therapy ◽

Healthy Humans ◽

Trigeminal Stimulation ◽

Β Blocker ◽

Β Blockers

Evidence from animal studies suggests that β-blockers can act within the central nervous system to increase cardiac vagal motoneuron activity. We have attempted to determine whether such an effect is evident in healthy humans, by examining the effects of lipophilic and hydrophilic agents on heart rate variability and cardiac vagal reflexes. A total of 20 healthy volunteers took part in the study. Autonomic studies were performed after 72 h of treatment with placebo, atenolol or metoprolol in a blinded cross-over design. ECG recordings were taken at rest and during mental and orthostatic stress. Heart rate variability was measured in the time and frequency domains. The effects on heart rate of two opposing cardiac vagal reflexes were examined. Trigeminal stimulation causing vagal stimulation, and isometric forearm muscle contraction (‘muscle heart reflex’) causing vagal inhibition, were performed alone and simultaneously. At rest, during mental stress and during trigeminal stimulation, β-blocker therapy was associated with significantly increased high-frequency beat-to-beat heart rate variability when compared with placebo. There were no significant differences in effects on heart rate or heart rate variability between atenolol and metoprolol. Analysis of the muscle heart reflex, alone and with simultaneous trigeminal stimulation, showed that the magnitude of the R–R interval response was significantly greater after β-blocker therapy compared with placebo, but the effects of atenolol and metoprolol were equivalent. β-Blocker therapy increased cardiac vagal activity, as shown by measures of high-frequency heart rate variability and reflex studies. Lipophilic and hydrophilic β-blockers appeared to be equally efficacious in increasing the cardiac vagal modulation of heart rate.

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Lipase Catalyzed Synthesis of Enantiopure Precursors and Derivatives for β-Blockers Practolol, Pindolol and Carteolol

Catalysts ◽

10.3390/catal11040503 ◽

2021 ◽

Vol 11 (4) ◽

pp. 503

Author(s):

Morten Gundersen ◽

Guro Austli ◽

Sigrid Løvland ◽

Mari Hansen ◽

Mari Rødseth ◽

...

Keyword(s):

Building Block ◽

Kinetic Resolution ◽

Enantiomeric Excess ◽

Catalytic Amount ◽

Building Blocks ◽

Β Blocker ◽

Β Blockers ◽

Optical Rotations ◽

Reported Data ◽

By Products

Sustainable methods for producing enantiopure drugs have been developed. Chlorohydrins as building blocks for several β-blockers have been synthesized in high enantiomeric purity by chemo-enzymatic methods. The yield of the chlorohydrins increased by the use of catalytic amount of base. The reason for this was found to be the reduced formation of the dimeric by-products compared to the use of higher concentration of the base. An overall reduction of reagents and reaction time was also obtained compared to our previously reported data of similar compounds. The enantiomers of the chlorohydrin building blocks were obtained by kinetic resolution of the racemate in transesterification reactions catalyzed by Candida antarctica Lipase B (CALB). Optical rotations confirmed the absolute configuration of the enantiopure drugs. The β-blocker (S)-practolol ((S)-N-(4-(2-hydroxy-3-(isopropylamino)propoxy)phenyl)acetamide) was synthesized with 96% enantiomeric excess (ee) from the chlorohydrin (R)-N-(4-(3-chloro-2 hydroxypropoxy)phenyl)acetamide, which was produced in 97% ee and with 27% yield. Racemic building block 1-((1H-indol-4-yl)oxy)-3-chloropropan-2-ol for the β-blocker pindolol was produced in 53% yield and (R)-1-((1H-indol-4-yl)oxy)-3-chloropropan-2-ol was produced in 92% ee. The chlorohydrin 7-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one, a building block for a derivative of carteolol was produced in 77% yield. (R)-7-(3-Chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one was obtained in 96% ee. The S-enantiomer of this carteolol derivative was produced in 97% ee in 87% yield. Racemic building block 5-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one, building block for the drug carteolol, was also produced in 53% yield, with 96% ee of the R-chlorohydrin (R)-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one. (S)-Carteolol was produced in 96% ee with low yield, which easily can be improved.

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Metabolic responses of the whole body, portal-drained viscera and hindquarter to adrenaline infusion: Effects of nonselective and selective β-adrenoceptor blockade

Canadian Journal of Animal Science ◽

10.4141/a94-082 ◽

1997 ◽

Vol 77 (2) ◽

pp. 307-316 ◽

Cited By ~ 3

Author(s):

J. O. O. Miaron ◽

R. J. Christopherson

Keyword(s):

Blood Flow ◽

Oxygen Consumption ◽

Portal Vein ◽

Influencing Factor ◽

External Iliac Artery ◽

Open Circuit ◽

Whole Body ◽

Organ Blood Flow ◽

Β Blocker ◽

Β Blockers

Propranolol, a nonselective β-blocker and selective β-blockers (metoprolol a β1-blocker and ICI 118551 a β2-blocker) were used to investigate the β-adrenoceptor-mediated adrenaline-induced increase in whole-body and organ VO2 in five whether sheep. Transit time blood flow probes were chronically implanted on the portal vein and the external iliac artery and sampling catheters were placed in the mesenteric artery, iliac vein and portal vein. Oxygen consumption by the whole body was measured by open circuit calorimetry, and oxygen consumption by the portal-drained viscera and the hindquarter was determined from A-VO2 differences and organ blood flow. Absolute pre-infusion VO2 values for the whole body, portal-drained viscera and hindquarters were 236 ± 7.4, 61 ± 6.0 and 13 ± 3.1 mL min−1 respectively. The mean changes in VO2 in response to infusion were 74 vs. 11, 26, 10 and 12 mL min−1 (SE = 9.1) for whole body; 31 vs. −2, −15, 13 and −4 mL min−1 (SE = 7.3) for portal-drained viscera and 8 vs. −0.4, 2.1, 1.0 and −2.7 mL min−1; SE = 4.3) for hindquarters during adrenaline, control, propranolol, metoprolol and ICI 118551 treatments, respectively. Adrenaline increased VO2 (P < 0.05) in the whole body and portal-drained viscera, but not hindquarters relative to controls. All β-blockers suppressed (P < 0.05) the adrenaline-induced increase in VO2 except for the portal-drained viscera where metoprolol was less effective and the hindquarters where β-blockers had no effect. The blood flow pattern was similar to VO2 responses for the portal-drained viscera. The nonselective β1 and β2 blockers were effective in reducing the adrenaline-induced increases in blood flow from the portal-drained viscera and to the hindquarters, with more pronounced β-adrenoceptor-mediated haemodynamic effects. The results indicate that the β-adrenoceptor system modulates whole body VO2, clearly establishes that adrenaline induces an increased VO2 in portal-drained viscera which can be reversed by a β2 or nonselective β blocker and implicates β adrenoceptors as an influencing factor in the maintenance energy requirements of ruminants. Key words: Calorimetry, adrenaline, β blockers, blood flow, sheep

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A preliminary study of bowel rest strategy in the management of Clostridioides difficile infection

Scientific Reports ◽

10.1038/s41598-020-79211-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Hiroshi Sugimoto ◽

Ayaka Yoshihara ◽

Takao Yamamoto ◽

Keisuke Sugimoto

Keyword(s):

Secondary Outcome ◽

Control Group ◽

Matched Cohort ◽

Full Cohort ◽

Clostridioides Difficile ◽

Significant Difference ◽

All Cause Mortality ◽

Clostridioides Difficile Infection ◽

Bowel Rest ◽

Preliminary Study

AbstractClostridioides difficile infection (CDI) is an important nosocomial infection and is the leading cause of infectious diarrhea in hospitalized patients. We aimed to assess the effect of bowel rest on the management of CDI. A single-center retrospective cohort study was conducted. The primary outcome was the composite of the all-cause mortality and CDI recurrence within 30 days. The main secondary outcome was switching from metronidazole to vancomycin. Of the 91 patients with CDI enrolled as the full cohort, 63 patients (69%) and 28 patients (31%) constituted the control group and the bowel rest group, respectively. After one-to-one propensity score matching, a total of 46 patients were included as the matched cohort. In the full cohort, the composite outcome occurred in 19.0% and 14.3% of the patients in the control and the bowel rest group, respectively (p = 0.768). In the matched cohort, it was 17.4% in each group. Although there was no statistically significant difference, the trend of switching was lower in the bowel rest group. The bowel rest may not affect the all-cause mortality and CDI recurrence within 30 days. However, in those prescribed bowel rest, switching from metronidazole to vancomycin may reduce.

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Cardiac autonomic associations on exercise and ambulatory capacity in individuals with lower-extremity artery disease

European Journal of Preventive Cardiology ◽

10.1093/eurjpc/zwab061.197 ◽

2021 ◽

Vol 28 (Supplement_1) ◽

Author(s):

I Roque Marcal ◽

N Cornelis ◽

R Buys ◽

I Fourneau ◽

EG Ciolac ◽

...

Keyword(s):

Heart Rate ◽

Autonomic Function ◽

Cardiopulmonary Exercise Test ◽

Treadmill Test ◽

Cardiopulmonary Exercise ◽

Sympathetic Modulation ◽

Β Blocker ◽

Β Blockers ◽

Artery Disease ◽

Lower Extremity Artery Disease

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): This work was in part supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP #2019/19596-7), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq #303399/2018-0). OnBehalf Exercise and Chronic Disease Research Laboratory - Bauru, Brazil; Research Group for Cardiovascular Rehabilitation - Leuven, Belgium. INTRODUCTION Lower-extremity artery disease (LEAD) characterized by progressive atherosclerotic build-up in leg arteries is becoming increasingly prevalent, affecting more than 200 million people worldwide. In line with other atherosclerotic disorders, LEAD is often associated with autonomic dysfunction as evidenced by a reduced heart rate variability (HRV). To date, little is known on the impact of cardiac autonomic function on exercise and ambulatory capacity. PURPOSE We aimed to investigate whether autonomic function is associated with ambulatory capacity and exercise capacity in patients with LEAD. METHODS Thirty-four patients (age≥17 years) diagnosed with LEAD (ankle brachial index: ABI ≤ 0.9 and/or 20% decrease after a maximal treadmill test) suffering from intermittent claudication (Rutherford I-III) were recruited in the PROSECO-IC trial. Patients were grouped based on beta-blocker medication (β-blocker and non β-blocker). Intervals between R waves (i-RR) obtained by heart rate (HR) signal were acquired beat-to-beat via a digital telemetry system (Polar®️ H10) during 15 min of supine rest and were used for 5-minute HRV analysis. Time domain indexes (mean i-RR, SNDD, pNN50%), and frequency domains (high frequency band (HF), low frequency (LF, very LF (VLF)) and the ratio (LF/HF). HRV was analyzed in absolute (abs), normalized (nu) and log units (log). Ambulatory capacity was assessed by means of a submaximal treadmill test, graded maximal treadmill test using Gardner protocol (GTM) and 6 minutes walking test (6MWT); exercise capacity was assessed by means of a graded maximal cardiopulmonary exercise test (HR, blood pressure (BP) and peak oxygen uptake (VO2peak)) at resting, 2 minutes, and peak of exercise. RESULTS Pearson test showed that sympathetic modulation indexes were moderate associated with pain free distance in GTM (LF/HF: r = 0.52, p = 0.04), and pain free time in 6MWT (LFlog: r=-0.62, p = 0.01; VLF: r=-0.52, p = 0.04), respectively, in patients without β-blocker. Similar HR associations with HRV (time and frequency domain) were observed during submaximal treadmill test and cardiopulmonary exercise test (p ≤ 0.05). Test-t demonstrated a significantly increased response intra-groups in HR and BP during both tests (p ≤ 0.05). Average BP were positive associated with the earlier stages of the cardiopulmonary test (resting to 2 min) with LFlog (r = 0.70, p= <0.001) in β-blocker while non-β-blocker were associated from 2 min to peak with LFabs (r = 0.67, p= <0.001) and LF/HF (r = 0.52, p = 0.03). CONCLUSION Sympathetic modulation was correlated with a longer pain free walking capacity in non-β-blockers. Yet, individuals treated by -β-blockers showed an earlier sympathetic modulation through exercise pressor response during the first stages of cardiopulmonary exercise compared to non-β-blockers with LEAD.

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Effect of Using Silver Nylon Dressings on Postoperative Pain after Cesarean Delivery

American Journal of Perinatology ◽

10.1055/s-0041-1739521 ◽

2021 ◽

Author(s):

Sheila Connery ◽

Jean Paul Tanner ◽

Linda Odibo ◽

Olivia Raitano ◽

Dusan Nikolic-Dorschel ◽

...

Keyword(s):

Postoperative Pain ◽

Cesarean Delivery ◽

Secondary Analysis ◽

Single Site ◽

Secondary Outcome ◽

P Value ◽

Scar Assessment ◽

Patient Reported ◽

The Impact ◽

Nonopioid Analgesic

Objective Silver dressings have been associated with a decrease in postoperative pain in selected populations, but it is unknown if the benefit can be observed after cesarean deliveries. We sought to evaluate the impact of silver nylon dressings in reducing postoperative pain after cesarean delivery. Study Design A secondary analysis of data from a blinded randomized clinical trial of women undergoing cesarean delivery scheduled and unscheduled at a single site was conducted. Women were recruited for participation from a single site and randomized to a silver nylon dressing or an identical-appearing gauze wound dressing. Wounds were evaluated in the outpatient clinic at 1 and 6 weeks after delivery and patient responded to the modified patient scar assessment scale. The primary outcome of this analysis was inpatient opioid and nonopioid analgesic dispensed. The secondary outcome was patient-reported pain at the 1- and 6-week postpartum visits. Data were analyzed using chi-square test, Student's t-test, Fisher's exact test, Wilcoxon–Mann–Whitney's test, and logistic regression where appropriate. A p-value of < 0.05 was considered significant. Results Among the 649 participants, women allocated to the silver nylon dressing group, when compared with the gauze group, were similar in the amount of dispensed opioid and nonopioid analgesic medications (morphine equivalent milligrams of opioids dispensed [82.5 vs. 90 mg, p = 0.74], intravenous nonsteroidal anti-inflammatory drugs (NSAIDs) [120 vs. 120 mg, p = 0.55], and oral NSAIDs [4,800 vs. 5,600 mg in the gauze group, p = 0.65]). After adjusting for confounding variables, postoperative wound infection (adjusted odds ratio [aOR]: 11.70; 95% confidence interval [CI]: 4.51–30.31) at 1-week postoperative and again at 6-week postoperative (aOR: 5.59; 95% CI: 1.03–30.31) but not gauze dressing was associated with patient-reported postoperative pain. Conclusion Among women undergoing cesarean delivery, silver nylon dressing was not associated with a reduction in postoperative pain. Key Points

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Effect of Oligohydramnios on Fetal Heart Rate Patterns during Term Labor Induction

American Journal of Perinatology ◽

10.1055/s-0038-1675152 ◽

2018 ◽

Vol 36 (07) ◽

pp. 715-722

Author(s):

Janine S. Rhoades ◽

Molly J. Stout ◽

George A. Macones ◽

Alison G. Cahill

Keyword(s):

Heart Rate ◽

Fetal Heart Rate ◽

Fetal Heart ◽

Secondary Analysis ◽

Neonatal Morbidity ◽

Fetal Monitoring ◽

Secondary Outcome ◽

Significant Difference ◽

Electronic Fetal Monitoring ◽

Consecutive Term

Objective To estimate the effect of oligohydramnios on fetal heart rate (FHR) patterns in patients undergoing induction of labor (IOL) at term. Study Design Secondary analysis of a prospective cohort study of consecutive term, singleton deliveries from 2010 to 2015. We included all patients who underwent IOL. Our primary outcomes were electronic fetal monitoring (EFM) characteristics in the 2 hours preceding delivery. Outcomes were compared between those induced with oligohydramnios and those induced without a diagnosis of oligohydramnios. Our secondary outcome was composite neonatal morbidity. Logistic regression was used to control for confounders. Results Of 3,787 patients who underwent IOL, 147 had a diagnosis of oligohydramnios and 3,640 were included in the no oligohydramnios group. There was no significant difference in EFM characteristics between the two groups. There was no difference in composite neonatal morbidity. In patients with oligohydramnios, EFM patterns with baseline tachycardia for 30 minutes or greater were significantly associated with composite neonatal morbidity (31.3 vs. 5.3% adjusted odds ratio 8.63, 95% confidence interval 2.18, 34.1]). Conclusion Term patients undergoing IOL with oligohydramnios had EFM patterns that did not differ from their induced peers.

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Effects of linagliptin on cardiovascular and kidney outcomes in people with normal and reduced kidney function: secondary analysis of the CARMELINA randomized trial

10.2337/figshare.12129993 ◽

2020 ◽

Author(s):

Vlado Perkovic ◽

Robert Toto ◽

Mark E Cooper ◽

Johannes FE Mann ◽

Julio Rosenstock ◽

...

Keyword(s):

Type 2 Diabetes ◽

Kidney Disease ◽

Secondary Analysis ◽

Cardiovascular Death ◽

Secondary Outcome ◽

First Occurrence ◽

Outcome Trial ◽

End Stage ◽

Reduced Kidney Function

Objective Type 2 diabetes is a leading cause of kidney failure, but few outcome trials proactively enrolled individuals with chronic kidney disease (CKD). We performed secondary analyses of cardiovascular and kidney outcomes across baseline eGFR categories (≥ 60, 45-<60, 30-<45 and < 30 ml/min/1.73 m2) in CARMELINA, a cardio-renal placebo-controlled outcome trial of the DPP-4 inhibitor linagliptin (NCT01897532). Research Design and Methods Participants with cardiovascular disease (CVD) and/or CKD were included. The primary outcome was time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (3P-MACE), with a secondary outcome renal death, end-stage kidney disease, or sustained ≥40% decrease in eGFR from baseline. Other endpoints included progression of albuminuria, change in HbA1c and adverse events (AEs) including hypoglycemia. Results 6979 subjects (mean age 65.9 years, eGFR 54.6 ml/min/1.73m2, 80.1% albuminuria) were followed for 2.2 years. Across eGFR categories, linagliptin as compared to placebo did not affect the risk for 3P-MACE (HR.1.02 [95% CI, 0.89, 1.17]), or the secondary kidney outcome (1.04 [0.89, 1.22]) (interaction p-values > 0.05). Regardless of eGFR, albuminuria-progression was reduced with linagliptin, as was HbA1c, without increasing risk for hypoglycemia. AEs were balanced between groups overall and across eGFR categories. Conclusions Across all GFR categories, in participants with type 2 diabetes and CKD and/or CVD, there was no difference in risk for linagliptin versus placebo on CV and kidney events. Significant reductions in risk for albuminuria progression and HbA1c, and no difference in AEs was observed.

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