Publications by authors named "Lawrence A Leiter"

369 Publications

Validating the NIH LDL-C Equation in a Specialized Lipid Cohort: Does it Add Up?

Clin Biochem 2021 Oct 14. Epub 2021 Oct 14.

Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada; Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada; Department of Laboratory Medicine, St. Michael's Hospital, Toronto, ON, Canada.

Background: Guideline recommendations for the management of lipids in patients at risk for cardiovascular disease is largely based on low-density lipoprotein cholesterol (LDL-C) concentration. LDL-C is commonly calculated by the Friedewald equation, which has many limitations. The National Institutes of Health (NIH) equation better estimates LDL-C, particularly in patients with hypertriglyceridemia and/or low LDL-C. We validated the NIH LDL-C equation at the first Canadian clinical laboratory to implement this equation.

Methods: A total of 3161 lipid ultracentrifugation results from a specialized lipid cohort of 2836 patients were included. LDL-C was calculated using the NIH and Friedewald equations and compared to LDL-C measured by ultracentrifugation. We determined the accuracy of these equations at treatment thresholds and developed NIH equation restriction criteria to ensure only accurate results are reported.

Results: Ultracentrifugation LDL-C more strongly correlated with NIH-calculated LDL-C (r=0.889) than Friedewald-calculated LDL-C (r=0.807) and resulted in fewer non-sensical negative LDL-C values. The correlation for NIH-calculated LDL-C improved to r=0.975 after applying our restriction criteria. The NIH equation showed equivalent or superior concordance with ultracentrifugation at treatment thresholds. The LDL-C mean absolute difference increased with increasing TG and decreasing LDL-C concentrations, although the NIH equation was more robust under both conditions.

Conclusions: We validated the NIH equation against ultracentrifugation in a cohort with a wide lipid concentration range, which supported its superiority over the Friedewald equation. We recommend clinical implementing the NIH equation for all patients except those with type III hyperlipoproteinemia or TG >9.04 mmol/L, with an LDL-C lower reporting limit of <0.50 mmol/L.
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http://dx.doi.org/10.1016/j.clinbiochem.2021.10.003DOI Listing
October 2021

A Biomarker-Based Score for Risk of Hospitalization for Heart Failure in Patients With Diabetes.

Diabetes Care 2021 Nov 17;44(11):2573-2581. Epub 2021 Sep 17.

TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Objective: Heart failure (HF) is an impactful complication of type 2 diabetes mellitus (T2DM). We aimed to develop and validate a risk score for hospitalization for HF (HHF) incorporating biomarkers and clinical factor(s) in patients with T2DM.

Research Design And Methods: We derived a risk score for HHF using clinical data, high-sensitivity troponin T (hsTnT), and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) from 6,106 placebo-treated patients with T2DM in SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53). Candidate variables were assessed using Cox regression. The strongest indicators of HHF risk were included in the score using integer weights. The score was externally validated in 7,251 placebo-treated patients in DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis in Myocardial Infarction 58). The effect of dapagliflozin on HHF was assessed by risk category in DECLARE-TIMI 58.

Results: The strongest indicators of HHF risk were NT-proBNP, prior HF, and hsTnT (each < 0.001). A risk score using these three variables identified a gradient of HHF risk (-trend <0.001) in the derivation and validation cohorts, with C-indices of 0.87 (95% CI, 0.84-0.89) and 0.84 (0.81-0.86), respectively. Whereas there was no significant effect of dapagliflozin versus placebo on HHF in the low-risk group (hazard ratio [HR] 0.98 [95% CI 0.50-1.92]), dapagliflozin significantly reduced HHF in the intermediate-, high-, and very-high-risk groups (HR 0.64 [0.43-0.95], 0.63 [0.43-0.94], and 0.72 [0.54-0.96], respectively). Correspondingly, absolute risk reductions (95% CI) increased across these latter 3 groups: 1.0% (0.0-1.9), 3.0% (0.7-5.3), and 4.4% (-0.2 to 8.9) (-trend <0.001).

Conclusions: We developed and validated a risk score for HHF in T2DM that incorporated NT-proBNP, prior HF, and hsTnT. The risk score identifies patients at higher risk of HHF who derive greater absolute benefit from dapagliflozin.
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http://dx.doi.org/10.2337/dc21-1170DOI Listing
November 2021

A randomized trial of icosapent ethyl in ambulatory patients with COVID-19.

iScience 2021 Sep 26;24(9):103040. Epub 2021 Aug 26.

Division of Vascular Surgery, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.

The coronavirus disease 2019 (COVID-19) pandemic remains a source of considerable morbidity and mortality throughout the world. Therapeutic options to reduce symptoms, inflammatory response, or disease progression are limited. This randomized open-label trial enrolled 100 ambulatory patients with symptomatic COVID-19 in Toronto, Canada. Results indicate that icosapent ethyl (8 g daily for 3 days followed by 4 g daily for 11 days) significantly reduced high-sensitivity C-reactive protein (hs-CRP) and improved symptomatology compared with patients assigned to usual care. Specifically, the primary biomarker endpoint, change in hs-CRP, was significantly reduced by 25% among treated patients (-0.5 mg/L, interquartile range [IQR] [-6.9,0.4], within-group p = 0.011). Conversely, a non-significant 5.6% reduction was observed among usual care patients (-0.1 mg/L, IQR [-3.2,1.7], within-group p = 0.51). An unadjusted between-group primary biomarker analysis was non-significant (p = 0.082). Overall, this report provides evidence of an early anti-inflammatory effect of icosapent ethyl in a modest sample, including an initial well-tolerated loading dose, in symptomatic outpatients with COVID-19. ClinicalTrials.gov Identifier: NCT04412018.
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http://dx.doi.org/10.1016/j.isci.2021.103040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388138PMC
September 2021

Obesity and effects of dapagliflozin on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus in the DECLARE-TIMI 58 trial.

Eur Heart J 2021 Aug 24. Epub 2021 Aug 24.

TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Suite 7022, Boston, MA 02115, USA.

Aims : We investigated the associations between obesity, cardiorenal events, and benefits of dapagliflozin in patients with type 2 diabetes mellitus (T2DM).

Methods And Results : DECLARE-TIMI 58 randomized patients with T2DM and either atherosclerotic cardiovascular (CV) disease or multiple risk factors to dapagliflozin vs. placebo. Patients were stratified by body mass index (BMI, kg/m2): normal (18.5 to <25), overweight (25 to <30), moderately obese (30 to <35), severely obese (35 to <40), and very-severely obese (≥40). Outcomes analysed were CV death, hospitalization for heart failure (HHF), renal-specific composite outcome, and atrial fibrillation or flutter (AF/AFL). Of 17 134 patients, 9.0% had a normal BMI, 31.5% were overweight, 32.4% were moderately, 17.2% severely, and 9.8% were very-severely obese. Higher BMI was associated with a higher adjusted risk of HHF and AF/AFL (hazard ratio 1.30 and 1.28, respectively, per 5 kg/m2; P < 0.001 for all). Dapagliflozin reduced body weight by similar relative amounts consistently across BMI categories (percent difference: -1.9 to -2.4%). Although relative risk reductions in CV and renal-specific composite outcomes with dapagliflozin did not significantly differ across the range of BMI (P for interaction ≥0.20 for all outcomes), obese patients (BMI ≥ 30 kg/m2) tended to derive greater absolute risk reduction in HHF and AF/AFL (P for interaction 0.02 and 0.09, respectively) than non-obese patients.

Conclusions : In DECLARE-TIMI 58, patients with T2DM and higher BMI were more likely to have HHF and AF/AFL. Whereas relative risk reductions in CV and renal outcomes with dapagliflozin were generally consistent across the range of BMI, absolute risk reduction in obesity-related outcomes including HHF and AF/AFL tended to be larger in obese patients with T2DM.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01730534.
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http://dx.doi.org/10.1093/eurheartj/ehab530DOI Listing
August 2021

Cardiovascular risk factor management in patients with diabetes: Does management differ with disease duration?

J Diabetes Complications 2021 Oct 21;35(10):107997. Epub 2021 Jul 21.

Terrence Donnelly Heart Centre, St. Michael's Hospital, Toronto, Canada; Department of Medicine, University of Toronto, Toronto, Canada. Electronic address:

Aims: Our objective was to examine risk factor modification targets and treatment in relation to duration of diabetes.

Methods: The Diabetes Mellitus Status in Canada (DM-SCAN) study collected data on 5109 patients with type 2 diabetes mellitus (T2DM) in 2012 in primary care. We compared the prevalence of vascular complications, treatment targets, and interventions between patients with diagnosed diabetes duration ≤10 and > 10 years.

Results: Physicians more frequently assigned HbA1c (glycated hemoglobin) targets of 7.1-8.5% (54-69 mmol/mol) to patients with longer duration of diabetes (n = 1647) (19.8% vs 9.5%, p < 0.001). Patients with longer duration of diabetes were less likely to achieve HbA1c targets of ≤7.0% (53 mmol/mol) (39% vs. 55%, p < 0.001), had similar likelihood of achieving blood pressure targets of ≤130/80 mmHg (38% vs. 36%, p = 0.26) and were more likely to achieve LDL-C targets of ≤2.0 mmol/L (≤77.3 mg/dL) (63% vs. 53%, p < 0.001) compared to patients with shorter duration of diabetes (n = 3462). Achievement of all three targets between both groups were similar (13% vs. 13%, p = 0.82). Overall, patients with longer duration of diabetes were more likely to be prescribed anti-hyperglycemic, anti-hypertensive, lipid-lowering medications and referred for diabetes education.

Conclusions: Only 13% of patients achieved glycemic, blood pressure, and LDL-C targets irrespective of duration of diabetes. Despite being managed with more medications, patients with longer duration of diabetes were less likely to achieve glycemic targets. More focus is needed on developing methods to bridge best care and real-world practice.
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http://dx.doi.org/10.1016/j.jdiacomp.2021.107997DOI Listing
October 2021

Treatment Inertia in Patients With Familial Hypercholesterolemia.

J Am Heart Assoc 2021 07 9;10(14):e020126. Epub 2021 Jul 9.

Li Ka Shing Knowledge InstituteSt. Michael's HospitalUniversity of Toronto Toronto ON Canada.

Background We studied care gap in patients with familial hypercholesterolemia (FH) with respect to lipid-lowering therapy. Methods and Results We enrolled patients with cardiovascular disease (CVD) or FH and low-density lipoprotein-cholesterol >2.0 mmol/L despite maximally tolerated statin therapy. During follow-up physicians received online reminders of treatment recommendations of 2009 patients (median age, 63 years, 42% women), 52.4% had CVD only, 31.7% FH only, and 15.9% both CVD and FH. Patients with FH were younger and more likely to be women and non-White with significantly higher baseline low-density lipoprotein-cholesterol level (mmol/L) as compared with patients with CVD (FH 3.92±1.48 versus CVD 2.96±0.94, <0.0001). Patients with FH received less statin (70.6% versus 79.2%, =0.0001) at baseline but not ezetimibe (28.1% versus 20.4%, =0.0003). Among patients with FH only, 45.3% were at low-density lipoprotein target (≥ 50% reduction from pre-treatment level or low-density lipoprotein <2.5 mmol/L) at baseline and increasing to 65.8% and 73.6% by visit 2 and 3, respectively. Among patients with CVD only, none were at recommended level (≤2.0 mmol/L) at baseline and 44.3% and 53.3% were at recommended level on second and third visit, respectively. When primary end point was analyzed as a difference between baseline and last available follow-up observation, only 22.0% of patients with FH only achieved it as compared with 45.8% with CVD only (<0.0001) and 55.2% with both FH+CVD (<0.0001). Conclusions There is significant treatment inertia in patients with FH including those with CVD. Education focused on patients with FH should continue to be undertaken.
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http://dx.doi.org/10.1161/JAHA.120.020126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483494PMC
July 2021

The Effect of Dapagliflozin on Albuminuria in DECLARE-TIMI 58.

Diabetes Care 2021 08 7;44(8):1805-1815. Epub 2021 Jul 7.

Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem, Israel.

Objective: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report albuminuria change in the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) cardiovascular outcome trial, which included populations with lower cardiorenal risk.

Research Design And Methods: DECLARE-TIMI 58 randomized 17,160 patients with type 2 diabetes, creatinine clearance >60 mL/min, and either atherosclerotic cardiovascular disease (CVD; 40.6%) or risk-factors for CVD (59.4%) to dapagliflozin or placebo. Urinary albumin-to-creatinine ratio (UACR) was tested at baseline, 6 months, 12 months, and yearly thereafter. The change in UACR over time was measured as a continuous and categorical variable (≤15, >15 to <30, ≥30 to ≤300, and >300 mg/g) by treatment arm. The composite cardiorenal outcome was a ≥40% sustained decline in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m, end-stage kidney disease, and cardiovascular or renal death; specific renal outcome included all except cardiovascular death.

Results: Baseline UACR was available for 16,843 (98.15%) participants: 9,067 (53.83%) with ≤15 mg/g, 2,577 (15.30%) with >15 to <30 mg/g, 4,030 (23.93%) with 30-300 mg/g, and 1,169 (6.94%) with >300 mg/g. Measured as a continuous variable, UACR improved from baseline to 4.0 years with dapagliflozin, compared with placebo, across all UACR and eGFR categories (all < 0.0001). Sustained confirmed ≥1 category improvement in UACR was more common in dapagliflozin versus placebo (hazard ratio 1.45 [95% CI 1.35-1.56], < 0.0001). Cardiorenal outcome was reduced with dapagliflozin for subgroups of UACR ≥30 mg/g ( < 0.0125, = 0.033), and the renal-specific outcome was reduced for all UACR subgroups ( < 0.05, = 0.480).

Conclusions: In DECLARE-TIMI 58, dapagliflozin demonstrated a favorable effect on UACR and renal-specific outcome across baseline UACR categories, including patients with normal albumin excretion. The results suggest a role for SGLT2i also in the primary prevention of diabetic kidney disease.
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http://dx.doi.org/10.2337/dc21-0076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385472PMC
August 2021

Permission to prescribe: do cardiologists need permission to prescribe diabetes medications that afford cardiovascular benefit?

Curr Opin Cardiol 2021 09;36(5):672-681

Division of Endocrinology and Metabolism, St Michael's Hospital.

Purpose Of Review: Antihyperglycemic therapies including sodium glucose contransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) have been demonstrated to confer significant cardiovascular benefit and reduce future events in patients with type 2 diabetes mellitus (T2DM). However, despite positive data from cardiovascular outcome trials, these therapies remain underutilized in a large proportion of patients who have clinical indications and meet coverage guidelines for their initiation. One of the causes of the observed gap between scientific evidence and clinical cardiology practice is therapeutic hesitancy (otherwise known as therapeutic inertia). The purpose of this review is to discuss the contributors to therapeutic hesitancy in the implementation of these evidence-based therapies and, more importantly, provide pragmatic solutions to address these barriers.

Recent Findings: Recent studies have demonstrated that clinicians may not initiate cardiovascular protective therapies due to a reluctance to overstep perceived interdisciplinary boundaries, concerns about causing harm due to medication side effects, and a sense of unfamiliarity with the optimal choice of therapy amidst a rapidly evolving landscape of T2DM therapies.

Summary: Herein, we describe a multifaceted approach aimed at creating a 'permission to prescribe' culture, developing integrated multidisciplinary models of care, enhancing trainees' experiences in cardiovascular disease prevention, and utilizing technology to motivate change. Taken together, these interventions should increase the implementation of evidence-based therapies and improve the quality of life and cardiovascular outcomes of individuals with T2DM.
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http://dx.doi.org/10.1097/HCO.0000000000000892DOI Listing
September 2021

Erectile function in men with type 2 diabetes treated with dulaglutide: an exploratory analysis of the REWIND placebo-controlled randomised trial.

Lancet Diabetes Endocrinol 2021 08 18;9(8):484-490. Epub 2021 Jun 18.

St John's Medical College, St John's National Academy of Health Sciences, Bangalore, India.

Background: Diabetes is a major risk factor for erectile dysfunction, however, the effect of GLP-1 receptor agonists on erectile dysfunction is unknown. We aimed to assess the incidence, prevalence, and progression of erectile dysfunction in men treated with dulaglutide compared with placebo, and to determine whether dulaglutide's effect on erectile dysfunction was consistent with its effect on other diabetes-related outcomes.

Methods: The Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial was a double-blind, placebo-controlled randomised trial of the effect of dulaglutide on cardiovascular outcomes. REWIND was done at 371 sites in 24 countries. Men and women aged older than 50 years with type 2 diabetes, who had either a previous cardiovascular event or cardiovascular risk factors, were randomly assigned (1:1) to receive either dulaglutide or placebo. Participating men were offered the opportunity to complete the standardised International Index of Erectile Function (IIEF) questionnaire at baseline, 2 years, 5 years, and study end. We did an exploratory analysis, in which we included participants who completed a baseline and at least 1 follow-up IIEF questionnaire. The primary outcome for these analyses was the first occurrence of moderate or severe erectile dysfunction following randomisation, assessed by the erectile function subscores on IIEF. This analysis was part of the REWIND trial, which is registered with ClinicalTrials.gov, NCT01394952.

Findings: Between Aug 18, 2011, and Aug 14, 2013, 3725 (70·1%) of 5312 male participants with a mean age of 65·5 years (SD 6·4 years) were analysed, of whom 1487 (39·9%) had a history of cardiovascular disease, and 2104 (56·5%) had moderate or severe erectile dysfunction at baseline. The incidence of erectile dysfunction following randomisation was 21·3 per 100 person-years in the dulaglutide group and 22·0 per 100 person-years in the placebo group (HR 0·92, 95% CI 0·85-0·99, p=0·021). Men in the dulaglutide group also had a lesser fall in erectile function subscore compared with the placebo group, with a least square mean difference of 0·61 (95% CI 0·18-1·05, p=0·006).

Interpretation: Long-term use of dulaglutide might reduce the incidence of moderate or severe erectile dysfunction in men with type 2 diabetes.

Funding: Eli Lilly and Company.
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http://dx.doi.org/10.1016/S2213-8587(21)00115-7DOI Listing
August 2021

Effect of Sotagliflozin on Total Hospitalizations in Patients With Type 2 Diabetes and Worsening Heart Failure : A Randomized Trial.

Ann Intern Med 2021 08 22;174(8):1065-1072. Epub 2021 Jun 22.

University of Michigan, Ann Arbor, Michigan (B.P.).

Background: In the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) trial, sotagliflozin, a sodium-glucose cotransporter-1 and sodium-glucose cotransporter-2 inhibitor, reduced total occurrences of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure relative to placebo by 33%.

Objective: To determine whether sotagliflozin increased the prespecified efficacy outcome of days alive and out of the hospital (DAOH) in the SOLOIST-WHF trial.

Design: Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT03521934).

Setting: 306 sites in 32 countries.

Participants: 1222 patients with type 2 diabetes and reduced or preserved ejection fraction who were recently hospitalized for worsening heart failure.

Intervention: 200 mg of sotagliflozin once daily (with a possible dose increase to 400 mg) or matching placebo.

Measurements: The primary analysis included hospitalizations for any reason on the basis of investigator-reported incidence and duration of admissions after randomization. Days alive and out of the hospital and its converse (days dead and days in the hospital) were analyzed using prespecified Poisson regression models.

Results: Although similar proportions of patients in the sotagliflozin and placebo groups were hospitalized at least once (38.5% vs. 41.4%), fewer patients in the sotagliflozin group were hospitalized more than once (16.3% vs. 22.1%). There were 64 and 76 deaths in the sotagliflozin and placebo groups, respectively. The DAOH rate in the sotagliflozin group was 3% higher than in the placebo group (rate ratio [RR], 1.03 [95% CI, 1.00 to 1.06]; = 0.027). This difference was primarily driven by a reduction in the rate of days dead (RR, 0.71 [CI, 0.52 to 0.99]; = 0.041) rather than by a reduction in the rate of days hospitalized for any cause. For every 100 days of follow-up, patients in the sotagliflozin group were alive and out of the hospital for 3% or 2.9 more days than those in the placebo group (91.8 vs. 88.9 days); this difference reflected a 2.6-day difference in days dead (6.3 vs. 8.9 days) and a 0.3-day difference in days in the hospital (1.9 vs. 2.2 days).

Limitation: Other than heart failure, the primary reason for each hospitalization was unspecified.

Conclusion: Sotagliflozin increased DAOH, a metric that may provide an additional patient-centered outcome to capture the totality of disease burden. Future studies are needed to quantify the consequences of increasing DAOH in terms of health economics and patient quality of life.

Primary Funding Source: Sanofi at initiation and Lexicon Pharmaceuticals at completion.
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http://dx.doi.org/10.7326/M21-0651DOI Listing
August 2021

Time to cardiovascular benefits of empagliflozin: a post hoc observation from the EMPA-REG OUTCOME trial.

ESC Heart Fail 2021 Aug 16;8(4):2603-2607. Epub 2021 Jun 16.

Yale University School of Medicine, New Haven, CT, USA.

Aims: In the EMPA-REG OUTCOME trial, in patients with type 2 diabetes and established atherosclerotic cardiovascular (CV) disease, empagliflozin vs. placebo reduced the risk of hospitalization for heart failure (HHF) by 35%, CV death/HHF by 34%, and CV death by 38%, with an early separation of the cumulative incidence curves. We explored at what time point after randomization these benefits became apparent.

Methods And Results: We expressed time trajectories for the effect of pooled empagliflozin doses vs. placebo on HHF, CV death/HHF, and CV death based on hazard ratios (95% confidence interval) and calculated the hazard ratio on the day the effect reached significance using Cox proportional hazards models. Overall, 7020 patients aged ≥18 years were treated with empagliflozin 10 mg (N = 2345), empagliflozin 25 mg (N = 2342), or placebo (N = 2333) once daily in addition to standard of care. Mean age (years ± SD) was 63.1 ± 8.6, and 72% were male. The benefit of empagliflozin on CV death first reached statistical significance on Day 59 (HR [95% confidence interval]) (0.28 [0.08, 0.96], P = 0.0424) and was generally sustained throughout the trial (overall 0.62 [0.49, 0.77], P < 0.0001). Risk reduction with empagliflozin on HHF reached statistical significance on Day 17 (0.10 [0.01, 0.87], P = 0.0372) and was sustained throughout the study (overall 0.65 [0.50, 0.85], P = 0.0017). For the composite outcome of CV death or HHF, risk reduction with empagliflozin reached statistical significance on Day 27 (0.28 [0.08, 0.97], P = 0.0445) and was sustained throughout follow-up (overall 0.66 [0.55, 0.79], P < 0.0001).

Conclusions: In EMPA-REG OUTCOME, the benefit of empagliflozin in reducing the risk of HHF, CV death/HHF, and CV death emerged within weeks after treatment initiation. The earliest benefit appears to be on HHF.
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http://dx.doi.org/10.1002/ehf2.13374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318423PMC
August 2021

Different Food Sources of Fructose-Containing Sugars and Fasting Blood Uric Acid Levels: A Systematic Review and Meta-Analysis of Controlled Feeding Trials.

J Nutr 2021 Aug;151(8):2409-2421

Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

Background: Although fructose as a source of excess calories increases uric acid, the effect of the food matrix is unclear.

Objectives: To assess the effects of fructose-containing sugars by food source at different levels of energy control on uric acid, we conducted a systematic review and meta-analysis of controlled trials.

Methods: MEDLINE, Embase, and the Cochrane Library were searched (through 11 January 2021) for trials ≥ 7 days. We prespecified 4 trial designs by energy control: substitution (energy-matched replacement of sugars in diets); addition (excess energy from sugars added to diets); subtraction (energy from sugars subtracted from diets); and ad libitum (energy from sugars freely replaced in diets) designs. Independent reviewers (≥2) extracted data and assessed the risk of bias. Grading of Recommendations, Assessment, Development, and Evaluation was used to assess the certainty of evidence.

Results: We included 47 trials (85 comparisons; N = 2763) assessing 9 food sources [sugar-sweetened beverages (SSBs), sweetened dairy, fruit drinks, 100% fruit juice, fruit, dried fruit, sweets and desserts, added nutritive sweetener, and mixed sources] across 4 energy control levels in predominantly healthy, mixed-weight adults. Total fructose-containing sugars increased uric acid levels in substitution trials (mean difference, 0.16 mg/dL;  95% CI:  0.06-0.27 mg/dL;  P = 0.003), with no effect across the other energy control levels. There was evidence of an interaction by food source: SSBs and sweets and desserts increased uric acid levels in the substitution design, while SSBs increased and 100% fruit juice decreased uric acid levels in addition trials. The certainty of evidence was high for the increasing effect of SSBs in substitution and addition trials and the decreasing effect of 100% fruit juice in addition trials and was moderate to very low for all other comparisons.

Conclusions: Food source more than energy control appears to mediate the effects of fructose-containing sugars on uric acid. The available evidence provides reliable indications that SSBs increase and 100% fruit juice decreases uric acid levels. More high-quality trials of different food sources are needed. This trial was registered at clinicaltrials.gov as NCT02716870.
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http://dx.doi.org/10.1093/jn/nxab144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349131PMC
August 2021

Potential kidney protection with liraglutide and semaglutide: Exploratory mediation analysis.

Diabetes Obes Metab 2021 09 1;23(9):2058-2066. Epub 2021 Jun 1.

The George Institute, UNSW, Sydney, New South Wales, Australia.

Aims: To investigate whether effects on chronic kidney disease risk factors could explain the apparent reduction in kidney outcomes (composite of macroalbuminuria, doubling of serum creatinine, renal replacement therapy, or renal death), primarily driven by changes in albuminuria, after treatment with the glucagon-like peptide-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide in patients with type 2 diabetes in the LEADER and SUSTAIN 6 trials.

Materials And Methods: We evaluated the mediation effect of glycated haemoglobin (HbA1c), systolic blood pressure (BP), and body weight on the kidney effects of GLP-1RAs. Diastolic BP, haemoglobin, heart rate, low-density lipoprotein and total cholesterol, and white blood cell count were also investigated. The mediation effect was estimated by the novel Vansteelandt statistical method. Subgroups with estimated glomerular filtration rate (eGFR) <60 and ≥60 mL/min/1.73 m were examined in LEADER.

Results: We observed that HbA1c mediated 25% (95% confidence interval [CI] -7.1; 67.3) and 26% (95% CI noncalculable), and systolic BP 9% (95% CI 2.8; 22.7) and 22% (95% CI noncalculable) of kidney effects of GLP-1RAs in LEADER and SUSTAIN 6, respectively. Small or no mediation was observed for the other parameters; for example, body weight mediated 9% (95% CI -7.9; 35.5) in the former and did not mediate effects in the latter study. Mediation by HbA1c was greater in patients with eGFR ≥60 mL/min/1.73 m (57%) versus those with eGFR <60 mL/min/1.73 m (no mediation).

Conclusions: Our results suggest that HbA1c and systolic BP may moderately mediate kidney benefits of liraglutide and semaglutide, with all other variables having a small to no effect. Potential kidney benefits may be driven by other mediators or potentially by direct mechanisms.
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http://dx.doi.org/10.1111/dom.14443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453827PMC
September 2021

Diabetes-Related Factors and the Effects of Ticagrelor Plus Aspirin in the THEMIS and THEMIS-PCI Trials.

J Am Coll Cardiol 2021 May;77(19):2366-2377

National Heart and Lung Institute, Imperial College, Royal Brompton Hospital, London, United Kingdom; French Alliance for Cardiovascular Trials, Paris, France; Université de Paris, Assistance Publique-Hôpitaux de Paris, Institut National de la Santé et de la Recherche Médicale 1148, Paris, France. Electronic address: https://twitter.com/gabrielsteg.

Background: THEMIS (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study) (n = 19,220) and its pre-specified THEMIS-PCI (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study-Percutaneous Coronary Intervention) (n = 11,154) subanalysis showed, in individuals with type 2 diabetes mellitus (median duration 10.0 years; HbA 7.1%) and stable coronary artery disease without prior myocardial infarction (MI) or stroke, that ticagrelor plus aspirin (compared with placebo plus aspirin) produced a favorable net clinical benefit (composite of all-cause mortality, MI, stroke, fatal bleeding, and intracranial bleeding) if the patients had a previous percutaneous coronary intervention.

Objectives: In these post hoc analyses, the authors examined whether the primary efficacy outcome (cardiovascular death, MI, stroke: 3-point major adverse cardiovascular events [MACE]), primary safety outcome (Thrombolysis In Myocardial Infarction-defined major bleeding) and net clinical benefit varied with diabetes-related factors.

Methods: Outcomes were analyzed across baseline diabetes duration, HbA, and antihyperglycemic medications.

Results: In THEMIS, the incidence of 3-point MACE increased with diabetes duration (6.7% for ≤5 years, 11.1% for >20 years) and HbA (6.4% for ≤6.0%, 11.8% for >10.0%). The relative benefits of ticagrelor plus aspirin on 3-point MACE reduction (hazard ratio [HR]: 0.90; p = 0.04) were generally consistent across subgroups. Major bleeding event rate (overall: 1.6%) did not vary by diabetes duration or HbA and was increased similarly by ticagrelor across all subgroups (HR: 2.32; p < 0.001). These findings were mirrored in THEMIS-PCI. The efficacy and safety of ticagrelor plus aspirin did not differ by baseline antihyperglycemic therapy. In THEMIS-PCI, but not THEMIS, ticagrelor generally produced favorable net clinical benefit across diabetes duration, HbA, and antihyperglycemic medications.

Conclusion: Ticagrelor plus aspirin yielded generally consistent and favorable net clinical benefit across the diabetes-related factors in THEMIS-PCI but not in the overall THEMIS population.
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http://dx.doi.org/10.1016/j.jacc.2021.03.298DOI Listing
May 2021

Lowering cholesterol, blood pressure, or both to prevent cardiovascular events: results of 8.7 years of follow-up of Heart Outcomes Evaluation Prevention (HOPE)-3 study participants.

Eur Heart J 2021 08;42(31):2995-3007

The Population Health Research Institute, Hamilton Health Sciences, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.

Aims: Rosuvastatin (10 mg per day) compared with placebo reduced major adverse cardiovascular (CV) events by 24% in 12 705 participants at intermediate CV risk after 5.6 years. There was no benefit of blood pressure (BP) lowering treatment in the overall group, but a reduction in events in the third of participants with elevated systolic BP. After cessation of all the trial medications, we examined whether the benefits observed during the active treatment phase were sustained, enhanced, or attenuated.

Methods And Results: After the randomized treatment period (5.6 years), participants were invited to participate in 3.1 further years of observation (total 8.7 years). The first co-primary outcome for the entire length of follow-up was the composite of myocardial infarction, stroke, or CV death [major adverse cardiovascular event (MACE)-1], and the second was MACE-1 plus resuscitated cardiac arrest, heart failure, or coronary revascularization (MACE-2). In total, 9326 (78%) of 11 994 surviving Heart Outcomes Prevention Evaluation (HOPE)-3 subjects consented to participate in extended follow-up. During 3.1 years of post-trial observation (total follow-up of 8.7 years), participants originally randomized to rosuvastatin compared with placebo had a 20% additional reduction in MACE-1 [95% confidence interval (CI), 0.64-0.99] and a 17% additional reduction in MACE-2 (95% CI 0.68-1.01). Therefore, over the 8.7 years of follow-up, there was a 21% reduction in MACE-1 (95% CI 0.69-0.90, P = 0.005) and 21% reduction in MACE-2 (95% CI 0.69-0.89, P = 0.002). There was no benefit of BP lowering in the overall study either during the active or post-trial observation period, however, a 24% reduction in MACE-1 was observed over 8.7 years.

Conclusion: The CV benefits of rosuvastatin, and BP lowering in those with elevated systolic BP, compared with placebo continue to accrue for at least 3 years after cessation of randomized treatment in individuals without cardiovascular disease indicating a legacy effect.

Trial Registration Number: NCT00468923.
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http://dx.doi.org/10.1093/eurheartj/ehab225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370761PMC
August 2021

From glucose lowering agents to disease/diabetes modifying drugs: a "SIMPLE" approach for the treatment of type 2 diabetes.

Cardiovasc Diabetol 2021 04 28;20(1):92. Epub 2021 Apr 28.

The Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, P.O. Box 12000, 9112001, Jerusalem, Israel.

During the last decade we experienced a surge in the number of glucose lowering agents that can be used to treat patients with type 2 diabetes. Especially important are the discoveries that sodium glucose co-transporter type 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve patients' cardiovascular and renal outcomes. Accordingly, various medical associations have updated their guidelines for the treatment of diabetes in this new era. Though not agreeing on every issue, these position-statements generally share a detailed and often complex workflow that may be too complicated for the busy and overworked primary care setting, where the majority of patients with type 2 diabetes are managed in many countries. Other guidelines, generally those from the cardiology associations focus primarily on the population of patients with high risk for or pre-existing cardiovascular disease, which represent only the minority of patients with type 2 diabetes. We believe that we should re-define SGLT2i and GLP-1 RA as diabetes/disease modifying drugs (DMDs) given the recent evidence of their cardiovascular and renal benefits. Based on this definition we have designed a SIMPLE approach in order to assist primary care teams in selecting the most appropriate therapy for their patients. We believe that most subjects newly diagnosed with type 2 diabetes should initiate early combination therapy with metformin and a prognosis changing DMD. The decision whether to use GLP-1 RA or SGLT2i should be made based on specific patient's risk factors and preferences. Importantly, DMDs are known to have a generally safe side-effect profile, with lower risk for hypoglycemia and weight gain, further promoting their wider usage. Early combination therapy with DMDs may improve the multiple pathophysiological abnormalities responsible for type 2 diabetes and its complications, thus resulting in the greatest long term benefits.
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http://dx.doi.org/10.1186/s12933-021-01281-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082901PMC
April 2021

Effect of Dapagliflozin on Cardiovascular Outcomes According to Baseline Kidney Function and Albuminuria Status in Patients With Type 2 Diabetes: A Prespecified Secondary Analysis of a Randomized Clinical Trial.

JAMA Cardiol 2021 Jul;6(7):801-810

TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Importance: Sodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, promote renal glucose excretion and reduce cardiovascular (CV) deaths and hospitalizations for heart failure (HHF) among patients with type 2 diabetes. The relative CV efficacy and safety of dapagliflozin according to baseline kidney function and albuminuria status are unknown.

Objective: To assess the CV efficacy and safety of dapagliflozin according to baseline estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR).

Design, Setting, And Participants: This secondary analysis of the randomized clinical trial Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 compared dapagliflozin vs placebo in 17 160 patients with type 2 diabetes and a baseline creatinine clearance of 60 mL/min or higher. Patients were categorized according to prespecified subgroups of baseline eGFR (<60 vs ≥60 mL/min/1.73 m2), urinary albumin to creatinine ratio (UACR; <30 vs ≥30 mg/g), and of chronic kidney disease (CKD) markers using these subgroups (0, 1, or 2). The study was conducted from May 2013 to September 2018.

Interventions: Dapagliflozin vs placebo.

Main Outcomes And Measures: The dual primary end points were major adverse cardiovascular events (myocardial infarction, stroke, and CV death) and the composite of CV death or HHF.

Results: At baseline, 1265 patients (7.4%) had an eGFR below 60 mL/min/1.73 m2, and 5199 patients (30.9%) had albuminuria. Among patients having data for both eGFR and UACR, 10 958 patients (65.1%) had an eGFR equal to or higher than 60 mL/min/1.73 m2 and an UACR below 30 mg/g (mean [SD] age, 63.7 [6.7] years; 40.1% women), 5336 patients (31.7%) had either an eGFR below 60 mL/min/1.73 m2 or albuminuria (mean [SD] age, 64.1 [7.1] years; 32.6% women), and 548 patients (3.3%) had both (mean [SD] age, 66.8 [6.9] years; 30.5% women). In the placebo group, patients with more CKD markers had higher event rates at 4 years as assessed using the Kaplan-Meier approach for the composite of CV death or HHF (3.9% for 0 markers, 8.3% for 1 marker, and 17.4% for 2 markers) and major adverse cardiovascular events (7.5% for 0 markers, 11.6% for 1 marker, and 18.9% for 2 markers). Estimates for relative risk reductions for the composite of CV death or HHF and for major adverse cardiovascular events were generally consistent across subgroups (both P > .24 for interaction), although greater absolute risk reductions were observed with more markers of CKD. The absolute risk difference for the composite of CV death or HHF was greater for patients with more markers of CKD (0 markers, -0.5%; 1 marker, -1.0%; and 2 markers, -8.3%; P = .02 for interaction). The numbers of amputations, cases of diabetic ketoacidosis, fractures, and major hypoglycemic events were balanced or numerically lower with dapagliflozin compared with placebo for patients with an eGFR below 60 mL/min/1.73 m2 and an UACR of 30 mg/g or higher.

Conclusions And Relevance: The effect of dapagliflozin on the relative risk for CV events was consistent across eGFR and UACR groups, with the greatest absolute benefit for the composite of CV death or HHF observed among patients with both reduced eGFR and albuminuria.

Trial Registration: ClinicalTrials.gov Identifier: NCT01730534.
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http://dx.doi.org/10.1001/jamacardio.2021.0660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047725PMC
July 2021

Glycemic Control and Cardiovascular Risk Factor Management in Adults With Type 2 Diabetes With and Without Chronic Kidney Disease Before Sodium-Glucose Cotransporter Protein 2 Inhibitors: Insights From the Diabetes Mellitus Status in Canada Survey.

Can J Diabetes 2021 Feb 24. Epub 2021 Feb 24.

Division of Cardiology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Objectives: Optimal control of cardiovascular risk factors in adults with type 2 diabetes (T2D) and chronic kidney disease (CKD) is challenging. Limited data are available from the primary care setting on achievement of guideline-recommended targets in this population before the use of sodium-glucose cotransporter protein 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists.

Methods: The Diabetes Mellitus Status in Canada survey included 5,172 patients with T2D seen by primary care physicians (PCPs) in November 2012. We compared treatment targets and therapeutic interventions in patients with and without CKD.

Results: Compared with those without CKD (n=3,804), patients with CKD (n=1,368) were older, more likely to be female, had a longer duration of diabetes and had more vascular complications. CKD patients more frequently had a less stringent glycated hemoglobin (A1C) target of ≤8.0% set by PCPs (10.3% vs 20%, p<0.001), and fewer CKD patients met the A1C target of ≤7.0% (50.9% vs 47.1%, p=0.016) than those without CKD. Both groups had a similar likelihood of achieving the blood pressure (BP) target of ≤130/80 mmHg (36.8% vs 34.8%, p=0.20), whereas CKD patients more frequently achieved a low-density lipoprotein cholesterol target of ≤2.0 mmol/L (54.8% vs 61.3%, p<0.001). Overall, only 12.5% in both groups achieved all 3 targets (12.3% vs 13.3%, p=0.33).

Conclusions: Only 1 of 8 T2D patients achieved optimal glycemic, BP and cholesterol targets, regardless of the presence or absence of CKD. Although more medical interventions were used in CKD patients, a lower proportion achieved guideline-recommended targets for A1C. These findings provide a benchmark for future comparison.
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http://dx.doi.org/10.1016/j.jcjd.2021.02.003DOI Listing
February 2021

2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults.

Can J Cardiol 2021 Aug 26;37(8):1129-1150. Epub 2021 Mar 26.

McGill University Health Centre, Montréal, Québec, Canada.

The 2021 guidelines primary panel selected clinically relevant questions and produced updated recommendations, on the basis of important new findings that have emerged since the 2016 guidelines. In patients with clinical atherosclerosis, abdominal aortic aneurysm, most patients with diabetes or chronic kidney disease, and those with low-density lipoprotein cholesterol ≥ 5 mmol/L, statin therapy continues to be recommended. We have introduced the concept of lipid/lipoprotein treatment thresholds for intensifying lipid-lowering therapy with nonstatin agents, and have identified the secondary prevention patients who have been shown to derive the largest benefit from intensification of therapy with these agents. For all other patients, we emphasize risk assessment linked to lipid/lipoprotein evaluation to optimize clinical decision-making. Lipoprotein(a) measurement is now recommended once in a patient's lifetime, as part of initial lipid screening to assess cardiovascular risk. For any patient with triglycerides ˃ 1.5 mmol/L, either non-high-density lipoprotein cholesterol or apolipoprotein B are the preferred lipid parameter for screening, rather than low-density lipoprotein cholesterol. We provide updated recommendations regarding the role of coronary artery calcium scoring as a clinical decision tool to aid the decision to initiate statin therapy. There are new recommendations on the preventative care of women with hypertensive disorders of pregnancy. Health behaviour modification, including regular exercise and a heart-healthy diet, remain the cornerstone of cardiovascular disease prevention. These guidelines are intended to provide a platform for meaningful conversation and shared-decision making between patient and care provider, so that individual decisions can be made for risk screening, assessment, and treatment.
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http://dx.doi.org/10.1016/j.cjca.2021.03.016DOI Listing
August 2021

Pooled Patient-Level Analysis of Inclisiran Trials in Patients With Familial Hypercholesterolemia or Atherosclerosis.

J Am Coll Cardiol 2021 03;77(9):1182-1193

Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Background: Inclisiran is a double-stranded small interfering RNA that suppresses proprotein convertase subtilisin-kexin type 9 (PCSK9) translation in the liver, leading to sustained reductions in low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipoproteins with twice-yearly dosing.

Objectives: The purpose of this study was to conduct a patient-level pooled analysis from 3 phase 3 studies of inclisiran.

Methods: Participants with heterozygous familial hypercholesterolemia (ORION-9 [Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH)]), atherosclerotic cardiovascular disease (ASCVD) (ORION-10 [Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol]), or ASCVD and ASCVD risk equivalents (ORION-11 [Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol]) taking maximally tolerated statin therapy, with or without other LDL-C-lowering agents, were randomly assigned in a 1:1 ratio to receive either inclisiran or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter for 540 days. The coprimary endpoints were the placebo-corrected percentage change in LDL-C level from baseline to day 510 and the time-adjusted percentage change in LDL-C level from baseline after day 90 to day 540. Levels of other atherogenic lipoproteins and treatment-emergent adverse events were also assessed.

Results: A total of 3,660 participants (n = 482, n = 1,561, and n = 1,617 from ORION-9, -10, and -11, respectively) underwent randomization. The placebo-corrected change in LDL-C with inclisiran at day 510 was -50.7% (95% confidence interval: -52.9% to -48.4%; p < 0.0001). The corresponding time-adjusted change in LDL-C was -50.5% (95% confidence interval: -52.1% to -48.9%; p < 0.0001). Safety was similar in both groups. Treatment-emergent adverse events at the injection site were more frequent with inclisiran than placebo (5.0% vs. 0.7%), but were predominantly mild, and none were severe or persistent. Liver and kidney function tests, creatine kinase values, and platelet counts did not differ between groups.

Conclusions: These pooled safety and efficacy data show that inclisiran, given twice yearly in addition to maximally tolerated statin therapy with or without other LDL-C lowering agents, is an effective, safe, and well-tolerated treatment to lower LDL-C in adults with heterozygous familial hypercholesterolemia, ASCVD, or ASCVD risk equivalents.
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http://dx.doi.org/10.1016/j.jacc.2020.12.058DOI Listing
March 2021

Cardiovascular, Renal, and Metabolic Outcomes of Dapagliflozin Versus Placebo in a Primary Cardiovascular Prevention Cohort: Analyses From DECLARE-TIMI 58.

Diabetes Care 2021 05 2;44(5):1159-1167. Epub 2021 Mar 2.

TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Objective: International guidelines propose prescribing sodium-glucose cotransporter 2 (SGLT2) inhibitors to patients with type 2 diabetes (T2D) as secondary prevention in patients with established atherosclerotic cardiovascular disease (ASCVD) or for primary prevention of cardiovascular events in high-risk patients with multiple risk factors (MRF) for ASCVD. The current analyses expand on the cardiovascular renal and metabolic effects of SGLT2 inhibitors in MRF patients.

Research Design And Methods: In DECLARE-TIMI 58, 17,160 patients with T2D and MRF (59.4%) or established ASCVD (40.6%) were randomized to dapagliflozin versus placebo; patients were followed for a median of 4.2 years. The cardiovascular and renal outcomes in the MRF cohort were studied across clinically relevant subgroups for treatment effect and subgroup-based treatment interaction.

Results: Among patients with MRF, the reduction with dapagliflozin in risk of cardiovascular death or hospitalization for heart failure (CVD/HHF) (hazard ratio [HR] 0.84, 95% CI 0.67-1.04) and the renal-specific outcome (HR 0.51, 95% CI 0.37-0.69) did not differ from that for patients with ASCVD ( 0.99 and 0.72, respectively). The effect on CVD/HHF was entirely driven by a reduction in HHF (HR 0.64, 95% CI 0.46-0.88). The benefits of dapagliflozin on HHF and on the renal-specific outcome, among the subset with MRF, were directionally consistent across clinically relevant subgroups. At 48 months, HbA, weight, systolic blood pressure, and urinary albumin-to-creatinine ratio were lower with dapagliflozin versus placebo and estimated glomerular filtration rate was higher ( < 0.001).

Conclusions: In patients with T2D and MRF, dapagliflozin reduced the risk of HHF and adverse renal outcomes regardless of baseline characteristics. These analyses support the benefit of dapagliflozin for important outcomes in a broad primary prevention population.
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http://dx.doi.org/10.2337/dc20-2492DOI Listing
May 2021

Efficacy and Safety of Dulaglutide in Older Patients: A post hoc Analysis of the REWIND trial.

J Clin Endocrinol Metab 2021 04;106(5):1345-1351

Mossakowski Medical Research Centre, Polish Academy of Sciences and Central Clinical Hospital MSWiA, Warsaw, Poland.

Context: Dulaglutide reduced major adverse cardiovascular events (MACE) in the Researching Cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial. Its efficacy and safety in older vs younger patients have not been explicitly analyzed.

Objective: This work aimed to assess efficacy and safety of dulaglutide vs placebo in REWIND by age subgroups (≥ 65 and < 65 years).

Methods: A post hoc subgroup analysis of REWIND was conducted at 371 sites in 24 countries. Participants included type 2 diabetes patients aged 50 years or older with established cardiovascular (CV) disease or multiple CV risk factors, and a wide range of glycemic control. Patients were randomly assigned (1:1) to dulaglutide 1.5 mg or placebo as an add-on to country-specific standard of care. Main outcomes measures included MACE (first occurrence of the composite of nonfatal myocardial infarction, nonfatal stroke, or death from CV or unknown causes).

Results: There were 5256 randomly assigned patients who were 65 years or older (mean = 71.0), and 4645 were younger than 65 years (mean = 60.7). Baseline characteristics were similar in randomized treatment groups. Dulaglutide treatment showed a similar reduction in the incidence (11% vs 13%) of MACE in older vs younger patients. The rate of permanent study drug discontinuation, incidence of all-cause mortality, hospitalizations for heart failure, severe hypoglycemia, severe renal or urinary events, and serious gastrointestinal events were similar between randomized treatment groups within each age subgroup. The incidence rate of serious cardiac conduction disorders was numerically higher in the dulaglutide group compared to placebo within each age subgroup but the difference was not statistically significant.

Conclusion: Dulaglutide had similar efficacy and safety in REWIND in patients65 years and older and those younger than 65 years.
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http://dx.doi.org/10.1210/clinem/dgab065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063250PMC
April 2021

Co-administration of viscous fiber, Salba-chia and ginseng on glycemic management in type 2 diabetes: a double-blind randomized controlled trial.

Eur J Nutr 2021 Sep 24;60(6):3071-3083. Epub 2021 Jan 24.

Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

Purpose: Viscous dietary fiber, functional seeds and ginseng roots have individually been proposed for the management of diabetes. We explored whether their co-administration would improve glycemic control in type 2 diabetes beyond conventional therapy.

Methods: In a randomized, double-blind, controlled trial conducted at two academic centers (Toronto, Canada and Zagreb, Croatia), individuals with type 2 diabetes were assigned to either an active intervention (10 g viscous fiber, 60 g white chia seeds, 1.5 g American and 0.75 g Korean red ginseng extracts), or energy and fiber-matched control (53 g oat bran, 25 g inulin, 25 g maltodextrose and 2.25 g wheat bran) intervention for 24 weeks, while on conventional standard of care. The prespecified primary endpoint was end difference at week 24 in HbA1c, following an intent-to-treat analysis adjusted for center and baseline.

Results: Between January 2016 and April 2018, 104 participants (60M:44F; mean ± SEM age 59 ± 0.8 years; BMI 29.0 ± 0.4 kg/m; HbA1c 7.0 ± 0.6%) managed with antihyperglycemic agent(s) (n = 98) or lifestyle (n = 6), were randomized (n = 52 test; n = 52 control). At week 24, HbA1c levels were 0.27 ± 0.1% lower on test compared to control (p = 0.03). There was a tendency towards an interaction by baseline HbA1c (p = 0.07), in which a greater reduction was seen in participants with baseline HbA1c > 7% vs ≤ 7% (- 0.56 ± 0.2% vs 0.03 ± 0.2%). Diet and body weight remained unchanged. The interventions were well tolerated with no related adverse events and with high retention rate of 84%.

Conclusions: Co-administration of selected dietary and herbal therapies was well-tolerated and may provide greater glycemic control as add-on therapy in type 2 diabetes. Registration: Clinicaltrials.gov NCT02553382 (registered on September 17, 2015).
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http://dx.doi.org/10.1007/s00394-020-02434-7DOI Listing
September 2021

Empagliflozin Reduces Myocardial Extracellular Volume in Patients With Type 2 Diabetes and Coronary Artery Disease.

JACC Cardiovasc Imaging 2021 06 13;14(6):1164-1173. Epub 2021 Jan 13.

Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Division of Cardiology, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada. Electronic address:

Objectives: This study sought to evaluate the effects of empagliflozin on extracellular volume (ECV) in individuals with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD).

Background: Empagliflozin has been shown to reduce left ventricular mass index (LVMi) in patients with T2DM and CAD. The effects on myocardial ECV are unknown.

Methods: This was a prespecified substudy of the EMPA-HEART (Effects of Empagliflozin on Cardiac Structure in Patients with Type 2 Diabetes) CardioLink-6 trial in which 97 participants were randomized to receive empagliflozin 10 mg daily or placebo for 6 months. Data from 74 participants were included: 39 from the empagliflozin group and 35 from the placebo group. The main outcome was change in left ventricular ECV from baseline to 6 months determined by cardiac magnetic resonance (CMR). Other outcomes included change in LVMi, indexed intracellular compartment volume (iICV) and indexed extracellular compartment volume (iECV), and the fibrosis biomarkers soluble suppressor of tumorgenicity (sST2) and matrix metalloproteinase (MMP)-2.

Results: Baseline ECV was elevated in the empagliflozin group (29.6 ± 4.6%) and placebo group (30.6 ± 4.8%). Six months of empagliflozin therapy reduced ECV compared with placebo (adjusted difference: -1.40%; 95% confidence interval [CI]: -2.60 to -0.14%; p = 0.03). Empagliflozin therapy reduced iECV (adjusted difference: -1.5 ml/m; 95% CI: -2.6 to -0.5 ml/m; p = 0.006), with a trend toward reduction in iICV (adjusted difference: -1.7 ml/m; 95% CI: -3.8 to 0.3 ml/m; p = 0.09). Empagliflozin had no impact on MMP-2 or sST2.

Conclusions: In individuals with T2DM and CAD, 6 months of empagliflozin reduced ECV, iECV, and LVMi. No changes in MMP-2 and sST2 were seen. Further investigation into the mechanisms by which empagliflozin causes reverse remodeling is required. (Effects of Empagliflozin on Cardiac Structure in Patients With Type 2 Diabetes [EMPA-HEART]; NCT02998970).
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http://dx.doi.org/10.1016/j.jcmg.2020.10.017DOI Listing
June 2021

The cost-effectiveness of dapagliflozin in treating high-risk patients with type 2 diabetes mellitus: An economic evaluation using data from the DECLARE-TIMI 58 trial.

Diabetes Obes Metab 2021 04 25;23(4):1020-1029. Epub 2021 Jan 25.

University of Liverpool, Liverpool, UK.

Aim: To undertake a cost-effectiveness analysis of dapagliflozin in treating high-risk patients with type 2 diabetes mellitus (T2DM), using both directly observed events in the DECLARE-TIMI 58 trial and surrogate risk factors to predict endpoints not captured within the trial.

Methods: An established T2DM model was adapted to integrate survival curves derived from the DECLARE-TIMI 58 trial, and extrapolated over a lifetime for all-cause mortality, hospitalization for heart failure, stroke, myocardial infarction, hospitalization for unstable angina, and end-stage kidney disease. The economic analysis considered the overall DECLARE trial population, as well as reported patient subgroups. Total and incremental costs, life-years and quality-adjusted life-years associated with dapagliflozin versus placebo were estimated from the perspective of the UK healthcare payer.

Results: In the UK setting, treatment with dapagliflozin compared to placebo was estimated to be dominant, with an expected increase in quality-adjusted life-years from 10.43 to 10.48 (+0.06) and a reduction in lifetime total costs from £39 451 to £36 899 (-£2552). Across all patient subgroups, dapagliflozin was estimated to be dominant, with the greatest absolute benefit in the prior heart failure subgroup (incremental lifetime costs -£4150 and quality-adjusted life-years +0.11).

Conclusions: The results of this study demonstrate that dapagliflozin compared to placebo appears to be cost-effective, when considering evidence reported from the DECLARE-TIMI 58 trial, at established UK willingness-to-pay thresholds. The findings highlight the potential of dapagliflozin to have a meaningful impact in reducing the economic burden of T2DM and its associated complications across a broad T2DM population.
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http://dx.doi.org/10.1111/dom.14308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048502PMC
April 2021

Relationship between baseline cardiac biomarkers and cardiovascular death or hospitalization for heart failure with and without sodium-glucose co-transporter 2 inhibitor therapy in DECLARE-TIMI 58.

Eur J Heart Fail 2021 06 29;23(6):1026-1036. Epub 2020 Dec 29.

TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Aims: Dapagliflozin reduced the risk of the composite of cardiovascular (CV) death or hospitalization for heart failure (HHF) in patients with type 2 diabetes mellitus in DECLARE-TIMI 58. We hypothesized that baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) levels would help identify patients who are at higher baseline risk and we describe the treatment effects of dapagliflozin in patients according to their baseline NT-proBNP and hsTnT levels.

Methods And Results: This was a pre-specified biomarker study from DECLARE-TIMI 58, a randomized, double-blind, placebo-controlled CV outcomes trial of dapagliflozin. Baseline NT-proBNP and hsTnT levels were measured in the TIMI Clinical Trials Laboratory in 14 565 patients. Among the included patients, 9143 patients (62.8%) were male, 1464 (10.1%) had a history of heart failure and the mean age was 63.9 years. The median baseline NT-proBNP and hsTnT levels were 75 pg/mL [interquartile range (IQR) 35-165] and 10.2 pg/mL (IQR 6.9-15.5), respectively. Patients with higher NT-proBNP and hsTnT quartiles had higher rates of CV death/HHF (Q4 vs. Q1: NT-proBNP: 4-year Kaplan-Meier event rates 13.7% vs. 1.0%; hsTnT: 11.8% vs. 1.4%; P-trend <0.001). Dapagliflozin consistently reduced the relative risk of CV death/HHF regardless of baseline NT-proBNP (P-interaction 0.72) or hsTnT quartiles (P-interaction 0.93). Given their higher baseline risk, patients with NT-proBNP and/or hsTnT levels above the median derived larger absolute risk reductions with dapagliflozin (NT-proBNP 1.9% vs. 0%, P-interaction 0.010; hsTnT 1.8% vs. 0.1%, P-interaction 0.026).

Conclusion: Patients with type 2 diabetes mellitus and higher NT-proBNP or hsTnT levels are at increased risk of CV death and HHF. Dapagliflozin reduced the relative risk of CV death/HHF irrespective of NT-proBNP and hsTnT levels, with greater absolute risk reductions seen in patients with higher baseline biomarker levels.
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http://dx.doi.org/10.1002/ejhf.2073DOI Listing
June 2021
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