Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk.

BACKGROUND: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels. METHODS: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. RESULTS: Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease. CONCLUSIONS: Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.).

Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors have been demonstrated to promote reverse cardiac remodeling in people with diabetes or heart failure. Although it has been theorized that sodium-glucose cotransporter 2 inhibitors might afford similar benefits in people without diabetes or prevalent heart failure, this has not been evaluated. We sought to determine whether sodium-glucose cotransporter 2 inhibition with empagliflozin leads to a decrease in left ventricular (LV) mass in people without type 2 diabetes or significant heart failure. METHODS: Between April 2021 and January 2022, 169 individuals, 40 to 80 years of age, without diabetes but with risk factors for adverse cardiac remodeling were randomly assigned to empagliflozin (10 mg/d; n=85) or placebo (n=84) for 6 months. The primary outcome was the 6-month change in LV mass indexed (LVMi) to baseline body surface area as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and LV end-systolic volumes indexed to baseline body surface area and LV ejection fraction. RESULTS: Among the 169 participants (141 men [83%]; mean age, 59.3±10.5 years), baseline LVMi was 63.2±17.9 g/m2 and 63.8±14.0 g/m2 for the empagliflozin- and placebo-assigned groups, respectively. The difference (95% CI) in LVMi at 6 months in the empagliflozin group versus placebo group adjusted for baseline LVMi was -0.30 g/m2 (-2.1 to 1.5 g/m2; P=0.74). Median baseline (interquartile range) NT-proBNP (N-terminal-pro B-type natriuretic peptide) was 51 pg/mL (20-105 pg/mL) and 55 pg/mL (21-132 pg/mL) for the empagliflozin- and placebo-assigned groups, respectively. The 6-month treatment effect of empagliflozin versus placebo (95% CI) on blood pressure and NT-proBNP (adjusted for baseline values) were -1.3 mm Hg (-5.2 to 2.6 mm Hg; P=0.52), 0.69 mm Hg (-1.9 to 3.3 mm Hg; P=0.60), and -6.1 pg/mL (-37.0 to 24.8 pg/mL; P=0.70) for systolic blood pressure, diastolic blood pressure, and NT-proBNP, respectively. No clinically meaningful between-group differences in LV volumes (diastolic and systolic indexed to baseline body surface area) or ejection fraction were observed. No difference in adverse events was noted between the groups. CONCLUSIONS: Among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, sodium-glucose cotransporter 2 inhibition with empagliflozin did not result in a meaningful reduction in LVMi after 6 months. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04461041.

Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure or death from cardiovascular causes among patients with stable heart failure. However, the safety and efficacy of SGLT2 inhibitors when initiated soon after an episode of decompensated heart failure are unknown. METHODS: We performed a multicenter, double-blind trial in which patients with type 2 diabetes mellitus who were recently hospitalized for worsening heart failure were randomly assigned to receive sotagliflozin or placebo. The primary end point was the total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure (first and subsequent events). The trial ended early because of loss of funding from the sponsor. RESULTS: A total of 1222 patients underwent randomization (608 to the sotagliflozin group and 614 to the placebo group) and were followed for a median of 9.0 months; the first dose of sotagliflozin or placebo was administered before discharge in 48.8% and a median of 2 days after discharge in 51.2%. Among these patients, 600 primary end-point events occurred (245 in the sotagliflozin group and 355 in the placebo group). The rate (the number of events per 100 patient-years) of primary end-point events was lower in the sotagliflozin group than in the placebo group (51.0 vs. 76.3; hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.85; P<0.001). The rate of death from cardiovascular causes was 10.6 in the sotagliflozin group and 12.5 in the placebo group (hazard ratio, 0.84; 95% CI, 0.58 to 1.22); the rate of death from any cause was 13.5 in the sotagliflozin group and 16.3 in the placebo group (hazard ratio, 0.82; 95% CI, 0.59 to 1.14). Diarrhea was more common with sotagliflozin than with placebo (6.1% vs. 3.4%), as was severe hypoglycemia (1.5% vs. 0.3%). The percentage of patients with hypotension was similar in the sotagliflozin group and the placebo group (6.0% and 4.6%, respectively), as was the percentage with acute kidney injury (4.1% and 4.4%, respectively). The benefits of sotagliflozin were consistent in the prespecified subgroups of patients stratified according to the timing of the first dose. CONCLUSIONS: In patients with diabetes and recent worsening heart failure, sotagliflozin therapy, initiated before or shortly after discharge, resulted in a significantly lower total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure than placebo. (Funded by Sanofi and Lexicon Pharmaceuticals; SOLOIST-WHF ClinicalTrials.gov number, NCT03521934.).

Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease.

BACKGROUND: The efficacy and safety of sodium-glucose cotransporter 2 inhibitors such as sotagliflozin in preventing cardiovascular events in patients with diabetes with chronic kidney disease with or without albuminuria have not been well studied. METHODS: We conducted a multicenter, double-blind trial in which patients with type 2 diabetes mellitus (glycated hemoglobin level, ≥7%), chronic kidney disease (estimated glomerular filtration rate, 25 to 60 ml per minute per 1.73 m2 of body-surface area), and risks for cardiovascular disease were randomly assigned in a 1:1 ratio to receive sotagliflozin or placebo. The primary end point was changed during the trial to the composite of the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure. The trial ended early owing to loss of funding. RESULTS: Of 19,188 patients screened, 10,584 were enrolled, with 5292 assigned to the sotagliflozin group and 5292 assigned to the placebo group, and followed for a median of 16 months. The rate of primary end-point events was 5.6 events per 100 patient-years in the sotagliflozin group and 7.5 events per 100 patient-years in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.63 to 0.88; P<0.001). The rate of deaths from cardiovascular causes per 100 patient-years was 2.2 with sotagliflozin and 2.4 with placebo (hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P = 0.35). For the original coprimary end point of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, the hazard ratio was 0.84 (95% CI, 0.72 to 0.99); for the original coprimary end point of the first occurrence of death from cardiovascular causes or hospitalization for heart failure, the hazard ratio was 0.77 (95% CI, 0.66 to 0.91). Diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis were more common with sotagliflozin than with placebo. CONCLUSIONS: In patients with diabetes and chronic kidney disease, with or without albuminuria, sotagliflozin resulted in a lower risk of the composite of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure than placebo but was associated with adverse events. (Funded by Sanofi and Lexicon Pharmaceuticals; SCORED ClinicalTrials.gov number, NCT03315143.).

Rationale and design of the effect of evolocumab in patients at high cardiovascular risk without prior myocardial infarction or stroke (VESALIUS-CV) trial.

BACKGROUND: The reduction of low-density lipoprotein cholesterol (LDL-C) with evolocumab, a fully human monoclonal antibody inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9i), reduces the risk of major adverse cardiovascular events in patients with established atherosclerotic cardiovascular disease (ASCVD) with a prior MI, prior stroke, or symptomatic peripheral artery disease, with no offsetting safety concerns. The effect of evolocumab on CV outcomes in lower risk patients without a history of MI or stroke has not been explored. STUDY DESIGN: VESALIUS-CV is a randomized, double-blind, placebo-controlled, global clinical trial designed to evaluate the effect of evolocumab on the risk of major cardiovascular events in patients at high cardiovascular risk but without a prior ischemic event. The study population consists of 12,301 patients with atherosclerosis or high-risk diabetes mellitus without a prior MI or stroke; an LDL-C ≥ 90 mg/dL, or non-high-density lipoprotein cholesterol (non-HDL-C) ≥ 120 mg/dL, or apolipoprotein B ≥ 80 mg/dL; and treated with optimized lipid-lowering therapy. Patients were randomized in a 1:1 ratio to evolocumab 140 mg subcutaneously every 2 weeks or matching placebo. The primary efficacy objective is to assess whether evolocumab reduces the risk of the dual primary composite endpoints of coronary heart disease (CHD) death, myocardial infarction (MI), or ischemic stroke (triple primary endpoint) and of CHD death, MI, ischemic stroke, or ischemia-driven arterial revascularization (quadruple primary endpoint). Recruitment began in June 2019 and completed in November 2021. The trial is planned to continue until at least 751 patients experience an adjudicated triple endpoint, at least 1254 experience an adjudicated quadruple endpoint, and the median follow-up is ≥4.5 years. CONCLUSION: VESALIUS-CV will determine whether the addition of evolocumab to optimized lipid-lowering therapy reduces cardiovascular events in patients at high cardiovascular risk without a prior MI or stroke. TRIAL REGISTRATION: NCT03872401.

Inclisiran in individuals with diabetes or obesity: Post hoc pooled analyses of the ORION-9, ORION-10 and ORION-11 Phase 3 randomized trials.

AIMS: To conduct a pooled analysis of Phase 3 trials investigating the efficacy and safety of inclisiran across glycaemic and body mass index (BMI) strata. MATERIALS AND METHODS: Participants were randomized 1:1 to receive 300 mg inclisiran sodium or placebo twice yearly, after initial and 3-month doses up to 18 months, with background oral lipid-lowering therapy. Analyses were stratified by glycaemic status (normoglycaemia, prediabetes, and diabetes) or BMI (<25, ≥25 to <30, ≥30 to <35, and ≥35 kg/m2). Co-primary endpoints were percentage and time-adjusted percentage change in low-density lipoprotein (LDL) cholesterol from baseline. Safety was also assessed. RESULTS: Baseline characteristics were balanced between treatment arms and across strata. Percent LDL cholesterol change (placebo-corrected) with inclisiran from baseline to Day 510 ranged from -47.6% to -51.9% and from -48.8% to -54.4% across glycaemic/BMI strata, respectively. Similarly, time-adjusted percentage changes after Day 90 and up to Day 540 ranged from -46.8% to -52.0% and from -48.6% to -53.3% across glycaemic/BMI strata, respectively. Inclisiran led to significant reductions in proprotein convertase subtilisin/kexin type 9 and other atherogenic lipids and lipoproteins versus placebo across the glycaemic/BMI strata. The proportions of individuals achieving LDL cholesterol thresholds of <1.8 mmol/L and <1.4 mmol/L with inclisiran increased with increasing glycaemic and BMI strata. Across the glycaemic/BMI strata, a higher proportion of individuals had mild/moderate treatment-emergent adverse events (TEAEs) at the injection site with inclisiran (2.8%-7.7%) versus placebo (0.2%-2.1%). CONCLUSION: Inclisiran provided substantial and sustained LDL cholesterol lowering across glycaemic/BMI strata, with a modest excess of transient mild-to-moderate TEAEs at the injection site.

Risk of new-onset diabetes and efficacy of pharmacological weight loss therapy.

AIMS: To develop a clinical risk model to identify individuals at higher risk of developing new-onset diabetes and who might benefit more from weight loss pharmacotherapy. MATERIALS AND METHODS: A total of 21 143 patients without type 2 diabetes at baseline from two TIMI clinical trials of stable cardiovascular patients were divided into a derivation (~2/3) and validation (~1/3) cohort. The primary outcome was new-onset diabetes. Twenty-seven candidate risk variables were considered, and variable selection was performed using multivariable Cox regression. The final model was evaluated for discrimination and calibration, and for its ability to identify patients who experienced a larger benefit from the weight loss medication lorcaserin in terms of risk of new-onset diabetes. RESULTS: During a median (interquartile range) follow-up of 2.3 (1.8-2.7) years, new-onset diabetes occurred in 1013 patients (7.7%). The final model included five independent predictors (glycated haemoglobin, fasting glucose, age, body mass index, and triglycerides/high-density lipoprotein). The clinical risk model showed good discrimination (Harrell's C-indices 0.802, 95% confidence interval [CI] 0.788-0.817 and 0.807, 95% CI 0.788-0.826) in the derivation and validation cohorts. The calibration plot demonstrated adequate calibration (2.5-year area under the curve was 81.2 [79.1-83.5]). While hazard ratios for new-onset diabetes with a weight-loss therapy were comparable across risk groups (annual risks of <1%, 1%-5%, and >5%), there was a sixfold gradient in absolute risk reduction from lowest to highest risk group (p = 0.027). CONCLUSIONS: The developed clinical risk model effectively predicts new-onset diabetes, with potential implications for personalized patient care and therapeutic decision making.

Effect of albiglutide on cardiovascular outcomes in older adults: A post hoc analysis of a randomized controlled trial.

AIM: To analyse the effects of albiglutide, a glucagon-like peptide 1 receptor agonist, on cardiovascular outcomes in older adults aged ≥65 years with type 2 diabetes and cardiovascular disease who participated in the Harmony Outcomes trial (NCT02465515). MATERIALS AND METHODS: We conducted a post hoc analysis of the primary endpoint of the Harmony Outcomes trial-time to first occurrence of a major adverse cardiovascular event-in subgroups of participants aged <65 and ≥65 years and <75 and ≥75 years at baseline. Hazard ratios and 95% confidence intervals (CIs) were generated using Cox proportional hazards regression. RESULTS: The analysis population included 9462 Harmony Outcomes participants, including 4748 patients ≥65 and 1140 patients ≥75 years at baseline. Hazard ratios for the prevention of major adverse cardiovascular events were 0.66 (95% CI, 0.53-0.82) in persons <65 and 0.86 (95% CI, 0.71-1.04) in those ≥65 years (age interaction p = .07), and 0.78 (95% CI, 0.67-0.91) in <75 and 0.70 (95% CI, 0.48-1.01) in ≥75 year age groups (interaction p = .6). When analysed as a continuous variable, age did not modify the effect of albiglutide on the primary endpoint. CONCLUSIONS: This post hoc analysis adds to the body of literature showing that glucagon-like peptide 1 receptor agonists added to standard type 2 diabetes therapy safely reduce the incidence of cardiovascular events in older adults with established cardiovascular disease. In this analysis, the risk-benefit profile was similar between younger and older age groups treated with albiglutide.

Inclisiran and cardiovascular events: a patient-level analysis of phase III trials.

BACKGROUND: Inclisiran, an siRNA administered twice-yearly, significantly reduced LDL cholesterol (LDL-C) in Phase III trials. Whether lowering LDL-C with inclisiran translates into a lower risk of cardiovascular (CV) events is not yet established. METHODS AND RESULTS: Patient-level, pooled analysis of ORION-9, -10 and -11, included patients with heterozygous familial hypercholesterolaemia, atherosclerotic CV disease (ASCVD), or ASCVD risk equivalent on maximally tolerated statin-therapy, randomized 1:1 to receive 284 mg inclisiran or placebo on Days 1, 90, and 6-monthly thereafter for 18 months. Prespecified exploratory endpoint of major cardiovascular events (MACEs) included non-adjudicated CV death, cardiac arrest, non-fatal myocardial infarction (MI), and fatal and non-fatal stroke, evaluated as part of safety assessments using a standard Medical Dictionary for Regulatory Activities basket. Although not prespecified, total fatal and non-fatal MI, and stroke were also evaluated. Mean LDL-C at baseline was 2.88 mmol/L. At Day 90, the placebo-corrected percentage reduction in LDL-C with inclisiran was 50.6%, corresponding to an absolute reduction of 1.37 mmol/L (both P < 0.0001). Among 3655 patients over 18 months, 303 (8.3%) experienced MACE, including 74 (2.0%) fatal and non-fatal MIs, and 28 (0.8%) fatal and non-fatal strokes. Inclisiran significantly reduced composite MACE [OR (95% CI): 0.74 (0.58-0.94)], but not fatal and non-fatal MIs [OR (95% CI): 0.80 (0.50-1.27)] or fatal and non-fatal stroke [OR (95% CI): 0.86 (0.41-1.81)]. CONCLUSION: This analysis offers early insights into the potential CV benefits of lowering LDL-C with inclisiran and suggests potential benefits for MACE reduction. These findings await confirmation in the larger CV outcomes trials of longer duration.

Efficacy and Safety of Dapagliflozin in Type 2 Diabetes According to Baseline Blood Pressure: Observations From DECLARE-TIMI 58 Trial.

BACKGROUND: Dapagliflozin improved heart failure and kidney outcomes in patients with type 2 diabetes (T2DM) with or at high risk for atherosclerotic cardiovascular disease in the DECLARE-TIMI 58 trial (Dapagliflozin Effect on Cardiovascular Events - Thrombolysis in Myocardial Infarction 58). Here, the aim was to analyze the efficacy and safety of dapagliflozin stratified according to baseline systolic blood pressure (SBP). METHODS: The DECLARE-TIMI 58 trial randomly assigned patients with T2DM and either previous atherosclerotic cardiovascular disease or atherosclerotic cardiovascular disease risk factors to dapagliflozin or placebo. Patients were categorized by baseline SBP levels: <120, 120 to 129, 130 to 139, 140 to 159, and ≥160 mm Hg (normal, elevated, stage 1, stage 2, and severe hypertension, respectively). Efficacy outcomes of interest were hospitalization for heart failure and a renal-specific composite outcome (sustained decrease in estimated glomerular filtration rate by 40%, progression to end-stage renal disease, or renal death). Safety outcomes included symptoms of volume depletion, lower extremity amputations, and acute kidney injury. RESULTS: The trial comprised 17 160 patients; mean age, 64.0±6.8 years; 37.4% women; median duration of T2DM, 11 years; 40.6% with prevalent cardiovascular disease. Overall, dapagliflozin reduced SBP by 2.4 mm Hg (95% CI, 1.9-2.9; P<0.0001) compared with placebo at 48 months. The beneficial effects of dapagliflozin on hospitalization for heart failure and renal outcomes were consistent across all baseline SBP categories, with no evidence of modification of treatment effect (Pinteractions=0.28 and 0.52, respectively). Among normotensive patients, the hazard ratios were 0.66 (95% CI, 0.42-1.05) and 0.39 (95% CI, 0.19-0.78), respectively, for hospitalization for heart failure and the renal-specific outcome. Events of volume depletion, amputation, and acute kidney injury did not differ with dapagliflozin overall or within any baseline SBP group. CONCLUSIONS: In patients with T2DM with or at high atherosclerotic cardiovascular disease risk, dapagliflozin reduced risk for hospitalization for heart failure and renal outcomes regardless of baseline SBP, with no difference in adverse events of interest at any level of baseline SBP. These results indicate that dapagliflozin provides cardiorenal benefits in patients with T2DM at high atherosclerotic cardiovascular disease risk independent of baseline blood pressure. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01730534.

Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia is characterized by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. Monoclonal antibodies directed against proprotein convertase subtilisin-kexin type 9 (PCSK9) have been shown to reduce LDL cholesterol levels by more than 50% but require administration every 2 to 4 weeks. In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia. METHODS: In this phase 3, double-blind trial, we randomly assigned, in a 1:1 ratio, 482 adults who had heterozygous familial hypercholesterolemia to receive subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450. The two primary end points were the percent change from baseline in the LDL cholesterol level on day 510 and the time-adjusted percent change from baseline in the LDL cholesterol level between day 90 and day 540. RESULTS: The median age of the patients was 56 years, and 47% were men; the mean baseline level of LDL cholesterol was 153 mg per deciliter. At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% confidence interval [CI], -43.7 to -35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of -47.9 percentage points (95% CI, -53.5 to -42.3; P<0.001). The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% (95% CI, -41.1 to -35.1) in the inclisiran group and an increase of 6.2% (95% CI, 3.3 to 9.2) in the placebo group, for a between-group difference of -44.3 percentage points (95% CI, -48.5 to -40.1; P<0.001). There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia. Adverse events and serious adverse events were similar in the two groups. CONCLUSIONS: Among adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile. (Funded by the Medicines Company; ORION-9 ClinicalTrials.gov number, NCT03397121.).

Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol.

BACKGROUND: Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin-kexin type 9. Previous studies suggest that inclisiran might provide sustained reductions in low-density lipoprotein (LDL) cholesterol levels with infrequent dosing. METHODS: We enrolled patients with atherosclerotic cardiovascular disease (ORION-10 trial) and patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose. Patients were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg) or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter over a period of 540 days. The coprimary end points in each trial were the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510 and the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540. RESULTS: A total of 1561 and 1617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (±SD) LDL cholesterol levels at baseline were 104.7±38.3 mg per deciliter (2.71±0.99 mmol per liter) and 105.5±39.1 mg per deciliter (2.73±1.01 mmol per liter), respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the ORION-10 trial and by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6) (P<0.001 for all comparisons vs. placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9% in the ORION-10 trial and 4.7% vs. 0.5% in the ORION-11 trial); such reactions were generally mild, and none were severe or persistent. CONCLUSIONS: Reductions in LDL cholesterol levels of approximately 50% were obtained with inclisiran, administered subcutaneously every 6 months. More injection-site adverse events occurred with inclisiran than with placebo. (Funded by the Medicines Company; ORION-10 and ORION-11 ClinicalTrials.gov numbers, NCT03399370 and NCT03400800.).

Effect of inclisiran on lipids in primary prevention: the ORION-11 trial.

AIMS: Patients often require combination therapies to achieve LDL cholesterol (LDL-C) targets for the primary prevention of atherosclerotic cardiovascular disease. This study investigates the effect of inclisiran, a small interfering ribonucleic acid targeting hepatic proprotein convertase subtilisin/kexin type 9 production, in primary prevention patients with elevated LDL-C despite statins. METHODS AND RESULTS: This pre-specified analysis of the placebo-controlled, randomized ORION-11 trial included 203 individuals at risk of, but without prior, cardiovascular events and LDL-C ≥2.6 mmol/L, despite maximally tolerated statins. Inclisiran 284 mg or placebo was administered on Days 1, 90, and thereafter every 6 months up to 540 days. Co-primary endpoints were percentage LDL-C change from baseline to Day 510 and time-adjusted change from baseline after Day 90 and up to Day 540. Key secondary endpoints included percentage and absolute changes in atherogenic lipoproteins. Safety was assessed over 540 days. The mean baseline (SD) LDL-C was 3.6 (1.5) mmol/L. At Day 510, the placebo-corrected LDL-C change with inclisiran was -43.7% [95% confidence interval (CI): -52.8 to -34.6] with a corresponding time-adjusted change of -41.0% (95% CI: -47.8 to -34.2); (P < 0.0001). The placebo-corrected absolute change in LDL-C at Day 510 with inclisiran was -1.5 mmol/L (95% CI: -1.8 to -1.2), with a respective time-adjusted change of -1.3 mmol/L (95% CI: -1.6 to -1.1). Inclisiran significantly lowered non-HDL cholesterol and apolipoprotein B (apoB) at Day 510 vs. placebo (P < 0.0001 for both), with a greater likelihood of attaining lipoprotein and apoB goals, and was well-tolerated except for mainly mild, treatment-emergent adverse events at the injection site. CONCLUSION: Inclisiran was generally well-tolerated in primary prevention patients with elevated LDL-C, who derived significant reductions in atherogenic lipoprotein levels with twice-yearly maintenance dosing.

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

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.

Effects of Semaglutide on Stroke Subtypes in Type 2 Diabetes: Post Hoc Analysis of the Randomized SUSTAIN 6 and PIONEER 6.

BACKGROUND: GLP-1 RA (glucagon-like peptide-1 receptor agonists), including semaglutide, may reduce stroke risk in people with type 2 diabetes. This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with type 2 diabetes at high cardiovascular risk. METHODS: SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and PIONEER 6 (Peptide Innovation for Early Diabetes Treatment) were randomized cardiovascular outcome trials of subcutaneous and oral semaglutide in people with type 2 diabetes at high cardiovascular risk, respectively. Time to first stroke and stroke subtypes were analyzed using a Cox proportional hazards model stratified by trial with pooled treatment as a factor. The impact of prior stroke, prior myocardial infarction or stroke, age, sex, systolic blood pressure, estimated glomerular filtration rate, and prior atrial fibrillation on treatment effects was assessed using interaction P values. Risk of major adverse cardiovascular event was analyzed according to prior stroke. RESULTS: A total of 106/6480 participants had a stroke (1.0 event/100 patient-years of observation [PYO]). Semaglutide reduced incidence of any stroke versus placebo (0.8 versus 1.1 events/100 PYO; hazard ratio, 0.68 [95% CI, 0.46-1.00]; P=0.048), driven by significant reductions in risk of small-vessel occlusion (0.3 versus 0.7 events/100 PYO; hazard ratio, 0.51 [95% CI, 0.29-0.89]; P=0.017). Hazard ratios for risk of any stroke with semaglutide versus placebo were 0.60 (95% CI, 0.37-0.99; 0.5 versus 0.9 events/100 PYO) and 0.89 (95% CI, 0.47-1.69; 2.7 versus 3.0 events/100 PYO) in those without and with prior stroke, respectively. Except for prior atrial fibrillation (Pinteraction=0.025), no significant interactions were observed between treatment effects on risk of any stroke and subgroups investigated, or between treatment effects on risk of major adverse cardiovascular event and prior stroke (Pinteraction >0.05 for all). CONCLUSIONS: Semaglutide reduced incidence of any first stroke during the trials versus placebo in people with type 2 diabetes at high cardiovascular risk, primarily driven by small-vessel occlusion prevention. Semaglutide treatment, versus placebo, lowered the risk of stroke irrespective of prior stroke at baseline. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01720446 and NCT02692716.

Ticagrelor in Patients with Stable Coronary Disease and Diabetes.

BACKGROUND: Patients with stable coronary artery disease and diabetes mellitus who have not had a myocardial infarction or stroke are at high risk for cardiovascular events. Whether adding ticagrelor to aspirin improves outcomes in this population is unclear. METHODS: In this randomized, double-blind trial, we assigned patients who were 50 years of age or older and who had stable coronary artery disease and type 2 diabetes mellitus to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with previous myocardial infarction or stroke were excluded. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria. RESULTS: A total of 19,220 patients underwent randomization. The median follow-up was 39.9 months. Permanent treatment discontinuation was more frequent with ticagrelor than placebo (34.5% vs. 25.4%). The incidence of ischemic cardiovascular events (the primary efficacy outcome) was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; hazard ratio, 0.90; 95% confidence interval [CI], 0.81 to 0.99; P = 0.04), whereas the incidence of TIMI major bleeding was higher (2.2% vs. 1.0%; hazard ratio, 2.32; 95% CI, 1.82 to 2.94; P<0.001), as was the incidence of intracranial hemorrhage (0.7% vs. 0.5%; hazard ratio, 1.71; 95% CI, 1.18 to 2.48; P = 0.005). There was no significant difference in the incidence of fatal bleeding (0.2% vs. 0.1%; hazard ratio, 1.90; 95% CI, 0.87 to 4.15; P = 0.11). The incidence of an exploratory composite outcome of irreversible harm (death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was similar in the ticagrelor group and the placebo group (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86 to 1.02). CONCLUSIONS: In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, those who received ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin. (Funded by AstraZeneca; THEMIS ClinicalTrials.gov number, NCT01991795.).

Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes.

BACKGROUND: The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined. METHODS: We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause. RESULTS: We evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval [CI], <1.3; P<0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P=0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3% vs. 0.1%, P=0.02), as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001). CONCLUSIONS: In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure. (Funded by AstraZeneca; DECLARE-TIMI 58 ClinicalTrials.gov number, NCT01730534 .).

Balance of benefit and risk of ticagrelor in patients with diabetes and stable coronary artery disease according to bleeding risk assessment with the CRUSADE score: Data from THEMIS and THEMIS PCI.

BACKGROUND: The THEMIS trial demonstrated that in high-risk patients with stable coronary artery disease and diabetes without previous myocardial infarction or stroke, ticagrelor, in addition to aspirin, reduced the incidence of ischemic events but increased major bleeding. Identification of patients who could derive the greatest net benefit from the addition of ticagrelor appears important. We used the CRUSADE bleeding risk score to risk stratify the THEMIS population. METHODS: The population was divided into tertiles: score ≤22, 23 to 33, and ≥34. In each tertile, primary efficacy (composite of cardiovascular death, myocardial infarction, or stroke) and safety (TIMI major bleeding) outcomes were analyzed. NACE (net adverse clinical events) was defined as the irreversible harm composite, in which all-cause death, myocardial infarction, stroke, amputations, fatal bleeds, and intracranial hemorrhage were counted. RESULTS: Patients in the lower risk tertile experienced fewer ischemic events with ticagrelor than placebo, whereas there was no significant benefit from ticagrelor in the other tertiles (Pinteraction = .008). Bleeding rates were consistently increased with ticagrelor across all tertiles (Pinteraction = .79). Ticagrelor reduced NACE in the first tertile (HR = 0.74, 95% CI = 0.61-0.90) but not in the others (HR = 1.03, 95% CI = 0.86-1.23 and HR = 1.05, 95% CI = 0.91-1.22, respectively; Pinteraction = .012). CONCLUSIONS: In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, only those at the lower end of the bleeding risk spectrum according to the CRUSADE score derived net benefit from ticagrelor.

Epidemiology of the diabetes-cardio-renal spectrum: a cross-sectional report of 1.4 million adults.

BACKGROUND: Type-2 diabetes (T2D), chronic kidney disease, and heart failure (HF) share epidemiological and pathophysiological features. Although their prevalence was described, there is limited contemporary, high-resolution, epidemiological data regarding the overlap among them. We aimed to describe the epidemiological intersections between T2D, HF, and kidney dysfunction in an entire database, overall and by age and sex. METHODS: This is a cross-sectional analysis of adults ≥ 25 years, registered in 2019 at Maccabi Healthcare Services, a large healthcare maintenance organization in Israel. Collected data included sex, age, presence of T2D or HF, and last estimated glomerular filtration rate (eGFR) in the past two years. Subjects with T2D, HF, or eGFR < 60 mL/min/1.73 m2 were defined as within the diabetes-cardio-renal (DCR) spectrum. RESULTS: Overall, 1,389,604 subjects (52.2% females) were included; 445,477 (32.1%) were 25- < 40 years, 468,273 (33.7%) were 40- < 55 years, and 475,854 (34.2%) were ≥ 55 years old. eGFR measurements were available in 74.7% of the participants and in over 97% of those with T2D or HF. eGFR availability increased in older age groups. There were 140,636 (10.1%) patients with T2D, 54,187 (3.9%) with eGFR < 60 mL/min/1.73m2, and 11,605 (0.84%) with HF. Overall, 12.6% had at least one condition within the DCR spectrum, 2.0% had at least two, and 0.23% had all three. Cardiorenal syndrome (both HF and eGFR < 60 mL/min/1.73m2) was prevalent in 0.40% of the entire population and in 2.3% of those with T2D. In patients with both HF and T2D, 55.2% had eGFR < 60 mL/min/1.73m2 and 15.8% had eGFR < 30 mL/min/1.73m2. Amongst those within the DCR spectrum, T2D was prominent in younger participants, but was gradually replaced by HF and eGFR < 60 mL/min/1.73m2 with increasing age. The congruence between all three conditions increased with age. CONCLUSIONS: This large, broad-based study provides a contemporary, high-resolution prevalence of the DCR spectrum and its components. The results highlight differences in dominance and degree of congruence between T2D, HF, and kidney dysfunction across ages.

A novel kidney disease index reflecting both the albumin-to-creatinine ratio and estimated glomerular filtration rate, predicted cardiovascular and kidney outcomes in type 2 diabetes.

BACKGROUND: The estimated glomerular filtration rate (eGFR) and the albumin-to-creatinine ratio (ACR) are risk factors for diabetes-related outcomes. A composite that captures information from both may provide a simpler way of assessing risk. METHODS: 9115 of 9901 Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) participants with both an ACR and eGFR at baseline were included in this post hoc epidemiologic analysis. The hazard of higher baseline levels of 1/eGFR and natural log transformed ACR (calculated as ln [ACR × 100] to eliminate negative values) and their interaction for incident major adverse cardiovascular events (MACE), kidney outcomes, and deaths was estimated. The hazard of the geometric mean of these two baseline measures (the kidney disease index or KDI) was also assessed. RESULTS: A non-linear relationship was observed between 1/eGFR and all three outcomes, and between ln [ACR × 100] and the kidney outcome. There was also a negative interaction between these two risk factors with respect to MACE and death. Conversely, a linear relationship was noted between the KDI and all three outcomes. People in the highest KDI fifth experienced the highest incidence of MACE, death, and the kidney outcome (4.43, 4.56, and 5.55/100 person-years respectively). C statistics for the KDI were similar to those for eGFR and albuminuria. CONCLUSIONS: The KDI combines the baseline eGFR and ACR into a novel composite risk factor that has a simple linear relationship with incident serious outcomes in people with diabetes and additional CV risk factors. Trial Registration clinicaltrials.gov NCT01394952.