The dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist, tirzepatide, improves lipoprotein biomarkers associated with insulin resistance and cardiovascular risk in patients with type 2 diabetes

Aim To better understand the marked decrease in serum triglycerides observed with tirzepatide in patients with type 2 diabetes, additional lipoprotein-related biomarkers were measured post hoc in available samples from the same study. Materials and Methods Patients were randomized to receive once-weekly subcutaneous tirzepatide (1, 5, 10 or 15 mg), dulaglutide (1.5 mg) or placebo. Serum lipoprotein profile, apolipoprotein (apo) A-I, B and C-III and preheparin lipoprotein lipase (LPL) were measured at baseline and at 4, 12 and 26 weeks. Lipoprotein particle profile by nuclear magnetic resonance was assessed at baseline and 26 weeks. The lipoprotein insulin resistance (LPIR) score was calculated. Results At 26 weeks, tirzepatide dose-dependently decreased apoB and apoC-III levels, and increased serum preheparin LPL compared with placebo. Tirzepatide 10 and 15 mg decreased large triglyceride-rich lipoprotein particles (TRLP), small low-density lipoprotein particles (LDLP) and LPIR score compared with both placebo and dulaglutide. Treatment with dulaglutide also reduced apoB and apoC-III levels but had no effect on either serum LPL or large TRLP, small LDLP and LPIR score. The number of total LDLP was also decreased with tirzepatide 10 and 15 mg compared with placebo. A greater reduction in apoC-III with tirzepatide was observed in patients with high compared with normal baseline triglycerides. At 26 weeks, change in apoC-III, but not body weight, was the best predictor of changes in triglycerides with tirzepatide, explaining up to 22.9% of their variability. Conclusions Tirzepatide treatment dose-dependently decreased levels of apoC-III and apoB and the number of large TRLP and small LDLP, suggesting a net improvement in atherogenic lipoprotein profile.Peer reviewe

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease

BACKGROUND: The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTS: At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91). CONCLUSIONS: Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .)

TRITON and Beyond: New Insights into the Profile of Prasugrel.

Prasugrel, a third-generation thienopyridine antiplatelet agent, demonstrated superior efficacy to clopidogrel but with an increased risk of bleeding in the phase III pivotal registration Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38). This article reviews and discusses select components of a large literature of prasugrel data that has emerged since the TRITON-TIMI 38 (TRITON) study primary disclosure

A Randomized, Double-Blind, Adaptive Phase 2 Multi-Center Study of Prasugrel Compared to Placebo in Adults with Sickle Cell Disease

Abstract Abstract 847FN2 Introduction: Platelet activation may play a role in the pathogenesis of various complications related to sickle cell disease (SCD). Older studies of antiplatelet agents in reducing the frequency and severity of pain in SCD have been inconclusive. Prasugrel is a third generation thienopyridine antiplatelet agent, an oral P2Y12 ADP receptor antagonist that is FDA-approved for use in patients with acute coronary syndrome undergoing percutaneous coronary intervention. We undertook a study to determine the safety, pharmacodynamics and possible efficacy of prasugrel in adult patients with SCD. Methods: This was a multicenter, randomized, double-blind phase 2 adaptive study design with a 2:1 prasugrel:placebo randomization ratio. Study drug was given once daily for 30 days. The primary endpoint was safety as measured by hemorrhagic events requiring medical attention. Secondary endpoints included pain frequency and severity assessed by pain diary and pharmacodynamic effects measured by VerifyNow” P2Y12 reactivity units (VN PRU) and vasodilator stimulated phosphoprotein (VASP) phosphorylation platelet reactivity index (PRI). If interim analysis of pharmacodynamic data revealed insufficient platelet inhibition in the first 16 patients randomized to 5 mg daily prasugrel, the dose was to be escalated to 7.5 mg. Results: Forty-one patients were randomized to the prasugrel arm and 21 to placebo. Mean age was 32 years; 48% were female; 60% HbSS, 5% HbS/b0thalassemia, 10% HbS/b+thalassemia, and 24% HbSC (1 patient was found not to have SCD but to only have b-thalassemia trait). Eighteen patients (44%) in the prasugrel and 9 (43%) in the placebo arm were on hydroxyurea prior to study drug initiation. These characteristics were balanced between the treatment arms, as was baseline pain intensity (average pain score on a scale of 0 to 9 over 7 days prior to study drug). No hemorrhagic event required medical attention. Eight (20%) of patients in the prasugrel arm had hemorrhagic adverse events of which 6 (15%) were possibly related to study drug versus 1 (5%) in the placebo arm; all were mild except one moderate menorrhagia in a prasugrel-treated patient. There were numerical decreases in median and mean pain rate (% of days with pain) and intensity in the prasugrel arm compared to placebo but this did not reach statistical significance (Figure 1). The proportion of pain episodes requiring medical attention was also numerically lower: 23% prasugrel versus 37% placebo. There was measurable platelet inhibition as assessed by both VerifyNow” PRU and VASP PRI such that no dose escalation was necessary (Figure 2). Conclusions: Prasugrel, 5 mg once daily for 30 days, had anticipated pharmacodynamic effect on platelets in adult patients with SCD, was well tolerated, and was not associated with serious hemorrhagic events. Despite the small size and short duration of this phase 2 study, there was a suggestion of decreased days with pain. These data provide a rationale for a Phase 3 study of prasugrel adequately powered to determine effects on relevant clinical outcomes such as pain rate, severity, and frequency of vaso-occlusive crisis. Disclosures: Wun: Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Off Label Use: This abstract discusses prasugrel treatment in patients with sickle cell disease. Please see USPI for most up-to-date information. Krishnamurti:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Kutlar:Celgene: Research Funding; Novartis: Research Funding; Hemaquest: Research Funding; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Ataga:Adventrx: Consultancy; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Heath:Eli Lilly and Company: Employment, Equity Ownership. Nwachuku:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Jakubowski:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership. Riesmeyer:Eli Lilly and Company: Employment, Equity Ownership. </jats:sec

Abstract 13426: The Dual GIP/GLP-1 Receptor Agonist Tirzepatide Improves Cardiovascular Risk Protein Biomarkers in Patients With Type 2 Diabetes

Introduction: The dual GIP/GLP-1 receptor agonist tirzepatide dose-dependently reduced HbA1c and body weight in patients with obesity and type 2 diabetes (T2D) in a Phase 2 trial. Hypothesis: In this post hoc analysis, additional biomarkers of inflammation, endothelial dysfunction, and cellular stress were measured to better understand possible additional effects of tirzepatide treatment on cardiovascular risk factors. Methods: Patients with T2D were randomly assigned to receive either once-weekly subcutaneous injection of tirzepatide (1, 5, 10, or 15 mg), GLP-1 receptor agonist dulaglutide (1.5 mg), or placebo for 26 weeks. Soluble ICAM-1 and VCAM-1, IL-6, NT-proBNP, hsCRP and GDF-15 were assessed by immunoassay at baseline and 26 weeks in stored serum or EDTA plasma samples. Results were analyzed in a modified intent-to-treat population using a mixed effect model for repeated measures. Results: At 26 weeks, tirzepatide dose-dependently decreased ICAM-1 levels compared to baseline (Table). ICAM-1 levels were also significantly lower with tirzepatide 15 mg than placebo or dulaglutide. Moreover, tirzepatide 15 mg significantly decreased hsCRP levels from baseline compared with placebo. GDF-15 levels were decreased from baseline with all tirzepatide doses and with dulaglutide; however, changes in GDF-15 levels with tirzepatide were not significantly different from those with placebo or dulaglutide. Levels of IL-6, VCAM-1 or NT-proBNP were unchanged in all groups. Conclusions: In a 26-week study in patients with obesity and T2D, treatment with tirzepatide dose-dependently decreased circulating levels of specific biomarkers of inflammation and endothelial dysfunction previously associated with cardiovascular events, thus suggesting a net improvement in the cardiovascular risk profile of these patients. Clinical relevance of these changes will be assessed in the planned cardiovascular outcome study SURPASS-CVOT (NCT04255433). </jats:p

Biomarkers of Hemostatic Activation in a Randomized, Double-Blind, Phase 2 Study of Prasugrel Compared to Placebo in Adults with Sickle Cell Disease

Abstract Abstract 2127 Introduction: Activation of the hemostatic cascade and platelet activation in particular, has been implicated in the pathogenesis of sickle cell disease (SCD). Prasugrel is a third generation thienopyridine antiplatelet agent, an oral P2Y12 ADP receptor antagonist that is FDA-approved for use in patients with acute coronary syndromes undergoing percutaneous coronary revascularization. We evaluated serial biomarkers of hemostatic activation from a trial of prasugrel in adult patients with SCD. Methods: This was a multicenter, randomized, double-blind phase 2 adaptive study design with a 2:1 prasugrel:placebo ratio. Study drug, prasugrel 5 mg or placebo, was given once daily for 30 days. The primary endpoint was safety as measured by hemorrhagic events requiring medical attention. Samples for biomarkers were collected prior to initiation of study drug, on day 10 ± 2, and on day 30 ± 3. Multi-color fluorescent activated cell sorting and monoclonal antibodies were used to determine platelet P-selectin expression, platelet-monocyte aggregates (PMA), and platelet-neutrophil aggregates (PNA) using previously published protocols. Soluble P-selectin (sP-selectin), soluble CD40 ligand (sCD40L), thromboxane B2 (serum TXB2), and prothrombin fragment F1.2 (F1.2) were determined using standard enzyme-linked immunoassays. Statistical comparison between prasugrel and placebo was performed using a mixed model with treatment, baseline measurement, genotype of SCD, visit and the interaction between visit and treatment as fixed effects and subjects as a random effect. Results: Forty-one patients were randomized to prasugrel 5 mg and 21 to placebo. Mean age was 32 years; 48% were female; 60% HbSS, 5% HbS/b0thalassemia, 10% HbS/b+thalassemia, and 24% HbSC (1 patient was found not to have SCD but to only have b-thalassemia trait). Eighteen patients in the prasugrel and 9 in the placebo arm were on hydroxyurea prior to study drug. Results are shown in the Figure. Compared to placebo, platelet P-selectin (unstimulated), sP-selectin, and sCD40L all achieved or approached significantly lower values in the prasugrel group on day 10 and 30, as did ADP-stimulated platelet P-selectin values (data not shown). TXB2 was significantly lower on day 10 but not on day 30 (Fig. 1), as were PMA/PNA unstimulated, and PMA/PNA in response to ADP ex vivo. F1.2 levels were not different between the groups at either day 10 or 30 (data not shown). Conclusions: As would be predicted by the mechanism of action, prasugrel resulted in decreased cellular and soluble biomarkers of platelet activation. There was no effect on coagulation as assessed by F1.2, a marker of thrombin generation. Clinical results reported elsewhere suggest a decrease in pain rate. Prasugrel 5 mg po daily clearly decreases markers of platelet activation in adult SCD patients. These biomarkers can be incorporated in future studies of prasugrel in SCD to correlate with clinical outcomes. Disclosures: Wun: Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Off Label Use: This abstract discusses prasugrel treatment in patients with sickle cell disease. Please see USPI for most up-to-date information. Knupp:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. McMahon:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Strouse:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Heath:Eli Lilly and Company: Employment, Equity Ownership. Nwachuku:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Jakubowski:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership. Riesmeyer:Eli Lilly and Company: Employment, Equity Ownership. </jats:sec