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 double-blind, randomized, multicenter phase 2 study of prasugrel versus placebo in adult patients with sickle cell disease

Abstract Background Platelet activation has been implicated in the pathogenesis of sickle cell disease (SCD) suggesting antiplatelet agents may be therapeutic. To evaluate the safety of prasugrel, a thienopyridine antiplatelet agent, in adult patients with SCD, we conducted a double-blind, randomized, placebo-controlled study. Methods The primary endpoint, safety, was measured by hemorrhagic events requiring medical intervention. Patients were randomized to prasugrel 5 mg daily (n = 41) or placebo (n = 21) for 30 days. Platelet function by VerifyNow® P2Y12 and vasodilator-stimulated phosphoprotein assays at days 10 and 30 were significantly inhibited in prasugrel- compared with placebo-treated SCD patients. Results There were no hemorrhagic events requiring medical intervention in either study arm. Mean pain rate (percentage of days with pain) and intensity in the prasugrel arm were decreased compared with placebo. However, these decreases did not reach statistical significance. Platelet surface P-selectin and plasma soluble P-selectin, biomarkers of in vivo platelet activation, were significantly reduced in SCD patients receiving prasugrel compared with placebo. In sum, prasugrel was well tolerated and not associated with serious hemorrhagic events. Conclusions Despite the small size and short duration of this study, there was a decrease in platelet activation biomarkers and a trend toward decreased pain.</p