Effect of Obicetrapib on New Onset Diabetes In Patients with Elevated LDL-C Receiving Maximally Tolerated Statin Therapy: Pooled Analyses of the Broadway and Brooklyn Trials

<h3>Funding</h3> The Broadway and Brooklyn trials were funded by New Amsterdam Pharma. <h3>Background</h3> Clinical trials and genetic studies indicate that the cardiovascular benefits of low-density lipoprotein cholesterol (LDL-C) lowering are proportional to their degree of LDL-C lowering, not the mechanism by which it is achieved. By contrast, the effects of LDL-C lowering on glycaemic control and new onset diabetes (NoD) vary by intervention. Although genetics predict an on-target effect on HMGCoA, NCP1L1 and PCSK9 lowering on risk of NoD, this has only been observed in trials of statins (HMGCoA inhibition). Obicetrapib is a cholesteryl ester transfer protein inhibitor (CETPi) that reduces LDL-C and Lp(a) and raises apoA1/HDL-C. Meta-analyses of early CETPi trials demonstrated a 16% lower risk of NoD. The effects of Obi on glycaemia and risk of NoD are unknown. <h3>Methods</h3> Pooled analysis of patients in the Broadway and Brooklyn trials which randomised patients with ASCVD or HeFH with elevated LDL-C despite maximally tolerated statins to Obicetrapib 10mg once daily or placebo for 1 year. The effect of Obicetrapib on HbA1c at days 84 and 365 and risk of NoD was assessed in patients without a known history of diabetes at baseline and by glycaemia strata (prediabetes, or normoglycaemia) using standard criteria with adjustment for baseline Hba1c, trial and statin use at baseline. We also conducted an updated meta-analysis of the risk of NoD with CETPi including Obicetrapib data assess whether any observed associations were consistent with prior class-level observations. <h3>Results</h3> A total of 1848 patients were included; mean age 63.4, women 38.1%, 89.7% on statin. Baseline median LDL-C was 96 mg/dl (IQR 78-126), HbA1c was 5.7% (5.4%-5.9%). Placebo corrected median changes in LDL-C, Lp(a) and HDL-C were -35.3%, -35.6%, and +136.7%, respectively, all P < 0.0001. Post-baseline HbA1c was lower with Obicetrapib vs Placebo, p < 0.0297), with consistent by glycemia stratum (Figure). The treatment HR for NoD was 0.77 (95% CI 0.57-1.04), p=0.09 (Figure) with consistent trends in those within normoglycaemia and prediabetes (Figure). In an updated meta-analysis, including obicetrapib data with that from 4 prior large RCTS produced an overall RR for NoD of 0.83 (CI 0.77-0.90), I² 13.5%, p-value for heterogeneity 0.493, consistent with an overall class effect for CETPi. <h3>Conclusion</h3> Obicetrapib reduced HbA1c with a trend towards a lower risk of NoD in those with prediabetes and normoglycemia at baseline. Although obicetrapib led to greater LDL-C reductions than other CETPi, the effects of Obiceterapib on NoD were consistent with other CETPi. As risk of NoD accrues over time, larger and longer trials are needed to determine the full degree of potential protective effects of Obicetrapib on risk of NoD.