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

Abstract

Therapeutic Area

Pharmacologic Therapy

Background

Clinical and genetic studies indicate LDL-C lowering cardiovascular benefits proportional to LDL-C degree reduction, not by its mechanism achieved; however, LDL-C lowering effect on glycemic control and new onset diabetes (NoD) vary by intervention. Although genetics predict on-target effect on HMGCoA, NCP1L1 and PCSK9 lowering of NoD risk, this has only been observed in statin trials. Obicetrapib, a cholesteryl ester transfer protein inhibitor (CETPi), reduces LDL-C, Lp(a) and raises apoA1/HDL-C. Metaanalyses of early CETPi trials demonstrated 16% lower NoD risk. Effects of obicetrapib on glycaemia and NoD risk are unknown.

Methods

Pooled analysis of BROADWAY and BROOKLYN trials which randomized ASCVD or HeFH patients with elevated LDL-C despite maximally tolerated statins to Obicetrapib 10mg once daily or placebo for 1 year, were conducted. Obicetrapib’s day 84 and 365 HbA1c effects and NoD risk in patients without known baseline diabetic history and glycaemia strata (prediabetes, or normoglycemia), were assessed - adjusted for baseline Hba1c, trial and statin use. An additional updated meta-analysis of NoD risk with CETPi including obicetrapib data was performed, determining whether any observed associations were consistent with prior class-level observations.

Results

1848 patients, mean age 63.4, women 38.1%, 89.7% on statin were included with baseline median LDLC, 96 mg/dl (IQR 78-126), HbA1c 5.7% (5.4%-5.9%). Placebo-corrected LDL-C, Lp(a), and HDL-C median changes were -35.3%, -35.6%, and +136.7% (all P < 0.0001. Post-baseline HbA1c was lower with Obicetrapib vs Placebo, p <0.0297), consistent by glycemia stratum (Figure). Treatment HR for NoD was 0.77 (95% CI 0.57-1.04), p=0.09 (Figure) with consistent trends in those within normoglycemia and prediabetes (Figure). The additional updated meta-analysis, including obicetrapib data from 4 prior large RCTS, produced an overall RR for NoD of 0.83 (CI 0.77-0.90), 13.5%, p-value for heterogeneity 0.493, consistent with CETPi overall class effect

Conclusions

Obicetrapib reduced HbA1c trending towards lower risk of NoD in prediabetic and normoglycemic patients at baseline. Although obicetrapib led to greater LDL-C reductions than other CETPi, Obicetrapib effects on NoD were consistent with other CETPi. As risk of NoD accrues over time, larger, longer trials are needed to determine full degree of potential protective effects of obicetrapib on NoD risk.