Effects of evolocumab in individuals with type 2 diabetes with and without atherogenic dyslipidemia: An analysis from BANTING and BERSON

(2021) 20:94 Lorenzatti et al. Cardiovasc Diabetol https://doi.org/10.1186/s12933-021-01287-6 Cardiovascular Diabetology ORIGINAL INVESTIGATION Open Access Effects of evolocumab in individuals with type 2 diabetes with and without atherogenic dyslipidemia: An analysis from BANTING and BERSON Alberto J. Lorenzatti1* , Maria Laura Monsalvo2, J. Antonio G. López2, Huei Wang3 and Robert S. Rosenson4 Abstract Background: Atherogenic dyslipidemia (AD), characterized by increased concentrations of apolipoprotein B (ApoB)containing particles, is often present in individuals with type 2 diabetes mellitus (T2DM). Non-high-density lipoprotein cholesterol (non-HDL-C), cholesterol transported by apolipoprotein B (ApoB)-containing particles), and total apoB are considered secondary goals of lipid-lowering therapy to guide treatment of residual cardiovascular risk. The BANTING and BERSON studies demonstrated that evolocumab added to statin therapy reduced atherogenic lipid and lipoproteins concentrations in patients with T2DM. Methods: This post-hoc analysis combined data from two randomized, placebo-controlled trials, BANTING and BERSON, to investigate the effect of evolocumab (140 mg every two weeks [Q2W] or 420 mg monthly [QM]) on atherogenic lipid (LDL-C, non-HDL-C, VLDL-C, remnant cholesterol) and lipoproteins (ApoB, lipoprotein(a) (Lp[a])), and achievement of 2019 European Society of Cardiology/European Atherosclerosis Society lipid treatment goals in individuals with and without AD. Results: In individuals with high TGs with (n = 389) and without (n = 196) AD receiving background statin therapy, evolocumab, compared with placebo, substantially reduced the cholesterol levels from all ApoB atherogenic lipoproteins (least squares (LS) mean LDL-C by 66.7% to 74.3%, non-HDL-C by 53.4% to 65.8%, median remnant cholesterol by 28.9% to 34.2%, VLDL-C by 16.1% to 19.6%) and median TGs levels (by 17.5% to 19.6%) at the mean of weeks 10 and 12. LS mean ApoB was significantly reduced by 41.5% to 56.6% at week 12. Results were consistent in diabetic individuals with normal TGs (n = 519). Evolocumab was also associated with a significant reduction in median Lp(a) by 35.0% to 53.9% at the mean of weeks 10 and 12. A majority (74.7% to 79.8%) of evolocumab-treated individuals achieved the goal of both an LDL-C < 1.4 mmol/L and an LDL-C reduction of at least 50%, > 75% achieved non-HDL-C < 2.2 mmol/L at the mean of weeks 10 and 12, and > 67% achieved ApoB < 65 mg/dL at week 12. Conclusions: Evolocumab effectively reduced LDL-C, non-HDL-C, ApoB, Lp(a), and remnant cholesterol in individuals with T2DM with and without AD. Evolocumab Q2W or QM enabled most individuals at high/very-high cardiovascular disease risk to achieve their LDL-C, non-HDL-C, and ApoB recommended goals. *Correspondence: ; 1 Clinical Research and Cardiology, Instituto Médico DAMIC/Fundación Rusculleda, Córdoba, Argentina Full list of author information is available at the end of the article © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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Cardiovasc Diabetol (2021) 20:94 Page 2 of 14 Keywords: Atherogenic dyslipidemia, Cardiovascular disease, Diabetes mellitus, Evolocumab, Lipid-lowering therapy, Lipoproteins, PCSK9 inhibition, Treatment goals Background The lipid profile of patients with atherogenic dyslipidemia (AD) is generally characterized by high triglycerides (TGs), low high-density lipoprotein cholesterol (HDL-C), and mildly elevated or even normal low-density lipoprotein cholesterol (LDL-C) levels. The lipoprotein assessment in these patients reveals an increase in triglyceride-rich lipoproteins (TRL) (chylomicrons, verylow-density lipoprotein [VLDL]), accumulation of lipoprotein remnants (chylomicron remnants, small VLDL, and intermediate-density lipoprotein), and predominantly small, dense LDL particles [1, 2]. The atherogenic nature is due to the increased number of apolipoprotein B (ApoB)-containing particles, also characterized by elevated non-HDL-C levels. Insulin resistance has been identified as the main factor for the development of AD, which is often present in patients with insulin resistance phenotypically captured by obesity, metabolic syndrome, impaired glucose tolerance, and type 2 diabetes mellitus (T2DM) [3–5]. Epidemiological, clinical, and genetic studies have supported the AD’s role as a causal factor for the development and progression of atherosclerotic cardiovascular disease (ASCVD) [6–12]. Many patients who attained their LDL-C goal with lipid-lowering therapies continue to experience cardiovascular events; the increase of other ApoB-containing lipoproteins likely contributes to the residual risk [13–18]. Thus, while LDL-C is the primary focus for dyslipidemia management and ASCVD prevention, it might not reflect the actual atherogenic burden in patients with AD. In these patients, measuring both nonHDL-C and ApoB levels is recommended for ASCVD risk assessment [5]. Moreover, the 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/ EAS) guidelines for the management of dyslipidemias have defined secondary goals for both non-HDL-C and ApoB to help guide lipid-lowering therapy adjustments after the achievement of an LDL-C goal [5]. Patients with type 2 diabetes mellitus (T2DM) are at exceptionally high risk of cardiovascular disease (CVD) morbidity and mortality; several society guidelines recommend an aggressive lipid management approach to reduce CVD risk [5, 19–21]. However, lipid levels in many patients with T2DM receiving statin therapy remain above the recommended thresholds. A second therapy is needed to attain lipid treatment goals and further reduce the risk of cardiovascular events [22, 23]. In two double-blind, randomized, phase 3 studies of individuals with T2DM (BANTING, NCT02739984; BERSON, NCT02662569), evolocumab, a fully human monoclonal antibody that is a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i), (...truncated)