Efficacy and safety
The participants included in this analysis from the DM-DYSLIPIDEMIA and DM INSULIN trials had both prior ASCVD and T2DM, and represent a population with a very high risk of CV events for which a target LDL-C < 70 mg/dL and non-HDL-C < 100 mg/dL were generally recommended at the time of study implementation [10, 11]. In our study population, statins at maximally tolerated doses were largely insufficient to achieve guideline-recommended lipid goals and thus it represents a group with high residual risk and an unmet therapeutic need. In the present analysis, significant reductions in LDL-C, non-HDL-C, and Apo B were observed with alirocumab versus controls, which is consistent with the results in the overall trial populations from the primary DM-DYSLIPIDEMIA and DM-INSULIN studies. Alirocumab treatment resulted in significant LDL-C reductions from baseline to week 24 compared with either UC or placebo (− 43.0% and − 49.0%, respectively; P < 0.0001) on background maximally tolerated statin therapy [4, 8]. Furthermore, alirocumab also significantly reduced non-HDL-C and ApoB at week 24 versus control, which better predict total atherogenic burden in this population, and results were consistent with the results of the primary studies [4, 8]. Finally, levels of low-density lipoprotein particle (LDL-P), which may more closely align with CV risk than LDL-C in diabetes, were also significantly reduced with alirocumab therapy.
This post hoc analysis confirmed similar adverse event patterns in alirocumab-treated individuals and controls already reported in other studies. In both studies, alirocumab was generally well tolerated, with comparable rates of TEAEs between alirocumab and UC or placebo. The overall incidence of injection-site reactions for both primary studies was low, with no greater incidence seen in alirocumab-treated individuals [4, 8]. However, in the overall alirocumab trial population, including both individuals with and without diabetes, injection-site reactions were found at a higher frequency with alirocumab compared with controls [8, 12]. In a real-world analysis of three datasets from a hospital registry (n = 164), and two pharmacovigilance databases, Lareb (n = 149) and VigiLyze (n = 15,554), PCSK9 inhibitors were found to be well tolerated with an overall safety profile comparable to currently available randomized clinical trials . The most common adverse events included influenza-like illness, nasopharyngitis, myalgia, and injection-site reactions, all of which resolved over time. Furthermore, while the benefit of PCSK9 inhibitors is primarily ascribed to their LDL-C reducing activity, data suggest that they may also influence platelet function and blood coagulation .
CV events and outcomes
Long-term CV outcome studies have shown that PCSK9 inhibitors reduce CV event rates similarly in individuals with and without T2DM and prior CV disease or recent acute coronary syndrome [15, 16]. However, absolute risk is higher among those with diabetes and established ASCVD and therefore these patients are expected to derive greater absolute benefits from further LLT. In the FOURIER trial, patients with diabetes and a baseline LDL-C level of around 90 mg/dL had a 5-point major adverse CV event rate of 17.1%, which decreased to 14.4% by reducing LDL-C to around 30 mg/dL . The latter event rate is only marginally higher than the 13.0% event rate among patients without diabetes, stable ASCVD, and LDL-C of around 90 mg/dL, highlighting the important role more intensive LDL-C lowering can have in mitigating the excess CV risk in high-risk states. In addition, a reduction in LDL-C levels to target concentrations of 25.1 mg/dL (0.65 mmol/L)–50.3 mg/dL (1.3 mmol/L) has been proposed to reduce CV events in patients with a recent ACS and diabetes . In an analysis of the ODYSSEY OUTCOMES trial, the effect of alirocumab on CV outcomes was assessed by baseline glycemic status (27.7% were patients with normoglycemia, 28.8% with diabetes, and 43.6% with pre-diabetes). Results demonstrated that after a recent ACS, treatment with alirocumab targeting the above-mentioned LDL-C concentrations produces about twice the absolute reduction in CV events among patients with diabetes as in those without diabetes . Furthermore, it has recently been reported that alirocumab on top of intensive statin therapy potentially reduces death after ACS, particularly in treatments for ≥ 3 years, if baseline LDL-C is ≥ 100 mg/dL, or if achieved LDL-C is low .
Current treatment guidelines recommend that LDL-C targets are set according to an individual’s CV risk. Individuals with T2DM and prior ASCVD are classified as being at extreme risk by the American Association of Clinical Endocrinologists (AACE), who recommend LDL-C targets of < 55 mg/dL, non-HDL-C targets of < 80 mg/dL, and ApoB targets of < 70 mg/dL for this patient population . In addition, the AACE recommends the consideration of PCSK9 inhibitors in individuals with clinical CV disease who are unable to reach LDL-C or non-HDL-C goals with maximally tolerated statin therapy . The published data from the FOURIER and ODYSSEY OUTCOMES trials further support this assertion; however, these more aggressive lipid targets have not been adopted by all guidelines to date. It is also important to note the influence that certain diabetic medications may have on PCSK9 expression. Liraglutide, a once-daily glucagon-like peptide-1 (GLP-1) agonist, was found to suppress PCSK9 expression via a hepatocyte nuclear factor 1 alpha (HNF1α)-dependent mechanism in the human hepatoma cell line, HepG2 . In this analysis, between 9 and 17% of patients received a GLP-1 agonist; however, it would not be appropriate to speculate the effects this may exert on the results.
It is noteworthy that in DM-DYSLIPIDEMIA, alirocumab was superior to moderate-dose fish oils and fenofibrate in improving the atherogenic lipid profile . Furthermore, results from the ACCORD-LIPID study demonstrated that combination therapy with fenofibrate and simvastatin did not significantly reduce CV event rates compared with statin monotherapy in patients with T2DM . Ongoing trials, including the CVOT PROMINENT (NCT03071692) study are further investigating the use of fibrates in this patient population. This is clinically relevant as fish oil and fenofibrate are considered by some as therapeutic options after statins in patients with mixed dyslipidemia. With that said, high dose eicosapentaenoic acid in the REDUCE-IT trial did reduce CV events despite achieving only modest reductions in triglycerides and ApoB . The reasons for this are unclear but could include beneficial pleiotropic effects beyond the change in atherogenic particle number.
Analysis of DM-DYSLIPIDEMIA and DM-INSULIN
DM-DYSLIPIDEMIA and DM-INSULIN were separate trials with different study designs (one versus UC and the other versus placebo); however, both studies were conducted exclusively in patients with diabetes. While patients in the DM-DYSLIPIDEMIA trial were enrolled because of elevated non-HDL-C, those in DM-INSULIN were enrolled only based on elevated LDL-C. In DM-DYSLIPIDEMIA, alirocumab significantly reduced non-HDL-C (the primary endpoint) and LDL-C versus UC (P < 0.0001) . In DM-INSULIN, alirocumab treatment resulted in significant LDL-C reductions compared with placebo (P < 0.0001) . As the study designs were different, we presented our analyses separately for each trial. However, it is worth noting that patients in the DM-INSULIN trial had similar ApoB and LDL-P levels to those patients in the DM-DYSLIPIDEMIA trial. Furthermore, insulin therapy is often the end stage of glucose-lowering medication intensification and the observation that patients on insulin had high levels of atherogenic lipoproteins only serves to reinforce the high CV risk of this patient population.
One major rationale for evaluating the subgroups with ASCVD in DM-DYSLIPIDEMIA and DM-INSULIN is because both studies investigated patients with increased levels of TGRL (non-HDL-C minus LDL-C). The average baseline level of TGRL was approximately 34 mg/dL and 48 mg/dL in DM-INSULIN and DM-DYSLIPIDEMIA, respectively [4, 8]. These studies therefore represent a different diabetic patient population than those included in the FOURIER and ODYSSEY OUTCOMES trials, with broader eligibility criteria regarding the type of CV disease. In both of these clinical outcomes trials, non-HDL-C levels were ≤ 125 mg/dL and TGRL levels were < 32 mg/dL [7, 16].