Introduction

In patients with atherosclerotic cardiovascular disease (ASCVD) the co-existence of diabetes mellitus (DM) brings a great excessive risk for recurrent, mainly ischemic major adverse cardiovascular events (MACE). In accordance with the well accepted 'the lower the better' hypothesis for LDL cholesterol (LDL-C) also in DM patients further reductions in LDL-C – below the targets set by the major guidelines – can lead to additional reductions in MACE. Recent evidence supports the safe and beneficial reduction of LDL-C to very low levels, and that a reduction in MACE may be expected regardless of the kind of hypolipidemic treatment chosen.¹

The prespecified sub-analysis of the mega ODYSSEY Outcomes trial demonstrated that diabetic patients (in comparison to their non-diabetic counterparts) who had recently suffered from acute coronary syndrome (ACS) gained about twice the absolute risk reduction (ARR) for MACE when treated with proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) alirocumab on top of the high-intensity statin therapy.² The core message about the benefits brought by alirocumab in this setting is very clear – a 'higher initial cardiovascular risk translates into higher benefits' of PCSK9i pharmacotherapy.

ODYSSEY Outcomes – General

The ODYSSEY Outcomes trial as a whole encompassed 18,924 patients with recent ACS and LDL-C levels of at least 70 mg/dL (1.8 mmol/L) despite maximum statin therapy.³ They were randomly assigned to either 75 mg of PCSK9i alirocumab every 2 weeks or placebo, and the doses of the study drug were increased blindly, to 150 mg, to reach LDL-C levels of 25-50 mg/dL (0.65 – 1.3 mmol/L). During a median 2.8 years of follow-up, the overall cumulative rate of MACE (coronary heart disease death, nonfatal MI, ischemic stroke, or hospitalization for unstable angina) was found in 9.5% of patients randomized to alirocumab, and 11.1% on placebo (i.e. 1.6% absolute risk reduction [ARR]), which translates into a statistically significant and clinically important overall 15% reduction in relative risk (RRR).

ODYSSEY Outcomes – Prespecified Analysis According to the Glycemic Status

With the prespecified analysis of the ODYSSEY Outcomes in question, investigators assessed the efficacy of alirocumab by glycemic status of the study population, defined on the basis of patient history, review of medical records, baseline HbA1c or fasting serum glucose.² At inclusion, diabetes was present in 5,444 patients (28.8%), while 8,246 (43.6%) had prediabetes, and important to note, only less than one third of the study population, 5,234 (27.7%) were normoglycemic. Across all three glycemic categories, no significant differences in median LDL-C were reported at baseline (2.20–2.28 mmol/L), after 4 months treatment with placebo (2.25–2.28 mmol/L), or after 4 months treatment with alirocumab (0.80 mmol/L).

During the study follow-up (of almost 3 years), the incidence of the primary endpoint in the placebo group was significantly greater in patients with DM (in 452 of 2,751 patients, or 16.4%) when compared to those with prediabetes (9.2%) or normoglycemia (8.5%) (hazard ratio (HR) for DM versus normoglycemia was 2.09, 95% CI 1.78–2.46, p<0.0001, and for DM versus prediabetes 1.90, 95% CI 1.65–2.17, p<0.0001). With alirocumab the cumulative rate of incident events was 14.1% (380 of 2,693 patients) in patients with DM, what gives us almost double the ARR of 2.3% (95% CI 0.4 - 4.2) in comparison to those with prediabetes or normoglycemia, with an ARR of 1.2% for both groups (ARR p_int=0.0019). This would indicate numbers needed to treat (NNT) of 43 compared to 83, respectively. Alirocumab resulted in a similar RRR in the incidence of the primary endpoint in each glycemic category (with HRs of 0.84 in diabetics (95% CI 0.74–0.97), 0.86 in prediabetes (95% CI 0.74–0.97), and 0.85 with normoglycemia (95% CI 0.70–1.03). Nevertheless, it's important to note that these relatively modest additional treatment effects were achieved in patients being basically treated with almost all available up-to-date evidence-based therapies. After being revascularized for the index ACS event, almost all received dual antiplatelet therapy, high-intensity statins, β-blockers and renin-angiotensin-aldosterone system inhibitors, and were found with the good control of blood glucose before and during the trial as well (mean baseline HbA_1c of 7.0% was reported in patients with DM).² One of the discussed limitations of the study was the very low use of the new classes of drugs, at the end of the study only 0.9% were receiving GLP-1 receptor agonists, and 1.5% SGLT2 inhibitors. It is uncertain whether greater use of these classes of drugs would affect the magnitude of the observed benefit of alirocumab treatment in patients with ACS and DM, although the evidence to date suggests that the benefits of newer diabetes treatments and lipid lowering are complementary.

Lipid Lowering Therapies and Increased Risk of DM

Several clinical trials, meta analyses, as well as Mendelian randomization studies found that statin treatment, especially when used in higher doses, can increase the risk of new-onset DM.^4,5 It was suggested that due to the long-term LDL-C lowering also the PCSK9i can trigger the same, but to what extent the treatment with these drugs itself affects the glucose metabolism is unclear. In FOURIER trial, although there was no overall increased risk of new-onset DM with the PCSK9i evolocumab compared with placebo, an increased nominal risk was detected among a subgroup of patients with normoglycemia at baseline.⁶

In ODYSSEY Outcomes, altogether 648 (9.6%) of patients without DM at inclusion developed it in the alirocumab group, and 676 (10.1%) in the placebo group.² This effectively means that the use of alirocumab did not increase the risk of new-onset DM (HR 1.00, 95% CI 0.89–1.11). As expected, developing diabetes during the trial was more common in patients with prediabetes at baseline (13.8% [570/4128] in the alirocumab, and 15.3% [614/4017] in the placebo group) than in those who were normoglycemic at baseline (3.0% [78/2635] and 2.4% [62/2589]). All these are in concordance with the data from the earlier pooled analysis from the 10 Phase 3 ODYSSEY program trials with alirocumab; but although reassuring, the treatment duration from this analysis is fairly small.⁷ In a model including the interaction with normoglycemia and prediabetes status, the subgroup HRs were 1.23 (95% CI 0.88–1.71) for those with baseline normoglycemia and 0.92 (0.82–1.03) for those with baseline prediabetes (p_int=0.11).

The most recent extensive meta-analysis of trials with contemporary (and intensive) lipid-lowering therapies demonstrated no independent association between reduction in LDL-C and incident DM.⁴ However, it was confirmed that the risk of incident DM was higher with statins, whereas in most of the trials PCSK9i had no association with risk of newly developed DM.⁵ This could probably be, at least in part, due to the relatively short treatment duration in these studies, so the additional data from large populations over a longer observation period are needed in order better to determine the glucometabolic safety of PCSK9 inhibition.

PCSK9i Cost Effectiveness in Patients with Concurrent ASCVD and DM

Diabetic patients who recently suffered an ACS belong to the "very-high", or even to the so-called "extremely-high", ASCVD risk group. The latter was first recognized in the 2017 American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of CVD by setting even lower LDL-C target in diabetics with ASCVD (to less than 55 mg/dL or 1.4 mmol/L).⁸ Such a recommendation followed the results of the IMPROVE-IT trial using add-on ezetimibe plus (simva)statin combination lipid lowering treatment, confirming the validity of the principle of "even lower is even better" regarding LDL-C in patients at a very high ASCVD risk (as post-ACS patients definitely are).  It was clearly demonstrated that additional, although modest LDL-C reduction prevents even more events, independently of the LDL-C reducing strategy.⁹ Further on, following the results of the FOURIER and ODYSSEY Outcomes mega clinical trials, the most recent European and US guidelines recommend the use of PCSK9i as appropriate in specific groups of patients at very high ASCVD risk in whom the recommended LDL-C levels cannot be achieved using the maximally tolerated doses of potent statins and/or ezetimibe.^3,10-12

However, for the wider acceptance and consistent implementation of current guidelines on PCSK9i use, it would be important to overcome the barriers of eventually existing, or in some cases only perceived (potentially biased), too high expense. For this reason, cost-effectiveness analyses are essential in order to assess whether, how, and when the PCSK9i treatment meets consensually agreed value for money in a particular setting or circumstances.^13,14 While there is no doubt that with regard to the eligibility for PCSK9i reimbursement the ODYSSEY Outcomes population is certainly very highly ranked, specific quality cost-effectiveness analysis related to the use of alirocumab in post-ACS patients with diabetes is lacking.¹⁵ For this reason, at this point only the "highest risk – highest benefit" principle can be recommended.¹⁶ Such an approach was used in a modelling attempt aiming to assure simple reading of evidence-based numbers needed-to-treat (NNT), considering both the initial absolute risk of MACE and the LDL-C levels. On this basis, the NNT with alirocumab in a typical ODYSSEY Outcomes patient with DM is somewhere between 14 and 22.¹⁶ The model is not intended only to help physicians in making decisions to prescribe PCSK9i or not, but can also be used by the payers' side, since the balance between the costs and health outcomes can be assumed from the model at a broad range of potential risk reductions and drug costs.^13,16

Conclusions

The presence of DM determines a group of patients with significantly increased risk of further events, among those with manifest ASCVD. In ODYSSEY Outcomes, the relative risk reduction for MACE achieved with alirocumab in patients on maximum statin therapy after an ACS was similar among patients with normoglycemia, prediabetes, or DM at baseline. However, since the event rate in patients with DM at baseline was two-times higher than in patients without, also the effect of the treatment with the PCSK9i translates into the almost double absolute risk reduction with alirocumab in diabetics compared to patients without DM, with a corresponding almost half the NNT.² These results are consistent with the previous observations of benefits in the same groups of patients, but more stable ASCVD receiving evolocumab from the FOURIER trial.⁶

On such a basis of data from large randomized clinical trials available until now, we can firmly conclude that in the setting of either stable ASCVD or post-ACS, individuals with diabetes derive extensively greater absolute benefit from the addition of a PCSK9i to background high-intensity statin therapy to achieve LDL-C levels well below current guideline recommendations. This implies also that in future guidelines the consideration should be given to recommending LDL-C goals in the 25-50 mg/dL (0.65–1.30 mmol/L) range for secondary prevention in these extremely high-risk individuals.

References

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3. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097–107.
4. Khan SU, Rahman H, Okunrintemi V, et al. Association of lowering low-density lipoprotein cholesterol with contemporary lipid-lowering therapies and risk of diabetes mellitus: a systematic review and meta-analysis. J Am Heart Assoc 2019;8:e011581.
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7. Colhoun HM, Ginsberg HN, Robinson JG, et al. No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies. Eur Heart J 2016;37:2981–9.
8. Jellinger PS, Handelsman Y, Rosenblit PD, et al. 2017 AACE/ACE Guidelines American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract 2017;23:Suppl 2:1–87.
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16. Annemans L, Packard CJ, Briggs A, Ray KK. 'Highest risk-highest benefit' strategy: a pragmatic, cost-effective approach to targeting use of PCSK9 inhibitor therapies. Eur Heart J 2018;39:2546-50.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Diabetes Mellitus, Metabolic Syndrome, Cholesterol, LDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Blood Glucose, Numbers Needed To Treat, Prediabetic State, PCSK9 protein, human, Proprotein Convertase 9, Cardiovascular Diseases, Hemoglobin A, Platelet Aggregation Inhibitors

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