–Insights into thecardio-protective effects of a novel alirocumab and statin combination therapy, presented at the American Diabetes Association’s 78th Scientific Sessions, Orlando, Florida, 22–26, June 2018.
Diabetes is a global and growing clinical and public health challenge. In 2015, 415 million adults were estimated to have diabetes, and this number is predicted to increase to 642 million by 2040.1Diabetes more than doubles the risk for cardiovascular disease (CVD) and there is a strong association between diabetes, lipid metabolism disorders, coronary artery disease and hypertension.2,3
Prediabetes is a condition defined by glucose levels that do not meet the criteria for diabetes but that are too high to be considered normal.4,5 Prediabetes is associated with hypertension,obesity, dyslipidaemia with low high-density lipoprotein cholesteroland/or high triglycerides. Individuals with prediabetes are at an increased risk of both diabetes and CVD.6
As both diabetes and prediabetes increase the risk of CVD, healthcare interventions aimed at reducing CVD risk factors in these populations are paramount.6,7
Acute coronary syndrome (ACS) is a collective term for cardiovascular symptoms caused by acute disruption of the supply of oxygen to the heart, a condition also known as acute myocardial ischaemia. ACS covers a spectrum of clinical conditions ranging from unstable angina to heart attack.8
Although cholesterol is an essential building block for all human cells, it is also one of the main causes of CVD. Cholesterol is transported in the blood as lipoprotein particles. Two types of cholesterol-containing particles, known as high- and low-density lipoprotein particles (HDL and LDL, respectively), are relevant for the pathophysiology of CVD. HDL is colloquially known as ‘good’ cholesterol, and LDL as ‘bad’ cholesterol, sincedecreased HDL and increased LDL in the blood increase the risk of CVD.9
Statins are a class of drug that lowers LDL cholesterol levels in the blood, and thereby reduces the risk of CVD.10Since the clinical introduction of the first statin in 1987, many clinical studies have reported that statin therapy reduces major cardiovascular events by reducing LDLcholesterol in the blood, which has led to a revolution in the management of CVD.11 Interestingly, the ‘lower is better’ LDL cholesterol hypothesis proposes that the more LDL cholesterol is reduced, the more the incidence of cardiovascular events is reduced. Combination therapies of statins with other lipid-lowering drugs are therefore predicted to further reduce the risk of CVD.12
Alirocumab is a human monoclonal antibody that inhibits PCSK9, a protein that facilitates the degradation of LDL receptors that capture and remove LDL particles from the blood.13Inhibition of PCSK9 leads to marked reductions in LDL levels and reduced cardiovascular and all-cause mortality.14 Alirocumab is currently approved to treat high LDL cholesterol levels, often in combination with cholesterol-lowering statins or other blood
The large ODYSSEY OUTCOMES phase III trial (Nn=18,924)compared the safety and efficacy of alirocumab as an add-on to intensive or maximum-tolerated statin therapy in patients with recent ACS.17
An analysis of the ODYSSEY OUTCOMES study data focusing on the benefit of alirocumab in combination with statins in normoglycaemic, prediabetic and diabetic patients who had recently experienced an ACS was presented at the American Diabetes Association’s 78th Scientific Sessions at the Orange County Convention Center, Orlando, Florida.
The study investigators focused on patients with LDL cholesterol levels above 70mg/dL, which is higher than the recommended American Association of Clinical Endocrinologists’ guidelines for people with cardiovascular disease.18
The study participants were grouped into one of three groups (normoglycaemic, prediabetic, or diabetic) based on their baseline diabetes status and randomly assigned to receive either alirocumab 75 mg or placebo.In some study participants,the alirocumab dose was blindly increased to 150 mg or decreased to placebo to achieve a final LDL cholesterol level in the range of 25–50mg/dL. The primary efficacy endpoint was length of time to first major adverse cardiac event (MACE), a composite endpoint that includes coronary heart disease death, nonfatal heart attack, ischaemic stroke, or hospitalisation for unstable angina.19
The overall results demonstrated a reduced MACE incidence, without evidence of effect modification by baseline glucometabolic status. The greatest absolute risk reduction was observed with alirocumab in study participants with diabetes. New onset diabetes did not increase with the use of alirocumab.
Professor Kausik Ray, MD, ChB, Professor of public health, Department of Public Health and Primary Care at the School of Public Health of Imperial College in London and lead investigator of this ODYSSEY OUTCOMES analysis, explained that the data clearly demonstrates that adding alirocumab to maximally tolerated statin doses reduces the overall incidence of MACE, and the absolute risk reduction is highest among those with diabetes, when compared to people with prediabetes or people without diabetes.
‘One reason for the success of the medication combination in this group is that their absolute risk was so high; the other groups that took the alirocumab also derived benefit, but the benefit was slightly less because their risk was lower.’
Prof. Ray was also pleased to point out that although some genetic studies have suggested that lowering LDL cholesterol with PCSK9 inhibitors might push people with prediabetes to diabetes, no evidence of new onset diabetes was identified in study participants treated with alirocumab.
‘These results suggest intensive cholesterol-lowering using the combination of statins and alirocumab offers us a means to significantly reduce heart disease risk in this patient population.’
In conclusion, statins revolutionised cardiovascular disease care when they were first approved in 1987. Now, 31 years’ later, the innovative ODYSSEY OUTCOMES study demonstrates that further health benefits can be achieved by combining statin therapy with LDL-lowering agents that act via different mechanisms of action, such as the monoclonal antibody alirocumab, and that this combination therapy appears to be particularly efficacious in patients with both diabetes and CVD, who are at the highest risk of MACE.
There is an urgent need to add new treatment regimens to our arsenal of CVD drugs, as we have not yet seen the peak of the formidable diabetes mountain that lies ahead of us, or its cardiovascular comorbidities. Encouraging results from the ODYSSEY OUTCOMES study suggest that alirocumab might be able to reduce the healthcare burden facing patients with both diabetes and CVD, andreduce the risk of serious cardiovascular events in this high-risk population.
1. Ogurtsova K et al. IDF Diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract. 2017;128:40-50.
2. Emerging Risk Factors Collaboration, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375:2215-22.
3. Kendir C, et al. Cardiovascular disease patients have increased risk for comorbidity: across-sectional study in the Netherlands. Eur J Gen Pract. 2018 ;24:45-50.
4. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183-97.
5. Genuth S, et al. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care.2003;26:3160-7.
6. American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2018. Diabetes Care 2018;41(Suppl 1):S13-S27.
7. Leon BM, et al. Diabetes and cardiovascular disease: epidemiology, biological mechanisms, treatment recommendations and future research. World J Diabetes. 2015;6:1246-58.
8. Kumar A, et al. Acute coronary syndromes: diagnosis and management, part I. Mayo Clin Proc. 2009;84:917-38.
9. Wadhera RK, et al. A review of low-density lipoprotein cholesterol, treatment strategies, and its impact on cardiovascular disease morbidity and mortality. J Clin Lipidol. 2016;10:472-89.
10. Endo A. A historical perspective on the discovery of statins. Proc JpnAcad Ser B Phys Biol Sci. 2010;86:484-93.
11. Lim SY. Role of statins in coronary artery disease. Chonnam Med J. 2013;49:1-6
12. Baigent C, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267-78.
13. Giugliano RP, et al. Are PCSK9 inhibitors the next breakthrough in the cardiovascular field? J Am Coll Cardiol. 2015;65:2638-51.
14. Navarese EP, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med. 2015;163:40-51.
15. Praluent EPAR. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003882/WC500194521.pdf( accessed 14 July 2018).
16. Praluent USPI. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125559Orig1s000lbledt.pdf(accessed 14 July 2018).
17. ODYSSEY OUTCOMES. Available at: https://www.acc.org/latest-in-cardiology/clinical-trials/2018/03/09/08/02/odyssey-outcomes(accessed 25 July 2018).
18. Jellinger PS, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. EndocrPract. 2017;23(Suppl 2):1-87.
19. Marx N, et al. Composite primary end points in cardiovascular outcomes trials involving type 2 diabetes patients: should unstable angina be included in the primary end point? Diabetes Care. 2017;40:1144-51.