For a patient with cardiovascular disease (CVD), a diagnosis of diabetes is associated with significantly worse clinical outcomes.¹ Although CVD mortality decreased from 1980 to 2015, diabetes prevalence rose 31% from approximately 333 million people in 2005 to nearly 435 million in 2015.^2,3 A major link between diabetes and CVD is "diabetic dyslipidemia" which occurs when a patient has high fasting and/or postprandial triglycerides, low HDL-cholesterol (HDL-C), average to high LDL-C, and predominantly small dense LDL particles.¹

Even for patients on lipid-lowering medications, many still are not on adequate statin intensity and still have elevated LDL-C.^4,5 The recent 2018 AHA/ACC Multi-Society Cholesterol Guidelines recommend that all adults with diabetes aged 40-75 with an LDL-C >70 should receive a moderate or high intensity statin. Additionally, the guidelines offer a IIb recommendation to initiating a statin in those age 20-39 with certain higher risk features. Although the prevalence of diabetes has risen dramatically, the trend for decreasing cardiovascular events in these patients appears to be somewhat less compared to adults without diabetes.^1,6

A meta-analysis of 156,381 patients demonstrated that elevated non-HDL-cholesterol correlated with an about 60% CVD risk increase for the general population and a 99% increase for those with type 2 diabetes.⁷ As a result, further elucidating optimal treatment plans to reduce CVD risk for individuals with diabetes is critical.¹

Lifestyle and Statins

Although lifestyle modifications are the backbone of reducing CVD, they may not be as effective in persons with diabetes. A diet with reduced saturated fat and minimal trans fat, like the Mediterranean or DASH diets, can help lower LDL-C and CVD risk. Additionally, the American Heart Association recommends moderate to vigorous exercise for 150 to 300 minutes per week. While diet and exercise improve weight loss and glycemic control, it has been hard to show that sustained lifestyle improvement significantly improve mortality in diabetics.^8,9

Statins are critical for lowering LDL-C in adults with diabetes and those without diabetes who are at high risk or established atherosclerotic cardiovascular disease (ASCVD). Adults with diabetes who maximize lifestyle modifications and initiate statin therapy remain at significantly elevated risk: about one in seven will still develop a major cardiovascular event within five years.¹⁰ While about one in 255 patients on statins may develop new-onset diabetes, the benefits of statin therapy far outweigh risk of mild elevation in glucose.¹¹

LDL-C lowering for patients with diabetes is important in reducing ASCVD risk. The 2018 AHA/ACC multi-society guidelines recommends that if a high-intensity statin does not achieve a ≥50% LDL reduction (and lifestyle changes and statin adherence have been addressed), clinicians should consider adding a non-statin agent, such as ezetimibe.¹²

Traditional Non-Statins

The effects of non-statin agents on CVD events have been studied in large, randomized controlled trials that included patients with diabetes and prediabetes. While fenofibrate significantly lowered myocardial infarctions (MI) and coronary revascularization for adults with diabetes in the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study, this effect was not significant for patients already on simvastatin in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, except those with high triglycerides (>200 mg/dL) and low HDL-C (<40 mg/dL) levels.^13,14

Niacin also increases HDL-C levels, but clinical trials have not found a significant positive effect on cardiovascular outcomes. Several studies suggest that omega-3 fatty acids improve patients' cardiometabolic profiles but not enough to affect event rates.^15-17 The recent data on high dose EPA in REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) will need to be evaluated by the FDA before that particular type of fish oil gets a distinct indication to lower ASCVD risk.

Ezetimibe

Ezetimibe is a cholesterol-reducing drug effective in combination with statins, including for those who have diabetes. The 2018 AHA/ACC cholesterol guidelines recommend ezetimibe as a first-line add-on treatment for patients already on a statin who have not reached their LDL-C goal.

In the randomized clinical trial EASE (Ezetimibe Add-on to Statin Therapy for Effectiveness Trial), the combination of a statin and ezetimibe lowered LDL-C more than those on statins and placebo at six weeks.¹⁸ Participants with diabetes in the VYTAL (Vytorin versus Atorvastatin in Patients with T2DM and Hypercholesterolemia) trial on combination therapy also had significantly improved lipid profiles compared to statin alone.¹⁹ However, despite the improvement in lipid levels, several studies did not find any significant improvement in the carotid intima-media thickness in patients on both statin and ezetimibe.^20-22

The 2015 IMPROVE-IT (Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin vs Simvastatin) study solidified ezetimibe's place among effective cholesterol therapies in high risk adults. With over 18,000 patients with a recent acute coronary syndrome, the study investigated the role of combination ezetimibe and simvastatin in reducing the combined event rates of cardiovascular death, myocardial infarction, hospital admission for unstable angina, coronary revascularization, and stroke.

IMPROVE-IT showed that the combination reduced the 7-year event absolute risk by 2% more than the statin monotherapy group.²³ Subgroup analysis of those with diabetes yielded a strong case for the use of ezetimibe: the combination therapy reduced the absolute risk by 5.5% compared to a 0.7% for patients without diabetes. Further analysis of IMPROVE-IT showed that patients with diabetes benefited regardless of risk level, while among patients without diabetes, the addition of ezetimibe only significantly helped those with a high TIMI risk score.²⁴

Given that ezetimibe has both has a favorable safety profile and is generic, clinicians should consider adding ezetimibe to statin therapy for patients with diabetes who have an LDL-C ≥70.²⁵

PCSK9 Inhibitors

PCSK9 inhibitors produce about a 60% reduction in LDL-C on top of statin therapy. There are two versions available for clinical use: evolocumab and alirocumab. Although highly effective at lowering lipid levels, they remain relatively expensive, and the new guidelines emphasize their use in those at the highest ASCVD risk.

Several trials have shown that PCSK9 inhibitors improve lipid levels similarly for patients both with and without diabetes.^26-28 The FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial also demonstrated that evolocumab-statin combination therapy reduced ASCVD event rates similarly across both groups. PSCK9 inhibition was not associated with new-onset diabetes.²⁹ The presentation of the ODYSSEY (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial further reinforced the effectiveness of alirocumab, as the ASCVD event rate and all-cause mortality were both significantly reduced.

Although PCSK9 can lower LDL-C levels even more than high intensity statins, the cost of PCSK9 is too high for routine use; it is restricted to high risk patients with known ASCVD and LDL-C that remains > 100 mg/dL on maximally tolerated statin and ezetimibe. For patients with high ASCVD event risk, a discussion about the cost compared to potential benefits with the patient is very important; much of the decision needs to be based on insurance coverage of the drug.

Creating a Medication Therapy Plan

When the additional LDL-C lowering desired is less 25%, ezetimibe is the best first option. The 2018 cholesterol guidelines recommend obtaining a lipid panel at the start of treatment, 4-12 weeks after the initiation/modification of LDL-lowering therapy, and every 3-12 months afterwards. The 2018 American Diabetes Association guidelines also support considering adding a non-statin therapy if maximally tolerated statins do not lower LDL below 70 mg/dL.²⁵

Since patients with diabetic dyslipidemia have a high risk of ASCVD events, it is important that these patients receive appropriate, evidence-based treatment, whether it is through lifestyle changes, statins, ezetimibe, rarely a PCSK9 inhibitor, or a combination. Residual risk after lifestyle changes and maximally tolerated statin therapy are best addressed by ezetimibe because it has a favorable safety profile and is more affordable than the PCSK9 inhibitor.

References

1. Warraich HJ, Rana JS. Diabetic dyslipidemia: epidemiology and prevention of cardiovascular disease and implications of newer therapies. Curr Cardiol Rep 2018;20:125.
2. Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation 2018;137:e67-492.
3. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016;388:1545-1602.
4. Wong ND, Chuang J, Zhao Y, Rosenblit PD. Residual dyslipidemia according to low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B among statin-treated US adults: National Health and Nutrition Examination Survey 2009-2010. J Clin Lipidol 2015;9:525-32.
5. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood pressure in adults (adult treatment panel III). JAMA 2001;285:2486-97.
6. Rawshani A, Rawshani A, Franzen S, et al. Mortality and cardiovascular disease in type 1 and type 2 diabetes. N Engl J Med 2017;376:1407-18.
7. Cao Y, Yan L, Guo N, et al. Non-high-density lipoprotein cholesterol and risk of cardiovascular disease in the general population and patients with type 2 diabetes: a systematic review and meta-analysis. Diabetes Res Clin Pract 2018. [Epub ahead of print]
8. Rock CL, Flatt SW, Pakiz B, et al. Weight loss, glycemic control, and cardiovascular disease risk factors in response to differential diet composition in a weight loss program in type 2 diabetes: a randomized controlled trial. Diabetes Care 2014;37:1573-80.
9. Look AHEAD Research Gropu, Wing RR, Bolin P, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013;369:145-54.
10. Cholesterol Treatment Trialists' (CTT) Collaborators, Kearney PM, Blackwell L, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008;37:117-25.
11. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735-42.
12. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2017 focused update of the 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology task force on expert consensus decision pathways. J Am Coll Cardiol 2017;70:1785-1822.
13. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849-61.
14. ACCORD Study Group, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.
15. Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risk: meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol 2018;3:228-34.
16. Bays HE, Maki KC, McKenney J, et al. Long-term up to 24-month efficacy and safety of concomitant prescription omega-3-acid ethyl esters and simvastatin in hypertriglyceridemic patients. Curr Med Res Opin 2010;26:907-15.
17. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090-8.
18. Pearson TA, Denke MA, McBride PE, Battisti WP, Brady WE, Palmisano J. A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the ezetimibe add-on to statin for effectiveness (EASE) trial. Mayo Clin Proc 2005;80:587-95.
19. Goldberg RB, Guyton JR, Mazzone T, et al. Ezetimibe/simvastatin vs atorvastatin in patients with type 2 diabetes mellitus and hypercholesterolemia: the VYTAL study. Mayo Clin Proc 2006;81:1579-88.
20. Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431-43.
21. Fleg JL, Mete M, Howard BV, et al. Effect of statins alone versus statins plus ezetimibe on carotid atherosclerosis in type 2 diabetes: the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial. J Am Coll Cardiol 2008;52:2198-205.
22. Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med 2009;361:2113-22.
23. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.
24. Giugliano RP, Cannon CP, Blazing M, et al. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation 2018;137:1571-82.
25. American Diabetes Association. Cardiovascular disease and risk management: Standards of medical care in diabetes-2018. Diabetes Care 2018;41:S86-104.
26. Sattar N, Preiss D, Robinson JG, et al. Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: a meta-analysis of individual patient data. Lancet Diabetes Endocrinol 2016;4:403-10.
27. Ginsberg HN, Farnier M, Robinson JG, et al. Efficacy and safety of alirocumab in individuals with diabetes mellitus: pooled analyses from five placebo-controlled phase 3 studies. Diabetes Ther 2018;9:1317-34.
28. Stroes E, Robinson JG, Raal FJ, et al. Consistent LDL-C response with evolocumab among patient subgroups in PROFICIO: a pooled analysis of 3146 patients from phase 3 studies. Clin Cardiol 2018;41:1328-35.
29. Sabatine MS, Leiter LA, Wiviott SD, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol 2017;5:941-50.

Keywords: Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Hypercholesterolemia, Fenofibrate, Cholesterol, HDL, Diabetes Mellitus, Type 2, Fatty Acids, Omega-3, American Heart Association, Weight Loss, Acute Coronary Syndrome, Cardiovascular Diseases, Risk Factors, Eicosapentaenoic Acid, Antibodies, Monoclonal, Angina, Unstable, Myocardial Infarction, Stroke, Life Style, Outcome Assessment, Health Care

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