The burden of cardiovascular disease (CVD), the major cause of morbidity and mortality around the world 1, is particularly high among patients with type 2 diabetes mellitus (T2DM) 2,3, with the proportion of CVD attributable to diabetes increasing in the general population 4. With the prevalence of diabetes itself rising, particularly among ethnic minorities, CVD risk reduction in this population is of great public health importance 5. Although lifestyle modifications and statins are the first-line interventions for CVD risk reduction in individuals with diabetes 6, they remain at considerable risk for adverse cardiovascular events 7,8.
In this narrative review, we review the pathophysiology of dyslipidemia in individuals with diabetes and summarize the key trials that report on cardiovascular risk reduction in these patients. We conclude by summarizing the positions of major professional bodies on the management of dyslipidemia in individuals with diabetes and conclude by presenting recommendations for future research in this area.
Mechanisms of dyslipidemia in individuals with diabetes
Patients with diabetes are at an elevated risk for adverse cardiovascular outcomes compared with controls 9,10. Although in nondiabetic individuals LDL is predictive of cardiovascular outcomes 11, the prevalence of LDL is similar between individuals with diabetes and nondiabetic individuals 12,13, and data suggest that the elevated risk for CVD in individuals with diabetes occurs independently of the serum LDL level 14. The pattern of dyslipidemia usually presents with elevated triglycerides and small dense LDL and reduced levels of high density lipoprotein cholesterol (HDL-C) 15. Increased LDL particle numbers from either elevated ApoB or LDL-P are a prominent feature of dyslipidemia in diabetes. Small dense LDL particles are more atherogenic and are associated with a higher rate of nephropathy 16. Individuals with diabetes have also been noted to have lower HDL levels 17.
Insulin resistance is the primary mechanism leading to lipid derangements in individuals with diabetes 18. Peripheral resistance to insulin increases the release of free fatty acids from adipose tissue, which are taken up by the liver; increased hepatic uptake of free fatty acids leads to more synthesis of triglycerides. Triglyceride synthesis subsequently stimulates hepatic production of triglyceride-rich very low density lipoprotein cholesterol (VLDL) and increased secretion of ApoB 19. Triglyceride-laden VLDL enrich LDL and HDL through the action of the cholesterol ester transfer protein, making them more cholesterol rich 20. These triglyceride-rich LDL molecules are then hydrolyzed by hepatic or lipoprotein lipase leading to the production of small dense LDL.
Therefore, the lipid derangements associated with diabetes are widespread, beyond just LDL elevation, making it challenging to rely on conventional means for cardiovascular risk reduction.
Lifestyle modifications: diet and exercise
Lifestyle modification in individuals with diabetes pertains to dietary restriction and physical exercise. Dietary restriction’s benefit is realized through weight loss. In this regard, caloric restriction is essential and any degree of weight loss is beneficial. In a randomized study, caloric restriction led to improvements in all markers, including glycemic control, HbA1c, and lipid profile, in obese and overweight individuals with diabetes 21. It remains unclear, however, as to what type of dietary modification is best for individuals with diabetes. Although both the American Diabetic Association 22 and the Adult Treatment Panel III guidelines 23 recommend a diet low in monosaturated fats, recent data support a low-carbohydrate diet. A trial in Spain randomizing patients to a fat-rich Mediterranean diet showed a significant reduction in cardiovascular events 24 and a lower incidence of diabetes compared with patients advised a low-fat diet 25. However, despite dietary modification improving some measures, no mortality benefit has yet been demonstrated in diabetic patients. One multicenter randomized controlled trial (Look Action for Health in Diabetes), which randomized overweight and obese individuals with diabetes to either caloric restriction and physical exercise or usual care, resulted in improvement in obesity, but was unable to show improvement in lipid profiles, cardiovascular events, or mortality 26. Similar to diet, exercise has been shown to result in better glycemic control 27 and lipid profiles 28–30; no reduction in cardiovascular events or mortality has ever been shown.
Statins are the first-line treatment for hyperlipidemia in all patients, including those with diabetes, and have the strongest evidence base of any intervention in patients with or without diabetes 31. The benefits of statins increase with dose intensity 32 and are independent of the patient’s initial lipid profile, as demonstrated in the CARDS trial 33,34. The cardiovascular risk reduction that individuals with diabetes accrue is independent of their individualized risk for future events 35.
One concern about statin use has been the increased incidence of T2DM in patients taking statins 36. In one trial, 270 patients on rosuvastatin developed diabetes versus 216 on placebo 37. The small increase in incidence is offset by the benefits of statin therapy. One meta-analysis showed that one of 255 patients would develop diabetes after being treated with statins for 4 years, most of whom were prediabetic; however, in this same cohort, 5.4 vascular events were prevented 38.
Residual risk in individuals with diabetes
There remains residual risk for CVD with all monotherapies, despite intensification of statins. Implementation of lifestyle modifications and the institution of statin therapy still leave patients with T2DM with a substantial risk for future CVD 39. One of seven individuals with diabetes on statins experience major adverse cardiovascular events within 5 years 31. In one trial, despite a multidimensional approach, 50% of patients went on to have microvascular complications from dyslipidemia 40. Although agents including ezetimibe, fibrates, niacin, and n-3 fatty acids have been used, they have no established role as monotherapy in statin-tolerant patients 41.
Combination therapy: a review of key clinical trials
The role of monotherapy with a nonstatin agent is only indicated in patients who are statin-intolerant. The role, if any, of adding a medication to supplement statin risk reduction has been extensively studied and here we summarize key clinical trials by pharmacologic category.
Ezetimibe is a cholesterol absorption inhibitor that reduces uptake from the intestine while also increasing the breakdown of LDL. Ezetimibe has been extensively tested in combination with statins (Table 1).
Many trials show improved lipid profile with the addition of ezetimibe to statins. In EASE, patients with at-goal LDL levels were randomized 2 : 1 to receive ezetimibe or placebo in combination with a statin and were found to have better LDL control after 6 weeks of treatment 42. In VYTAL, 1229 individuals with diabetes were randomized for 6 months to receive ezetimibe and simvastatin or atorvastatin alone, with the ezetimibe/simvastatin combination demonstrating better lipid profiles 43. In ENHANCE, 720 patients with familial hypercholesterolemia receiving simvastatin were randomized to receive ezetimibe or placebo and found that, although LDL was lower, there was no difference in CIMT in the combination group 44. A substudy of SANDS, which randomized 499 diabetic patients with intensive lipid and blood pressure control or conventional control for 3 years, showed no additional benefit when ezetimibe was added to statin therapy with regard to CIMT regression or LDL. 45. ARBITER 6-HALTS analyzed the addition of niacin or ezetimibe to ongoing statin therapy and showed greater CIMT regression and lower cardiovascular events (1 vs. 5%, P=0.04) with niacin compared with ezetimibe 46.
IMPROVE-IT was a double-blind trial enrolling 18 144 high-risk patients within 10 days of an acute coronary syndrome, which randomized patients to receive simvastatin and ezetimibe or simvastatin and placebo with an LDL less than 125 mg/dl. The trial demonstrated a 6.4% relative risk reduction in the primary endpoint, which was a composite of cardiovascular death, myocardial infarction (MI), hospital admission for unstable angina, coronary revascularization more than a month after randomization, and stroke 47. Results in the prespecific diabetic subpopulation were presented at the European Society of Cardiology conference, which showed a 14% relative risk reduction over placebo in the ezetimibe arm compared with 2% for nondiabetic individuals for major adverse cardiovascular outcomes 48. Although the manuscript has not yet been published, these results suggest that ezetimibe may have a future possible role as an agent for treating diabetic dyslipidemia in combination with statins.
Fibrates enhance ApoA1 synthesis, resulting in increased levels of HDL and also reduce hepatic triglyceride production 49. In a placebo-controlled trial, fenofibrate resulted in a significant reduction in nonfatal MIs and revascularization in individuals with diabetes 50. This benefit was not realized when fibrates were administered in combination with statins. In the ACCORD trial, which randomized 5518 patients on statin therapy to addition of fenofibrate or placebo, there was no reduction in cardiovascular events 51. However, in the prespecified group with high triglycerides and low HDL, there was a reduction in clinical events that approached significance (12.4 vs. 17.3%, P=0.057); a subsequent meta-analysis showed a reduction in cardiovascular events in this high triglycerides and low HDL-C diabetic population 52.
N-3 fatty acid ethyl esters
The addition of n-3 fatty acids has been analyzed in two randomized clinical trials. The JELIS trial randomized 18 645 Japanese patients on statins with total cholesterol more than 6.5 mmol/l to eicosapentoic acid versus placebo. These patients were followed up for a mean of 4.6 years. This trial demonstrated fewer adverse cardiovascular events in patients with known coronary artery disease (8.7 vs. 10.7%, P=0.01) but not in those without 53. Another RCT randomized 188 patients without prior CAD on simvastatin, with triglycerides between 200 and 500 mg/dl and tight LDL control, to omega-3-acid ethyl esters versus placebo. Although a reduction in HDL was noted, no improvement was noted in clinical events 54.
Niacin, a nicotinic acid derivative, slows the hepatic uptake of HDL by downregulating hepatic HDL-ApoA1 receptors and increases HDL production. Clinical studies have demonstrated that niacin produces a very robust increase in serum HDL 55 more so than even statins in one study 56. However, success in improving clinical outcomes in combination with statins has not been demonstrated (Table 2). The combination of niacin with a statin was compared with statin in placebo in ARBITER 2 showing an improvement in HDL but none in CIMT regression 57. ARBITER 3, however, did show a difference in CIMT regression between the niacin-statin group and the statin-placebo group 58. Similarly, patients treated with niacin-statin in the OXFORD-NIASPAN study showed a greater reduction in carotid wall area on magnetic resonance imaging compared with the statin-placebo group 62.
AIM-HIGH randomized 3414 patients with known CVD to extended release niacin or placebo 59. This trial was stopped after 3 years due to lack of clinical efficacy and an increase in serious infections and gastrointestinal disorders. Results from HPS-2 Thrive, in which 25 673 patients were randomized to extended release niacin-laropiprant versus placebo in patients on statins and tight LDL control, were similarly disappointing 61. Not only was there an absence of any clinical benefit with niacin after 3.9 years of median follow-up but also a wide array of serious adverse effects including new onset diabetes and worsening of pre-existing diabetes was noted. The manufacturer removed this compound from the market after these results were released. Results from either trial did not show any difference based on the presence of diabetes. Although a post-hoc analysis of AIM-HIGH suggested that patients with high triglycerides and low HDL demonstrated a trend toward possible benefit 60, given a negative result and a wide array of serious adverse events, there appears to be no role at present for niacin in statin-tolerant patients.
The recent American Heart Association/American College of Cardiology guidelines for cholesterol management have rightly made statins the cornerstone for dyslipidemia management 63. They recommend that diabetes be treated with statins if patients are between 40 and 75 years of age. If the diabetic patient’s 10-year atherosclerotic CVD risk is at least 7.5% based on the pooled cohort risk calculator, a high-intensity statin such as atorvastatin 80 mg or rosuvastatin 40 mg is recommended. However, the guidelines authors have clarified subsequently that ‘clinicians treating high-risk patients who have a less-than-anticipated response to statins, who are unable to tolerate a less-than-recommended intensity of a statin, or who are completely statin intolerant may consider the addition of a nonstatin cholesterol-lowering therapy’ 64. They denoted that individuals with diabetes between 40 and 75 years of age were in the high-risk group and pointed to ezetimibe as a potential option in this situation (IMPROVE-IT had not been published at the time the guidelines were published) 64. Additional guidelines have also been published by other established organizations such as the American Diabetes Association, the European Society of Cardiology, the National Lipid Association, and the National Clinical Guideline Center in the UK 65. Subtle differences in the guidelines pertain to risk stratification of patients and use of lipid targets for tailored and targeted therapy. Although most organizations do not make a specific recommendation for combination therapy, the European Society of Cardiology guidelines did indicate that ezetimibe may be added to statins after intensification of statin therapy in individuals with diabetes (level of evidence IIa) 66. However, the Food and Drug Administration refused to approve ezetimibe as combination therapy citing modest benefit, missing data in the ezetimibe arm, and questioning the relevance of the reduction in nonfatal strokes and MIs that drove the risk reduction seen in the intervention arm.
Promising agents: ezetimibe and PCSK9 inhibitors
Despite the plethora of research in this area, the role of combination therapy in diabetic dyslipidemia remains controversial. However, the favorable results of the IMPROVE-IT trial may point to a role of ezetimibe as an adjunct to statin therapy, particularly if results are similarly positive in the diabetic subpopulation. PCSK-9 inhibitors, of whom Alirocumab (Regeneron Pharmaceuticals Inc., Eastview, New York, USA) and Evolocumab (Amgen Inc., Thousand Oaks, California, USA) have been approved, have emerged as a category that has shown significant reductions in LDL 67. A recent meta-analysis of three 12-week trials showed significant LDL lowering in individuals with diabetes 68. However, data assessing clinical outcomes in individuals with diabetes remains scant and are being investigated in ongoing trials such as FOURIER (NCT01764633), ODYSSEY (NCT01663402), SPIRE-1 (NCT01975389), and SPIRE-2 (NCT01975376). However, at present there is no approved role for PCSK9 inhibitors specific to individuals with diabetes, although this is a rapidly evolving field 69.
For now, statins remain the mainstay of therapy in patients with dyslipidemia of diabetes with the role of combination therapy as yet unknown. Although there currently is an abundance of lipid-modifying options available for the reduction of lipid-related residual risk (i.e. elevated LDL-C, non-HDL-C, ApoB, and LDL-P) in the clinical setting of primary and secondary prevention of ASCVD, there is a dearth of appropriately designed clinical trials to enhance the desirable level of evidence 1A for combination studies. Studies with statins combined with fibrates and omega-3 FAs are recruiting or ongoing and additional information is still required about the impact of their addition to statin therapy. We await the results of the ongoing trials with PCSK9 inhibitors.
Conflicts of interest
Jamal S. Rana received Institutional research grant from Regeneron and Sanofi. For the remaining author there are no conflicts of interest.
1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27:1047–1053.
2. Fox CS, Pencina MJ, Wilson PW, Paynter NP, Vasan RS, D’Agostino RB Sr. Lifetime risk of cardiovascular disease among individuals with and without diabetes stratified by obesity status in the Framingham heart study. Diabetes Care 2008; 31:1582–1584.
3. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. Jama 1979; 241:2035–2038.
4. Fox CS, Coady S, Sorlie PD, D’Agostino RB Sr, Pencina MJ, Vasan RS, et al. Increasing cardiovascular disease burden due to diabetes mellitus: the Framingham Heart Study. Circulation 2007; 115:1544–1550.
5. Geiss LS, Wang J, Cheng YJ, Thompson TJ, Barker L, Li Y, et al. Prevalence and incidence trends for diagnosed diabetes among adults aged 20 to 79 years, United States, 1980–2012. Jama 2014; 312:1218–1226.
6. Mooradian AD. Cardiovascular disease in type 2 diabetes mellitus
: current management guidelines. Arch Intern Med 2003; 163:33–40.
7. Waters DD, Guyton JR, Herrington DM, McGowan MP, Wenger NK, Shear C, et al. Treating to New Targets (TNT) Study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit? Am J Cardiol 2004; 93:154–158.
8. Fitchett DH, Leiter LA, Goodman SG, Langer A. Lower is better: implications of the treating to new targets (TNT) study for Canadian patients. Can J Cardiol 2006; 22:835–839.
9. Saely CH, Drexel H. Is type 2 diabetes really a coronary heart disease risk equivalent? Vascul Pharmacol 2013; 59:11–18.
10. Whiteley L, Padmanabhan S, Hole D, Isles C. Should diabetes be considered a coronary heart disease risk equivalent?: results from 25 years of follow-up in the Renfrew and Paisley survey. Diabetes Care 2005; 28:1588–1593.
11. Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA 1986; 256:2823–2828.
12. U.K. Prospective Diabetes Study 27. Plasma lipids and lipoproteins at diagnosis of NIDDM by age and sex. Diabetes Care 1997; 20:1683–1687.
13. Kannel WB. Lipids, diabetes, and coronary heart disease: insights from the Framingham Study. Am Heart J 1985; 110:1100–1107.
14. Almdal T, Scharling H, Jensen JS, Vestergaard H. The independent effect of type 2 diabetes mellitus
on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up. Arch Intern Med 2004; 164:1422–1426.
15. Mooradian AD. Dyslipidemia in type 2 diabetes mellitus
. Nat Clin Pract Endocrinol Metab 2009; 5:150–159.
16. Hirano T, Naito H, Kurokawa M, Ebara T, Nagano S, Adachi M, et al. High prevalence of small LDL particles in non-insulin-dependent diabetic patients with nephropathy. Atherosclerosis 1996; 123:57–72.
17. Parish S, Offer A, Clarke R, Hopewell JC, Hill MR, Otvos JD, et al. Lipids and lipoproteins and risk of different vascular events in the MRC/BHF Heart Protection Study. Circulation 2012; 125:2469–2478.
18. Brunzell JD, Hokanson JE. Dyslipidemia of central obesity and insulin resistance. Diabetes Care 1999; 22 (Suppl 3):C10–C13.
19. Adiels M, Boren J, Caslake MJ, Stewart P, Soro A, Westerbacka J, et al. Overproduction of VLDL1 driven by hyperglycemia is a dominant feature of diabetic dyslipidemia. Arterioscler Thromb Vasc Biol 2005; 25:1697–1703.
20. Taskinen MR. Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia 2003; 46:733–749.
21. Rock CL, Flatt SW, Pakiz B, Taylor KS, Leone AF, Brelje K, 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; 37:1573–1580.
22. American Diabetes Association. Standards of medical care in diabetes – 2014. Diabetes Care 2014; 37 (Suppl 1):S14–S80.
23. Safeer RS, Ugalat PS. Cholesterol treatment guidelines update. Am Fam Physician 2002; 65:871–880.
24. Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, Aros F, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013; 368:1279–1290.
25. Salas-Salvado J, Bullo M, Estruch R, Ros E, Covas MI, Ibarrola-Jurado N, et al. Prevention of diabetes with Mediterranean diets: a subgroup analysis of a randomized trial. Ann Intern Med 2014; 160:1–10.
26. Look ARG, Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013; 369:145–154.
27. Sigal RJ, Kenny GP, Boule NG, Wells GA, Prud’homme D, Fortier M, et al. Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial. Ann Intern Med 2007; 147:357–369.
28. Halverstadt A, Phares DA, Ferrell RE, Wilund KR, Goldberg AP, Hagberg JM. High-density lipoprotein-cholesterol, its subfractions, and responses to exercise training are dependent on endothelial lipase genotype. Metabolism 2003; 52:1505–1511.
29. Ruano G, Seip RL, Windemuth A, Zollner S, Tsongalis GJ, Ordovas J, et al. Apolipoprotein A1 genotype affects the change in high density lipoprotein cholesterol subfractions with exercise training. Atherosclerosis 2006; 185:65–69.
30. Wilund KR, Ferrell RE, Phares DA, Goldberg AP, Hagberg JM. Changes in high-density lipoprotein-cholesterol subfractions with exercise training may be dependent on cholesteryl ester transfer protein (CETP) genotype. Metabolism 2002; 51:774–778.
31. Cholesterol Treatment, Trialists C, Kearney PM, Blackwell L, Collins R, Keech A, Simes J, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008; 371:117–125.
32. Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011; 305:2556–2564.
33. Cholesterol Treatment, Trialists C, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010; 376:1670–1681.
34. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004; 364:685–696.
35. Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2013; 1:CD004816.
36. Rajpathak SN, Kumbhani DJ, Crandall J, Barzilai N, Alderman M, Ridker PM. Statin therapy and risk of developing type 2 diabetes: a meta-analysis. Diabetes Care 2009; 32:1924–1929.
37. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet 2012; 380:565–571.
38. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010; 375:735–742.
39. Fruchart JC, Sacks F, Hermans MP, Assmann G, Brown WV, Ceska R, et al. The residual risk reduction initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol 2008; 102 (Suppl):1K–34K.
40. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003; 348:383–393.
41. Hamilton SJ, Watts GF. Atherogenic dyslipidemia and combination pharmacotherapy in diabetes: recent clinical trials. Rev Diabet Stud 2013; 10:191–203.
42. 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; 80:587–595.
43. Goldberg RB, Guyton JR, Mazzone T, Weinstock RS, Polis A, Edwards P, et al. Ezetimibe/simvastatin vs atorvastatin in patients with type 2 diabetes mellitus
and hypercholesterolemia: the VYTAL study. Mayo Clin Proc 2006; 81:1579–1588.
44. Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008; 358:1431–1443.
45. Fleg JL, Mete M, Howard BV, Umans JG, Roman MJ, Ratner RE, 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; 52:2198–2205.
46. Taylor AJ, Villines TC, Stanek EJ, Devine PJ, Griffen L, Miller M, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med 2009; 361:2113–2122.
47. Cannon CP. IMPROVE IT Investigators. IMPROVE-IT trial: a comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes after acute coronary syndromes. Chicago, IL: American Heart Association Scientific Sessions; 2014.
48. Giugilano RP, Cannon CP, Blazing MA, Nicolau JC, Corbalan R, Spinar J, et al.; On behalf of the IMPROVE-IT Investigators. Benefitof adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with vs without diabetes: the IMPROVE-IT trial
. London, UK: European Society of Cardiology Congress; 2015.
49. Gervois P, Fruchart JC, Staels B. Drug Insight: mechanisms of action and therapeutic applications for agonists of peroxisome proliferator-activated receptors. Nat Clin Pract Endocrinol Metab 2007; 3:145–156.
50. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, 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; 366:1849–1861.
51. Group AS, Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, et al. Effects of combination lipid therapy in type 2 diabetes mellitus
. N Engl J Med 2010; 362:1563–1574.
52. Lee M, Saver JL, Towfighi A, Chow J, Ovbiagele B. Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis. Atherosclerosis 2011; 217:492–498.
53. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007; 369:1090–1098.
54. Bays HE, Maki KC, McKenney J, Snipes R, Meadowcroft A, Schroyer R, 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; 26:907–915.
55. Jun M, Foote C, Lv J, Neal B, Patel A, Nicholls SJ, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 2010; 375:1875–1884.
56. Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 1990; 323:1289–1298.
57. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004; 110:3512–3517.
58. Taylor AJ, Lee HJ, Sullenberger LE. The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3. Curr Med Res Opin 2006; 22:2243–2250.
59. Investigators AH, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011; 365:2255–2267.
60. Albers JJ, Slee A, O’Brien KD, Robinson JG, Kashyap ML, Kwiterovich PO Jr, et al. Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes). J Am Coll Cardiol 2013; 62:1575–1579.
61. HTC Group, Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014; 371:203–212.
62. Lee JM, Robson MD, Yu LM, Shirodaria CC, Cunnington C, Kylintireas I, et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study. J Am Coll Cardiol 2009; 54:1787–1794.
63. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129 (Suppl 2):S1–S45.
64. Stone NJ, Merz CN, Watson KE, Smith SC Jr. Getting guidelines correct: their evidence-based recommendations for use of nonstatins added to statins and the need for follow-up lipid testing. J Am Coll Cardiol 2015; 65:2051–2052.
65. Ganda OP, Mitri J. Current Consensus and Controversies in Guidelines for Lipid and Hypertension Management in Diabetes. Curr Cardiol Rep 2016; 18:114.
66. European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32:1769–1818.
67. Seidah NG. Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors in the treatment of hypercholesterolemia and other pathologies. Curr Pharm Des 2013; 19:3161–3172.
68. Sattar N, Preiss D, Robinson JG, Djedjos CS, Elliott M, Somaratne R, 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 Diab Endocrinol 2016; 4:403–410.
69. Santos RD. PCSK9 inhibition in type 2 diabetes: so far so good, but not there yet. Lancet Diab Endocrinol 2016; 4:377–379.