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.
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