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Emerging Targets for Lipid-lowering Therapy in Type 2 Diabetes

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Patients with type 2 diabetes have an approximate 3-fold to 6-fold increased myocardial infarction (MI) or stroke event rate. The accelerated atherosclerosis that contributes to the increased risk in these patients proceeds through several potential pathways.¹ Although the pro-inflammatory, procoagulant, and hyperglycemic states may all play a role, this increased risk is also significantly related to lipoprotein abnormalities that accompany diabetes, insulin resistance, and obesity.

During the past several decades, statins have been established as effective lipid-modifying agents that successfully reduce cardiovascular risk in patients with diabetes. The Collaborative Atorvastatin Diabetes Study (CARDS) enrolled 2,838 patients with diabetes,² and the Heart Protection Study, which examined simvastatin, included 5,963 patients with diabetes among more than 20,000 participants.³ Patients with diabetes in both studies achieved a significant reduction in the rate of major coronary heart disease events; in fact, because of this, the CARDS study was stopped early because it clearly established a benefit. Results of these and other trials prompted the recommendation in most clinical guidelines that patients with diabetes should be treated with statins as first-line therapy for their lipid abnormalities and for reducing their cardiovascular disease risk.

However, even in patients treated with statins there is a residual increased risk of MI and major coronary events. A meta-analysis of 12 trials included patients with and without diabetes who were followed for a mean weighted follow-up of 5.1 years while on lipid-lowering therapy, which comprised mainly statins but also included trials that examined other lipid-lowering therapies (Figure).⁴ The lipid-lowering therapy was equally efficacious in patients with and without diabetes, with a risk reduction of 21% (95% confidence interval [CI], 10-31; P = .0005) in patients with diabetes and 23% (95% CI, 19-26; P < .00001) in patients without diabetes. However, when data were examined comparing patients with and without diabetes in both the placebo and treatment groups, patients with diabetes in both groups had a significantly increased risk of major coronary events compared with patients without diabetes (hazard ratio [HR] for placebo group, 1.53; HR for treatment group, 1.59; P < .00001 for both). These results indicated that even though lipid-lowering therapy reduced cardiovascular risk in patients with diabetes, a residual incremental risk remained in comparison with patients without diabetes treated with lipid-lowering therapies. In fact, the risk of the treated patients with diabetes was higher than that of untreated patients who did not have diabetes. Physicians must be aware of strategies to reduce this residual incremental risk.

Figure. Effect of Lipid-lowering Treatment in Patients with and without Diabetes: a Meta-analysis of Secondary Prevention Trials

Even though lipid-lowering therapy reduces cardiovascular risk in patients with diabetes, a residual incremental risk remains in comparison with patients without diabetes treated with lipid-lowering therapy.
Source: Reproduced from Costa J, et al. BMJ. 2006;332:1115-1124, with permission from BMJ Publishing Group Ltd.

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Addressing Residual Risk

Lipoprotein abnormalities are believed to be the major contributor to this residual incremental risk that persists in statin-treated patients with diabetes or who are insulin-resistant and/or obese. These abnormalities include:

• Increased postprandial lipemia;
• Increased low density lipoprotein (LDL) particle number and apolipoprotein B (apoB) levels;
• Reduced high density lipoprotein (HDL) cholesterol and particle number;
• Altered HDL particle composition;
• Cholesterol enrichment of triglyceride-rich lipoproteins.

Understanding lipoprotein structure

Most lipoproteins are spherical, with a polar surface and a nonpolar lipid inner core. For example, in triglyceride-rich lipoproteins the core consists of neutral lipid triglyceride. In addition to the polar lipids on the surface, the lipoprotein particle surface contains apolipo­­­­proteins, which serve as ligands for receptors that are present on cells throughout the body. Therefore, these apolipoproteins direct the metabolism and flux of these particles. Two primary apolipoproteins are apoB, associated with atherogenic lipoproteins, and apoA-I, associated with HDL.

Lipoprotein particles are classified into groups based on their physical size, density, core cholesterol and triglyceride content, and surface apolipoproteins present. Very low density lipoprotein (VLDL), LDL, and HDL are the most common classes. In addition, subparticles of each class are identified by further density and size differentiation. Chylomicrons are derived from the intestine and are not usually present in fasting plasma. Chylomicron remnants are also usually not present in fasting plasma, but may be in the fasting plasma of patients with poorly controlled diabetes who have extremely high triglyceride levels. The plasma quantities of the other lipo­protein particles vary among individuals. In addition, concentrations among the classes can be affected within an individual by comorbidities, diet, activity, and medication. Statins mainly exert their effects by modifying LDL, with minor effects on VLDL particles and HDL.

Conventional lipid assays determine the amount of cholesterol or triglyceride carried by all particles within a lipoprotein class. This approach provides generalizations about the lipoproteins involved in lipid transport. However, it does not allow quantification of the number or size of individual lipo­protein particles present.

LDL, intermediate den­sity lipoprotein (IDL), VLDL, and chylomicron remnant particles have apoB on their surface. These are all atherogenic lipoproteins, especially in the setting of diabetes and insulin resistance. Multiple abnormalities in the number and composition of these particles are observed in patients with diabetes. Because of the consistent presence of surface apoB on these atherogenic particles, apoB can be quantified to assess risk in patients with diabetes, including residual risk that persists in patients treated with statins that may be conferred by VLDL and IDL particles, which are not strongly influenced by statins. However, apoB is not easily or routinely measured in most lab­oratories. Rather, HDL cholesterol, which is easily measured in the laboratory, is subtracted from total cholesterol, which yields the total cholesterol contained in LDL, IDL, VLDL, and chylomicron remnants. This value is referred to as non-HDL cholesterol and is a valid surrogate for atherogenic particles, measurement of apoB, and for the assessment of residual incremental risk in patients receiving statin therapy.

HDL particles do not contain apoB on their surface, but they do contain apoA-I, which is believed to be athero­­protective based on observational studies. Accordingly, they have become an important focus of research exploring the mechanism of this protection as well as therapeutic benefits that may be conferred by increasing their levels.

Guideline Recommendations

In a consensus statement released by the American Diabetes Association (ADA) and the American College of Cardiology (ACC) in 2008, non-HDL cholesterol was adopted as an acceptable surrogate for apoB measurement and for the assessment of residual incremental risk in patients treated with statins.⁵ In addition to LDL, apoB and non-HDL cholesterol targets were emphasized in the consensus statement to address residual risk, with target levels specified for highest risk as well as high-risk patients (Table). These lipoprotein goals, considered in association with patient lipoprotein status, can be used to facilitate decision-making regarding intensification of statin therapy in patients with diabetes. The consensus statement also recommends statin therapy for most patients with diabetes.

Table. Residual Risk Targets: ADA/ACC Consensus Statement 2008

Source: Brunzell JD, et al. Diabetes Care. 2008;31:811-822.

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Guidance can also be obtained from the ADA Standards of Care, published annually in Diabetes Care.⁶ Recommendations for 2011 include providing statin therapy regardless of lipid levels for patients with diabetes who have overt cardiovascular disease (CVD), and for patients with diabetes without overt CVD who are older than 40 years of age and have at least 1 CVD risk factor. Their LDL cholesterol targets are the same as those in the 2008 ADA/ACC consensus statement, targets for triglycerides were < 150 mg/dL, and HDL targets were > 40 mg/dL for men and > 50 mg/dL for women. Women usually have higher HDL levels than men; accordingly, target levels are greater for women than men.

Beyond LDL — Achieving Lipoprotein Goals

The effect of statins on LDL is well-established in clinical trials. Achieving triglyceride and HDL goals requires different approaches. Lifestyle changes including diet, exercise, weight loss, and smoking cessation can be used as appropriate. However, addressing multiple lipoprotein abnormalities is the most practical path for addressing residual incremental risks in statin-treated patients with diabetes. Observational studies have shown that elevated apoB or non-HDL cholesterol and low HDL cholesterol are important predictors of future adverse cardiovascular events.⁷ Data from other studies are emerging that are providing additional support for the importance of non-LDL targets in lipoprotein management.

For example, data are available from trials that used surrogate endpoints for cardiovascular events to evaluate the effects of lipid changes. In some studies, atherosclerosis or atherosclerosis progression were measured instead of actual event rates. The Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone (CHICAGO) study included 400 patients with diabetes who were randomized to receive a sulfon­ylurea or a thiazolidinedione (TZD), with the primary endpoint of progression of carotid atherosclerosis.⁸ More than 50% of the patients were on statins with an LDL cholesterol level of 107 mg/dL. Coronary atherosclerosis, as determined by coronary artery calcium, was measured at the beginning and end of the trial, after 72 weeks of treatment. The most important predictors of atherosclerosis progression were triglyceride-rich lipoprotein cholesterol, combined LDL cholesterol and non-HDL cholesterol, and apoB levels. These results were confirmed in other trials that included direct determinations of atherosclerosis.⁹ Patients in this study were, on average, close to the LDL goal, which emphasizes that apoB and non-HDL levels are important in patients whose LDL cholesterol may be adequately controlled.

Carotid intima media thickness (CIMT), which reflects the degree of subclinical atherosclerosis, was also measured in the CHICAGO trial using noninvasive ultrasound.¹⁰ In this trial, treatment with the TZD suppressed atherosclerosis progression, and improvements were reported for several cardiac risk factors. However, after adjustment for the values of these risk factors after 24 weeks on treatment, the beneficial effect on CIMT was related only to changes in insulin and HDL. A 5% to 16% increase in HDL cholesterol at 24 weeks was a significant predictor of reduced CIMT progression at 72 weeks. Data obtained from these surrogate endpoints suggest that improving residual lipoprotein abnormalities in statin-treated patients with diabetes can suppress atherosclerosis, and may also suppress cardiovascular event rate in these patients.

The Coronary Drug Project was a nationwide secondary prevention randomized controlled trial undertaken in the pre-statin era more than 30 years ago. This study investigated the efficacy and safety of lipid-modifying drugs used for the long-term therapy of coronary heart disease (CHD) in 8,341 men aged 30 to 64 years who had previous MI.¹¹ Patients were randomized into groups who received 1 of these interventions: conjugated estrogens at 1 of 2 doses, clofibrate, dextrothyroxine sodium, niacin, or a lactose placebo. The 2 estrogen and dextrothyroxine sodium groups were stopped early in response to adverse events. The primary endpoint was total mortality, and 1 of several secondary endpoints was to determine if the degree of serum lipid modification correlated with an effect on morbidity and mortality. At 5 years, the cumulative rate of nonfatal MI was 27% lower in patients treated with niacin (8.9%) compared with those given placebo (12.2%; P < .004). However, total mortality was not significantly different between the 2 groups.

HDL and LDL cholesterol were not fractionated in this study. However, niacin treatment is known to raise HDL cholesterol. Patients with diabetes in the niacin group benefited more than patients without diabetes. In the current era, where most people with diabetes are taking statins, the possible effect on event rate of these agents given as combination therapy is under investigation.

The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) trial was a multicenter clinical trial with approximately 90 sites in the United States and Canada. The study began enrolling patients in 2006 and was scheduled to finish in 2012. AIM-HIGH was designed to test whether adding high-dose extended-release niacin to a statin (simvastatin) was more effective than a statin alone in reducing long-term cardiovascular events in participants whose LDL cholesterol was controlled and who had a history of CVD, low levels of HDL cholesterol, and high levels of triglycerides. The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health stopped the AIM-HIGH clinical trial 18 months earlier than planned due to futility. The trial found that adding high-dose extended-release niacin to statin treatment in people with heart and vascular disease did not reduce the risk of cardiovascular events, including MI and stroke. This clinical trial has yet to be published.

In summary, management of CVD risk in diabetes dictates that most of these patients should be on statin therapy. However, even patients with diabetes who are treated with statins continue to have increased risk compared with statin-treated patients without diabetes. This risk is presumed to be associated with lipoprotein particle number and composition abnormalities, which can be assessed by measuring non-HDL cholesterol or apoB levels. These results can be used to guide decisions regarding whether to intensify statin therapy to reach targets. Observational and surrogate endpoint studies suggest that managing low HDL cholesterol levels will be important in reducing risk. However, data from intervention studies with hard endpoints in patients on statins are necessary.

Discussion

Are advanced lipoprotein methodologies that evaluate the density and size of LDL and HDL beneficial in further assessing risk in these patients?

Theodore Mazzone, MD, FACP: That is a controversial area. I believe that in routine clinical use, outside of research trials, non-HDL cholesterol and perhaps the measurement of apoB gives the needed information.

Henry Ginsberg, MD: Approximately 90% of patients with insulin resistance and diabetes have small dense LDL. Therefore, their LDL cholesterol level is not as indicative of how many LDL particles they have compared with a person who has a similar LDL cholesterol level but does not have diabetes or insulin resistance and has normal triglycerides. Knowing this, the approach to treating the patient with insulin resistance or diabetes is to lower the LDL cholesterol more than would be done in a person without diabetes or to consider non-HDL cholesterol or apoB. Estimating particle number is not necessary, as non-HDL cholesterol or apoB serve as an index of particle number.

Does apoB measurement add any value in risk assessment in a patient with diabetes on a statin who has an LDL level of 90 mg/dL, an HDL level of 36 mg/dL, and high triglycerides?

Alan R. Tall, MD: There may be some issues with standardization of apoB measurements across the country. Therefore, I believe it is more feasible to measure non-HDL cholesterol.

Mazzone: Patients with hypertriglyceridemia and low HDL are the population in which non-HDL cholesterol can be beneficial for predicting residual risk, as shown by population studies. Non-HDL gives the same index of risk as apoB, as it includes non-LDL atherogenic particles such as VLDL and IDL. Furthermore, because there are standardization issues with apoB, I prefer non-HDL for measuring residual risk.

Are apoB target levels of 80 mg/dL and 90 mg/dL in patients with diabetes low enough in terms of the atherosclerotic burden associated with atherogenic lipoproteins?

Ginsberg: No. Target values are chosen for several reasons, and these targets should be attainable. However, the goals that are set are often not achieved by the practicing physician. I believe an apoB target of 70 mg/dL is more appropriate than a target of 80 mg/dL. There are some epidemiological data that suggest a lower target is preferable. However, apoB has not been widely measured in large studies. The apoB/apoA-I ratio has been measured. However, this was mainly in cross-sectional and case control studies. I believe that if a person with diabetes achieves an LDL of 70 mg/dL, the apoB will probably not be much higher than 80 mg/dL or 85 mg/dL. This is an ongoing debate. The IMPROVE-IT study is planned to explore LDL cholesterol in the 50 mg/dL range compared with levels in the 60 mg/dL range. If the lower LDL cholesterol targets yield positive results, apoB targets may be more appropriately set at 70 mg/dL or 75 mg/dL.

Tall: The IMPROVE-IT trial will provide important answers if it reaches its endpoint. In epidemiological data, the curve relating LDL cholesterol to risk is not linear down to zero. Although it continues to decrease, the curve begins to flatten at LDL cholesterol levels of approximately 90 mg/dL.

Mazzone: However, there does not appear to be a disadvantage of achieving low LDL cholesterol levels. A clinician contemplating whether the statin dose should be reduced for a patient whose apoB level became 65 mg/dL after initiating the statin is not unusual. The answer is no. Developing therapeutic targets also includes consideration of drug costs and potential side effects. These are in constant flux as drugs become less expensive and new treatments are approved.

Robert H. Eckel, MD: Goals for HDL were established by the American Diabetes Associa­tion, not by the National Cholesterol Education Program (NCEP) Adult Treatment Panel Guidelines (ATP) III. The ATP guidelines are currently being updated, and ATP IV will take HDL targets into consideration.

What would be your choice of a second drug in the patient who has achieved LDL levels of 85 mg/dL but has triglycerides of 240 mg/dL and HDL of 36 mg/dL?

Mazzone: I may be more conservative than many of my colleagues, as I may not add a second drug to that patient’s treatment regimen.

Tall: I would consider using niacin. However, this is hampered by the recent early stopping of the AIM-HIGH study of high-dose extended-release niacin administered with statins, when the rate of clinical events was the same in both niacin and placebo-treated patients.¹² The Data and Safety Monitoring Board concluded that evidence indicated that continuing the trial would not produce a change in outcome, and the trial was stopped in May 2011.

Ginsberg: Although the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial of fibrates added to statins in patients with type 2 diabetes had a negative overall result, the prespecified subgroup of patients who had triglycerides > 204 mg/dL and HDL < 34 mg/dL experienced a benefit in the primary outcome of first occurrence of nonfatal MI, nonfatal stroke, or death from cardiovascular causes. There was a nearly significant (P = .06) interaction between dyslipidemia status and efficacy of fenofibrate to reduce the primary endpoint.¹³ That subgroup analysis was consistent with subgroup analyses of several monotherapy fibrate studies. These patients should receive a fibrate, not patients with triglycerides of 150 mg/dL. Many patients with diabetes have triglycerides of 130 mg/dL to 150 mg/dL but have very low HDL levels, especially patients from different racial groups. Until recently I thought niacin would have been a good choice for a second agent in that group, but with the results of the AIM-HIGH study, I am uncertain. However, it is important to note that the results of AIM-HIGH have yet to be published.

References

1. Libby P, Plutzky J. Diabetic macrovascular disease: The glucose paradox? Circulation. 2002;106:2760-2763.
2. Colhoun HM, Betteridge DJ, Durrington PN, et al; CARDS investigators. 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.
3. Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: A randomised placebo-controlled trial. Lancet. 2003;361:2005-2016.
4. Costa J, Borges M, David C, Vaz Carneiro A. Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: Meta-analysis of randomised controlled trials. BMJ. 2006;332:1115-1124.
5. Brunzell JD, Davidson M, Furberg CD, et al; American Diabetes Association; American College of Cardiology Foundation. Lipoprotein management in patients with cardiometabolic risk: Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008;31:811-822.
6. American Diabetes Association. Standards of medical care in diabetes — 2011. Diabetes Care. 2011;34:S11-S61.
7. Jiang R, Schulze MB, Li T, et al. Non-HDL cholesterol and apolipoprotein B predict cardiovascular disease events among men with type 2 diabetes. Diabetes Care. 2004;27:1991-1997.
8. Davidson MH, Beam CA, Haffner S, Perez A, D'Agostino R Sr, Mazzone T. Pioglitazone versus glimepiride on coronary artery calcium progression in patients with type 2 diabetes mellitus: A secondary end point of the CHICAGO Study. Arterioscler Thromb Vasc Biol. 2010;30:1873-1876.
9. Grønholdt ML, Nordestgaard BG, Wiebe BM, Wilhjelm JE, Sillesen H. Echo-lucency of computerized ultrasound images of carotid atherosclerotic plaques are associated with increased levels of triglyceride-rich lipoproteins as well as increased plaque lipid content. Circulation. 1998;97:34-40.
10. Davidson M, Meyer PM, Haffner S, et al. Increased high-density lipoprotein cholesterol predicts the pioglitazone-mediated reduction of carotid intima-media thickness progression in patients with type 2 diabetes mellitus. Circulation. 2008;117:2123-2130.
11. Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA. 1975;231:360-381.
12. AIM-HIGH: Blinded Treatment Phase of Study Stopped. AIM-HIGH Cholesterol Management Program. http://www.aimhigh-heart.com/. Accessed July 23, 2011.
13. ACCORD Study Group, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563-1574.