Atherogenic dyslipidemia is a key modifiable risk factor for macrovascular events and continues to be problematic. Prevention and treatment of dyslipidemia, as well as tight control of BP and glycemia, are part of the optimal approach to reducing residual vascular risk in patients with type 2 diabetes mellitus (T2DM). The American College of Cardiology/American Heart Association (ACC/AHA) released the new guideline for the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults.1 Lifestyle therapy and treatment with HMG-CoA reductase inhibitors (statins) (according to the four major statin groups and a new global risk assessment tool) provide early interruption to the natural progression of atherosclerosis.1-5
Significance of the problem
Cardiovascular disease (CVD) is the largest contributor to the direct and indirect costs of diabetes.6 Common conditions coexisting with T2DM, such as hypertension and dyslipidemia, are clear risk factors for CVD. Epidemiologic studies and clinical trials have demonstrated that patients with diabetes are at increased risk for CVD and that T2DM itself confers independent risk. Numerous studies have demonstrated the importance of controlling individual cardiovascular risk factors and the positive impact of preventing or slowing CVD in patients with T2DM. Dyslipidemia is an important, modifiable risk factor in patients at risk for coronary events and represents a key area for intervention in patients with T2DM.1-3,6,7
Typical diabetic dyslipidemia includes hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), and mildly elevated low-density lipoprotein cholesterol (LDL-C) with a predominance of small, dense LDL particles.2,3,6,8 The smaller LDL particles can infiltrate the arterial wall more readily, are more easily oxidized, and do not bind as efficiently to the LDL receptor. This ultimately results in impaired hepatic clearance of cholesterol. The mechanisms leading to hypertriglyceridemia directly relate to insulin resistance and hyperglycemia. The end result is overproduction of triglyceride-rich lipoproteins from the liver, decreased clearance of triglyceride-rich lipoproteins, and, in some cases, an altered postprandial lipoprotein metabolism. This complex dyslipidemia (termed atherogenic dyslipidemia, diabetic dyslipidemia, or dyslipidemia of insulin resistance) is indicative of underlying insulin resistance and plays a key role in the increased cardiovascular risk in patients with T2DM.6,9
Current practice guidelines
The updated American College of Cardiology (ACC) and American Heart Association (AHA) guideline for the treatment of blood cholesterol was published in 2013.1 Recommendations include lowering LDL-C as the primary target followed by increasing HDL-C and lowering triglycerides (TG). The new guideline differs significantly from the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults in that the ACC/AHA makes no recommendation for specific LDL-C or non-HDL targets for the primary and secondary prevention of atherosclerotic CVD. Instead, the focus is on finding the appropriate intensity of statin therapy in order to achieve relative reductions in LDL-C.1,10
Four groups of primary and secondary prevention patients have been identified. The four major statin groups include: individuals with clinical atherosclerotic CVD; individuals with LDL-C levels at or above 190 mg/dL (such as those with familial hypercholesterolemia); individuals with diabetes ages 40 to 75 years with LDL-C levels between 70 and 189 mg/dL and without evidence of atherosclerotic CVD; and individuals without evidence of CVD or diabetes but who have LDL-C levels between 70 and 189 mg/dL and a 10-year risk of atherosclerotic CVD at or above 7.5%.1 For patients with diabetes ages 40 to 75 years, a moderate-intensity statin (defined as a drug that lowers LDL-C 30% to 49%) should be used. A high-intensity statin is a reasonable choice if the patient also has a 10-year risk of atherosclerotic CVD at or above 7.5%.1,10
Lifestyle modification. The ACC/AHA guideline advocates for lifestyle modification as the first step toward improving the lipid profile in patients with T2DM.1 Lifestyle modifications, including reductions in dietary cholesterol, reductions in saturated and trans fatty acids, and increased physical activity remain central to any therapeutic program.3 Weight loss (if indicated) and increased physical activity are initially recommended to improve the lipid profile. Additionally, enhanced glycemic control can improve plasma lipid levels, especially in patients with T2DM who have very high TG levels.2,11
Effective lipid-lowering strategies in patients at high risk for CVD, such as those with T2DM, require the management of not only the LDL-C but also of the HDL-C and TG levels. The American Diabetes Association (ADA) recommends medical nutrition therapy (MNT), which includes a reduction in saturated fat, trans fat, and cholesterol intake.6 Additionally, the 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk recommends therapeutic lifestyle changes, which include a diet low in saturated fat and cholesterol, use of plant stanols/sterols, and increased consumption of soluble fiber.11 In addition, the guideline emphasizes weight reduction and exercise/increased physical activity. TG levels can be decreased and HDL-C levels can be increased with weight loss and increased physical activity. Lifestyle changes may also produce a modest lowering of LDL-C. Also of note, tighter glycemic control can improve plasma lipid levels, especially in patients with T2DM who have very high TG.2,5,7
Pharmacologic management with statins
The ADA recommends pharmacologic (primarily statin) therapy to reduce CVD risk and mortality.6 Multiple studies have shown significant primary and secondary prevention of CVD events in patients with diabetes who use statins. Meta-analyses from 14 randomized controlled trials of statin therapy demonstrate a 9% proportional reduction in all-cause mortality and 13% reduction in vascular mortality for each mmol/L reduction in LDL-C. There is evidence for significant LDL-C lowering from even extremely low, less than daily statin use.6
Statin use in patients with diabetes is associated with significant reductions in cardiovascular morbidity and mortality for both primary and secondary prevention.1,6 Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, inhibiting the rate-limiting step in cholesterol biosynthesis, and competitively inhibiting HMG-CoA reductase.2,12 Statins primarily lower LDL-C but also have secondary effects of lowering TG and increasing HDL-C levels. Furthermore, statins may increase the particle size of LDL-C to allow less circulation of smaller, dense LDL-C.5,12
Overall, statins are well tolerated. The more common adverse reactions are headache, nonspecific muscle and joint pain, nausea, diarrhea, constipation, and abdominal pain. Significant elevation of liver enzymes can occur, and discontinuation of statins is recommended when those values reach greater than three times the upper limit of normal. Because of the risk of myopathy and rhabdomyolysis with statin use, patients are encouraged to immediately report any unexplained muscle weakness, tenderness, pain, or fever to their healthcare provider.12 The benefits of statins outweigh the risks in patients with known CVD. However, new labeling recommended by the FDA, warns of a higher risk of diabetes or cognitive impairment.13 A slight increase in blood glucose levels and the development of T2DM has been reported in patients who are taking statins.13 If diabetes occurs or worsens, the statin should not be automatically stopped. It should be explained that statins' cardiovascular benefits are even greater in patients with diabetes than those without.5 Regarding cognitive impairment, the FDA is investigating cognitive impairment associated with statin use.13 Again, each patient must be considered individually, with risks and benefits fully addressed.
Examples of statins include: atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin. A baseline lipid profile, serum creatine kinase (CK), liver function tests, and serum creatinine should be obtained before starting statin therapy. Serum CK levels should be checked upon report of any muscle pain or discomfort. Fasting lipid profiles should be measured at least annually in most adult patients with diabetes.6 The measurement of LDL-C is an important marker of adherence to medication/statin use and one of the best methods of identifying the dose of statin each patient can tolerate.10
The ADA and ACC/AHA recommendations state that when maximally tolerated, statin doses fail to significantly lower LDL-C (less than 30% reduction from patient's baseline), there is no strong evidence that combination therapy should be used to achieve additional LDL-C lowering.1,6 The ADA and ACC/AHA further concur that niacin, fenofibrate, ezetimibe, and bile acid sequestrants all offer additional LDL-C lowering to statins alone; however, there is insufficient evidence that such combination therapy for LDL-C lowering provides a significant increment in CVD risk reduction over exclusive statin therapy.1,6
Special populations and considerations
Statins are contraindicated during pregnancy.1,6,7 Current guidelines recommend discontinuation of the medication immediately upon recognition of pregnancy or before conception if pregnancy is planned. Until more data are available, statins should be avoided during pregnancy, and pregnant women exposed to cholesterol-lowering drugs should be monitored closely.
The 2013 ACC/AHA guideline applies to the geriatric population as well. Emphasis is placed on treating dyslipidemia with statins but not to target levels. MNT, supplemented Mediterranean diet, enhanced physical activity, and weight loss have also been shown to play a role in improving cardiovascular risk profiles in older adults with T2DM.1,14 The American Geriatrics Society guidelines update reinforces glycemic control recommendations customized to burden of comorbidity, functional status, and life expectancy.14 The update also emphasizes patient-centered recommendations for lifestyle modification because of increased evidence of its importance for healthy older adults with T2DM.1,6,14 Statin use is supported for lipid-lowering in older adults with T2DM who are younger than 75, but more data are needed for patients age 80 and older.14
Providers must continue to educate patients with diabetes about how to manage the risk of macrovascular complications associated with their disease in addition to managing blood glucose and HbA1c. Patients must become actively involved in their care. Each patient's desire to make lifestyle changes should be assessed. Patient education should focus on the importance of adhering to cholesterol-lowering lifestyle changes and medication therapy to help prevent the complications of diabetes that are seen in patients who do not have their lipid levels adequately managed.12
Motivational interviewing is an excellent technique to consider and utilizes these underlying principles: active listening, expressing empathy, developing discrepancy, avoiding argumentation, rolling with resistance, and supporting self-efficacy (motivationalinterviewing.org). Providers should help the patient identify his or her stage of change and should work as a team to accomplish step-by-step goals toward healthier living.
The prevalence of diabetes has increased dramatically in recent decades. Now is the time to implement prevention and appropriate therapy to reduce cardiovascular events in patients with T2DM. Aggressive treatment of diabetic dyslipidemia, a major modifiable risk factor, will reduce cardiovascular events in this patient population.1,6,12
The LDL-C appears to have the greatest role in premature and early atherosclerosis and the development of CVD. It must be treated as aggressively as hyperglycemia to reduce CVD risk in patients with T2DM. Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels, for patients with T2DM who have overt CVD or without CVD if they are over 40 years old and have one or more other CVD risk factors, such as a family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria.6 Becoming familiar with lipid treatment goals/degree of stain intensity and the importance of individualized treatment will result in implementation of the most beneficial, therapeutic approach to dyslipidemia in patients with T2DM.
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. 2014;129(25 suppl 2):S76–S99.
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