Dyslipidemia/lipid management

2. Dyslipidemia/lipid management



* In adult patients, test for lipid disorders at least annually and more often if needed to achieve goals. In adults with low-risk lipid values (LDL <100 mg/dl, HDL >50 mg/dl, and triglycerides <150 mg/dl), lipid assessments may be repeated every 2 years. (E)

Treatment recommendations and goals

* Lifestyle modification focusing on the reduction of saturated fat and cholesterol intake, weight loss (if indicated), and increased physical activity has been shown to improve the lipid profile in patients with diabetes. (A)
* In individuals without overt CVD
??? The primary goal is an LDL <100 mg/dl (2.6 mmol/l). (A)
??? For those over the age of 40 years, statin therapy to achieve an LDL reduction of 30??“40% regardless of baseline LDL levels is
recommended. (A)
??? For those under the age of 40 years but at increased risk due to other cardiovascular risk factors who do not achieve lipid goals with lifestyle modifications alone, the addition of pharmacological therapy is appropriate. (C)

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* In individuals with overt CVD
??? All patients should be treated with a statin to achieve an LDL reduction of 30??“40%. (A)
??? A lower LDL cholesterol goal of <70 mg/dl (1.8 mmol/l), using a high dose of a statin, is an option. (B)
* Lower triglycerides to <150 mg/dl (1.7 mmol/l) and raise HDL cholesterol to >40 mg/dl (1.15 mmol/l). In women, an HDL goal 10 mg/dl higher (>50 mg/dl) should be considered. (C)
* Lowering triglycerides and increasing HDL cholesterol with a fibrate is associated with a reduction in cardiovascular events in patients with clinical CVD, low HDL, and near-normal levels of LDL. (A)
* Combination therapy using Statins and other lipid-lowering agents may be necessary to achieve lipid targets but has not been evaluated in outcomes studies for either CVD event reduction or safety. (E)
* Statin therapy is contraindicated in pregnancy. (E)

Patients with type 2 diabetes have an increased prevalence of lipid abnormalities that contributes to higher rates of CVD. Lipid management aimed at lowering LDL cholesterol, raising HDL cholesterol, and lowering triglycerides has been shown to reduce macrovascular disease and mortality in patients with type 2 diabetes, particularly in those who have had prior cardiovascular events. In studies using HMG (hydroxymethylglutaryl)-CoA reductase inhibitors (statins), patients with diabetes achieved significant reductions in coronary and cerebrovascular events. In two studies using the fibric acid derivative gemfibrozil, reductions in cardiovascular end points were also achieved.

Target lipid levels are shown in Table 6. Lifestyle intervention, including MNT, increased physical activity, weight loss, and smoking cessation, should allow some patients to reach these lipid levels. Nutrition intervention should be tailored according to each patient??™s age, type of diabetes, pharmacological treatment, lipid levels, and other medical conditions and should focus on the reduction of saturated fat, cholesterol, and transunsaturated fat intake. Glycemic control can also beneficially modify plasma lipid levels. Particularly in patients with very high triglycerides and poor glycemic control, glucose lowering may be necessary to control hypertriglyceridemia. Pharmacological treatment is indicated if there is an inadequate response to lifestyle modifications and improved glucose control. However, in patients with clinical CVD and LDL >100 mg/dl, pharmacological therapy should be initiated at the same time that lifestyle intervention is started. In patients with diabetes aged <40 years, similar consideration for LDL-lowering therapy should be given if they have increased cardiovascular risk (e.g., additional cardiovascular risk factors or long duration of diabetes). Very little clinical trial data exist in patients in this age-group.

The first priority of pharmacological therapy is to lower LDL cholesterol to a target goal of <100 mg/dl (2.60 mmol/l) or therapy to achieve a reduction in LDL of 30??“40%. For LDL lowering, Statins are the drugs of choice. Other drugs that lower LDL include Nicotinic Acid, ezetimbe, bile acid sequestrants, and fenofibrate.

The Heart Protection Study demonstrated that in individuals with diabetes over the age of 40 years with a total cholesterol >135 mg/dl, LDL reduction of 30% from baseline with the statin simvastatin was associated with an 25% reduction in the first event rate for major coronary artery events independent of baseline LDL, preexisting vascular disease, type or duration of diabetes, or adequacy of glycemic control. Similarly, in the Coronary Artery Diabetes Study (CARDS), patients with type 2 diabetes randomized to 10 mg atorvastatin daily had a significant reduction in cardiovascular events including stroke.

Recent clinical trials in high-risk patients, such as those with acute coronary syndromes or previous cardiovascular events, have demonstrated that more aggressive therapy with high doses of Statins to achieve an LDL of <70 mg/dl led to a significant reduction in further events. The risk of side effects with high doses of Statins is significantly outweighed by the benefits of such therapy in these high-risk patients. Therefore, a reduction in LDL to a goal of <70 mg/dl is an option in very-high-risk patients with overt CVD. The combination of Statins with other lipid-lowering drugs such as ezetimibe may allow achievement of the LDL goal with a lower dose of a statin in such patients, but no data are available as to whether such combination therapy is more effective than a statin alone in preventing cardiovascular events.

Relatively little data are available on lipid-lowering therapy in subjects with type 1 diabetes. In the Heart Protection Study, 600 patients with type 1 diabetes had a proportionately similar, but not statistically significant, reduction in risk compared with patients with type 2 diabetes. Although the data are not definitive, consideration should be given for similar lipid-lowering therapy in type 1 diabetic patients as in type 2 diabetic patients, particularly if they have other cardiovascular risk factors or features of the metabolic syndrome.

If the HDL is <40 mg/dl and the LDL is between 100 and 129 mg/dl, a fibric acid derivative or niacin might be used. Niacin is the most effective drug for raising HDL but can significantly increase blood glucose at high doses. More recent studies demonstrate that at modest doses (750??“2,000 mg/day), significant benefit with regards to LDL, HDL, and triglyceride levels are accompanied by only modest changes in glucose that are generally amenable to adjustment of diabetes therapy.

Combination therapy, with a statin and a fibrate or statin and niacin, may be efficacious for patients needing treatment for all three lipid fractions, but this combination is associated with an increased risk for abnormal transaminase levels, myositis, or rhabdomyolysis. The risk of rhabdomyolysis seems to be lower when Statins are combined with fenofibrate than gemfibrozil. There is also a risk of a rise in plasma creatinine, particularly with fenofibrate. It is important to note that clinical trials with Fibrates and niacin have demonstrated benefits in patients who were not on treatment with Statins and that there are no data available on reduction of events with such combinations. The risks may be greater in patients who are treated with combinations of these drugs with high doses of Statins.

3. Antiplatelet agents


* Use aspirin therapy (75??“162 mg/day) as a secondary prevention strategy in those with diabetes with a history of CVD. (A)
* Use aspirin therapy (75??“162 mg/day) as a primary prevention strategy in those with:
??? Type 2 diabetes at increased cardiovascular risk, including those who are >40 years of age or who have additional risk factors (family
history of CVD, hypertension, smoking, dyslipidemia, or albuminuria). (A)
??? Type 1 diabetes at increased cardiovascular risk, including those who are >40 years of age or who have additional risk factors (family
history of CVD, hypertension, smoking, dyslipidemia, or albuminuria). (C)
* Consider aspirin therapy in people between the age of 30 and 40 years, particularly in the presence of other cardiovascular risk factors. (E)
* Aspirin therapy should not be recommended for patients under the age of 21 years because of the increased risk of Reye??™s syndrome associated with aspirin use in this population. People <30 years have not been studied. (E)
* Combination therapy using other antiplatelet agents such as clopidrogel in addition to aspirin should be used in patients with severe and progressive CVD. (C)
* Other antiplatelet agents may be a reasonable alternative for high-risk patients with aspirin allergy, bleeding tendency, receiving anticoagulant therapy, recent gastrointestinal bleeding, and clinically active hepatic disease who are not candidates for aspirin therapy. (E)

The use of aspirin in diabetes is reviewed in detail in the ADA technical review and position statement on aspirin therapy. Aspirin has been recommended as a primary and secondary therapy to prevent cardiovascular events in diabetic and nondiabetic individuals. One large meta-analysis and several clinical trials demonstrate the efficacy of using aspirin as a preventive measure for cardiovascular events, including stroke and myocardial infarction. Many trials have shown an 30% decrease in myocardial infarction and a 20% decrease in stroke in a wide range of patients, including young and middle-aged patients, patients with and without a history of CVD, males and females, and patients with hypertension.

Dosages used in most clinical trials ranged from 75 to 325 mg/day. There is no evidence to support any specific dose, but using the lowest possible dosage may help reduce side effects. There is no evidence for a specific age at which to start aspirin, but at ages <30 years, aspirin has not been studied.

Clopidogrel has been demonstrated to reduce CVD rates in diabetic individuals. Adjunctive therapy in very-high-risk patients or as alternative therapy in aspirin-intolerant patients should be considered.

4. Smoking cessation


* Advise all patients not to smoke. (A)
* Include smoking cessation counseling and other forms of treatment as a routine component of diabetes care. (B)

Issues of smoking in diabetes are reviewed in detail in the ADA technical review and position statement on smoking cessation. A large body of evidence from epidemiological, case-control, and cohort studies provides convincing documentation of the causal link between cigarette smoking and health risks. Cigarette smoking contributes to one of every five deaths in the U.S. and is the most important modifiable cause of premature death. Much of the prior work documenting the impact of smoking on health did not separately discuss results on subsets of individuals with diabetes, suggesting that the identified risks are at least equivalent to those found in the general population. Other studies of individuals with diabetes consistently found a heightened risk of morbidity and premature death associated with the development of macrovascular complications among smokers. Smoking is also related to the premature development of microvascular complications of diabetes and may have a role in the development of type 2 diabetes.

A number of large randomized clinical trials have demonstrated the efficacy and cost-effectiveness of counseling in changing smoking behavior. Such studies, combined with others specific to individuals with diabetes, suggest that smoking cessation counseling is effective in reducing tobacco use.

The routine and thorough assessment of tobacco use is important as a means of preventing smoking or encouraging cessation. Special considerations should include assessment of level of nicotine dependence, which is associated with difficulty in quitting and relapse.

5. CHD screening and treatment


* In patients >55 years of age, with or without hypertension but with another cardiovascular risk factor (history of CVD, dyslipidemia, microalbuminuria, or smoking), an ACE inhibitor (if not contraindicated) should be considered to reduce the risk of cardiovascular events. (A)
* In patients with a prior myocardial infarction or in patients undergoing major surgery, ??-blockers, in addition, should be considered to reduce mortality. (A)
* In asymptomatic patients, consider a risk factor evaluation to stratify patients by 10-year risk and treat risk factors accordingly. (B)
* In patients with treated CHF, metformin use is contraindicated. The TZDs are associated with fluid retention, and their use can be complicated by the development of CHF. Caution in prescribing TZDs in the setting of known CHF or other heart diseases, as well as in patients with preexisting edema or concurrent insulin therapy, is required. (C)

CHD screening and treatment are reviewed in detail in the ADA consensus statement on CHD in people with diabetes. To identify the presence of CHD in diabetic patients without clear or suggestive symptoms of CAD, a risk factor??“based approach to the initial diagnostic evaluation and subsequent follow-up is recommended. However, a recent study concluded that using current guidelines fails to detect a significant percentage of patients with silent ischemia.

At least annually, cardiovascular risk factors should be assessed. These risk factors include dyslipidemia, hypertension, smoking, a positive family history of premature coronary disease, and the presence of micro- or macroalbuminuria. Abnormal risk factors should be treated as described elsewhere in these guidelines. Patients at increased CHD risk should receive aspirin and may warrant an ACE inhibitor.

Candidates for a diagnostic cardiac stress test include those with 1) typical or atypical cardiac symptoms and 2) an abnormal resting ECG. The screening of asymptomatic patients remains controversial.

Studies have demonstrated that a significant percentage of patients with diabetes who have no symptoms of CAD have abnormal stress tests, either by ECG or echo and nuclear perfusion imaging. Some of these patients, though clearly not all, have significant coronary stenoses if they proceed to angiography. It has also been demonstrated that patients with silent myocardial ischemia have a poorer prognosis than those with normal stress tests. Their risk is further accentuated if cardiac autonomic neuropathy coexists. Candidates for a screening cardiac stress test include those with 1) a history of peripheral or carotid occlusive disease and 2) sedentary lifestyle, age >35 years, and plans to begin a vigorous exercise program. There are no data to suggest that patients who start to increase their physical activity by walking or similar exercise increase their risk of a CVD event and therefore are unlikely to need a stress test.

It has previously been proposed to screen those with two or more additional cardiac risk factors. However, this likely includes the vast majority of patients with type 2 diabetes (given that the risk factors frequently cluster). The Detection of Silent Myocardial Ischemia in Asymptomatic Diabetic Subjects (DIAD) study suggested that conventional cardiac risk factors did not help to identify those patients with abnormal perfusion imaging.
Current evidence suggests that noninvasive tests can improve assessment of future CHD risk. There is, however, no current evidence that such testing in asymptomatic patients with risk factors improves outcomes or leads to better utilization of treatments.


1.  Bode BW (Ed.): Medical Management of Type 1 Diabetes. 4th ed. Alexandria, VA, American Diabetes Association, 2004
2.  Zimmerman BR (Ed.): Medical Management of Type 2 Diabetes. 4th ed. Alexandria, VA, American Diabetes Association, 1998
3.  Kilingensmith G (Ed.): Intensive Diabetes Management.  3rd ed.  Alexandria, VA, American Diabetes Association, 2003
4.  The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183-1197, 1997
4a.World Health Organization:  Diabetes Mellitus: Report of a WHO Study Group. Geneva, World Health Org., 1985 (Tech. Rep. Ser., no. 727)
5.  The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 26:3160 - 3167, 2003
6.  Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaaniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344:1343-1350, 2001
7.  Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, Hu ZX, Lin J, Xiao JZ, Cao HB, Liu PA, Jiang XG, Jiang YY, Wang JP, Zheng H, Zhang H, Bennett PH, Howard BV: Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the DaQing IGT and Diabetes Study. Diabetes Care 20:537- 544, 1997
8.  The Diabetes Prevention Program Research Group:  Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393- 403, 2002
9.  Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M: Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomized trial. Lancet 359:2072-2077, 2002
10.  Sjostrom L, et al: XENDOS ( Xenical in the prevention of diabetes in obese subjects):  a landmark study.  Poster presented at the International Congress on Obesity (ICO), San Paulo, Brazil, 2002
11.  Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Tan S, Berkowitz, Hodis HN, Azen SP: Preservation of pancreatic β-cell function and prevention of type 2 diabetes by pharmacological trewatment of insulin resistance in high-risk hispanic women. Diabetes 51:2796 -2803, 2002
12.  Engelgau ME, Narayan KMV, Herman WH:  Screening for type 2 diabetes (Technical Review).  Diabetes Care 23:1563-1580, 2000 [erratum appears in Diabetes Care 23:1868 -1869, 2000]
13.  American Diabetes Association: Type 2 diabetes in children and adolescents (Consensus Statement).  Diabetes Care 23:381-389, 2000
14.  American Diabetes Association: Gestational diabetes mellitus (Position Statement). Diabetes Care 27 (Suppl. 1):S88 - S90, 2004
15.  The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus. N Engl J Med 329: 977-986, 1993
16.  The UK Prospective Diabetes Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352: 837- 853, 1998
17.  The UK Prospective Diabetes Study Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854 -865, 1998

May 27, 10 • Diabetes mellitus