Steve V. Edelman, MD
Robert R. Henry, MD
Lipid abnormalities that accelerate atherosclerosis and increase the risk of CV disease are significantly more common in patients with type 2 diabetes than in nondiabetic individuals. In addition, central obesity associated with type 2 diabetes is also a risk factor for CV disease. These combined factors have resulted in CV disease becoming a major cause of morbidity and mortality in type 2 diabetes. The characteristic lipid abnormalities in type 2 diabetes are….
- Hypertriglyceridemia usually due to elevated triglyceride-rich, very low-density lipoprotein (VLDL) levels and sometimes increased chylomicrons as well;
- Decreased HDL levels;
- Phenotype B pattern (excessive amounts of small, dense LDL and intermediate-density lipoprotein particles), which contributes to an increased CV risk.
Given this higher risk of premature CV disease in type 2 diabetes, all patients should be screened for lipid abnormalities at the initial evaluation using a fasting lipid profile to determine serum triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol levels. Shown in Table 15.3 are acceptable, borderline, and high-risk lipid levels for adults. LDL cholesterol is calculated from the formula:
This calculation is not accurate if the triglycerides are >400 mg/dL, and LDL should be measured directly by ultracentrifugation. The recommendations for treatment decisions based on elevated LDL are shown in Table 15.4. Pharmacologic therapy should be initiated after nutrition and behavioral interventions. However, when clinical CV disease is present or LDL is very high (>200 mg/dL), pharmacologic therapy should be initiated at the same time.
Because lipid abnormalities often reflect poor glycemic control, the first treatment approach to dyslipidemia in type 2 diabetes should be optimizing diabetes control with diet, exercise, and pharmacologic therapy as needed. As glycemic control improves, lipid levels also usually improve, particularly when insulin resistance is the underlying metabolic abnormality responsible for the lipid disorder.
Limiting calories and saturated fat intake has proved to be highly effective in improving, but not usually normalizing, the dyslipidemia of type 2 diabetes. Increased intake of soluble fiber, particularly from oat and bean products, has been shown to reduce LDL cholesterol levels. The NCEP has designed a stepped approach for restricting dietary fat and cholesterol that can be modified to incorporate specific requirements for diabetic nutrition.
The following guidelines should be implemented with the assistance of a registered dietitian:
- Step 1 diet guidelines: limit saturated fat intake to 8% to 10% of daily calories, with 30% of calories from total fat; limit cholesterol to
- Step 2 diet guidelines: limit saturated fat intake to <7% of daily calories; limit cholesterol intake to
- If triglycerides are >1000 mg/dL, all dietary fats should be reduced to lower circulating chylomicrons.
Recommendations for effective diet therapy for the treatment of lipid disorders in diabetes are shown in Table 15.5.
TABLE 15.5 — Diet Recommendations for the Treatment of Lipid Disorders in Diabetes
- Calorie restriction and increased physical activity for weight loss as indicated
- Saturated and trans-unsaturated fat intake <10% and preferably <7% of total energy intake
- Total dietary cholesterol intake
- Emphasis on complex carbohydrates (at least five portions per day of fruits/vegetables); soluble fibers (legumes, oats, certain fruits/vegetables) have additional benefits on total cholesterol, LDL cholesterol level, and glycemic control
- Replacing saturated fat with carbohydrate or monounsaturated fats (e.g., canola oil, olive oil)
Lipid-lowering pharmacologic agents are usually necessary when the lipid profile does not normalize in response to diet, exercise, and other efforts to improve glycemic control. The ADA follows an order of priority for the treatment of diabetic dyslipidemia (Table 15.6). LDL cholesterol is considered the first priority, followed by HDL cholesterol raising, triglyceride lowering, and treatment of combined hyperlipidemia. Commonly used pharmacologic agents for the treatment of dyslipidemia are listed in Table 15.7:
TABLE 15.6 — Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults
- LDL cholesterol lowering:
- Lifestyle interventions
- Preferred: HMG CoA reductase inhibitor (statin)
- Others: bile-acid binding resin, cholesterol absorption inhibitor, fenofibrate, or niacin
- HDL cholesterol raising:
- Lifestyle interventions
- Nicotinic acid or fibrates
- Triglyceride lowering:
- Lifestyle interventions
- Glycemic control
- Fibric acid derivative (gemfibrozil, fenofibrate), niacin, high-dose statins (in those who also have high LDL cholesterol)
- Combined hyperlipidemia:
- First choice: improved glycemic control plus high-dose statin
- Second choice: improved glycemic control plus statin plus fibric acid derivative
- Third choice: improved glycemic control plus statin plus nicotinic acid
Decision for treatment of high LDL cholesterol before elevated triglycerides is based on clinical trial data indicating safety as well as efficacy of the available agents. The combination of statins with nicotinic acid, fenofibrate, or especially gemfibrozil may carry an increased risk of myositis. Patients with triglyceride levels >400 mg/dL require special consideration. Adapted from American Diabetes Association. Diabetes Care. 2004;27 (suppl 1):S69.
- When elevated LDL cholesterol is the primary lipoprotein abnormality: HMG-CoA reductase inhibitors (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin) are indicated. These agents reduce cholesterol synthesis and are useful as monotherapy for the familial forms of hypercholesterolemia, or in combination with BASs. Most HMG-CoA reductase inhibitors are indicated for the reduction of both LDL cholesterol and triglyceride levels. When serum triglycerides are consistently elevated >200 mg/dL, with or without low HDL levels, medication is warranted in addition to a low-fat diet.
- BASs (Colestid, Questran, Welchol) have several disadvantages in patients with diabetes. The older bile binders, in particular, must be taken 1 hour before or 4 hours after other oral medications so there is no interference with absorption. Bile binders also cause fairly significant constipation, and this is especially bothersome in the diabetic population because it exacerbates the constipation of diabetic gastroparesis. In addition, bile binders also can worsen hypertriglyceridemia in patients with diabetes. The newest BAS, colesevelam (Welchol) may provide an additional benefit in patients with type 2 diabetes with dyslipidemia since it is not only indicated for the treatment of primary dyslipidemia as monotherapy or in combination with a HMG-CoA reductase inhibitor, but was recently approved to improve glycemic control in adults with type 2 diabetes (see Chapter 8, Oral Agents) and appears to be better tolerated, in terms of GI adverse events (e.g., constipation), than the older BASs.
- Nicotinic acid is highly effective at improving all lipoprotein parameters, although it significantly worsens glucose intolerance and is contraindicated in most patients with type 2 diabetes. Niaspan is a new slow-release niacin preparation that may be tolerated in a subset of severe dyslipidemic individuals with diabetes.
- Despite earlier warnings that HMG-CoA reductase inhibitors should not be used with gem-fibrozil (Lopid) or fenofibrate (Tricor) in patients with mixed disorders, they offer a safe and effective approach to diabetic patients with elevated triglycerides and LDL cholesterol values. When adding one medication to the other, creatinine phosphokinase (CPK) should be measured and LFTs should be performed in 3 weeks and again in 6 weeks, along with a lipoprotein profile. Once a stable dose is maintained and the CPK and LFTs monitoring these values frequently becomes unnecessary. Caution should be used if the patient is on other medications that could cause hepatitis or myositis. Last, this combination should only be used in compliant patients who will not get lost to medical follow-up.
- When hypertriglyceridemia is the primary lipid abnormality (triglyceride levels consistently >200 mg/dL with or without low HDL levels), a fibric acid derivative is the drug of choice; gemfibrozil reduces triglyceride levels usually with small decreases in LDL cholesterol and small increases in HDL cholesterol. Fenofibrate is a fenofibric acid derivative that may lower LDL cholesterol in addition to reducing triglyceride values and increasing HDL levels. These agents are particularly effective at decreasing hepatic VLDL production and enhancing the clearance of VLDL triglycerides by stimulating lipoprotein lipase, and they are well tolerated.
- Low HDL levels are extremely difficult to treat. Nicotinic acid can be of benefit but often leads to deterioration in glucose control. Fibrates also improve HDL modestly. Perhaps the best medications to increase HDL in type 2 diabetic subjects are the glitazones, which can increase HDL up to 20%.
- An effective therapeutic option for combined dyslipidemia is the use of an HMG-CoA reductase inhibitor that is indicated for the treatment of elevated LDL cholesterol and triglyceride levels. LDL cholesterol can be reduced up to 60% and triglycerides up to 40% with an HMG-CoA reductase inhibitor.
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