Dyslipidemia in a Patient With Type 2 Diabetes

C.W. is a 51-year-old white man diagnosed with type 2 diabetes in March 2002. At the time of diagnosis, he had typical symptoms of weight loss,polyuria, and polydipsia. Examination revealed a healthy male with height of 6'1” and weight of 224 lb (BMI 29.6 kg/m²). Laboratory evaluation was remarkable for a random glucose of 580 mg/dl, triglycerides of 5,777 mg/dl, total cholesterol of 550 mg/dl, HDL cholesterol of 102 mg/dl, LDL cholesterol not calculable secondary to triglycerides, and a hemoglobin A_1c (A1C) of 13.6%.

Over the next several months, he did remarkably well on combinations of sulfonylurea and metformin, with fenofibrate added to reduce the severe hypertriglyceridemia. His A1C was 5.9%, LDL 97 mg/dl, HDL 39 mg/dl, and triglycerides 236 mg/dl by August 2002.

He has remained in good physical health but has continued to struggle with control of his dyslipidemia over the last year, despite the addition of a statin. His HDL has decreased to < 30 mg/dl with a gradual, steady increase in his triglycerides.

On 28 June 2006, he presented to the office, with examination revealing a weight of 250 lb. (BMI 33.0 kg/m²) and blood pressure of 110/76 mmHg. His medications were reviewed and are listed as follows:

• Fenofibrate, 145 mg daily

• Simvastatin, 40 mg at bedtime

• Glimepiride, 4 mg daily

• Metformin XL, 500 mg 2 tablets twice daily

• Aspirin, 81 mg daily

Laboratory studies revealed a fasting triglyceride level of 1,158 mg/dl,cholesterol of 204 mg/dl, HDL of 28 mg/dl, LDL not calculable, and A1C of 6.9%.

He has since been evaluated and undergone extensive counseling by a dietitian, revealing a diet high in saturated fats and red meat. He is continuing to exercise and attempt dietary modifications to improve control of both his dyslipidemia and his diabetes. He is scheduled for follow-up evaluation and assessment of his progress in the next 2 months.

1. What are the goals of lipid management in patients with type 2 diabetes?

2. Which pharmacological agents are available for use with statins to help raise HDL cholesterol and lower triglycerides?

3. Is there evidence that use of a fenofibrate in combination with statins improves cardiovascular end points?

In patients with type 2 diabetes without overt cardiovascular disease(CVD), the primary goal of therapy is an LDL cholesterol of < 100 mg/dl. In addition, the use of statin therapy to achieve an LDL reduction of 30-40% is recommended for those > 40 years of age, regardless of their initial LDL levels. Given the proven reduction in coronary and cerebrovascular events with statin use, it should generally be considered as initial therapy for treatment of dyslipidemia in patients with diabetes. C.W.'s case is unique in that the severity of his hypertriglyceridemia necessitated treatment with fibrate therapy shortly after diagnosis.

A variety of pharmacological agents are available to address the secondary goals for lipid management in patients with diabetes: to lower triglycerides to 150 mg/dl and raise HDL cholesterol to 40 mg/dl in men and 50 mg/dl in women. Gemfibrozil is a fibric acid derivative proven to lower triglycerides and raise HDL and has been shown to achieve reductions in cardiovascular end points. Its limitations include the need to take the drug twice daily, which affects adherence, but more importantly its potential for significant interactions with statins. These may result in increased risk for abnormal transaminase levels, myositis, and life-threatening rhabdomyolysis. Conversely, fenofibrate is a oncedaily medication shown to significantly reduce triglycerides and raise HDL and may have less potential for interaction with statins.

Niacin has also proven effective in treating the secondary goals of lipid management in patients with diabetes, but the adverse effect of flushing limits its tolerability. Even with concomitant use of aspirin therapy or extended-release formulations to combat the flushing, many patients will not adhere to a prolonged course of therapy. In addition, niacin has been associated with worsening glycemic control and increased insulin resistance,limiting its use in some patients with diabetes.

Omega-3 fatty acids have been proven to raise HDL and lower triglycerides and are generally well tolerated. There are no known interactions with statin medications, but treatment in patients with very high triglycerides (≥ 500 mg/dl) can result in significant elevations of LDL cholesterol, adversely affecting the overall lipid profile.

C.W.'s case is common among patients with type 2 diabetes and demonstrates that combination therapy for management of dyslipidemia is frequently required. Fenofibrate is a reasonable option among the alternatives to use in combination with a statin. The recent Fenofibrate Intervention and Event Lowering in Diabetes trial suggested the safety of fenofibrate/statin combination therapy in addition to showing effectiveness in primary prevention of total cardiovascular events in patients with type 2 diabetes.

Despite the use of combination therapy in patients with type 2 diabetes,achieving target goals for triglycerides and HDL cholesterol is often difficult. Clinicians should also remember that good glucose control is also crucial in controlling hypertriglyceridemia in the setting of diabetes. Development of newer statins have provided increased efficacy and potency, and LDL reductions associated with these drugs have enabled clinicians to better meet primary goals in their patients. In contrast, the other available pharmacological agents demonstrate only mild HDL-raising capacity and are often inadequate to lower triglycerides to target levels when initial values are very high.

The pending arrival of new drugs to raise HDL, such as torcetrapib, may help clinicians better manage lipid disorders in their patients with diabetes. Until then, the prudent use of combination therapy for management of dyslipidemia, glucose control, intensive dietary modifications, and exercise remain the mainstays of therapy.

• Use of combination pharmacological therapy is common in treating hypertension and achieving glucose control in patients with diabetes. The same principle may be necessary to manage dyslipidemia.

• The use of a statin/fenofibrate combination is a reasonable option for many patients, with demonstrated safety and reduction in cardiovascular end points.

• Currently available pharmacological agents for lowering triglycerides and raising HDL cholesterol are frequently inadequate in patients with diabetes,and newer HDL-raising drugs should help in meeting secondary goals of therapy.