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In the Slide Library section:
Final Results in Patients With Type 2 Diabetes
  Framingham Heart Study 30-Year Follow-Up: CVD Events in Patients With Diabetes (Ages 35-64)
  UKPDS: Intensive Blood-Glucose vs Conventional Treatment in Patients With Type 2 Diabetes
  UKPDS: Tight Blood-Pressure Control vs Less Tight Control in Patients With Type 2 Diabetes
60-Year-Old Postmenopausal Female With Claudication and Chest Pain

The following case was provided by Alexandra J. Lansky, MD, and Gishel New, MD, PhD. Dr Lansky, an NLEC Faculty Member, is Director, Angiographic Core Laboratory and Women’s Health Initiative, at the Cardiovascular Research Foundation, Lenox Hill Heart and Vascular Institute, New York, New York. Dr New is Director of Clinical Research at the Cardiovascular Research Foundation, Lenox Hill Interventional Cardiology, New York, New York.

Disclosure Information for Dr Lansky: Speaker’s bureau: Novartis, AstraZeneca, Lilly, Novoste, Guidant Corp; Research Grants: Cordis, Johnson & Johnson, Abbott, Novoste, Radiance, Boston Scientific, Medtronic AVE, Guidant Corp.
Disclosure Information for Dr New: None.

LA, a 60-year-old postmenopausal female, was referred for evaluation of bilateral lower extremity claudication after walking just one block. She also complained of chest pain and shortness of breath on exertion. The pain in her legs limits her activity; her right leg pain is worse than that of the left leg. Her past medical history includes 15 years of hypertension (currently well-controlled with medication), hyperlipidemia, type 2 diabetes, and known coronary artery disease with bypass surgery performed 10 years earlier.

Her physical examination is notable for significantly diminished pulses in her right femoral and her right and left popliteal, posterior tibial, and dorsalis pedis arteries, with an ankle-brachial index (ABI) of 0.4 on the right and 0.65 on the left. She was admitted for cardiac and peripheral angiographies.

Discussion
This postmenopausal female presents with a constellation of risk factors and advanced coronary and peripheral atherosclerosis that carries an exceedingly poor prognosis. The combination of established severe coronary disease, severe peripheral arterial disease (PAD), and the presence of type 2 diabetes, hypertension, and poorly controlled mixed dyslipidemia (high LDL-C, low HDL-C, and high TG) represents a therapeutic challenge for the immediate and long-term treatment of this patient.
   
PAD is an important manifestation of systemic atherosclerosis that tends to affect women and men equally. PAD is highly prevalent (up to 40%) in patients with coronary heart disease (CHD); conversely, patients with CHD frequently have concomitant PAD (up to 60%, depending on the severity of disease). The severity of PAD, as measured by the ABI (see Table 1), is closely associated with all-cause cardiovascular mortality—with an annual mortality rate of 20% to 25% in patients with critical PAD or in the presence of coexisting CHD. Recognizing the prognostic implications of PAD, the National Cholesterol Education Program Third Adult Treatment Panel (NCEP ATP III) now classifies patients with PAD alone at equal risk to that of patients with established CHD. Similarly, type 2 diabetes is associated with a marked increase in CHD mortality such that, in the absence of other risk factors, it also is classified as a CHD risk equivalent.1



Diabetes Risk in Women
Diabetes has long been considered a stronger risk factor for CHD mortality in women than in men. Similarly, diabetes has been shown to be a greater risk factor for claudication in women than in men.2 A recent report evaluated the changes in CHD mortality rates in patients with and without diabetes during 1971 to 1975 in the Second National Health and Nutrition Examination Survey (NHANES II) and 1982 to 1984 in the Third National Health and Nutrition Examination Survey (NHANES III). In the latter decade, a mortality reduction was observed in nondiabetic men (44%) and in nondiabetic women (20%); the reduction was attenuated in diabetic men (16.6%), but mortality actually increased in diabetic women (10.7%).3 This showed the need for aggressive risk-factor detection and modification, especially in the female diabetic population. While intensive glycemic control is important in reducing cardiovascular risk in diabetic patients (HbA1c should be routinely monitored with a goal of attaining levels below 7%), recent data from the United Kingdom Prospective Diabetes Study demonstrate that it does not fully eliminate risk.4 Furthermore, the most important predictor of CHD mortality in patients with type 2 diabetes is elevated LDL-C, followed by low HDL-C, high HbA1c levels, systolic hypertension, and history of smoking.5
   
Secondary prevention with aggressive lipid lowering therapy is essential in a patient with PAD and coexisting coronary artery disease and diabetes, as is the case with LA. Based on ATP III, each risk, independently and in combination, warrants aggressive implementation and follow-up to improve treatment compliance and adherence.1 Treatment goals should aim to achieve LDL-C levels below 100 mg/dL and TG levels below 150 mg/dL. Despite pravastatin therapy, this patient has remained inadequately treated.





Lipid Triad
This case patient, LA, has the typical lipid triad associated with diabetes—elevated TG, low HDL-C, and elevated LDL-C.
A number of studies suggest that patients with mixed hyperlipidemia are at the highest risk for CHD events and stand to benefit the most from lipid-lowering therapy. Furthermore, many of the primary and secondary lipid-lowering prevention trials have demonstrated this therapy’s effectiveness in the diabetic subpopulation (see Table 2). The elevated serum TG levels confer additional independent risk for CHD in this patient. A number of etiologies and contributing factors may explain those elevated TG levels, including the presence of type 2 diabetes, inactivity, high carbohydrate intake, or a genetic disorder such as familial combined hyperlipidemia.
   
Triglyceride elevation is common in type 2 diabetes, occurring in up to 30% of women with diabetes compared with only 3% of women without diabetes in the Framingham Offspring Study. The primary goal of therapy in patients with high TG levels (up to 500 mg/dL) and elevated LDL-C is to first achieve the LDL-C goal and then target the non–HDL-C goal (30 mg/dL higher than LDL-C goal). However, in patients with very high TG levels (>500 mg/dL), reducing the TG level becomes a primary goal in order to prevent pancreatitis. In addition to a very-low-fat diet, weight reduction, and exercise, combination therapy with an HMG-CoA reductase inhibitor (statin) and either nicotinic acid or a fibrate may be required to achieve optimal control because of the modest effect many statins have on TG levels.6,7
   
The Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) confirmed the benefit of gemfibrozil in reducing TG levels and in reducing events in nondiabetics and diabetics equally.8 In our patient, high-dose atorvastatin (80 mg) was substituted for pravastatin, and gemfibrozil 600 mg bid was added with the aim of reducing her TG levels, along with the specific recommendation of a very-low-fat diet.
    
With presenting symptoms of progressive and limiting claudication, a critical stenosis of the right common femoral artery, and a significant stenosis of the left superficial femoral artery, LA underwent successful percutaneous angioplasty of the right common femoral artery, with the goal of relieving symptoms, improving walking capacity, and ultimately preventing ischemic complications. Either percutaneous or surgical revascularization can be expected to have similar patency rates at 5 years in the range of 50% to 70%.9

LA was discharged on daily aspirin 325 mg, cilostazol 50 mg qd, gemfibrozil 600 mg bid, and atorvastatin 80 mg qd in addition to her admitting medications (with the exception of pravastatin). She was referred to cardiac rehabilitation to initiate a regular exercise program and a low-fat diet. Her lipid profile will be followed up during her next visit, with the intent of performing a staged intervention of the left superficial artery and LADA intervention after 3 weeks.

Concluding Remarks
Although the guidelines for secondary prevention are clear, evidence continues to suggest that over 50% of patients with known cardiovascular atherosclerotic disease (especially PAD) and hyperlipidemia are undertreated.10 Unfortunately, as this case illustrates, even among patients with established advanced atherosclerotic disease where lipid-lowering therapy has been initiated, achieving treatment goals still remains a significant challenge; for women, it is estimated to occur in less than 10% of cases. The ATP III guidelines recognize and continue to emphasize the importance of a multidisciplinary approach to implement and sustain preventive therapy in order to realize the full potential of CHD risk reduction.

References
1.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.

2.

TASC Working Group. Management of peripheral arterial disease.
J Vasc Surg. 2000;31(suppl 1):S1-S296.
3. Gu K, Cowie CC, Harris MI. Diabetes and decline in heart disease mortality in US adults. JAMA. 1999;281:1291-1297.
4. Straton IM, Adler GI, Neil HA, et al. Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405-412.
5. Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus (UKPDS 23). BMJ. 1998;316:823-828.
6. Grundy SM. Consensus statement: role of therapy with “statins” in patients with hypertriglyceridemia. Am J Cardiol. 1998;81:1B-6B.
7. NIH Consensus Statement. Triglyceride, high density lipoprotein, and coronary heart disease. 1992;10:1-28.
8. Rubins HB, Robins SJ, Collins D, et al, for the Veteran Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341:410-418.
9. Wilson SE, Wolf GL, Cross AP. Percutaneous transluminal angioplasty versus operation for peripheral arteriosclerosis: report of a prospective randomized trial in a selected group of patients. J Vasc Surg. 1989;9:1-9.
10. McDermott MM, Mehta S, Ahn H, et al. Atherosclerotic risk factors are less intensively treated in patients with peripheral artery disease than in patients with coronary artery disease. J Gen Intern Med. 1997;12:209-215.