Primary prevention of coronary artery disease in patients with type 2 diabetes mellitus

Jarrod M. Harrall, DO Andrea Tufo, OMS IV

T

he Centers for Disease Control and Prevention (CDC) estimated that 18.8 million people in the United States had diagnosed diabetes mellitus in 2010, with an additional 7 million people having diabetes that was undiagnosed.1

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urrently, the diagnosis of diabetes mellitus is made with repeat testing based on 1 of the following 3 findings:

C

(1) glycosylated hemoglobin (HbA1c) level is ⬎ 6.5%; (2) fasting plasma glucose level is ⬎ 126 mg/dL; (3) 2-hour plasma glucose level is ⬎ 200 mg/dL during an oral glucose tolerance test.2,3 Adults with diabetes mellitus are 2 to 4 times more likely to die of cardiovascular disease (CVD) or stroke than are adults without diabetes.1 Although mortality from CVD has decreased among patients with type 2 diabetes mellitus (T2DM) in recent years, the rate of CVD-related death remains higher in the population with T2DM than in the population without this disease.1 In 2004, heart disease was listed as the cause of death on 68% of death certificates for people older than 65 years with diabetes mellitus.1 Therefore, it is especially important to decrease cardiovascular risk factors in this population. According to the CDC, control of low-density lipoprotein cholesterol (LDL-C levels), as well as blood pressure, can substantially reduce the risk of CVD in individuals with diabetes mellitus.1

global risks of patients with diabetes mellitus have been discussed in consensus statements published by the ADA and the American Heart Association (AHA): the Framingham Heart Study risk calculator (http://hp2010.nhlbihin.net/atpiii/calculator. asp?usertype=prof), the United Kingdom Prospective Diabetes Study (UKPDS) risk engine (www.dtu.ox.ac.uk/riskengine/), and the ADA’s Diabetes Personal Health Decisions (PhD) risk assessment tool.5 However, the ADA retired the diabetes PhD risk assessment tool at the end of 2011, intending to have a new, improved online risk assessment tool available sometime in the first half of 2012.6 Furthermore, it is important to note that the ADA has recently questioned the validity of the Framingham risk calculator, noting that the Framingham Risk Score may overestimate risk by assuming that all patients with diabetes are at high risk of developing CVD.3,4

calorie diet and 175 minutes of physical activity each week. Risk factors evaluated at the end of the study were weight, fitness, HbA1c level, systolic blood pressure, diastolic blood pressure, LDL-C levels, high-density lipoprotein cholesterol (HDL-C) levels, and triglyceride levels. With the exception of LDL-C levels, which were significantly greater in the ILI group than in the DSE group (P = .009), all of the CVD risk factors measured in the Look AHEAD study were decreased in members of the ILI group (P ⬍ .001 to P = .01).7 The study also found that when compared to the number of members in Cardiovascular disease risk the DSE group, fewer members of the ILI assessment group began to take diabetic medications An important aspect of the management of over the 4-year period. diabetes mellitus is assessing CVD risk to Specific ADA lifestyle recommendadetermine the individual goals for each tions and goals for decreasing the risk of patient. Despite the known increased risk CVD include moderate weight loss (ie, of CVD in individuals with diabetes, there 7% - 10% of body weight per year) and remains a large population of such individdietary modification.2 Dietary guidelines uals who do not meet the goals outlined in include several recommendations for the the American Diabetes Association (ADA) Lifestyle modification limitation of fat. Patients should limit fat standards of medical care in diabetes.2 By Appropriate lifestyle modifications have intake to 25% to 35% of total daily calories, taking multiple factors into account, the been shown to stabilize glycemic control and any fats consumed should consist of physician can tailor the treatment goals of and to prevent and decrease CVD risk mainly monounsaturated and polyunsatueach patient to improve care and meet the factors. In a 4-year study, the Look rated fats. Saturated fats should be limited ADA goals. This is especially important for AHEAD (Action for Health in Diabetes) to less than 7% of energy intake, and high-risk patients, in whom the disease research group examined the effects of dietary cholesterol intake should be less tends to be the least well controlled.4 The lifestyle modifications on CVD risk factors.7 than 200 mg/day. Recommendations also key factors in defining these goals appear to In the study, participants were divided into include fiber intake of at least 14 grams per be the patient’s age, duration of disease, a “diabetes support and education group” 1000 calories. lipid panel results, degree of blood pressure (DSE, the control group) and an “intensive In addition to diet, physical activity is an control, HbA1c level, and tobacco use. lifestyle intervention group” (ILI).7 The ILI important lifestyle intervention for decreasThree calculators used to determine group was told to adhere to a 1200-1800ing CVD risk. Patients should be chal-

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lenged to achieve at least 150 minutes of moderate-intensity aerobic activity, or at least 90 minutes of vigorous aerobic activity, each week. Smoking is another modifiable risk factor of CVD. Patients who smoke should be counseled and advised to quit as soon as possible. Those patients who are willing to stop smoking should be offered access to cessation programs.

numbers do not provide a complete picture. The 2001 National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III),10 as well as the 2004 updated guidelines, maintain that, although LDL-C should be the primary treatment target in diabetes mellitus, there is considerable benefit in risk stratification of patients based on secondary treatment goals.11 An important point that should be Lipid control kept in mind is that the lipid profile in The ADA recommends that patients with diabetes mellitus but without known CVD patients with diabetes is more atherogenic than in those without diabetes, making the maintain an LDL-C level of less than 100 mg/dL as a primary goal.2 Patients with full lipid profile crucial to treatment decisions. Another reason to consider treatdiabetes mellitus and known CVD should strive for an even lower LDL-C goal, of less ment targets in addition to LDL-C is the complicated cascade of events in the lipid than 70 mg/dL.2 Research suggests that metabolism of people with diabetes. HDL-C and triglycerides have less In patients with diabetes mellitus, 2 influence than LDL-C on cardiovascular major consequences of insulin resistance events in people with diabetes.l,2,8,9 In the occur in lipid metabolism—the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, the addition unrestricted release of hormone-sensitive lipase and the functional loss of lipoprotein of fenofibrate to statin therapy led to an increase in HDL-C levels and a decrease in lipase, both of which result in increases in free fatty acids, triglycerides, and very-lowtriglyceride levels in a group of individuals with T2DM.8,9 However, these changes did density lipoprotein cholesterol (VLDLC).12 With an increase in triglycerides, not result in a decreased incidence of there is also an increase in cholesterol ester cardiovascular events compared to the transfer proteins, resulting in structural group receiving statin therapy alone.8,9 changes in the LDL-C and HDL-C partiIt appears, however, that the raw

cles. These changes make the cholesterol particles easier targets for lipolysis by hepatic lipase. When acted on by hepatic lipase, LDL-C is converted from large, buoyant (ie, “fluffy, puffy”) particles into smaller, denser, and more numerous particles known to be more atherogenic. The increase in triglycerides causes HDL-C to be catabolized by the kidneys, thus directly lowering the HDL-C level. The burden of lipoproteins other than LDL-C that contribute to atherogenesis can be determined by calculating either the apolipoprotein B (ApoB) or non-HDL-C level. Apolipoprotein B is present in each particle of chylomicron, LDL-C, VLDL-C, intermediate-density lipoprotein, and lipoprotein-a, all of which are considered atherogenic. Non-HDL-C reflects the sum of LDL, VLDL-C, intermediate-density lipoprotein, and lipoprotein-a. Both ApoB and non-HDL-C have been shown to be better predictors of cardiovascular events than LDL-C.10,13,14 The level of ApoB can be obtained only by direct laboratory measurement. The level of non-HDL-C can be determined with a basic lipid profile (by subtracting HDL-C from total cholesterol) in a nonfasting state. In the consensus conference report from the ADA and the American College of Cardiology Foundation (ACCF), the goals for ApoB, LDL-C, and non-HDL-C in patients at cardiometabolic risk are as follows:14 䡲 High risk: ApoB is ⬍ 90 mg/dL, LDL-C ⬍ 100 mg/dL, non-HDL-C ⬍ 130 mg/dL 䡲 Very high risk: ApoB is ⬍ 80 mg/dL, LDL-C ⬍ 70 mg/dL, non-HDL-C ⬍ 100 mg/dL Consideration of these additional factors will allow clinicians to increase the accuracy of CVD risk prediction for patients with diabetes mellitus.

Blood pressure control Current ADA recommendations for blood pressure control in patients with diabetes mellitus include the initiation of drug therapy if systolic blood pressure (SBP) is more than 140 mm Hg and if diastolic blood pressure (DBP) is more than 90 mm Hg, based on 2 measurements on

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separate days.2 In patients with confirmed SBP ranging between 130 and 139 mm Hg, or confirmed DBP ranging between 80 and 89 mm Hg, lifestyle modification alone should be tried for 3 months. If after these lifestyle modification efforts, SBP of less than 130 mm Hg or DBP of less than 80 mm Hg is not achieved, treatment with pharmaceutical agents should be started.2 The ACCORD trial compared standard blood pressure control (target SBP is ⬍ 140 mm Hg) with intensive blood pressure control (target SBP is ⬍ 120 mm Hg) in patients with diabetes mellitus.9,15 The researchers used the rate of cardiovascular events as an indicator of optimal blood pressure control. The investigators found no statistically significant difference in the total number of cardiovascular events in the intensive vs the standard blood pressure control group. They did note, however, that patients in the intensive control group had a higher incidence of adverse effects from medications and used a larger number of antihypertensive medications compared with patients in the standard control group.9,15

Glycemic control The ADA recommends an HbA1c level of less than 7% as a goal for glycemic control in patients with diabetes mellitus.2 This laboratory value should be monitored every

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6 months in patients with stable glycemic control.2 In an investigation of the benefits of tight glycemic control in patients with diabetes, the ACCORD researchers divided participants into an intensive therapy group and a standard therapy group.9,16 The intensive therapy group was given the goal of keeping their HbA1c level below 6.0%, and the standard therapy group was given the goal of keeping their HbA1c level between 7.0% and 7.9%. Participants in the intensive therapy group were forced to quit treatment before the study was completed because they had a higher risk of mortality than the standard care group.9,16 The investigators concluded that standard glycemic control, such as that recommended by the ADA, along with control of other cardiovascular risk factors, is the best overall approach to treatment of patients with T2DM.2,9,16 The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study and the UKPDS have demonstrated that HbA1c levels less than 7% will decrease the incidence of CVD.17,18 In the DCCT/EDIC study, in which patients with type 1 diabetes mellitus were followed up for 17 years, a 42% reduction in CVD risk was found in those patients undergoing intensive glycemic

control.17 In the UKPDS, which followed up patients with T2DM for 10 years, the risk of myocardial infarction was decreased by 15% to 33% in individuals using intensive glycemic treatment.18 Authors of the ACCORD trial concluded that other comorbidities were the cause of the higher mortality observed in the intensive treatment group.19 Because of the discrepancy in outcomes between standard glycemic control and intensive glycemic control, some authors have suggested that patients with longstanding diabetes mellitus or other comorbidities be given more time to achieve their glycemic goals (eg, 6 months to 1 year). In addition, if a patient has a longstanding diagnosis of diabetes (eg, 10-15 years), HbA1c goals should remain at 7.0%. By contrast, a more recent diagnosis of diabetes may prompt an HbA1c goal of 6.0.20

Aspirin in primary prevention In 2007, the ADA and AHA jointly recommended that low-dose aspirin (acetylsalicylic acid, 75-162 mg/day) be used as a primary prevention strategy in patients with diabetes mellitus who are at increased cardiovascular risk.21 After publication of this recommendation, the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes22 and the Prevention of Progression of Arterial Disease and Diabetes23 trials raised doubts about the efficacy of low-dose aspirin in patients with diabetes mellitus. As a result of those results, the ADA, AHA, and ACCF convened in 2009 to review and synthesize available evidence and update recommendations.21 During the evaluation to determine the updated recommendations, the joint committee considered not only the benefits of aspirin for preventing coronary artery disease, but also the known problem of gastrointestinal bleeding with daily use of aspirin. The joint committee concluded that lowdose aspirin (75-162 mg/day) for CVD prevention is “reasonable” for adults with diabetes mellitus who have no history of vascular disease but who are at increased risk of CVD (10-year risk is ⬎ 10%) and are not at increased risk of bleeding.12 The committee added that aspirin should not be recommended for CVD prevention if patients are at low risk of CVD (10-year risk

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is ⬍ 5%), noting that the potential adverse effects from bleeding offset the potential benefits. Low-dose aspirin “might be considered” for CVD prevention in patients with diabetes who are at intermediate risk of CVD (10-year risk = 5%-10%).12 The joint committee also stressed that all modifiable CVD risk factors should be addressed and optimally managed for patients using aspirin. Helping patients reach their individual cardiovascular goals through such management will decrease their 10-year CVD risk, meaning that fewer patients with diabetes mellitus will need to continue taking aspirin and be at risk for the adverse effects of this medication.

Final notes It is evident that prevention of CVD in patients with T2DM requires a multifactorial approach. This approach includes management of CVD risk factors with both pharmaceutical interventions and lifestyle modifications. Many patients with diabetes mellitus are currently not achieving recommended treatment goals and targets. By improving the quality of care for these patients, we can decrease the occurrence of CVD and promote a happier and healthier life for individuals with diabetes mellitus.

References 1. Centers for Disease Control and Prevention. National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States, 2011. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011. pdf. Accessed February 20, 2012.

the American Heart Association and the American Diabetes Association. [Published online before print December 27, 2006]. Circulation. 2007;115(1):114126. 6. Living with diabetes: diabetes PhD. American Diabetes website. http://www.diabetes.org/livingwith-diabetes/complications/diabetes-phd/. Accessed February 20, 2012. 7. The Look AHEAD Research Group. Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the Look AHEAD trial. Arch Intern Med. 2010;170(17):15661575. 8. The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus [published online ahead of print March 14, 2010]. N Engl J Med. 2010;362(17):1563-1574. 9. Buse JB; ACCORD Study Group. Action to control cardiovascular risk in diabetes (ACCORD) trial: design and methods [published online ahead of print April 16, 2007]. Am J Cardiol. 2007;99(12A):21i-33i. 10. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 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) final report. Circulation. 2002;106(25):3143-3421. 11. Grundy SM, Cleeman JI, Merz CNB, et al. Implications of Recent Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. [published correction appears in Circulation. 2004;110(6):763] Circulation. 2004;110(2):227-239. 12. Duez H, Lewis GF. Chapter 4. Fat Metabolism in Insulin Resistance an Type 2 Diabetes. In: Feinglos MN, Bethel MA (Eds.), Type 2 Diabetes Mellitus: An Evidence-Based Approach to Practical Management. Durham, NC: Humana Press;2009:49-74.

2. American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care. 2011;34(suppl 1):S11-S61. doi:10.2337/dc11-S011.

13. Sniderman AD, Furberg CD, Keech A, et al. Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment. Lancet. 2003;361(9359):777-780.

3. Preis SR, Hwang SJ, Coady S, et al. Trends in allcause and cardiovascular disease mortality among women and men with and without diabetes mellitus in the Framingham Heart Study, 1950 to 2005 [published online ahead of print March 23, 2009]. Circulation. 2009;119(13):1728-1735.

14. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2008;51(15):1512-1524.

4. Davidson MH, Maki KC, Pearson TA, et al. Results of the National Cholesterol Education (NCEP) Program Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) II survey and implications for treatment under the recent NCEP Writing Group recommendations. Am J Cardiol. 2005;96(4):556563.

15. ACCORD Study Group, Cushman WC, Evans GW, Byington RP, et al. Effects of intensive bloodpressure control in type 2 diabetes mellitus [published online ahead of print March 14, 2010]. N Engl J Med. 2010;362(17):1575-1585.

5. Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from

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16. ACCORD Study Group, Gerstein HC, Miller ME, Genuth S, et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011;364(9):818-828.

17. Nathan DM, Cleary PA, Backlund JY, et al; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25):2643-2653. 18. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577-1589. 19. ACCORD Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-2559. 20. Ismail-Beigi F, Moghissi E, Tiktin M, et al. Individualizing glycemic targets in type 2HW diabetes mellitus: implications of recent clinical trials. Ann Intern Med. 2011;154(8):554-559. 21. Pignone M, Alberts MJ, Colwell JA, et al; American Diabetes Association, American Heart Association, American College of Cardiology Foundation. Aspirin for primary prevention of cardiovascular events in people with diabetes: a position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation. Diabetes Care. 2010;33(6):1395-1402. 22. Ogawa H, Nakayama M, Morimoto T, et al; Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Investigators. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial [published online ahead of print November 9, 2008]. JAMA. 2008;300(18):2134-2141. 23. Belch J, MacCuish A, Campbell I, et al; Prevention of Progression of Arterial Disease and Diabetes Study Group; Diabetes Registry Group; Royal College of Physicians Edinburgh. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomized placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ. 2008;337:a1840. doi:10.1136/bmj.a1840. HW

Jarrod M. Harrall, DO, practices sports medicine and family practice in the Private Family Medicine Clinic for Primary Care Plus in Leawood, Kansas. He can be reached at the jharrall@primarycare pluskc.com. Andrea Tufo, OMS IV, is a fourth-year medical student at Kansas City University of Medicine and Biosciences. She will continue her medical training at the Fort Wayne Medical Education Program, Family Medicine Residency in Fort Wayne, Indiana.

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