Editor's Note: Commentary based on Fox CS, Golden SH, Anderson C, et al. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation 2015;132:691-718.

Summary of Article

This new American Heart Association (AHA)/American Diabetes Association (ADA) scientific statement recognizes important recent changes in cardiovascular disease (CVD) risk factor control for primary prevention of CVD in those with type 2 diabetes. The authors reviewed the current literature and key clinical trials pertaining to blood pressure (BP) and blood glucose control, cholesterol management, aspirin therapy, and lifestyle modification and have proposed new guidelines and clinical targets, including screening for kidney and subclinical CVD.

The first joint statement of the AHA and ADA on this topic was published in 1999, and a second one was published in 2007. Since then, there have been new clinical trials that have changed the clinical practice of CVD risk management in those with diabetes.

Since 2010, the ADA has included A_1c in its recommendations for the diagnosis of diabetes, suggesting an A_1c value of >6.5% can be used in the diagnosis of diabetes, or fasting glucose criteria of >126 mg/dl or non-fasting levels of >200 mg/dl. The authors of the AHA/ADA statement have discussed the strengths and limitations of the A_1c approach but note that the updated diagnostic criteria are in line with current evidence regarding the association of A_1c with long-term complications.

The new statement has synthesized established clinical guidelines and, wherever possible, has utilized the AHA/American College of Cardiology (ACC) Class of Recommendation/Level of Evidence (LOE) grading system or the ADA evidence grading system for clinical practice recommendations. The writing group has made the following clinical recommendations for CVD risk factor management in type 2 diabetes:

1. Nutrition: Reduction of energy intake for overweight or obese patients (ADA LOE A); individualized medical nutrition therapy for all patients with diabetes (ADA LOE A); carbohydrate monitoring as an important therapy in glycemic control (ADA LOE B); consumption of fruits, legumes, vegetables, whole grains, and dairy products in place of other carbohydrate sources (ADA LOE B); Mediterranean-style dietary pattern, which may improve glycemic control and CVD risk factors (ADA LOE B); and limitation of sodium intake to <2,300 mg/d (ADA LOE B).
2. Obesity: Counselling of overweight and obese patients on lifestyle changes for a 3-5% rate of weight loss that can have meaningful health benefits (ACC/AHA Class I, LOE A), and consideration of bariatric surgery for those with a body mass index >40 or >35 with obesity-related comorbidities (AHA/ACC Class IIa, LOE A).
3. Blood Glucose: Lower A_1c to <7% in most patients (ADA LOE B), with more stringent targets (e.g., <6.5%) that may be considered in select patients, such as those with short disease duration, long life expectancy, and no significant CVD) if this can be achieved without significant hypoglycemia or adverse effects (ADA LOE C), but less stringent targets (e.g., <8% or even slightly higher) in those with a history of severe hypoglycemic, limited life expectancy, advanced complications, cognitive impairments, or extensive comorbidities (ADA LOE B).
4. BP: For most individuals achieve a goal of <140/90 mm Hg, with lower targets appropriate for some individuals (Expert Opinion, Grade E), pharmacologic therapy with an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB) (ADA LOE B); in those with chronic kidney disease, antihypertensive treatment should include an ACEI or ARB (Expert Opinion, Grade E); systolic BP control of <140 mm Hg (ADA LOE A), but lower targets (e.g., <130 mm Hg) may be appropriate for certain patients, such as those who are younger, if it can be achieved without undue treatment burden (ADA LOE C).
5. Cholesterol: Patients with diabetes aged 40-75 years with low-density lipoprotein cholesterol (LDL-C) 70-189 mg/dl should be treated with a moderate-intensity statin (ACC/AHA Class I, LOE A, ADA LOE A), high-intensity statin if >7.5% estimated atherosclerotic cardiovascular disease (ASCVD) risk in 10 years (ACC/AHA Class IIa, LOE B). The benefit of statin treatment should be evaluated in those aged <40 years or >75 years (ACC/AHA Class IIa, LOE C); evaluate and treat those with fasting triglycerides >500 mg/dl.

In addition, the statement reminds us of recommendations for aspirin use, which state that low-dose aspirin (75-162 mg/d) is reasonable for those at 10-year CVD risk of at least 10% without increased risk of bleeding (ACC/AHA Class IIa, LOE B, ADA LOE C) and in those with diabetes at intermediate risk defined as 5-10% 10-year CVD risk (ACC/AHA Class IIb, LOE C, ADA LOE Expert Opinion).

Another important update provided by this article are specific recommendations for the use of screening tests for asymptomatic coronary artery disease in those with diabetes, which can be summarized as follows:

1. Electrocardiogram (ECG): A resting ECG is reasonable for CVD risk assessment in those with hypertension or diabetes (ACC/AHA, Class IIa – LOE C).
2. Ankle Brachial Index (ABI): Reasonable for CVD risk assessment in adults at intermediate risk (ACC/AHA, Class IIa, LOE B).
3. Stress Myocardial Perfusion Imaging: May be considered for advanced CVD risk assessment in those with diabetes or a strong family history of coronary heart disease or when previous risk assessment suggests a high risk of coronary heart disease (e.g., coronary artery calcium (CAC) score ≥400) (ACC/AHA, Class IIb, LOE C); not recommended in those who are at low or intermediate risk (ACC/AHA, Class III, LOE C).
4. CAC Scoring: Measurement of CAC reasonable for CVD risk assessment in those with diabetes aged 40 years (ACC/AHA, Class IIa, LOE B).

The article concludes by noting several key needs of controversy and future research needed to advance CVD prevention issues in type 2 diabetes. This includes the need to better understand the following: 1) the role of intensity and specific drug therapy for reducing CVD events in type 2 diabetes and whether any drug will emerge as having a clear advantage; 2) the role of bariatric surgery in remission of diabetes and other CVD risk factors; 3) the burden of hypoglycemia and accompanying risks on the cardiovascular system; 4) the possible protective role of aggressive BP lowering in high-risk stroke populations; 5) the potential role and efficacy of triglyceride lowering in diabetes and whether CVD event risk can be reduced; and 6) whether screening for subclinical CAD with newer markers and modalities can help improve overall patient outcomes.

Commentary

The new AHA/ADA scientific statement by Fox et al.¹ provides an excellent synthesis of the literature regarding recent clinical trials and guidelines in the area of CVD risk reduction in persons with diabetes. The guidance regarding recommendations for nutrition, obesity, and BP control is clear and should be disseminated by AHA, ADA, ACC, and other societies to provide for maximum impact.

The nutrition recommendations importantly note the role of individualized nutrition therapy, carbohydrate monitoring, and consumption of fruits, legumes, vegetables, whole grains, and dairy products, as well as a Mediterranean diet and sodium restriction. The recommendations also note that in overweight and obese patients, even modest weight loss of 3-5% can result in clinically meaningful health benefits. As the 2013 ACC/AHA/TOS Guideline for the Management of Overweight and Obesity in Adults² has mentioned is the crucial role of the lifestyle interventionist and appropriateness of >14 sessions such specialists over a six-month period to effect adequate lifestyle behavior change (Class I, LOE A). Overweight and obese individuals form the vast majority of those with type 2 diabetes and the health care system needs to better reimburse for these services.

The blood glucose, BP, and cholesterol guidelines suggested are reasonable based on the most recent guidelines published. While the now higher goal for BP of <140/90 mm Hg is based on the 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report from the Panel Members Appointed to the Eighth Joint National Committee (JNC8),³ we are to be reminded of the benefit in the pre-specified secondary endpoint of stroke seen in the Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD BP) study among those treated to a systolic BP of <120 mm Hg versus <140 mm Hg;⁴ thus, those subjects with diabetes mellitus at potentially high risk of stroke might benefit from such a greater BP lowering. For cholesterol control, it will be important to observe what role newer drugs such as the proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies may have in addressing residual dyslipidemia in those with diabetes who for one reason or another do not tolerate statin therapy and/or do not reach specified recommended targets (e.g., >50% LDL-C lowering on a high-intensity statin). While the currently marketed PCSK9 inhibitors are indicated only for those with pre-existing clinical ASCVD or familial hypercholesterolemia, it will be interesting to see if their indication is expanded at some point to include patients with diabetes (or selected subsets of those with diabetes, such as those with significant risk factor burden or subclinical disease) who also carry a high lifetime risk of CVD. Finally, while each risk factor is discussed separately, it is key to remember that while individual control of risk factors (A_1c, BP, and LDL-C, for instance) may be achieved ≥50% of the time, composite control of all three factors remains poor. Even among recent cohorts of U.S. adults, only a fourth are at goal for all three factors, emphasizing the need for health care systems to better address multiple risk factor control.⁵

An important feature of the new AHA/ADA statement is the excellent summary of the evidence and recommendations for screening tests for asymptomatic coronary artery disease. Reasonable evidence and recommendations are given for consideration of resting ECG screening, ABI screening, CAC screening, and also stress MPI in selected adults with diabetes. It is important to appreciate the cost and radiation associated with stress MPI and its limitations in assessing for functional deficit; thus, the role of lower-cost tests to assess atherosclerotic burden with substantially less radiation (e.g., CAC) that have proven added risk stratification are preferred for mer general CVD risk assessment in patients with diabetes. While carotid intimal media thickness (CIMT) is a well-established subclinical CVD marker and has been part of earlier guidelines, it was not part of the most recent ACC/AHA 2013 Guideline for Cardiovascular Risk Assessment.⁶ In those with diabetes, it has been shown that CIMT alone provides limited CVD risk stratification compared to CAC;⁷ however, it will be important to know whether the combination of CIMT and carotid plaque can be valuable in risk stratification in those with diabetes mellitus.

In summary, the new AHA/ADA statement on prevention of CVD in diabetes is an important update that should be valuable in guiding CVD risk factor management in those with diabetes to better close the gap in care responsible for the excess burden of CVD still present in those with diabetes. It provides the foundation for a "call to action" by the ACC along with the AHA and ADA to promote strategies that will improve quality of care aimed at prevention of CVD in this important population.

References

1. Fox CS, Golden SH, Anderson C, et al. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation 2015;132:691-718.
2. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol 2014;63:2985-3023.
3. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311:507-20.
4. ACCORD Study Group, Cushman WC, Evans GW, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575-85.
5. Wong ND, Patao C, Wong K, Malik S, Franklin SS, Iloeje U. Trends in control of cardiovascular risk factors among US adults with Type 2 diabetes 1999-2010: comparison by prevalent cardiovascular disease status. Diab Vasc Dis Res 2013;10:505-13.
6. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2935-59.
7. Malik S, Budoff MJ, Katz R, et al. Impact of subclinical atherosclerosis on cardiovascular disease events in persons with metabolic syndrome and diabetes: the Multiethnic Study of Atherosclerosis. Diabetes Care 2011;34:2285-90.

Keywords: Adult, American Heart Association, Angiotensin-Converting Enzyme Inhibitors, Ankle Brachial Index, Antibodies, Monoclonal, Antihypertensive Agents, Aspirin, Bariatric Surgery, Blood Glucose, Blood Pressure, Body Mass Index, Calcium, Cardiovascular Diseases, Cholesterol, Cholesterol, LDL, Cognition, Comorbidity, Coronary Artery Disease, Counseling, Diabetes Mellitus, Type 2, Diet, Mediterranean, Dihydrotachysterol, Electrocardiography, Energy Intake, Expert Testimony, Fabaceae, Glucose, Hyperlipoproteinemia Type II, Hypertension, Hypoglycemia, Hypoglycemic Agents, Life Expectancy, Life Style, Lipoproteins, LDL, Myocardial Perfusion Imaging, Obesity, Overweight, Primary Prevention, Proprotein Convertases, Renal Insufficiency, Chronic, Risk Assessment, Risk Factors, Risk Reduction Behavior, Sodium, Stroke, Subtilisins, Triglycerides, Weight Loss

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