Mr. Joseph is a 69-year-old man who has had type 2 diabetes (T2D) for 10 years, which he manages with diet and metformin. He’s a nonsmoker. He had a myocardial infarction one year ago, and was recently hospitalized for heart failure (HF). His HbA1c is 9.2 percent and LDL-C is 99 mg/dL, with a blood pressure (BP) of 138/88 mm Hg. In addition to metformin, the patient is on 80 mg of atorvastatin and is taking daily aspirin.

What other information would be helpful to know and what else could we do to optimize reduction of his risk for future cardiovascular disease events?

Lifestyle Management

First, because lifestyle management is the foundation for cardiovascular risk reduction, it’d be useful to know what type of diet he’s on, along with his metformin, and whether it’s maximally cardioprotective. Also, information on his physical activity routine would be helpful.

Mr. Joseph would likely benefit from multiple sessions over at least a three- to six-month period with a lifestyle interventionalist. Ideally this would be a registered dietitian and an exercise physiologist to individually assess and tailor the patient’s diet and physical activity in accordance with his current comorbidities. For instance, guidance to follow a DASH-like dietary pattern and moderate intensity activity of 30 to 40 minutes on three to four days a week has been generally recommended by the ACC/AHA Lifestyle Management Guideline.¹ Adding resistance training is suggested given he has T2D.

Further, few patients suffering a cardiac event enroll and successfully complete a cardiac rehabilitation program, for which there is a large evidence base relating this to a reduction in hospital readmissions and improved outcomes.² Few physicians take advantage of or are even aware of referrals available for such lifestyle interventionalists. Some resources are the Academy of Nutrition and Dietetics’ Sports, Cardiovascular and Wellness Nutrition group, which provides dietitians specializing in cardiovascular risk reduction and diabetes, as well as the American College of Sports Medicine, which certifies exercise physiologists.

A Second Agent?

Importantly, Mr. Joseph’s HbA1c is still not ideal. The recent American Diabetes Association Standards of Diabetes Care recommends a second agent of proven cardiovascular benefit for persons whose HbA1c remains ≥9 percent when they have atherosclerotic cardiovascular disease (ASCVD) in addition to diabetes.³ The SGLT-2 inhibitor empagliflozin currently has a U.S. Food and Drug Administration (FDA) indication for reduction of cardiovascular mortality. The GLP-1 agonist liraglutide has an FDA indication for cardiovascular disease risk reduction in patients who have both diabetes and ASCVD.

For Mr. Joseph, who has T2D, ASCVD and a history of recent HF hospitalization, empagliflozin may be the preferred second agent. Empagliflozin has been shown to be effective in reducing HF hospitalizations by 35 percent, a secondary endpoint demonstrated in the EMPA-REG OUTCOME clinical trial, besides the 14 percent overall reduction in the primary cardiovascular disease composite endpoint and the reported 38 percent reduction in cardiovascular disease death.⁴ Of interest, empagliflozin and other SGLT-2 inhibitors are currently being tested in large outcomes trials of both primary and secondary prevention of HF.

While liraglutide was shown in the LEADER trial to reduce by 13 percent the composite cardiovascular disease endpoint (and reduce cardiovascular death by 22 percent), there was no significant reduction in HF hospitalizations.⁵

Lipid Management

Mr. Joseph’s dose of atorvastatin is maximized, yet his LDL-C remains at 99 mg/dL. Most guidelines, including the ACC’s 2017 pathway on nonstatin use,⁶ leaves room for consideration of adding a nonstatin to further reduce ASCVD risk when the LDL-C is not reduced by ≥50 percent or remains at ≥70 mg/dL despite maximal statin use. In addition, the recent American Association of Clinical Endocrinologists (AACE) guidelines would classify our patient in the newly defined “extreme risk” category, where they recommend an LDL-C target of <55 mg/dL.⁷

While this target is based on the treated LDL-C level seen in the intervention group of the IMPROVE-IT trial,⁸ Mr. Joseph’s LDL-C is not likely to be reduced to <55 mg/dL or even <70 mg/dL on ezetimibe, nor might the IMPROVE-IT trial be relevant to our patient since he is not within 10 days of an acute coronary syndrome, a key inclusion criterion of the study.

Furthermore, the ACC’s nonstatin pathway notes that if a ≥25 percent further reduction in LDL-C is desired, then a PCSK9 inhibitor (such as alirocumab or evolocumab) may be preferred as the first nonstatin agent in higher risk patients with ASCVD and comorbidities, such as Mr. Joseph. Importantly, both the FOURIER and ODYSSEY Outcomes trials have now demonstrated similar ASCVD risk reduction, both in those patients with and without diabetes (in addition to prior ASCVD), although with a greater absolute risk reduction and a favorable number needed to treat (below 50) given the higher baseline risk of those with both ASCVD and diabetes.^9,10

Multiple Risk Factors

Most experts would agree Mr. Joseph’s BP is not ideally controlled. While the most recent ACC/AHA guidelines for hypertension control¹¹ recommend further BP control to <130/80 mm Hg both in those with and without diabetes and those with and without cardiovascular disease, other societies, namely the American Diabetes Association, still retain a more conservative target of <140/90 mm Hg. The key trial of patients with diabetes, ACCORD, showed no benefit in the composite cardiovascular disease endpoint with a target <120/80 mm Hg as compared with <140/90 mm Hg, although there was a significant benefit in stroke reduction.¹² The high risk of stroke in a patient like Mr. Joseph could arguably call for a BP target of <130/80 mm Hg if tolerable.

Ultimately, the importance of simultaneous, multiple risk factor control in the high-risk patient with both T2D and ASCVD, such as Mr. Joseph, cannot be understated. Among the best evidence we have for the efficacy for multiple risk factor control in these patients derives from the BARI 2D trial. In this trial, patients with 0-2 risk factors controlled (no smoking, non–HDL-C <130 mg/dL, triglycerides <150 mg/dL, BP [systolic <130 mm Hg; diastolic <80 mm Hg], glycosylated hemoglobin <7 percent) had a two-fold higher risk of death and 1.7-fold higher risk of cardiovascular events, compared with those with 4-6 risk factors controlled.¹³

Moreover, the STENO-2 trial has recently demonstrated among patients with T2D but no cardiovascular disease at baseline, a similar survival advantage extending over 21 years (over 13 years beyond the end of the original trial).¹⁴ In a study from my group pooling three U.S. prospective studies comprising over 2,000 patients with T2D (no cardiovascular disease at baseline) showed an approximate 60 percent lower risk of a future cardiovascular disease event over 10 years of follow-up in those at target for all three key parameters (HbA1c, LDL-C, BP) compared with being at target for none of the parameters.¹⁵

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This article was authored by Nathan D. Wong, PhD, FACC. He is professor and director of the Heart Disease Prevention Program in the Division of Cardiology, University of California, Irvine. Wong serves as editor of the ACC Diabetes and Cardiometabolic Clinical Topic Collection on ACC.org and as chair of ACC’s Research and Publications Subcommittee of the Diabetes Collaborative Registry.

References

1. Eckel RH, Jakicic JM, Ard JD, et al. J Am Coll Cardiol 2014;63:2960-84.
2. Lawler PR, Filion KB, Eisenberg MJ. Am Heart J 2011;162:571-84.e2.
3. American Diabetes Association. Diabetes Care 2018;41: S73-S85.
4. Zinman B, Wanner C, Lachin JM, et al. N Engl J Med 2015;373:2117-28.
5. Marso SP, Daniels GH, Brown-Frandsen K, et al. N Engl J Med 2016;375:311-22.
6. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. J Am Coll Cardiol 2017;70:1785-1822.
7. Jellinger PS, Handelsman Y, Rosenblit PD, et al. Endocr Pract 2017;23(Suppl 2):1-87.
8. Cannon CP, Blazing MA, Giugliano RP, et al. N Engl J Med 2015;372:2387-97.
9. Sabatine MS, Leiter LA, Wiviott SD, et al. Lancet Diabetes Endocrinol 2017;5:941-50.
10. Ray KK, Colhoun H, Szarek M, et al. Diabetes 2018 Jul; 67(Supplement 1) (abstract).
11. Whelton PK, Carey RM, Aronow WS, et al. J Am Coll Cardiol 2018;71:e127-e248.
12. ACCORD Study Group, Cushman WC, Evans GW, Byington RP, et al. N Engl J Med;362:1575-85.
13. Bittner V, Bertolet M, Barraza Felix R, et al. J Am Coll Cardiol 2015;66:765-73.
14. Gæde P, Oellgaard J, Carstensen B, et al. Diabetologia 2016;59:2298-2307.
15. Wong ND, Zhao Y, Patel R, et al. Diabetes Care 2016;39:668-76.

Keywords: ACC Publications, Cardiology Magazine, Acute Coronary Syndrome, Antibodies, Monoclonal, Aspirin, Benzhydryl Compounds, Blood Pressure, Cardiac Rehabilitation, Cardiovascular Diseases, Comorbidity, Diabetes Mellitus, Diabetes Mellitus, Type 2, Diet, Dietetics, Antibodies, Monoclonal, Exercise, Follow-Up Studies, Global Health, Glucagon-Like Peptide 1, Glucose, Glucosides, Glycated Hemoglobin A, Heart Failure, Hospitalization, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertension, Hypoglycemic Agents, Life Style, Metformin, Myocardial Infarction, Numbers Needed To Treat, Nutritionists, Patient Readmission, Prospective Studies, Referral and Consultation, Resistance Training, Risk Factors, Risk Reduction Behavior, Secondary Prevention, Sports, Stroke, Triglycerides, United States Food and Drug Administration

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