Mortality reduction in patients with diabetes mellitus is complex, and multifactorial intervention strategies assume a special importance due to high prevalence of other comorbid conditions.¹ Unlike its role in microvascular complication prevention, aggressive glucose control, by itself, probably contributes only modestly in reducing macrovascular events like myocardial infarction.² Optimal medical therapy (OMT) to simultaneously target other risk factors (like hypertension and dyslipidemia) with medications and lifestyle modification, in addition to blood sugar control are needed for cardiovascular complication and mortality reduction in diabetic patients.

There aren't many randomized control trials that have evaluated the benefit of simultaneous risk factor control. The Steno-2 trial compared simultaneous intensive risk factor modification (with the goal A1C < 6.5%, cholesterol < 175 mg/dl, triglyceride level < 150 mg/dl, blood pressure < 130/80 mm Hg) to lenient control in 160 diabetic patients, and found a highly significant 20% absolute risk reduction in mortality seen in the intensive treatment arm after 13.3 years of follow-up.³ Unfortunately, the results of this small but important trail have not been duplicated in larger studies.

Comprehensive risk factor control assumes an even more important role in patients with diabetes and preexisting stable ischemic heart disease (SIHD) as together they confer a higher mortality risk than either of the conditions alone.⁴ The efficacy of comprehensive OMT in SIHD, however, is presumed, and there has not been a trial during which OMT was not offered to a comparison arm. In the absence of direct trial evidence, Bittner et al.'s analysis of the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial provides important reassurance that OMT is effective in reducing cardiovascular adverse outcomes, including mortality in patients with diabetes and SIHD.⁵

BARI 2D was a prospective randomized control trial evaluating the efficacy of early revascularization and OMT compared with OMT alone in patients with diabetes and SIHD that showed no difference in mortality or cardiovascular events at 5 years of follow-up.⁶ Bittner et al. report a post-hoc observational analysis of the BARI 2D trial to establish the relationship between number of controlled risk factors (non–high-density lipoprotein cholesterol [HDL-C] < 130 mg/dl, triglycerides < 150 mg/dl, blood pressure [systolic < 130 mm Hg; diastolic < 80 mm Hg], hemoglobin A1C < 7%, and smoking cessation) by use of OMT and cardiovascular outcomes. OMT used in the trial included pharmacological therapy for hypertension, dyslipidemia, and hyperglycemia, as well as regular feedback on smoking cessation and counseling on diet and exercise. Though the mean number of risk factors in control increased from 3.5 at baseline to 4.2 after 5 years, only 15% of patients achieved control of all six risk factors by the end of the study. The authors used this internal variation in risk factor control to elicit differences in outcomes. The primary analysis looked at risk factors control at 1 year (since the greatest up-titration of OMT was achieved within the first year) and found that patients with zero to two risk factors in control had a 2-fold higher risk of mortality and 1.7-fold higher risk of cardiovascular events (composite endpoint of death, myocardial infarction, or stroke) by the end of 5 years, compared with those with all six risk factors in control. These findings, though not revelatory, are relevant and reassuring and confirm our belief in the effectiveness of OMT and comprehensive risk factor reduction in diabetic patients with SIHD. They behoove further confirmation in the form of a randomized controlled trial with a-priori hypothesis.

Perhaps as important as the conclusion of the study is the question of why only a small minority (15%) of patients achieved all the risk factor control targets. This troublesome finding is not unique to BARI 2D trial. In fact, in most trial populations in which OMT is supposedly administered in a more controlled and monitored setting, risk factor control targets are seldom achieved. In the quest to find the ideal revascularization strategy in these patients, OMT seems to have taken the back seat. Farkouh et al. analyzed pooled data from the BARI 2D, Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes (FREEDOM), and diabetic subgroup of Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trials to evaluate proportion of patients achieving guideline-based treatment targets for systolic blood pressure (< 130 mm Hg), low-density lipoprotein cholesterol (< 100 mg/dl; < 70 mg/dl in FREEDOM), hemoglobin A1c (< 7%) and smoking cessation.⁷ OMT consisting of coronary artery disease (CAD) modifying agents (aspirin, statins, renin-angiotensin inhibitors, thienopyridines as needed), anti-anginal therapy (beta-blockers, calcium channel blockers, nitrates) and lifestyle interventions (nutrition counseling, weight loss, exercise, smoking cessation) were administered in all trials. Even though some improvement was seen in all groups, only 18% of the COURAGE diabetes subgroup, 23% of BARI 2D patients, and 8% of FREEDOM patients met all four pre-specified treatment targets at 1 year of follow-up.

Real world data reflects similar trends and shows widespread lack of risk factor control in the general population. The National Health and Nutrition Examination Surveys (NHANES) analysis from 2007-2010 shows that a mere 18.8% of the surveyed diabetic patients in the community achieved all three predefined targets of blood pressure, hemoglobin A1C and LDL.⁸ Similarly, data from a national representative cohort of the REGARDS study shows that less than a fourth of 3,167 CAD patients met ≥ five of the seven risk factor targets as defined in the COURAGE trial and only 16% met all three goals for aspirin use, blood pressure, and low-density lipoprotein cholesterol (LDL-C).⁹

Multiple patient factors like cost, burden of taking multiple medications, and side effects may contribute to poor risk factor control. Patient education, improving health care access, and innovative strategies like the polypill may help in enhancing patient adherence to OMT. However, physician factors are perhaps even more important as there are significant gaps in the prescription of evidence based OMT to qualifying patients. A study of the American College of Cardiology National Cardiovascular Data Registry shows that less than half of the patients getting percutaneous coronary intervention (PCI) for SIHD are on OMT before the procedure.¹⁰ It is even more disheartening that only two-thirds of patients who receive PCI leave the hospital on OMT.¹⁰ An analysis of the Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial showed significant under-prescription of OMT (at least one antiplatelet drug, statin, beta-blocker, and renin-angiotensin system inhibitor) in patients with complex CAD.¹¹ It also showed that not only was the prescription of OMT an independent predictor of survival but was also, in fact, a stronger predictor than the revascularization strategy.¹¹

Bittner et al.'s analysis of the BARI 2D trial goes a step forward because it evaluates not only the prescription but also the effectiveness of OMT as evidenced by risk factor control. The authors convincingly show that a higher number of controlled risk factors can potentially translate to better cardiovascular outcomes. This important study serves as a reminder for physicians to make a concerted effort to improve the prescription of evidence-based, guideline-directed OMT in patients with diabetes and SIHD. Furthermore, these patients need regular and close follow-up with frequent titration of medical regimen to ensure the effectiveness of therapy (in terms of target achievement) and to avoid adverse events from very tight control.¹² There needs to be a paradigm shift in the management of diabetic patients with SIHD, and the emphasis needs to move away from isolated revascularization (when justified) and towards comprehensive and simultaneous risk factor control to effectively reduce cardiovascular mortality.

References

1. Preis SR, Pencina MJ, Hwang SJ, et al. Trends in cardiovascular disease risk factors in individuals with and without diabetes mellitus in the Framingham Heart Study. Circulation 2009;120:212-20.
2. Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA Diabetes Trials: a position statement of the American Diabetes Association and a Scientific Statement of the American College of Cardiology Foundation and the American Heart Association. J Am Coll Cardiol 2009;53:298-304.
3. Gaede P, Lund-Andersen H, Parving H-H, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358:580-91.
4. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229-34.
5. Bittner V, Bertolet M, Barraza Felix R, et al. Comprehensive cardiovascular risk factor control improves survival: the bARI 2D trial. J Am Coll Cardiol 2015;66:765-73.
6. BARI 2D Study Group, Frye RL, August P, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:2503-15.
7. Farkouh ME, Boden WE, Bittner V, et al. Risk factor control for coronary artery disease secondary prevention in large randomized trials. J Am Coll Cardiol 2013;61:1607-15.
8. Stark Casagrande S, Fradkin JE, Saydah SH, et al. The prevalence of meeting A1C, blood pressure, and LDL goals among people with diabetes, 1988-2010. Diabetes Care 2013;36:2271-9.
9. Brown TM, Voeks JH, Bittner V, et al. Achievement of optimal medical therapy goals for U.S. adults with coronary artery disease: results from the REGARDS Study (REasons for Geographic And Racial Differences in Stroke). J Am Coll Cardiol 2014;63:1626-33.
10. Borden WB, Redberg RF, Mushlin AI, Dai D, Kaltenbach LA, Spertus JA. Patterns and intensity of medical therapy in patients undergoing percutaneous coronary intervention. JAMA 2011;305:1882-9.
11. Iqbal J, Zhang YJ, Holmes DR, et al. Optimal medical therapy improves clinical outcomes in patients undergoing revascularization with percutaneous coronary intervention or coronary artery bypass grafting: insights from the Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial at the 5-year follow-up. Circulation 2015;131:1269-77.
12. Cooper-DeHoff RM, Gong Y, Handberg EM, et al. Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease. JAMA 2010;304:61-8.

Keywords: Angioplasty, Angiotensins, Aspirin, Blood Glucose, Blood Pressure, Calcium Channel Blockers, Cholesterol, HDL, Cholesterol, LDL, Coronary Artery Disease, Diabetes Mellitus, Dyslipidemias, Follow-Up Studies, Hemoglobins, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperglycemia, Hypertension, Life Style, Lipoproteins, HDL, Myocardial Infarction, Nitrates, Percutaneous Coronary Intervention, Platelet Aggregation Inhibitors, Prospective Studies, Registries, Renin, Renin-Angiotensin System, Risk Factors, Smoking Cessation, Stroke, Taxus, Thienopyridines, Triglycerides, Weight Loss

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