There is little doubt that in the realm of cardiovascular disease, diabetes mellitus (DM) is one of the most important risk factors. From 1980 through 2014, the number of US adults with diabetes has nearly quadrupled from 5.5 million to 21.9 million.¹ This remarkable statistic serves as a somber reminder that efforts to prevent DM as well as its impact on cardiovascular disease remains of utmost importance.

Almost 18 years ago, Haffner et al.² reported that adults with DM had the same risk for future myocardial infarction (MI) as adults with previous MI and without DM. Consequently, the National Cholesterol Education Program (NECP) Adult Treatment Panel (ATP) III guidelines in 2001 recommended that all individuals with DM be considered as "coronary heart disease risk equivalent."³ The assertion that all patients with DM are coronary heart disease equivalent has been controversial since the publication of a systematic review and meta-analyses in 2009.⁴ This matter remained unresolved, as it was pointed out that studies included in that analyses were relatively small and most of the studies comprised cohorts from the 1990s. Some later studies had been limited to a single gender^5,6 while others lacked the ability to adjust for important confounding risk factors^7,8 and only a few studies have been able to evaluate the impact of the duration of diabetes.^5,9,10 There was also a paucity of data among relatively young (30-40 years) patients with DM. For all these reasons, updated evidence from a contemporary population was needed to inform our understanding of coronary heart disease risk in DM patients.

A recent study from Kaiser Permanente Northern California (KPNC), a large integrated health care delivery system, compared the risk of a coronary heart disease event among individuals with and without a history of diabetes or coronary heart disease among a large (n = 1,586,061), ethnically diverse, contemporary, real-world cohort of patients in usual care over a period of 10 years (January 1, 2002, through December 31, 2011). Over the follow-up period (~10,980,800 person-years), 80,012 new coronary heart disease events were observed. Compared to individuals without a history of DM or coronary heart disease, prevalent DM was associated with approximately double, and prior coronary heart disease was associated with triple the coronary heart disease risk, respectively. Individuals with DM had significantly lower risk of coronary heart disease across all age and sex strata compared to those with prior coronary heart disease (12.2 vs. 22.5 per 1000 person-years). The risk of future coronary heart disease for patients with a history of either DM or CHD was similar only among those with DM of long duration (≥ 10 years). This study had the ability to explore the heterogeneity in coronary heart disease risk in both men and women, and across a very wide age range of 30 to 90 years.

The rates of coronary heart disease were less than reported previously in observational studies, however they were consistent with contemporary findings from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort study¹² which reported that the unadjusted coronary heart disease rate for 45- to 84-year-old MESA participants with diabetes (n = 881) was 15.2/1,000 person-years (1.5 % annually). The KPNC study also showed that coronary heart disease rates were extremely low among 30- to 40-year-old subjects with DM (annual coronary heart disease rates 0.5% and 0.3% for men and women, respectively).

These findings differ substantively from the influential findings in the original Haffner et al. study,² possibly due to the greatly intensified primary prevention efforts to reduce the risk for coronary heart disease in individuals with DM in the last 15 years. Furthermore, they lend support for the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) risk assessment guidelines' inclusion of diabetes as a predictor rather than an automatic coronary heart disease risk equivalent, and consideration of global risk assessment (e.g., with the Pooled Cohort Risk Calculator) to help discriminate those with DM who are at higher versus lower risk.¹³ Of note, a prior report based on Framingham risk scoring notes that approximately half of women and a third of men with DM did not reach the previous >20% cardiovascular risk (or have prior cardiovascular disease) indicative of risk equivalent status.¹⁴

Cardiac imaging has also helped illuminate the heterogeneity in the prevalence of coronary disease and outcomes among individuals with diabetes. Studies that evaluated coronary artery calcium (CAC) in individuals with diabetes found that a large proportion of middle-aged individuals with diabetes have no evidence of coronary atherosclerosis.¹⁵ For instance, Malik et al. from the study in the MESA cohort revealed that 38% of participants with diabetes had no CAC, and absence of CAC was associated with a low annual rate (< 1%) of CHD events.¹²

Contemporary data, both from population and cardiac imaging cohorts, suggests that there is marked heterogeneity in risk among persons with DM, and that we should not routinely label all individuals with diabetes as one and the same. From a practical stand point, the question arises: can we "de-risk" a subset of patients with the help of CAC testing. Another MESA study evaluating the recent 2013 ACC/AHA cholesterol guidelines, showed that among those considered eligible for statin therapy, there was marked variability in the actual presence of CAD.¹⁶ Absence of CAC reclassified approximately one-half of candidates to low risk, suggesting that testing for CAC could be used to identify some individuals in whom treatment with statins could be deferred. However, in the case of DM population, we also need to take into account the higher lifetime risk.¹⁷

Recently, the ACC Imaging Council comprehensively reviewed the evidence regarding the use of noninvasive testing to stratify asymptomatic patients with DM.¹⁸ They summarized that at present, CAC screening offers the most sensitive tool for asymptomatic individuals with DM. Further, CAC imaging is currently a Class IIa recommendation by ACC/AHA guidelines for screening in such a population. The writing group added that functional stress testing may further refine risk estimation for patients who have high CAC. They also note that although this approach has been shown to improve the stratification in such a population, it has not yet been shown to result in improved outcomes; this knowledge gap requires future clinical trials.

These days, there is increasing focus on "Precision Medicine," an emerging approach for disease treatment and prevention that considers individual variability in genes, environment, and lifestyle for each person.¹⁹ Although existing data are not sufficient to recommend any changes in treatment recommendations, the recognition that not all individuals with DM are coronary heart disease risk equivalents is an important step forward.

References

1. Centers for Disease Control and Prevention. Number (in Millions) of Civilian, Non-institutionalized Adults with Diagnosed Diabetes, United States, 1980-2014 (CDC website). 2015. Available at: www.cdc.gov/diabetes/statistics/prev/national/figadults.htm. Accessed on 3/1/2016.
2. Haffner SM, Lehto S, Ronnemaa T, Pyorala 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 JMed 1998;339:229-34.
3. 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;285:2486-97.
4. Bulugahapitiya U, Siyambalapitiya S, Sithole J, Idris I. Is diabetes a coronary risk equivalent? systematic review and meta-analysis. Diabet Med 2009;26:142-48.
5. Wannamethee SG, Shaper AG, Whincup PH, Lennon L, Sattar N. Impact of diabetes on cardiovascular disease risk and all-cause mortality in older men: influence of age at onset, diabetes duration, and established and novel risk factors. Arch Intern Med 2011;171:404-10.
6. Daniels LB, Grady D, Mosca L, Collins P, et al. Is diabetes mellitus a heart disease equivalent in women? Results from an international study of postmenopausal women in the Raloxifene Use for the Heart (RUTH) Trial. Circ Cardiovasc Qual Outcomes 2013;6:164-70.
7. Pajunen P, Koukkunen H, Ketonen M, et al. Myocardial infarction in diabetic and non-diabetic persons with and without prior myocardial infarction: the FINAMI Study. Diabetologia 2005;48:2519-24.
8. Schramm TK, Gislason GH, Køber L, et al. Diabetes patients requiring glucose-lowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people. Circulation 2008;117:1945-54.
9. Hu FB, Stampfer MJ, Solomon CG, et al. The impact of diabetes mellitus on mortality from all causes and coronary heart disease in women: 20 years of follow-up. Arch Intern Med 2001;161:1717-23.
10. Huang ES, Laiteerapoing N, Liu J, John PM, Moffet HH, Karter AJ. Rates of complications and mortality in older diabetes patients: the diabetes and aging study. JAMA Intern Med 2014;174:251-8.
11. Rana JS, Liu JY, Moffet HH, Jaffe M, Karter AJ. Diabetes and prior coronary heart disease are not necessarily risk equivalent for future coronary heart disease events. J Gen Intern Med 2015 Dec 14. [Epub ahead of print]
12. Malik S, Budoff MJ, Katz R, Blumenthal RS, et al. al. Impact of subclinical atherosclerosis on cardiovascular disease events in individuals with metabolic syndrome and diabetes: the multi ethnic study of atherosclerosis. Diabetes Care 2011;34:2285-90.
13. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 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.
14. Wong ND, Glovaci D, Wong K, et al. Global cardiovascular disease risk assessment in United States adults with diabetes. Diab Vasc Dis Res 2012;9:146-52.
15. Silverman MG, Blaha MJ, Budoff MJ, et al. Potential implications of coronary artery calcium testing for guiding aspirin use among asymptomatic individuals with diabetes. Diabetes Care 2012;35:624-6.
16. Nasir K, Bittencourt MS, Blaha MJ, et al. Implications of coronary artery calcium testing among statin candidates according to American College of Cardiology/American Heart Association cholesterol management guidelines: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2015;66:1657-68.
17. Valenti V, Hartaigh BÓ, Cho I, et al. Absence of coronary artery calcium identifies asymptomatic diabetic individuals at low near-term but not long-term risk of mortality: a 15-year follow-up study of 9,715 patients. Circ Cardiovasc Imaging 2016;9:e003528.
18. Budoff MJ, Raggi P, Beller GA, et al. Noninvasive cardiovascular risk assessment of the asymptomatic diabetic patient: the Imaging Council of the American College of Cardiology. JACC Cardiovasc Imag 2016;9:176-92.
19. National Institutes of Health. Precision Medicine Initiative Cohort Program: Scale and Scope (NIH website). 2016. Available at: https://www.nih.gov/precision-medicine-initiative-cohort-program/scale-scope. Accessed on 3/1/2016.

Keywords: Atherosclerosis, Cholesterol, Cohort Studies, Coronary Artery Disease, Diabetes Mellitus, Follow-Up Studies, Life Style, Myocardial Infarction, Prevalence, Primary Prevention, Risk Assessment, Risk Factors, Metabolic Syndrome, Acute Coronary Syndrome

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