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Commentaries on both new and classic studies of importance for the treatment of diabetes are posted here monthly.

Diabetes and Cardiovascular Mortality

Comment on:
Donahoe SM, Stewart GC, McCabe CH, et al. Diabetes and mortality following acute coronary syndromes. JAMA. 2007;298:765-775.

Background
Cardiovascular disease (CVD) is the leading cause of death in people with diabetes mellitus. In a Finnish population followed for 7 years, the risk of myocardial infarction (MI) and death from coronary heart disease in people with diabetes was similar to that of people without diabetes but with prior MI. Among those who had diabetes and prior MI, the risk was even higher (Haffner et al, 1998). These results prompted the third adult panel of the National Cholesterol Education Program (Adult Treatment Panel III, 2001) to consider diabetes as a coronary risk equivalent (ie, in the high-risk category) and to establish very tight goals, particularly for lipids, in this special population. Once a person with diabetes suffers a coronary event, the risk of death from CVD becomes very high, and the lipid goals become even tighter. In the same trend, a Swedish study proved that very tight glucose control, done at least initially with intensive insulin therapy, reduced mortality around 30% after an MI in patients with diabetes (Malmberg et al, 1995), and this became standard practice in the coronary care unit, even though a second study could not confirm the decisive role of the insulin treatment. All of this has produced a significant change in the way primary and secondary prevention of CVD is carried out in people with diabetes, including the management of acute coronary syndromes (unstable angina and MI). Therefore, it should be expected that the mortality after these events has decreased in the last decade or so, but this had not been prospectively studied until now.

Methods and Key Results
Donahoe and collaborators analyzed the data of patients with diabetes included in 11 independent clinical trials conducted during the last decade to evaluate thrombolysis in MI (TIMI study clinical trials) and compared their mortality at 30 days and 1 year following an acute coronary syndrome versus patients without diabetes. The number of subjects was impressive (more than 62,000 from 55 countries of which 17% had diabetes), and the results were discouraging. After adjusting in a multivariate analysis for baseline characteristics including age, sex, cardiovascular risk factors, history of CVD, and treatment before and during the event (including revascularization procedures), diabetes was still independently associated with higher mortality at 30 days and 1 year. By 1 year following an acute coronary syndrome, patients with diabetes who had only unstable angina and/or an MI without ST-segment elevation (UA/NSTEMI) had a risk of death similar to that of patients without diabetes who developed a full MI with ST-segment elevation (STEMI) (7.2% and 8.1%, respectively). As expected, those patients with diabetes who suffered a STEMI had the highest mortality rate (13.2%). Thus, the independent risk of death (odds ratio) among patients with diabetes compared with those without diabetes, 30 days after UA/NSTEMI or STEMI,  was  1.78 (95% CI 1.24 to 2.56) and 1.40 (95% CI 1.24 to 1.57), respectively. Similarly, after 1 year, the risk of death (hazard ratio) was 1.65 (95% CI 1.30 to 2.10) and 1.22 (95% CI 1.08 to 1.38), respectively.

Clinical Implications
The authors concluded that despite “modern therapies” for acute coronary syndrome, diabetes remains a significant independent risk factor for death and that current strategies are “insufficient” to control it. Unfortunately, we do not know whether these strategies included the tight glucose control now recommended in most guidelines, because the authors were unable to assess the type of diabetes management, serial blood glucose levels, and/or HbA_1c results. What we do know is that the lipid control was far from adequate, since only 19% of the patients with diabetes were on hypolipidaemic therapy prior to randomization and still 36% were discharged without it. Most guidelines, including the recent global proposal by the International Diabetes Federation, recommend statin therapy for all patients with diabetes who are above 40 years of age (IDF Clinical Guidelines, 2005). Although not all those who are at the primary prevention level may need statin therapy to achieve the lipid goals, it certainly should be the case for all patients on secondary prevention, particularly during the acute phase of a coronary event. Renin-angiotensin system blockers are also recommended as an option, and only 62% had them on discharge.

So we should ask ourselves: Is the excess risk of death attributable to diabetes following an acute coronary syndrome due to the lack of understanding all the risk factors involved? or due to the lack of sufficient therapies? or rather due to the fact that we are still not following the recommendations of evidence-based guidelines? The answer is probably all of the above, but only the latter is in our hands as clinicians taking care of this very high-risk group of patients with diabetes following an acute coronary syndrome.

References 

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;285:2486-2496.

IDF Clinical Guidelines Task Force. Global Guideline for Type 2 Diabetes. Brussels, Belgium: International Diabetes Federation; 2005.

Haffner S, 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;339:229-234.  

Malmberg K, Rydén L, Efendic S, et al. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol.1995;26:57-65.

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