The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 6 2108-2110
Copyright © 2000 by The Endocrine Society
Is All Coronary Heart Disease Prevention in Type 2 Diabetes Mellitus Secondary Prevention?
Steven M. Haffner
Department of Medicine
University of Texas Health Science Center at San Antonio San
Antonio, Texas 78284-7873
Address correspondence to: Robert A. Kreisberg, M.D., Dean and Vice President for Health Affairs, University of South Alabama, CSAB 170, Mobile, Alabama 36688-0002.
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Introduction
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DIABETES IS associated with a 2- to 4-fold increase in
coronary heart disease (CHD) (1, 2, 3). In the overall population,
clinically established CHD is associated with a 3- to 7-fold increase
in CHD mortality (4). Plasma cholesterol levels are a strong predictor
of risk in patients with clinical CHD (4) and diabetes (3). The much
higher risk of CHD in patients with clinical CHD and diabetes has led
both the National Cholesterol Education Program (NCEP) (5) and the
American Diabetes Association (ADA) (6) to recommend lower goals for
low-density lipoprotein cholesterol (LDL-C) in these risk groups.
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Clinical trials of lowering of LDL-C in diabetic subjects with
clinical CHD: subgroup analyses
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The possible role of lipid lowering to reduce CHD in diabetic
patients has been enhanced since the publication of data on the
efficacy of lipid lowering with simvastatin (7, 8) and pravastatin (9)
in diabetic subgroups with preexisting CHD. In the Scandinavian
Simvastatin Survival Study (n = 202) (4S) (8), diabetic patients
received more benefit from lipid lowering than did nondiabetic patients
(55% vs. 32% reduction, respectively) in lowering major
CHD (fatal + nonfatal CHD); in the Cholesterol and Recurrent Events
(CARE) study (n = 586) (9), similar benefits were seen in diabetic
and nondiabetic subgroups [27% vs. 25% reduction in CHD
events (major CHD + revascularizations)]. Unfortunately, no current
data exist on possible effectiveness of statins in diabetic patients
without CHD. The Helsinki Heart Study (10) gemfibrozil reduced CHD in
diabetic patients by 60%, although the result was not significant
because of the small number of subjects (n = 135) and the lower
event rate in this primary prevention cohort.
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Diagnosis of CHD in diabetic subjects compared with nondiabetic
subjects
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Diabetic patients with CHD have a worse prognosis than nondiabetic
patients with CHD (11, 12, 13). Because of high case fatality rates in
diabetic patients with preexisting CHD (11, 12, 13) and previous data on
the effectiveness of LDL-C lowering in diabetic subjects (8, 9), it has
been suggested that new statin vs. placebo-controlled trials
in the prevention of CHD should not be "initiated" in diabetic
patients with preexisting CHD (14).
The 1-yr case fatality rate for first myocardiol infarction (MI)
(from the onset of symptoms, thus including prehospitalization
mortality) in the FINMONICA (13) was 45% in diabetic men and
39% in diabetic women. These 1-yr case fatality rates were
significantly higher than the rates in nondiabetic patients (38% and
25%, respectively). Of the diabetic patients who died, 50% of men and
25% of women died before hospitalization. These patients, by
definition, could not benefit from secondary prevention strategies,
indicating that aggressive management of cardiovascular risk factors in
diabetic subjects (especially diabetic men) should precede the onset of
clinical CHD.
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Current recommendations for treatment of dyslipidemia
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The NCEP (5) suggests an initiation level for pharmacological
therapy in subjects with clinical CHD more than 130 mg/dL and a
treatment goal of less than 100 mg/dL. The recent ADA recommendation
(6) modifies the above recommendation by suggesting the initiation
level be 100 mg/dL or greater, whereas the goal remains less than 100
mg/dL. The lower initiation level was, in part, based on the greater
risk of recurrent CHD in diabetic than in nondiabetic patients with
clinical CHD. It may be questioned why the goal for diabetic subjects
with prior CHD should not be much lower than 100 mg/dL (i.e.
LDL <70 mg/dL); however, in the absence of clinical trial data in
either diabetic or nondiabetic patients of better outcomes for much
lower LDL cutpoints than with an LDL-C of 100 mg/dL, this was not
indicated.
The current NCEP guidelines (5) for diabetic subjects without clinical
CHD varies depending on the presence of at least two other
cardiovascular risk factors. Thus, the LDL-C level for initiation of
therapy varies from 160–190 mg/dL, and the LDL-C goal varies from
130–160 mg/dL. The new ADA guidelines (6) are considerably more
aggressive. Considering that diabetic women are relatively (although
perhaps not absolutely) at greater risk of CHD than diabetic men, the
ADA considered all diabetic patients as having "2 risk factors." In
addition, the ADA recommends that the LDL-C level for initiation
of therapy and the goal of therapy be set at 130 mg/dL. A footnote to
one of the tables in the ADA report suggested that the goal for LDL-C
might be less than 100 mg/dL if there were additional CHD risk factors
(smoking, family history of CHD, low high-density lipoprotein
cholesterol, hypertension, or microalbuminuria). It is expected that
many, if most, diabetic patients have additional risk factors for
CHD.
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Vascular disease in diabetic and nondiabetic patients with and
without CHD
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One possibility in assessing whether diabetic patients,
irrespective of the presence of CHD, should have as aggressive lipid
lowering as patients with clinically established CHD is to examine the
risk of CHD and cardiovascular disease events in diabetic subjects with
and without prior CHD (relative to nondiabetic subjects with and
without prior CHD). In previous reports, the excess of CHD risk in
patients with prior MI (3- to 7-fold) (4) is higher than the excess
risk of CHD in diabetic patients (2- to 4-fold) (1, 2, 3), but comparisons
are difficult across different populations. Furthermore, patients with
diabetes are overrepresented in patients with prior MI (1, 2, 3), and
diabetic patients with MI have a worse prognosis than nondiabetic
patients with CHD (11, 12, 13). Thus, the risk of recurrent CHD in the
overall population might be overestimated by the inclusion of diabetic
patients in previous studies.
We have recently examined this issue in a 7-yr follow-up in 1373
nondiabetic subjects and 859 diabetic subjects from the East West
study, a population-based study of diabetes in Finland (15). The 7-yr
incidence of MI in nondiabetic patients with and without MI at baseline
was 18.8% and 3.5%, respectively (P < 0.001),
whereas the 7-yr incidence of MI in diabetic patients with and without
MI at baseline was 45.0% and 20.2%, respectively (P
< 0.001). The hazard ratio for CHD mortality for diabetic patients
without prior MI compared with nondiabetic patients with prior MI was
not significant (hazard ratio, 1.4; 95% confidence interval, 0.7, 2.6)
after adjustment for age and gender, suggesting similar prognosis in
the two groups.
To further assess this issue (16), we compared the intima-media wall
thickness (IMT) in the common carotid artery (CCA) and internal carotid
artery (ICA) in 43 diabetic patients with clinical CHD, 446 diabetic
patients without clinical CHD, 47 nondiabetic subjects with clinical
CHD, and 975 nondiabetic subjects without clinical CHD in the Insulin
Resistance Atherosclerosis Study (IRAS). Both diabetes and CHD were
associated with increased atherosclerosis in the CCA. Likewise,
diabetes was significantly associated with increased atherosclerosis in
the ICA; however, CHD was not associated with ICA IMT. As expected,
diabetic patients with coronary artery disease had the greatest IMT CCA
(0.948 mM), whereas nondiabetic patients without
coronary artery disease had the least atherosclerosis (CCA, 0.792
mM). Subjects with diabetes but without CHD had
slightly greater IMT (CCA, 0.868 mM) than
nondiabetic subjects with CHD (CCA, 0.861 mM),
although these differences were not statistically significant. These
two preliminary reports suggest that diabetic patients without
preexisting vascular disease have similar risk of CHD as nondiabetic
subjects with vascular disease.
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Would treating all diabetic patients as if they had clinical CHD be
too costly?
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If diabetic patients were treated to the same goal as nondiabetic
patients with prior CHD, as defined by NCEP (5), the initiation level
for pharmacological treatment of LDL-C would be more than 130 mg/dL and
the LDL cholesterol goal would be less than 100 mg/dL; in this case,
most diabetic patients would be eligible for pharmacologic lipid
lowering therapy. This could imply a large increase in pharmacological
therapy and, thus, could produce an objectionable increase in health
care expenditures. No cost benefit data are available for lipid
lowering in diabetic patients. Recent data based on 4S study
(i.e. secondary prevention) suggest a 34% reduction in
hospitalization (17), which would markedly reduce the cost of HMG-CoA
reductase inhibitor therapy. In a further analyses of the 4S data (18),
the investigators suggested that for some patients, pharmacologic
therapy might be cost-saving, once indirect costs associated with
morbidity of CHD were taken into account. Because the risk of CHD in
diabetic patients without prior CHD is similar to that of nondiabetic
subjects with prior CHD, it is possible that lipid lowering might be
cost effective in diabetic patients even without prior CHD. However,
cost-benefit studies should be done specifically for diabetic
patients.
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Conclusions
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Diabetic subjects without prior CHD have a similar degree of
atherosclerosis and rate of CHD as nondiabetic patients with prior CHD.
Because LDL-C lowering with HMG-CoA reductase inhibitors seems to be at
least as effective in diabetic patients as in nondiabetic patients, a
strong case can be made that diabetic patients without vascular disease
should be treated similarly to nondiabetic patients with vascular
disease, with respect to aggressive treatment of lipid therapy.
Definitive data, however, need to be collected from clinical trials in
diabetic patients without vascular disease.
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Footnotes
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"Clinical Perspectives" are an occasional feature of
The Journal of Clinical Endocrinology & Metabolism. They
present the opposing views of invited contributors on a topic. All
reprints must include the complete Clinical Perspective, so that each
section can be read in context.
Accepted March 6, 2000.
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Introduction
Clinical trials of lowering...