Download Primary prevention of coronary artery disease in patients

Primary prevention
of coronary artery disease
in patients with type 2
diabetes mellitus
Jarrod M. Harrall, DO
Andrea Tufo, OMS IV
T
he Centers for Disease
Control and Prevention
(CDC) estimated that
18.8 million people in the United States
had diagnosed diabetes mellitus in 2010,
with an additional 7 million people having
diabetes that was undiagnosed.1
May 2012 DOs Against DIABETES
AOA Health Watch
9
urrently, the diagnosis of diabetes
mellitus is made with repeat testing
based on 1 of the following 3 findings:
C
(1) glycosylated hemoglobin (HbA1c)
level is ⬎ 6.5%;
(2) fasting plasma glucose level is
⬎ 126 mg/dL;
(3) 2-hour plasma glucose level is
⬎ 200 mg/dL during an oral
glucose tolerance test.2,3 Adults
with diabetes mellitus are 2 to 4
times more likely to die of
cardiovascular disease (CVD) or
stroke than are adults without
diabetes.1
Although mortality from CVD has
decreased among patients with type 2
diabetes mellitus (T2DM) in recent years,
the rate of CVD-related death remains
higher in the population with T2DM than
in the population without this disease.1 In
2004, heart disease was listed as the cause
of death on 68% of death certificates for
people older than 65 years with diabetes
mellitus.1 Therefore, it is especially important to decrease cardiovascular risk factors
in this population. According to the CDC,
control of low-density lipoprotein
cholesterol (LDL-C levels), as well as blood
pressure, can substantially reduce the risk
of CVD in individuals with diabetes
mellitus.1
global risks of patients with diabetes
mellitus have been discussed in consensus
statements published by the ADA and the
American Heart Association (AHA): the
Framingham Heart Study risk calculator
(http://hp2010.nhlbihin.net/atpiii/calculator.
asp?usertype=prof), the United Kingdom
Prospective Diabetes Study (UKPDS) risk
engine (www.dtu.ox.ac.uk/riskengine/), and
the ADA’s Diabetes Personal Health
Decisions (PhD) risk assessment tool.5
However, the ADA retired the diabetes
PhD risk assessment tool at the end of
2011, intending to have a new, improved
online risk assessment tool available
sometime in the first half of 2012.6
Furthermore, it is important to note that
the ADA has recently questioned the validity of the Framingham risk calculator,
noting that the Framingham Risk Score
may overestimate risk by assuming that all
patients with diabetes are at high risk of
developing CVD.3,4
calorie diet and 175 minutes of physical
activity each week. Risk factors evaluated at
the end of the study were weight, fitness,
HbA1c level, systolic blood pressure,
diastolic blood pressure, LDL-C levels,
high-density lipoprotein cholesterol
(HDL-C) levels, and triglyceride levels.
With the exception of LDL-C levels,
which were significantly greater in the ILI
group than in the DSE group (P = .009), all
of the CVD risk factors measured in the
Look AHEAD study were decreased in
members of the ILI group (P ⬍ .001 to
P = .01).7 The study also found that when
compared to the number of members in
Cardiovascular disease risk
the DSE group, fewer members of the ILI
assessment
group began to take diabetic medications
An important aspect of the management of
over the 4-year period.
diabetes mellitus is assessing CVD risk to
Specific ADA lifestyle recommendadetermine the individual goals for each
tions and goals for decreasing the risk of
patient. Despite the known increased risk
CVD include moderate weight loss (ie,
of CVD in individuals with diabetes, there
7% - 10% of body weight per year) and
remains a large population of such individdietary modification.2 Dietary guidelines
uals who do not meet the goals outlined in
include several recommendations for the
the American Diabetes Association (ADA) Lifestyle modification
limitation of fat. Patients should limit fat
standards of medical care in diabetes.2 By
Appropriate lifestyle modifications have
intake to 25% to 35% of total daily calories,
taking multiple factors into account, the
been shown to stabilize glycemic control
and any fats consumed should consist of
physician can tailor the treatment goals of
and to prevent and decrease CVD risk
mainly monounsaturated and polyunsatueach patient to improve care and meet the factors. In a 4-year study, the Look
rated fats. Saturated fats should be limited
ADA goals. This is especially important for AHEAD (Action for Health in Diabetes)
to less than 7% of energy intake, and
high-risk patients, in whom the disease
research group examined the effects of
dietary cholesterol intake should be less
tends to be the least well controlled.4 The
lifestyle modifications on CVD risk factors.7 than 200 mg/day. Recommendations also
key factors in defining these goals appear to In the study, participants were divided into include fiber intake of at least 14 grams per
be the patient’s age, duration of disease,
a “diabetes support and education group”
1000 calories.
lipid panel results, degree of blood pressure (DSE, the control group) and an “intensive
In addition to diet, physical activity is an
control, HbA1c level, and tobacco use.
lifestyle intervention group” (ILI).7 The ILI important lifestyle intervention for decreasThree calculators used to determine
group was told to adhere to a 1200-1800ing CVD risk. Patients should be chal-
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DOs Against DIABETES May 2012
lenged to achieve at least 150 minutes of
moderate-intensity aerobic activity, or at
least 90 minutes of vigorous aerobic activity, each week.
Smoking is another modifiable risk
factor of CVD. Patients who smoke should
be counseled and advised to quit as soon as
possible. Those patients who are willing to
stop smoking should be offered access to
cessation programs.
numbers do not provide a complete
picture. The 2001 National Cholesterol
Education Program Expert Panel on
Detection, Evaluation, and Treatment of
High Blood Cholesterol in Adults (Adult
Treatment Panel III),10 as well as the 2004
updated guidelines, maintain that, although
LDL-C should be the primary treatment
target in diabetes mellitus, there is considerable benefit in risk stratification of
patients based on secondary treatment
goals.11 An important point that should be
Lipid control
kept in mind is that the lipid profile in
The ADA recommends that patients with
diabetes mellitus but without known CVD patients with diabetes is more atherogenic
than in those without diabetes, making the
maintain an LDL-C level of less than
100 mg/dL as a primary goal.2 Patients with full lipid profile crucial to treatment
decisions. Another reason to consider treatdiabetes mellitus and known CVD should
strive for an even lower LDL-C goal, of less ment targets in addition to LDL-C is the
complicated cascade of events in the lipid
than 70 mg/dL.2 Research suggests that
metabolism of people with diabetes.
HDL-C and triglycerides have less
In patients with diabetes mellitus, 2
influence than LDL-C on cardiovascular
major consequences of insulin resistance
events in people with diabetes.l,2,8,9 In the
occur in lipid metabolism—the
ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, the addition unrestricted release of hormone-sensitive
lipase and the functional loss of lipoprotein
of fenofibrate to statin therapy led to an
increase in HDL-C levels and a decrease in lipase, both of which result in increases in
free fatty acids, triglycerides, and very-lowtriglyceride levels in a group of individuals
with T2DM.8,9 However, these changes did density lipoprotein cholesterol (VLDLC).12 With an increase in triglycerides,
not result in a decreased incidence of
there is also an increase in cholesterol ester
cardiovascular events compared to the
transfer proteins, resulting in structural
group receiving statin therapy alone.8,9
changes in the LDL-C and HDL-C partiIt appears, however, that the raw
cles. These changes make the cholesterol
particles easier targets for lipolysis by
hepatic lipase. When acted on by hepatic
lipase, LDL-C is converted from large,
buoyant (ie, “fluffy, puffy”) particles into
smaller, denser, and more numerous particles known to be more atherogenic. The
increase in triglycerides causes HDL-C to
be catabolized by the kidneys, thus directly
lowering the HDL-C level.
The burden of lipoproteins other than
LDL-C that contribute to atherogenesis
can be determined by calculating either the
apolipoprotein B (ApoB) or non-HDL-C
level. Apolipoprotein B is present in each
particle of chylomicron, LDL-C, VLDL-C,
intermediate-density lipoprotein, and
lipoprotein-a, all of which are considered
atherogenic. Non-HDL-C reflects the sum
of LDL, VLDL-C, intermediate-density
lipoprotein, and lipoprotein-a. Both ApoB
and non-HDL-C have been shown to be
better predictors of cardiovascular events
than LDL-C.10,13,14 The level of ApoB can
be obtained only by direct laboratory
measurement. The level of non-HDL-C
can be determined with a basic lipid profile
(by subtracting HDL-C from total cholesterol) in a nonfasting state.
In the consensus conference report
from the ADA and the American College
of Cardiology Foundation (ACCF), the
goals for ApoB, LDL-C, and non-HDL-C
in patients at cardiometabolic risk are as
follows:14
䡲 High risk: ApoB is ⬍ 90 mg/dL,
LDL-C ⬍ 100 mg/dL, non-HDL-C
⬍ 130 mg/dL
䡲 Very high risk: ApoB is ⬍ 80 mg/dL,
LDL-C ⬍ 70 mg/dL, non-HDL-C
⬍ 100 mg/dL
Consideration of these additional factors
will allow clinicians to increase the accuracy
of CVD risk prediction for patients with
diabetes mellitus.
Blood pressure control
Current ADA recommendations for blood
pressure control in patients with diabetes
mellitus include the initiation of drug
therapy if systolic blood pressure (SBP) is
more than 140 mm Hg and if diastolic
blood pressure (DBP) is more than
90 mm Hg, based on 2 measurements on
May 2012 DOs Against DIABETES
AOA Health Watch 11
separate days.2 In patients with confirmed
SBP ranging between 130 and 139 mm Hg,
or confirmed DBP ranging between 80 and
89 mm Hg, lifestyle modification alone
should be tried for 3 months. If after these
lifestyle modification efforts, SBP of less
than 130 mm Hg or DBP of less than
80 mm Hg is not achieved, treatment with
pharmaceutical agents should be started.2
The ACCORD trial compared standard
blood pressure control (target SBP is ⬍
140 mm Hg) with intensive blood pressure
control (target SBP is ⬍ 120 mm Hg) in
patients with diabetes mellitus.9,15 The
researchers used the rate of cardiovascular
events as an indicator of optimal blood
pressure control. The investigators found
no statistically significant difference in the
total number of cardiovascular events in the
intensive vs the standard blood pressure
control group. They did note, however, that
patients in the intensive control group had
a higher incidence of adverse effects from
medications and used a larger number of
antihypertensive medications compared
with patients in the standard control
group.9,15
Glycemic control
The ADA recommends an HbA1c level of
less than 7% as a goal for glycemic control
in patients with diabetes mellitus.2 This
laboratory value should be monitored every
12 AOA Health Watch
6 months in patients with stable glycemic
control.2
In an investigation of the benefits of
tight glycemic control in patients with
diabetes, the ACCORD researchers
divided participants into an intensive
therapy group and a standard therapy
group.9,16 The intensive therapy group was
given the goal of keeping their HbA1c level
below 6.0%, and the standard therapy
group was given the goal of keeping their
HbA1c level between 7.0% and 7.9%.
Participants in the intensive therapy group
were forced to quit treatment before the
study was completed because they had a
higher risk of mortality than the standard
care group.9,16 The investigators concluded
that standard glycemic control, such as that
recommended by the ADA, along with
control of other cardiovascular risk factors,
is the best overall approach to treatment of
patients with T2DM.2,9,16
The Diabetes Control and Complications Trial/Epidemiology of Diabetes
Interventions and Complications
(DCCT/EDIC) study and the UKPDS
have demonstrated that HbA1c levels less
than 7% will decrease the incidence of
CVD.17,18 In the DCCT/EDIC study, in
which patients with type 1 diabetes mellitus
were followed up for 17 years, a 42%
reduction in CVD risk was found in those
patients undergoing intensive glycemic
control.17 In the UKPDS, which followed
up patients with T2DM for 10 years, the
risk of myocardial infarction was decreased
by 15% to 33% in individuals using intensive glycemic treatment.18
Authors of the ACCORD trial
concluded that other comorbidities were
the cause of the higher mortality observed
in the intensive treatment group.19 Because
of the discrepancy in outcomes between
standard glycemic control and intensive
glycemic control, some authors have
suggested that patients with longstanding
diabetes mellitus or other comorbidities be
given more time to achieve their glycemic
goals (eg, 6 months to 1 year). In addition,
if a patient has a longstanding diagnosis of
diabetes (eg, 10-15 years), HbA1c goals
should remain at 7.0%. By contrast, a more
recent diagnosis of diabetes may prompt an
HbA1c goal of 6.0.20
Aspirin in primary prevention
In 2007, the ADA and AHA jointly recommended that low-dose aspirin
(acetylsalicylic acid, 75-162 mg/day) be
used as a primary prevention strategy in
patients with diabetes mellitus who are at
increased cardiovascular risk.21 After publication of this recommendation, the Japanese Primary Prevention of Atherosclerosis
With Aspirin for Diabetes22 and the
Prevention of Progression of Arterial
Disease and Diabetes23 trials raised doubts
about the efficacy of low-dose aspirin in
patients with diabetes mellitus. As a result
of those results, the ADA, AHA, and ACCF
convened in 2009 to review and synthesize
available evidence and update recommendations.21 During the evaluation to
determine the updated recommendations,
the joint committee considered not only
the benefits of aspirin for preventing
coronary artery disease, but also the known
problem of gastrointestinal bleeding with
daily use of aspirin.
The joint committee concluded that lowdose aspirin (75-162 mg/day) for CVD
prevention is “reasonable” for adults with
diabetes mellitus who have no history of
vascular disease but who are at increased
risk of CVD (10-year risk is ⬎ 10%) and are
not at increased risk of bleeding.12 The
committee added that aspirin should not be
recommended for CVD prevention if
patients are at low risk of CVD (10-year risk
DOs Against DIABETES May 2012
is ⬍ 5%), noting that the potential adverse
effects from bleeding offset the potential
benefits. Low-dose aspirin “might be considered” for CVD prevention in patients with
diabetes who are at intermediate risk of
CVD (10-year risk = 5%-10%).12
The joint committee also stressed that
all modifiable CVD risk factors should be
addressed and optimally managed for
patients using aspirin. Helping patients
reach their individual cardiovascular goals
through such management will decrease
their 10-year CVD risk, meaning that fewer
patients with diabetes mellitus will need to
continue taking aspirin and be at risk for
the adverse effects of this medication.
Final notes
It is evident that prevention of CVD in
patients with T2DM requires a multifactorial approach. This approach includes
management of CVD risk factors with both
pharmaceutical interventions and lifestyle
modifications. Many patients with diabetes
mellitus are currently not achieving recommended treatment goals and targets. By
improving the quality of care for these
patients, we can decrease the occurrence of
CVD and promote a happier and healthier
life for individuals with diabetes mellitus.
References
1. Centers for Disease Control and Prevention. National
Diabetes Fact Sheet: National Estimates and
General Information on Diabetes and Prediabetes in
the United States, 2011. Atlanta, GA: US
Department of Health and Human Services, Centers
for Disease Control and Prevention; 2011.
http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.
pdf. Accessed February 20, 2012.
the American Heart Association and the American
Diabetes Association. [Published online before print
December 27, 2006]. Circulation. 2007;115(1):114126.
6. Living with diabetes: diabetes PhD. American
Diabetes website. http://www.diabetes.org/livingwith-diabetes/complications/diabetes-phd/.
Accessed February 20, 2012.
7. The Look AHEAD Research Group. Long-term effects
of a lifestyle intervention on weight and
cardiovascular risk factors in individuals with type
2 diabetes mellitus: four-year results of the Look
AHEAD trial. Arch Intern Med. 2010;170(17):15661575.
8. The ACCORD Study Group. Effects of combination
lipid therapy in type 2 diabetes mellitus [published
online ahead of print March 14, 2010]. N Engl J
Med. 2010;362(17):1563-1574.
9. Buse JB; ACCORD Study Group. Action to control
cardiovascular risk in diabetes (ACCORD) trial:
design and methods [published online ahead of
print April 16, 2007]. Am J Cardiol.
2007;99(12A):21i-33i.
10. National Cholesterol Education Program (NCEP)
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III). Third Report of the
National Cholesterol Education Program (NCEP)
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Implications of Recent Trials for the National
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Panel III Guidelines. [published correction appears
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MN, Bethel MA (Eds.), Type 2 Diabetes Mellitus:
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2. American Diabetes Association. Standards of
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2011;34(suppl 1):S11-S61. doi:10.2337/dc11-S011.
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Apolipoproteins versus lipids as indices of coronary
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2003;361(9359):777-780.
3. Preis SR, Hwang SJ, Coady S, et al. Trends in allcause and cardiovascular disease mortality among
women and men with and without diabetes
mellitus in the Framingham Heart Study, 1950 to
2005 [published online ahead of print March 23,
2009]. Circulation. 2009;119(13):1728-1735.
14. Brunzell JD, Davidson M, Furberg CD, et al.
Lipoprotein management in patients with
cardiometabolic risk: consensus conference report
from the American Diabetes Association and the
American College of Cardiology Foundation.
J Am Coll Cardiol. 2008;51(15):1512-1524.
4. Davidson MH, Maki KC, Pearson TA, et al. Results
of the National Cholesterol Education (NCEP)
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E-Technology (NEPTUNE) II survey and implications
for treatment under the recent NCEP Writing Group
recommendations. Am J Cardiol. 2005;96(4):556563.
15. ACCORD Study Group, Cushman WC, Evans GW,
Byington RP, et al. Effects of intensive bloodpressure control in type 2 diabetes mellitus
[published online ahead of print March 14, 2010].
N Engl J Med. 2010;362(17):1575-1585.
5. Buse JB, Ginsberg HN, Bakris GL, et al. Primary
prevention of cardiovascular diseases in people
with diabetes mellitus: a scientific statement from
May 2012 DOs Against DIABETES
16. ACCORD Study Group, Gerstein HC, Miller ME,
Genuth S, et al. Long-term effects of intensive
glucose lowering on cardiovascular outcomes.
N Engl J Med. 2011;364(9):818-828.
17. Nathan DM, Cleary PA, Backlund JY, et al; Diabetes
Control and Complications Trial/Epidemiology of
Diabetes Interventions and Complications
(DCCT/EDIC) Study Research Group. Intensive
diabetes treatment and cardiovascular disease in
patients with type 1 diabetes. N Engl J Med.
2005;353(25):2643-2653.
18. Holman RR, Paul SK, Bethel MA, et al. 10-year
follow-up of intensive glucose control in type 2
diabetes. N Engl J Med. 2008;359(15):1577-1589.
19. ACCORD Study Group, Gerstein HC, Miller ME, et
al. Effects of intensive glucose lowering in type 2
diabetes. N Engl J Med. 2008;358(24):2545-2559.
20. Ismail-Beigi F, Moghissi E, Tiktin M, et al.
Individualizing glycemic targets in type 2HW
diabetes
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Intern Med. 2011;154(8):554-559.
21. Pignone M, Alberts MJ, Colwell JA, et al;
American Diabetes Association, American Heart
Association, American College of Cardiology
Foundation. Aspirin for primary prevention of
cardiovascular events in people with diabetes: a
position statement of the American Diabetes
Association, a scientific statement of the American
Heart Association, and an expert consensus
document of the American College of Cardiology
Foundation. Diabetes Care. 2010;33(6):1395-1402.
22. Ogawa H, Nakayama M, Morimoto T, et al;
Japanese Primary Prevention of Atherosclerosis
With Aspirin for Diabetes (JPAD) Trial
Investigators. Low-dose aspirin for primary
prevention of atherosclerotic events in patients
with type 2 diabetes: a randomized controlled trial
[published online ahead of print November 9,
2008]. JAMA. 2008;300(18):2134-2141.
23. Belch J, MacCuish A, Campbell I, et al; Prevention
of Progression of Arterial Disease and Diabetes
Study Group; Diabetes Registry Group; Royal
College of Physicians Edinburgh. The prevention of
progression of arterial disease and diabetes
(POPADAD) trial: factorial randomized placebo
controlled trial of aspirin and antioxidants in
patients with diabetes and asymptomatic
peripheral arterial disease. BMJ. 2008;337:a1840.
doi:10.1136/bmj.a1840. HW
Jarrod M. Harrall, DO, practices sports
medicine and family practice in the
Private Family Medicine Clinic for
Primary Care Plus in Leawood, Kansas.
He can be reached at the
jharrall@primarycare pluskc.com.
Andrea Tufo, OMS IV, is a fourth-year
medical student at Kansas City University
of Medicine and Biosciences. She will
continue her medical training at the Fort
Wayne Medical Education Program,
Family Medicine Residency in Fort
Wayne, Indiana.
AOA Health Watch 13