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Photocopy and distribute this plain-language review
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This issue's article: The Heart
Health Quiz |
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Antonio
M. Gotto, Jr, MD, DPhil
Joan and Sanford I. Weill Medical
College of Cornell University |
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Elizabeth
Barrett-Connor, MD
University of California, San Diego,
School of Medicine
Peter Ganz, MD
Harvard Medical School
Brigham and Women's Hospital
Scott
M. Grundy, MD, PhD
University of Texas Southwestern
Medical Center at Dallas
Steven
M. Haffner, MD
University of Texas Health Science Center
Donald B. Hunninghake, MD
University of Minnesota Medical School
Ronald M. Krauss, MD
Lawrence Berkeley National Laboratory
University of California, Berkeley
John C. LaRosa, MD
SUNY Downstate Medical Center
Peter Libby, MD
Harvard Medical School
Brigham and Women's Hospital
Harry L. Metcalf, MD
SUNY/Buffalo School of Medicine and
Biomedical Sciences
Copyright © 2003 Thomson Professional Postgraduate Services®
(PPS), 150 Meadowlands Parkway, Secaucus, NJ 07094-2304
USA. All rights reserved.
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Supported by an unrestricted educational
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Dyslipidemia
and Type 2 Diabetes
What Do Clinical Trial Results Mean to Practicing Clinicians?
Dyslipidemia is common
in persons with type 2 diabetes—which accounts for 90% to
95% of all cases of diabetes1—and
contributes significantly to their two- to fourfold increased risk
of developing coronary heart disease (CHD).2
Medical practitioners may expect to treat an increasing number of
patients with diabetes and dyslipidemia: In addition to the approximately
17 million people with diagnosed diabetes, an additional 16 million
have prediabetes that may progress to frank diabetes. Practitioners
are in a position to reduce the incidence of CHD and other vascular
disorders in their patients by appropriate treatment of diabetes
and diabetic dyslipidemia, which is modifiable.2
Diabetic dyslipidemia is characterized
by elevated TG, decreased HDL-C, and a predominance of atherogenic
small, dense LDL particles.2 Levels
of LDL-C usually do not differ significantly from those in individuals
who do not have diabetes. This article summarizes the diabetes- specific
results of four recently published studies that addressed antidyslipidemia
drug therapy and suggests how these results may be applicable in the
management of dyslipidemic patients with diabetes. The overall conclusion
that may be drawn from the collective studies is that HGM-CoA reductase
inhibitor (statin) therapy should be considered for all patients with
diabetes who are at increased risk for CHD and major vascular events.
| HPS
Substudy: First Major Vascular Event by LDL-C and Prior
Diabetes Status |
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| HPS
Collaborative Group. Lancet. 2003;361:2005-2016. |
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The Medical Research Council/British Heart Foundation Heart Protection
Study (HPS) compared simvastatin with placebo in high-risk
patients.3
The study enrolled patients from July 1994 to May 1997 and followed
them for 5 years. Patients 40 to 80 years old had TC levels of >135
mg/dL and at least one of the following risk factors: diabetes, CHD,
occlusive disease of noncoronary arteries, or treated hypertension
(males older than 65 years). In all, 5,963 patients with diabetes
and 14,573 persons without diabetes were randomly allocated to receive
simvastatin 40 mg daily or placebo. In the substudy of subjects with
diabetes, treatment effect was based on the incidence of a first major
coronary event (a nonfatal myocardial infarction [MI] or coronary
death), a first major vascular event (a major coronary event, stroke,
or revascularization procedure), and subsequent vascular events.
Results: The following
results of simvastatin therapy in patients with diabetes are all
statistically significant compared with placebo. The rate of first
major coronary events was reduced by 27%: first nonfatal MI, by
37%, and coronary mortality, by 20%. There was also a 22% reduction
in the rate of first major vascular events: first nonfatal or fatal
stroke, by 24%, and first revascularization procedure, by 17%. Lowering
of LDL-C by an average of 40 mg/dL reduced the risk for major vascular
events by about a quarter. The reduction in rate of major vascular
events was 33% among diabetic participants who did not have occlusive
arterial disease at study entry and 27% among diabetic participants
whose pretreatment LDL-C was <116 mg/dL.
Among those patients who had a first major
vascular event following randomization, simvastatin reduced the
rate of subsequent events. Thus, simvastatin prevented both first
and subsequent major vascular events.3
Similar effects of simvastatin allocation on first major vascular
event were seen in subjects with type 1 diabetes and in those with
type 2 diabetes, although there were only 615 subjects in the type
1 category.
Significance for practice:
Study authors wrote that statin therapy should be considered routinely
for all patients with diabetes who are at high risk for major vascular
events, irrespective of their initial cholesterol concentration—even
if they do not already have manifest CHD or hypercholesterolemia.
In patients with diabetes, treatment with simvastatin 40 mg daily
reduced the rate of first major vascular events by about a quarter
(and may have reduced it by about one-third had they been more compliant
with therapy).
| ASCOT-LLA:
Primary End Point in Subgroups |
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| Note:
Area of squares is proportional to the amount of statistical
information. Sever PS et al. Lancet. 2003;361:1149-1158. |
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The Anglo-Scandinavian Cardiac Outcomes Trial Lipid-Lowering
Arm (ASCOT-LLA) randomly assigned patients who had hypertension
and a nonfasting TC level of <250 mg/dL to receive atorvastatin
10 mg daily or placebo, in addition to the antihypertensive regimen
they were receiving as participants in the basic ASCOT trial.4
Patients were recruited between February 1998 and May 2000, with
plans for an average 5-year follow-up. The primary outcome was nonfatal
MI or CHD death. ASCOT-LLA had 10,305 participants, aged 40 to 79
years. In addition to hypertension, they had at least three other
CHD risk factors. There were 1,258 patients with diabetes assigned
to receive atorvastatin and 1,274 patients with diabetes assigned
to receive placebo.
Results: ASCOT-LLA was
stopped after a median follow-up period of only 3.3 years, because
154 primary events had occurred in the placebo group compared with
only 100 primary events in the atorvastatin group (hazard ratio
[HR] 0.64; 95% CI 0.50–0.83; P=0.0005). The benefit
of atorvastatin therapy was evident in the first year of the study.
In the entire group of patients, atorvastatin therapy resulted in
a significant reduction in the incidence of total cardiovascular
and total CHD events and strokes compared with placebo. In the subgroup
of patients with diabetes, atorvastatin also resulted in a relative
reduction in CHD events; this reduction was not significantly different
from the reduction in the entire group of ASCOT-LLA patients, and
in itself was not of statistical significance.
The relative reduction in the primary end
point among patients with diabetes was less than that among patients
without diabetes: The HR was 0.84 for patients with diabetes and
0.56 for patients without diabetes. There may have been an insufficient
number of patients in the diabetes subgroup to provide statistical
significance: There were only 84 CHD events in the diabetes subgroup.
The shortened follow-up period of the trial may have contributed
to the relatively low number of CHD events.
Discussion: ASCOT elicited
many opinions after results were published. In several letters to
the editor, some questions were raised about the methodological
issues used, the lack of benefit with atorvastatin vs placebo among
women (HR=1.10; P=0.769), and the early termination of
the trial.5
The authors replied to these queries with
a lengthy letter to the editor.5
They contended that the concerns raised about the benefit in women
can be explained by limited power; supportive evidence was based
on analyses of the larger number of major CV events and procedures
in women, showing that those on atorvastatin had 20% fewer such
events than those on placebo (P=0.17). In response to questions
about early termination, the authors wrote that the decision was
made by the data safety monitoring board on the grounds that the
predetermined stopping rules for the primary end point had been
exceeded, with significant differences between the atorvastatin
and placebo groups (P=0.0005); the decision was also supported
by a significant reduction in stroke in the atorvastatin group (P=0.02).5
In patients with diabetes, the reduction
in the incidence of primary end-point events was not statistically
significant. This may be explained by the absolute number of events
(only 84), inadequate power, or treatment crossover (14% of placebo
patients with diabetes began using a statin compared with 8% placebo
patients without diabetes).4
However, patients who had diabetes did experience a significant
23% reduction in total cardiovascular events with atorvastatin vs
placebo.
Significance for practice:
Atorvastatin may be expected to reduce the incidence of major cardiovascular
events in moderately high-risk patients who have diabetes and treated
hypertension.
| Steno-2:
Effect of Therapies on Selected Risk Factors |
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| Gaede
P et al. N Engl J Med. 2003;348:383-393. |
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The Steno-2 Study from the Steno Diabetes Center in Copenhagen,
Denmark, was an 8-year trial that ended in December 2001.6
It was a randomized, open-label, parallel study of modifiable risk
factors for cardiovascular disease (CVD) in patients with type 2 diabetes
and microalbuminuria, comparing conventional treatment in 80 patients
vs targeted intensified multifactorial intervention in 80 patients.
The primary end point was a composite of death from cardiovascular
causes, nonfatal MI, nonfatal stroke, revascularization, amputation
resulting from ischemia, or vascular surgery for peripheral atherosclerotic
disease. The mean age of patients was 55.1 years; the mean follow-up
period was 7.8 years.
Conventional treatment followed Danish national
guidelines. Intensive treatment targeted hyperglycemia, hypertension,
dyslipidemia, microalbuminuria, and secondary prevention of CVD
through stepwise implementation of behavior modification (diet,
exercise, smoking cessation) and pharmacologic therapy. This therapy
consisted of an ACE inhibitor equivalent to captopril 50 mg bid
or an angiotensin II–receptor antagonist equivalent to losartan
50 mg bid, a multivitamin-mineral supplement, aspirin 150 mg/day,
oral hypoglycemic medication and insulin if indicated, antihypertensive
medication, a statin for elevated fasting cholesterol or combined
dyslipidemia, and a fibrate for isolated hypertriglyceridemia.
Results: The intensified
multifactorial intervention significantly reduced both the primary
end point of CVD and the secondary end points of microvascular events
(nephropathy, retinopathy, neuropathy). Compared with the conventional-therapy
group, the intensive-therapy group had statistically significant
declines in glycosylated hemoglobin values (0.2% conventional vs
-0.5% intensive; P<0.001), systolic BP (-3 mm Hg vs
-14 mm Hg; P<0.001), diastolic BP (-8 mm Hg vs -12 mm
Hg; P=0.006), fasting serum TC (-3 mg/dL vs -50 mg/dL;
P<0.001), fasting serum TG (9 mg/dL vs -41 mg/dL; P=0.015),
and urinary albumin excretion rates (30 mg/24 hr vs -20 mg/24 hr;
P=0.007). Patients in the intensive-therapy group also
had a significantly lower risk for CVD (HR 0.47; 95% CI 0.24–0.73),
nephropathy (HR 0.39; 95% CI 0.17–0.87), retinopathy (HR 0.42;
95% CI 0.21–0.86), and autonomic neuropathy (HR 0.37; 95%
CI 0.18–0.79).
Significance for practice: “A
target-driven, long-term, intensified intervention aimed at multiple
risk factors in patients with type 2 diabetes and microalbuminuria
reduces the risk of cardiovascular and microvascular events by about
50%.”6
| ALLHAT-LLT:
All-Cause Mortality |
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| ALLHAT
Collaborative Research Group. JAMA. 2002;288:2998-3007. |
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The Lipid-Lowering Trial component of the Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT-LLT)
compared the effect of pravastatin vs usual care on all-cause mortality
and CHD events (MI or fatal CHD).7
The nonblinded trial was conducted from February 1994 through March
2002, with follow-up up to 8 years (mean follow-up of 4.8 years).
Trial participants had hypertension and at least one other CHD risk
factor, were at least 55 years of age and moderately hypercholesterolemic
(fasting LDL-C 120–189 mg/dL if they were not known to have
CHD, or 100–129 mg/dL if they were known to have CHD), and had
a fasting TG level <350 mg/dL. Of the 10,355 persons in the trial,
35% had type 2 diabetes and 14% had CHD. Patients were randomized
to receive pravastatin 40 mg/day (n=5,170) or usual care (n=5,185).
There were 1,855 patients with type 2 diabetes in the pravastatin
group and 1,783 in the usual-care group.
For patients in the pravastatin group, physicians
were permitted to reduce the dose of pravastatin or discontinue
the drug if adverse events occurred, and to prescribe cholesterol-lowering
drugs other than pravastatin. For the usual-care group, physicians
used their own discretion in prescribing LDL-C–lowering treatment,
but vigorous therapy was discouraged unless warranted by a change
in clinical circumstances.
Results: The presence of
diabetes made no significant difference in the outcome of therapy
between patients assigned to pravastatin or usual care. Overall,
there was a greater lowering of TC and LDL-C levels in the pravastatin
group compared with the usual-care group: At year 4 of the trial,
TC levels were reduced by 17% in the pravastatin group and by 8%
in the usual-care group, while LDL-C levels were reduced by 28%
and 11%, respectively. There was no significant difference between
the pravastatin and usual-care groups in all-cause mortality or
cardiac event rates: At year 6, the all-cause mortality rate was
14.9% for the pravastatin group and 15.3% for the usual-care group,
and the CHD event rate was 9.3% and 10.4%, respectively.
Discussion: Pravastatin
did not significantly reduce either all-cause mortality or CHD events
when compared with usual care of dyslipidemia. This was likely due
to the design and execution of the trial, which resulted in a diminished
difference between the two treatment groups (owing to high crossover
rate in the usual-care group and a low adherence rate in the pravastatin
group) and not to the lack of efficacy of pravastatin in patients
who have hypertension. ALLHAT-LLT was intended to make the two therapies—pravastatin
and usual care—different enough from each other, and the groups
large enough, to demonstrate significant differences in outcomes.
As it turned out, the difference in therapy decreased over the course
of the trial.8
Some patients who were allocated to receive pravastatin discontinued
the drug (77% adherence by year 6) or had the dose lowered, effectively
making their therapy usual care, and almost a third of the patients
in the usual-care group had a statin or other lipid-lowering drug
added, effectively making them part of the pravastatin group.7
This “crossover” of therapy was made easier because
patients and physicians knew which patients were receiving pravastatin.8
At year 4, the differences between the pravastatin
and usual-care groups in percent lowering of TC (9.6% difference)
and LDL-C (16.7% difference) were less than those effected by statins
vs placebo in other clinical trials.7
Moreover, in ALLHAT-LLT, the reported decrease in LDL-C was calculated
in a random subset of patients, not in the total sample. It is also
important to note that ALLHAT-LLT enrolled too few patients—fewer
than planned—to be able to demonstrate statistically significantly
reduced mortality and CHD event rates based on a diminished difference
between the atorvastatin and usual-care groups.8
Significance for practice:
Despite evidence from other large trials that statins do benefit
those with lipid disorders, ALLHAT-LLT did not demonstrate a reduction
in all-cause mortality or CHD events with pravastatin compared with
usual care. This probably arose from faults in trial design and
execution, including the fact that private physicians were permitted
to make certain alterations in therapy as needed to improve results.
The outcome of ALLHAT-LLT should not discourage the use of statins
in patients with diabetes. Rather, the trial highlights the importance
of adherence to therapy for the reduction of risk in clinical practice.
ALLHAT-LLT, like ASCOT-LLA, had about 10,000
lipid subjects, and both studies were embedded within larger hypertension
trials. The important thing to note in these trial arms is the degree
of LDL-C lowering that was seen.
References*
| 1. |
MADA. http://www.diabetes.org/main/homepage.jsp.
Accessed July 29, 2003. |
| 2. |
ADA. Diabetes Care. 2003;26(suppl
1):S83-S86. |
| 3. |
Collins R et al. Lancet.
2003;361:2005-2016. |
| 4. |
Sever PS et al. Lancet.
2003;361:1149-1158. |
| 5. |
Letters to the Editor. Lancet.
2003;361:1985-1988. |
| 6. |
Gaede P et al. N Engl J Med.
2003;348:383-393. |
| 7. |
ALLHAT Collaborative Research
Group. JAMA. 2002;288:2998-3007. |
| 8. |
Pasternak RC. JAMA. 2003;288:3042-3044. |
*For
complete citations, please click here.
This article has been reviewed by NLEC Steering Committee
member Steven M. Haffner, MD, Professor of Medicine, University of
Texas Health Science Center, San Antonio, Texas.
This article was reviewed for medical accuracy by Antonio M. Gotto,
Jr, MD, DPhil, chairman of the National Lipid Education Council®.
Dr Gotto has indicated a financial interest or affiliation as noted:
consultant for AstraZeneca, Bayer Corporation, Bristol-Myers Squibb
Company, Merck & Co., Inc., Pfizer Inc, and Reliant Pharmaceuticals.
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