LDL Cholesterol Lowering in Type Diabetes: What Is the Optimum Approach?
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F e a t u r e a r t i c l e
LDL Cholesterol Lowering in Type 2 Diabetes:
What Is the Optimum Approach?
Richard W. Nesto, MD
C
urrent estimates indicate that 21 and with ST-segment elevation MI (8.5 The typical lipid disorder in patients
million U.S. adults—roughly vs. 5.4%; P < 0.001).8 with diabetes, diabetic dyslipidemia, is
10% of the adult popula- The U.K. Prospective Diabetes Study characterized by elevated triglycerides,
tion—have diabetes.1 Owing in part to (UKPDS) established the importance low levels of HDL cholesterol, and
the growing epidemic of obesity in the of tight glycemic control in patients increased numbers of small, dense LDL
United States, the prevalence of diabetes with diabetes.9 Yet in isolation, control particles.11,12
is expected to more than double to 48 of hyperglycemia is not sufficient to The implementation of treatment
million people by 2050.2,3 Nearly 30 decrease the high burden of cardiovas- goals for diabetes is challenging,
years ago, the Framingham Heart Study cular disease (CVD) in this population.10 however, and has been suboptimal
established that individuals with diabetes Efforts to reduce cardiovascular morbid- in most clinical settings.11 Data from
have a two to three times higher risk of ity and mortality in people with diabetes the 1999–2000 National Health and
cardiovascular events than nondiabetic have therefore focused on overall or Nutrition Examination Survey showed
people.4 More recent studies have deter- global risk factor management, includ- that only 37% of adults with diagnosed
mined that diabetes is a coronary heart diabetes achieved a hemoglobin A1c goal
ing weight loss and increased physical
disease (CHD) risk equivalent based on of < 7%, only 36% achieved a blood
activity, tight control of blood pressure
findings that risk for coronary events pressure goal of < 130/80 mmHg, and
and blood glucose, and intensive
in diabetic patients without previous just 48% achieved a total cholesterol
management of diabetic dyslipidemia.
goal of < 200 mg/dl.13 Moreover, only
CHD is equivalent to that of nondiabetic
a very small minority (< 10%) of
people with a history of CHD.5,6 Heart In Brief
people with diabetes achieved all three
disease mortality, however, is two to four
treatment goals.13 Achievement rates of
times higher in patients with diabetes Managing the high risk for cardio-
LDL cholesterol goals are particularly
compared with those without diabetes.1 vascular morbidity and mortality in
poor among high-risk individuals with
The risk of death is particularly high in diabetic patients is a challenge for
diabetes.14,15 For example, in one recent
the early period after a CHD event. In practicing clinicians. Reducing the
survey, 40% of patients with both
the FINMONICA myocardial infarction burden of cardiovascular disease in
diabetes and CHD had LDL cholesterol
(MI) register study, 28-day mortality diabetes should begin with assess-
levels greater than the goal of < 100
after hospitalization for a first MI was ment and treatment of elevated LDL
cholesterol. Statins are the preferred mg/dl recommended by the third
nearly twofold higher in men with National Cholesterol Education Program
diabetes and almost threefold higher in treatment, and intensive statin
therapy may be necessary to meet Adult Treatment Panel (NCEP ATP III)
women with diabetes compared with guidelines, and nearly 80% had levels
their nondiabetic counterparts.7 In a the current goal of < 100 mg/dl
or the optional goal of < 70 mg/dl above the optional goal of < 70 mg/dl.15
recent analysis of pooled data from Although the difficulty of achiev-
recommended for high-risk patients
11 trials of 62,036 patients with acute ing aggressive LDL cholesterol
and to address other components
coronary syndromes conducted by the goals in diabetic patients—many of
of diabetic dyslipidemia. Along
Thrombolysis in Myocardial Infarction whom are receiving multiple drug
with aggressive glucose and blood
Study Group, mortality at 30 days was pressure control, intensive treatment therapies and have concomitant medical
significantly higher among diabetic of LDL cholesterol in patients with problems—has often been cited as one
than nondiabetic patients presenting diabetes can substantially affect factor contributing to poor control rates,
with unstable angina/non–ST-segment long-term health outcomes. a review of medical records of nearly
elevation MI (2.1 vs. 1.1%; P < 0.001) 48,000 CHD patients both with and
Volume 26, Number 1, 2008• Clinical DiabetesF e a t u r e A r t i c l e
without diabetes has shown that lipid dense particles characterize the LDL Beyond the importance of even
management in general needs to be fraction in diabetic individuals. These modest elevations in LDL cholesterol
improved in patients with diagnosed dia- particles contain less cholesterol than in people with diabetes, it also appears
betes. Despite overall increases in rates normal-sized LDL particles, but they are that LDL cholesterol interacts with risk
of lipid testing and treatment, patients exceptionally atherogenic.10,18,19 Thus, factors of the metabolic syndrome to
with CHD and diabetes are still 26% levels of LDL may appear deceptively magnify the risk of CVD.10,12,20,21 The
less likely to have had a lipid profile and “normal” in cholesterol measurements. strong association between increased
17% less likely to receive lipid-lowering Small, dense LDL particles are small, dense LDL particles and elevated
medication than are patients with CHD considered more atherogenic than the triglycerides, for example, appears to be
but without diabetes.16 larger, buoyant LDL particles because linked to the altered insulin sensitivity
As these data suggest, there are they are more readily oxidized and common in the metabolic syndrome and
a number of ongoing opportunities glycated, which make them more likely type 2 diabetes.18,20 Insulin resistance in
to improve overall diabetes care. In to invade the arterial wall.10,19 This skeletal muscle promotes the conversion
particular, achievement of the intensive can initiate atherosclerosis or lead to of energy from ingested carbohydrate
LDL cholesterol goals recommended increased migration and apoptosis into increased hepatic triglyceride
by both the NCEP and the American of vascular smooth muscle cells in synthesis, which in turn generates large
Diabetes Association (ADA) has the existing atherosclerotic lesions.10,19 As a numbers of atherogenic triglyceride-rich
potential to substantially improve consequence, elevated or “normal” LDL lipoprotein particles, such as very-low-
long-term cardiovascular outcomes.12,17 cholesterol may be more pathogenic in density lipoprotein (VLDL).20,22 As a
To this end, this review addresses three people with diabetes. further consequence, through the action
key issues related to lowering the risks
associated with diabetic dyslipidemia:
1) the substantial CHD risk associated
with relatively normal LDL cholesterol;
2) the value of lowering LDL cholesterol
and normalizing atherogenic LDL
particles in reducing cardiovascular risk;
and 3) the role of intensive statin therapy
in achieving aggressive LDL cholesterol
goals.
What Is Average LDL Cholesterol in
Diabetes, and Why Is It a Concern?
Patients with diabetes frequently have
lipid profiles that appear more benign
than those of other high-risk people
without diabetes. In general, LDL
cholesterol levels in people with diabetes
are not higher than those in people
without diabetes who are matched for
age, sex, and body weight.12 In fact,
the most common LDL cholesterol
level in diabetes is “borderline high”
(130–159 mg/dl).12 Moreover, high LDL
cholesterol levels (≥ 160 mg/dl) do not
occur at higher-than-average rates in
people with diabetes. Nonetheless, LDL Figure 1. Plasma lipid exchange. In the presence of increased concentrations of
VLDL in the circulation, cholesteryl ester transfer protein (CETP) will exchange
cholesterol does not play less of a role in
VLDL triglyceride (TG) for cholesteryl ester (CE) in the core of LDL and HDL
cardiovascular risk in people with type 2 particles. This triglyceride can then be converted to free fatty acids by the actions of
diabetes. In fact, LDL cholesterol levels plasma lipases, primarily hepatic lipase. The net effect is a decrease in size and an
may underestimate cardiovascular risk increase in density of both LDL and HDL particles. Copyright 2001. The Endocrine
in diabetes.17 A large number of small, Society. Reprinted with permission from Ref. 19.
Clinical Diabetes • Volume 26, Number 1, 2008 F e a t u r e A r t i c l e
of cholesteryl ester transfer protein, a with a 36% reduction in CHD risk.9 had a significant 27% (P = 0.0007)
significant amount of the triglyceride Current guidelines for patients with reduction in risk of first major vascular
content of VLDL is exchanged for cho- diabetes recommend statins as first-line events.25 Overall, the Cholesterol Treat-
lesterol in LDL particles, leading to the lipid-lowering therapy.11,12,24 ment Trialists’ meta-analysis of > 90,000
formation of triglyceride-enriched (and In patients with type 2 diabetes, patients in randomized statin trials found
cholesterol-depleted) LDL (Figure 1).19 statin therapy has been shown to signifi- that in people with a history of diabetes
These LDL particles are now primed cantly reduce LDL cholesterol, reduce (including those without a previous
to become smaller and denser through elevated triglycerides, and modestly history of vascular disease), statins
the actions of hepatic lipase-mediated increase HDL cholesterol.25–29 In large, reduced the 5-year incidence of major
triglyceride hydrolysis.19,20 Thus, randomized, controlled trials of statins coronary events by ~ 25% for each
adverse changes in LDL particles occur in patients with type 2 diabetes, such as 39 mg/dl reduction in LDL cholesterol
as triglyceride levels increase. Once the Collaborative Atorvastatin Diabetes (P < 0.0001).30
triglyceride levels exceed 100 mg/dl, Study (CARDS) (n = 2,838), statin
small, dense LDL particles predominate therapy was associated with significant Is Intensive LDL Cholesterol
(Figure 2).23 reductions in LDL cholesterol of 40% Reduction With Statins Effective in
and triglycerides of 19% and increases Diabetes?
Is the Therapeutic Focus on LDL in HDL cholesterol of 1% relative to In treating people with diabetes, clini-
Cholesterol Justified? placebo (all, P < 0.001).26 cians should carefully adhere to current
LDL cholesterol is the primary target In general, the therapeutic focus on treatment guidelines, which recommend
of lipid-lowering therapy in guidelines LDL cholesterol lowering with statins is reduction of LDL cholesterol to < 100
from both the ADA and the NCEP ATP justified by clinical outcome results of mg/dl regardless of baseline lipid lev-
III.11,12 Once LDL cholesterol levels randomized, controlled trials. Consistent, els.12,17 Recent studies suggest that LDL
reach borderline-high levels (130–159 significant reductions in the incidence lowering to < 70 mg/dl may provide even
mg/dl), guidelines indicate that LDL- of major vascular events were observed greater cardiovascular benefits, and the
lowering therapy is a vital component in the diabetic population enrolled in latest guidelines recommend < 70 mg/dl
of treatment to reduce cardiovascular CARDS (37%, P = 0.001) and in the as an optional LDL goal in very–high-
risk, and it is particularly important if diabetic subgroup (n = 5,963) of the risk patients, such as those with diabetes
other risk factors are present.11,12,24 As Heart Protection Study (HPS) (22%, and existing CVD.11,31 Intensive lowering
shown by the UKPDS investigators, a P < 0.0001).25,26 In the HPS, diabetic of LDL cholesterol may be necessary to
39 mg/dl decrease in LDL cholesterol patients with a pretreatment LDL choles- achieve the 30–50% reductions in LDL
in subjects with diabetes was associated terol level of < 116 mg/dl (n = 2,426) cholesterol that guidelines recommend
to bring most high-risk patients to goal.31
When baseline LDL cholesterol is high
(e.g., ≥ 160 mg/dl), a reduction of > 50%
may be needed.31
Studies have confirmed that aggres-
sive LDL reductions in patients with
diabetes contribute to the achievement
of LDL cholesterol goals. Significant
reductions in other highly atherogenic
lipids and lipoproteins, such as
apolipoprotein B, non-HDL cholesterol,
and triglyceride-rich lipoproteins,
are also possible with intensive statin
therapy.28,29,32–34 Non-HDL cholesterol,
which is composed of LDL cholesterol
and VLDL cholesterol, is also a viable
treatment target in patients with type 2
diabetes and “normal” LDL cholesterol
levels. The NCEP ATP III guidelines
Figure 2. Cumulative distribution of adjusted triglyceride levels showing prevalence
consider non-HDL cholesterol a
of LDL phenotype A (large, buoyant LDL particles) and phenotype B (small, dense
LDL particles). Reprinted with permission from Ref. 23. secondary treatment target (after LDL
10 Volume 26, Number 1, 2008 • Clinical DiabetesF e a t u r e A r t i c l e
cholesterol) in patients with elevated intermediate-density lipoprotein by levels ≤ 60 mg/dl (17–25% of whom had
triglyceride levels (≥ 200 mg/dl), which 53–57%; P ≤ 0.001 vs. placebo).34 diabetes) had significantly fewer major
includes many diabetic people, because cardiac events than did patients whose
it is a better measure of atherogenic Is Intensive Statin Therapy Safe? achieved LDL levels were between 80
cholesterol than LDL cholesterol alone.12 Despite the benefits of intensive statin and 100 mg/dl (Figure 3).42
The goal level for non-HDL cholesterol therapy, clinicians may hesitate to fully In general, experts believe that
is 30 mg/dl higher than that for LDL implement this treatment strategy in muscle injury from statin therapy is
cholesterol,12 or < 130 mg/dl in diabetic patients with diabetes owing to safety related to the plasma concentration of
patients. concerns. Overall, standard doses of the statin (which is influenced by the
In the Diabetes Atorvastatin statins are well tolerated, and cases of drug’s pharmacokinetics and potential
Lipid Intervention study, intensive muscle-related toxicity and elevated for drug-drug interactions), statin dose,
therapy with 80 mg atorvastatin liver enzymes are low, particularly when and the patient’s risk factors.41 When
was significantly (P < 0.001) more standard doses are used in appropriately administered at recommended doses, the
effective in lowering LDL cholesterol selected patients.35–39 In large, random- more efficacious statins (atorvastatin,
(–52%) and apolipoprotein B (–40%) ized clinical trials with a large diabetic rosuvastatin) have a risk of rhabdomy-
than atorvastatin 10 mg (41 and population, rates of these adverse events olysis similar to that observed with less
31%, respectively).32 In the Use of were no different than the rates observed potent agents.30,35,39
Rosuvastatin Versus Atorvastatin in Type with placebo.26,40 Importantly, neither
2 Diabetes Mellitus study, 10–40 mg absolute LDL cholesterol level nor Conclusions
rosuvastatin significantly reduced lipid percentage decrease in LDL cholesterol Diabetes carries an exceptionally high
and lipoprotein fractions compared with appears to be linked to the risk of burden of disease, including a higher
10–80 mg atorvastatin during 16 weeks, myopathy or rhabdomyolysis in statin- mortality from CVD. Primary cardiovas-
including LDL cholesterol (52 vs. 46%), treated patients.41 Data from the large cular prevention is particularly important
non-HDL cholesterol (45 vs. 40%), and Pravastatin or Atorvastatin Evaluation in this population because diabetic
apolipoprotein (apo) B (45 vs. 40%) and Infection Therapy–Thrombolysis individuals suffering a first MI are
(all, P < 0.0001).28 Both rosuvastatin in Myocardial Infarction 22 trial, much more likely to die than are their
(10–40 mg) and atorvastatin (20–80 mg) for example, showed no relationship nondiabetic counterparts. Adherence to
significantly reduced LDL cholesterol between achieved LDL cholesterol levels lipid guidelines is crucial to improving
(54 and 48%, respectively), non-HDL from 100 mg/dl to as low as < 40 mg/dl clinical outcomes in diabetic patients. A
cholesterol (50 and 44%, respectively), and the frequency of adverse events.42 number of roadblocks to the successful
and the apoB/apoA1 ratio (41 and 36%, Moreover, patients with LDL cholesterol implementation of lipid guidelines have
respectively) (all, P < 0.001 vs. placebo)
in the 18-week Compare Rosuvastatin
with Atorvastatin on ApoB/ApoA1 Ratio
in Patients with Type 2 Diabetes Mellitus
and Dyslipidemia study.29 In studies of
intensive statin therapy, the aggressive
lipid treatment effects were also associ-
ated with significantly larger proportions
(> 90%) of patients achieving LDL
cholesterol goals.28,29,33
Data from the In the Simvastatin
in Low HDL Cholesterol Diabetes
Treatment Trial of Efficacy substudy
(n = 151) showed that intensive statin
therapy can also improve LDL particle
composition in type 2 diabetes; 40 and
80 mg simvastatin lowered all four LDL Figure 3. Hazard ratios for the primary end point by subgroup of achieved LDL
subclasses by 19–48% (P ≤ 0.001 vs. cholesterol (adjusted for age, sex, baseline calculated LDL cholesterol, diabetes,
placebo) and can reduce the presence of and prior MI) in the Pravastatin or Atorvastatin Evaluation and Infection Therapy–
atherogenic triglyceride-rich lipoproteins Thrombolysis in Myocardial Infarction 22 trial. Reprinted from Ref. 42 with permis-
(lowering VLDL by 32–40% and sion from Elsevier.
Clinical Diabetes • Volume 26, Number 1, 2008 11F e a t u r e A r t i c l e
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