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 Diabetes
F 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

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F 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                                                                                        11
F e a t u r e                   A r t i c l e

been identified. Among the most com-                     tality after the first myocardial infarction. Diabetes   LDL-cholesterol associated increases in carotid
                                                         Care 21:69–75, 1998                                      atherosclerosis. Intern Med 44:1232–1238, 2005
mon are failure to recognize that 1) the                     8                                                         22
                                                              Donahoe SM, Stewart GC, McCabe CH, Mo-                     Petersen KF, Dufour S, Savage DB, Bilz S,
borderline LDL cholesterol elevations                    hanavelu S, Murphy SA, Cannon CP, Antman AM:             Solomon G, Yonemitsu S, Cline GW, Befroy D,
common in diabetic patients are associ-                  Diabetes and mortality following acute coronary          Zemany L, Kahn BB, Papademetris X, Rothman
                                                         syndromes. JAMA 298:765–775, 2007                        DL, Shulman GI: The role of skeletal muscle insu-
ated with substantial cardiovascular risk                                                                         lin resistance in the pathogenesis of the metabolic
                                                              9
                                                               Turner RC, Millns H, Neil HAW, Stratton IM,
because of their small, dense composi-                   Manley SE, Matthews DR, Holman RR, for the
                                                                                                                  syndrome. Proc Natl Acad Sci U S A 104:12587–
                                                                                                                  12594, 2007
tion and the high CHD risk already                       U.K. Prospective Diabetes Study Group: Risk fac-
                                                                                                                       23
                                                         tors for coronary artery disease in non-insulin de-             Austin MA, King M-C, Vranizan KM,
present in this population; 2) seemingly                 pendent diabetes mellitus (UKPDS: 23). BMJ               Krauss RM: Atherogenic lipoprotein phenotype: a
mild abnormalities in LDL cholesterol                    316:823–828, 1998                                        proposed genetic marker for coronary heart disease
                                                                                                                  risk. Circulation 82:495–506, 1990
interact with other lipid abnormalities                       10
                                                                Krentz AJ: Lipoprotein abnormalities and               24
                                                         their consequences for patients with type 2 diabe-              Snow V, Aronson MD, Hornbake ER, Mot-
to further heighten risk; and 3) intensive                                                                        tur-Pilson C, Weiss KB, for the Clinical Efficacy
                                                         tes. Diabetes Obes Metab 5 (Suppl. 1):S19–S27,
LDL cholesterol reduction in this setting                2003                                                     Assessment Subcommittee of the American Col-
                                                                                                                  lege of Physicians: Lipid control in the manage-
results in significant reductions in                         11
                                                               American Diabetes Association: Standards of        ment of type 2 diabetes mellitus: a clinical practice
cardiovascular morbidity and mortality.                  medical care in diabetes: 2007. Diabetes Care 30         guideline from the American College of Physi-
                                                         (Suppl. 1):S4–S41, 2007                                  cians. Ann Intern Med 140:644–649, 2004
Indeed, the opportunity to substantially                      12
                                                                The Expert Panel: Third Report of the Na-              25
                                                                                                                         Heart Protection Study Collaborative Group:
improve cardiovascular outcomes by                       tional Cholesterol Education Program (NCEP) Ex-          MRC/BHF Heart Protection Study of cholesterol-
assessing and treating the atherogenic                   pert Panel on Detection, Evaluation, and Treat-          lowering with simvastatin in 5963 people with dia-
                                                         ment of High Blood Cholesterol in Adults (Adult          betes: a randomised placebo-controlled trial. Lan-
diabetic dyslipidemia characteristic of                  Treatment Panel III): final report. Circulation          cet 361:2005–2016, 2003
this population should not be missed.                    106:3143–3421, 2002                                           26
                                                                                                                         Colhoun HM, Betteridge DJ, Durrington PN,
                                                             13
                                                                Saydah SH, Fradkin J, Cowie CC: Poor con-         Hitman GA, Neil HAW, Livingstone SJ, Thoma-
       Acknowledgments                                   trol of risk factors for vascular disease among          son MJ, Mackness MI, Charlton-Menys V, Full-
                                                         adults with previously diagnosed diabetes. JAMA          er JH, on behalf of the CARDS Investigators: Pri-
The author wishes to thank Nancy                         291:335–342, 2004                                        mary prevention of cardiovascular disease with
Hudson of Landmark Programs for                               14
                                                                                                                  atorvastatin in type 2 diabetes in the Collabora-
                                                                Zafrir B, Cohen S: Primary prevention in          tive Atorvastatin Diabetes Study (CARDS): multi-
editorial assistance, supported by                       high-risk dyslipidemic patients without an estab-        centre randomised placebo-controlled trial. Lancet
                                                         lished cardiovascular disease: undertreatment and        364:685–696, 2004
AstraZeneca.                                             rationale for lipid-lowering therapy. Eur J Intern            27
                                                         Med 17:495–499, 2006                                            Knopp RH, D’Emden M, Smilde JG, Pocock
               References                                     15
                                                                                                                  SJ, on behalf of the ASPEN Study Group: Efficacy
                                                                Davidson MH, Maki KC, Pearson TA, Pas-            and safety of atorvastatin in the prevention of car-
     1
     Centers for Disease Control and Prevention:         ternak RC, Deedwania PC, McKenney JM, Fonar-             diovascular end points in subjects with type 2 di-
National diabetes fact sheet [article online]. Avail-    ow GC, Maron DJ, Ansell BJ, Clark LT, Ballantyne         abetes: the Atorvastatin Study for Prevention of
able from http://www.cdc.gov/diabetes/pubs/pdf/          CM: Results of the National Cholesterol Educa-           Coronary Heart Disease Endpoints in Non-Insulin-
ndfs_2005                                                tion Program (NCEP) Evaluation Project Utilizing         Dependent Diabetes Mellitus (ASPEN). Diabetes
    2
                                                         Novel E-Technology (NEPTUNE) II survey and               Care 29:1478–1485, 2006
     Mokdad AH, Bowman BA, Ford ES, Vinicor              implications for treatment under the recent NCEP              28
F, Marks JS, Koplan JP: The continuing epidemics         Writing Group recommendations. Am J Cardiol                     Berne C, Siewert-Delle A, the URANUS
of obesity and diabetes in the United States. JAMA       96:556–563, 2005                                         Study Investigators: Comparison of rosuvas-
286:1195–1200, 2001                                                                                               tatin and atorvastatin for lipid lowering in patients
                                                             16
     3
                                                               Massing MW, Foley KA, Sueta CA, Chowd-             with type 2 diabetes mellitus: results from the
     Beller GA: Noninvasive screening for coro-          hury M, Biggs DP, Alexander CM, Simpson RJ Jr:           URANUS study [article online]. Cardiovasc
nary atherosclerosis and silent ischemia in asymp-       Trends in lipid management among patients with           Diabetol 4:7, 2005. Available from http://www.car-
tomatic type 2 diabetic patients: is it appropriate      coronary artery disease. Diabetes Care 26:991–           diab.com/content/4/1/7
and cost-effective? J Am Coll Cardiol 49:1918–           997, 2003                                                    29
1923, 2007                                                                                                              Wolffenbuttel BHR, Franken AAM, Vin-
     4
                                                             17
                                                               Buse JB, Ginsberg HN, Bakris GL, Clark             cent HH, on behalf of the Dutch CORALL Study
     Kannel WB, McGee DL: Diabetes and cardio-           NG, Costa F, Eckel R, Fonseca V, Gerstein HC,            Group: Cholesterol-lowering effects of rosuvastatin
vascular risk factors: the Framingham Study. Cir-        Grundy S, Nesto RW, Pignone MP, Plutzky J, Porte         compared with atorvastatin in patients with type 2
culation 59:8–13, 1979                                   D, Redberg R, Stitzel KF, Stone NJ: Primary pre-         diabetes: CORALL study. J Intern Med 257:531–
    5
     Haffner SM, Lehto S, Rönnemaa T, Pyörälä            vention of cardiovascular diseases in people with        539, 2005
K, Laakso M: Mortality from coronary heart dis-          diabetes mellitus. Diabetes Care 30:162–172, 2007             30
                                                                                                                         Cholesterol Treatment Trialists’ Collabo-
ease in subjects with type 2 diabetes and in nondi-          18
                                                              Marcovina S, Packard CJ: Measurement and            rators: Efficacy and safety of cholesterol-lower-
abetic subjects with and without prior myocardial        meaning of apolipoprotein AI and apolipoprotein B        ing treatment: prospective meta-analysis of data
infarction. N Engl J Med 339:229–234, 1998               plasma levels. J Intern Med 259:437–446, 2006            from 90 056 participants in 14 randomised trials of
     6
      Malmberg K, Yusuf S, Gerstein HC, Brown J,             19
                                                                                                                  statins. Lancet 366:1267–1278, 2005
                                                               Goldberg IJ: Diabetic dyslipidemia: causes
Zhao F, Hunt D, Piegas L, Calvin J, Keltai M, Bu-        and consequences. J Clin Endocrinol Metab
                                                                                                                       31
                                                                                                                         Grundy SM, Cleeman JI, Bairey Merz CN,
daj A, for the OASIS Registry Investigators: Im-         86:965–971, 2001                                         Brewer HB Jr, Clark LT, Hunninghake DB, Paster-
pact of diabetes on long-term prognosis in patients                                                               nak RC, Smith SC, Stone NJ, for the Coordinat-
                                                             20
with unstable angina and non-Q-wave myocardi-                  Kathiresan S, Otvos JD, Sullivan LM, Keyes         ing Committee of the National Cholesterol Educa-
al infarction: results of the OASIS (Organization to     MJ, Schaefer EJ, Wilson PWF, D’Agostino RB, Va-          tion Program: Implications of recent clinical trials
Assess Strategies for Ischemic Syndromes) Regis-         san RS, Robins SJ: Increased small low-density li-       for the National Cholesterol Education Program
try. Circulation 102:1014–1019, 2000                     poprotein particle number: a prominent feature of        Adult Treatment Panel III guidelines. Circulation
      7                                                  the metabolic syndrome in the Framingham Heart           110:227–239, 2004
       Miettinen H, Lehto S, Salomaa V, Mahonen          Study. Circulation 113:20–29, 2006                            32
M, Niemela M, Haffner SM, Pyörälä K, Tuomileh-                                                                           The Diabetes Atorvastatin Lipid Interven-
                                                             21
to J, for the FINMONICA Myocardial Infarction                Kawamoto R, Tomita H, Oka Y, Kodama A,               tion (DALI) Study Group: The effect of aggres-
Register Study Group: Impact of diabetes on mor-         Kamitani A: Metabolic syndrome amplifies the             sive versus standard lipid lowering by atorvastatin

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on diabetic dyslipidemia: the DALI Study: a dou-         lipid lowering with atorvastatin in patients with           McKenney JM, Davidson MH, Jacobson
ble-blind, randomized, placebo-controlled trial in       stable coronary disease. N Engl J Med 352:1425–       TA, Guyton JR: Final conclusions and recommen-
patients with type 2 diabetes and diabetic dyslipid-     1435, 2005                                            dations of the National Lipid Association Statin
emia. Diabetes Care 24:1335–1341, 2001                        38                                               Safety Assessment Task Force. Am J Cardiol 97
                                                                 Pedersen TR, Faergeman O, Kastelein JJP,      (Suppl.):89C–94C, 2006
    33
       Betteridge DJ, Gibson JM, on behalf of the        Olsson AG, Tikkanen MJ, Holme I, Larsen ML,
                                                                                                                    42
ANDROMEDA Study Investigators: Effects of ro-            Bendiksen FS, Lindahl C, Szarek M, Tsai J, for the           Wiviott SD, Cannon CP, Morrow DA, Ray
suvastatin on lipids, lipoproteins and apolipopro-       Incremental Decrease in End Points Through Ag-        KK, Pfeffer MA, Braunwald E, for the PROVE IT-
teins in the dyslipidaemia of diabetes. Diabet Med       gressive Lipid Lowering (IDEAL) Study Group:          TIMI 22 Investigators: Can low-density lipopro-
24:541–549, 2007                                         High-dose atorvastatin vs usual-dose simvastatin      tein be too low? The safety and efficacy of achiev-
     34                                                  for secondary prevention after myocardial infarc-     ing very low low-density lipoprotein with intensive
       Miller M, Dobs A, Yuan Z, Battisti WP,            tion: the IDEAL study: a randomized controlled        statin therapy: a PROVE IT-TIMI 22 substudy.
Palmisano J: The effect of simvastatin on triglycer-     trial. JAMA 294:2437–2445, 2005                       J Am Coll Cardiol 46:1411–1416, 2005
ide-rich lipoproteins in patients with type 2 diabet-
                                                             39
ic dyslipidemia: a SILHOUETTE trial sub-study.                 Cannon CP, Braunwald E, McCabe CH,
Curr Med Res Opin 22:343–350, 2006                       Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill
    35
      Davidson MH: Rosuvastatin safety: lessons
                                                         KA, Pfeffer MA, Skene AM, for the Pravastatin         Richard W. Nesto, MD, is an associate
                                                         or Atorvastatin Evaluation and Infection Thera-
from the FDA review and post-approval surveil-           py–Thrombolysis in Myocardial Infarction 22 In-       professor of medicine at Harvard Medi-
lance. Expert Opin Drug Saf 3:547–557, 2004              vestigators: Intensive versus moderate lipid lower-   cal School and chairman of the Depart-
     36
       de Lemos JA, Blazing MA, Wiviott SD, Lew-         ing with statins after acute coronary syndromes. N
is EF, Fox KAA, White HD, Rouleau J-L, Peder-            Engl J Med 350:1495–1504, 2004                        ment of Cardiovascular Medicine, Lahey
sen TR, Gardner LH, Mukherjee R, Ramsey KE,                   40
                                                                Sever PS, Dahlöf B, Poulter NR, Wedel H,       Clinic, in Burlington, Mass.
Palmisano J, Bilheimer DW, Pfeffer MA, Cal-              Beevers G, Caulfield M, Collins R, Kjeldsen SE,
iff RM, Braunwald E, for the A to Z Investiga-           Kristinsson A, McInnes GT, Mehlsen J, Nieminen
tors: Early intensive vs a delayed conservative sim-     M, O’Brien E, Östergren J, for the ASCOT Inves-
vastatin strategy in patients with acute coronary                                                              Note of disclosure: Dr. Nesto has
                                                         tigators: Prevention of coronary and stroke events
syndromes: phase Z of the A to Z Trial. JAMA             with atorvastatin in hypertensive patients who have   served on a speaker’s bureau for Pfizer,
292:1307–1316, 2004                                      average or lower-than-average cholesterol con-        Inc., which manufactures pharma-
    37
      LaRosa JC, Grundy SM, Waters DD, Shear             centrations, in the Anglo-Scandinavian Cardiac
C, Barter P, Fruchart J-C, Gotto AM, Greten H,           Outcomes Trial—Lipid Lowering Arm (ASCOT-             ceutical products for the treatment of
Kastelein JJP, Shepherd J, Wenger NK, for the            LLA): a multicentre randomised controlled trial.      dyslipidemia.
Treating to New Targets Investigators: Intensive         Lancet 361:1149–1158, 2003

Clinical Diabetes • Volume 26, Number 1, 2008                                                                                                                  13
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