Update in Endocrinology

1
Update in Endocrinology

• ? ? ? ? ?
• ???????????
• 95-05-05
• Annals of internal Medicine 1 Nov. 2005
• Vol. 143 Issue 9 P. 673-682

2
Outline

• DM
• Thyroid Disease
• Lipid-Lowering Therapy
• Adrenal Function

3
Myocardial Perfusion Imaging Should Be Considered
To Detect Silent CAD in Diabetic p'ts (DM Care.
2004271954-61.)

• ADA guidelines recommend routine exercise ECG
  stress testing to detect silent CAD in diabetic
  p'ts when 2 or more additional risk factors are
  present. The Detection of Ischemia in
  Asymptomatic Diabetics (DIAD) study tested the
  effectiveness of these guidelines.
• P'ts with type 2 DM ranging in age from 50 to 75
  years (n 1123) with no known CAD were randomly
  assigned to 2 groups One group (n 522)
  underwent standard exercise ECG stress testing
  followed by ECG-gated regional myocardial
  perfusion imaging by single-photon emission
  computed tomography (SPECT) at rest and after
  exercise, whereas the second group (n 522) did
  not undergo testing. Both groups were reevaluated
  5 years later.

4

• The results indicated that 22 of the p'ts who
  underwent testing (n 113) were found to have
  evidence of silent coronary disease on the basis
  of moderate to large perfusion defects (n 33),
  ventricular dilatation, ventricular dysfunction
  at rest, or adenosine-induced ST-segment
  depression.
• The strongest predictors for coronary disease
  were male sex (odds ratio, 2.5 P lt 0.03),
  duration of DM (odds ratio, 5.2 P lt 0.002), and
  abnormal response to the Valsalva maneuver (odds
  ratio, 5.6 P lt 0.001). The researchers reported
  that 60 of the p't sample (n 306) had 2 or
  more risk factors, which made them eligible for
  screening by ADA guidelines, whereas 204 p'ts had
  fewer than 2 risk factors. Of these 204 p'ts, 45
  had abnormal test results.
• Thus, CAD would not have been detected in these
  p'ts if their physicians used only the ADA
  guidelines to screen for eligibility for testing.

DM Care. 2004271954-61.
5

• The authors concluded that, on the basis of
  results of perfusion imaging, more than 20 of
  asymptomatic p'ts with type 2 DM have CAD
  therefore, the current ADA screening guidelines
  do not sufficiently address this substantial
  risk.
• The findings indicate that stress myocardial
  perfusion imaging should be considered even in
  asymptomatic p'ts on the premise that earlier
  detection of myocardial ischemia in p'ts with
  type 2 DM could reduce morbidity and mortality.

DM Care. 2004271954-61.
6
Insulin Lispro Was Safe and More Cost-Effective
than Standard intensive Care for Management of
DKA (Am J Med. 2004117291-6. )

• The aim of this study was to determine whether
  DKA requires Tx in an ICU. The specific question
  was whether Tx of DKA by SC lispro insulin on a
  medical ward is as safe and effective as low-dose
  IV insulin therapy in the ICU.
• The study was a randomized, controlled trial of
  therapy for 20 p'ts with DKA. Ten p'ts were
  assigned to a regular medical ward and treated
  with SC lispro insulin (0.3 U/kg of BW initially,
  followed by 0.1 U/kg /hr until plasma glucose
  levels decreased to 250 mg/dL or less 14
  mmol/L, followed by 0.05 to 0.1 U/kg /hr until
  plasma pH levels increased to 7.3).
• The 10 p'ts randomly assigned to care in an ICU
  received RI IV. (0.1 U/kg initially, followed by
  infusions of 0.1 U/kg /hr until plasma glucose
  levels decreased to 250 mg/dL or less 14
  mmol/L, then 0.05 to 0.1 U/kg /hr until plasma
  pH increased to at least 7.3 and serum
  bicarbonate levels increased to 18 mmol/L or
  higher).

7

• The time required to correct the hyperglycemia
  and acidosis was the same in the 2 regimens 7
  hours (SD, 3) for the p'ts receiving lispro
  insulin compared with 7 hours (SD, 2) for those
  receiving RI (P 0.29). The length of stay,
  incidence of hypoglycemia, and amount of
  administered insulin were also similar. The ICU
  regimen was associated with 39 higher
  hospitalization charges (14429 compared with
  8801).
• The researchers concluded that Tx of DKA on a
  routine medical ward with hourly administration
  of SC lispro insulin is just as safe as standard
  ICU management and is more cost-effective.
• Their findings suggest that such strategies could
  prevent unnecessary use of high-cost ICU beds.
  Although standard ward management was equally
  effective in this study, it may not be feasible
  in most general hospitals given such practical
  considerations as nursing shortages.

Am J Med. 2004117291-6.
8
HbA1c Should Be Considered an independent and
Progressive Risk Factor for CV Disease (Ann
intern Med. 2004141413-20. )

• The aim of this study was to determine whether
  HbA1c levels are related to CVD and mortality
  and, consequently, whether glycosylated
  hemoglobin levels may serve as a predictor for CV
  events. The authors used an ongoing prospective
  community-based study of 25623 men and women in
  Norfolk, United Kingdom, to analyze this
  relationship in 4662 men and 5570 women.
• HbA1c levels averaged 8.0 in the participants
  with DM compared with 5.3 in those without DM.
  An increase in HbA1c levels of 1 percentage point
  (for example, from 7.0 to 8.0) was associated
  with a statistically significant increased risk
  for death from any cause (odds ratio, 1.26 95
  CI, 1.04 to 1.52). This risk relationship was
  present at all levels of HbA1c and was
  independent of all other known risk factors,
  including DM.
• Of importance, individuals with HbA1c levels in
  the range of 5.0 to 6.9 accounted for more than
  70 of the increased CV risk attributable to
  elevated HbA1c levels.

9

• The authors concluded that HbA1c is associated
  with a progressive and continuous increase in
  risk for both CV disease and mortality across the
  entire range of HbA1c values. The study is unique
  because of the large number of study participants
  (including many women) and indicates that the
  threshold level between "normal" and "abnormal"
  HbA1c levels should be revised downward.
• These data are important because they demonstrate
  that HbA1c level can be considered an independent
  and progressive risk factor for CV disease in
  diabetic p'ts.
• An increase in glycosylated HbA1c level of 1
  percentage point predicts a 20 to 30 average
  relative increase in frequency of CV events
  across the range of HbA1c levels in the study
  sample.
• The meta-analysis performed by Selvin and
  coworkers confirmed these findings.

Ann intern Med. 2004141413-20.
10
Liraglutide Effectively Improves Glycemic Control
and Islet Cell Function in Type 2 DM (DM.
2004531187-94. )

• This study reports results with a new and novel
  approach to DM management. Glucagon-like
  peptide-1 (GLP-1), an incretin mimetic, is a
  naturally occurring insulin secretagogue that is
  released by the intestine in response to
  ingestion of food. Research has shown that GLP-1
  agonists that bind to the GLP-1 receptors on ß
  cells improve glucose homeostasis by several
  mechanisms.
• Unique to the action of GLP-1 is its relationship
  to serum glucose levels It stops stimulating
  insulin secretion after glucose levels normalize,
  thereby avoiding hypoglycemia. The GLP-1 agonists
  also inhibit glucagon release, which reduces
  glycemia after meals. After a person ingests
  food, the inhibition of glucagon ceases when
  glucose levels normalize, which reduces the risk
  for hypoglycemia. The GLP-1 peptide is rapidly
  degraded, however, and its very short half-life
  has been a barrier to developing a therapeutic
  agent.
• The GLP-1 derivative liraglutide is longer acting
  because of noncovalent coupling to albumin. This
  study explored the effects of liraglutide on
  glycemia, free fatty acids, insulin secretion,
  and gluconeogenesis.

11

• This study was a double-blind, placebo-controlled
  crossover trial in 13 p'ts with type 2 DM treated
  with SC liraglutide (6 µg/kg of BW once daily).
• Liraglutide therapy significantly reduced 24-hour
  plasma glucose and glucagon levels without
  altering free fatty acids or 24-hour insulin
  secretion rates.
• This outcome occurs because liraglutide
  stimulates insulin release primarily during
  intervals of hyperglycemia and not during the
  entire 24 hours.
• Arginine is a potent insulin secretagogue
  independent of plasma glucose and will also
  increase serum glucagon levels. In this study,
  insulin secretion increased in response to
  arginine without increasing glucagon secretion.
  Reduced glycogenolysis resulted in decreased
  glucose release from the liver.

DM. 2004531187-94.
12

• These very exciting (albeit preliminary) findings
  indicate that the GLP-1 derivative liraglutide
  effectively improves glycemic control and islet
  cell function in type 2 DM. This peptide is
  arguably the most exciting therapeutic agent
  under consideration for the control of glycemia
  in type 2 diabetic p'ts. The reduced plasma
  glucagon levels may lead to greater insulin
  sensitivity, which would account for the observed
  reduction in blood glucose level in the presence
  of unchanged insulin levels.
• To confirm both the safety and efficacy of these
  agents, we must await large-scale clinical trials
  of longer duration that include a broad range of
  p'ts with type 2 DM.
• Similar results were obtained by Ahren and
  colleagues, who evaluated a new inhibitor of
  dipeptidyl peptidase-4, the enzyme that degrades
  GLP-1 and thereby increases blood levels of
  GLP-1. In this study, the drug reduced plasma
  glucagon, plasma glucose, and HbA1c levels.

DM. 2004531187-94.
13
Rosiglitazone Reduces in-Stent Restenosis in
Diabetic p'ts with CAD (DM Care. 2004272654-60.
)

• This study evaluated the effect of rosiglitazone
  on preventing in-stent restenosis in diabetic
  p'ts with CAD and coronary stents.
• The rationale for the study hypothesis is that
  rosiglitazone, a thiazolidinedione used for
  therapy for DM, also reduces lipid levels,
  systemic inflammation, and vascular intimamedia
  thickness.
• In this study, p'ts were randomly assigned to a
  control group (n 48) or a rosiglitazone therapy
  group (n 47) both groups underwent
  quantitative coronary angiography at study entry
  and at 6 months. The rate of restenosis was the
  primary end point.

14

• Rosiglitazone therapy reduced serum levels of
  insulin and CRP and the rate of stent restenosis
  (17.6 with rosiglitazone vs. 38.2 in the
  control group P 0.03).
• Rosiglitazone reduced serum CRP levels by 2.31
  mg/L (SD, 2.14) compared with a 0.52 mg/L
  reduction in the control group (P lt 0.05). Both
  groups received adjunctive therapy with statins,
  exercise, and diet, and both had similar mean
  levels of HbA1c and serum lipids.
• The authors concluded that rosiglitazone therapy
  reduces in-stent restenosis in diabetic p'ts with
  CAD. The mechanism of action is likely to be
  inhibition of the immunomodulators and cytokines
  associated with atherogenesis.
• The authors imply that rosiglitazone might
  represent a relatively safe and inexpensive
  alternative to brachytherapy or drug-eluting
  stents.

DM Care. 2004272654-60.
15
Telmisartan Is Comparable to Enalapril for
Protecting Renal Function (N Engl J Med.
20043511952-61. )

• This prospective study examined whether
  angiotensin-receptor blockers are as effective as
  ACE inhibitors in protecting renal function in
  p'ts with type 2 DM.
• The authors compared telmisartan, an
  angiotensin-receptor blocker that reduces
  progression to end-stage renal disease (ESRD) in
  diabetic p'ts with nephropathy, with traditional
  first-line therapy with the ACEI enalapril.

16

• This multicenter, double-blind study randomly
  assigned 250 diabetic p'ts to receive 80 mg of
  telmisartan per day (n 130) or 20 mg of
  enalapril per day (n 120) over 5 years. The
  p'ts had early nephropathy 82 had
  microalbuminuria, and 18 had macroalbuminuria.
  The primary end point was a change in GFR.
  Secondary end points were serum Cr and urine
  albumin levels, BP, rates of ESRD, CV events, and
  deaths.
• After 5 years of follow-up, GFRs had declined at
  the same rate with telmisartan (17.9 mL/min per
  1.73 m2) and enalapril (14.9 mL/min per 1.73 m2).
  The outcomes for secondary end points were also
  the same. Both groups experienced adverse
  effects, and 20 p'ts in the enalapril group had
  to discontinue the medication.
• The authors' conservative conclusion was that the
  renal protective effects of telmisartan are not
  inferior to those of enalapril. Only 1 short-term
  study had previously compared these 2 types of
  drugs.

17
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18
Risk for Fetal Loss Is increased in Subclinical
Hyperthyroidism (JAMA. 2004292691-5. )

• The aim of this study was to determine if high
  circulating levels of thyroid hormone have
  adverse effects on the fetus in pregnant women
  with the syndrome of resistance to thyroid
  hormone (RTH). In this syndrome, circulating
  levels of thyroid hormone are high, but serum TSH
  levels are normal (rather than suppressed, as
  would be expected).
• The authors asked whether the high serum thyroid
  hormone levels increased miscarriage rates in
  these pregnant p'ts even though they had normal
  serum TSH levels and were euthyroid. The
  analogous (and much more common) model for this
  situation is "subclinical hyperthyroidism" during
  pregnancy.

19

• The authors retrospectively compared miscarriage
  rates in 9 women with the syndrome (high serum
  free thyroxine and triiodothyronine levels with
  normal TSH concentrations) with rates in
  unaffected relatives. Affected women had a
  miscarriage rate of 22.9 compared with 4.4 (P lt
  0.002) in unaffected relatives. Furthermore, the
  pregnancies of affected women may result in a
  healthy, unaffected infant or an infant with the
  syndrome, depending on whether the abnormal gene
  is transmitted to the infant.
• In this study, healthy infants born to women with
  the syndrome had lower birthweights than those of
  affected infants. Also, the healthy infants had
  suppressed TSH levels, whereas the affected
  infants had detectable serum TSH levels.
• Thus, the high thyroid hormone levels were
  nonphysiologic (as indicated by the suppressed
  TSH levels) and deleterious to the outcome of the
  pregnancy.
• The authors concluded that the high thyroid
  hormone levels that are characteristic of the
  syndrome are toxic to the fetus and cause a high
  miscarriage rate. Presumably only fetuses
  unaffected by the RTH receptor mutation would be
  vulnerable.

JAMA. 2004292691-5.
20

• Although the syndrome of RTH is rare, it is
  probably a good model for the effects of a much
  more common problem, "subclinical
  hyperthyroidism.
• In the United States, subclinical hyperthyroidism
  is most commonly due to iatrogenic overdose with
  L-thyroxine.
• We know that mild deficiency of thyroid hormone
  (subclinical hypothyroidism) has an adverse
  effect on infant intelligence and is associated
  with increased rates of fetal loss.
• Elegantly employing the model of RTH in
  pregnancy, this study also demonstrates the
  potential for fetal loss in subclinical
  hyperthyroidism.
• Pregnant women may also be at risk if they have
  inadequately treated hyperthyroidism associated
  with Graves disease or nodular goiters.

JAMA. 2004292691-5.
21
Periodic Thyroid Screening Is indicated for Men
Receiving Therapy for Hepatitis C (Arch intern
Med. 20041642371-6. )

• Women who receive interferon and ribavirin for
  hepatitis C virus (HCV) infection are at
  increased risk for thyroid dysfunction. This
  study examined the frequency and outcomes of
  thyroid dysfunction caused by HCV therapy in men
  undergoing combination Tx with interferon- 2b and
  ribavirin. The study's purpose was to determine
  whether HCV Tx poses the same risk to men as it
  does to women.
• The protocol consisted of prospective screening
  of serum TSH levels every 12 weeks in 225
  HCV-infected men during therapy with interferon-
  2b (3 million U SC 3 times per week) and
  ribavirin (1 to 1.2 g orally once daily) for 24
  to 48 weeks. Overt hypothyroidism was defined as
  a serum TSH level greater than 5.5 mIU/L with low
  concentrations of serum thyroxine and
  triiodothyronine subclinical hypothyroidism was
  defined as a serum TSH level greater than 5.5
  mIU/L with normal levels of serum thyroxine and
  triiodothyronine.

22

• Overt or subclinical thyroid disease developed in
  6.7 and 4 of the participants, respectively.
• Antithyroid antibodies were detected in p'ts with
  overt hypothyroidism, and antibodies against the
  TSH receptor were detected in two thirds of p'ts
  with overt hyperthyroidism.
• After therapy with interferon- 2b and ribavirin
  was discontinued, 10 of 12 overtly hypothyroid
  p'ts, 2 of 3 overtly hyperthyroid p'ts, and all 9
  p'ts with subclinical thyroid disease became
  euthyroid.

Arch intern Med. 20041642371-6.
23

• The authors concluded that periodic screening for
  thyroid disease is indicated for men undergoing
  therapy for HCV infection. Thyroid dysfunction is
  readily managed once detected and treated.
  Abnormal thyroid function after interferon
  therapy has been a recognized entity for some
  time, and this study confirms that dysfunction
  also occurs with combined therapy with interferon
  and ribavirin.
• The risk is greatest in p'ts with a family
  history of autoimmune thyroid disease (either
  Hashimoto thyroiditis or Graves disease), and
  such individuals should be regularly screened for
  thyroid dysfunction both before and during
  therapy.

Arch intern Med. 20041642371-6.
24
Combination Therapy with Thyroxine and
Triiodothyronine Offers No Advantage over Tx with
Thyroxine Alone(Clin Endocrinol (Oxf).
200460750-7. )

• Some hypothyroid p'ts who take L-thyroxine have
  symptoms that they believe are caused by
  inadequate thyroid hormone replacement even
  though their serum TSH levels are normal.
• The aim of this study was to examine whether
  adding L-triiodothyronine to L-thyroxine therapy
  in a physiologically appropriate molar ratio
  (141) would be associated with an improved sense
  of well-being.
• For this double-blind study, 23 hypothyroid p'ts
  were randomly assigned to receive L-thyroxine
  alone (100 to 175 µg/d) or a combination
  L-thyroxinel-triiodothyronine regimen
  (l-triiodothyronine was substituted for 5 of the
  L-thyroxine dose) for 12-week Tx periods.
  Measurements included standardized psychological
  testing to examine cognitive performance and
  mood.

25

• All of the p'ts receiving combination therapy had
  suppressed serum TSH levels compared with only 2
  participants taking L-thyroxine alone. As has
  been reported very recently by other
  investigators, the p'ts receiving combination
  therapy otherwise experienced hormonal,
  metabolic, and CV responses that were similar to
  those of p'ts receiving L-thyroxine alone.
• Furthermore, combination therapy offered no
  significant benefit for mood or cognitive
  performance in fact, mood was substantially
  impaired in 8 of 23 p'ts receiving the
  combination therapy, all of whom had suppressed
  TSH.
• Thus, L-thyroxinel-triiodothyronine combination
  therapy for hypothyroidism had no advantage over
  L-thyroxine alone, even when administered in an
  appropriate physiologic molar ratio as in this
  study.
• In view of the suppressed serum TSH levels, p'ts
  receiving combination therapy may be at risk for
  the consequences of subclinical hyperthyroidism
  because of the supplemental triiodothyronine.

Clin Endocrinol (Oxf). 200460750-7.
26

• Only 1 study has shown any benefit of combination
  therapy, and 5 studies have clearly shown no
  benefit.
• Because of the short half-life of
  triiodothyronine, a delayed-release or
  slow-release preparation might be more
  physiologically complementary, but no such
  formula has been shown to be efficacious.
• Instead, the use of L-triiodothyronine as an
  adjunct to L-thyroxine is likely to be imprecise
  and nonphysiologic, presenting a risk for either
  overdosing or underdosing that could cause
  subclinical hyperthyroidism or subclinical
  hypothyroidism, respectively.

Clin Endocrinol (Oxf). 200460750-7.
27
Subclinical Hypothyroidism increases Risk for
Atherogenesis (J Clin Endocrinol Metab.
2004893365-70. )

• The expression subclinical hypothyroidism,
  although an unsatisfactory designation, is
  commonly used to describe p'ts with early or mild
  thyroid failure manifested as slight elevations
  of TSH levels with normal levels of serum
  thyroxine and triiodothyronine.
• This study investigated whether an association
  exists between subclinical hypothyroidism,
  atherogenesis, and mortality.
• This research question addresses 1 possible
  reason for treating subclinical hypothyroidism,
  which is a subject of continuing controversy.

28

• The study was a cross-sectional comparison of a
  control group of 2293 participants and a group of
  257 p'ts with normal thyroxine and
  triiodothyronine levels and serum TSH levels
  greater than 5.0 mIU/L (only 17 of whom had serum
  TSH levels of gt10 mIU/L).
• Mild thyroid dysfunction was associated with
  increased ischemic heart disease (odds ratio, 2.5
  CI, 1.1 to 5.4 in all p'ts and 4.0 CI, 1.4 to
  11.5 in men) independent of age, BMI, total
  cholesterol level, or history of smoking or DM.
  All-cause mortality increased longitudinally
  during 10 years of follow-up, but only in years 3
  to 6 and only in men.
• These findings strengthen the case for measuring
  serum TSH to detect mild thyroid dysfunction and
  to initiate L-thyroxine therapy if serum TSH
  levels are elevated.

J Clin Endocrinol Metab. 2004893365-70.
29

• This report adds to a growing body of work
  demonstrating that chronic mild or subclinical
  hypothyroidism adversely affects lipids and
  increases atherogenesis. The findings of this
  cohort study are consistent with a recent
  placebo-controlled study reported by Monzani and
  colleagues.
• They found that p'ts with early thyroid failure
  who received L-thyroxine therapy had lower mean
  levels of serum total and LDL cholesterol, lower
  serum apolipoprotein B, and decreased
  intimamedia thickness of the carotid arteries.
• However, a controversial consensus panel
  recommended against therapeutic intervention for
  subclinical hypothyroidism.

J Clin Endocrinol Metab. 2004893365-70.
30
Pregnant Women with Hypothyroidism Require
increased L-Thyroxine Dose Early in the First
Trimester (N Engl J Med. 2004351241-9. )

• This report relates to the issue of increased
  L-thyroxine replacement requirements when women
  with hypothyroidism become pregnant . Increased
  estrogen production during pregnancy leads to
  increased binding capacity of thyroid hormone
  transport proteins. This effect would cause
  subphysiologic levels of free thyroxine and
  elevated levels of TSH if not for stimulation of
  thyroid hormone production by chorionic
  gonadotropin.
• Current evidence suggests that pregnant women
  with elevated serum TSH levels may need Tx with
  L-thyroxine to avoid adverse pregnancy outcomes,
  such as a higher frequency of premature birth,
  low-birthweight offspring, placental abruption,
  gestational hypertension, miscarriage or fetal
  death, and offspring with a lower IQ.
• These adverse outcomes occur with overt
  hypothyroidism, but they may also occur in women
  with "subclinical hypothyroidism".
• In women with primary hypothyroidism, the thyroid
  gland cannot respond to the increased demand
  during pregnancy, and it becomes necessary to
  increase the dose of exogenous thyroid hormone.
  The increased requirement for L-thyroxine during
  pregnancy begins early in the first trimester.
  This study was designed to determine the optimal
  time during pregnancy to increase the dose of
  L-thyroxine and the optimal dose.

N Engl J Med. 2004351241-9.
31

• The protocol involved hypothyroid women who were
  planning to become pregnant. Thyroid function was
  measured before conception, every 2 weeks during
  the first trimester, and then monthly until
  delivery. By the end of the study, 20 pregnancies
  in 19 women resulted in 17 full-term births. The
  researchers adjusted each participant's dose of
  L-thyroxine to maintain preconception levels of
  serum TSH. An incremental increase in L-thyroxine
  dose was necessary in 17 pregnancies.
• The mean increase was 47, and 8 weeks' gestation
  was the median point at which an increase was
  required to maintain preconception levels of
  serum TSH. Additional increases in doses were not
  necessary after 16 weeks' gestation, but
  maintenance of the increased dose was required
  until delivery.

N Engl J Med. 2004351241-9.
32

• The study shows that hypothyroid women have an
  increased requirement for L-thyroxine as early as
  week 5 of pregnancy. In order to forestall any
  potential consequences of maternal thyroid
  hormone deficiency on the pregnancy, the authors
  recommended an automatic 30 increase in the
  L-thyroxine dose as soon as pregnancy is
  confirmed. This concept is important for primary
  care physicians to know because they are the
  principal providers of care to hypothyroid women
  of childbearing age.
• Internists and family physicians must advise
  young women with hypothyroidism to obtain thyroid
  function testing as soon as they become pregnant
  and to expect to increase their L-thyroxine dose
  early in pregnancy.
• Moreover, I recommend that physicians obtain a
  repeated serum TSH determination monthly during
  each prenatal visit (at least until week 20) and
  adjust the L-thyroxine dose to maintain the
  preconception level of serum TSH. After delivery,
  the dose of L-thyroxine typically may be reduced
  back to the prepartum level.

N Engl J Med. 2004351241-9.
33
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34
Diabetic p'ts with Preexisting Coronary Disease
Are Most Likely To Benefit from Lipid-Lowering
Therapy (Ann intern Med. 2004140650-8. )

• The aim of this study was to determine whether
  lipid-lowering therapy will reduce frequency of
  CV events in diabetic p'ts and whether p'ts with
  evidence of preexisting coronary disease benefit
  more than those without.
• The authors performed a meta-analysis of 12
  randomized, controlled trials evaluating the
  effect of statins and fibrates on major CV events
  in p'ts with type 2 DM. Four trials focused on
  primary prevention (6460 participants), 6 focused
  on secondary prevention (2515 participants), and
  2 examined both primary and secondary prevention
  (6586 participants).
• Participants in control groups received placebo
  in 11 of 12 trials, and 1 trial compared moderate
  versus aggressive lipid lowering. Major end
  points included MI, stroke, and CV death.

35

• In the 8 secondary prevention trials, the
  relative risk for a CV event was 0.76 (CI, 0.59
  to 0.93) the absolute risk reduction was 0.07
  (CI, 0.03 to 0.12). in the primary prevention
  trials, the relative risk was 0.78 (CI, 0.67 to
  0.89) after an average of 4.3 years of therapy,
  and the absolute risk reduction was 0.03 (CI,
  0.01 to 0.04). Tx of 34 to 35 p'ts was needed
  to prevent a major CV event in 1 p't. Not
  surprisingly, the benefit of lipid lowering to
  prevent cardiac events in diabetic p'ts is most
  clear in p'ts with preexisting CADmore than
  double the reduction seen in diabetic p'ts
  without known CAD.
• The investigators concluded that lipid-lowering
  therapy in type 2 DM lowers the frequency of CV
  events in all p'ts but to a greater degree in
  those with known coronary disease. The data
  suggest that type 2 diabetic p'ts who are at very
  low risk for CV events may not benefit
  significantly from therapy with lipid-lowering
  agents. Of note, this analysis serves as the
  evidence underlying the current American College
  of Physicians guidelines that recommend statins
  to all p'ts with type 2 DM and CAD regardless of
  their serum cholesterol levels.

Ann intern Med. 2004140650-8.
36
Aggressive Statin Therapy Was Superior to
Low-Dose Therapy for Improving Cardiac Outcomes
(Arch intern Med. 20041641427-36. )

• Wilt and colleagues conducted a meta-analysis of
  randomized trials of the effect of statins on
  mortality and nonfatal MI in p'ts with CAD. They
  had 4 goals to determine how much to lower serum
  LDL cholesterol levels to reduce coronary risk
  to determine the optimal initial serum LDL
  concentration at which to start therapy to see
  whether aggressive reduction of serum LDL levels
  led to better outcomes than moderate reduction
  and to determine the optimal target level for
  serum LDL cholesterol.
• Two reviewers abstracted data from 25 published
  randomized trials of statins versus control. The
  studies enrolled a total of 69 511 individuals
  between 1966 and 2002. To be included, a study
  had to have at least 100 p'ts per group and
  report clinical outcomes. The mean pretherapy
  serum LDL level was 3.85 mmol/L (149 mg/dL).
  Statin Tx reduced nonfatal MIs by 25, coronary
  heart disease mortality by 23, and all-cause
  mortality by 16. No data confirmed that lowering
  serum LDL levels to less than 2.59 mmol/L (lt100
  mg/dL) was more beneficial than lowering levels
  to between 2.85 and 3.37 mmol/L (110 to 130
  mg/dL).

37

• However, individuals with preTx serum LDL levels
  of less than 2.59 mmol/L (lt100 mg/dL) had a
  significantly lower risk for mortality and
  nonfatal MI than those whose levels were higher
  16.4 with statin therapy versus 21 without
  therapy. Thus, statin therapy lowered serum LDL
  levels by 20 to 40 and reduced coronary heart
  disease mortality and nonfatal MIs by 25.
  Benefit was detectable within 2 years of starting
  therapy and was present across the range of preTx
  serum LDL levels.
• This important study provides some new insights
  into lipid management in diabetic p'ts. The data
  showed that lipid lowering reduced cardiac risk
  in p'ts without preexisting coronary disease,
  although especially low-risk p'ts did not
  benefit. Statin therapy reduced all-cause
  mortality and coronary heart diseasespecific
  mortality by 16 and 24, respectively, in women
  and men (including elderly p'ts). P'ts with
  post-Tx levels less than 2.59 mmol/L (lt100 mg/dL)
  did not have greater benefit than p'ts with
  levels ranging from 2.85 to 3.37 mmol/L (100 to
  130 mg/dL).

Arch intern Med. 20041641427-36.
38

• Although this analysis did not compare the
  effectiveness of different statins, a recent
  study by Cannon and associates found atorvastatin
  to be superior to pravastatin p'ts with postTx
  serum LDL levels of 1.55 mmol/L or lower (lt60
  mg/dL) also had better outcomes than those with
  higher postTx levels.
• More recently, LaRosa and colleagues demonstrated
  additional clinical benefit from aggressively
  reducing serum LDL levels to a target of less
  than 2.59 mmol/L (lt100 mg/dL) in a comparison of
  80 mg of atorvastatin per day versus 10 mg /d.
  With an average preTx serum LDL level of 3.94
  mmol/L (152 mg/dL), aggressive therapy with the
  higher dose lowered levels to 1.99 mmol/L (77
  mg/dL) versus 2.62 mmol/L (101 mg/dL) with
  low-dose therapy.

Arch intern Med. 20041641427-36.
39
Simvastatin Was Shown To Be a Cost-Effective
Means for Reducing incidence of Stroke (Lancet.
2004363757-67. )

• The effect of cholesterol lowering on stroke risk
  has been controversial, partly because of the
  lack of convincing prospective trials. The
  purpose of this study was to determine whether
  statin therapy lowers stroke risk.
• This trial randomly assigned 20536 adults who
  ranged in age from 40 to 80 years to receive 40
  mg of simvastatin daily or a placebo. Of the
  participants, 3280 were known to have
  cerebrovascular disease and 17256 had other
  arterial disease or DM. The authors monitored
  coronary or vascular events over the 5-year
  study, which took place in 69 sites in the United
  Kingdom.

40

• The results were impressive.
• Simvastatin therapy was associated with a 25
  (CI, 15 to 34) reduction in the first stroke
  event, a 28 (CI, 19 to 37) reduction in
  ischemic strokes, and a very slight but
  significant reduction in transient ischemic
  attacks and the rate of carotid endarterectomy or
  angioplasty.
• The frequency of hemorrhagic strokes did not
  change. The stroke rate did not change in
  individuals with a history of cerebrovascular
  disease and stroke, but their coronary risk
  decreased.
• In contrast, statins reduced the incidence of
  ischemic stroke and coronary disease in p'ts
  without a history of stroke.

Lancet. 2004363757-67.
41

• Several authors have criticized the study.
  Nevertheless, the weight of the evidence is
  convincing because several previous studies
  yielded similar results, although the statin
  effect may be relatively small.
• A large trial of stroke incidence after
  cholesterol reduction is ongoing until
  publication of the report, consideration of
  statin therapy may be prudent in p'ts with stroke
  who present with transient ischemic attacks that
  resulted from atheromatous disease. A recent
  publication from the Heart Protection Study
  showed that statin therapy is cost-effective in a
  broad range of p'ts with DM or vascular disease
  and reduced the incidence of stroke by 25 to 33
  (depending on p't adherence to therapy).

Lancet. 2004363757-67.
42
Combination Therapy with Ezetimibe and
Simvastatin Was Superior to Statin Therapy Alone
(Mayo Clin Proc. 200479620-9. )

• Combining a statin with other lipid agents is
  good strategy after statins alone fail to reduce
  serum cholesterol to target levels.
• Statins work by reducing endogenous cholesterol
  synthesis, whereas ezetimibe is an inhibitor of
  GI absorption of ingested cholesterol. Hence,
  combination therapy offers the promise of
  additional benefit compared with either Tx alone.
  This short-term study measured the effect of
  adding ezetimibe therapy to a statin to treat
  hypercholesterolemia.
• This multicenter, double-blind trial randomly
  assigned p'ts to 1 of 10 Tx groups 10 mg of
  ezetimibe per day plus placebo simvastatin in a
  dose of 10, 20, 40, or 80 mg per day plus
  placebo, or both drugs. The primary end point was
  reduction in serum LDL level.

43

• Combination therapy was more effective (P lt
  0.001) at every dose of simvastatin. More p'ts
  reached target levels of serum LDL with
  combination therapy the same held true for serum
  total cholesterol, TG, and apolipoprotein B
  levels.
• The combination regimen was equally safe and well
  tolerated. Thus, presumably because of its
  different mechanism of action, ezetimibe
  complements statins.
• These exciting data open the door for a tablet
  containing a statin and ezetimibe, a 2-pronged
  attack that would address both synthesis and GI
  absorption of cholesterol and allow many more
  p'ts to reach target serum LDL levels.
• The results were similar to other recent studies
  of combination simvastatin and ezetimibe or of
  ezetimibe and atorvastatin.

Mayo Clin Proc. 200479620-9.
44
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45
High-Dose Corticosteroid Therapy May Not Reduce
Mortality in p'ts with Septic Shock (BMJ.
2004329480. )

• The effect of corticosteroids on outcomes of
  septic shock is controversial this meta-analysis
  examined the accumulated evidence. Two pairs of
  reviewers examined all randomized and
  quasi-randomized trials comparing corticosteroids
  with placebo. The authors selected 16 of the 23
  trials for analysis.
• The authors concluded that corticosteroids had no
  salutary effect on mortality at 28 days or at
  hospital discharge, although 4 trials did show
  reduced mortality in the ICU setting.
• The authors went further to conclude that
  corticosteroids did not reduce mortality
  regardless of dose or duration of therapy except
  for an effect with longer-term, lower-dose
  therapy.

46

• These conclusions are of great interest because
  high mortality rates and presumed evidence for
  adrenal insufficiency in septic shock have led to
  the widespread use of corticosteroids in septic
  shock. Perhaps because the trials were very
  heterogeneous, we lack convincing evidence for a
  beneficial effect of high-dose corticosteroids
  for septic shock.
• Indeed, high-dose steroids may cause harm by
  predisposing p'ts to infections.
• Given the evidence that long-term, low-dose
  steroid therapy is effective, the authors
  surprisingly recommended giving corticosteroids
  in a dose of 200 to 300 mg/d immediately after
  performing a short ACTHstimulation test.
• Other researchers might conclude that the
  heterogeneity of the Tx employed and the p't
  samples precludes a strong recommendation from
  this study.

BMJ. 2004329480.
47
Low-Dose Corticosteroids Were Superior to
High-Dose, Short-Term Therapy for Improving
Survival in Sepsis (Ann intern Med.
200414147-56. )

• Continuing the theme of the previous article,
  Minneci and colleagues compared the results of
  trials of high-dose corticosteroids for septic
  shock with more recent trials of low-dose
  therapy. The investigators examined the results
  of 5 randomized, controlled trials that were
  published between 1998 and 2003 and compared the
  outcomes with those of 8 trials published before
  1989.
• Compared with high-dose, short-term therapy given
  in trials before 1989, the 5 recent trials
  employed a lower total dosage of corticosteroids
  given over a longer period. These trials
  demonstrated a consistent beneficial effect on
  shock reversal and survival. Low-dose steroid Tx
  was associated with survival from septic shock,
  whereas higher doses were associated with an
  adverse outcome.
• The investigators concluded that 5- to 7-day
  courses of low-dose corticosteroids increased the
  likelihood of reversing shock and improving
  survival in sepsis. An appropriate dose should be
  enough to ensure an adequate response to stress,
  such as 150 mg of hydrocortisone over 24 hours.

48

• This article and the preceding article appear to
  agree however, the rationale for administering
  corticosteroids in the absence of adrenal
  insufficiency is arguable, particularly because
  the diagnosis of adrenal insufficiency usually
  rests on an inappropriately low level of serum
  total cortisol before or after ACTH stimulation.
• As Loriaux recently explained, changes in protein
  binding of cortisol in acute illness affect total
  hormone levels, whereas the metabolically
  important free concentration of hormone may be
  physiologically appropriate or elevated depending
  on the stress associated with the clinical
  situation.
• The same changes in protein binding occur for
  thyroid hormones in the euthyroid sick syndrome.
• Uncertainty about adrenal insufficiency in septic
  shock notwithstanding, low-dose steroid therapy
  appears to be beneficial in septic shock.

Ann intern Med. 200414147-56.
49
Free Plasma Cortisol Determination Is More
Meaningful than Total Plasma Cortisol Levels for
Assessing Adrenal Function in Hypoproteinemic
p'ts (N Engl J Med. 20043501629-38. )

• This study describes the important distinction
  between total and free plasma cortisol levels in
  diagnosing adrenal insufficiency in critically
  ill p'ts.
• Like thyroxine, cortisol circulates in blood
  largely bound to protein. The much smaller amount
  of unbound hormone is responsible for its
  metabolic effects.
• In the past, physicians caring for critically ill
  p'ts have equated a plasma total cortisol level
  below or at the low end of the reference range
  with a diagnosis of adrenal insufficiency, which
  is a rationale for corticosteroid therapy.
• This study examined the influence of stress on
  the corticosteroid-binding globulin and the
  consequent effects on total and free plasma
  cortisol levels in the ICU setting. The results
  should lead us to rethink the rationale for
  giving corticosteroids to critically ill p'ts.

50

• From this very important study, we might conclude
  that free plasma cortisol levels are more
  meaningful than total plasma cortisol levels for
  assessing adrenal function in critically ill
  hypoproteinemic p'ts. Moreover, adrenal function
  may actually be normal in critically ill
  hypoproteinemic p'ts who have low total plasma
  cortisol levels both before and after ACTH
  stimulation.
• Somewhat amazingly, we have been aware for many
  decades that the difference between total
  protein-bound and free thyroid hormone in thyroid
  disease is important physiologically, but until
  now we have overlooked the parallels to adrenal
  dysfunction.
• Thus, we have probably overdiagnosed adrenal
  insufficiency in the ICU setting for decades and
  have overtreated p'ts with potentially harmful
  doses of steroids.
• In the future, physicians should interpret the
  importance of cortisol levels in the ICU within
  the context of this article.

N Engl J Med. 20043501629-38.
51

• If a p't's serum albumin level is low, the
  physician should measure free plasma cortisol as
  well as total plasma cortisol. Although empirical
  corticosteroid therapy is often reasonable, it
  could be discontinued if the laboratory report
  shows elevated levels of free plasma cortisol and
  low levels of total plasma cortisol and serum
  albumin. We should measure free plasma cortisol
  levels in critically ill p'ts and take
  appropriate action.
• Thus, this study is valuable for showing that a
  low total plasma cortisol level in a
  hypoproteinemic p't will probably lead us to an
  erroneous diagnosis of adrenal insufficiency.
• It does not, however, answer an important
  question Does a measured "normal" free plasma
  cortisol level reflect a sufficient level of
  corticosteroid for sick, stressed p'ts?

N Engl J Med. 20043501629-38.
52
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