Update in Endocrinology

郝 立 智 醫 師郝 立 智 醫 師永康榮民醫院新陳代謝科永康榮民醫院新陳代謝科

95-05-0595-05-05

Annals of internal Medicine: 1 Nov. 2005 | Vol. 143 Issue 9 | P. 673-682

HLJ

Outline1. DM

2. Thyroid Disease

3. Lipid-Lowering Therapy

4. Adrenal Function

HLJ

Myocardial Perfusion Imaging Should Be Considered To Detect Silent

CAD in Diabetic p'ts (DM Care. 2004;27:1954-61.)

• 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.

HLJ

• 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 < 0.03]), duration of DM (odds ratio, 5.2 [P < 0.002]), and abnormal response to the Valsalva maneuver (odds ratio, 5.6 [P < 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. 2004;27:1954-61.

HLJ

• 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. 2004;27:1954-61.

HLJ

Insulin Lispro Was Safe and More Cost-Effective than Standard intensive

Care for Management of DKA (Am J Med. 2004;117:291-6. )

• 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).

HLJ

• 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. 2004;117:291-6.

HLJ

HbA1c Should Be Considered an independent and Progressive Risk Factor for CV

Disease (Ann intern Med. 2004;141:413-20. )

• 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.

HLJ

• 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. 2004;141:413-20.

HLJ

Liraglutide Effectively Improves Glycemic Control and Islet Cell Function in Type 2 DM (DM. 2004;53:1187-

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.

HLJ

• 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. 2004;53:1187-94.

HLJ

• 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. 2004;53:1187-94.

HLJ

Rosiglitazone Reduces in-Stent Restenosis in Diabetic p'ts with CAD (DM Care. 2004;27:2654-60. )

• 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 intima–media 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.

HLJ

• 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 < 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. 2004;27:2654-60.

HLJ

Telmisartan Is Comparable to Enalapril for Protecting Renal Function (N Engl J Med. 2004;351:1952-61. )

• 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.

HLJ

• 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.

HLJ

HLJ

Risk for Fetal Loss Is increased in Subclinical Hyperthyroidism (JAMA. 2004;292:691-5. )

• 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.

HLJ

• 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 < 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. 2004;292:691-5.

HLJ

• 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. 2004;292:691-5.

HLJ

Periodic Thyroid Screening Is indicated for Men Receiving Therapy for Hepatitis C (Arch intern Med. 2004;164:2371-6. )

• 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.

HLJ

• 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. 2004;164:2371-6.

HLJ

• 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. 2004;164:2371-6.

HLJ

Combination Therapy with Thyroxine and Triiodothyronine Offers No Advantage over Tx with Thyroxine Alone(Clin Endocrinol (Oxf). 2004;60:750-7. )

• 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 (14:1) 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-thyroxine–l-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.

HLJ

• 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-thyroxine–l-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). 2004;60:750-7.

HLJ

• 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). 2004;60:750-7.

HLJ

Subclinical Hypothyroidism increases Risk for Atherogenesis (J Clin Endocrinol Metab. 2004;89:3365-70. )

• 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.

HLJ

• 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 >10 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. 2004;89:3365-70.

HLJ

• 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 intima–media thickness of the carotid arteries.

• However, a controversial consensus panel recommended against therapeutic intervention for subclinical hypothyroidism.

J Clin Endocrinol Metab. 2004;89:3365-70.

HLJ

Pregnant Women with Hypothyroidism Require increased L-Thyroxine Dose Early in the First Trimester (N Engl J Med. 2004;351:241-9. )

• 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. 2004;351:241-9.

HLJ

• 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. 2004;351:241-9.

HLJ

• 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. 2004;351:241-9.

HLJ

不要輕視微小 人類的視角和視野

從不是最寬廣的 有時候 甚至顯得太小

HLJ

Diabetic p'ts with Preexisting Coronary Disease Are Most Likely To Benefit from Lipid-Lowering Therapy (Ann intern Med. 2004;140:650-8. )

• 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.

HLJ

• 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 CAD—more 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. 2004;140:650-8.

HLJ

Aggressive Statin Therapy Was Superior to Low-Dose Therapy for Improving Cardiac Outcomes (Arch intern Med. 2004;164:1427-36. )

• 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 (<100 mg/dL) was more beneficial than lowering levels to between 2.85 and 3.37 mmol/L (110 to 130 mg/dL).

HLJ

• However, individuals with preTx serum LDL levels of less than 2.59 mmol/L (<100 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 disease–specific 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 (<100 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. 2004;164:1427-36.

HLJ

• 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 (<60 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 (<100 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. 2004;164:1427-36.

HLJ

Simvastatin Was Shown To Be a Cost-Effective Means for Reducing incidence of Stroke (Lancet. 2004;363:757-67. )

• 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.

HLJ

• 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. 2004;363:757-67.

HLJ

• 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. 2004;363:757-67.

HLJ

Combination Therapy with Ezetimibe and Simvastatin Was Superior to Statin Therapy Alone (Mayo Clin Proc. 2004;79:620-9. )

• 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.

HLJ

• Combination therapy was more effective (P < 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. 2004;79:620-9.

HLJ

都說人類是最感性的動物 但有些人所謂的親情 還不如叢林深處的這一家

HLJ

High-Dose Corticosteroid Therapy May Not Reduce Mortality in p'ts with Septic Shock (BMJ. 2004;329:480. )

• 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.

HLJ

• 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 ACTH–stimulation 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. 2004;329:480.

HLJ

Low-Dose Corticosteroids Were Superior to High-Dose, Short-Term Therapy for Improving Survival in Sepsis (Ann intern Med. 2004;141:47-56. )

• 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.

HLJ

• 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. 2004;141:47-56.

HLJ

Free Plasma Cortisol Determination Is More Meaningful than Total Plasma Cortisol Levels for Assessing Adrenal Function in Hypoproteinemic p'ts (N Engl J Med. 2004;350:1629-38. )

• 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.

HLJ

• 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. 2004;350:1629-38.

HLJ

• 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. 2004;350:1629-38.

HLJ

珍重再見 願上帝祝福您