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【进展】内分泌进展瞭望窗口(2008-5-26罗格列酮与匹格列酮：怎么使用？) [精华]

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这个帖子发布于13年零223天前，其中的信息可能已发生改变或有所发展。

感谢小小东方版主与cplamst战友的《内分泌新闻导读员招募》，因为西医进展太快，很多观点就是要及时领悟到，从别人那学习思维。如果战友有好的帖子（最好是影响因子大于2分的杂志或较好的中文综述），对临床诊治有帮助也可以跟贴。

想来想去，这个贴如果更深一步对我和大家都有好处，因为西医是一个进展神速的科学技术，内分泌临床治疗观点在不断变化，及时了解最新进展是每个医师向往的，所以改为《内分泌进展瞭望窗口》，通过这里您可以了解最新的相关内分泌的进展。

发贴要求：

1、新：内容新颖，可能是没有涉及的领域或突破性的观点

2、全：对老的内容的进一步深入，形成了完整的要点

3、权威：权威报道、资深专家、循证医学结论等

4、热点：医学界争论内容、关注内容等

注意事项：

禁止普通新闻类内容、灌水贴、与临床无关、大众化内容，一经发现，删除/扣分/除名

下面是今年上半年的部分经典文献的简介及专家的评论，总结一下奉献给大家。

Type 2 Diabetes

From
The New England Journal of Medicine
May 21, 2007

Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death From Cardiovascular Causes

Nissen SE, Wolski K
N Engl J Med. 2007 May 21; [Epub ahead of print]

In this recent meta-analysis, Nissen and Wolski found that rosiglitazone was associated with a significant increase in myocardial infarction (MI) and an increased risk for death from cardiovascular causes that approached statistical significance. Not surprisingly, the article has ignited a fiery debate, and has received considerable attention from mainstream media.

The analysis included 40 studies of rosiglitazone vs placebo or other antihyperglycemic agents that were part of a GlaxoSmithKline (GSK) regulatory submission to the US Food and Drug Administration (FDA) or were included on GSK's clinical trials registry Web site, all of which were at least 24 weeks in duration. These 40 studies combined involved about 10,000 rosiglitazone users and 6000 control subjects. Results from 2 other large postmarketing studies with much longer follow-up, Diabetes Reduction Assessment with Ramipiril and Rosiglitazone (DREAM)[1] and A Diabetes Outcome Prevention Trial (ADOPT),[2] were also included. DREAM and ADOPT studied 2635 and 1456 rosiglitazone subjects, respectively, with a like number of control subjects in each study. In all of the included studies, cardiovascular events and death were reported as adverse events, not outcomes. Because patient-level data were not available to the study authors, the meta-analysis could only include studies that had a randomized comparator group and were of similar duration of treatment. Meta-analysis prohibits the use of studies in which no events (MI or death) occurred; 6 studies were excluded on that basis. In addition to comparisons between rosiglitazone and all other treatments combined, comparisons between placebo, metformin, sulfonylureas, and insulin were individually analyzed.

The main finding was that, overall, rosiglitazone was associated with a statistically significant 43% increase in risk for MI (odds ratio 1.43; 95% confidence interval [CI], 1.03-1.98; P = .03) and an increased risk for death from cardiovascular causes that did not reach statistical significance (odds ratio 1.64; 95% CI, 0.98-2.74; P = .06). None of the subanalyses of rosiglitazone vs placebo or the individual drugs were statistically significant. In addition, no statistically significant differences were found when the 40 small studies were combined and analyzed separately (ie, excluding DREAM and ADOPT).

Comment
Under almost any circumstances, a study reporting an increased risk for MI or death associated with a treatment must be taken seriously, especially when that treatment is a pharmaceutical for which alternatives exist. Despite the headline-generating findings of this meta-analysis, these results are far from conclusive. The study authors concede some important limitations, the most important of which is that the findings were based on very few events: Only 86 MIs were reported in 14,371 rosiglitazone subjects for an event proportion of 0.60%. In the control group, 72 MIs out of 11,634 subjects were reported. Note that this overall event proportion of 0.62% is actually slightly higher than the rosiglitazone group, but because meta-analysis compares effect sizes of the included studies and does not analyze patient level data, the resulting odds ratio is a statistically significant 1.43. The inability to analyze patient-level data is a limitation that the study authors note.

It is also important to note that none of the subgroup analyses reached statistical significance. The analysis of the 40 small trials combined was the most suggestive of increased cardiotoxic effects, relative to DREAM and ADOPT. These 40 studies contributed over 70% of the subjects. Because the meta-analysis is weighted according to the number of subjects in each included study, these 40 studies, which were of much shorter follow-up, influence the findings to a greater extent than the longer duration DREAM and ADOPT studies. In addition, none of the individual comparisons between rosiglitazone and other antihyperglycemics approached statistical significance. Because they were all in the same direction as placebo (greater than 1.0), the study authors argued that the findings were not the result of protective effects of comparator drugs --maybe, but sample size could also have played a role.

Perhaps most important, GSK is currently sponsoring a randomized trial of rosiglitazone in which cardiovascular death and hospitalization are the primary outcomes. The Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD)[3] has been running since 2001, with results expected in 2009. Had rosiglitazone shown a 43% increase in the primary outcome over the short or even medium term, the trial would have been stopped long ago.

Although there are a number of shortcomings of the Nissen and Wolski meta-analysis, it nevertheless raises questions about the safety of rosiglitazone that deserve further exploration. That exploration is currently under way. Until more conclusive results become available, this meta-analysis could be used to increase caution in prescribing rosiglitazone, but is far from sufficient to avoid the drug altogether.

References
The DREAM Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomized controlled trial. Lancet. 2006;368:1096-1105.
Kahn SE, Haffner SM, Heise MA, et al; ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427-2443.
Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD): study design and protocol. Diabetologia. 2005;48:1726-1735.

From
Diabetes Care
February 2007 (Volume 30, Number 2)

Comparison of Vildagliptin and Rosiglitazone Monotherapy in Patients With Type 2 Diabetes

Rosenstock J, Baron MA, Dejager S, Mills D, Schweizer A
Diabetes Care. 2007;30:217-223

This 24-week, double-blind, randomized study performed in 11 countries was designed as a head-to-head comparison of the efficacy and tolerability of vildagliptin and rosiglitazone as monotherapy in drug-naive type 2 diabetes patients. Seven hundred eighty-six adult subjects (age 18-80 years) with glycated hemoglobin (A1C) levels in the range of 7.5% to 11.0% and who did not have cardiovascular disease, congestive heart failure, liver disease, or various laboratory abnormalities were randomized on a 2:1 ratio to 100 mg vildagliptin (n = 519) or 8 mg rosiglitazone (n = 267), and were assessed at weeks 4, 12, 16, and 24 of active treatment. Analyzed on an intent-to-treat basis, the primary efficacy variable was change from baseline A1C after 24 weeks. Secondary variables were changes in fasting glucose, fasting lipids, and body weight.

A1C improved by -1.1% among vildagliptin users and -1.3% among rosiglitazone users, meeting the statistical criterion for noninferiority. It is interesting that a stratified analysis showed that greater A1C reductions among the vildagliptin group were achieved by those with body mass index (BMI) < 30 kg/m2, whereas rosiglitazone appeared more efficacious in patients with BMI ≥ 30 kg/m2. Fasting glucose levels decreased more with rosiglitazone compared with vildagliptin, and high-density lipoprotein increases also favored rosiglitazone. However, body weight increased by 1.6 kg among rosiglitazone-treated patients, but did not change in the vildagliptin group. In addition, compared with rosiglitazone, vildagliptin significantly decreased triglycerides as well as total and low-density lipoprotein cholesterol.

Comment
Vildagliptin is in the new dipeptidyl peptidase (DPP)-IV inhibitor class of antihyperglycemic drugs that increases alpha- and beta-cell responsiveness to glucose.[1] Its apparent ability to reduce A1C without inducing weight gain makes it a promising new agent. The favorable lipid effects are also intriguing, and need further study. Rosiglitazone is a thiazolidinedione that targets insulin resistance by enhancing peripheral and hepatic insulin action.[2] Although the end result is similar (reduction in A1C), the vastly different mechanistic actions of these 2 drugs likely explain some of the differences found in the secondary outcomes. In theory, the fact that vildagliptin worked best in subjects who were not obese suggests that this drug may be preferred when substantial beta-cell failure is the primary cause of hyperglycemia. On the other hand, rosiglitazone worked better in obese subjects and had a greater effect on fasting glucose, suggesting that it might be preferred in those with high insulin resistance. Such patients are often obese. Weight gain is never desirable; it may be of less concern in already obese patients, especially if body fat is being redistributed.[2] In reality, beta-cell failure and insulin resistance usually coexist, and there is debate over which is the dominant cause of diabetes. The key point is that clinicians now have more options than ever to appropriately treat the variations of hyperglycemia that we singularly call type 2 diabetes.

References
Mari A, Sallas WM, He Yl, et al. Vildagliptin, a dipeptidyl peptidase IV inhibitor, improves model-assessed beta-cell function in patients with type 2 diabetes. J Clin Endocrinol Metab. 2005;90:4888-4894.
Yki-Jarvinen H. Thiazolidinediones. N Engl J Med. 2004;351:1106-1118.

Abstract

Retinopathy Predicts Cardiovascular Disease Mortality in Type 2 Diabetic Men and Women
Juutilainen A, Lehto S, Rönnemaa T, Pyörälä K, Laakso M
Diabetes Care. 2007;30:292-299

This 18-year follow-up of 824 Finnish subjects with type 2 diabetes who were free of cardiovascular disease (CVD) at baseline was designed to evaluate the predictive value of retinopathy for all-cause, CVD, and coronary heart disease (CHD) mortality. The study population was 425 men and 399 women who underwent an ophthalmoscopic examination at baseline (1982-1984). Retinal findings were classified according to the status of the worse eye as no retinopathy, background retinopathy, or proliferative retinopathy. Copies of death certificates of patients who subsequently died were obtained as well as hospital and autopsy records, if available. These data were used to identify CVD (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 390-459), CHD (ICD-9-CM codes 410-414), and all-cause mortality.

A little over two thirds of subjects died during follow-up, and about two thirds of those died of CVD, whereas nearly half died of CHD. Death rates were nearly identical for men and women. After adjusting for age, sex, glycated hemoglobin (A1C), smoking, hypertension, total and high-density lipoprotein (HDL) cholesterol, duration of diabetes, and urinary protein, proliferative retinopathy more than tripled the risk for all 3 outcomes (P < .001) compared with subjects with no retinopathy. Background retinopathy increased the risk for death (all-cause) by 48% (P < .001), CVD death by 52% (P = .003), and CHD death by 47% (P = .02). However, when the analyses were stratified by sex, background retinopathy was even more predictive of mortality among women (61% increase for all-cause, P = .003; 71% for CVD, P = .006; 79% for CVD, P = .014), but no longer predicted mortality among men. Sex stratification did not affect proliferative retinopathy results: They all remained highly significant.

Comment
A number of previous studies have shown that microvascular complications predict CVD mortality, and at least 2 studies have shown that retinal arterial narrowing is more strongly associated with CHD in women than in men. The current study provides an interesting twist, demonstrating that milder retinopathy predicts mortality in women but not men. It is important to note that diabetes medical care was quite different in the early 1980s when baseline measures were taken. For example, mean A1C was around 10% and systolic blood pressure averaged about 150 mm Hg. Both of these levels are quite high by today's standards, and could certainly affect both microvascular disease and mortality.[1,2] In addition, patients today are living longer, leading some to speculate that improved survival increases the prevalence of retinal disease by increasing time available for its occurrence.[3] In the current epidemiologic study, retinal status was only measured at baseline. It is therefore likely that status could have changed prior to death. If retinopathy subsequently developed at different rates among men vs women, the reported findings may not apply.

References
UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.
UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38). BMJ. 1998;317:703-712.
Brown JB, Pedula KL, Summers KH. Diabetic retinopathy: contemporary prevalence in a well-controlled population. Diabetes Care. 2003;26:2637-2642.

Abstract

March 2007 (Volume 30, Number 3)

Impaired Fasting Glucose and Impaired Glucose Tolerance: Implications for Care

Nathan DM, Davidson MB, DeFronzo RA, et al
Diabetes Care. 2007;30:753-759

The American Diabetes Association (ADA) convened a consensus development conference in October 2006, focusing on the prediabetic states of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Following that conference, an expert panel developed this consensus statement. In addition to reviewing and restating the definitions, natural history, and pathogenesis of IFG and IGT, the panel reviewed whether the natural history can be altered, and whether prevention of progression from these prediabetic states to diabetes also prevents the development of diabetes-related microvascular complications, cardiometabolic risk factors, or cardiovascular events. On the basis of these reviews, the panel addressed whether there are adequate data to recommend interventions to prevent or delay diabetes in IFG or IGT. Finally, the panel evaluated who should be screened for IFG/IGT, what methods should be used, and how often.

Although IFG and IGT probably have different pathophysiologic mechanisms, both greatly increase the risk of developing diabetes. Patients may have isolated IFG, isolated IGT, or both IFG and IGT, with the greatest risk for diabetes occurring in the latter combined category. There are now numerous studies demonstrating that diabetes prevention or delay is possible in IFG/IGT, but it is not clear whether this occurs by lowering glycemia without changing the underlying rate of progression (what the study authors termed "resetting the clock") or by improving beta-cell function and/or insulin sensitivity, thereby slowing the rate of progression. Although diabetes prevention should lead to a decrease in microvascular complications, direct data to confirm this do not exist. The panel also concluded that it remains unclear whether cardiovascular disease risk factors or events can be reduced. Nevertheless, they concluded that lifestyle intervention, which has the greatest impact on progression to diabetes, undoubtedly provides health benefits. Therefore, the panel recommended lifestyle modification in patients with IFG or IGT. In addition, in patients with IFG and IGT, the panel recommended metformin treatment in individuals who are either younger (< 60 years of age), obese (body mass index > 35 kg/m2), hypertriglyceridemic, hypertensive, have a first-degree relative with diabetes, have reduced high-density lipoprotein cholesterol, or have a glycated hemoglobin (A1C) level > 6.0%.

Comment
This consensus statement provides an excellent summary of what is currently known about prediabetes and diabetes prevention. On the basis of the recommendations, it appears that the ADA may be recommending oral glucose tolerance testing in more individuals than it has previously. However, the panel notes that oral glucose tolerance testing is only necessary in persons who have first been identified with IFG, and then only if metformin treatment is being considered. Once IFG/IGT is identified, the panel recommended semiannual A1C monitoring in metformin-treated patients, and annual follow-up for those not on drug therapy. Curiously, there were no explicit recommendations on how frequently IFG or IGT should be reevaluated. The panel did not recommend any pharmacologic therapy other than metformin, but did leave the door open for other medications if they prove to be effective, safe, tolerable, and of low cost.

Abstract

Prevalence and Treatment of Low HDL Cholesterol Among Primary Care Patients With Type 2 Diabetes: An Unmet Challenge for Cardiovascular Risk Reduction

Grant RW, Meigs JB
Diabetes Care. 2007;30:479-484

In an observational study of a primary care-based population in Massachusetts, electronic records of 7692 patients with type 2 diabetes were examined to identify the prevalence and predictors of low high-density lipoprotein (HDL) cholesterol, characterize current lipid therapy, and estimate the theoretical benefit of more effective HDL-raising methods. The study authors identified use of statin and nonstatin HDL cholesterol-raising medications; prevalence of cardiovascular disease; and low-density lipoprotein (LDL), HDL, and glycated hemoglobin (A1C) levels among a relatively diverse population.

The vast majority of study subjects were treated for major cardiovascular disease (CVD) risk factors: Over 80% were receiving an antihypertensive agent; 82% of those with CVD and ~61% of those without CVD were receiving a statin drug. Overall, risk factor control was quite good. Mean A1C was about 7.5%; mean blood pressure was 130/74 mm Hg; and mean LDL was < 90 mg/dL (about 68% were below 100 mg/dL). In contrast, only 7.9% were receiving nonstatin lipid therapy, despite 45% of men and 54% of women having HDL levels below target (40 mg/dL for men and 50 mg/dL for women). The presence of CVD, current smoking, younger age, white race, and higher A1C were associated with below-goal HDL levels. Even among those with low HDL levels and existing CVD, the prevalence of nonstatin lipid therapy was less than 20%. Among the 436 patients of the current study who met the entrance criteria for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT),[1] the study authors estimated that 44 major CVD events could be prevented with gemfibrozil treatment. They also estimated that 80 major CVD events could be avoided with fenofibrate treatment as applied to the 5670 current study patients who met the study criteria for the Fenofibrate Intervention and Event Lowering in Diabetes trial.[2]

Comment
Statin therapy is now widely accepted as general practice in type 2 diabetes, yet substantial CVD risk remains. Low HDL and high triglycerides are quite common in type 2 diabetes. As these data from a heavily treated and well-controlled population show, low HDL is not commonly addressed. This may be because current methods of raising HDL do not produce dramatic results. The VA-HIT study showed that every 5-mg/dL increase in HDL produced an 11% reduction in coronary heart disease events. However, gemfibrozil treatment raised HDL by a mean of about 2 mg/dL (5.4%), whereas an increase of 16% would have been necessary to achieve a 5-mg/dL increase. Nevertheless, as the current study estimates, CVD event prevention from even modest HDL increases is achievable.

References
Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol: Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Study Group. N Engl J Med. 1999;341:410-418.
The FIELD Study Investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes (the FIELD study): randomized controlled trial. Lancet. 2005;366:1849-1861.

Abstract

Progressive Loss of Beta-Cell Function Leads to Worsening Glucose Tolerance in First-degree Relatives of Subjects With Type 2 Diabetes

Cnop M, Vidal J, Hull RL, et al
Diabetes Care. 2007;30:677-682

This study of 33 nondiabetic first-degree relatives of individuals with type 2 diabetes sought to explore the roles of insulin resistance and beta-cell function in the pathogenesis of impaired glucose tolerance (IGT) and diabetes. Subjects had a frequently sampled intravenous glucose tolerance test (FSIGT), and 26 of the 33 subjects had an oral glucose tolerance test (OGTT) at baseline. Both tests were given to all subjects 7-9 years later. Insulin sensitivity was quantified as the insulin sensitivity index with the minimal model of glucose kinetics. The study authors estimated beta-cell function by the disposition index, which is calculated as sensitivity index times the acute insulin response to glucose.

Subjects averaged about 37.9 years of age at first assessment, and 24 of the 33 were women. Over a mean follow-up of 7.3 years, weight gain averaged 7.6 kg, resulting in an increase in mean body mass index (BMI) from 28.6 to 31.4 kg/m2. The weight gain occurred centrally: Waist circumference increased, but hip circumference did not. Of the 26 who had a baseline OGTT, 16 had normal glucose tolerance, 6 of whom developed IGT at follow-up. Over time, insulin sensitivity decreased by 12% in the progressors, but only 3% in the nonprogressors. Beta-cell function declined by 38% in the progressors vs 20% among the nonprogressors (P = .05). In a linear regression model adjusting for baseline beta-cell function, progression to IGT was associated with lower follow-up beta-cell function. However, in a similar analysis of insulin sensitivity, no association was found. Among the 10 subjects who initially had IGT, beta-cell function declined in the 4 who developed diabetes, but improved in the 6 who did not.

Comment
The relative importance of insulin resistance and beta-cell function in the development of type 2 diabetes has long been debated. These data suggest that progressive loss of beta-cell function characterizes the deterioration of glucose tolerance in the early stages of hyperglycemia. However, as the study authors note, subjects were already relatively insulin-resistant at baseline. Thus, it is possible that insulin resistance was already near maximal. Beta-cell function was also poor at first assessment, but continued to decline. This suggests that although insulin resistance likely contributes to the pathogenesis of diabetes, the progressive loss of beta-cell function may be the critical determinant for disease progression. The debate continues.

Abstract

From
Diabetologia
March 2007 (Volume 50, Number 3)

Adiposity, Physical Fitness and Incident Diabetes: The Physical Activity Longitudinal Study

Katzmarzyk PT, Craig CL, Gauvin L
Diabetologia. 2007;50:538-544

This subanalysis of the Physical Activity Longitudinal Study used baseline data from the 1988 Campbell's Survey on Well-Being in Canada and survey data collected in 2002-2004 to assess diabetes incidence as a function of measures of physical fitness, adiposity, and self-reported physical activity among 1543 participants who were fee of diabetes at baseline. Measures of adiposity included waist circumference, body mass index (BMI), and waist-to-hip ratio. Cardiorespiratory fitness was assessed in terms of maximal oxygen consumption with a modified version of the Canadian Aerobic Fitness Test, and musculoskeletal fitness was assessed with several performance tests, such as push-ups, sit-ups, and grip strength, which were combined into a composite score. Physical activity was assessed with a variation of the Minnesota Leisure Time Physical Activity Questionnaire. (Considerable detail on all assessments is contained in the article.) The outcome of interest -- development of diabetes over the follow-up period -- was based on self-reported data.

Individual logistic regression models indicated that all measures of adiposity predicted development of diabetes, with odds ratios between 2 and 3 per standard deviation of the variable after adjustment for age, sex, smoking, alcohol consumption, and parental history of diabetes. Cardiorespiratory fitness was associated with a 70% reduction in diabetes development (per standard deviation), and the composite score for musculoskeletal fitness was associated with a 61% reduction. However, the physical activity measure did not significantly predict incident diabetes.

Comment
Lifestyle interventions, such as those tested by the Diabetes Prevention Program, typically include a significant exercise component. The underlying objective of the interventions is to lose weight, and the results of the current study support the importance of weight reduction. However, these results also suggest that physical activity alone is not sufficient to reduce diabetes risk unless the activity leads to better fitness. Of course, that is expected to be the case, but the correlations between physical activity and cardiorespiratory and musculoskeletal fitness in this study were only 0.17 and 0.23, respectively. This suggests that physical activity and fitness are not the same thing, at least not as measured here. Because physical activity was self-reported, it may be that subjects overstated their true level of activity, something clinicians should be cautious of when querying patients about their exercise habits.

Highlights From the American Diabetes Association 54th Annual Advanced Postgraduate Course CME
Zachary T. Bloomgarden, MD
Disclosures

Introduction
The prevention of diabetes, the assessment of inflammation, and the treatment of obesity were among the topics addressed during the American Diabetes Association (ADA) 54th Annual Advanced Postgraduate Course.

IFG/IGT: How Should We Treat Prediabetic Hyperglycemia?
Ronald B. Goldberg, MD,[1] University of Miami, Florida, reviewed the projections for huge increases in the global burden of diabetes[2] and discussed approaches to the prediabetic hyperglycemic states of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).

It is not clear what strategy should be employed in diabetes prevention. Dr. Goldberg began with a discussion of the benefits of lifestyle intervention.[3] He acknowledged that some have argued that the lifestyle intervention used in the Diabetes Prevention Program (DPP), in which patients worked with a lifestyle manager, might be difficult to translate into clinical practice.[4] However, the approach used in the 3234-person DPP was effective: Subjects in the lifestyle intervention arm achieved a 7-kg weight loss at 6 months. Weight loss was stable at 1 year, although not fully sustained to the conclusion of the study at 3 years, when the mean weight loss was 4 kg. Those receiving metformin lost 2 kg, and the control group did not gain weight, which Dr. Goldberg pointed out "presumably represents a modest treatment effect." In a multivariate analysis of the components of the lifestyle intervention, the only significant determinant was the degree of weight reduction; physical activity presumably had its effect on decreasing diabetes through weight reduction. A lower risk for progression to diabetes was also associated with smaller waist circumference, lower fasting insulin (implying less insulin resistance), and a higher insulin/glucose ratio (implying better insulin secretion).

The 532-person Finnish Diabetes Prevention Study[5] compared persons with IGT who were randomized to an intensive lifestyle intervention group or a control group. The 4-year progression to diabetes rates were 11% in the intervention group vs 23% in the control group. A recent 3-year postintervention follow-up showed that among persons who had not developed diabetes at the conclusion of the study, 20.5% of controls subsequently developed diabetes compared with 14% of those in the intervention group, for an ongoing 38% reduction in diabetes.[6]

It is interesting that in a recent diabetes prevention study[7] conducted in India, participants with IGT had a baseline body mass index (BMI) of 25 kg/m2 but a very high rate of progression to diabetes of 18.3% per year among controls, which decreased to 13% per year with a lifestyle intervention. These results demonstrate that the benefits of lifestyle intervention apply to a variety of populations at varying risks of developing diabetes.

A number of pharmacologic approaches to diabetes prevention have been explored. In STOP-NIDDM (Study To Prevent Non-insulin-dependent Diabetes Mellitus),[8] treatment with acarbose achieved a 25% relative risk reduction in the development of type 2 diabetes. In the XENDOS (Xenical in the Prevention of Diabetes in Obese Subjects) study,[9] treatment with orlistat achieved a 36% reduction. In the TRIPOD (Troglitazone in the Prevention of Diabetes) study,[10] troglitazone achieved a 56% reduction, and in the DPP the drug was associated with a 75% reduction, although the agent was administered for less than 1 year prior to its withdrawal. In the DREAM (Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication) trial,[11] treatment with rosiglitazone achieved a 62% reduction.

Dr. Goldberg concluded by addressing the question: "Should we be considering drugs?" He explained that the "key unanswered question . . . [is] whether these interventions will prevent the development of complications in the long term," and he speculated that "If you can prevent hyperglycemia you're likely to be able to prevent microvascular disease." A number of studies have shown that microangiopathy does occur with IGT. In the DPP, 8% of nondiabetic participants had retinopathy.[12] Other studies have shown that albuminuria is present in 11% to 43% and neuropathy in 11% to 16% of persons with IGT.[13] The cardiovascular story, however, is less clear, and the ADA does not currently suggest that pharmacologic treatment of prediabetes is indicated, although the DPP Outcome Study may provide information on these questions over the coming 3-8 years. Dr. Goldberg noted, however, that the 2002 ADA guidelines suggested a glycated hemoglobin (A1C) goal of 8%, but the 2005 guidelines called for a goal of 7%, and the 2006 guidelines for a goal of 6%, reflecting the growing agreement that aggressive control of diabetes -- and by extension, aggressive prevention of diabetes -- is of great importance.

Inflammation: Measurement and Treatment
Vivian Fonseca, MD, Tulane University Medical Center, New Orleans, Louisiana, discussed a number of considerations related to the association of inflammation and diabetes.[14] He noted that there was a substantial decline in heart disease mortality among nondiabetic persons from the mid-1970s to the 1980s, with a considerably smaller decline among diabetic men, and an actual increase among diabetic women,[15] suggesting that there are factors associated with diabetes that must worsen outcome. Established risk factors, such as blood pressure, lipids, obesity, and smoking, explain part of this association, but nontraditional risk factors are also likely to be involved, including insulin resistance, endothelial dysfunction, homocysteine levels, microalbuminuria, and postprandial hyperglycemia. However, inflammation -- and the associated hypercoagulation and abnormal fibrinolysis -- has emerged as a prime candidate for the adverse consequences of diabetes. The concept, then, that atherosclerosis is an inflammatory disease[16] has been extended by studies showing that C-reactive protein (CRP) levels appear to increase risk in a complementary fashion to that of lipids and other established risk factors. CRP is associated with obesity,[17] metabolic syndrome,[18] and CVD risk,[19] and is particularly useful as a risk marker in persons with intermediate risk levels[20] for whom higher CRP levels would be a useful rationale for more aggressive treatment. Other inflammation-related factors include plasminogen activator inhibitor-1,[21] interleukin (IL)-6, and fibrinogen.[22]

A number of approaches may be taken to the treatment of inflammation, including lifestyle modification; high-dose aspirin; other salicylates; glucocorticoids; insulin; insulin sensitizers, particularly the peroxisome proliferator-activated receptor (PPAR)gamma agonists; and statins. In a study of obese postmenopausal women, weight loss led to a decrease in CRP from 3 mg/L to 1.5 mg/L.[23] Similarly, leptin, tumor necrosis factor (TNF)-alpha, and IL-6 levels decrease with diet and exercise, and adiponectin levels increase, particularly among persons with diabetes. Thiazolidinediones are effective in decreasing CRP levels, and a placebo-controlled study showed a 26% greater decrease in CRP in persons with diabetes receiving rosiglitazone compared with controls.[24] Insulin treatment to euglycemia in intensive care unit patients was associated with a greater decrease in CRP than was conventional glycemic treatment, and the reduction in CRP was associated with better outcomes.[25] Dr. Fonseca pointed out that persons with diabetic ketoacidosis have greatly increased levels of CRP and proinflammatory cytokines, which respond to the resumption of insulin treatment.[26] The effect of insulin appears to involve a reduction in intracellular nuclear factor (NF)-kappaB.[27] A meta-analysis of 20 studies of 4 different statins showed consistent reduction in CRP.[28] When administered at high (7-g/day) doses, aspirin decreases CRP and improves glucose levels, a phenomenon initially reported in the late 1800s and recently rediscovered.[29] Aspirin reduces NF-kappaB[30,31] and salsalate, which is insoluble at acidic pH and safer than aspirin; when administered at a 4.5-g daily dose, it reduces fasting glucose and triglyceride levels, although it is associated with the development of tinnitus. Dr. Fonseca described a dose-finding study, the Targeting INflammation with SALsate in Type 2 Diabetes (TINSAL-T2D), and plans for subsequently performing a randomized controlled trial with the optimal dose.

Should We Measure Waist Circumference?
Michael D. Jensen, MD, Mayo Clinic, Rochester, Minnesota,[32] addressed the usefulness of measuring waist circumference vs BMI vs waist-to-hip ratio. Waist circumference may be thought of as a reflection of both visceral and subcutaneous abdominal fat. It is not clear where waist circumference should be measured: midway between the lowest rib and iliac crest, at the umbilicus, at the narrowest or widest area, just below the lowest rib, or just above the iliac crest. Typically, waist circumference is measured standing, but Dr. Jensen noted that for some persons with lax abdominal musculature "a lot of that [abdominal fat] can go south when you have them stand!"

BMI and waist circumference correlate well with total body fat, but waist circumference has a stronger correlation with total intra-abdominal fat. There is reproducible evidence that lower body obesity is associated with normal levels of circulating free fatty acids (FFA) but that upper body obesity is associated with high levels of circulating FFA, and persons with elevated FFA have increased FFA release both in the basal state and after insulin infusion.[33,34] Elevated levels of circulating FFA are associated with insulin resistance in skeletal muscle; increased glucose release by the liver; and, acutely, with increased insulin secretion and vascular effects that lead to peripheral vasoconstriction.

Dr. Jensen reviewed the ability of the waist circumference measurement to predict health outcomes. Waist circumference is more strongly associated with type 2 diabetes and coronary heart disease[35] than is BMI, and gives important information about mortality risk.[36,37] A particularly ominous pattern may be excess upper body fat with a deficiency of lower body fat. It is not, however, certain that waist measurement will identify at-risk persons who would not be identified on the basis of BMI. Only 15% to 20% of women with a BMI of 25-29.9 have a waist circumference > 35 in, and only 4% to 10% of men with a BMI in this range have a waist circumference > 40 in. Furthermore, the optimal waist circumference for identifying abnormality is not known, and it may be necessary to use age-, sex-, and ethnicity-corrected norms. Dr. Jensen reviewed an analysis of National Health and Nutrition Examination Survey (NHANES) data showing that > 99% of men and 98% of women would not have their treatment changed on the basis of adding waist circumference measurements to BMI. He concluded that measuring waist circumference is unnecessary in persons with a BMI > 35, particularly when blood pressure, lipids, and glucose are known. However, waist measurement may be useful in determining which persons should be evaluated in more detail for blood pressure, lipids, and glucose, and also may be useful in monitoring the response to lifestyle interventions.

Obesity Management
Robert T. Ferraro, MD, Albuquerque, New Mexico,[38] introduced his discussion by reviewing the myriad interrelationships between obesity and diabetes, including the high prevalence of eating disorders and depression among persons with diabetes, the high prevalence of obstructive sleep apnea in this population, and the adverse effects of many drugs used for psychiatric illness (including antipsychotics, antidepressants, and therapies for painful neuropathy), in causing weight gain.

Americans, Dr. Ferraro stated, "are the fattest people on the planet Earth," but we are in the midst of a pandemic of obesity that affects all of the world's populations.[39] Weight loss is, however, achievable.[40,41] Moreover, there is evidence that lifestyle and behavioral weight-loss interventions are effective in reducing weight and improving glycemia in persons with type 2 diabetes. Dr. Ferraro suggested several practical clinical pearls for understanding obesity:

*Sucrose-sweetened drinks should be avoided because they increase energy intake rather than replace calorie intake from other foods;[42]

*The frequency of eating out is associated with the degree of fatness;[43]

*Foods of greater palatability increase food intake;[44]

*Large portion sizes, which consistently increase energy intake, should be avoided;[45] and

*Prepackaged meals may enhance weight loss.

The practitioner must establish the patient's readiness to lose weight. Dr. Ferraro suggested that there is a hierarchy of approaches to obesity, from lifestyle modification to pharmacotherapy -- with bariatric surgery as "the backup plan." Dr. Ferraro recommended a weight-reducing diet with ≥ 55% carbohydrates, ≤ 30% fat, and approximately 15% protein, with the target being a 10% 6-month weight loss. He characterized this level of weight loss as safe and achievable, but recognized that a 5% weight loss also is beneficial. Even harder than losing weight, he pointed out, is keeping weight off, an observation that has led to the concept that "slow weight loss is just as good as fast weight loss." Weight-loss maintenance requires ongoing physical activity.

Considering pharmacotherapy, phentermine is the most commonly used agent, although only orlistat and sibutramine have been approved for long-term use. Phentermine is inexpensive, costing approximately $15 per month for one half of a scored tablet daily. The agent is effective in achieving sustained weight loss even when used on an "as-needed" basis,[46] suggesting that its use in appropriate cases should be reconsidered. In the XENDOS trial, orlistat was associated with a 5.9-kg weight loss at 4 years, twice the 3-kg weight loss of a group receiving placebo but similarly intensive dietary counseling. Sibutramine has benefits that are similar to those of phentermine. Dr. Ferraro reviewed a 1102-person study comparing placebo, 15 mg sibutramine daily for 48 weeks and 15 mg sibutramine daily for 12 weeks, then 6 weeks on therapy and 6 weeks off for the next 36 weeks, showing a 0.2-kg weight gain and 3.8- and 3.3-kg weight loss, respectively, suggesting that intermittent treatment with this agent is also effective.[47]

From Prediabetes to Diabetes to Cardiovascular Complications: Is the Progression Preventable? CME
Jorge Plutzky, MD
Disclosures

Carotid intima-media thickness (CIMT) is an intermediate phenotype for early atherosclerosis. Because CIMT can be measured relatively simply and noninvasively with ultrasonography, it is well suited for use in large-scale population studies. A recently published meta-analysis of 8 studies, which included more than 37,000 patients who were followed for 5 years, demonstrated that CIMT was a strong predictor of future vascular events (Table 1).[1] This meta-analysis confirms the value of CIMT as a surrogate marker in endpoint studies evaluating the potential impact of existing and emerging drug therapies on cardiovascular disease (CVD); it also raises the potential usefulness of CIMT in screening patients who do not yet have a history of CVD.[1]

Table 1. Relative Risk of Myocardial Infarction and Stroke With Increases in CIMT
Risk for -------------------------------------------Relative Risk---------------- 95% CI
MI per standard deviation IMT difference ---------1.26--------------------- 1.21-1.30
MI per 0.10-mm IMT difference --------------------1.15 ---------------------1.12-1.17
Stroke per standard deviation IMT difference -----1.32 ---------------------1.27-1.38
Stroke per 0.10-mm IMT difference ---------------1.18 ----------------------1.16-1.21
MI = myocardial infarction; CIMT = carotid intima-media thickness; CI = confidence interval

A study published in The New England Journal of Medicine discussed the association of rosiglitazone and ischemic events. GlaxoSmithKline, manufacturer of rosiglitazone, provided the US Food and Drug Administration (FDA) with information about this association last August. The FDA believed that more information was needed to make a determination about the safety of the drug. The American Heart Association, American College of Cardiology, and the American Diabetes Association stated that "This study deserves serious thought and follow-up. As estimated here, the overall level of risk associated with rosiglitazone appears to be small, but nonetheless one that must be considered carefully."[2] At this time, the FDA is encouraging physicians to have patients stay on their medication until more information is available.

CIMT has been applied in studies of CVD among subjects with diabetes. Several, large-scale, clinical trials have investigated the effects of controlling glycemia as well as other risk factors on carotid changes and presumably the risk for future CVD events (Figure). Recent trials with the insulin-sensitizing thiazolidinedione (TZD) antidiabetic drug class have assessed CIMT as part of the evaluation of the effects of TZDs on atherosclerosis progression and cardiovascular (CV) outcomes.[3-5] In general, these results have supported the hypothesis that TZDs may have direct and/or indirect effects that reduce atherosclerosis.

Figure. Large multicenter trials on cardiovascular disease prevention in diabetes or prediabetes.

The Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone (CHICAGO) study was presented at the 2006 American Heart Association meeting and published concurrently in JAMA.[3] This study was a randomized, double-blind, comparator-controlled trial that included 462 patients with type 2 diabetes and was conducted at 28 clinical sites in the Chicago, Illinois, metropolitan area. Patients were randomized to receive 72 weeks of treatment with either pioglitazone or glimepiride, titrated to the glycemic goal of a fasting glucose level of 140 mg/dL with 1 of 3 doses of each agent per day, that is, pioglitazone 15-45 mg or glimepiride 1-4 mg.[3]

At baseline, patients had a mean duration of diabetes of 7.7 years, a mean glycated hemoglobin (A1C) value of 7.4%, and well-controlled blood pressure. About 55% of subjects in both groups (pioglitazone and glimepiride) were receiving statins. Study participants were either newly diagnosed with type 2 diabetes or were being treated at study enrollment with diet and exercise, sulfonylurea, metformin, insulin, or a combination of these agents. Patients were excluded if they already had significant CV or cerebrovascular disease. CIMT images were captured by a single ultrasonographer at 1 center and read by a single expert sonogram reader blinded to treatment assignment and using automated edge-detection technology to optimize consistency and to keep the study unbiased.[3]

The primary outcome measure was the absolute change from baseline to the final visit at 72 weeks in the mean posterior-wall CIMT of the left and right common carotid arteries (Table 2). The secondary outcome measure was the absolute change in maximal CIMT from baseline to final visit.[3]

Table 2. CHICAGO: Progression of Mean CIMT at Week 72 With Pioglitazone vs Glimepiride
Endpoint-------------------Pioglitazone -Glimepiride---- Difference(95% CI)------- P Value
Primary outcome (mm)__-0.001-------+0.012_____-0.013 (-0.024 to 0.002)-------.02
Secondary outcome (mm) +0.002-----+0.026——— -0.024 (-0.042 to 0.006)----- .008

CHICAGO = Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone study
This study found that treatment with pioglitazone was associated with less thickening of the carotid artery than treatment with glimepiride in patients with type 2 diabetes.[3] Similarly, pioglitazone slowed the progression of maximum CIMT compared with glimepiride. However, this study was not powered to look at clinical outcomes. It is important to note that glucose control was nearly matched between these groups, supporting the hypothesis that peroxisome proliferator-activated receptor-gamma agonists (eg, pioglitazone, rosiglitazone) might have direct vascular effects independent of effects on glucose levels.

Adverse events occurred in approximately 89% of patients in both groups; serious adverse events occurred in 25 of the pioglitazone recipients (10.9%) vs 30 (13.2%) of those taking glimepiride. The most common adverse events included hypoglycemia, nasopharyngitis, peripheral edema, and arthralgia.

The most recent CIMT outcome study, which was presented at the American College of Cardiology 56th Annual Scientific Session in New Orleans, Louisiana, is the Study of Atherosclerosis with Ramipril and Rosiglitazone (STARR). In STARR, 1425 prediabetes patients enrolled in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial underwent carotid ultrasound at baseline and again at the end of the trial (mean time, 3 years).[4] Patients were randomized in a 2 x 2 factorial design to ramipril or placebo and then to rosiglitazone or placebo.[4] In the larger DREAM study, rosiglitazone had a major, statistically significant effect on the development of new type 2 diabetes in patients with prediabetes (defined as impaired fasting glucose levels, impaired glucose tolerance, or both) at baseline, reducing diabetes development by ~60%. Ramipril had no effect.[6] The primary outcome in STARR was the average change in IMT per year in 12 segments of the carotid artery (Table 3). The secondary outcome was the change of 2 IMT measurements in the common carotid far wall.

Table 3. STARR: Change in CIMT With Rosiglitazone and Placebo
Endpoint ------------------------------------------Rosiglitazone ---------------Placebo -----------P
Change in primary IMT measurement (mm/y) 0.0069 ---------------------0.0091 --------.17
Change in secondary IMT measurement (mm/y) 0.0018------------------ 0.0060--------- .017

Lonn E, et al. American College of Cardiology 2007 Scientific Sessions. March 27, 2007
The data presented at the American College of Cardiology meeting suggested that the primary outcome in STARR did not reach statistical significance; however, there was a trend toward stabilization of carotid vascular disease with rosiglitazone treatment. The secondary outcome did demonstrate a statistically significant effect on vascular wall thickness in response to rosiglitazone. Of note, ramipril did not have an effect on either the primary or secondary CIMT endpoint. Various factors, including differences in patient populations, limit the ability to directly compare or combine the STARR and CHICAGO datasets, but together these studies support the potential vascular benefits of TZDs. Full integration of these data into treatment options awaits review of the final published data, but data from STARR and DREAM continue to raise issues about how best to intervene in patients with "prediabetes," the prospect for altering their CV risk, and the potential of TZDs as a tool for these ends.

The data from STARR and CHICAGO should be seen in the context of the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) study, the first randomized, double-blind, placebo-controlled study to examine macrovascular outcomes in patients with type 2 diabetes. The study enrolled 5238 patients with type 2 diabetes at high risk for CV events because of the presence of macrovascular disease, including previous stroke, myocardial infarction (MI), revascularization, or peripheral artery disease, and objective evidence of coronary artery disease.[5] This study was designed to examine a combined endpoint of various CV events, including peripheral revascularization among patients with type 2 diabetes who had matched A1C values. In contrast with patients in the CHICAGO study, none of these patients were newly diagnosed with type 2 diabetes and all had CVD. The duration of the study was shorter than expected (36 months vs a planned 48 months). The primary composite endpoint was not significantly different, although this may have been influenced by the inclusion of endpoints, such as peripheral vascular disease. There was a 16% reduction in relative risk of a secondary composite endpoint consisting of all-cause mortality, nonfatal MI (excluding silent MI), or stroke (P = .027).[5] A difference was also noted in the incidence of recurrent strokes.[7] PROactive did not include CIMT as an endpoint.

Current and Future Treatment Strategies
TZDs have shown considerable promise in preventing or slowing the progression from prediabetes to diabetes and from diabetes to CV complications. Their effects on insulin resistance and myriad intermediates of CVD (eg, lipids, inflammatory cytokines) suggest potential benefits for at-risk patients that may extend beyond improved glucose control. One endpoint supporting the possible impact of TZDs is CIMT. The noninvasive nature of CIMT measurement and the growing database supporting its relationship to atherosclerosis continue to demonstrate that this procedure is a useful marker for clinical research and may have utility in clinical practice.

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2007-06-18 08:48 浏览 : 17349 回复 : 55

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漂亮瓶编辑于 2008-05-26 22:43

• 【规培笔记128】—工作报告偶遇，颅脑MR，据说工作中很罕见——肾性脑病！

scarletbing

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谢谢版主，真是好东西呀

2007-06-18 12:58

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• 一图解读｜血常规化验单

iloveice

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支持，漂亮瓶版主上任后动作不断，支持中！投一票！

2007-06-18 19:34

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• 普外医话:术后出现并发症，如何看待二进宫?

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漂亮瓶

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评论：HDL胆固醇一直在我们心目中是有益的，IDEAL研究结论：HDL胆固醇在校正apoA-1及其它血脂变量后是不利的风险因子，对心血管疾病无保护作用，不是越高越好。这是一个全新的观点。

IDEAL: High Levels of HDL Cholesterol a Poor Marker of Cardioprotection When Adjusted for ApoA-1 and ApoB

Michael O'Riordan

June 13, 2007 (Helsinki, Finland) - An analysis of the Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) study suggests that high levels of HDL cholesterol, when adjusted for apolipoprotein A1 (apoA-1) and other lipoprotein variables, might be an adverse risk factor for cardiovascular disease and a poor marker of cardioprotection [1].

Presenting the findings from the analysis at the European Atherosclerosis Society (EAS) 76th Congress in Helsinki, Finland, investigators showed that increased levels of HDL cholesterol, when adjusted for apoB and apoA-1, were associated with an increased risk of major cardiac events, particularly at levels greater than 70 mg/dL.

"Epidemiologic data suggest that HDL cholesterol is an independent, inverse predictor of coronary heart disease risk," lead investigator Dr Ingar Holme (Ullevål University Hospital, Oslo, Norway) explained during the late-breaking plenary session. "But recent findings from the torcetrapib trials have suggested that high HDL-cholesterol levels might have an adverse effect on CHD risk. On this basis, we looked at the relationship between high HDL-cholesterol levels and coronary-event rates."

Legacy of torcetrapib spurs analysis

As previously reported by heartwire, torcetrapib was a high-profile cholesteryl-ester-transfer protein (CETP) inhibitor designed to increase HDL cholesterol and decrease, to a small degree, LDL-cholesterol levels, a typically antiatherogenic profile. The much-anticipated and heavily hyped drug was stopped in development in early 2007 when investigators showed it increased the risk of death and cardiovascular events.

With these concerns in mind, that high levels of HDL cholesterol might actually be harmful, the IDEAL investigators performed a post hoc analysis of their data to assess the relationship between HDL-cholesterol levels and coronary heart disease events. Special emphasis was placed on HDL-cholesterol levels >70 mg/dL, especially when apoA-1 and apoB were kept constant. The group also wanted to evaluate the predictive ability of increased apoA-1 on major cardiac-event risk, again when HDL cholesterol and apoB were constant.

IDEAL, in a nutshell
The IDEAL study, previously reported by heartwire, was a prospective, randomized, open-label, blinded-end-point evaluation trial conducted in 8888 patients aged 80 years or younger with a history of acute MI. The primary end point of coronary death, acute MI, or cardiac arrest with resuscitation occurred in 463 patients (10.4%) in the simvastatin group and in 411 patients (9.3%) in the atorvastatin group and was not statistically significantly different between the two study arms. The composite secondary end point of a major cardiovascular event, defined as major coronary events and stroke, was significantly reduced in patients treated with atorvastatin. Similarly, there were reductions in the risk of nonfatal MI, any CHD event, and any cardiovascular event.

As presented earlier at the EAS meeting, Holme noted that the incidence of major cardiovascular events in the IDEAL study declined with increasing HDL-cholesterol levels. However, he said that there was wide variation in the highest quintile, including patients with an HDL-cholesterol level >54.1 mg/dL, and investigators were interested in the relationship with coronary events at this high level. After adjustment for various lipoproteins, the risk of major cardiac events was shown to increase with increasing levels of HDL cholesterol.

Relationship of HDL cholesterol to major cardiac events
Adjustment variable----------------Hazard ratio per each 12-mg/dL increase in HDL cholesterol---------p
None-------------------------------------------------------0.92-----------------------------------------------0.043
LDL cholesterol-------------------------------------------0.91------------------------------------------------0.021
ApoA-1---------------------------------------------------1.05------------------------------------------------0.59
ApoA-1, LDL cholesterol--------------------------------1.11-------------------------------------------------0.26
ApoA-1, apoB--------------------------------------------1.21------------------------------------------------0.038
ApoA-1, LDL cholesterol, apoB-------------------------1.26------------------------------------------------0.020
One standard-deviation increase in HDL cholesterol=12 mg/dL

Relationship of apoA-1 to risk of major cardiac events
Adjustment variable----------------Hazard ratio per each 0.22-g/L increase in apoA-1------------------p
None------------------------------------------------------0.90-----------------------------------------------0.012
HDL cholesterol------------------------------------------0.86-----------------------------------------------0.108
HDL cholesterol, apoB-----------------------------------0.74-----------------------------------------------0.002
One standard-deviation increase in apoA-1=0.22 g/L

"If we adjust for LDL cholesterol, not much happens," said Holme. "However, once we start to adjust for apoA-1, this benefit is turned in the direction of risk. If we also adjust for LDL cholesterol and apoB, a better predictor of risk than LDL cholesterol, then the risk of major cardiac events starts to become significant." He said that by adjusting for apoA-1 statistically and increasing HDL cholesterol, the analysis reflects the effects of increasing HDL particle size.

Increased levels of apoA-1, on the other hand, whether or not adjustments were made for HDL cholesterol and apoB, were associated with decreased risk, said Holme.

"When adjusting for apoA-1 and other lipoprotein variables, a high level of HDL cholesterol might be a poor marker of cardioprotection," said Holme. "In contrast, apoA-1 may be associated with decreased major cardiac events across the whole range, whether or not adjustments for HDL cholesterol and apoB are made."

Holme noted that there are limitations with the analysis, the post hoc nature of the study being one of them. Adjustments for lifestyle, concomitant medications, or other considerations were not made either, he noted, adding that these are observational findings from the combined treatment groups and not from the randomized comparisons.

Why no clinical benefit with the CETP inhibitor?

A second study, by Dr Wim van der Steeg (Academic Medical Center, Amsterdam, the Netherlands), also suggests that very large HDL particles do not confer protection against cardiovascular disease, at least when levels of apoA-1 and apoB are kept constant [2].

Presenting the results during the same late-breaking plenary session, van der Steeg, who works with lipid expert Dr John Kastelein (Academic Medical Center), said the hypothesis of the present study was that an increase in HDL particle size, induced by CETP inhibitors like torcetrapib, might affect its antiatherogenic capacity and might result in less functional and possibly even dysfunctional HDL cholesterol.

In this case-control study, investigators studied 858 cases of fatal and nonfatal MI in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk Population Study and 1491 matched controls. HDL particle size was measured by nuclear magnetic resonance spectroscopy. The focus of the analysis was the relationship between HDL particle size and cardiovascular events, particularly with very large HDL particles.

After adjustment for classical cardiovascular risk factors, as well as for apoA-1 and apoB, very large HDL particles, those >9.5 nm, were associated with an increased cardiovascular risk. Very high levels of HDL cholesterol also showed a trend toward increased cardiovascular risk. Very high levels of apoA-1, following an adjustment for classic cardiovascular risk factors as well as HDL cholesterol and apoB, were not associated with an increased risk, the group found.

referrence

1、Holme I, Kastelein JJ, Faergeman O, et al. High HDL-C and CHD risk in statin-treated CHD patients: Analysis of the Incremental Decrease in Endpoints Through Aggressive Lipid-Lowering (IDEAL) trial. European Atherosclerosis Society 76th Congress; June 12, 2007; Helsinki, Finland.
2、van der Steeg, Holme I, Boekholdt SM, et al. Relationship between high-density lipoprotein particle size and coronary artery disease risk in the EPIC-Norfolk Prospective Study. European Atherosclerosis Society 76th Congress; June 12, 2007; Helsinki, Finland.

2007-06-20 11:37

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漂亮瓶编辑于 2007-06-20 11:55

• 回应：饶毅发文称“正式举报裴钢为通讯作者的文章涉嫌学术不端”

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【进展】内分泌进展瞭望窗口(2008-5-26罗格列酮与匹格列酮：怎么使用？) [精华]

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