他汀的心血管益处似大于糖尿病风险

《柳叶刀》(Lancet)8月9日在线发表的有关JUPITER(一级预防中应用他汀类药物的理由：评价瑞舒伐他汀的干预试验)数据的最新分析显示，他汀类药物治疗的心血管益处大于发生糖尿病的风险，即使在合并多种糖尿病危险因素的患者中也是如此(Lancet 2012;380:565-71)。

鉴于近期有证据提示所有他汀类药物与2型糖尿病风险轻微增加有关，因此波士顿布里格姆妇女医院的Paul Ridker博士及其同事采用随机、双盲、安慰剂对照JUPITER研究的数据，评估了他汀类药物的血管益处与糖尿病风险。

Paul Ridker博士

研究者根据入组时的糖尿病危险因素将17,603例受试者分成2组，评价瑞舒伐他汀(Crestor) (20 mg/d，连用5年)对心血管和死亡风险及糖尿病风险的影响。

在该研究队列中，6,095例患者入组时无主要糖尿病危险因素，11,508例患者合并≥1种主要危险因素，包括代谢综合征、空腹血糖受损、体重指数≥30 kg/m2和血红蛋白A1c(HbA1c)＞6％。与无糖尿病危险因素的患者相比，合并多种危险因素的患者中女性比例更高，基线血压、HbA1c、血糖和甘油三酯水平较高，并且基线HDL胆固醇水平较低。随访期间，合并多种糖尿病危险因素的患者发生糖尿病的风险增加，发生率为1.88例/100人-年，而无糖尿病危险因素患者的糖尿病发生率为0.18例/100人-年。

瑞舒伐他汀组的糖尿病病例多于安慰剂组(270例vs. 216例)，危险比(HR)为1.25。瑞舒伐他汀组和安慰剂组发生糖尿病的患者从随机化至诊断的平均时间分别为84.3周和89.7周。瑞舒伐他汀组糖尿病风险增加的患者基本上为基线时空腹血糖受损的患者。

在瑞舒伐他汀组中，有和无糖尿病危险因素的患者的主要终点事件(心肌梗死、卒中、因不稳定型心绞痛入院、动脉血运重建或心血管死亡)发生率分别降低39%和52%。此外，在瑞舒伐他汀组中，合并糖尿病危险因素的患者的血栓栓塞发生率降低36%，总死亡率降低17%，糖尿病发生率增加28%，而无糖尿病危险因素的患者的静脉血栓栓塞发生率降低53%，总死亡率降低22%，糖尿病风险未见增加。

从绝对数量来看，在瑞舒伐他汀组合并糖尿病危险因素的患者中，每新增54例糖尿病的同时，就可总共避免134起心血管事件或死亡，而在该组无糖尿病危险因素的患者中，瑞舒伐他汀的使用在不增加新糖尿病病例的同时可避免共86起心血管事件或死亡。

在主要心血管终点方面，在合并糖尿病危险因素的患者中观察到的归因于瑞舒伐他汀的相对治疗益处与在无糖尿病危险因素的患者中观察到的相似。此外，瑞舒伐他汀对所有主要和次要终点事件的相对益处和风险基本一致，在所有亚组中也是如此，并且随着糖尿病危险因素数量的增加，瑞舒伐他汀相关糖尿病风险并未发生显著改变。

研究者对研究期间发生糖尿病的486例患者进行观察发现，这些患者发生18起主要心血管终点事件，其中8起在瑞舒伐他汀组(1.10/100人-年)，10起在安慰剂组(1.73/100人-年)。因此，糖尿病患者服用瑞舒伐他汀的心血管益处与试验总体人群一致。

该分析结果表明，在有和无主要糖尿病危险因素的患者中，他汀类药物治疗的心血管和生存益处均大于糖尿病风险。

然而，该分析结果存在一些局限性，例如，所有患者的血清C反应蛋白(hsCRP)水平均较高，而hsCRP是2型糖尿病和心血管事件的危险标志物。因此，分析结果或许不能外推至hsCRP＜2 mg/L者。此外，尽管所有他汀类药物均可增加糖尿病风险，但该分析结果仅限于单种剂量的瑞舒伐他汀。JUPITER研究的中位随访时间为2年，因此不应将此分析结果视为长期结果。

在随刊述评中，西澳大利亚大学的Gerald F. Watts博士和Esther M. Ooi博士指出，该分析结果再次肯定了他汀类药物在心血管疾病一级预防中的净收益。在进行心血管疾病的一级或二级预防时，临床医生需向合并主要糖尿病危险因素的患者(特别是空腹血糖受损的患者)告知他汀类药物的风险，定期监测有无高血糖，并建议患者减肥和规律锻炼，以降低发生糖尿病的风险(Lancet 2012;380:541-3)。

上述分析和JUPITER试验由阿斯利康公司资助。Ridker博士及其同事声明与阿斯利康等公司存在利益关系。Watts博士声明从阿斯利康等公司获得酬金或演讲费。Ooi博士报告称无经济利益冲突。

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By: DIANA MAHONEY, Cardiology News Digital Network

The cardiovascular benefits of statin treatment outweigh the risk of developing diabetes, even among individuals with multiple diabetes risk factors, according to a new analysis of data from the JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial reported online ahead of print in the Lancet on Aug. 9.

In light of recent evidence suggesting a small increased risk of incident type 2 diabetes associated with all statins, Dr. Paul Ridker of Brigham and Women’s Hospital in Boston and his colleagues sought to evaluate the balance of vascular benefits and the diabetes hazard of statin use in JUPITER trial participants.
 
Toward this end, they divided 17,603 individuals who took part in the randomized, double-blind, placebo-controlled JUPITER trial into two groups based on diabetes risk factors at study entry, and assessed the impact of rosuvastatin (Crestor) allocation (20 mg/day for up to 5 years) on cardiovascular and mortality risk and the risk of developing incident diabetes.

Of the study cohort, 6,095 individuals had no major risk factors for diabetes at study entry, and 11,508 had one or more major risk factors, defined as metabolic syndrome, impaired fasting glucose, body mass index of 30 kg/m2 or higher, and hemoglobin A1c greater than 6%. Subjects in the latter category were more likely to be female; have higher baseline blood pressure, HbA1c, glucose, and triglyceride values; and have lower baseline HDL cholesterol levels, the authors wrote.

Predictably, those patients with one or more diabetes risk factors had an increased risk of developing diabetes during trial follow-up, with an incidence rate of 1.88 per 100 person-years, compared with 0.18 per 100 person-years in those with no diabetes risk factors, the authors reported (Lancet 2012;380:565-71).

Incident diabetes occurred more frequently in the rosuvastatin group than in the placebo group, with a hazard ratio of 1.25 (270 vs. 216 cases, respectively). Among those who developed diabetes, the average time from randomization to diagnosis was shorter in the statin group, at 84.3 weeks vs. 89.7 weeks. "Almost all the excess risk of diabetes associated with rosuvastatin occurred in participants with baseline evidence of impaired fasting glucose," the authors noted.

In participants with and without diabetes risk factors, random allocation to rosuvastatin was associated with 39% and 52% reductions, respectively, in the study’s primary end point (myocardial infarction, stroke, hospital admission for unstable angina, arterial revascularization, or cardiovascular death), the authors wrote. Further, among those with diabetes risk factors, statin use was associated with a 36% reduction in thromboembolism, a 17% reduction in total mortality, and a 28% increase in diabetes, while statin use in the risk-free group led to a 53% reduction in venous thromboembolism, a 22% reduction in total mortality, and no increase in diabetes risk.

In absolute terms, among those with one or more diabetes risks, a total of 134 cardiovascular events or deaths were avoided in the statin users for every 54 new cases of diabetes, and among those with no diabetes risks, 86 total cardiovascular events or deaths were avoided with no excess new cases of diabetes diagnosed.

With respect to the primary cardiovascular end point, "the relative treatment benefits attributable to rosuvastatin were similar in participants with and without diabetes risk factors," the authors wrote. They also noted that the relative benefits and risks of rosuvastatin were generally consistent for all components of the primary and secondary end points and in all subgroups evaluated, and the risks of diabetes associated with rosuvastatin use did not change substantially as the number of diabetes risk factors increased.

The investigators also looked specifically at participants who developed diabetes during the trial and observed that, of the 486 total, 18 primary cardiovascular end points occurred, including 8 among rosuvastatin patients (1.10 per 100 person-years) and 10 in placebo patients (1.73 per 100 person-years). Thus, the authors reported, "the cardiovascular risk reduction associated with rosuvastatin was consistent with that for the trial as a whole."

The findings suggest that the cardiovascular and mortality benefits of statin therapy exceed the diabetes hazard in individuals with and without major diabetes risk, the authors stated.

They acknowledged, however, that the findings are limited by the fact that all of the study participants had elevated serum C-reactive protein (hsCRP) levels, which is a risk marker for both incident type 2 diabetes and incident cardiovascular events. "Thus, care should be used when considering these primary prevention data for those with hsCRP less than 2 mg/L," they cautioned. Other limitations of the findings include the fact that data from this analysis were limited to rosuvastatin at one dose, even though all statins increase diabetes risk, and the fact that the median JUPITER follow-up was 2 years, so "long-term data for benefits and risks cannot be gleaned from this study," they said.

In an accompanying commentary, Dr. Gerald F. Watts and Dr. Esther M. Ooi of the University of Western Australia, Perth, noted that although the findings reaffirm the net value of statins in the primary prevention of cardiovascular disease, "the diabetogenic effect of these drugs is highest in individuals with risk factors for diabetes, including raised C-reactive protein," while the risk of diabetes is negligible in the absence of statins. As such, they wrote, "a major take-home message for the clinician involved in either primary or secondary prevention of cardiovascular disease is that all individuals on a statin who have major risk factors for diabetes, particularly impaired fasting glucose, need to be informed about the risk, monitored regularly for hyperglycemia, and advised to lose weight and take regular physical exercise to mitigate the emergence of diabetes" (Lancet 2012;380:541-3).

This analysis and the JUPITER trial were funded by AstraZeneca. Dr. Ridker and some of his coinvestigators disclosed financial relationships with AstraZeneca, Merck, Isis, and other companies. Dr. Watts disclosed receiving honoraria or lecture fees from AstraZeneca, Pfizer, Merck Sharp & Dohme, and other companies. Dr. Ooi declared that she had no financial conflicts of interest.