ORLANDO (EGMN) –Rosuvastatin proved markedly effective for the primary prevention of major cardiovascular events in patients with impaired fasting glucose in a secondary analysis from the JUPITER trial.
This is the first solid proof of a primary prevention benefit for statin therapy in patients with impaired fasting glucose (IFG). While statins are guideline-recommended for nearly all diabetes patients, until now there has been little supporting evidence of a cardiovascular benefit in otherwise healthy individuals with IFG.
That is, until JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin), which included 5,504 participants with baseline IFG, Dr. Aruna Pradhan observed at the annual scientific sessions of the American Heart Association.
On the downside, rosuvastatin therapy also was associated with a significantly increased rate of new-onset diabetes compared with placebo. The risk was of similar magnitude in rosuvastatin-treated subjects with baseline IFG and in those with normal fasting glucose. This phenomenon appears to be a statin class effect, as it has also been consistently seen in major placebo-controlled trials involving other statins, said Dr. Pradhan of Brigham and Women’s Hospital, Boston.
JUPITER randomized 17,802 men and women with no prior cardiovascular disease or diabetes to 20 mg/day of rosuvastatin (Crestor) or placebo. Of note, all participants had a high-sensitivity C-reactive protein level of 2.0 mg/L or more and an LDL cholesterol below 130 mg/dL. The prevalence of metabolic syndrome was 74% among subjects with baseline IFG and 27% in those with normal fasting glucose.
JUPITER was halted after a median 1.9 years of follow-up, after the data and safety monitoring board determined that rosuvastatin had an “unequivocal benefit” on coronary-related death and disability. At that time, the rosuvastatin-treated subjects with IFG had a 32% reduction in the risk of the primary composite end point, comprised of MI, stroke, hospitalization for unstable angina, coronary revascularization, or cardiovascular death, compared with placebo-treated participants with IFG. This benefit was not significantly different in magnitude from the 49% relative risk reduction seen in rosuvastatin-treated subjects with baseline normal fasting glucose, according to Dr. Pradhan.
There were 182 cases of physician-diagnosed incident diabetes in subjects with IFG on rosuvastatin, compared with 145 arising in those on placebo, representing a 30% increase in risk. This was statistically similar to the 26% relative risk associated with rosuvastatin in the normal fasting glucose group, although not surprisingly, the absolute number of cases of diabetes in subjects with baseline normal fasting glucose was far smaller: 54 cases in rosuvastatin-treated subjects compared with 43 in controls.
Dr. Pradhan noted that this finding of a rosuvastatin-associated increase in new-onset diabetes in JUPITER is consistent with the results of a recent meta-analysis led by investigators at Albert Einstein College of Medicine in New York.
The meta-analysis included nearly 58,000 participants in nine major placebo-controlled randomized statin trials. During a mean follow-up of 3.9 years, more than 2,000 cases of new-onset diabetes occurred. Only the first of the trials—the West of Scotland Coronary Prevention Study (WOSCOPS)—found that statin therapy reduced new-onset diabetes. The next eight studies, including such landmark trials as the Heart Protection Study (HPS) and the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), as well as JUPITER, collectively showed a significant 13% increase in incident diabetes in statin-treated subjects (Diabetes Care 2009;32:1924-9).
One audience member wondered aloud whether diabetes arising in statin-treated patients might behave differently, perhaps with less associated cardiovascular risk. Dr. Pradhan replied that JUPITER is unlikely to provide an answer. Because the trial was halted after a median of just 1.9 years, there was not enough time for a large number of cardiovascular events to accrue following the diagnosis of diabetes.
“That’s a very important issue for future determination, though: Is the type of diabetes that patients get on statin therapy relatively cardiovascular disease free?” she said.
JUPITER was funded by AstraZeneca. Dr. Pradhan disclosed having no relevant financial conflicts.
Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
奥兰多(EGM)——JUPITER试验的二次分析证实，瑞舒伐他汀用于空腹血糖受损(IFG)患者重大心血管事件的一级预防，效果显著。
这是IFG患者中他汀类药物初级预防收益的首个有力证据。然而，他汀类药物仅被指南推荐用于几乎所有糖尿病患者，迄今为止，其在相对健康的IFG患者中的心血管益处仍缺乏证据支持。
然而，这一情况随着JUPITER(初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)的问世而改变。Aruna Pradhan 博士在美国心脏学会（AHA）科学年会上报告了针对5,504例IFG患者的JUPITER结果。这是他汀类药物对IFG患者具有一级预防获益的首个确凿证据。
然而，与安慰剂相比，瑞舒伐他汀治疗还伴有新发糖尿病的显著升高。在基线IFG患者和空腹血糖正常者中，这一风险程度相似。因为在涉及其他他汀类药物的主要的安慰剂对照试验中均观察到这一现象，所以这似乎是他汀类药物的共性。
JUPITER将17,802例既往无心血管疾病或糖尿病的男女性参与者随机分为瑞舒伐他汀(Crestor)20 mg/d组或安慰剂组。值得注意的是，所有参与者的高敏C反应蛋白水平均≥2.0 mg/L，LDL-C均<130 mg/dl。基线IFG患者和空腹血糖正常者中，代谢综合征的患病率分别为74%和27%。
由于数据和安全监测委员会判定瑞舒伐他汀组在冠脉相关死亡和残疾方面具有“明确益处”，故JUPITER中位随访至1.9年即被终止。Pradhan 博士指出，研究终止时，接受瑞舒伐他汀治疗的IFG患者主要复合终点(包括心肌梗死、卒中、因不稳定型心绞痛住院、冠脉血运重建或心血管死亡)风险比安慰剂组IFG患者降低了32%。这一获益程度同在基线空腹血糖正常者中接受瑞舒伐他汀治疗相对风险降低49%相比，无显著性差异。
在接受瑞舒伐他汀治疗的IFG患者中，瑞舒伐他汀组182例被诊断为偶发糖尿病，而安慰剂组为145例，提示瑞舒伐他汀使IFG患者的新发糖尿病风险增加30%。这在统计学上类似于瑞舒伐他汀在空腹血糖正常者中的相对风险(增加26%)，然而这不足为奇，因为基线空腹血糖正常者中的糖尿病绝对病例数少得多：瑞舒伐他汀组与安慰剂组分别有54例和43例新发糖尿病。
Pradhan博士指出，JUPITER中瑞舒伐他汀与新发糖尿病风险增加的关联，与近期纽约Albert Einstein医学院研究人员所进行的一项Meta分析结果一致。
这项Meta分析纳入了9项大规模安慰剂对照他汀类药物试验的近58,000例患者。在平均随访3.9年期间，新发糖尿病2,000多例。这9项试验中，仅有最早的一项研究——西苏格兰冠心病预防研究(WOSCOPS)——显示，他汀类药物治疗可减少新发糖尿病。其他8项研究，包括诸如心脏保护研究(HPS)、盎格鲁-斯堪地纳维亚心脏终点试验(ASCOT)等具有里程碑意义的临床试验，以及JUPITER的汇总结果显示，他汀类药物治疗者的糖尿病发病率显著增加13% (Diabetes Care 2009;32:1924-9)。
一位与会者提问，他汀类药物治疗者发生的糖尿病是否可能有所不同，例如相关心血管风险是否可能较低。Pradhan博士回答说，JUPITER不太可能给出答案，因为这项试验仅中位随访1.9年即被终止，故对新发糖尿病在诊断后增加的很多心血管事件的随访时间不足。
Pradhan 博士说：“这是将来研究的重要课题，然而：接受他汀类药物治疗的患者罹患的糖尿病类型是否相对无心血管疾病风险呢？”
JUPITER由AstraZeneca资助。Pradhan博士称其无相关经济利益冲突。
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