Yusuf, Kaul launch rocket attack at JUPITER; Ridker responds

JUPITER substantially overestimates the benefits of rosuvastatin, according to Salim Yusuf and colleagues, in a comment in the Lancet, and Sanjay Kaul, in a response provided to CardioBrief. JUPITER leader Paul Ridker disagrees, of course, in a comment to CardioBrief.

In their Lancet comment, Yusuf et al note that the benefits observed in JUPITER were considerably greater than would be expected from previous trials with the drug. The “real benefit” of rosuvastatin is “unlikely to be larger than a 20-30% reduction in relative risk for ischemic events, and a 10% reduction for total mortality. Both estimates are within the 95% CI of the estimates on specific events observed in JUPITER.” In addition, “the role of CRP as a predictor of risk remains controversial.”

Ridker responded to the comment by emphasizing the “real world” aspect of JUPITER and questioning Yusuf’s motivations, as he is involved with the competing prevention strategy of the polypill:

Unless I am mistaken, JUPITER was not a theoretical concept, but a real trial performed in the real world. It is quite understandable, however, why Professor Yusuf and colleagues might feel the need to suggest that the benefits observed in JUPITER are not real since their stated and laudable goal is to launch a polypill trial using three anti-hypertensives, aspirin, and a low dose statin. JUPITER poses quite a problem for such a trial, however. After all,  if a single statin agent given at a full dose demonstrates a 50 percent reduction in risk in the absence of any bleeding effects or dizzyness, why would one risk the side effects of aspirin and anti-hypertensives on top of a low dose statin? What if a full-dose statin is already the perfect “polypill”?

Sanjay Kaul agrees with Yusuf, emphasizing the likelihood that the magnitude of effect may have been magnified because the trial was stopped early:

Yusuf et al. make many important points that I concur with. The results of the recently published AURORA trial in patients on hemodialysis add to the observations described by Yusuf et al in their commentary. As in CORONA and GISSI-HF trials, treatment with rosuvastatin reduced LDL levels as well as hsCRP (11% compared to 37% in JUPITER), without impacting cardiovascular outcomes. So why should treatment with rosuvastatin result in a cardiovascular outcome benefit in primary prevention, but not in secondary prevention? A likely explanation is that truncated trials are notorious for producing implausibly large (“too good to be true”) treatment effects. Such “random high” observations seen at early time points invariably “regress to the mean” (truth) upon longer follow-up. There are numerous examples of this phenomenon in the clinical trial literature. This then begs the question whether JUPITER should have been stopped early. In my opinion, trials should ideally be stopped for safety or futility concerns, not for “implausibly large” treatment effects. Event the all-cause mortality benefit appears to be driven by cancer mortality, likely a spurious observation. This has important implications for interpretation of overall benefit-risk. It is likely that benefit of statin therapy in JUPITER was overestimated and risk underestimated due to early stopping, suboptimal compliance and enrollment of highly selective population. Moreover, increased risk of incident diabetes in statin arm appears to be worrisome. Finally, not being able to know the long-term safety of “ultra-low LDL” levels is quite frankly a lost opportunity.

In conclusion, to paraphrase Victor Montori and Gordon Guyatt et al. (JAMA 2005), “overly sanguine estimates of treatment effect can result in misleading benefit-risk ratios, misguided policy decisions and practice recommendations, and suboptimal clinical practice”.


  1. Marilyn Mann says

    There was a recent meta-analysis on the effect of statins on development of type 2 diabetes:

    Curr Med Res Opin. 2008 May;24(5):1359-62.
    The effect of statins on the development of new-onset type 2 diabetes: a meta-analysis of randomized controlled trials.
    Coleman CI, Reinhart K, Kluger J, White CM.

    OBJECTIVE: To determine the ability of statins to prevent the development of new-onset type 2 diabetes mellitus through a meta-analysis of randomized, controlled trials. RESEARCH DESIGN AND METHODS: A systematic literature search through November 6, 2007 was conducted to identify randomized, placebo-controlled trials of statins that reported data on the incidence of new-onset diabetes mellitus. Incidence of new-onset type 2 diabetes mellitus was treated as a dichotomous variable. Weighted averages were reported as relative risk (RR) with associated 95% confidence intervals (CI). A random-effects model was used. RESULTS: Five prospective, randomized controlled trials (n = 39,791) were identified. Upon meta-analysis, the use of a statin did not significantly alter a patient’s risk of developing new-onset type 2 diabetes mellitus (relative risk, 1.03; 95% confidence interval 0.89-1.19). Subgroup and sensitivity analyses did not significantly change the results. There was statistical heterogeneity that stemmed from pravastatin’s tendency towards a reduction in risk and the other statins showing an increase in risk. The funnel plot could not rule out publication bias. CONCLUSIONS: Statins, as a class, do not demonstrate a statistically significant positive or negative impact on a patient’s risk of developing new-onset type 2 diabetes mellitus.

    That’s not to say that it isn’t possible that rosuvastatin could cause type 2 diabetes. The other rosuvastatin clinical trial data should be examined to investigate this possibility.

    I agree that stopping the JUPITER trial early could have exaggerated the treatment effect.


  1. […] will be a voting member on Tuesday. In the past, Kaul has been highly critical of JUPITER, as we reported last April. Discussing  a highly critical comment by Salim Yusuf and colleagues in the Lancet about JUPITER, […]

  2. […] New York Times: broader indication for rosuvastatin once again raises risk vs benefit in healthy population Posted on March 31, 2010 by Larry Husten Statins may not be as safe as many people think, and the recently granted expanded indication for rosuvastatin may create new problems while providing few benefits, according to an article in the New York Times by Duff Wilson. The Times article places before the wider public the ongoing debate that has been taking place in cardiology circles since the presentation of the JUPITER results. (For just one example, see this earlier CardioBrief story.) […]

  3. […] In the second paper on JUPITER, Sanjay Kaul, Ryan Morrissey, and George Diamond offer their own perspective on the trial, elaborating on a perspective Kaul provided to CardioBrief in April 2009. […]

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