I’m a few months late, but I want to mention an editorial by Rodney Hayward that was published in The BMJ in December 2015. His topic is treatment of diabetes, but the principles he discusses also apply to other areas of medicine. The key concept is that even in high risk conditions such as diabetes, adding a second or third medication brings diminishing absolute returns as residual risk decreases as each additional treatment is added. He starts by describing the disturbing consequences of untreated or poorly managed diabetes, and how things have changed with modern therapies.
When I began my medical training in 1980, I commonly encountered patients whose bodies were ravaged by end stage complications of diabetes. These patients often had marked visual impairment, debilitating neuropathy, myopathies, and diabetes related renal insufficiency, well before age 65 years. I still occasionally see such individuals, but they are rare, and tend to come from the 10-15% of patients who still have poor glycemic control. Improvement in diabetes care is a medical success story, but increasing evidence suggests that overly aggressive treatment is an under-appreciated problem.
The problem is that focusing on relative treatment effects ignores the law of diminishing returns; past a certain point, additional reductions in HbA1c have limited benefit in absolute terms for most older patients with type 2 diabetes. Hayward explains:
Diminishing returns is a mathematical fact, not a theory. Try this simple experiment. Serially tear a piece of paper in half and throw one half away. You will notice that the relative effects never diminish (you reduce the piece of paper by half each time), but it doesn’t take long for the 50% you throw away to become tiny. The many patients with end stage diabetes we saw in the 1980s often spent years with poor control of both glycemia and blood pressure. They had no access to metformin, home blood glucose monitoring, angiotensin converting enzyme inhibitors, calcium channel blockers, and a host of other modern interventions. Each of these interventions substantially reduces disease progression and has an even larger effect on end stage diabetes complications. Because each intervention substantially reduces end stage complications, it should not be surprising that recent evidence has found intensive glycemic control to have a small absolute effect on end stage complications for most patients with type 2 diabetes. The law of diminishing returns predicts this result. Also, as the benefits of tighter glycemic control become smaller, the chances that treatment harms will outweigh treatment benefits become much greater.
Hayward ends by stating that the public good would best be served by focusing on the minority of diabetes patients who continue to be at substantial risk of diabetes-related morbidity and mortality and promoting more shared decision making with older diabetes patients who already have at least moderate blood glucose control.
The same principle of diminishing returns applies in other areas of medicine, such as in medications that reduce cardiovascular risk by lowering blood pressure or cholesterol. As the second and third medication is added, the patient’s risk of experiencing a cardiovascular event diminishes and in some cases a point can be reached where the absolute benefits become very small and it becomes difficult to tell whether benefits outweigh harms. When benefits become small, it can sometimes be hard to determine whether they exist at all or, perhaps, exist in only in patients with certain characteristics. See this post by Harlan Krumholz for a discussion of these issues in the area of treatment of high blood pressure.
In the area of cholesterol-lowering drugs, the new PCSK9 inhibitors have been in the news and I’ve previously discussed them on this blog (here, here and here). Two of these drugs, evolocumab and alirocumab, are approved in the U.S. and so far aren’t selling well. There are several reasons for that, including that the outcomes trials haven’t been completed yet and that the drugs are much more expensive than statins, almost all of which are available as generics. Another reason, related to the first two, is that insurance companies have imposed strict preauthorization requirements for these drugs. Another reason relates to the theme of this post, namely the diminishing returns from adding additional drugs. I’m going to take the treatment of heterozygous familial hypercholesterolemia (HeFH) as an example, specifically patients with HeFH who do not have clinical atherosclerotic cardiovascular disease and who are thus being treated to prevent a first event (i.e., “primary prevention”).
HeFH greatly increases the risk of developing premature atherosclerotic cardiovascular disease compared to individuals with normal levels of cholesterol. Before statins became available, the drugs that were available were not very effective. However, in recent decades, first moderate intensity and then high intensity statins were instituted as standard treatment of HeFH, often with additional drugs such as ezetimibe. According to UpToDate, atorvastatin can reduce LDL by up to 54% and rosuvastatin can reduce LDL by up to 63%. Ezetimibe can lower LDL by another 15% or so in patients on a statin. Given that most patients with HeFH have LDL in the 200s or below, a reduction of 50-60% achieves very reasonable LDL levels. There is evidence that even moderate doses of statins greatly reduce the risk of heart disease in HeFH patients who are being treated for primary prevention. A study published in JAMA in 2014 showed that young adults with HeFH have near-normal levels of atherosclerosis 10 years after initiation of statin therapy. The use of high intensity statins has been shown to greatly reduce the progression of atherosclerosis in adult HeFH patients (see here and here) even when compared to moderate statin therapy. Thus, HeFH patients who start treatment early and are able to reduce their LDL to normal or near-normal levels over many years with a statin or statin + ezetimibe often do not need an additional drug, as their risk is greatly reduced.
So which HeFH patients do need an additional LDL-lowering therapy, such as a PCSK9 inhibitor? To my knowledge, there are no risk calculators available to guide decisions in this area. HeFH patients who start with very high LDL, who can’t tolerate high doses of statins or can’t tolerate statins at all, who started treatment late, who have additional cardiovascular risk factors, or who have had imaging that shows significant subclinical atherosclerosis, are going to be at higher risk, on average. There is quite a bit of uncertainty involved, as with estimation of cardiovascular risk in general. In addition, there are personal preferences involved, as people vary greatly in terms of how much risk they are willing to live with.
Interestingly, a task force of the International Atherosclerosis Society just published a consensus statement in The Lancet Diabetes & Endocrinology that discusses some of the factors involved in determining cardiovascular risk in FH. Although the criteria they propose for use of additional therapies are more stringent than I foresee being adopted in the U.S., the paper contains some very useful discussion of the heterogeneity of cardiovascular risk in FH and ways of trying to predict who is at higher risk. I’m pasting in their proposed criteria below, in case anyone is interested, but I do recommend the entire paper.
The long-awaited IMPROVE-IT trial was presented last month at the American Heart Association Scientific Sessions. Here are the presentation slides:
IMPROVE-IT was a trial that tested the ability of ezetimibe (Zetia) to lower the risk of heart attacks and strokes when added to simvastatin. See Larry Husten’s background post here, and if you type “ezetimibe” in the search box on this blog or on the Gooznews blog, you will find some previous posts of mine relating to ezetimibe. I admit I was a bit surprised that the trial was positive. I was expecting it to be negative, based on the negative results of the ENHANCE trial. Still, the benefit was small, a 6.4% reduction in risk of the primary endpoint (composed of cardiovascular death, heart attack, unstable angina requiring hospitalization, coronary revascularization, and stroke). In the high-risk trial participants — all patients who had been hospitalized for acute coronary syndrome within the 10 days before randomization — this translated to a 2% absolute benefit over 7 years. Of note, there was no reduction in all-cause or cardiovascular mortality.
I only want to make a few comments now, but I intend to write more when the trial is published. First, a 6.4% reduction is risk is a very small benefit, and many people would only consider that reduction in risk meaningful in a high risk population. Second, it is regrettable that we had to wait 12 years after the drug’s approval to find out whether it improves outcomes.
Addendum, May 5, 2015: Unfortunately, the GoozNews blog is no longer up on the web. I asked Merrill Goozner what happened and he said he decided to stop paying the annual fee for the website. So the posts I wrote on ezetimibe for GoozNews are no longer up.
For the past several years I have been following the ezetimibe controversy (see these posts on Gooznews and this blog here, here, here, here, here, here, here, here, here, here, here, here, here, here, and here). In my view, we continue to lack evidence of ezetimibe’s clinical benefit, or even safety, 10 years after FDA approval.
I have a Google Scholar Alert for ezetimibe, so often links to articles on ezetimibe arrive in my email inbox. Recently, two review articles on ezetimibe were published that were a study in contrasts. The first, by Sheila Doggrell, takes a skeptical view toward ezetimibe and reaches the following conclusion:
The comparison of clinical trials with simvastatin and ezetimibe alone and together has clearly shown that simvastatin decreases LDL-cholesterol and this is associated with improved clinical outcomes. Also, ezetimibe alone or in the presence of simvastatin lowers LDL-cholesterol. However, ezetimibe alone or in the presence of simvastatin has not been shown to have any irrefutable beneficial effects on clinical outcomes. Thus, until/unless the use of ezetimibe is clearly shown to improve clinical outcomes, its use should be largely restricted to clinical trials investigating clinical outcomes, and ezetimibe should not be used routinely in everyday practice.
The second, by Binh An Phan, Thomas Dayspring and Peter Toth, takes a much more optimistic view:
In the current treatment of cardiovascular disease, many subjects fail to reach LDL-C targets or remain at high risk for CHD events despite optimal statin and medical therapy. Ezetimibe inhibits intestinal cholesterol absorption and is effective in lowering cholesterol as monotherapy or in combination with statins in several populations, including those with FH, sitosterolemia, and insulin resistance. Significant controversy has been generated regarding the clinical effectiveness of ezetimibe, particularly after the publication of ENHANCE and ARBITER-6 despite both trials having significant methodological flaws that limited their ability to evaluate the benefit of ezetimibe. Growing data suggest that ezetimibe in combination with statin has a positive effect on the progression of atherosclerosis and reduces cardiovascular events in subjects at risk for CHD, including those with chronic kidney disease. Results from IMPROVE-IT are forthcoming and may help to guide better the use of ezetimibe in very high-risk CHD populations. Until that time and based upon the current available data, ezetimibe should remain a viable adjunct to statin therapy in the treatment of hypercholesterolemia.
Dr. Phan and colleagues find reasons to dismiss the negative results of ENHANCE and ARBITER 6-HALTS as due to “methodological flaws” and use copious amounts of hand-waving to find support for ezetimibe in the SEAS and SHARP trials, even though those trials compared the combination of simvastatin and ezetimibe with placebo and thus can tell us nothing about what, if anything, ezetimibe added to those results. Could the differing views of Doggrell and Phan et al. have anything to do with the fact that Dr. Doggrell declares no conflicts of interest relating to ezetimibe, while Phan, Dayspring and Toth declare the following conflicts:
Binh An Phan is a speaker for Abbott. Thomas Dayspring consults for Abbott, GSK, Health Diagnostic Labs, Kowa Company, Eli Lilly, Merck, Genentech, The Roche Group, Genzyme, and Omthera. He is on the Lecture Bureau for Abbott, GSK, Health Diagnostic Labs, Kowa, Eli Lilly, LipoScience, Merck. Peter P Toth is a speaker for Abbott, AstraZeneca, Amylin, Boehringer-Ingelheim, GSK, Kowa, Merck and consults for Abbott, Aegerion, AstraZeneca, Atherotech, Genzyme, Genentech, Kowa, and Merck.
It is not too surprising that authors who are consultants and on the speaker’s bureau for Merck would take a favorable view of ezetimibe. What is surprising is that anyone would take their word for it.
Doggrell SA. The ezetimibe controversy — can this be resolved by comparing the clinical trials with simvastatin and ezetimibe alone and together? Expert Opin. Pharmacother. (2012) 13(10):1469-1480.
Phan BAP, et al. Ezetimibe therapy: mechanism of action and clinical update. Vascular Health and Risk Management 2012:8:415-427.
Addendum, May 5, 2015: Unfortunately, the GoozNews blog is no longer up on the web.
David Rind recently revived his blog Evidence in Medicine and has a post up on the SHARP trial. The SHARP trial, which I discussed recently on this blog and on Gooznews, is the basis for Merck’s application for a new indication for its drugs Vytorin (ezetimibe/simvastatin) and Zetia (ezetimibe). David explains why the results in SHARP are consistent with previous evidence on the effect of statins in patients with chronic kidney disease, both pre-dialysis and on dialysis.
Kevin Lomangino has an article up on the “portfolio diet,” which is a diet that emphasizes foods that lower cholesterol. Kevin explains that most of the cholesterol-lowering from this diet comes from the inclusion of foods containing added plant sterols. As I previously discussed on this blog, while plant sterols lower LDL, their effect on cardiovascular events is unknown, making the portfolio diet a bit of a crapshoot healthwise.
I have a guest post up at Merrill Goozner’s blog explaining why Merck’s application for a new indication for its drugs Vytorin (simvastatin/ezetimibe) and Zetia (ezetimibe) should not be approved. The proposed indication is for the reduction of major cardiovascular events in patients with chronic kidney disease and is based on the results of the SHARP trial. However, because SHARP compared the combination of simvastatin and ezetimibe with placebo — there was no simvastatin arm — we have no way of knowing if ezetimibe contributed anything to the result. The FDA requires that combination drugs have additive effects over either drug alone. Merck has not shown that ezetimibe contributed anything to the effect in SHARP, so the new indication should not be approved.
Addendum January 25, 2012: Merck issued a press release today stating that the FDA did not approve the new indication. “Because SHARP studied the combination of simvastatin and ezetimibe compared with placebo, it was not designed to assess the independent contributions of each drug to the observed effect; for this reason, the FDA did not approve a new indication for VYTORIN or for ZETIA® (ezetimibe) and the study’s efficacy results have not been incorporated into the label for ZETIA.” The SHARP results were incorporated into the Vytorin label (see pages 27-28).
Addendum, May 5, 2015: Unfortunately, the GoozNews blog is no longer up on the web.
I just want to highlight this profile on my friend Harlan Krumholz in Yale Alumni Magazine. Harlan is a Yale cardiologist who is a leader in the field of outcomes research — figuring out what works in the real world and applying those lessons to improve outcomes for patients. In the process, he has not been afraid to take on powerful interests, as he did by testifying in the Vioxx trials (described in Snigdha Prakash’s new book All the Justice Money Can Buy) and publishing articles on how the Vioxx debacle happened and what we can learn from it (see here, here, here and here).
I first contacted Harlan after reading about his presentation on the ENHANCE trial at the March 2008 American College of Cardiology meeting. The ENHANCE trial was designed to test whether ezetimibe, a drug that lowers LDL, added any benefit to a statin in slowing the progression of atherosclerosis, as measured by carotid intima-media thickness. My daughter, who has heterozygous familial hypercholesterolemia, had been on ezetimibe at one point, so I was particularly interested in the trial. Unfortunately, ezetimibe added no benefit at all and Harlan, representing a panel of cardiologists, was not afraid to state that it is not enough to know a drug’s effect on laboratory markers such as LDL. Rather, we need to know whether a drug improves clinical outcomes, such as heart attacks, strokes and death. As Harlan put it,
There are 3 possibilities with this drug. Eventually—one day, when outcomes studies are finally done—we may recognize that it is an effective medication for reducing cardiovascular risk. The ENHANCE study makes that less likely, but it is not impossible.
It could be that ezetimibe is simply an expensive placebo, and its principal harm is that it drains precious resources from our health care system and possibly leads people to use fewer of the drugs that have been shown to be beneficial. The ENHANCE study suggests that this may be true.
Third, it could be harmful. We do not know enough about the clinical risks of this drug. It is well tolerated and there are no obvious safety problems, but we cannot say if there is an increased risk of acute myocardial infarction or death or another important health problem.
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This study heralds the need for clinical research to guide us in decisions for our patients; ideally, this work must be done early in the drug’s development. It is not right that we are this far down the line with this drug and we have so much uncertainty about its balance of risks and benefits. We must understand the effect of new drugs on people and that relying on a drug’s effect on a set of laboratory tests may not tell the whole story. We have learned this lesson before. It appears that we must learn it again.
Addendum: Just published in Circulation: Cardiovascular Quality and Outcomes, this editor’s perspective by Harlan Krumholz entitled “Patient-Centered Medicine: The Next Phase in Health Care.” Here’s an excerpt:
What matters most to patients are outcomes: Did I recover? Is my quality of life better? Patients want to know what has been accomplished by the tests and treatments they have undergone and what has been achieved by the time and resources that have been expended. It is time for us to fully embrace patient-centered medicine, which is ultimately outcomes oriented, with a focus on what patients experience and, among the range of medically reasonable options, gives precedence to what patients prefer.