Evolocumab, Are You Joking Me?
by Jeffrey Dach MD
Ralph is a 48 year old divorce lawyer who arrives in my office with a history of familial hypercholesterolemia. Every lab panel since he was a kid showed a cholesterol of 340. Other family members had the same genetic abnormality, and some even died of heart attack at early age. About six months ago Ralph switched to a new doctor whor was alarmed by his high cholesterol. The new doctor started him on a statin drug which reduced his LDL cholesterol down to 95. However, thinking this was insufficient, the new doctor added Evolocumab, to drive the LDL cholesterol even lower. Header image courtesy of LongevityFacts.com
FDA Approved in Dec 2017
Amgen’s Evolocumab (Repatha), was recently FDA approved, and requires an injection every two weeks. At $14,000 a year, Evolocumab is the most expensive cholesterol drug on the market. A similar PCSK9 inhibitor drug, bococizumab, under development by Pfizer was discontinued after a failed study.(7)
Lowest LDL in History
After the Evolocumab drug was added to the statin drug, Ralph’s labs showed an LDL cholesterol of 30, the lowest in the history of Western Civilization in a human. I looked at Ralph and asked him if he was all right. Not exactly, he said. Ralph has trouble sleeping ever since starting the cholesterol lowering drugs. He has been experiencing troublesome tingling and burning sensations on his arms at night while trying to sleep. In a nutshell, Ralph is miserable, and wants to know if he can safely stop the cholesterol medication.
“A Lifesaving Miracle Drug”
Many newspapers and Cardiologists proclaim Evolocumab is a “lifesaving” miracle drug.(1)(27) Let us see the data showing the number of lives saved. Here is the data table (below) from Dr Marc Sabatine’s FOURIER study .(2) In this study, 27,500 patients on statin drugs for atherosclerotic heart disease were randomized to either drug (Evolocumab) or placebo. The drug reduced the LDL-cholesterol by 60%, from 90 to 30 mg/dl.
Below Image Table 2 FOURIER Study courtesy of Sabatine, Marc S., et al. “Evolocumab and clinical outcomes in patients with cardiovascular disease.” New England Journal of Medicine 376.18 (2017): 1713-1722.(2) Red arrow and circle=drug group. Green arrow and circle=placebo group.
Cardiovascular Death- No Lives Saved
At the end of the 2.2 year study period there were eleven more deaths in the drug treated group. There were 251 cardiovascular deaths in the drug group (red arrow and circle), and only 240 in the placebo group (green arrow and circle). No lives saved.
Death from Any Cause – No Lives Saved
There were 444 deaths in the drug group (red arrow and circle), and only 426 in the placebo group (green arrow and circle). No lives saved. Eighteen more deaths in the drug treated group.
Hospitalization for Unstable Angina- No Difference
There were about the same number of hospitalizations for unstable angina in each group.
A Lifesaving Drug that Actually Kills More People Than Placebo ?
Perhaps someone can explain to me how this can be called a “lifesaving” miracle drug, when in fact, more people died in the drug group, and no lives were actually saved by the drug?
The Miraculous Benefit of Intensive Lowering of LDL Cholesterol
If one is coldly objective about the data coming in, one might say the PCSK9 drug trials have actually falsified the cholesterol theory of heart disease. Here we have the lowest LDL cholesterol ever achieved in the history of medicine, yet no lives are saved. Bryan Hubbard says in May 2017:
The PCSK9 drug trials are inadvertently challenging the cholesterol-heart disease theory. The drugs are bringing down ‘bad’ LDL cholesterol to unprecedented levels, and yet similar numbers of people are dying from heart attack and stroke whether taking the drug or a placebo.(20)
Wait Just A Minute, Fourier Showed Reduction in MI’s
The Fourier study data (above) showed 171 fewer Myocardial Infarctions (MI) in the PCSK9 Evolocumab drug group. Isn’t this a real benefit of the drug? Here is what Dr Harumi Okuyama had to say about that.(55) The data is biased and faked:
“The composite end point included measures that were less objective; hence, the accuracy of these measures as used across 49 different countries could have been biased, with the exception of mortality. For example, troponin level is known to be elevated after coronary angioplasty, leading to more frequent diagnosis of MI in the placebo group….However, we speculate that the reported data do not substantiate the conclusions made by the original authors, and we recommend against accepting their conclusions as an endorsement of PCSK9 inhibitors.
Heart Attacks Kill People, Don’t They?
I think we are all in agreement with the statement: “Heart attacks kill people”. You might ask, how many people? According to Dr Viola Vaccarino in the New England Journal from 1999, early mortality after myocardial infarction is 16.7 per cent in men and 11.5 per cent in women.(57) If we have two randomized groups, and one group has more heart attacks, then this should translate into increased mortality for that group. This is just common sense. The Fourier Evolocumab drug study showed the opposite. The placebo group had 171 more heart attacks, yet did not show increased mortality compared to the drug group. Exactly how an FDA committees can overlook this blatantly obvious contradiction is mind boggling.
Effect of Intensive Cholesterol Lowering on Calcium Score
We have made the case for annual calcium score progression as our most important tool in the management of coronary artery disease. Where is the calcium score data for the FOURIER Evolocumab study? There is none. The study neglected to obtain annual calcium scores.
Remember, statin cholesterol lowering drugs were studied with annual calcium score by Dr Paolo Raggi in 2004. His study showed that 41 of 500 patients on statins had heart attacks over 6 years in spite of cholesterol lowering. The feature which defined the heart attack group was greater than 15 % annual calcium score progression, not the cholesterol level which was identical for both drug and placebo groups. Dr Paolo Raggi showed progression of calcium score and myocardial infarction in 41 patients in spite of statin treatment. Will Amgen’s Evolocumab yield similar results? We await these studies.
Non-Statin Cholesterol Lowering Drugs Abandoned
Non-statin cholestrol lowering drugs have not fared well in the past. Statin drugs have the advantage over these newer drugs because statins not only lower cholesterol, they also have pleomorphic effects (anti-inflammatory effects) which some would say provide the real benefit.
High hopes were raised for the non-statin CETP inhibitor drugs including Eli Lilly’s Anacetrapib and Merc’s Evacetrapib. Both were highly effective for reducing LDL cholesterol, yet both failed to reduce the rate of cardiovascular events in patients with high risk cardiovascular disease. Because of failed clinical trials, both drugs were abandoned and never brought to market. In retrospect, perhaps the newer non-statin PCSK9 inhibitor drugs should all share this same fate.(7) In my opinion, lack of mortality benefit should have prevented FDA approval of Evolocumab, which was approved anyway, raising the question of behind the scenes political influence. It is indeed a difficult thing to walk away from a 500 million dollar investment.
Concern for Adverse Neurocognitive Effects
The FOURIER Evolocumab study reported no adverse effects from intensive lipid lowering. I find this difficult to believe in view of the FDA warning letter asking for a prospective study of neurocognitive adverse effects in the PCSK9 Inhibitor treated group.(29,30) Neurocognitive effect is a polite way to say loss of ability to focus, think and remember. In other words, drug induced dementia.
Dr Kristopher Swiger wrote an article in 2015 Drug Safety entitled: “PCSK9 Inhibitors and Neurocognitive Adverse Events: ” (31). He says:
On both theoretical and empirical grounds, concern for adverse neurocognitive effects currently extends to PCSK9 inhibitors.(31) These events included delirium, cognitive and attention disorders and disturbances, dementia, disturbances in thinking and perception, and mental impairment disorders.(32)
Adverse Psychiatric Reactions with Intensive Cholesterol Lowering
Lower cholesterol level is associated with a number of adverse psychiatric reactions, such as increased risk of suicidal and violent behavior, depression, aggression, and impulsivity . (35-37) Dr Eriksen wrote in Psychiatry Research 2017:
“low cholesterol is a risk marker for inpatient and post-discharge violence in acute psychiatry.”(39)
People with low cholesterol are more likely to commit violent crimes.(41) Dr Beatrice Golomb found that low cholesterol was associated with:
“severe irritability homicidal impulses, threats to others, road rage, generation of fear in family members, and damage to property.”(42)
Dr Michael Tatley writes about “Psychiatric adverse reactions with statins, fibrates and ezetimibe.” in Drug Safety 2007(43). He says:
“The reactions mentioned … include depression, memory loss, confusion and aggressive reactions….The observation that other lipid-lowering agents have similar adverse effects supports the hypothesis that decreased brain cell membrane cholesterol may be important in the aetiology of these psychiatric reactions.”
Dr Repo-Tiihonen investigated “associations between Total Cholesterol levels, violent and suicidal behavior, age of onset of the conduct disorder (CD) and the age of death among 250 Finnish male criminal offenders with ASPD (Antisocial Personality Disorder)”, finding lower cholesterol a prognostic marker for early unnatural death, and violent crimes. (44)
We Cannot Ignore the Massive Data of Negative Impact
In 2016 Drug Safety, Drs Cham, Koslik, and Golomb reoorted on “Mood, Personality, and Behavior Changes During Treatment with Statins: A Case Series.“ Adverse events related to cholesterol lowering drugs included violent ideation, irritability, depression, and suicide. These problems resolved when the drug was stopped and recurred when the drug restarted. (45)
Dr Alfonso Troisi says in Neuroscience & Biobehavioral Reviews 2009 :
“we cannot ignore the mass of data showing a negative impact of low cholesterol in some clinical populations or healthy subjects.”(38)
U Shaped Curve Associates Low Cholesterol With Increased Mortality
The finding of increased mortality at low cholesterol levels is not surprising, and has been known for decades. Back in the 1990’s, accumulated data from multiple studies showed that low cholesterol is associated with increased mortality.(46-53) The cholesterol data chart reveals U shaped curve in all the cohort studies such as the J-Lit, HUNT-2, and MRFIT.(46-53) Both left and right arms of the curve show increased mortality. Dr Petursson from Norway says in 2012:(48)
“Regarding the association between total cholesterol and mortality, our results generally indicated U-shaped or inverse linear curves for total and CVD mortality….Our results contradict the guidelines’ well-established demarcation line (200 mg/dl ) between ‘good’ and ‘too high’ levels of cholesterol. They also contradict the popularized idea of a positive, linear relationship between cholesterol and fatal disease. Guideline-based advice regarding CVD prevention may thus be outdated and misleading, particularly regarding many women who have cholesterol levels in the range of (200-270 mg/dl) and are currently encouraged to take better care of their health….recommendations regarding the ‘dangers’ of cholesterol should be revised. This is especially true for women, for whom moderately elevated cholesterol (by current standards) may prove to be not only harmless but even beneficial.”(48)
In Circulation 1992, Dr Judith Walsh says :
There is an association between low blood cholesterol and noncardiovascular deaths in men and women. There is no association between high blood cholesterol and cardiovascular deaths in women.”(50)
In 1993, Dr Jacobs speculated on the reason why low cholesterol is associated with risk of non-atherosclerotic death. He says: (49)
“Cholesterol affects the fluidity of cell membranes, membrane permeability, transmembrane exchange, signal transmission, and other cell properties. Cholesterol is a precursor for five major classes of steroid hormones. It affects gluconeogenesis and immune function; its transport forms, the lipoproteins, also serve as vehicles for fat-soluble vitamins, antioxidants, drugs, and toxins. Thus, cholesterol plays general, fundamental, and highly specific roles in the economy of the body. …Several authors have recently suggested caution in the pursuit of low Total Cholesterol, recommending against Total Cholesterol lowering in persons with Total Cholesterol less than 225 mg/dl.”(49)
Review and Meta-Analysis of PCSK9 Drug Trials
In 2018, Dr Alessandro Battaggia reviewed all the PCSK9 studies and says there was no benefit. Even in trials recruiting familial hypercholesterolemia patients, there is “tendency to harm” (56) :
“No beneficial relationship was found between LDL-C lowering and cardiovascular events explored by meta-regression; instead, there was a trend toward harm. For any of the other outcomes there was no significant association between LDL-C lowering and risk…..A separate meta-analysis of trials recruiting familial hypercholesterolemia patients have showed a tendency to harm for almost all outcomes….Therefore, at the moment, the data available from randomized trials does not clearly support the use of these antibodies.”(56)
Evolocumab Found to Increase Risk of All-Cause Mortality.
Contrary to the headlines declaring evolocumab a “life saving drug”, a recent meta-analysis reveals that the drug actual INCREASES all cause mortality. !!!! Dr van Brugen writes in June 2020:
“Our meta-analysis of clinical events registered on ClinicalTrials.gov did not show that PCSK9 inhibitors improve cardiovascular health. Evolocumab increased the risk of all-cause mortality.”(60)
Conclusion: The lack of mortality benefit reported in the FOURIER study, in spite of the lowest LDL levels in medical history is not surprising, since increased mortality associated with low cholesterol has been known for decades. In addition, it is clear from both failed CETP inhibitor drug trials, and the PCSK9 drug trials, that lowering cholesterol with a non-statin drug is a futile exercise which provides no health benefit. I would agree with Dr Alessandro Battaggia’s report, that intensive cholesterol lowering with expensive non-statin drugs has a “tendency to harm”.(56) This is a medical practice that should be halted immediately.
Articles with Related Interest:
Jeffrey Dach MD
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Links and References
Header image courtesy of LongevityFacts.com
Evolocumab and clinical outcomes in patients with cardiovascular disease.” New England Journal of Medicine
1) New wonder drug can ‘slash the risk of heart attack, stroke or death by a QUARTER’ compared with just statins. The Sun U.K. Prof Sir Nilesh Samani, of the British Heart Foundation, said: “Creating new treatments with this approach could prove life-saving for patients with high cholesterol and those who cannot tolerate statins.”
2) Sabatine, Marc S., et al. “Evolocumab and clinical outcomes in patients with cardiovascular disease.” New England Journal of Medicine 376.18 (2017): 1713-1722.
In terms of individual outcomes, evolocumab had no observed effect on cardiovascular mortality
……no observed effect on the rates of hospitalization for unstable angina, cardiovascular death or hospitalization for worsening heart failure, or death from any cause (Table 2).
3) Correspondence. Evolocumab in Patients with Cardiovascular Disease August 24, 2017 . N Engl J Med 2017; 377:785-788
The FOURIER trial showed no benefit of evolocumab on cardiovascular mortality after 26 months, and there was a nonsignificant increase in deaths from any cause among patients who received evolocumab as compared with those who received placebo (444 deaths vs. 426 deaths).
However, there was a 1.2-percentage-point absolute difference in the rate of myocardial infarction in the evolocumab group. One explanation is that most of the myocardial infarctions in the trial were not ST-segment elevation myocardial infarctions (STEMIs) but were related to elevated troponin levels of unclear clinical significance. These myocardial infarctions of lesser severity could be related to the fact that more patients underwent revascularization (which is associated with elevated troponin levels) in the placebo group than in the evolocumab group. Could the authors provide rates of STEMI, non-STEMI with a risk of a Thrombolysis in Myocardial Infarction (TIMI) risk score greater than 2, and non-STEMI with a TIMI risk score of 2 or less?
Rita F. Redberg, M.D.
University of California, San Francisco, San Francisco, CA
Under the assumption that the annual list price of evolocumab is $14,350,1 preventing one such event would cost approximately $861,000 in North America and $3,314,850 in Europe.
4) Mar 22, 2017 Forbes Magazine. Not All Cardiologists Trust Amgen’s Cholesterol Drug Study John LaMattina , Contributor
Amgen did pay for this study–I would guess about $500 million or so.
5) Questioning the safety and benefits of evolocumab
Luca Mascitelli, Mark R Goldstein Published: January 2018
PCSK9 inhibitor treatment added to statins might be of little benefit.
6) Cholesterol lowering – proven or not? Repatha malcolm Kendrick. The downside is when you look at cardiovascular deaths. The total number of deaths from cardiovascular disease in the Repatha group was 251. The total number of deaths from cardiovascular disease in the placebo group was 240. So, 11 more people died of cardiovascular disease in the Repatha group.
The total number of, overall, deaths in the Repatha group was 444
The total number of, overall, deaths in the placebo group was 426
So, there were 18 more deaths in those taking Repatha.
7) Pfizer Ends Development Of Its PCSK9 Inhibitor ‘November 1, 2016 by Larry Husten CardioBrief
Immune issues and diminishing efficacy doomed the new drug.
Pfizer announced on Tuesday that it was discontinuing development of bococizumab, its cholesterol-lowering PCSK9 inhibitor under development.
8) Is the drug industry honest? Uffe Ravsnskov MD
You have probably heard or read about the recent trial named FOURIER where the drug company Amgen has tested a new cholesterol-lowering drug named Evolocumab (a so-called PCSK9-inhibitor) on almost 30,000 patients with heart disease. Half of them got the drug injected twice a month; the other half was injected with an innocent liquid (probably saltwater)., and both groups received statin treatment as well. The “bad” LDL-cholesterol was lowered by 59%; from 92 mg/dl (2.4 mmol/l) to 30 mg/dl (0.78 mmol/l). Very few cholesterol-lowering trials have succeeded with that before.
How do they explain that 444 died in the treatment group, but only 426 among the untreated? I mean, if the “bad” high LDL-cholesterol was the cause of atherosclerosis and heart disease, then we should expect that a 59% lowering of this “poisonous” molecule should lower mortality, not increase it.
9) Does the New Cholesterol Drug Repatha Save Lives?
Is evolocumab (Repatha) a breakthrough for treating high cholesterol? Or is it an expensive drug that won’t save any lives?
Joe GraedonMarch 27, 2017
10) The cholesterol and calorie hypotheses are both dead — it is time to focus on the real culprit: insulin resistance Clinical Pharmacist14 JUL 2017By Maryanne Demasi, Maryanne Demasi , Robert H Lustig , Aseem Malhotra
Similarly, the recent report of the efficacy of the latest ‘blockbuster’ drug evolocumab (Repatha, a PCSK-9 inhibitor) was underwhelming, despite the media hype. Published in The New England Journal of Medicine, the paper reported that evolocumab (together with a statin) lowered LDL-C by a whopping 60%, yet translated into only a 1.5% reduction in (non-fatal) CVD events. Furthermore, evolocumab did not reduce total or cardiovascular mortality. Rather, there was a non-significant increase in mortality from CVD (n=251) compared with placebo (n=240), and a non-statistically significant increase in overall mortality in the experimental group (n=444) compared with placebo (n=426).
11) Dixon, Dave L., et al. “Clinical utility of evolocumab in the management of hyperlipidemia: patient selection and follow-up.” Drug design, development and therapy 11 (2017): 2121.
FOURIER trial. In March 2017, the FOURIER trial was published.9 This outcomes trial randomized 27,564 patients with ASCVD and LDL-C >70 mg/dL to receive evolocumab or placebo in addition to background statin therapy. Nearly 70% of patients were receiving high-intensity statins, and the median LDL-C was 92 mg/dL (IQR 80–109). The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization.
There were no significant differences in cardiovascular death, death from any cause, or hospitalization for unstable angina.
12) ACCP CARDIOLOGY PRN JOURNAL CLUB NEWSLETTER March 2017 |Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease (FOURIER) Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease
the lack of mortality benefit and the large price tag of evolocumab therapy propagate controversy regarding its clinical utility.
As was reported in the meta-analysis of statin randomized trials, the reduction in MIs, strokes, and revascularization was greater in years 2+ than in the first year of therapy. However, the lack of reduction in CVD death overall and in years 2+ is concerning. Similar findings have been observed in other trials of intensification therapy. For instance, in the IMPROVE-IT trial, the addition of ezetimibe reduced cardiovascular disease event rates, but did not reduce CVD mortality (HR 1.00, 95% CI 0.89 -1.13).9
It is also concerning that there was no trend toward a reduction in death from cardiovascular disease and the increase in mortality was greater in years 2+ than it was in the first year of the trial. Studies of statin therapy for secondary prevention have consistently demonstrated a reduction in CVD and total mortality. Thus, we give evolocumab added to statin therapy an ICER rating of C+ (comparable or better) based on moderate certainty of a small net benefit compared to statin therapy alone . We considered a B+ rating (incremental or better), but the uncertainty introduced by the non -significant trend towards increased cardiovascular mortality in years 2+ of the trial (HR 1.12, 95% CI 0.88-1.42) led us to the more conservative assessment.
14) Will Evolocumab Help With Coronary Heart Disease?
By Naveed Saleh, MD, MS | Reviewed by Richard N. Fogoros, MD
Updated April 03, 2018
15) Amgen’s FOURIER cardiovascular outcomes trial. While the landmark study proved Repatha’s heart benefits, results showed the drug had no statistically significant effect on cardiovascular death.
16) Giugliano, Robert P., et al. “Clinical Efficacy and Safety of Evolocumab in High-Risk Patients Receiving a Statin: Secondary Analysis of Patients With Low LDL Cholesterol Levels and in Those Already Receiving a Maximal-Potency Statin in a Randomized Clinical Trial.” JAMA cardiology 2.12 (2017): 1385-1391.
17) Mar 10, 2018 The ODYSSEY Trial Ends Well — But Will It Be Enough? Larry Husten , Contributor Forbes
ODYSSEY compared alirocumab (Praluent, Sanofi/Regeneron) with placebo in 18,924 patients with a recent (1-12 months) heart attack (MI) or unstable angina.
The investigators also reported a significant reduction in overall mortality, from 4.1% in the placebo group to 3.5% in the alirocumab group (HR=0.85; CI: 0.73-0.98, p = 0.026). Because, in accordance with the predetermined statistical analysis plan, the reduction in CHD mortality did not achieve statistical significance, the reduction in overall mortality was considered an observational finding. As a result, this means the company will not be able to make a mortality reduction claim without qualification. Sanjay Kaul (Cedars-Sinai) commented that the mortality finding should not be considered robust.
CHD death: 2.2% for alirocumab versus 2.3%, p=0.38
(The drugs now have a list price of more than $14,000 per year but are usually discounted to about $9,000.)
18) Praluent Cuts Deaths by 29% for Those With Highest Cholesterol Levels, ODYSSEY Finds Mary Caffrey Coverage of the 67th Scientific Session of the American College of Cardiology.
A year ago, FOURIER showed evolocumab produced an overall reduction in cardiac events, especially heart attacks, and that benefit increased after the first year. But there was a slight, nonsignificant increase in all-cause death, and payers were not impressed with the results.
19) Dark arts pushing heart drugs Jerome Burne | 20th March 2016
20) The new pretender by Bryan Hubbard May 2017 (Vol. 28 Issue 2)
The PCSK9 drug trials are inadvertently challenging the cholesterol-heart disease theory. The drugs are bringing down ‘bad’ LDL cholesterol to unprecedented levels, and yet similar numbers of people are dying from heart attack and stroke whether taking the drug or a placebo (see main story).
21) How To Save Zero Lives For The Low, Low Cost Of Two Million Dollars And Change, Tom Naughton April 19, 2018
22) More cholesterol craziness 08/07/2017 DRUG BUST by Alan Cassels
23) Sick Pharma Commercial: Repatha – Pay or Die! Uncle Vince
24) https://vimeo.com/210502210 Repatha_Commercial
25) New Cholesterol Drugs Protect High Risk Heart Patients: MORE FAKE NEWS! Mar 17 2017 David Brownstein MD
26) Inflammatory and Cholesterol Risk in the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) Erin A. Bohula, Robert P. Giugliano, Lawrence A. Leiter, Subodh Verma, Jeong-Gun Park, Peter S. Sever, Armando Lira Pineda, Narimon Honarpour, Huei Wang, Sabina A. Murphy, Anthony Keech, Terje R. Pedersen, Marc S. Sabatine
LDL-C reduction with evolocumab reduces cardiovascular events across hsCRP strata with greater absolute risk reductions in patients with higher-baseline hsCRP. Event rates were lowest in patients with the lowest hsCRP and LDL-C.
27) THE WALL STREET JOURNAL June 20 2017 Sumathi Reddy A Cholesterol Drug Tug-of-War Patients struggle for insurance approvals of PCSK9 inhibitors, powerful drugs that lowerbad cholesterol when statins don’t work
Some doctors believe PCSK9 inhibitors could be a lifesaving solution for millions of heart-disease patients.
28) The ODYSSEY trial is first clinical trial to show a mortality benefit with a PCSK9 inhibitor—there was no such reduction observed in the FOURIER trial. TCTMD HeartBeat. ACC2018 By Michael O’Riordan March 10, 2018
For de Lemos, the mortality reduction is an important finding, but he pointed out the absolute difference between the placebo- and alirocumab-treated patients was just 0.6% over nearly 3 years. “It’s ‘lifesaving’ with a very small L,” he said.
Underberg, as well as Andrew Foy (Penn State Health, Hershey, PA), questioned the clinical applicability of the mortality benefit, with Foy somewhat underwhelmed by the absolute risk reduction.
Foy suggested post-ACS treatment would include high-intensity statin therapy followed by ezetimibe (Zetia, Merck/Schering-Plough), with use of a PCSK9 inhibitor reserved for patients with elevated LDL cholesterol levels.
ODYSSEY suggests that 64 patients need to be treated to prevent one MACE and 163 patients to prevent one death, said Steg. Among patients with LDL cholesterol levels ≥ 100 mg/dL, the number needed to treat to prevent one MACE is 29 and to prevent one death is 60.
29) This ‘miracle drug’ is really nothing but a dangerous dud
Health Sciences Institute 3/27/17.
Early on in the approval game, the FDA sent a letter to drugmakers who were tinkering with these PCSK9 meds (there’s another one on the market now called Praluent), warning about the very real potential of “neurocognitive adverse events” with them. Or, to say that more simply, dementia. These PCSK9 drugs can drop cholesterol levels to such unheard-of, dangerous lows that, as we’ve told you before, they are basically a prescription for losing your ability to focus, think and remember.
30) FDA CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER 125559Orig1s000 SUMMARY REVIEW
Applicant is seeking approval of alirocumab PRALUENT is indicated for long-term treatment of adult patients with primary hypercholesterolemia (non-familial and heterozygous familial)
Because the etiology of the rare post-marketing reports of cognitive impairment associated with statin use (class safety labeling change in 20 12) remains uncertain, the potential for PCSK9 inhibitors to have neurocognitive effects has been a focus of attention.
The table below from Dr. Roberts’s review summarizes the results. In the placebo -controlled trials, the preferred terms “confusional state” and “memory impairment” both occurred at a higher incidence in the alirocumab group (0.2% for each) than in the placebo group (<0.1% for each). There were 3 (0.1%) and 2 (0.2%) neurocognitive SAEs in the alirocumab and placebo groups, respectively.
The reviewer recommended a randomized long term controlled trial that prespectively evaluates changes in neurocognitive function as a post marketing requirement
31) Swiger, Kristopher J., and Seth S. Martin. “PCSK9 Inhibitors and Neurocognitive Adverse Events: Exploring the FDA Directive and a Proposal for N-of-1 Trials.” Drug Saf 38 (2015): 519-526.
On both theoretical and empirical grounds, concern for adverse neurocognitive effects currently extends to PCSK9 inhibitors.
32) Early Evidence Linking PCSK9 Inhibitors to Neurocognitive Adverse Events: Does Correlation Imply Causation?Jun 01, 2015 | Kristopher Swiger, MD; Seth Shay Martin, MD, MHS, FACC Expert Analysis
two phase III efficacy and safety trials2,3 reported a greater incidence of CAEs in the PCSK9 treatment group.cognitive adverse events
The Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) study4 was the first to report increased CAEs in the PCSK9 treatment group and likely prompted the FDA directive. The study enrolled 1,104 hypercholesterolemic patients, randomized them to receive 420 mg of evolocumab + standard of care or standard of care alone, and monitored the incidence of adverse events over one year. CAEs were more common in the evolocumab group with three reporting amnesia (<1%) and five with memory or mental impairment (<1%). No events were reported in the standard of care group.
Earlier in 2015, the OSLER program released additional data2 from 4,465 participants with 11-month follow-up also that showed increased CAEs in the evolocumab group (0.9%) relative to the standard of care group (0.3%). These events were heterogeneous, including delirium, cognitive and attention disorders and disturbances, dementia, disturbances in thinking and perception, and mental impairment disorders.
Researchers from Johns Hopkins crunched the clinical data and found that in one trial, patients were three times as likely to suffer serious cognitive problems – and in another, they were more than twice as likely. The problems included delirium, amnesia, difficulty in thinking and reasoning, and even dementia.
FDA did something shockingly out of character. It actually sent a letter to the companies developing the drugs warning them of “neurocognitive adverse events.”
34) Praluent: New Cholesterol Drugs Get Riskier By The Day Editor | January 15, 2015
Low cholesterol associated with Suicide
35) Kunugi, Hiroshi, et al. “Low serum cholesterol in suicide attempters.” Biological Psychiatry 41.2 (1997): 196-200.
Previous studies have shown an association between low serum cholesterol concentration and suicide; however, conflicting results have also been reported. To examine this potential association, cholesterol levels in 99 patients admitted to an emergency ward following an attempted suicide were compared with those in 74 nonsuicidal psychiatric inpatients, and those in 39 psychiatrically normal individuals with accidental injuries. Cholesterol concentrations in suicide attempters were found to be significantly lower compared with both psychiatric and normal controls, when sex, age, psychiatric diagnosis, and physical conditions (serum total protein and red blood cell count) were adjusted for. This significant relationship was observed in mood disorders and personality or neurotic disorders, but not in schizophrenia spectrum disorders. These results support the previous claim that lower cholesterol level is associated with an increased risk of suicidal behavior.
36) Vevera, J., et al. “Cholesterol concentrations in violent and non-violent women suicide attempters.” European Psychiatry 18.1 (2003): 23-27. The aim of this study was to evaluate whether women with a history of violent suicide attempts have lower serum cholesterol concentrations than those who attempted suicide by non-violent methods. Our retrospective study used a case-control design to compare serum total cholesterol concentration, hematocrit, red blood cell count and body mass index (BMI) in women with a history of violent (n = 19) or non-violent (n = 51) suicide attempts and of non-suicidal controls (n = 70) matched by diagnosis and age. Analysis of covariance (ANCOVA) with age as the covariate was used to analyze differences in cholesterol levels in groups according to violence. Violence was found to be a significant factor (P = 0.016). Using the Scheffé test, a significant difference (P = 0.011) was revealed between the group of violent and non-violent suicide attempters and between the violent suicide attempters and the control group. Patients with a violent suicidal attempt have significantly lower cholesterol levels than patients with non-violent attempts and the control subjects. Our findings suggest that suicide attempts should not be considered a homogeneous group. They are consistent with the theory that low levels of cholesterol are associated with increased tendency for impulsive behavior and aggression and contribute to a more violent pattern of suicidal behavior.
37) Stevenson, R. J., and H. M. Francis. “The role of cholesterol in disorders of brain and behavior: human and animal perspectives.” Handbook of cholesterol. Wageningen Academic Publishers, 2016. 291-298..
Abnormal cholesterol metabolism is likely to have significant adverse impacts on the functioning of the brain and hence on behavior, given its key role in membrane function. In this chapter we examine the animal and human literature pertaining to links between abnormal cholesterol metabolism and impaired brain and behavioral function. In particular we focus on Alzheimer’s disease, suicide, depression, aggression, impulsivity, and autism. The literature indicates associations between all of these conditions and abnormalities in cholesterol metabolism, although the evidence base indicates substantial heterogeneity of outcome. An especially important line of evidence has come from lipid lowering medications, which have provided key causal data. This has suggested that abnormal cholesterol metabolism may have a more specialized role than was once first thought, affecting particular subgroups (e.g. violent suicides), rather than populations in general.
38) Troisi, Alfonso. “Cholesterol in coronary heart disease and psychiatric disorders: same or opposite effects on morbidity risk?.” Neuroscience & Biobehavioral Reviews 33.2 (2009): 125-132.Cholesterol in coronary heart disease psychiatric disorders effects on morbidity Troisi Alfonso Neuroscience Biobehavioral Reviews 2009
“we cannot ignore the mass of data showing a negative impact of low
cholesterol in some clinical populations or healthy subjects.”
39) Eriksen, Bjørn Magne S., et al. “Low cholesterol level as a risk marker of inpatient and post-discharge violence in acute psychiatry–A prospective study with a focus on gender differences.” Psychiatry research 255 (2017): 1-7.
Several studies indicate an association between low levels of serum cholesterol and aggressive behaviour, but prospective studies are scarce. In this naturalistic prospective inpatient and post-discharge study from an acute psychiatric ward, we investigated total cholesterol (TC) and high-density lipoprotein (HDL) as risk markers of violence. From March 21, 2012, to March 20, 2013, 158 men and 204 women were included. TC and HDL were measured at admission. Violence was recorded during hospital stay and for the first 3 months post-discharge. Univariate and multivariate binary logistic regression were used to estimate associations between low TC and low HDL and violence. Results showed that HDL level was significantly inversely associated with violence during hospital stay for all patients. For men, but not for women, HDL level was significantly inversely associated with violence the first 3 months post-discharge. Results indicate that low HDL is a risk marker for inpatient and post-discharge violence in acute psychiatry and also suggest gender differences in HDL as a risk marker for violence.
40) Banach, M., et al. “Intensive LDL-cholesterol lowering therapy and neurocognitive function.” Pharmacology & therapeutics 170 (2017): 181.
The key lipid-lowering target is to achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) levels, usually by using statins. The new treatment strategies for lipid-lowering therapy include using proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors as an exciting approach to reduce residual risk of cardiovascular diseases (CVD). However, concerns about possible adverse effects, including neurocognitive disorders, were issued by the Food and Drug Administration (FDA). The current disputable evidence does not allow definite conclusions as to whether statins contribute to, or cause, clinically meaningful cognitive impairment. Some evidence indicates a high rate of memory loss, while other evidence suggests a benefit in dementia prevention. This debate should not discourage appropriate statin and other lipid-lowering drug administration. However, prescribers should be aware of such potential drug-related side effects. Prospective controlled studies comparing the short- and long-term effects of different statins on cognitive function are warranted. The effects of intensive LDL-C lowering on neurocognition might be attributed to an off-target effect. It is also possible that pre-existing pathology and vascular risk may already be present outweighing any effect related to lipids. Gender, genetic, LDL-C-related genotypes and aging-related changes should also be considered. Some data indicate that carriers of apolipoprotein E (apoE) ε-4 allele, with low levels of apoA1 and high-density lipoprotein cholesterol have a distinct plasma lipid profile and may be more susceptible to neurocognitive dysfunction. Future research on lipid-lowering drugs and cognition is needed; careful study design and analysis will be critical.
Low Cholesterol Associated with Increased criminal violence
41) Golomb, Beatrice A., Håkan Stattin, and Sarnoff Mednick. “Low cholesterol and violent crime.” Journal of Psychiatric Research 34.4-5 (2000): 301-309.
BACKGROUND:Community cohort studies and meta-analyses of randomized trials have shown a relation between low or lowered cholesterol and death by violence (homicide, suicide, accident); in primates, cholesterol reduction has been linked to increased behavioral acts of aggression (Kaplan J, Manuck S. The effects of fat and cholesterol on aggressive behaviour in monkeys. Psychosom. Med 1990;52:226-7; Kaplan J, Shively C, Fontenot D, Morgan T, Howell S, Manuck S et al. Demonstration of an association among dietary cholesterol, central serotonergic activity, and social behaviour in monkeys. Psychosom. Med 1994;56:479-84.). In this study we test for the first time whether cholesterol level is related to commission of violent crimes against others in a large community cohort.
METHODS:We merged one-time cholesterol measurements on 79,777 subjects enrolled in a health screening project in Varmland, Sweden with subsequent police records for arrests for violent crimes in men and women aged 24-70 at enrollment; and with information on covariates. We performed a nested case control comparison of cholesterol in violent criminals – defined as those with two or more crimes of violence against others – to cholesterol in nonoffenders matched on age, enrollment year, sex, education and alcohol, using variable-ratio matching, with a nonparametric sign test.
RESULTS:One hundred individuals met criteria for criminal violence. Low cholesterol (below the median) was strongly associated with criminal violence in unadjusted analysis (Men: risk ratio 1.94, P=0.002; all subjects risk ratio 2.32, P<0.001). Age emerged as a strong confounder. Adjusting for covariates using a matching procedure, violent criminals had significantly lower cholesterol than others identical in age, sex, alcohol indices and education, using a nonparametric sign test (P=0.012 all subjects; P=0.035 men).
CONCLUSIONS:Adjusting for other factors, low cholesterol is associated with increased subsequent criminal violence.
42) Golomb, Beatrice A., T. Kane, and Joel E. Dimsdale. “Severe irritability associated with statin cholesterol-lowering drugs.” Qjm 97.4 (2004): 229-235.
Methods: Six patients referred or self-referred with irritability and short temper on statin cholesterol-lowering drugs completed a survey providing information on character of behavioural effect, time-course of onset and recovery, and factors relevant to drug adverse effect causality.
Results: In each case the personality disruption, once evident, was sustained until statin use was discontinued; and resolved promptly with drug cessation. In four patients, re-challenge with statins occurred, and led to recrudescence of the problem. All patients experienced other recognized statin adverse effects while on the drug. Manifestations of severe irritability included homicidal impulses, threats to others, road rage, generation of fear in family members, and damage to property.
43) Tatley, Michael, and Ruth Savage. “Psychiatric adverse reactions with statins, fibrates and ezetimibe.” Drug Safety 30.3 (2007): 195-201.
The HMG-CoA reductase inhibitors (‘statins’) have come into widespread use internationally. There has been a long history of their use in New Zealand and this use has increased in recent years. There has also been an increase in the number of reports to the New Zealand Centre for Adverse Reactions Monitoring (CARM) of suspected psychiatric adverse reactions associated with statins. The reactions mentioned in these reports include depression, memory loss, confusion and aggressive reactions. Convincing reports to CARM of recurrence of these reactions upon rechallenge add weight to recent studies reporting serious psychiatric disturbances in association with statin treatment. Aggressive reactions associated with statins are poorly documented in the literature. These observations emphasise the need to be vigilant in looking for these reactions as they can have a significant personal impact on a patient. The observation that other lipid-lowering agents have similar adverse effects supports the hypothesis that decreased brain cell membrane cholesterol may be important in the aetiology of these psychiatric reactions.
44) Repo-Tiihonen, E., et al. “Total serum cholesterol level, violent criminal offences, suicidal behavior, mortality and the appearance of conduct disorder in Finnish male criminal offenders with antisocial personality disorder.” European archives of psychiatry and clinical neuroscience 252.1 (2002): 8.
Associations between low total serum cholesterol (TC) levels and antisocial personality disorder (ASPD), violent and suicidal behavior have been found. We investigated the associations between TC levels, violent and suicidal behavior, age of onset of the conduct disorder (CD) and the age of death among 250 Finnish male criminal offenders with ASPD. The CD had begun before the age of 10 two times more often in non-violent criminal offenders who had lower than median TC levels. The violent criminal offenders having lower than median TC levels were seven times more likely to die before the median age of death in the study material. The violent offenders having lower than median TC levels were eight times more likely to die of unnatural causes. The mean TC level of these male offenders with ASPD was lower than that of the general Finnish male population. Low TC levels are associated with childhood onset type of the CD, and premature and unnatural mortality among male offenders with ASPD. The TC level seems to be a peripheral marker with prognostic value among boys with conduct disorder and antisocial male offenders.
45) Cham, Stephanie, Hayley J. Koslik, and Beatrice A. Golomb. “Mood, Personality, and Behavior Changes During Treatment with Statins: A Case Series.“ Drug safety-case reports 3.1 (2016): 1.
We sought to elicit history of central nervous system/behavioral changes in connection with statin and/or cholesterol-lowering drug use.
Participants (n = 12) reported mood/behavior change that commenced following statin initiation and persisted or progressed with continued use.
Reported problems included violent ideation, irritability, depression, and suicide. Problems resolved with drug discontinuation and recurred with rechallenge where attempted.
(1) Simvastatin 80 mg was followed in 5 days by irritability/depression culminating in suicide in a man in his 40s (Naranjo criteria: possible causality).
(2) Simvastatin 10 mg was followed within 2 weeks by depression in a woman in her 50s (probable causality).
(3) Atorvastatin 20 mg was followed in ~1 month by depression and irritability/aggression in a male in his 50s (probable causality).
(4) Atorvastatin 10 mg was followed in several months by aggression/irritability and depression culminating in suicide in a man in his 40s (possible causality).
(5) Fenofibrate + rosuvastatin (unknown dose), later combined with atorvastatin were followed in 1 month by aggression/irritability in a male in his 30s (probable causality).
(6) Lovastatin (unknown dose and time-course to reaction) was followed by depression, dyscontrol of bipolar disorder, and suicide attempts in a male in his 40s (possible causality).
(7) Atorvastatin 20 mg was followed within 2 weeks by cognitive compromise, and nightmares, depression, and anxiety culminating in suicide in a man in his teens (definite causality).
(8) Simvastatin 10 mg was followed (time-course not recalled) by depression, aggression/irritability culminating in suicide in a man in his 60s (possible causality).
(9) Simvastatin 20 mg then atorvastatin 10 mg were followed (time-course not provided) by irritability/aggression in a man in his 60s (definite causality).
(10) Atorvastatin 10 then 20 then 40 mg were followed shortly after the dose increase by violent ideation and anxiety in a man in his 30s (probable causality).
(11) Atorvastatin 20 mg and then simvastatin 20 mg were followed in 2 weeks by aggression/irritability in a man in his 50s (definite causality).
(12) Lovastatin, rosuvastatin, atorvastatin, and simvastatin at varying doses were followed as quickly as 1 day by aggression, irritability, and violent ideation in a man in his 40s (definite causality). ADRs had implications for marriages, careers, and safety of self and others. These observations support the potential for adverse mood and behavioral change in some individuals with statin use, extend the limited literature on such effects, and provide impetus for further investigation into these presumptive ADRs.
Low Choesterol and Increased Mortality
46) Nago N, Ishikawa S, Goto T, Kayaba K. Low cholesterol is associated with mortality from stroke, heart disease, and cancer: the Jichi Medical School Cohort Study. J Epidemiol 2011;21:67–74.
We investigated the relationship between low cholesterol and mortality and examined whether that relationship differs with respect to cause of death.
A community-based prospective cohort study was conducted in 12 rural areas in Japan. The study subjects were 12,334 healthy adults aged 40 to 69 years who underwent a mass screening examination. Serum total cholesterol was measured by an enzymatic method. The outcome was total mortality, by sex and cause of death. Information regarding cause of death was obtained from death certificates, and the average follow-up period was 11.9 years.
RESULTS: As compared with a moderate cholesterol level (4.14-5.17 mmol/L), the age-adjusted hazard ratio (HR) of low cholesterol (<4.14 mmol/L) for mortality was 1.49 (95% confidence interval [CI]: 1.23-1.79) in men and 1.50 (1.10-2.04) in women. High cholesterol (≥6.21 mmol/L) was not a risk factor. This association was unchanged in analyses that excluded deaths due to liver disease, which yielded age-adjusted HRs of 1.38 (95% CI, 1.13-1.67) in men and 1.49 (1.09-2.04) in women. The multivariate-adjusted HRs and 95% CIs of the lowest cholesterol group for hemorrhagic stroke, heart failure (excluding myocardial infarction), and cancer mortality significantly higher than those of the moderate cholesterol group, for each cause of death.
CONCLUSIONS: Low cholesterol was related to high mortality even after excluding deaths due to liver disease from the analysis. High cholesterol was not a risk factor for mortality.
In conclusion, we observed that low cholesterol was associated with increased risks of cancer, hemorrhagic stroke, and heart failure excluding myocardial infarction.
U Shaped mortality curve
47) Jeong, Su-Min, et al. “Association of change in total cholesterol level with mortality: A population-based study.” PloS one 13.4 (2018): e0196030.
Changes in cholesterol levels in either direction to low cholesterol or persistently low cholesterol levels were associated with higher risk of mortality.
previous studies have revealed a U-shaped relationship between cholesterol and mortality
48) Petursson, Halfdan, et al. “Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid? Ten years prospective data from the Norwegian HUNT 2 study.” (2011). Journal of evaluation in clinical practice 18.1 (2012): 159-168.
Regarding the association between total cholesterol and mortality, our results generally indicated U-shaped or inverse linear curves for total and CVD mortality.
Our results contradict the guidelines’ well-established demarcation line (5 mmol L−1) between ‘good’ and ‘too high’ levels of cholesterol. They also contradict the popularized idea of a positive, linear relationship between cholesterol and fatal disease. Guideline-based advice regarding CVD prevention may thus be outdated and misleading, particularly regarding many women who have cholesterol levels in the range of 5–7 mmol L−1 and are currently encouraged to take better care of their health.
If our findings are generalizable,clinical and public health recommendations regarding the ‘dangers’ of cholesterol should be revised. This is especially true for women, for whom moderately elevated cholesterol (by current standards) may prove to be not only harmless but even beneficial
49) . Why is low blood cholesterol associated with risk of nonatherosclerotic disease death Jacobs David Annual review of public health 1993 Jacobs Jr, David R. “Why is low blood cholesterol associated with risk of nonatherosclerotic disease death?.” Annual review of public health 14.1 (1993): 95-114.
cholesterol affects the fluidity of cell membranes, membrane permeability, transmembrane exchange, signal transmission, and other cell properties. Cholesterol is a precursor for five major classes of steroid hormones. It affects gluconeogenesis and immune function; its transport forms, the lipoproteins, also serve as vehicles for fat-soluble vitamins, antioxidants, drugs, and toxins. Thus, cholesterol plays general, fundamental, and highly specific roles in the economy of the body.
Several authors have recently suggested caution in the pursuit of low TC.
Frank et al (41) recommended against TC lowering in persons with TC
< 225 mg/dl,
50) Hulley, Stephen B., Judith MB Walsh, and Thomas B. Newman. “Health policy on blood cholesterol. Time to change directions.” Circulation 86.3 (1992): 1026-1029. Health policy on blood cholesterol Time to change directions Hulley Stephen Judith Walsh Circulation 1992
A U-shaped association between the level of blood cholesterol and subsequent mortality has been reported in many studies over the past two decades.1-3 The right-hand limb of the U is the well known higher risk of death from coronary heart disease (CHD) at higher levels of blood cholesterol; this positive association, shown in clinical trials to be causal and reversible, is the cornerstone of U.S. policies directed at lowering high bloodcholesterol.4 The left-hand limb of the U is the higher risk of deaths from non-CHD causes at lower levels of blood cholesterol; the basis for this negative association remains poorly understood, and its implications for health policy have received inadequate attention.5,6
There is an association between low blood cholesterol and noncardiovascular deaths in men and women. There is no association between high blood cholesterol and cardiovascular deaths in women.
51) Muldoon, Matthew F., et al. “Low or lowered cholesterol and risk of death from suicide and trauma.” Metabolism 42.9 (1993): 45-56.
For four decades, serum cholesterol has been intensively studied in relation to atherosclerosis, and it is now generally agreed that high cholesterol concentrations are causally related to coronary heart disease (CHD). However, recent evidence suggests that mortality from a variety of non-CHD causes is elevated in persons with low or lowered serum cholesterol. Because such relationships may offset the anticipated health benefits of long-term cholesterol reduction, it is of obvious importance to understand the physiologic changes occasioned by cholesterol modification, and to identify those changes having possibly deleterious effects on health. In this review, we focus on one potential negative consequence of cholesterol reduction, namely the unexplained association between low or lowered cholesterol and death from suicide, accident, or trauma (so-called nonillness mortality [NIM]).
52) Kaplan, Jay R., et al. “Assessing the observed relationship between low cholesterol and violence‐related mortality.” Annals of the New York Academy of Sciences 836.1 (1997): 57-80
Health advocacy groups advise all Americans to restrict their dietary intake of saturated fat and cholesterol as an efficacious and safe way to lower plasma cholesterol concentrations and thus reduce the risk of coronary heart disease and other atherosclerotic disorders. However, accumulating evidence suggests that naturally low or clinically reduced cholesterol is associated with increased nonillness mortality (principally suicide and accidents). Other evidence suggests that such increases in suicide and traumatic death may be mediated by the adverse changes in behavior and mood that sometimes accompany low or reduced cholesterol. These observations provided the rationale for an ongoing series of studies in monkeys designed to explore the hypothesis that alterations in dietary or plasma cholesterol influence behavior and that such effects are potentiated by lipid-induced changes in brain chemistry. In fact, the investigations in monkeys reveal that reductions in plasma cholesterol increase the tendency to engage in impulsive or violent behavior through a mechanism involving central serotonergic activity. It is speculated that the cholesterol-serotonin-behavior association represents a mechanism evolved to increase hunting or competitive foraging behavior in the face of nutritional threats signaled by a decline in total serum cholesterol (TC). The epidemiological and experimental data could be interpreted as having two implications for public health: (1) low-cholesterol may be a marker for risk of suicide or traumatic death and (2) cholesterol lowering may have adverse effects for some individuals under some circumstances.
53) Iso, Hiroyasu, et al. “Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial.” New England Journal of Medicine 320.14 (1989): 904-910.
54) Kim, Yong‐Ku, et al. “Low serum cholesterol is correlated to suicidality in a Korean sample.” Acta Psychiatrica Scandinavica 105.2 (2002): 141-148.
55) Okuyama, Harumi, et al. “A Critical Review of the Consensus Statement from the European Atherosclerosis Society Consensus Panel 2017.” Pharmacology 101.3-4 (2018): 184-218.
On Fourier: However, we speculate that the reported data do not substantiate the conclusions made by the original authors, and we recommend against accepting their conclusions as an endorsement of PCSK9 inhibitors.
No significant beneficial effects of statins for the reduction of CVD mortality have been reported since 2004/2005.
56) Battaggia, Alessandro, Andrea Scalisi, and Alberto Donzelli. “The systematic review of randomized controlled trials of PCSK9 antibodies challenges their “efficacy breakthrough” and “the lower, the better” theory.” Current medical research and opinion just-accepted (2018): 1-12.
Background: A Cochrane review with meta-analysis showed controversial results about the efficacy of PCSK9 antibodies in the prevention of cardiovascular diseases. This review gives the opportunity to test the relationship between LDL-C levels and cardiovascular events.
Methods: The authors analyzed the relationship between the calculated LDL-C lowering and the risk of all-cause mortality, fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, any adverse event, cardiovascular events and cardiovascular disease mortality.
Results: No beneficial relationship was found between LDL-C lowering and cardiovascular events explored by meta-regression; instead, there was a trend toward harm. For any of the other outcomes there was no significant association between LDL-C lowering and risk. Furthermore, the authors calculated the efficacy that would be expected through the LDL-C lowering showed in the meta-analysis, considering widely accepted predictions. These were respected only for stroke, while the observed efficacy on other cardiovascular events was significantly lower than the expected, and no significant result was observed at all for fatal outcomes. A separate meta-analysis of trials recruiting familial hypercholesterolemia patients have showed a tendency to harm for almost all outcomes.
Conclusions: The relationship between LDL-C lowering and cardiovascular events has not showed any significant association (and even a tendency toward harm), challenging the “lower the better” theory. A separate meta-analysis of trials recruiting familial hypercholesterolemia patients has showed a tendency to harm for all outcomes with PCSK9 antibodies. Therefore, at the moment, the data available from randomized trials does not clearly support the use of these antibodies.
57) Vaccarino, Viola, et al. “Sex-based differences in early mortality after myocardial infarction.” New England journal of medicine 341.4 (1999): 217-225.
The overall mortality rate during hospitalization was 16.7 percent among the women and 11.5 percent among the men.
58) Ravnskov, Uffe, et al. “LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature.” Expert review of clinical pharmacology 11.10 (2018): 959-970. LDL-C does not cause cardiovascular disease Ravnskov Uffe Expert rev clin pharm 2018
59) Matsuzaki, Masunori, et al. “Large Scale Cohort Study of the Relationship Between Serum Cholesterol Concentration and Coronary Events With Low-Dose Simvastatin Therapy in Japanese Patients With Hypercholesterolemia. Primary Prevention Cohort Study of the Japan Lipid Intervention Trial (J-LIT).” Circulation journal 66.12 (2002): 1087-1095 Serum Cholesterol and Coronary Events With Low-Dose Simvastatin Japan Lipid Intervention Trial J-LIT
The J-curve association was observed between average TC or LDL-C concentrations and total mortality.
60) van Bruggen, F H et al. “Serious adverse events and deaths in PCSK9 inhibitor trials reported on ClinicalTrials.gov: a systematic review.” Expert review of clinical pharmacology, 10.1080 29 Jun. 2020,
Our meta-analysis of clinical events registered on ClinicalTrials.gov did not show that PCSK9 inhibitors improve cardiovascular health. Evolocumab increased the risk of all-cause mortality.
jeffrey Dach MD