STATIN Use After A Heart Attack & Side Effects

The battle continues . . .

At the beginning of the week, I received a call from an irritable cardiologist that my patient was not on the STATIN medication he was placed on when discharged from the hospital.

This patient had diabetes. Life had gotten in the way and he had not been controlling his blood sugar or his diet for the last few years.

It caught up with up with him . . .

He knew better . . .

But, he had a heart attack . . . and it was a “come to Jesus” moment in his life.

At the time of his discharge from the hospital, he was placed on five different medications.

He could barely stand up when he came to my office . . .

Exhausted, scared and overmedicated . . . he wasn’t sure what to do.

He was told by his cardiologist that he and the “American Heart Association Guidelines” insist that he take all of these pills. Yet, the pills were making it impossible for him to function.

He had already changed his diet since being home and he was back on his ketogenic regimen . . .

With this dietary change, he had already dropped 10 lbs since his discharge from the hospital.

His blood sugars were now superb. His insulin was superb, his C-RP was normal.

But, he was aching and hurting. . .

The STATIN drug was making his entire body ache, to the point he couldn’t exercise . . .

He could hardly walk due to pain in his legs.

“Doc, I’ve had this heart attack. But, I’ve changed my diet. Do I need to take this STATIN drug?”

That is where the battle continued . . .

“Why would you let this patient stop his STATIN drug when the benefit of taking it outweighs all the risk of side effects?!” this cardiologist barked at me.

“But, does it? Really?” I asked.

“Of course, it does,” he continued to bark at me as if I was a fool. It does more than just lower LDL-C. It’s the plaque stabilization, the pleotropic effects, they stabilize the arteries and decrease reoccurring heart attacks by 15% or more . . .” he claimed.

He repeated this claim over and over every time I questioned him on the absolute risk reduction of placing this patient on a STATIN drug he was not tolerating.

If a 15% reduction in absolute risk were actually true, I would not be writing this email, I’d be personally writing STATIN drugs for every single one of my patients with any signs of heart disease or atherosclerosis . . .

Yesterday, I told you about the miniscule effects (only 1-2% CVD reduction) of STATIN drugs on stopping coronary vascular disease (CVD) and strokes in patients with no previous history of these diseases.

Use Of Statins In Those With Heart Disease or Previous Stroke

What about the effect of STATIN medications on patient’s who’ve had a heart attack, stroke or other heart disease?

Are the benefits really as great as Mr. Angry Cardiologist was touting?

Are they great enough to push aside the side effects as if they are nothing to worry about?

In a very large meta-analysis published in Atherosclerosis last year (2022), the authors looked at 64,401 patients [29]. The incidence of major arterial coronary events (MACE) was 18.7% among patients without early STATIN therapy vs. 16.6% among patients with early STATIN therapy (sHR 1.15; CI 1.09–1.21; p < 0.0001) at 1-year in the matched cohort.

At 10-years, the cumulative incidence of MACE was 58.0% without early STATIN therapy vs. 56.0% with STATIN therapy (sHR 1.15; CI 1.11–1.19; p < 0.0001). Again, the absolute risk ratio (ARR) of these findings at 1 year and 10 years are both approximately a 2% reduction in risk of heart attack.

In another meta-analysis of absolute risk reductions looking at 21 trials completed in 2022, the absolute risk reduction was found to be 0.8% for all-cause mortality (death by all causes), 1.3% for myocardial infarction and 0.4% for stoke in those randomized to STATIN treatment.

A conclusive association between absolute reductions in LDL-C levels and individual clinical outcomes was not established despite this and other study authors explaining these reductions as “pleotropic.”

The fact that these studies are presented to clinicians and the public with large relative risk reductions, the absolute risk reductions in these findings underscore the importance of discussing absolute risk reductions when making informed clinical decisions with each individual patient.

Just to put this into a comparison that you or your family member can understand:

  • Your absolute risk of reducing a second heart attack with continuous high dose STATINs is at best 1.3-2%
  • Your absolute risk of dying from falling down are 0.9%
  • Your absolute risk of dying from a gun assault are 0.5%

The British Heart Protection Study (HPS) included more than 20,000 adults aged 40–80 years with prior evidence of CVD and/or diabetes. Half of the study population was allocated simvastatin (40 mg/day) and the other half a placebo for the 5-year study.

The findings from this trial were discussed in an accompanying editorial [1] which praised the effects of cholesterol lowering in this trial, as well as in a press release with the headline: “LIFE-SAVER: World’s largest cholesterol-lowering trial reveals massive benefits for high-risk patients.” The Lancet editorial stated that “the implications of these findings are profound.” Professor Rory Collins, the Director of the study, was overjoyed with praise in a news report by stating “This is a stunning result, with massive public health implications. We’ve found that cholesterol lowering treatment . . . can prevent strokes as well as heart attacks.” He further stated that the study “provides the first direct evidence that cholesterol lowering therapy cuts the risk of heart attacks and strokes by at least one-third.” In the trial report, it was stated that there was an “18% reduction” in the coronary mortality rate, and an “extreme 38% proportional reduction [RRR] in the incidence rate of first nonfatal MI.” Overall, the investigators reported “a 27% . . . reduction in the incidence rate of nonfatal MI or coronary death.”

Wow! With a single pill you can stop 38% of people from having a heart attack?! Sign me up right now . . .

No wonder Mr. Angry Cardiologist was barking in my ear . . .

But, wait . . . did he actually read these studies, or is he just quoting the relative risk reduction he was told about by the beautiful blond Drug Representative that took him to lunch?

(Oh, yes, believe me, I’ve met her too . . .)

Just to be thorough for this patient, however, maybe we should look at the actual risk reduction (ARR) instead of the relative risk reduction (RRR) . . . ?

In the simvastatin group above, 781 (7.6%) had died because of CVD, in the placebo group the number was 937 (9.1%). Thus, the actual risk reduction (ARR) with simvastatin was only 1.5 % (9.1–7.6) and the number needed to treat (NNT) was 67. That means that you must give 40 mg of simvastatin to 67 people to stop one fatal heart attack.

(That 38% doesn’t look so hot anymore . . . does it?!)

Now I must admit, stopping one heart attack in 67 people is not bad . . . if there are no side effects in the other 66 people.

But, in the words of the barking cardiologist above . . . side effects from STATINs “don’t matter.”

What About the Side Effects?

A notably undiscussed, but very significant, feature of this study, which is common to STATIN trials in general, was that 26% of all eligible subjects withdrew from this study after being on simvastatin for just one month before the formal initiation of the study (the run-in period). Interestingly, the reason for their withdrawal was never provided, but a likely explanation may be that they did not tolerate the adverse effects of the drug. Thus, any study that has a period in which subjects with adverse events may withdraw before formal study initiation has an inherent bias against providing a representation of the actual rate of adverse events. Hence, the rate of statin adverse effects cannot be determined from such studies.

I have mention in my previous emails that a 1-2% reduction in coronary events is still a reduction in heart attacks and death. And, if 2% of the population had fewer heart attacks, that is still a good thing. And, I again emphasize, that this would be great, if there were no side effects.

But, there are side effects, and they are substantial. Let’s talk about them, should we?

Cancer

Many STATIN trials have reported an increase in the incidence of cancer. Four of them showed that this increased risk was statistically significant.

Did you know that?

The CARE trial was a study to see if using a STATIN after diagnosis of heart disease was effective. It included 4159 patients (576 women and 3583 men) with myocardial infarctions (heart attacks) and average cholesterol levels [2]. Half of the patients were administered 40 mg pravastatin, half of them were given a placebo.

After 5 years of treatment, 24 (1.15%) had died because of CHD in the treatment group and 38 (1.83%) in the placebo group, resulting in an ARR of 0.6%. Yet, the most serious adverse event was breast cancer, which occurred in 12 of the women (4.2%) in the pravastatin group but in only one of the women (0.34%) in the placebo group. Although the difference in the incidence between the groups was statistically significant (p = 0.002), the authors dismissed the increased risk by stating: “There is no known potential biologic basis . . . the totality of evidence suggests that these findings in the CARE trial could be an anomaly and may be best interpreted in the context of the trial’s very low event rates and statistical testing of many adverse events.”

So, the authors care if STATINs decrease death by heart attack by 1%, but they don’t care if it increases breast cancer death by more than 4% . . . really?!

By the way, we have known for a long time that if you decrease total cholesterol to less than 170 mg/dL by a low-fat, vegan diet, vegetarian diet or by STATIN drug use, estrogen dominance occurs in many women. Estrogen dominance is the driver for breast cancer [3,4].

At least nine cohort studies have show that low cholesterol levels measured 10-30 years previously is a risk factor for cancer later in life [5]. Yep, no one ever told you that, did they?!

Several case-controlled studies of cancer patients and healthy controls have show the cancer patients had been using statins significantly more often than the control subjects [5]. And, at least two non-statin cholesterol-lowering trials have also reported a statistically significant excess of cancer cases in the treatment groups [6,7].

In the PROSPER trial involving 5804 men and women age 70-82 with a history of atherosclerosis, half were given pravastatin and the other half a placebo. Improvement in absolute risk of death from heart attack improved by 0.9%, however, 199 of the control group got cancer, and 245 of the treatment group was found with cancer (24 actually died from cancer). The authors discounted this finding [8].

In the SEAS trial, 1873 patients with aortic stenosis and mean total cholesterol of 222 mg/dL (5.7 meq/L) were included. Half of the patients were treated with simvastatin and ezetimibe and the other half with placebo. After 4.3 years, no significant benefit was noted in cardiac disease or heart attack. However, cancer appeared in 11.1% (105 patients) of those treated and in only 7.5% (70 patients) of those on placebo. This was statistically significant.

One last note is that most cholesterol trials only last 2-5 years. It takes much longer for cancer to develop and really show up. To make my point, one long-term (10 year) study demonstrated that ductal and lobular breast cancer rates doubled in those women using statins for > 10 years [9].

We still don’t know if STATINs are carcinogenic, but no one has been willing to look at this question despite the strong evidence and associated risk [9].

Hemorrhagic Stroke

Mr. Angry Cardiologist sent me six studies to prove his point, yet they all said the same thing as the studies I quoted above. The absolute risk reduction was 1-2%.

However, one of those studies pointed out that the risk of hemorrhagic stroke with high dose STATIN use was even higher than the reduction in heart attacks.

In a meta analysis of 16 studies that included 26,497 patients. The relative risk ratio of major atherosclerotic cardiovascular events (MACE) treated with high dose STATINs was 0.77. There were 1121 incidents of MACE (8.4%) in the high dose STATIN group (13,293 patients) and 1373 MACE incidents (10%) in the moderate dose STATIN group (13,204 patients). High dose STATINs only reduce the absolute rate of adverse coronary events again by 1.6%. However, all of the 16 studies point to the fact that adverse side effects, including hemorrhagic stroke increases by 5%. And 2% of those that stayed in the study had elevated liver enzymes due to the use of STATINs. Though a consistent reduction of MI occurred in 2%, a reduction in all-cause mortality did NOT go up at all.

Risk of hemorrhagic stroke is found to increase by 2-5% in most of the high dose studies currently in the medical literature.

Myopathy

It is widely accepted that myopathy (muscle aching) is the most common adverse effect from STATIN use. Reports in as many as one out of four people experience muscle weakness and pain with exercise [10-13]. It is also noted that 17 out of 22 profession athletes with familial hypercholesterolemia stopped their STATINs due to this side effect [13].

In almost all of the studies on STATINs, authors report that muscle damage only occurs in 1% of treated patients. Yet, to get to that low number, the authors only record muscular damage in those patients with an elevated or high creatine kinase (CK). High is defined as 10 times the normal value on two successive draws. What about those patients who had only 9 times the normal value? Yet, many people experience muscle problems without a risk in CK. I see this in my office all the time. Evidence reveals that people will have microscopic evidence of muscle damage that are symptom free [14,15].

Brain Pathology, Nerves, Mood and Cognitive Disorders

In a meta-analysis of cholesterol-lowering research, Muldoon et al. [16] found a statistically significant increase in the number of deaths from accidents, suicide or violence in the treatment groups. Although fewer people died because of a heart attack, more died because of neurological causes.

The authors also noted that low blood cholesterol levels are seen more often in criminals, in people with diagnoses of violent or aggressive-conduct disorders, in homicidal offenders with histories of violence and suicide attempts related to alcohol, and in people with poorly internalized social norms and low self-control.

These findings have been confirmed by other authors in a review four years later. In this review by Boston et al., [17], they concluded that lowering cholesterol levels have been associated with an increase in violent deaths in cardiovascular primary prevention studies, and that altered cholesterol levels are often found in relation to other psychiatric disorders. Finally, Asellus et al. [18] found that in patients with serum cholesterol below the median, the correlation between exposure to violence as a child and adult violence was significant.

A low serum cholesterol level has also been found to serve as a biological marker of major depression and suicidal behavior, where a higher total cholesterol is protective [19-22].

Lowering of LDL-C to less than100 mg/dL has been shown to increase the risk of all forms of dementia [23]. And, lowering total cholesterol to less than 170 mg/dL dramatically increases the risk of Alzheimer’s dementia and all other types of dementia [24, 26, 27].

Johann et al. found that there is a linear relationship with STATIN doses and diabetic neuropathy. The higher the dose of STATIN, the greater the neuropathy [25]. In fact, in studying 465,000 people in Denmark, researchers found that the risk for neuropathy is 16 times higher if you are taking a STATIN medication and even higher if you have used that STATIN for longer than two years [28].

Testosterone & Erectile Dysfunction

STATINS lower testosterone and cause erectile dysfunction to worsen. When LDL-C is lowered below 100 mg/dL there is a significant negative impact on the integrity of the somatosensory pathway, which plays a role in erectile function. Reducing LDL-C with a statin was associated with both decreased testosterone levels and erectile dysfunction [34, 35].

All of these neurological adverse effects, if even mentioned on the drug labels, are characterized as “rare.”

It is important to note that these cognitive effects appear gradually over months or years after starting the STATIN drug. Because of this, these symptoms may be attributed to advancing age or dementia.

No Trial Has Demonstrated Degree of Cholesterol Lowering and Absolute Risk

To date, no clinical trial has shown any association between the degree of cholesterol lowering and the outcome using absolute risk statistics. Yet, the 2018 cholesterol guidelines continue to be followed religiously. There is little evidence that STATINs provide a substantial benefit in primary or secondary prevention. Almost all trials have found that the NNT to avoid a fatal CHD in a 5-year period is at least 50, and in most of them it is over 100.

Based on this information, it is my professional opinion from clinical experience and extensive review of the literature that there is no legitimate reason a person over age 70 should be taking STATIN drugs. And, despite the current American Heart Association (AHA) Guidelines, you should highly question any recommendation to take STATIN drugs at any age. Despite what the current AHA guidelines say, data clearly demonstrates that the risk does not outweigh the benefit using these drugs.

Multiple lines of research demonstrate that the longer you take these drugs the worse your cognition and functioning will become.

What Do I Recommend?

After 20+ years of treating cholesterol and closely monitoring CHD, the most powerful effect you can have on vascular disease is carbohydrate restriction. Low carbohydrate, ketogenic and carnivorous diets dramatically lower small LDL particles (the atherogenic component), triglycerides, C-RP and insulin back to normal ranges [30, 31, 32,33]. These changes improve over one to twelve months when consistent dietary regimens are followed.

  1. Follow a ketogenic or carnivorous diet.  To see plaque reversal you must keep your total carbohydrate intake less than 20 grams per day
  2. Exercise at least 4-5 days per week.
  3. Use Curcumin 1-3 grams daily
  4. Regularly monitor your small LDL particle and metabolic markers including triglycerides hemoglobin A1c, fasting blood sugar, fasting insulin, and C-RP if you cannot get an insulin level.

The key is individualizing your diet and activity based on your response to these metabolic markers.

Click HERE to read Part III of this series:  STATIN Use and COVID-19

References:

  1. Yusuf S. Two decades of progress in preventing vascular disease. Lancet 2002;360:2-3
  2. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and recurrent events trial investigators. N Engl J Med 1996;335:1001-9
  3. Samavat H, Kurzer MS. Estrogen metabolism and breast cancer. Cancer Lett. 2015 Jan 28;356(2 Pt A):231-43. doi: 10.1016/j.canlet.2014.04.018. Epub 2014 Apr 28. PMID: 24784887; PMCID: PMC4505810.
  4. Sun YS, Zhao Z, Yang ZN, Xu F, Lu HJ, Zhu ZY, Shi W, Jiang J, Yao PP, Zhu HP. Risk Factors and Preventions of Breast Cancer. Int J Biol Sci. 2017 Nov 1;13(11):1387-1397. doi: 10.7150/ijbs.21635. PMID: 29209143; PMCID: PMC5715522.
  5. Chen Z, Keech A, Collins R, et al. Prolonged infection with hepatitis B virus and association between low blood cholesterol concentration and liver cancer. BMJ 1993;306:890-4
  6. Dayton S, Pearce ML, Hashimoto S, et al. A controlled clinical trial of a diet high in un-saturated fat in preventing complications of atherosclerosis. Circulation 1969; 40(suppl II):1-63
  7. Oliver MF. Cholesterol-lowering and cancer in the prevention of cardiovascular disease. QJM 2010;103:202
  8. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Lancet 2002;360:1623-30
  9. Ravnskov U, Rosch PJ, McCully KS. The statin-low cholesterol-cancer conundrum. QJM 2012;105:383-8
  10. Golomb BA, Evans MA, Dimsdale JE, et al. Effects of statins on energy and fatigue with exertion: results from a randomized controlled trial. Arch Intern Med 2012;172: 1180-2
  11. Golomb BA. Statins and activity: proceed with caution. JAMA Intern Med 2014;174: 1270-2
  12. Sinzinger H, Wolfram R, Peskar BA. Muscular side effects of statins. J Cardiovasc Pharmacol 2002;40:163-71
  13. Sinzinger H, O’Grady J. Professional athletes suffering from familial hypercholesterolaemia rarely tolerate statin treatment because of muscular problems. Br J Clin Pharmacol 2004;57:525-8
  14. Phillips PS, Haas RH, Bannykh S, et al. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med 2002;137:581-5
  15. Draeger A, Monastyrskaya K, Mohaupt M, et al. Statin therapy induces ultrastructural damage in skeletal muscle in patients without myalgia. J Pathol 2006;210:94-102
  16. Muldoon MF, Manuck SB, Matthew HA. Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials. BMJ 1990;301:309-14
  17. Boston PF, Dursun SM, Reveley MA. Cholesterol and mental disorder. Br J Psychiatry 1996;169:682-9
  18. Asellus P, Nordstro¨m P, Nordstro¨m AL, et al. Cholesterol and the “Cycle of Violence” in attempted suicide. Psychiatry Res 2014;215:646-50
  19. Agargu¨n MY, Algu¨n E, Sekerog˘lu R. Low cholesterol level in patients with panic disorder: the association with major depression. J Affect Disord 1998;50:29-32
  20. Kim JM, Stewart R, Shin IS, et al. Low cholesterol, cognitive function and Alzheimer s disease in a community population with cognitive impairment. J Nutr Health Aging 2002;6:320-3
  21. Ozer OA, Kutanis¸ R, Agargun MY. Serum lipid levels, suicidality, and panic disorder. Compr Psych 2004;45:95-8
  22. VilibicM, JukicV, Pandzic-Sakoman M, et al. Association between total serum cholesterol and depression, aggression, and suicidal ideations in war veterans with posttraumatic stress disorder: a cross-sectional study. Croat Med J 2014;55:520-9
  23. Ding Ding, Fen Zhou, Yang Cao, Xiaoniu Liang, Wanqing Wu, Zhenxu Xiao, Qianhua Zhao, Wei Deng, Cholesterol profiles and incident cognitive decline among older adults: the Shanghai Aging Study, Age and Ageing, Volume 50, Issue 2, March 2021, Pages 472–479.
  24. Kim JM, Stewart R, Shin IS, Yoon JS. Low cholesterol, cognitive function and Alzheimer s disease in a community population with cognitive impairment. J Nutr Health Aging. 2002;6(5):320-3. PMID: 12474022
  25. Johann ME, et al., JAMA Network Open, 2019;2(5):3194789. doi:10.1001/jamanetworkopen.2019.4798
  26. Hoyer S, Riederer P. Alzheimer disease—no target for statin treatment. Neurochem Res 2007;32:695-706
  27. Kim YK, Lee HJ, Kim JY, et al. Low serum cholesterol is correlated to suicidality in a Korean sample. Acta Psychiatr Scand 2002;105:141-8
  28. Gaist D, Jeppesen U, Andersen M, et al. Statins and risk of polyneuropathy: a case-control study. Neurology 2002;58: 1333-7
  29. Kyto V, Saraste A, Tornio A. Early Statin Use and Cardiovascular Outcomes After Myocardial Infarction: A population-based case-control study. Atherosclerosis. Aug 2022. 354:p8-14. DOI:https://doi.org/10.1016/j.atherosclerosis.2022.06.101
  30. Hoogeveen RC, et al. Small Dense Low-Density Lipoprotein-Cholesterol Concentrations Predict Risk for Coronary Heart Disease. Arteriosclerosis, Thrombosis, and Vascular Biology. 2014;34:1069–1077
  31. Garvey WT, et al., Effects of Insulin Resistance and Type 2 Diabetes on Lipoprotein Subclass Particle Size and Concentration Determined by Nuclear Magnetic Resonance. Diabetes Feb 2003, 52 (2) 453-462
  32. Berneis K. K., Krauss R. M. Metabolic origins and clinical significance of LDL heterogeneity. Journal of Lipid Research. 2002;43(9):1363–1379.
  33. Gerber PA, Thalhammer C, Schmied C, Sprink S, Amann-Vesti B, et al. Small, dense LDL particles predict changes in intima media thickness and insulin resistance in men with type 2 diabetes and prediabetes – a prospective cohort study. PLOS One. 2013. 8(8): e72763 doi:10.1371/journal.pone.0072763
  34. Baspınar O, Bayram F, Korkmaz S, Aksu M, Kocer D, Dizdar OS, Simsek Y, Toth PP. The effects of statin treatment on adrenal and sexual function and nitric oxide levels in hypercholesterolemic male patients treated with a statin. J Clin Lipidol. 2016 Nov-Dec;10(6):1452-1461. doi: 10.1016/j.jacl.2016.09.004. Epub 2016 Sep 13. PMID: 27919363.
  35. de Keyser CE, de Lima FV, de Jong FH, Hofman A, de Rijke YB, Uitterlinden AG, Visser LE, Stricker BH. Use of statins is associated with lower serum total and non-sex hormone-binding globulin-bound testosterone levels in male participants of the Rotterdam Study. Eur J Endocrinol. 2015 Aug;173(2):155-65. doi: 10.1530/EJE-14-1061. Epub 2015 Jun 1. PMID: 26034077.