Statins for the Healthy are Harmful

Current government guidelines recommending mass medication of healthy people with cholesterol-lowering statins pose unacceptable health risks according to independent evidence from randomized control trials and population studies Dr. Mae-Wan Ho

Excerpt from Water Carnival - the images of organisms discovered in Mae-Wan Ho's laboratory within a quantum jazz soundscape. Download the full video from the online store.

Controversial new guidelines put extra millions of healthy people on statins

UK’s pharmaceutical regulatory agency NICE sparked a controversy with its new guideline in issued July 2014, recommending statins for healthy people with a 10 % or greater ten-year risk of cardiovascular disease (CVD) [1]. This was a dramatic departure from its previous 2006 guideline, which recommended statins for people whose ten-year risk of developing CVD was 20 % or greater, or whose risk was increased because of diabetes, or those in high-risk ethnic groups. The new guideline inflates the number of people eligible for statins by 4.5 million. It followed a revision in US guideline recommending statins for people with a 7.5 % or greater ten-year risk, which added ~13 million healthy people.

In response, the General Practitioners Committee (GPC) of the British Medical Association issued a statement expressing concern [2] “that there is insufficient evidence of significant overall benefit to low-risk individuals to allow GPs to have confidence in the recommendation to reduce the risk-threshold for prescribing cholesterol-lowering drugs.” Results of a survey of 560 British GPs published in October 2014 showed that two thirds [3] “had not begun prescribing statins at the 10 % risk threshold.”

Meta-analysis of clinical trials by the pharmaceutical industry unravels on re-analysis

The rationale for the new guidelines was a Cochrane review published in 2013 [4], which radically overturned its previous 2011 review of statins for the primary prevention of CVD [5] that was consistent with the 2006 NICE guidelines. The 2013 Cochrane review [4] concluded that statins reduce all-cause mortality and cardiovascular events without increasing the risk of adverse events among people at low risk of CVD of less than 10 % risk over ten years. The change from its 2011 review was based largely on a meta-analysis by the Cholesterol Treatment Trialists’ (CTT) Collaboration published a year earlier [6].

The CTT 2012 meta-analysis [6] was designed to assess the “overall net benefit” of cholesterol lowering with statins in the subgroup of participants at low risk of cardiovascular disease - defined as five year risk <10 % - in 27 clinical trials published by the end of 2009. The average five-year risk in participants in this group was 2.6 %. The authors concluded that statin therapy significantly reduces the risk of all-cause mortality by 9.1 % and of major vascular events, including major coronary events (non-fatal myocardial infarction or coronary death), strokes and coronary revascularization procedures – by about 20 % per 1.0 mmol/L reduction in low density lipoprotein (LDL) cholesterol, regardless of baseline risk level. The authors calculated that in low risk patients, statins prevented 11 major vascular events per 1 000 people treated for five years for each 1.0 mmol/L reduction in LDL cholesterol. They concluded that this significant benefit of statins in low risk patients “greatly [exceeded] any known hazards of statin therapy.”

However, John Abramson at Harvard Medical School and three colleagues in US and Canadian universities re-evaluated the 2012 CTT meta-analysis and published their results in the BMJ in October 2013 [7]. They found that for people with less than a 10 % five-year risk of CVD, there was no significant reduction in overall mortality with statin treatment. Concentrating on ‘hard cardiovascular events’, i.e., cardiovascular death, myocardial infarction and stroke, as the most reliable endpoints least vulnerable to bias in judgement, which constitute 65 % of major vascular events that occurred in people with a five year risk of <10 %, the was 7.15 per 1 000 low risk patients treated for five years. In other words, 140 people with a five-year risk of less than 10 % need to be treated with statins for five years in order to prevent one heart attack or stroke, but with no reduction in overall mortality and no reduction in serious adverse events overall.

Serious adverse events from statin therapy not included in meta-analysis

In order to judge the net effect of a treatment on overall health, it is necessary to know the total number of serious adverse events, including death from all causes, hospital admissions, prolongation of admission, cancer, or permanent disability. Despite having access to patient-level data, the CTT meta-analysis [6] did not consider the effect of statins on serious adverse events. Only 3 or the 5 largest trials included in the meta-analysis reported data on serious adverse events, none of which reported a reduction associated with statin.

The 2013 Cochrane review [4] relied on two earlier reviews that included only published data to conclude that the rate of serious adverse events was similar in the statin and placebo groups. Abramson and colleagues [7] listed known side effects from the literature: myopathy at 100 to 400 times the rate reported by the CTT meta-analysis of 0.5 per 1 000 patient, diabetes at more than five times the 5 per 1 000 reported by CCT meta-analysis, and a string of others including liver dysfunction, acute renal failure and cataracts, cognitive symptoms, neuropathy and sexual dysfunction, decreased energy and exertional fatigue, and psychiatric symptoms including depression, memory loss, confusion, and aggressive reactions. One positive association is a decreased risk of oesophageal cancer. However, they misinterpreted an epidemiological study that side-effects could be as high as 18 – 20 %, which was later corrected [8].

Opposing statins “a serious disservice to British and international medicine”

On 21 March 2014, Sir Rory Collins, professor of medicine and epidemiology at the Clinical Trial Service Unit of Oxford University and head of the CTT collaboration, told The Guardian that the Abramson et al paper was “a serious disservice to British and international medicine” [9], and claimed it was probably killing more people than had been harmed as the result of the paper on the MMR vaccine by Andrew Wakefield (but see [10] MMR Controversy Reignites, SiS 66). Collins claimed they have “good data from over 100 000 people that show statins are very well tolerated, with only one or two well-documented [problematic] side effects.” Myopathy, or muscle weakness, occurred in one in 10 000, he said, and there was a small increase in diabetes. However, he had refused to release the data to the public.

On 15 February 2015, Collins had changed his tune. He told the Sunday Express [11] that his team will carry out a “challenging” reassessment of the evidence which will include studying all reported side effects. They had looked at only heart and cancer risks in the original research, and had not examined other side effects.

Fiona Godlee, editor in chief of BMJ, which has led calls for access to statins data, said: “This is of real concern. We wrongly assumed all the details of possible side effects had been thoroughly assessed before new guidance effectively made tens of thousands of people eligible for this drug. We now know this is not the case and would urge any re-analysis is done in the most transparent way.”

Meanwhile, Dr. Sarah Wollaston, Chair of the Commons Health Select Committee, called for drug companies to release all their trial data. Her demand was echoed by experts at BMJ, asking the authors of all the major statin trials to release the findings for independent analysis.

Collins had requested BMJ to retract the paper of Abramson and colleagues [7]. An independent panel appointed by the editor of BMJ ruled unanimously (6 to 0) against Collins [12].

Serious conflict of interest in statin clinical trials

Abramson and colleagues highlighted the limitations of the research data in the CTT meta-analysis [7]. All of the randomized controlled trials included were funded by the manufacturer of the statin being studied. A recent Cochrane review found that industry sponsored clinical trials are significantly more likely than non-commercially funded studies to report favourable efficacy and safety results and conclusions [13].

They also drew attention to “possible mechanisms by which adverse effect might be minimized in clinical trials”, which “include exclusion of up to 30 % of patients with comorbidities (such as liver, kidney, muscle or inflammatory diseases), prerandomisation run-in periods in which people who fail to tolerate statins are excluded, 10 % dropout rates, failure to assess for specific potential adverse events (like myopathy or cognitive changes) and under-ascertainment and selective reporting of adverse events (including serious adverse events).” These sources of biases have been pointed out by other commentators [14].

“Additionally, the benefit of statins found in clinical trials may be exaggerated because prerandomisation screening procedures include monitoring for compliance with therapy, which led to adherence rates in five of the landmark clinical trials included in the CTT meta-analysis of 70-94%.” In community-based studies, at least 50 % of patients discontinue statin therapy within one year, and adherence to statin therapy for primary prevention in people over 65 was only 25 % after two years [15].

The CCT trials suffer from two major flaws, says Abramson [12]. First, CTT agreed that the patient-level data will be held in strict confidence; it would not be shared without the permission of those who conducted the studies. Consequently, the CTT, part of the Clinical Trial Service Unit of Oxford, which is heavily dependent on pharmaceutical company money for its research, was given sole access to patient-level data [12] “without allowing for review by independent experts or even the possibility of adequate peer review of its published meta-analyses.” Second, although evaluation of the effectiveness of medicines must always be counterbalanced by evidence of harm, the CTT’s arrangement to receive effectiveness data did not include such a balance. The frequency of adverse events cited in the 2012 CTT meta-analysis relied on published reports rather than patient-level data.

The 2013 Cochrane review relied on the 2012 CTT meta-analysis but did not have access to the patient-level data. Similarly, the NICE guideline expert panel (8 out of 12 with financial ties to statin manufacturers) did not have access to patient-level data. “In fact, even the CTT did not have patient-level data for most adverse events.” Abramson pointed out [12]. “The bottom line is that practically all that we think we know about the efficacy and safety of statins has been brought to us by commercial interests that hold the actual data as proprietary secrets. Since we cannot verify commercial claims of efficacy and safety, healthy people should use statins with caution.”

Statins for the healthy increases health risks

The statin controversy is not new. A meta-analysis carried out in the 1990s of results from 35 randomized controlled trials of cholesterol lowering treatments [16] showed that cholesterol lowering drugs reduced mortality in only a small proportion of patients at very high risk of death from coronary heart disease. There was no net effect in a medium risk group, and in the low risk group, there were adverse treatment effects (OR (odds ratio) 1.22 CI 1.06-1.42). Increased mortality was seen from causes other than coronary heart disease in trials of drug treatments: OR 1.21 CI 1.05-1.42.

A new study published in 2015 finds increased risk of diabetes with statin treatment associated with impaired insulin sensitivity and insulin secretion [17]. Markku Laakso and colleagues at University of Eastern Finland investigated the mechanisms underlying the risk of type 2 diabetes associated with statin treatment in a healthy population of men followed up for 5.9 years. A total of 8 749 non-diabetic participants aged 45-73 years old were part of the cohort of 10 197 men originally randomly selected from the population register of Kuopio, Eastern Finland (population 95 000) for the Metabolic Syndrome in Men study 2005-2010. An oral glucose tolerance test was performed. Participants with previously diagnosed type 1 diabetes, newly or previously diagnosed type 2 diabetes were excluded, leaving a total of 8 749 men without diabetes at baseline.

Out of the 8 749 non-diabetic participants at baseline, 625 developed diabetes during the 5.9 year follow-up. Statin treatment was given to 2 142 of the 8749 non-diabetic men at baseline: 65.9 % on simvastatin, 18.1 % on atorvastatin, 8.6 % on rosuvastatin, 3.8 % on fluvastatin, 2.3 % on lovastatin and 1.3 % on pravastatin.

Participants treated with statins developed diabetes more often than those without statin treatment (11.2 % vs 5.8 % p<0.001). Statin treatment increased the risk of type 2 diabetes by twofold during the follow-up (HR(hazards ratio) 2.01, CI 1.71-2.36) After adjusting for age, BMI, waist circumference, physical activity, smoking, alcohol intake, family history of diabetes, beta-blocker and diuretic treatment, the risk was 1.46, CI 1.22-1.74.

Both simvastatin and atorvastatin increased the risk of type 2 diabetes compared with no statin treatment: HR 2.11, CI 1.76-2.54; and HR 1.5, CI 1.3-1.73 respectively; these associations remained significant after adjusting for confounding factors: HR 1.49, 95 % CI 1.22-1.83; and HR 1.21 95 % CI 1.04-1.40 respectively. Other statins also increased the risk of diabetes, but did not attain significance, as the numbers involved were much smaller. The risk of diabetes was dose dependent for both simvastatins and atorvastatin.

Statin treatment significantly increased the levels of 2hPG and the glucose response (AUC) at follow-up, and nominally the levels of FPG at follow-up after adjusting for confounding factors. Statin treatment was also associated with 24.3 % reduced insulin sensitivity (Matsuda ISI) in the lowest category of FPG (<5.0mmo/l) and with a 19.5 % reduced insulin sensitivity in the lowest category of 2hPG (<5.0 mmol/l) compared with individuals without statin treatment. Statin treatment reduced insulin secretion (DI) by 12.0 % in the lowest category of FPG compared with individuals without statin treatment. The reduction in Matsuda ISI in different glucose tolerance categories (from <5.0 to 6.9 mmol/l for FPG, and from <5.0 to 7.99 mmol/L for 2h PG) remained significant after adjusting for confounding factors whereas the reduction in DI in the FPG and 2hGP categories lost its statistical significance after adjustment for confounding factors in all categories except for FPG <5.0 mmol/l).

Treatment with either simvastatin or atorvastatin was associated with significant reduction in insulin sensitivity of 21.9% and 24.4 % respectively and insulin secretion of 7.6 and 7.4 % respectively. There was a significant decrease in insulin sensitivity with increasing dose of simvastatin and atorvastatin and decrease in insulin section with increasing dose.

The increased risk of type 2 diabetes in this new study is higher than those previously reported. An Irish study reported a 20 % increase. A Canadian study a 10-22 % increase and a Taiwanese study a 15 % increase. In the Women’s Health Initiative study statin therapy was associated with a 48 % increase in the risk of self-reported type 2 diabetes. In a collaborative meta-analysis of 13 randomised statin trials (N = 91 140) statin therapy was associated with a 9 % increased risk for type 2 diabetes based on FPG or physician-reported diagnosis of diabetes. The authors commented that [17] previous studies may have underestimated the risk.

To conclude

Biased clinical trials and biased reporting have greatly exaggerated the benefits of statin therapy while substantially underplaying serious side-effects and health risks. Independent random clinical trials and population studies lend no support to the prescription of statins for lowering cholesterol and preventing heart disease. On the contrary, evidence suggests that mass medication of healthy populations increases risk of adverse treatment effects and death.

Article first published 15/04/15

References

Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. NICE clinical guideline 181. National Institute for Health and Care Excellence, July 2014 (modified January 2014), http://www.nice.org.uk/guidance/cg181/resources/guidance-lipid-modification-cardiovascular-risk-assessment-and-the-modification-of-blood-lipids-for-the-primary-and-secondary-prevention-of-cardiovascular-disease-pdf GPC statement on NICE Lipid Modification Clinical Guidance CG181. 18 July 2014, Bma.org.uk Price C. Two-thirds of GPs disregard NICE advice to offer statins to more patients. Pulse 22 October 2014. Taylor F, Huffman MD, Macedo AF et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2013, 1:CD004816. Taylor F, Ward K, Moore THM et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2011, 1:CD004816. Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. The Lancet 2012, 380, 581–590. Abramson JD, Rosenberg HG Jewell N, and Wright JM. Should people at low risk of cardiovascular disease taken a statin? BMJ 2013, 347: 16123 doi: 10.1136/bmj.f6123 (Published 22 October 2013). Abramson JD, Rosenberg HG Jewell N, and Wright JM. Should people at low risk of cardiovascular disease taken a statin? Corrections. BMJ 2014, 348: g3329 “Doctors’ fears over statins may cost lives, says top medical researcher”, Sarah Boseley, The Guardian, 21 March 2014, http://www.theguardian.com/society/2014/mar/21/-sp-doctors-fears-over-statins-may-cost-lives-says-top-medical-researcher Ho MW. MMR controversy reignites. Science in Society 66 (to appear) 2015. “Exclusive: statins expert calls for safety checks over the drug”, Lucy Johnston, Sunday Express, 15 February 2015, http://www.express.co.uk/news/uk/558249/statins-expert-heart-drug-rory-collins Abramson J. Prescribing statins time to rein it in. Pharmaceutical Journal 2015, 294,

o 7854/5 online, http://www.pharmaceutical-journal.com/opinion/comment/prescribing-statins-time-to-rein-it-in/20068145.article#fn_8 Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research outcome. Cochrane Database Syst Rev 2012, 12:MR000033. Mansi I, Mortensen E. The controversy of a wider statin utilization: why? Expert Opin Drug Saf 2013:12:327-37. Maningat P, Gordon BR, Breslow JL. How do we improve patient compliance and adherence to long-term statin therapy? Curr Atheroscler Rep 2013, 15, 291-8. Smith GD, Son F and Sheldon TA. Cholesterol lowering and mortality: the importance of considering initial level of risk. BMJ 1993, 306 1367-73. Cederberg H, Stančáková A and Yaluri N, Modi S, Kuusisto J an Laako M. Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort. Diabetologia DOI 10.1007/s00125-015-3528-5

Got something to say about this page? Comment on this article Comments may be published. All comments are moderated. Name and email details are required. Anti spam question: