LDL lowering to remarkably low levels is safe and effective for cardiovascular disease prevention

LDL low

I’m grateful to Dr. Robert P. Giugliano insights into this very important topic presented in October 2017 in Boston during the educational program ‘Advances in Lipid Management and Cardiovascular Risk Reduction: New Horizons for 2018’.  He is a cardiovascular medicine specialist at BWH and an associate professor of medicine at Harvard Medical School. In addition, he is a senior investigator of BWH’s Thrombolysis in Myocardial Infarction (TIMI) Study Group.  I will give a brief overview of his presentation.

Low LDL 22

We have wonderful randomised double blinded placebo controlled trials (RDBPC) going back >20 years starting with the 4S trial in 1994 demonstrating that reducing high (> 200 mg/dL or > 5.2 mmol/L) LDL-C was effecting in reducing atherosclerotic vascular disease (ASCVD) events.

Since 1994 there have been a plethora of RDBPC trials demonstrating the benefit of lowering average LDL-C levels (140 mg/dL or 3.6 mmol/L) and that ultimately “lower-is-better” with LDL reduction.   The most recent trials (TNT; Improve-IT and Fourier) have given us great insight into the efficacy and safety over lowering LDL to remarkably low levels of LDL-C never previously thought could be achieved.  The remarkably low LDL-C was achieved with combinations of Statin, Ezetimibe and PCSK9-Inhibitors.

Low LDL 4Improved cardiovascular outcome was seen in the Prove IT-TIM 22 trial to achieve very low LDL-C levels < 80 mg/dL (< 2.0 mmol/L) with a 40% risk reduction of events at < 40 mg/dL (1.0 mmol/L).  Safety concerns were not an issue despite this aggressive LDL-C lowering.

Low LDL 5


There was no significant difference between myalgia, elevation of muscle enzymes (CK) or liver enzymes (ALT), retinal bleeds or hemorrhagic stroke between different levels of LDL-C reduction with this statin therapy.

LDL-C lowering was taken to even lower levels with the IMPROVE-IT trail comparing Simvastatin 40 mg/d alone verses Simvastatin 40 mg/d + Ezetrol 10 mg/d.

Low LDL 7

Low LDL 8




Comparing safety in the lowest group of LDL < 0.8 mmol/L comprising 6% of the population treated, there was again no adverse signal difference across many adverse events including myalgia; discontinuation of drugs; elevated liver enzymes; gall bladder issues or neurocognitive decline.

Low LDL 9

There were also no differences in hemorrhagic stroke; heart failure; non cardiovascular deaths or cancer in the differing LDL-C groups.

I have discussed in detail the FOURIER trial (last blog posted) evaluating risk reduction in patients with stable ASCVD on high potency Statin therapy with added PCSK9-inhibition to achieve extremely low LDL-C levels.

Low LDL 16

The LDL-C levels at 4-weeks on statin alone (the blue placebo graph) were ± 74-104 mg/dL compared to the LDL-C levels (red graph) achieved adding Evolocumab (PCSK9-I) reducing LDL-C to 21-45 mg/L (0.5 to 1.0 mmol/L).

The really low LDL-C levels were maintained throughout the duration of the FOURIER study (2-4 years) consistently.

Low LDL 17

The safety results looking at the different groups of achieved LDL-C groups again demonstrated no safety signals across multiple adverse events.

Low LDL 18




Of the total FOURIER cohort there were 504 patients with ultra-low LDL-C ± 0.26 mmol/l (10 mg/dL).  These patients enjoyed further risk reduction for the primary and secondary end points with no adverse safety signals whatsoever.

Low LDL 21

Remarkably 30 years ago published in SCIENCE, two Nobel prize winners (Brown & Goldstein) suggested in their acceptance speech that humans only needed 25 mg/dL LDL-C to nourish cells with cholesterol and that this level of LDL-C was the physiological norm.  This is borne out in the animal kingdom with species with this level of LDL-C having zero atherosclerotic vascular disease.

Conclude low LDL

The conclusions from an astonishing 30 years research into the pathophysiology; prevention and management of atherosclerotic disease suggest in 2018:

  • LDL-C can be reduced to unprecedented low levels with statins + Ezetimibe + PCSK9-Inhibitors to achieve LDL-C << 1 mmol/L or < 40 mg/dL.
  • There is a strong progressive relationship of achieved LDL-C and cardiovascular events down to LDL-C < 0.26 mmol/L or < 10 mg/dL.
  • There does NOT appear to be any safety signals or issues with very low achieved LDL-C.
  • Based on the totality of the data this would suggest advocating targeting of LDL-C levels to as close to 0.35-0.5 mmol (20-25 mg/dL) for LIFE.

Have fun in 2018.

Blessings Cardiologydoc


LDL (Apo B containing Lipoprotein) target confirmed for modification of Atherosclerotic Vascular Disease – FOURIER data presented

Low lp-28density lipoprotein (LDL) and the other atherogenic lipoproteins (VLDL; IDL and Lipoprotein”a”) the Apo B containing lipoproteins are the cornerstone of the pathophysiology of atherosclerotic vascular disease (ASCVD).  The continued debate as well-established modifiable risk factors for cardiovascular disease, is how low to drive these lipoproteins in the prevention and management of ASCVD.

Monoclonal antibodies that inhibit proprotein convertase subtilisin–kexin type 9 (PCSK9) have emerged as a new class of drugs that effectively lower Apo B containing lipoproteins.  See my post PCSK9 story continues to intrigue and tantalise….posted on March 19, 2015


Published in NEJM and announced at the 2017 American Heart Association meeting 17 March was the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk).  This was a dedicated cardiovascular outcomes trial that tested the clinical efficacy and safety of evolocumab when added to high-intensity or moderate-intensity statin therapy in patients with clinically evident atherosclerotic cardiovascular disease.

The FOURIER trial was a randomized, double-blind, placebo-controlled, multinational clinical trial in which 27 564 patients at 1242 sites in 49 countries underwent randomization.  Patients were eligible for participation in the trial if they were between 40 and 85 years of age and had clinically evident atherosclerotic cardiovascular disease (ASCVD), defined as a history of myocardial infarction, non-hemorrhagic stroke, or symptomatic peripheral artery disease, as well as additional characteristics that placed them at higher cardiovascular risk.  Patients had to have a fasting LDL cholesterol level of 70 mg per deciliter (1.8 mmol per liter) or higher or a non–high-density lipoprotein (HDL) cholesterol level of 100 mg per deciliter (2.6 mmol per liter) or higher while they were taking an optimized regimen of lipid-lowering therapy, which was defined as preferably a high-intensity statin but must have been at least Atorvastatin at a dose of 20 mg daily or its equivalent, with or without ezetimibe.

Eligible patients were randomly assigned in a 1:1 ratio to receive subcutaneous injections of evolocumab (either 140 mg every 2 weeks or 420 mg every month, according to patient preference) or matching placebo.

The primary efficacy end point was major cardiovascular events, defined as the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke.

When added to statin therapy, the PCSK9 inhibitor evolocumab lowered LDL cholesterol levels by 59% from baseline levels as compared with placebo, from a median of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter). This effect was sustained without evidence of attenuation.

Fourier LDL reduction

In this dedicated cardiovascular outcomes trial, the addition of evolocumab to statin therapy significantly reduced the risk of cardiovascular events, with a 15% reduction in the risk of the primary composite end point of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization and a 20% reduction in the risk of the more clinically serious key secondary end point of cardiovascular death, myocardial infarction, or stroke.

The data from this trial provide insight into the benefit of decreasing Apo B containing lipoproteins to median levels lower than those in previous trials.  These observations align well with the effects of evolocumab and aggressive LDL reduction on coronary atherosclerotic plaque volume in the Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) trial.  See my post Atherosclerotic plaque regression with intense Apo B lipoprotein lowering posted on November 17, 2016

Optimal risk reduction

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Let’s talk Cardiovascular Disease 2017

The size of the problem?

 CVD 5

The World Health Organisation has identified cardiovascular disease as the commonest cause of death worldwide.  Projected to 2030 ischemic heart disease (atherosclerosis of coronary arteries) and stroke (atherosclerosis of head and neck arteries) will be two out of the top three killers in the world.  Even more worrying though, cardiovascular disease disables many more people than it kills.

What is atherosclerosis?


Atherosclerosis (ath”er-o-skleh-RO’sis) comes from the Greek words athero (meaning gruel or paste) and sclerosis (hardness). It is a chronic inflammatory process in which deposits of fatty substances (lipoproteins), cellular waste products, calcium and other substances build up in the wall and inner lining of an artery. This build up is called “plaque” (atherosclerotic plaque). It usually affects large and medium-sized arteries and is a progressive disease over the decades of life starting in some, as early as 20-30 years old.


Plaque develop over time to grow large enough to significantly reduce the blood’s flow through an artery, but most of the damage occurs when plaque become fragile and rupture and cause blood clots to form that can block blood flow or break off and travel to vital organs.  The vulnerability of plaque to rupture is due to the inflammatory content of the plaque and the local forces the plaque is exposed to within the artery (blood pressure and artery wall stress in particular).


Ruptured atherosclerotic coronary plaque

There is a misconception that women are less at risk than men.  who-burden-of-diseaseWhile women do tend to be protected from cardiovascular disease throughout their childbearing years, this protection falls away rapidly after the menopause, when they are more likely to die from cardiovascular disease than from any other illness.

The spectrum of cardiovascular disease?

spectrum-of-cvdAtherosclerosis of our arteries is a diffuse disease generally affecting many vascular
beds.  When this occurs in the arteries that supply blood to the heart this may
manifest as heart attack, angina, arrhythmia, sudden death or heart failure.  Atherosclerosis of the head and neck vessels may lead to stroke, dementia or
other cognitive dysfunction (memory loss).  Arterial disease of the peripheral arteries may
cause poor circulation to the legs, kidneys or bowel and even lead to aneurysms
(swelling and rupture of the weakened arteries).

Who is at risk for cardiovascular disease?

conventional-cv-risks People with established cardiovascular disease require the most intensive lifestyle and medication intervention.

Seemingly “healthy” individuals who are at risk, can be identified by genetic predisposition to vascular disease with strong family history of members succumbing to heart attack, heart failure, dementia, stroke and peripheral vascular disease. They can also be identified by their own risk factor profile (by identifying conventional risks for cardiovascular disease) and the presence or absence of sub clinical vascular disease (atherosclerosis and vascular disease not clinically apparent).

High risk individuals with increased short term (next 10 years) or high LIFE TIME risk should receive intensive lifestyle counselling and aggressive risk factor modification with modern medication where appropriate.

High prevalence of “sub-clinical” cardiovascular disease

The development of atherosclerotic vascular disease is a “silent” process actually starting from childhood.  Advanced imaging technology (vascular ultrasound) has demonstrated plaque in coronary arteries of high risk teenage children.  Clinical cardiovascular examination and risk stratification shows a high rate of cardiovascular disease in otherwise “healthy” individuals with up to one third of all healthy 50-60 yr men and women (of normal weight) and ½ of overweight 50-60 yr men and woman already have significant sub-clinical cardiovascular disease.  Using trans-vascular ultrasound we often see significant atherosclerosis in otherwise completely healthy people.  Aggressive risk reduction and therapy in these asymptomatic individuals reduces the risk of subsequent vascular events through plaque stabilization and plaque reduction over time.


How to reduce your risk of developing atherosclerotic cardiovascular disease?

  1.  Never smoke or stop smoking all forms of tobacco (including E-cigarettes) – it triples the risk of heart disease and prematurely ages your arteries by 10 to 15 years.
  2. Make healthy food choices.  A healthy diet reduces cardio vascular risk by several mechanisms including weight reduction, lowering blood pressure, improved effects on lipoproteins, control of glucose and reduction of the development of arterial blood clots.  Foods should be varied, and energy intake (based on calories) must be adjusted to maintain an ideal body weight.  No one diet “fits all” but generally Mediterranean style diets rich in fruits, vegetables, whole grain, dairy products; oily fish and lean meat should be encouraged.  Low carbohydrate & high “good” fat (LCHF) style diets are particularly useful those with carbohydrate intolerance (Insulin resistance) or “metabolic syndrome”.

    Patients with high blood pressure, diabetes (glucose abnormalities) and lipoprotein abnormalities should receive dietary advice such as salt and carbohydrate restriction but may need medication to reduce risk.

  3. Exercise regularly.  Physical activity should be promoted in all age groups from children to the elderly.  High risk individuals need special care to increase their physical activity safely to reduce vascular disease.  Although the goal is at least half an hour to an hour of physical activity on most days of the week, more moderate intense activity (averaging 75% of their maximum heart rate for their age) appears to offer better health benefits.
  4. Lose weight.  Weight reduction is recommended for obese people with a body mass index (BMI) > 30 (weight in kg/height in m2); or overweight individuals with BMI > 25-30 kg/m2.  Particularly at risk are those with increased abdominal (visceral) fat as indicated by a waist > 102 cm in men and > 88 cm in Women.
  5. Manage your blood pressure.  The risk of cardiovascular disease increases continuously as blood pressure rises from the lowest risk at 110/70.  The decision to start treatment, however, depends not only on the level of blood pressure but also on assessment of total cardiovascular risk and the presence or absence of target organ damage.  In patients with established hypertension the choice of anti-hypertensive drug depends on the exact underlying cardiovascular disease.  In most patients the goal of therapy is blood pressure < 140/90 mm Hg but lower (< 130/80) for high risk people.
  6. Manage your lipoproteins.  Lifelong it is important to keep atherogenic lipoproteins (Apo B containing lipoproteins) as low as possible whist maintaining the anti-atherogenic Apo A1 containing lipoproteins.  lp-28With optimal lifestyle; diet and exercise oxidation and glycation of lipoproteins is reduced leading to lower “systemic” inflammation and lower rates of plaque instability. Apparently healthy individuals, should be assessed for total cardiovascular risk over the short term (10 years) and their lifetime as clinical trials have shown improved survival rates with aggressive Apo B lowering with extremely low Apo B/ Apo A1 ratio.  The reduction in morbidity and mortality is through plaque stabilization and plaque reduction.

    If this is not achieved with diet, lifestyle and exercise, modern potent effective Statin therapy or PCSK9-inhibitors (a group of lipoprotein lowering drugs) will be required as lifelong therapy.

  7. Manage your sugar.  If you have “impaired glucose tolerance” (fasting Glucose > 5.5), or Insulin resistance try to prevent or delay the onset of diabetes mellitus by healthy lifestyle intervention (low carbohydrate high good fat lifestyle).  Good metabolic control prevents vascular complications, by far the commonest cause of death and disability in the diabetic patient.
  8. Be evaluated for the “Metabolic Syndrome” as it increases your risk for vascular disease by 3-5 times.  Sufferers require intense lifestyle changes, particularly to reduce body weight and increase physical activity. Elevated blood pressure, sugar and lipoproteins may need additional drug treatment.  The syndrome is confirmed when three or more of the following features are present.
  • Waist circumference > 102 cm in males and > 88 cm in females
  • Serum triglycerides > 1.7 mmol/l
  • HDL cholesterol < 1.0 in males and < 1.2 in females
  • Blood pressure > 130/85
  • Plasma (fasting) glucose > 6.1 mmol/l

Early Cardiovascular Screening?

Whilst early screening for asymptomatic cancers such as breast, colon and prostate cancer is widely acceptable, screening for atherosclerotic cardiovascular is not widely practiced despite more than 19 million deaths worldwide per year from cardiovascular disease, compared to about 8 million deaths from all cancers combined.

Fortunately new insights into the development and progression cardiovascular disease, innovative technologies to assess it, and effective therapy to slow it down have been the subject of successful research over the past decade.  By focusing on functional and structural abnormalities of the arteries and heart, it is possible to identify and track the progression of disease.  There is therefore a tremendous incentive for active and aggressive preventative programs to delay vascular disease to the end of life (compression of morbidity theory) and to live without chronic cardiovascular or respiratory disease and good quality of life.

Compression of morbidity

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Atherosclerotic plaque regression with intense Apo B lipoprotein lowering

The results of GLAGOV, reported at AHA Scientific Sessions and now published in JAMA (1) are of keen interest to the clinical community, with the major outcomes study FOURIER with evolocumab expected early in 2017.


GLAGOV is the first intravascular ultrasound (IVUS trial to evaluate the impact of combination treatment of a non-statin lipid lowering agent (LLT), in this instance a PCSK9 inhibitor (evolocumab), with a statin on coronary atherosclerosis progression. It should also be noted that GLAGOV is also the first (IVUS) trial in patients with incident coronary atherosclerosis that was performed on a background of optimized, stable background statin therapy, as reflected in the lowest mean baseline low-density lipoprotein cholesterol level (LDL-C, 93.0 mg/dl) of any IVUS trial to date.

Over a treatment period of 76 weeks (one of the shortest duration of any IVUS trial involving LLTs to date), LDL‑C decreased by 60% to 36.6 mg/dl in the evolocumab-treated group, well below the ESC/EAS recommended LDL-C goal of 70 mg/dl for very high risk patients. Analysis of the primary endpoint, percentage change in atheroma volume (PAV), revealed a least squares mean of 0.95% plaque regression in the intervention group (n=484) relative to an increase of 0.05% in the placebo (background statin treatment alone). The secondary endpoint, change in total atheroma volume, also was indicative of significantly greater plaque regression in the evolocumab arm versus placebo. In fact, PAV regressed in 64% of individuals on evolocumab plus statin compared to 47% on statin alone. Thus, in summary, the greater reduction in LDL-C with the addition of the PCSK9 inhibitor evolocumab to statin therapy resulted in greater regression of atheroma when compared with statin alone.

The key question is: How do these results compare to those in earlier statin monotherapy trials (ASTEROID and SATURN) using IVUS technology?

ASTEROID (2), which showed a significant degree of coronary atherosclerosis regression (0.79% as median PAV, p<0.001) with intensive statin therapy (rosuvastatin 40 mg/day) compared with baseline, was conducted in statin-naïve patients for a period of 24 months. This degree of regression may have resulted from a predominance of vulnerable lipid-rich, “virgin” plaque in these statin-naïve patients. In SATURN (3) coronary plaque regression of 1.22% was obtained with the same intensive statin regimen as ASTEROID over a 24-month period; in this trial, some 60% of patients had received statin treatment for up to 3 months in the year preceding trial inclusion.

The results of GLAGOV clearly show that for patients at very high risk who are on stable intensive or moderate statin therapy with on-treatment LDL-C levels of about 90 mg/dl, stable statin treatment can achieve significantly greater regression when their LDL-C levels are reduced further. Thus, LDL-C lowering mediated by a nonstatin drug, in this case a PCSK9 inhibitor, on top of stable intensive statin therapy, can provide significant additional plaque regression. Importantly, further LDL lowering to levels significantly below the ESC/EAS goal of 70 mg/dl (36 mg/dl) with the addition of evolocumab, is consistent with greater clinical benefit, as judged by additional plaque regression over and above that obtained with intensive statin therapy alone.

Finally, it is important to bear in mind that coronary plaque regression induced by statin therapy has been shown to be synonymous with plaque remodeling, favouring plaque stabilization, and ultimately reductions in cardiovascular events. It can therefore be inferred that the additional 1% of plaque regression induced in the GLAGOV trial by a PCSK9 inhibitor on top of background statin may favour enhanced plaque stability. Insight into the potential for translation of the antiatherosclerotic action of the evolocumab/statin combination into reduction in cardiovascular outcomes over and above that provided by statin therapy alone will be provided by the ongoing FOURIER intervention trial.


  1. Nicholls SJ, Puri R, Anderson T et al. Effect of evolocumab on progression of coronary disease in statin-treated patients. The GLAGOV randomized clinical trial. JAMA. doi:10.1001/jama.2016.16951. Published online November 15, 2016.
  2. Nissen SE, Nicholls SJ, Sipahi I et al; ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556-65. PUBMED www.ncbi.nlm.nih.gov/pubmed/16533939
  3. Nicholls SJ, Ballantyne CM, Barter PJ et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med 2011;365:2078-87. PUBMED www.ncbi.nlm.nih.gov/pubmed/22085316

Statin use and Cancer 2015

cancer“Statin sceptics” often cite increased risk of cancer in statin users. The American Society of Clinical Oncology (ASCO) 2015 Annual Meeting (abstracts 1506 and 5018, presented May 30, 2015) suggests the opposite, with statin use associated with a significant reduction in cancer mortality. This was concluded from two separate studies, one in women and the other in men.

Specifically, statin use was associated with a 22% reduction in deaths from various cancer types in women and a 55% reduction in deaths from bone/connective tissue cancers. The study in men looked at statin use together with the anti-diabetes medication metformin and found a 40% reduction in prostate cancer mortality, with the effect more pronounced in men with obesity/metabolic syndrome.

cancer_biologyThe researchers speculate that statins interfere with cell growth and metastasis by blocking cholesterol production, thereby affecting molecular pathways and the inflammatory response.

Statin Use Analysis of WHI Study Data

The results in women came from the data examined from the Women’s Health Initiative (WHI), the 15-year research program involving postmenopausal women aged 50 to 79 years who were enrolled between 1993 and 1998 at 40 centers in the United States.

WHI Logo

WHI Logo

The observation was between patients’ never having used statins, current statin use, and past statin use, as well as the incidence and number of deaths from cancer among 146,326 women. The median follow-up period was a substantial 14.6 years.

Among the participants, there were 23,067 cases of incident cancer for which complete follow-up data were available. There were 7411 all-cause deaths, including 5837 deaths from cancer, 613 cardiovascular deaths, and 961 deaths from other causes. In all, 3152 cancer deaths were included in the analysis, of which 708 were among current statin users and 2443 among patients who had never used statins. Importantly, multivariate analysis demonstrated that statin use was not associated with cancer incidence, and there was no association between past statin use and cancer mortality.

However, compared with never having used statins, current statin use was associated with a significant reduction in cancer mortality, with an adjusted hazard ratio (aHR) of 0.78 vs. never use (P < .0001). The association was unaffected by statin potency, lipophilicity/ hydrophobicity, type, or duration.

Statin use was associated with significant reductions in deaths from multiple cancers including breast (aHR = 0.60), ovarian (aHR = 0.58), colorectal (aHR = 0.57), digestive (aHR = 0.68), and bone/connective tissue cancers (aHR = 0.45), but not from lung cancer (aHR = 1.17).

Clearly as this was a prospective post hoc analysis of the WHI data no definitive causality could be established but the data are certainly reassuring for statin users given the widespread use and growing use of statins under the new US, NICE and ESC guidelines and the high burden of cancer,

Reduction in Prostate Cancer Death

The other study quoted at the ASCO 2015 meeting showed a reduction in prostate cancer mortality in both statin and metformin users. The researchers used Surveillance, Epidemiology and End Results–Medicare linked data to follow 22,110 patients diagnosed with high-risk prostate cancer, defined as a prostate-specific antigen (PSA) score of ≥20, a Gleason score of 8-10, or stage III or IV cancer.

There were 1365 deaths from prostate cancer between 2007 and the end of 2009. The majority of metformin users were also prescribed statins. Patients who took both statins and metformin (n = 1315) were more likely than other patients to have a comorbidity score of ≥2 and to have obesity/metabolic syndrome. Patients who took metformin alone (n = 455) experienced no reduction in overall mortality.

Patients who took both statins and metformin had a substantial reduction in both overall mortality (HR, 0.66). A similar pattern was seen in patients who took statins alone (n = 4353; HR, 0.75).

The impact of combined statin and metformin therapy on overall mortality was more pronounced in patients with documented obesity/metabolic syndrome, although the differences did not reach statistical significance.

Several UK newspapers have added voice with a press release issued by Cancer Research UK suggesting that the balance of evidence indicate statins have an anticancer effect.

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Does lowering LDL matter? Insights from recent Mendelian Randomization studies

Meta-analyses of numerous randomized trials have demonstrated that lowering low density lipoprotein (LDL) by inhibiting HMG-CoA reductase (HMGCR) with a statin reduces the risk of major cardiovascular events by approximately 20% for each mmol/L lower LDL.1 Remarkably however, there are still those who debunk the “lipoprotein theory of atherosclerosis” and heavily criticize statin therapy.  The sceptics often cite the several randomized trials which have failed to demonstrate that further lowering LDL by adding niacin, a fibrate or a CETP inhibitor to a statin further reduces the risk of cardiovascular events.2 3 4 5 6. Naturally randomized genetic data from recent Mendelian randomization studies may help to resolve this uncertainty. 7 14

Numerous polymorphisms* in the genes that encode the targets of various LDL lowering medications, including the statins, ezetimibe and the PCSK9 inhibitors, are associated with lower LDL; and each of these polymorphisms is inherited approximately randomly at the time of conception in a process sometimes referred to as Mendelian randomization.

Therefore, inheriting a LDL lowering allele in one of these genes is analogous to being randomly allocated to treatment with a LDL lowering therapy, while inheriting the other allele is analogous to being randomly allocated to usual care. If the polymorphism under study is associated with only LDL but not with other lipid or non-lipid pleiotropic effects, and if allocation is indeed random, then comparing the risk of CVD among persons with and without such a polymorphism should provide a naturally randomized and unconfounded estimate of the causal effect of lower LDL on the risk of cardiovascular disease (CVD) in a manner analogous to a long-term randomized trial.

Mendelian randomization studies have demonstrated that polymorphisms in multiple different genes are associated with both lower LDL and a lower risk of CVD8 15 9, providing confirmation that LDL is causally associated with the risk of CVD. These studies have included not only polymorphisms in the genes that encode the targets of statins and ezetimibe, but also both common polymorphisms and the less common “loss-of-function” mutation* in the PCSK9 gene that motivated the discovery of monoclonal antibodies directed against PCSK9. Taken together, these studies can be thought of as a portfolio of “naturally randomized trials”, each evaluating a different mechanism of lowering LDL.

In these studies, polymorphisms with the largest effect on LDL were also associated with the greatest corresponding reduction in CVD risk.10 16 Indeed, when the effect of each polymorphism on LDL is plotted against its effect on the risk of CVD, there appears to be a log-linear association between genetically mediated lower LDL and the risk of CVD, independent of the mechanism by which LDL is lowered (Figure). Furthermore, when adjusted for a standard decrement in LDL change, each of these polymorphisms appears to have a remarkably similar effect on the risk of CVD per unit lower LDL (Figure). Therefore, the naturally randomized genetic evidence strongly argues that the effect of lower LDL on the risk of CVD is independent of the mechanism by which LDL is lowered.

LDL lowering curve survival

The totality of the genetic evidence suggests that the effect of lower LDL on the risk of CVD appears to be determined by the absolute magnitude of exposure to lower LDL, regardless of how LDL is lowered.

This hypothesis was directed tested in a recent Mendelian randomization study that compared the effect of lower LDL on the risk of CVD mediated by polymorphisms in the NPC1L1 gene (the target of ezetimibe), the HMGCR gene (the target of statins) or both (the targets of combination therapy) in a “naturally randomized IMPROVE-IT Trial”. This study found that polymorphisms that mimic the effect of ezetimibe and polymorphisms that mimic the effect of statins had approximately the same effect on the risk of CVD per unit lower LDL, and when present together they had independent linearly additive effects on LDL and a log-linearly additive effects on CVD risk.11 The naturally randomized genetic data from this study therefore predicted that adding ezetimibe to a statin should reduce the risk of CVD proportional to the absolute achieved reduction in LDL.

Indeed, the naturally randomized genetic data precisely predicted the results of the recently completed IMPROVE-IT trial. In IMPROVE-IT, adding ezetimibe to a statin resulted in a linearly additive 15 mg/dl further reduction in LDL and a log-linearly additive 6.4% lower risk of the primary composite endpoint and a 10% lower risk of the secondary composite endpoint of CVD death, MI or stroke. 12 The magnitude of this risk reduction is approximately what would be expected based on the absolute reduction in LDL observed during the trial as estimated by the Cholesterol Treatment Trialists’ Collaborators meta-analysis of statin trials.13

The close agreement between the results of the Mendelian randomization studies and the results of landmark IMPROVE-IT trial suggest that the effect of both genetically and pharmacologically mediated lower LDL on the risk of CVD appears to be determined by the absolute magnitude of exposure to lower LDL, regardless of how LDL is lowered (Figure).

This finding may explain the failure of the niacin, fibrate and dalcetrapib CETP inhibitor trials. In these studies, the absolute magnitude of the achieved LDL reduction was too small and the number of events accrued too few to reliably demonstrate a numerically stable reduction in the risk of CVD. Furthermore, the close agreement between the naturally randomized genetic data and the results of IMPROVE-IT strongly suggest that lowering LDL with a statin or with ezetimibe or with combination therapy or with any other method of lowering LDL should each reduce the risk of CVD by approximately the same amount per unit lower LDL regardless of which treatment is used.

Importantly, these data therefore also suggest that inhibiting PCSK9 with a monoclonal antibody should reduce the risk of CVD by approximately the same amount as do statins per unit lower LDL. Indeed, based on previous (and ongoing) Mendelian randomization studies one would predict that the eagerly anticipated PCSK9 outcome trials are likely to demonstrate that further lowering LDL cholesterol by adding a PCSK9 inhibitor to a statin will reduce the risk of CVD by approximately 20% for each mmol/L reduction in LDL cholesterol observed in the trial, because the effect of lower LDL on the risk of CHD appears to be independent of the mechanism by which LDL is lowered.

* What is the difference between “polymorphism” and “mutation”?

A mutation is generally defined as a change in DNA sequence away from normal, thus implying that there is a normal allele in the population and that the mutation changes it to an abnormal variant. By contrast, a polymorphism is a change in DNA sequence that is common, where no single allele is regarded as the normal allele. In general, mutations are rare while polymorphisms, by definition, are common.  


1, 13. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-81.
2. AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255-67.
3. HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371:203-12.
4. ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563-74.
5. dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089-99.
6. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2889-934.
7, 8, 10. Ference BA, Yoo W, Alesh I, et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol. 2012;60:2631-9.
9. Global Lipids Genetics Consortium. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013;45:1274-83.
11, 14, 15, 16. Ference BA, Majeed F, Penumetcha R, Flack JM, Brook RD. Effect of naturally randomvallocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 x 2 factorial Mendelian randomization study. J Am Coll Cardiol 2015;65:1552–61.
12. Cannon CP, for the IMPROVE-IT Investigators. IMPROVE-IT Trial: A Comparison of Ezetimibe/Simvastatin versus Simvastatin Monotherapy on Cardiovascular Outcomes After Acute Coronary Syndromes. Presented at: American Heart Association Scientific Sessions; November, 17 2014; Chicago, IL.

PCSK9 story continues to intrigue and tantalise….

The Holy Grail for clinicians is reducing the high “residual” cardiovascular risk that persists in high-risk patients despite our best evidence-based treatment including statins. Overwhelming evidence still backs LDL as the primary target for intervention. Yet, beyond statin therapy, to date only the IMPROVE-IT trial has shown modest benefit (by 6.4%) in reducing cardiovascular outcomes by adding non-statin treatment – Ezetimibe, a cholesterol absorption inhibitor – to statin therapy in high cardiovascular risk patients.

PCSK9Hope has focused on PCSK9 inhibition as a therapeutic strategy that may address this unmet clinical need. Indeed, in individuals with genetic variants in PCSK9, lifelong reduction in LDL concentration was associated with up to 88% reduction in coronary events over a 15 year follow-up period.1 The development of monoclonal antibodies to PCSK9 heralds a new era in LDL lowering and cardiovascular disease prevention. The accumulating evidence shows that these PCSK9 inhibitors reduce LDL consistently by 50-60%, across a spectrum of patients and concomitant LDL-lowering therapy including statins. Of great interest these treatments also reduce lipoprotein (a), an established cardiovascular risk factor and potential contributor to residual cardiovascular risk, by 25-30%.2 8

Two urgent questions remain. Does this substantial LDL lowering translate to reduction in cardiovascular outcomes in high cardiovascular risk patients?

Well we now have early data to suggest that the promise of PCSK9 inhibition may deliver. At an eagerly anticipated hotline at the American Congress of Cardiology 2015, just a few day ago, a pre-specified, exploratory analysis of the OSLER studies, showed that the PCSK9 monoclonal antibody evolocumab reduced low-density lipoprotein (LDL) by 61%, and that this was associated with a 53% reduction in cardiovascular events over nearly 12 months in high cardiovascular risk patients, including those with familial hypercholesterolaemia (inherited high cholesterol, FH).

The results were consistent with those from a post hoc analysis from the ODYSSEY LONGTERM study with alirocumab, first reported at the European Society of Cardiology Congress, Barcelona, 2014. Both reports were simultaneously published online at The New England Journal of Medicine.

OSLER analysis

This analysis was based on data from 4,465 patients with mean age 58 years, 80% with at least one cardiovascular risk factor including 10% with FH, 70% on statins. Patients were randomly allocated in OSLER-1 and OSLER-2 to open-label treatment with evolocumab (140 mg every 2 weeks or 420 mg every month, n=2976) on top of standard therapy, or standard therapy alone (n=1489).


After 12 weeks, evolocumab reduced LDL from 120 mg/dL (3.1 mmol/L) at baseline to a median of 48 mg/dL (1.2 mmol/L), representing a 61% reduction versus standard therapy. At this time, 90.2% of patients attained an LDL target <100 mg/dL (2.6 mmol/L) versus 26.0% on standard therapy alone, and 73.6% attained an LDL target <70 mg/dL (1.8 mmol/l) versus 3.8% on standard therapy alone. Evolocumab treatment also reduced lipoprotein (a) by 25.5%. These lipid changes were generally sustained over the 11.1 month follow-up. In a pre-specified exploratory analysis, treatment with evolocumab reduced cardiovascular events (a composite of death, myocardial infarction, unstable angina requiring hospitalisation, coronary revascularisation, stroke, transient ischaemic attack and heart failure requiring hospitalisation) by 53% (Kaplan Meier estimates at 1 year, 0.95% with evolocumab and 2.18% with standard therapy, Hazard ratio 0.47, 95% CI 0.29-0.78, p=0.003).


Safety analyses showed that adverse event rates were generally similar between the two groups, (overall event rates 69.2% and 64.8%). There was no evidence of any increase in muscle-related symptoms (6.4% versus 6.0%), liver enzyme elevation > 3 x upper limit of normal (1.0% and 1.2%) and creatine kinase increase > 5 x upper limit of normal (0.6% versus 1.1%). Neurocognitive events, although few, were reported more with evolocumab than standard therapy (27 [0.9%] versus 4 [0.3%]). However, the risk of adverse events, including neurocognitive events did not correlate with the extent of LDL reduction, and was no more prevalent in those subjects who attained LDL levels below 25 mg/dL (0.65 mmol/L). The authors acknowledged a number of limitations to the report, including the open-label design, the heterogeneity of patients, the low event rates, short follow-up and the fact that the study design only allowed patients who had successfully tolerated evolocumab in the parent study to enter OSLER-1 and OSLER-2. Despite these reservations, the authors highlight the potential of evolocumab treatment, in addition to standard therapy, including statin, for reducing cardiovascular outcomes in high cardiovascular risk patients.

ODYSSEY analysis

The analysis from the ODYSSEY LONG TERM trial included 2,341 high cardiovascular patients with mean age 60 years, 18% with inherited high cholesterol (FH) with LDL levels of 70 mg/dL (1.8 mmol/L) or greater, despite maximally tolerated statin therapy, with or without other lipid-lowering therapy. Baseline LDL was 122 mg/dL (3.2 mmol/L). All patients were randomised to double-blind treatment with alirocumab (150 mg every 2 weeks, n=1553) or placebo (n=788), in addition to standard treatment, every 2 weeks for up to 78 weeks. After 24 weeks, there was a 62% reduction in LDL versus placebo, with mean absolute LDL levels 48 mg/dL (1.2 mmol/L) with alirocumab versus 119 mg/dL (3.1 mmol/L) with placebo. Regardless of risk level, 79.3% of patients in the alirocumab group achieved an LDL goal <70 mg/dL (1.8 mmol/L), compared with 8.0% for the placebo group. Consistent LDL reductions with alirocumab were maintained over the 78 weeks of follow-up. Lipoprotein (a) was reduced by 25.6% at 24 weeks. Using the same endpoint as in ODYSSEY OUTCOMES (major adverse cardiovascular events [MACE], defined as coronary heart disease death, non-fatal MI, ischaemic stroke and unstable angina requiring hospitalisation), a post hoc analysis showed a 48% reduction in MACE over the 78 weeks (absolute event rates 1.7% versus 3.3%, Hazard ratio 0.52, 95% CI 0.31 to 0.90, p=0.02). While it is intriguing that this reduction was on top of statin therapy, caution is needed given that these are findings from a post hoc analysis, based on few events over a relatively short duration of follow-up.


Safety data was broadly balanced between the two groups (overall rates 81.0% versus 82.5% on placebo). Myalgia rates were higher with alirocumab than placebo (5.4% versus 2.9%), although there was no increase in the numbers of patients with liver enzyme elevations, or with creatine kinase increases greater than 3 x upper limit or normal (3.7% versus 4.9%). As seen with the OSLER studies, there was a small excess of neurocognitive disorders (18 [1.2%] on alirocumab versus 4 [0.5%] on placebo), although it should be borne in mind that absolute numbers of events in each group were small. Additionally, these events were self-reported and not evaluated using a specific neurocognitive tool. It is, however, unlikely that this effect is attributable to the LDL lowering, given that in the OSLER analysis, the risk of adverse events, including neurocognitive events did not correlate with the extent of LDL reduction.

Furthermore, there is no evidence that the presence of loss of function PCSK9 variants is associated with any detrimental effect on neurocognitive function.  A dedicated neurocognitive sub study for evolocumab is investigating this issue.3 Clearly, these outcomes and safety data are promising. Ultimately, however, we need to wait for the results of long-term outcomes studies – FOURIER with evolocumab,4 ODYSSEY OUTCOMES with alirocumab,5 and SPIRE-1 and SPIRE-2 with bococizumab,6 7 with these agents to definitively assess the benefit versus risk of PCSK9 inhibition as a therapeutic strategy to reduce residual cardiovascular risk in high risk patients. In addition, as the genetic studies would suggest, in order to eliminate “residual risk” we probably need to treat those at high risk, such as patients with inherited high lipoproteins – familial hypercholesterolaemia (FH) – earlier and more aggressively, in order to delay, or even prevent, the onset of cardiovasular disease.

Watch this space for more on PCSK9 – inhibitors in modifying atherosclerotic vascular disease…….




1. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354):1264-72. PUBMED abstract: http://www.ncbi.nlm.nih.gov/pubmed/16554528
2. Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Langslet G, Bays H, Blom D, Eriksson M, Dent R, Wasserman SM, Huang F, Xue A, Albizem M, Scott R, Stein EA. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol 2014;63:1278-88. PUBMED abstract: http://www.ncbi.nlm.nih.gov/pubmed/24509273
3. EBBINGHAUS (Evaluating PCSK9 Binding antiBody Influence oN coGnitive HeAlth in High cardiovascUlar Risk Subjects) [Substudy of FOURIER]. ClinicalTrials.gov Identifier: NCT02207634
4. Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk. ClinicalTrials.gov Identifier: NCT01764633
5. ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab). ClinicalTrials.gov Identifier: NCT01663402
6. SPIRE-1 (Evaluation of Bococizumab in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects) ClinicalTrials.gov Identifier: NCT01975376
7. SPIRE-2 (Evaluation of Bococizumab in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects). ClinicalTrials.gov Identifier: NCT01975389
8. Nordestgaard BG, Chapman MJ, Ray K, Borén J, Andreotti F, Watts GF, Ginsberg H, Amarenco P, Catapano A, Descamps OS, Fisher E, Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L, Reiner Z, Taskinen MR, Tokgözoglu L, Tybjærg-Hansen A; European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844-53. PUBMED abstract: http://www.ncbi.nlm.nih.gov/pubmed/20965889