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.

Blessings Cardiologydoc

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:
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:
3. EBBINGHAUS (Evaluating PCSK9 Binding antiBody Influence oN coGnitive HeAlth in High cardiovascUlar Risk Subjects) [Substudy of FOURIER]. Identifier: NCT02207634
4. Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk. Identifier: NCT01764633
5. ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab). Identifier: NCT01663402
6. SPIRE-1 (Evaluation of Bococizumab in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects) Identifier: NCT01975376
7. SPIRE-2 (Evaluation of Bococizumab in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects). 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:

Cereal Killers #2 – “Run on Fat”

I have just finished watching the pre-release of Cereal Killers #2: “Run on Fat” and can say this is going to be absolutely game-changing in endurance performance.

run on fat

For those of you that don’t know, “Run on Fat” charts world-class Iron Man and triathlete Sami Inkinen’s transition from a pre-diabetic sugar burner to a faster, healthier, fat fueled endurance athlete under the guidance of Dr Stephen Phinney, leading researcher and author of ‘The Art and Science of Low Carbohydrate Living’ and ‘The Art and Science of Low Carbohydrate Performance’.  It was a five-year transition for Sami, away from sports drinks, gels, and pasta to a low-carb, high-fat (LCHF) diet.

When Sami embarks on an epic anti-sugar crusade with his wife Meredith – rowing 4,000 km unsupported from California to Hawaii – their remarkable journey reveals the astonishing performance benefits of successful fat fueling strategies for athletic performance. Sami and Meredith provide a fantastic real-life example of the future of endurance performance. Their row was the equivalent of two marathons a day with zero refined carbohydrates or carbohydrate loading with months of preparation with fat adaptation.

“Run of Fat” features a number of fat adapted world-class athletes including my own experience with long distance cold water endurance swimmer: Dr Otto Thaning, with his world record conquering the English Channel in September 2014 at age 73.

“Run on Fat” challenges the very foundations of sports nutrition (carbohydrate loading)and supports what I have been teaching and preaching for 5 yr about the benefits of low carbohydrate high fat (LCHF) ketogenic diets for endurance athletes.

For those of you that are still on the carbohydrate train, or sitting on the fence about the benefits of LCHF and real food fueling, I challenge you to open your mind and consider that there may be a healthier way.



IBIS 4 – High-Dose Rosuvastatin Shrinks Coronary Plaque

Women and CVDOne year of treatment with the highest dose of the cholesterol-lowering drug Rosuvastatin can shrink plaque inside the arteries of patients who have had a certain type of heart attack known as ST-segment elevation myocardial infarction (STEMI), according to a new study presented at European Society of Cardiology Congress 2014.

BARCELONA, Spain – Tuesday 2 September 2014: One year of treatment with the highest dose of the cholesterol-lowering drug Rosuvastatin can shrink plaque inside the arteries of patients who have had a certain type of heart attack known as ST-segment elevation myocardial infarction (STEMI), according to a new study presented at ESC Congress 2014 (

Although STEMI patients often undergo a revascularization procedure (angioplasty or stent insertion) to unblock the “culprit” artery that caused their heart attack, they remain at increased risk for similar events due to plaque formation in other untreated coronary arteries.

The IBIS-4 study, which was published simultaneously in the European Heart Journal is the first to use ultrasound imaging inside coronary arteries both at the time of heart attack and after 13 months of treatment to show the benefit of high-dose statin therapy on plaque burden. The study was an investigator-initiated trial performed at five sites in Europe (University Hospitals of Bern, Copenhagen, Geneva and Zürich and Cardiocentro Lugano) without support from a pharmaceutical cholesterol-lowering manufacturer.

Previous work has shown that high-dose Rosuvastatin can reduce plaque size in patients with stable chronic atherosclerotic vascular (coronary) disease, but until now this has not been specifically investigated in arteries of patients with acute heart attacks, a setting known to harbour additional high risk plaques that can be the source for future cardiovascular events.

IVUS 3This is also the first study is the first to use intracoronary ultrasound to assess the actual plaque composition and the plaque phenotype, and to observe how both respond to high dose potent statin treatment.

IBIS-4 included 103 acute heart attack patients who were first successfully treated to unblock the culprit vessel. Subjects then underwent imaging, both at the start of the study and then after 13 months of high-intensity Rosuvastatin treatment (40 mg/d), to assess the drug’s impact on their non-culprit arteries. Rosuvastatin was given at a dose of 40 mg daily. After 13 months, ultrasonography showed that 85% of patients had regression of plaque in at least one artery, and 56% had regression in both. Overall, intracoronary plaque volume was reduced by a mean of -0.9% (p=0.007), with a mean change of the total atheroma volume of -13.7 mm3 (p=0.006). Although the reduction in plaque volume was independent from cholesterol levels at baseline, it was directly related to the extent of cholesterol reduction at 13 months. As expected, Rosuvastatin also had beneficial effects on lipoprotein levels. Low-density lipoprotein (LDL) decreased from a median of 3.29 mmol/L at baseline to 1.89 mmol/L (p<0.001), corresponding to a 43% reduction. A total of 44% of patients achieved a guideline-recommended LDL level of less than 1.8mmol/L. The beneficial effects of high-dose statin therapy on coronary plaque regression previously observed in patients with stable coronary artery disease (ASTEROID study) can be extended to those at highest risk for cardiovascular complications, namely patients with acute heart attacks. This explains at least in part the clinical benefit of high-dose statin therapy in patients with heart attacks.


Elevated ‘Lipid-Years’ in Young Adulthood Tied to Later Cardiovascular Disease

The concept of LIFETIME cardiovascular disease (CVD) risk is beautifully demonstrated in the study published online January 26, 2015 in Circulation [1].

Fifty-five-year-olds who had prolonged moderately elevated non–HDL (total atherogenic lipoproteins) levels (>160 mg/dL/ 4.0 mmol/L) when they were young adults were much more likely than their peers to have coronary heart disease by the time they were 70. In an analysis based on the Framingham Offspring Cohort the risk of cardiovascular disease (defined as myocardial infarction, angina, coronary insufficiency, or death from CVD) increased with exposure to elevated non-HDL levels in a dose-dependent way.

Specifically, during follow-up, 16.5% of the middle-aged adults who had abnormal atherogenic lipoproteins in the past 11 to 20 years developed CVD, but only 8.1% of those with elevated non-HDL in the past 1 to 10 years developed CVD. In contrast among the adults without elevation of non-HDL, only 4.4% developed CVD.

Atherogenic LP

Having decades of exposure to what many would consider to be mild to moderately elevated atherogenic lipoproteins is associated with a significantly elevated risk of cardiovascular disease. Thus, the way we think about smoking in terms of pack-years, we should be thinking about ‘atherogenic lipid-years’ [of exposure to high non-HDL].

For young adults, we really need to remember that the foundation for cardiovascular disease is being laid in our 20s, 30s, and 40s, so aggressive risk-factor modification at that age is really important. For middle-aged adults, “in the same way that a 55-year-old with a family history of cardiovascular disease [or] an increased coronary calcium score would be considered higher risk, we should take into consideration the duration of exposure to high non-HDL . . . to stratify risk.”

CVD 31

Decades of High Atherogenic Lipoproteins: A New CVD Risk Factor?

Atherosclerosis develops slowly over many years starting in childhood, and the effects of prolonged exposure to elevated atherogenic lipoproteins in young adulthood have previously not been well-defined. This research group examined data from 1478 individuals in the offspring cohort of the Framingham Heart Study who were approximately 55 years old and did not have a history of CVD when they were enrolled during 1987 to 1998.

Participants were stratified into three groups based on hyperlipidaemia (non–HDL >160 mg/dL/ 4.0 mmol/L) at enrolment. A total of 512 participants had no hyperlipidaemia; 389 participants had 1 to 10 years of hyperlipidaemia; and 577 had 11 to 20 years of hyperlipidaemia.

Only 85 participants (5.8%) were on lipid-lowering treatment at baseline.

During a median follow-up of 15 years, there were 136 cardiac events. The unadjusted risk of CVD doubled for every 10 years of exposure to hyperlipidaemia during age 35 to 55 (HR 2.0, 95% CI 1.63–2.45 per decade of hyperlipidaemia).

The association was attenuated but remained statistically significant after adjustment for sex, age, systolic blood pressure, antihypertensive therapy, smoking status, HDL, diabetes, and non–HDL cholesterol at baseline (adjusted HR 1.39, 95% CI 1.05–1.85 per decade of hyperlipidaemia). The association also remained significant after adjustment for lipid-lowering–therapy use at baseline and follow-up.

10 yr and lifetime risk

Based on the 2013 ACC/AHA Cholesterol Guidelines (using the 10-year CVD risk threshold of >7.5%), among the 55-year-old adults who had been exposed to high non-HDL for 11 to 20 years, 15.1% would have met the criteria for statin therapy at age 40 and 34.8% would have met criteria at age 50. However, this study was not designed to determine whether early statin intervention in young adults “on the hyperlipidaemia trajectory” would decrease future CVD risk.

However, it’s certainly not a stretch to say that at least adults in their 50s who have had long-term exposure to high atherogenic non-HDL (total ApoB) should be considered for statin therapy, and there are [randomized clinical trial] data to support the efficacy in that group.

This study used non–HDL cut-offs, since HDL was measured directly whereas LDL was calculated. Typically, non–HDL is 30 mg/dL/ 0.75 mmol/L higher than LDL, and the researchers found similar results using a LDL level of >130 mg/dL/ 3.2 mmol/L.

Individuals who had average non–HDL levels during the preceding 20 years that were below 125 mg/dL/ 3.1 mmol/L had a similar low risk of CVD, and those with levels above 195 mg/dL/ 4.8 mmol/L had a similar high risk of CVD. For every 10-point increase in non–HDL between 125 and 195 mg/dL, there was a 33% increased risk of CVD.

This begs the question as to what constitutes the normal range of non-HDL but in my hands I aim to keep atherogenic lipoproteins (non-HDL or total Apo B) less than 120 mg/dL/ 3.0 mmol/L or 0.8 for Apo B.

Nevertheless, this study identifies adults who may benefit from more aggressive primary prevention and again flies in the face of those sceptics who treat (atherogenic) lipoproteins with no respect.

7 things to reverse CVDThese findings suggest that adults with longstanding moderate elevations in non–HDL levels should be added to those already identified by the current guidelines as candidates for an informed patient-physician discussion about appropriate lipid-management strategies to reduce future risk of heart disease.


  1. Navar-Boggan A, Peterson E, D’Agostino R, et al. Hyperlipidaemia in young adulthood increases long-term risk of coronary heart disease. Circulation 2015

Blessings Cardiologydoc

Women Benefit from Statin Therapy

Billed as the most comprehensive of its kind, a large meta-analysis (all of the large statin trials are represented in this analysis) suggests that statin benefits in reducing “major vascular events” are about the same in women as in men when adjusted for predicted cardiovascular risk [1].


Bearing in mind that approximately 20 million will die worldwide this year from cardiovascular disease, with 55% of the epidemic expressed in women. It’s therefore unfortunate that the idea has grown up in some places that women don’t benefit as much as men from statin therapy, and I think this idea has arisen because people haven’t taken into account the fact that women in general develop vascular disease later in life than men.

It is critical to identify women who are at risk for cardiovascular disease and offer them statin therapy if they exceed a certain threshold of risk, because vascular disease is common, especially in older women, and prevention of that disease could be facilitated by wider use of statin therapy.


The study was published online on January 9, 2015 in the Lancet.

The Cholesterol Treatment Trialists’ (CTT) Collaboration performed meta-analyses on data from 22 trials of statin therapy vs controls and five trials of more intensive vs less intensive statin therapy. A total of 46 675, or 27% of 174 149 randomly assigned participants in these trials, were women. Individual participant data were available from all 27 trials.

In each group of trials, mean concentrations of total and LDL cholesterol at baseline were similar in women as they were in men.

All trials (n=27)

Group Total cholesterol, mmol/L LDL cholesterol, mmol/L HDL cholesterol, mmol/L Triglycerides, mmol/L
Women 5.6 3.4 1.3 1.5
Men 5.3 3.3 1.1 1.6

Major Vascular Events

Among all 27 trials, statins reduced the risk of major vascular events by 21% for each 1.0-mmol/L reduction in LDL cholesterol (rate ratio 0.79, 95% CI 0.77–0.81; P<0.0001), with significant reductions in both women and women.

Major vascular events included MI, stroke, the need for coronary revascularization, and cardiac death.

The proportional reductions in major vascular events for each 1.0-mmol/L reduction in LDL cholesterol seemed slightly smaller in women than in men among the 22 trials of statin vs controls, but they were still highly significant (P<0.0001) in both women, at a rate ratio (RR) of 0.85 (99% CI 0.78–0.92), and men (RR 0.78, 95% CI 0.75–0.82).

Among the five trials where more intensive therapy was compared with less intensive therapy, the proportional reductions in major vascular events among women were similar to those in men. The proportional reductions in major vascular events were also similar among individuals with a definite history of vascular disease.

Somewhat in contrast, statin effects in subjects with no known history of vascular disease seemed slightly greater in men (RR 0.72, 99% CI 0.66–0.80) than in women (RR 0.85, 95% CI 0.72–1.00).

Among all 27 trials, statin therapy reduced the risk of major coronary events by 24% for each 1.0-mmol/L reduction in LDL cholesterol, with significant reductions in both women (RR 0.83, 99% CI 0.74–0.93; P<0.0001) and men (RR 0.74, 99% CI 0.70–0.78; P<0.0001). Statin therapy also reduced coronary-revascularization procedures by the same 24% percent for each 1.0-mmol/L drop in LDL cholesterol, again with no significant sex differences evident overall.

The overall proportional reduction of 15% in any stroke for each 1.0-mmol/L reduction in LDL cholesterol (RR 0.85, 95% CI 0.80–0.89) was also similar between women and men and again broadly similar at all levels of CVD risk. Importantly, reductions in major vascular events were also broadly similar irrespective of sex at all levels of CVD risk, including among women and men whose 5-year risk of having a major vascular event was low, at <10%.

Overall, statin therapy also produced a highly significant 12% proportional reduction in vascular mortality (RR 0.88, 95% CI 0.84–0.91) for each 1.0-mmol/L reduction in LDL cholesterol and a nominally significant reduction in deaths from unknown causes.

Finally, after adjustment for non-sex differences, there were similar proportional reductions in all-cause mortality for each 1.0-mmol/L reduction in LDL cholesterol of 10% in men (RR 0.90, 99% CI 0.86–0.95) and 9% in women (RR 0.91; 99% CI 0.84–0.99).

Importantly statin treatment had no significant effect on cancer or cancer mortality, and there was no evidence of any difference in the safety of statin therapy between women and men.

This report is critical to preventative cardiology as we have powerful statins at full dose (Rosuvastatin & Atorvastatin) capable of reducing LDL by 3-4 mmol/L. With statin associated independent reduction of us-CRP (inflammatory marker) we potentially can reduce individual morbidity and mortality by 80%.

Mediterranean diet 3

Coupling statin therapy with aggressive lifestyle intervention with appropriate diet, exercise, sleep and stress reduction we can achieve excellent results, particularly in women.

Quote on life


  1. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of LDL-lowering therapy among men and women: Meta-analysis of individual data from 174,000 participants in 27 randomised trial. Lancet 2015; DOI:10.1016/S0140-6736(14)61368-4

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