Oral contraceptive use and atherosclerosis

International Women's Day

Being International Women’s Day I raise a topic that has bothered me for years.  As a preventative non-invasive cardiologist I have had the privilege of seeing many women age 35-65 years who look particularly gorgeous on the “outside” but have advanced sub-clinical atherosclerosis on the “inside”. A common feature in these women is prolonged use of oral contraception (OC) during their lives. 

To introduce discussion on OC use and “premature” atherosclerosis I show you a carotid ultrasound of a healthy 60 year woman free of sub-clinical atherosclerosis.

Low risk IMTThis is a longitudinal view of the carotid artery with “edge-detection” software tracking the intima-media (IM) interface.  In this woman  the IM is pristine reflecting no thickening, no irregularity and no plaque (free of sub-clinical disease).

Plaque 1

By contrast this 45-year-old woman has a very large 0.24 cm “soft” atherosclerotic plaque at the origination of the internal carotid artery.

Plaque 3This plaque has filled 50% of the diameter of the proximal internal carotid artery and thus reflects quite severe (advanced)  sub-clinical atherosclerosis in a “well woman” who has had prolonged exposure to oral contraceptive therapy (OC) and was at the time of this examination still taking a low dose mixed estrogen/ progestogen containing OC .

So what data is available to suggest an association of OC to atherosclerosis?

OC

Jamil and Siddiq write a compelling article:

“Comparison of CVD risk associated with the long term use of contraceptives in young females” J App Pharm Sci. 2012; 2 (11): 062-066.

They correctly point out abnormal lipid profiles have been associated with major risk factors for cardiovascular disease (CVD) which is one of the most dominant causes of death in the world and is mainly due to vascular atherosclerosis.

I have previously indicated that cardiovascular disease is the leading cause of adult mortality, with women comprising 55% of the epidemic.

Extensive use of hormonal contraception by females through their reproductive life has led to the concern about the effects of oral contraceptives on the risk factors for coronary heart disease. OC-induced changes in both carbohydrate and lipoprotein risk factors may contribute to the increased risk of vascular disease as orally administered estrogens increase hepatic triglyceride synthesis and VLDL secretion. Estrogens increase the rates of elimination of LDL, VLDL and chylomicrons; suppress the synthesis of key enzymes of lipoprotein metabolism, hepatic and lipoprotein lipase, and increase synthesis of the principal apo-protein of HDL, Apo-A1. Interestingly though, although estrogens have been shown to elevate HDL, the subtype of HDL has been shown to be “non-functional” in reverse transporation of atherogenic LDL from the plaque back to the liver. So the high HDL in women taking estrogen based hormone therapy may be misleading and lead the individual (and the doctor) into a false sense of security.

So oral contraception usage has been found to be associated with adverse findings in several metabolic, cardiovascular and inflammatory parameters, which is consistent with an increased future risk of cardiovascular and metabolic disease. These findings should invite more criticism of recent trends that encourage the prescription of oral contraceptives for years during reproductive life and especially in pre-menopausal women.

In general, progestogens oppose estrogen effects on lipoproteins according to type and dose leading to a range of different lipoprotein profiles including abnormally low HDL level; abnormally high LDL level and an increase in the LDL: HDL cholesterol ratio. The decline in HDL is associated more with androgenic progestins.

OC and dyslipidaemia

This study compared the extent of cardiovascular atherosclerotic risk associated with the lipid metabolism in women using hormonal contraceptives in an urban population of low socio-economic group. The conclusion was that the use of OC’s was associated with the highest atherogenic index and the authors suggested that hormonal contraception should be used under close monitoring until further studies conducted to completely eradicate the risk associated with hormonal preparations.

Plaque 5

Perhaps more compelling research comes from a team of Belgian researchers who made the surprise discovery that women who have used oral contraceptives (OC’s) for some time appear to be at increased risk of atherosclerosis in the carotid and femoral arteries. They also found that those taking the pill had three times higher C-reactive protein (CRP) levels than those not using it.  

This data was presented by Dr Ernest Rietzschel (Ghent University, Belgium) at the American Heart Association (AHA) 2007 Scientific Sessions. This was the first documentation of the Pilllarge elevations in CRP seen in women taking the pill. 

It’s staggering that for a drug that is being used by 80% of women at some point in their lives, there is so little information about the long-term safety. This study is important and provocative, because it raises new questions about the long-term safety of a widely used class of drugs.

CRP increased threefold in those taking OC’s:

Rietzschel and colleagues started out by assessing novel risk factors for atherosclerosis in women participating in the Asklepios study, a blinded sample of women volunteers aged 35 to 55 years in the Belgian population who were free from overt cardiovascular disease.

Of 1301 women (mean age 45.7 years) in Asklepios, 27.4% were taking OC’s and 10.0% were taking hormone replacement therapy (HRT). Past OC use was much higher, however, with 81% of women having taken it for at least one year, with a median exposure of 13 years.

After multivariate adjustment, women who were not taking OC’s or HRT had high-sensitivity CRP of 1.0 mg/L compared with 1.2 for those currently taking HRT and 3.3 for women currently taking OC’s

OC’s an important factor in global atherosclerotic burden:

The researchers found an increase in the prevalence of carotid and femoral atherosclerosis in this group of otherwise young, apparently healthy women. Their data suggest a 20% to 30% increased prevalence of plaque in the carotid and femoral arteries per 10 years of OC exposure. In the light of widespread and usually prolonged OC use, these results suggested OC use could be an important factor in the global atherosclerotic burden.

OC CVA AMI

NEJM

Perhaps the article which raises the most concern is this very recent paper in NEJM June 2012. A massive number of women taking OC were followed (1,626,158) contributing 14,251,063 person-years of observation during which 3311 thrombotic strokes (21.4 per 100,000 person-years) and 1725 myocardial infarctions (10.1 per 100,000 person-years) occurred. 

CVD with OC use

The table taken from the paper shows the STAGGERING increase in incidence in stroke and coronary deaths with increasing age and exposure to the OC’s.

So my concern:

Birth Control Pill ContainerFor a drug that is used widely amongst young women there seems to be some data suggesting increased lifetime risk of atherosclerosis predisposing to increased morbidity and mortality in the woman’s lifetime.

Women seeking oral contraception present a unique opportunity for doctors to give advice on the prevention of cardiovascular disease at an early age. “Young women have an idea that they won’t succumb to cardiovascular disease, which is entirely wrong, because more women die of cardiovascular disease than men. Maybe this is a good time to start talking to young women. Okay, you want to take the pill, but think about the long-term implications. You should stop smoking, check your weight, and be more physically active. Also, we know the pill has effects on blood pressure and lipid profiles, so these should be checked and managed.”

Blessings to all the women of the worldDr PBM tradepic – take care of yourselves.

Cardiologydoc

Diabetes Mellitus and Statins – the whole deal

This topic is very close to my heart as a “preventative, non-invasive” cardiologist.  I have 20 years practical experience in both primary prevention (in heathy individuals) and aggressive secondary risk modification (in those with established vascular disease) and have a database of ~ 10 000 individuals treated with both weak and potent Statin therapy, in high and low doses over many years.

The association of statin use and new onset diabetes mellitus has been known since 2010 but only hit the headline with 2 major publications in 2012 and the FDA announcement that clinicians should be aware of this association (February 2012). 

The debate has centred on the following:

  1. Is this a real effect of statins?
  2. Is there “cause and effect” or is the association driven by confounding factors?
  3. What is the clinical relevance?
  4. Should we in any way change our practice of prescribing (high dose potent) statins?

 risk benefit and cost Ultimately anything we do in life shares this very important paradigm of RISK versus BENEFIT and the costs involved.  Driving an incredibly dangerous weapon (your motor car) at slow or high-speed carries profound risk-benefit. Investing in your future economic well-being and preventing the commonest disease process on planet earth has exactly the same implications.  Investing in your cardiovascular health through prevention of atherosclerosis of your arteries requires dedicated attention to detail life-long.  The one thing we do know is that attainment of “ideal cardiovascular health” is extremely difficult to achieve just with lifestyle and diet.

Ideal CV Health  CirculationOnly 1/1000 healthy individuals (age ~ 50) achieved all 7 of the health behaviors and factors.

CVD 20

The prevalence of “sub clinical” atherosclerosis and cardiovascular disease is equally VERY high in “so-called” healthy 50 year individuals.

CVD 22

Prev sub clinical CVD

So what are the risks of diabetes with statin therapy?

Statins have been available since the 1980s but their risk of inducing diabetes did not surface for nearly 20 years. When all the data available from multiple studies was pooled in 2010 for more than 91,000 patients randomly assigned to be treated with a statin or a sugar pill (placebo), the risk of developing diabetes with any statin was one in every 255 patients treated.

The weaker statins like pravastatn introduced in the early 1990’s seemingly do not carry any clear-cut risk. It is only with the more potent statins like Zocor (simvastatin), Lipitor (atorvastatin) and Crestor (rosuvastatin), particularly at higher doses, that the risk of diabetes shows up. The cause-and-effect is unequivocal, because the multiple large trials of the more potent statins had a consistent excess of diabetes.

Overall the incidence of new onset diabetes mellitus is 9-12% over 5 years of statin therapy with high dose more potent statins offering the higher risk.  This has to be balanced by the benefit in cardiovascular reduction over the same period of 5 years ~25-50% or with potent high dose Statins 20% risk reduction per 1 mmol/l reduction LDL. 

Essentially a nice way of looking at risk verses benefit  is to look at the number of people needed to treat (NNT) to prevent ONE MAJOR cardiovascular event (CVE) verses the number needed to treat to HARM (NNH) one patient (in this case a new onset of diabetes).

Risk benefit

With statin therapy in primary prevention the NNT is 90 people over 2 years & 65 over 5 years.  With secondary prevention the NNT is 150 over one year and only 10-40 over 5 years to save one major CVE.  The NNH is 250 over a 5 year; 300 over 2 year & 500 over 1 year. In other words we will generally see one new case of diabetes in 500 treated with generally a high potency high dose statin.  

With potent statins like rosuvastatin (Crestor) and high dose atorvastatin (Lipitor) the benefit in reducing MCE is very impressive due to plaque reduction and plaque stabilisation.

CVD 15 CVD 16

For every 1 mmol of LDL reduced (with statins) there is approximately 20% risk reduction independent of the risk of the person (<5%  to high risk > 30%).

Of importance is the typical phenotype predicting which patients develop diabetes on statin therapy.  Those individuals with “metabolic syndrome” with elevated fasting blood sugar, increase visceral adiposity, high normal blood pressure or hypertension, and elevated triglycerides are those at risk for developing diabetes on statins.  If patients had  four of these risk factors, they have a 25% risk of developing diabetes. If they have none of these risks factors, their risk was just 2%. That is not surprising, as we know these are just the factors that predict new onset diabetes.

The possible confounding factors relating statins to new onset diabetes are also relevant.  Many people who take statins to lower atherogenic lipoproteins (LDL) rely on the “pill approach” rather than a holistic approach with correct lifestyle, exercise and nutrition and as I see every day the risks for progressive metabolic syndrome are exacerbated despite statin therapy. In my practice we focus on all 10 of the parameters that drive cardiovascular disease and consequently I see extremely few cases of diabetes on statin therapy:

  1. ApoB/ ApoA1 (total atherogenic/ non atherogenic lipoproteins)
  2. Ultrasensitive CRP < 1.0
  3. Non smoking of all tobacco products
  4. BMI < 25%
  5. Optimal nutrition tailor prescribed for the individual phenotype
  6. Moderate intensity exercise on most daily/ week
  7. BP ~ 120/80
  8. GLucose < 6.0
  9. Alcohol in moderation
  10. Stress reduction

Remember the cumulative effect of statin therapy on our arteries over many decades is profound and forms the basis of the philosophy of “optimal medical management.”  This accounts for the incredible outcome in trials like STENO-2; BARI-2D and COURAGE where major cardiac event rate was impressively reduced compared to conventional management and even invasive (coronary stents) or surgical intervention (coronary bypass surgery).

So in summary:

The consistency of the statin clinical-trial findings, the temporal association and the dose-dependency of the effect all provide a strong argument for causality for statins and diabetes.

Whilst the precise mechanism for cause-and-effect is NOT known further work is needed to elucidate the mechanisms of action at hepatic, skeletal-muscle, adipocyte, beta-cell, and mitochondrial levels that could impair insulin action and glucose homeostasis. There is certainly no evidence to support statin worsening insulin resistance nor evidence to suggest increasing risk via accelerated oxidised LDL due to statin.

The bottom line is a fairly simple, straightforward clinical message. Even in a lower-risk primary-prevention population, the cardiovascular benefits of statin therapy outweigh the diabetes hazard, even among those with highest risks for diabetes (metabolic syndrome).

With the incredible benefit and low NNT in secondary prevention the risk-benefit ratio greatly favors benefit in treating patients to goal (generally LDL < 1.8 and ApoB/ ApoA1 0.3- 0.5) with high potency high dose statin therapy.

In other words the clinical RELEVANCE of new onset of diabetes mellitus with statin therapy is minimal as the benefit of major cardiac event reduction outweighs any proposed negative effect of the diabetes.

Blessings

Cardiologydoc