Lipid guidelines – are we heading in the right direction? Anna Fenton and Nick Panay EDITORS-IN-CHIEF
Cardiovascular disease (CVD) is the leading killer of women globally and in industrialized nations. More women die from CVD than all cancers combined and most CVD is preventable. We know from the Framingham study that the risk factor burden and total cholesterol at 50 years of age predict the lifetime incidence of CVD in women1. Risk assessment models based on the Framingham data or those developed specifically for use in women, such as the Reynold’s model, take into account a number of clinical and biochemical risk factors and calculate a 5- or 10-year risk of CVD. Lipids, blood pressure, a family history of premature coronary artery disease, smoking, diabetes, obesity, physical inactivity and inflammatory markers may be included in these models. High triglycerides, low high density lipoprotein (HDL) cholesterol and high non-HDL cholesterol or the cholesterol ratio appear to be best lipid predictors of risk in women and the best international advice is that we should screen all women over the age of 20 years every 5 years for dyslipidemia and assess CVD risk every 4–6 years from the same age. Secondary causes of elevated low density lipoprotein (LDL) cholesterol or triglycerides should be sought and this might include assessing alcohol intake, refined carbohydrate intake, medications and the presence of biliary or renal disease, hypothyroidism and diabetes. In late 2013, the American Heart Association and the American College of Cardiology (AHA/ACC) released new guidelines for assessing and managing CVD risk2. The consensus panel agreed that the previous approach of aiming for specific target levels of LDL cholesterol based on patient risk was flawed and lacked supportive research data. As the benefit of treatment is proportional to baseline CVD risk, they suggest using cholesterol-lowering drug therapy in individuals over the age of 40 years without clinical CVD, even if LDL levels are normal, if their 10-year risk ⫺ ⬎ 7.5% and also in individuals with diabetes who have a risk of 5–7.5% or greater. This lowers the previous treatment threshold substantially and also aggregates advice for both men and women despite data showing women respond very differently to lipidlowering therapy. It is not surprising therefore that the new recommendations have met with controversy3. Statins have been the mainstay of treating hyperlipidemia and there is clear evidence of their benefit in women with
© 2014 International Menopause Society DOI: 10.3109/13697137.2014.889366
diabetes and where they are used for secondary prevention. However, there is substantial controversy as to their effects in primary prevention in women4,5. This is in part related to the low numbers of women and non-Caucasians enrolled in studies. Of the three primary prevention studies in women, only the JUPITER study has shown any benefit and that is seen only when ‘soft’ endpoints (hospitalization for unstable chest pain, the ‘need’ for revascularization) are included in the analysis6. The 0.1% absolute risk reduction based on ‘hard’ endpoints was not significant. The Cochrane Collaboration has accepted that statins do reduce CVD and all-cause mortality but also noted significant under-reporting of events in most studies7. A number of randomized controlled trials (RCTs) suggest women develop more side-effects with statin therapy and this includes diabetes and myopathy8,9. So, if we significantly increase the number of women we might treat with statin therapy, we also need to be mindful of side-effects and achieving the correct balance of clinical benefit and harm. The new risk factor assessment tool developed by the AHA/ ACC in conjunction with the treatment guidelines, known as the pooled cohort risk assessment equation, can be downloaded from the AHA website and is easy to use. It is promoted as a means of assessing how aggressively we should treat our patients with lipid-lowering therapy. However, there is no RCT of cholesterol-lowering therapy that has used a risk score to enroll patients. Baseline CVD risk does not appear to predict response to statins and the risk score performs poorly when applied to primary prevention study event rates. What we can agree on is that all patients with an unfavorable lipid profile should reduce total, trans and saturated fat in their diet, lose weight, engage in aerobic exercise, eat a diet rich in fruit and vegetables and avoid tobacco smoking. Unfortunately, the results from this approach may take 6–12 months to materialize and require significant patient motivation. We must not forget the role of hormone replacement therapy in managing dyslipidemia and reducing coronary artery disease risk and all-cause mortality. The Women’s Health Initiative showed a 34–45% reduction in a variety of outcomes in the estrogen-only study among women within 10 years of menopause10. Overall mortality was reduced by 30% in both the estrogen-only and the estrogen–progestin
Editorial studies. The Danish Osteoporosis Prevention Study, with 10 years of follow-up following randomization, also demonstrated a significantly reduced risk of death, myocardial infarction and heart failure among women beginning hormone therapy close to menopause11. However, hormone therapy is not indicated for secondary prevention and we need to balance the risks and benefits if we consider use of hormone therapy in older women. CVD is a major health concern for women. Too often women are overlooked for appropriate care because of
Fenton and Panay myths that women don’t suffer heart disease or strokes. Women are different to men in relation to risk factors and response to treatment. Widening the population that might use statin therapy for primary prevention without clear evidence that the new risk assessment tool is valid and that the treatment will make a difference to women at low risk is a potentially risky proposition. We have rejected the previous approach to managing dyslipidemia but it is not clear that we are following a more clearly lit evidencebased pathway.
References 1. Lloyd-Jones DM, Leip EP, Larson MG, et al. Prediction of lifetime risk of CVD by risk factor burden at age 50. Circulation 2006;113:791–8 2. Stone NJ, Robinson J, 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 2013 Nov 7. pii: S0735–1097(13)06028–2. Epub ahead of print 3. Ridker P, Cook N. Statins: new American guidelines for prevention of cardiovascular disease. Lancet 2013;382:1762–5 4. Hodis H, Collins P, Mack WJ, Schierbeck LL. The timing hypothesis for coronary heart disease prevention with hormone therapy: past, present and future in perspective. Climacteric 2012;15:217–22 5. Fenton A, Panay N. Statins in women for primary prevention – is there evidence to back up their use? Climacteric 2010;13:403–4 6. Mora S, Glynn R, Hsia J, MacFadyen J, Genest J, Ridker P. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia. Results from the Justification for the use of Statins in Prevention:
An Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Circulation 2010;121:1069–77 Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2013, Jan 31;1:CD004816 Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735–42 Harper CR, Jacobson TA. The broad spectrum of statin myopathy: from myalgia to rhabdomyolysis. Curr Opin Lipidol 2007;18:401–8 Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative Randomized trials. JAMA 2013;310:1353–68 Schierbeck LL, Rejnmark L, Landbo Tofteng C, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012; 345:e6409
Copyright of Climacteric is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.