Marshall Tulloch-Reid, MD, MPhil, DSc, FACE Epidemiology Research Unit Tropical Medicine Research Institute The University of the West Indies, Mona,

Transcription

1 Marshall Tulloch-Reid, MD, MPhil, DSc, FACE Epidemiology Research Unit Tropical Medicine Research Institute The University of the West Indies, Mona, Jamaica

2 At the end of this presentation the participant should be able to discuss the main findings of recent studies addressing the following controversies that are likely to influence the management of lipid disorders Adverse effects of statin therapy, type 2 diabetes & statins and cancer risk & statins Raising HDL-cholesterol Supplement use for lipid management New drug therapies

3 Increasing cholesterol is associated with an increased risk of cardiovascular events Dyslipidemia is associated with other CVD risk factors which work synergistically to produce adverse outcomes May also increase the risk of complications from other diseases diabetic nephropathy

4 There has been some concern that low levels of blood cholesterol increase the risk of mortality from causes other than coronary heart disease, including cancer, respiratory disease, liver disease and accidental/violent death. The potential adverse effects of statins among people at low risk of CVD are poorly reported and unclear & so a systematic review was conducted Cochrane Database Syst Rev 2011 Jan 19;(1):CD

5 STUDIES INCLUDED Randomised controlled trials (RCTs) comparing treatment with statins for at least 12 months with placebo or usual care. Minimum of 6 months follow up time from enrolment Men and women (aged 18 or more) with no restrictions on total, low or high density lipoprotein cholesterol levels & 10 year CVD risk score < 10%. OUTCOMES EVALUATED death from all causes fatal and non-fatal CHD, CVD and stroke events combined endpoint (fatal and non-fatal CHD, CHD and stroke events) adverse events quality of life cost

6 16% reduction in all-cause mortality RR (95%CI) of fatal and non-fatal CVD event was 0.74 ( ) in statin compared to other groups No difference in adverse effects between the groups RR= 0.99 ( ) Cochrane Database Syst Rev 2011 Jan 19;(1):CD

7 No increased risk of cancer Rhabdomyalysis occurred in 0.03% of statin users, Myalgia in 7.4% of statin users, 4.4% had raised liver enzymes but no statistically significant differences between the statin and comparison groups May be cost effective in primary prevention (data from a single study) Limited information on impact on quality of life Cochrane Database Syst Rev 2011 Jan 19;(1):CD

8 Statins effectively reduce the risks of death from any cause, death due to cardiovascular disease, fatal myocardial infarction, the need for revascularization, and stroke A 1 mmol/l (39 mg/dl) decline in the level of LDLcholesterol translates into a 9% reduction in the risk of death from any cause among patients with diabetes and a 13% reduction among those without diabetes over 4 years. NEJM 2012; 366:

9 JUPITER study was the first to show an increased risk of type 2 diabetes in patients on statin therapy. Subsequent meta-analysis of several studies clinical trials involving the use of statins found an overall increase in the risk of this outcome more pronounced if the WOSCOPS study was not included.

10 Meta-analysis of clinical trials evaluating the effects of statins on diabetes risk. Copyright 2011 American Diabetes Association, Inc. Rajpathak S N et al. Dia Care 2009;32:

11 Statins appear to have a class effect, unrelated to the individual statin, its potency, or its lipophilic or hydrophilic properties. Their effect also appears to be dose-dependent with a higher incidence of diabetes with more intensive dosing NEJM 2012; 366:

12 In light of the evidence, the Food and Drug Administration (FDA) added information to statin labels regarding an effect of these agents on diabetes, noting that increases in glycosylated hemoglobin (HbA1c) and fasting serum glucose levels have been reported with statin use, FDA continues to believe that the cardiovascular benefits of statins outweigh these small increased risks.

13 A reduction in the availability of cholesterol may limit the cellular proliferation required for cancer growth and metastasis Registry data for the entire Danish population who had received a diagnosis of cancer between 1995 and 2007, with follow-up until December 31, 2009 to compare survival in statin users and non-statin users NEJM 2012; 367:

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15 Multivariable-adjusted hazard ratios for statin users, as compared with patients who had never used statins, were 0.85 (95% CI, 0.83 to 0.87) for death from any cause 0.85 (95% CI, 0.82 to 0.87) for death from cancer. NEJM 2012; 367:

16 Any three of the following five criteria: Elevated Waist Circumference - population and ethnic specific cut points Elevated Triglycerides - 1.7mmol/L or on treatment for high triglycerides Low HDL-cholesterol - 1.0mmol/L in men / 1.3mmol/L in women or on treatment for low HDL-cholesterol Elevated Blood Pressure systolic 130 mmhg or diastolic 85mmHg or drug treatment for hypertension Elevated fasting glucose - 5.6mmol/L or on treatment for elevated blood glucose

17 Pattern of dyslipidemia is not the same in Black compared to white populations Obesity / Hypertension and low HDL-cholesterol most common components in our setting Low prevalence of hypertriglyceridemia - a result of differences in lipoprotein lipase activity or apolipoprotein CIII

18 Men Women 10 0 WC Low HDL High BP High gluocose High TG Low HDL 1.3mmol/L in women / 1.0mmol/L in men, glucose 5.6mmol/L, triglycerides 1.7mmol/L, WC 80cm in women, 94cm in men

19 Low HDL 1.3mmol/L in women / 1.0mmol/L in men, glucose 5.6mmol/L, triglycerides 1.7mmol/L, WC 80cm in women, 94cm in men

20 The anti-atherogenic effect of HDL is mediated by macrophage cholesterol efflux HDL-cholesterol may also promote maintenance of endothelial function protect against oxidation of LDL protect against inflammation interfere with the thrombotic component of atherosclerosis

21 LDL cholesterol is consistently associated with a higher risk of cardiovascular events & there is strong evidence that LDL-lowering reduces cardiovascular risk However LDL-lowering had the most beneficial effect in those with low HDL cholesterol & HDL cholesterol has been inversely relate to the risk of cardiovascular disease

22 The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial - tested whether extended-release niacin added to intensive statin therapy, as compared with statin therapy alone, would reduce the risk of cardiovascular events in patients with established atherosclerotic cardiovascular disease and atherogenic dyslipidemia (low levels of HDL cholesterol, elevated triglyceride levels, and small, dense particles of LDL cholesterol). NEJM 2011; 365:

23 Eligibility criteria Age 45 years old Established cardiovascular disease (stable coronary heart disease, cerebrovascular or carotid disease, or peripheral arterial disease) Low baseline levels of HDL cholesterol (<40 mg/dl [1.03 mmol/l] for men; <50 mg/dl [1.29 mmol/l] for women) Elevated triglyceride levels (150 to 400 mg/dl [1.69 to 4.52 mmol/l]) LDL cholesterol levels lower than 180 mg/dl (4.65 mmol per liter) if they were not taking a statin at entry. NEJM 2011; 365:

24 3414 patients were randomized to receive extended-release niacin, 1500 to 2000 mg per day, or matching placebo. All patients received simvastatin, 40 to 80 mg per day (plus ezetimibe 10 mg per day if needed), to maintain an LDL cholesterol level of 40 to 80 mg/dl ( mmol/l). The primary end point was the first event of the composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization. NEJM 2011; 365:

25 Percent Change during study Niacin Group Placebo Group HDL + 25% + 9.8% Triglycerides % - 8.1% LDL - 12% - 5.5% 25% discontinuation of therapy in Niacin vs 20% discontinuation of therapy in placebo group. 75% adherence with medication in both groups NEJM 2011; 365:

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27 The primary end point occurred in 282 patients in the niacin group (16.4%) and 274 in the placebo group (16.2%) (hazard ratio with niacin, 1.02; 95% confidence interval [CI], 0.87 to 1.21; P=0.80) An unexpected increase in early ischemic stroke in niacin group as first CVD event (27 patients [1.6%] vs. 15 patients [0.9%]) lead to early termination of the study. NEJM 2011; 365:

28 Exercise Weight loss (in overweight subjects) Smoking cessation Substitution of monounsaturated for saturated fatty acids Consider discontinuing medications that lower HDL-cholesterol (beta blockers, benzodiazepines, and androgens) if possible

29 Nicotinic acid most effective in HDL raising if there are no other lipid abnormalities In patients who also have low HDL and high LDLcholesterol levels, attainment of goal LDL-cholesterol should first be achieved, usually with a statin. Rousouvastain and Simvastatin have least adverse effects on HDL-cholesterol When the low HDL-cholesterol is accompanied by a high triglyceride level and mild LDL-cholesterol elevation, fibrate therapy can be beneficial +/- Statin or Ezetamide.

30 The use of n 3 fatty acids may have beneficial effects on arrhythmias, elevated triglyceride levels, atherosclerotic plaque, impaired endothelial function, platelet aggregation, and inflammation. Epidemiologic studies have shown a reduced risk of cardiovascular events among persons who consume fish regularly or who take supplements containing n 3 fatty acids. NEJM 2012; 367:

31 The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial evaluated the effect of long-term supplementation with n 3 fatty acids on the rate of cardiovascular events in patients with diabetes 12,611 patients were randomized to 1 g of n 3 fatty acids (containing 465 mg of eicosapentaenoic acid [EPA] and 375 mg of docosahexaenoic acid [DHA]) or placebo containing approximately 1 g of olive oil and followed for 6 years. NEJM 2012; 367:

32 The primary outcome was death from cardiovascular causes. Secondary outcomes included the composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; death from any cause; and death from arrhythmia No difference in cardiovascular mortality or in cardiovascular events between treatment groups NEJM 2012; 367:

33 Xuezhikang is a partially purified extract of fermented red yeast rice (Monascus purpureus) & used in China for over two thousand years. Several clinical trials have suggested there is benefit to use of the supplement Put forward as an alternative to statins in statin-intolerant patients

34 Evid Based Complement Alternat Med. 2012;2012: Systematic Review of randomised Clinical Trials examining the use of this medication performed Standard and Chinese databases Most clinical trials identified had high risk of bias methodological issues that increase the risk of error

35 Evid Based Complement Alternat Med. 2012;2012: Xuezhikang showed Significant benefit on the incidence of all-cause deaths, CHD deaths, myocardial infarction, and revascularization as compared with placebo Lower total cholesterol, LDL-cholesterol and Triglycerides compared with the placebo or inositol nicotinate group, which was similar to statins group Raised HDL-Cholesterol compared to placebo or no intervention, which was similar to Inositol nicotinate and slightly inferior to statins. The incidence of adverse events did not differ between the Xuezhikang and control group.

36 Evid Based Complement Alternat Med. 2012;2012: Systematic Review of randomised Clinical Trials examining the use of this medication performed Standard and Chinese databases Most clinical trials identified had high risk of bias methodological issues that increase the risk of error

37 Cholesteryl ester transfer protein (CETP) promotes the transfer of cholesteryl esters from HDL to other lipoproteins; the inhibition of this protein raises HDL cholesterol levels and decreases low-density lipoprotein (LDL) cholesterol levels.

38 15,067 patients underwent randomization at 260 centers in seven countries to either atorvastatin (at a dose established during the run-in period) plus 60 mg of torcetrapib or atorvastatin plus placebo. NEJM :

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41 There was also an increased risk of cardiovascular events (hazard ratio, 1.25; 95% confidence interval [CI], 1.09 to 1.44; P=0.001) and death from any cause (hazard ratio, 1.58; 95% CI, 1.14 to 2.19; P=0.006). For death from any cause, higher rates were observed in association with greater decreases in potassium and greater increases in bicarbonate NEJM :

42 Anacetrapib no adverse clinical outcomes Dalcetrapib no clinically significant effects seen all studies stopped Evacetrapib - no adverse clinical outcomes

43 Serum proprotein convertase subtilisin/kexin 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors, increasing the degradation of LDL receptors and reducing the rate at which LDL cholesterol is removed from the circulation. REGN727/SAR (SAR236553), a fully human PCSK9 monoclonal antibody, increases the recycling of LDL receptors and reduces LDL cholesterol levels. NEJM 2012; 367:

44 Phase 2 clinical trial of 92 patients randomly assigned to receive 8 weeks of treatment with i. 80 mg of atorvastatin daily plus SAR once every 2 weeks, ii. 10 mg of atorvastatin daily plus SAR once every 2 weeks, or iii. 80 mg of atorvastatin daily plus placebo once every 2 weeks NEJM 2012; 367:

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