Approach to identifying and managing atherogenic dyslipidemia: A metabolic consequence of obesity and diabetes

N. John Bosomworth

Abstract

Objective To review the evidence for recognition and management of atherogenic dyslipidemia.

Sources of information High-quality randomized trials and meta-analyses were available to address most questions. North American and European guidelines were reviewed. Of these, the Canadian Cardiovascular Society lipid guidelines were most congruent with current literature.

Main message Atherogenic dyslipidemia is characterized by low levels of high-density lipoprotein (HDL), high levels of triglycerides, and a high low-density lipoprotein (LDL) particle number. The condition is highly associated with cardiovascular disease (CVD) and is poorly reflected in Framingham risk score and LDL measurements. Obesity, glucose intolerance, diabetes, and metabolic syndrome are rapidly becoming more common, and are often associated with atherogenic dyslipidemia, affecting long-term CVD risk. Recognition in the office is best achieved by non-HDL or total cholesterol–HDL ratio testing. Treatment success lies in optimizing diet and exercise. Of available medications, statins produce the most benefit and can be titrated to patient tolerance rather than to LDL target levels, which have a poor evidence base. The addition of fenofibrate can be considered in patients with high triglyceride and low HDL levels who have responded poorly to or have not tolerated statins.

Conclusion Growing obesity prevalence creates a CVD risk that might be missed by LDL cholesterol testing alone. Simple calculations from results of a non-fasting lipid panel produce non-HDL levels and total cholesterol–HDL ratio, both of which are superior for predicting risk in all patients. These metrics should be available in lipid panels.

The end of the human race will be that it will eventually die of civilization.
Ralph Waldo Emerson

Case description

J.E. is a 55-year-old businessman seen for follow-up of mild hypertension. He is not physically active and he admits to eating “too much.” He does not abuse alcohol. He has no new complaints. His body mass index is 27 kg/m², and his waist circumference is now 100 cm. His blood pressure is 130/85 mm Hg while taking 25 mg of hydrochlorothiazide daily. He is a non-smoker and has no family history of heart disease. His mother died at age 71 and was overweight and had diabetes. Laboratory findings were as follows: fasting blood glucose, 5.5 mmol/L; total cholesterol (TC), 5.19 mmol/L; low-density lipoprotein (LDL) level, 3.17 mmol/L, high-density lipoprotein (HDL) level, 0.75 mmol/L; triglyceride (TG) level, 2.54 mmol/L. What would your cardiovascular disease (CVD) risk assessment and treatment recommendations be?

Many of our patients are obese and have diabetes or glucose intolerance, and it is becoming apparent that the proportion of the population with these conditions is increasing. Management of their unique risk profiles is of increased importance to family physicians. This metabolic profile consists of borderline-high LDL levels, small LDL particles, high TG levels, and low HDL levels, characterizing atherogenic or mixed dyslipidemia.¹ Evaluation of such patients is poorly served by current treatment thresholds and targets that reference LDL cholesterol alone.^2–4 These patients are at increased cardiometabolic risk, and can be identified by unique physical and laboratory parameters. Changes in management can further reduce CVD events.⁵

Cardiovascular mortality rates have fallen almost 40% in the past several decades,^6,7 with half of this reduction being the result of known risk factor modification based on targeting LDL levels.⁸ Hidden in these data, however, is a trend toward a marked slowing in the rate of decline in cardiovascular events and mortality documented in the United States,⁹ the United Kingdom,¹⁰ and Australia.¹¹ This trend might reflect the steady increase in obesity since the 1970s in developed countries, with resulting parallel increases in diabetes and metabolic syndrome.¹² Overweight and obese individuals now represent 66% of the population in the United States, with Canada somewhat lower at 52%.¹³ The prevalence of metabolic syndrome in adults is now 34.3% in the United States¹⁴ and 19.1% in Canada.¹⁵

While obesity, metabolic syndrome, and diabetes can increase cardiometabolic risk through conventional risk factors, there are emerging risk factors being identified that could be playing an increasing role in residual and unrecognized CVD risk. Some of these factors are implicit in the definition of metabolic syndrome itself, which is a particularly potent predictor of risk in women.¹⁶ A harmonized definition of metabolic syndrome is outlined in Table 1.¹⁷ Additional emerging risk factors for CVD and death were identified in the INTERHEART study,¹⁸ which compared more than 15 000 patients following myocardial infarction with matched controls. Conventional and emerging risk factors are summarized in Table 2.^6,7,17,18

View this table:

Table 1.

Harmonized criteria for metabolic syndrome diagnosis: 3 of 5 positive measures are necessary for diagnosis.

View this table:

Table 2.

Conventional and emerging cardiometabolic risk factors

It has been recognized that conventional risk factors are less predictive of events in young people and in women.^18,19 Indeed, in adults, fully half of cardiovascular events occur in patients with no conventional risk factors.^20,21 Patient risk can be further clarified if we consider the emerging concept of the long-term risk of developing cardiovascular events. Conventional short-term risk scores, such as the Framingham score, are influenced overwhelmingly by fixed factors such as age and sex.²² Over a lifetime, multiple borderline factors might interact. Among people with Framingham risk scores of 10 or less over 10 years, half to two-thirds are at high lifetime risk,^19,21 and many of these are women and young men. On the other hand, if a patient retains a low Framingham score at age 50, lifetime risk is likely to be low.^23–25 The defining features of metabolic syndrome might become particularly useful as relative indicators of lifetime risk,^6,7,26,27 as increasing obesity begins to offset the improvements in coronary artery disease mortality achieved in the past few decades.²¹

Sources of information

References provided with the existing lipid guidelines in North America and Europe^6,7,28,29 were initially reviewed. PubMed and the Cochrane database were searched using the key words atherogenic or mixed and dyslipidemia, restricted to English-language clinical trials, randomized controlled trials, and meta-analyses in humans. Articles referencing surrogate outcomes were excluded. References from appropriate retrieved articles were also reviewed. Good-quality evidence was available in the form of randomized trials and meta-analyses to inform most questions.

Main message

Physiology of atherogenic dyslipidemia

The lipid triad composed of elevated LDL, low HDL, and high TG levels is traditionally believed to lead to increased development of CVD. It is known, however, that as LDL levels trend lower, HDL and TG levels become relatively more predictive of CVD events.^2,4,30–32 In the presence of abdominal adiposity or diabetes, which usually accompany this lipid combination, glucose is not easily used because of insulin resistance.³³ Energy must then be obtained from fat stores, with release of free fatty acids, which prompts increased hepatic production of TGs enclosed within large, highly atherogenic, very low– density lipoprotein (VLDL) particles. The VLDL exchanges this TG for cholesterol with both LDL and HDL particles, and the TG in these smaller particles is then hydrolyzed, producing large numbers of even smaller, denser particles (Figure 1). Small, dense LDL particles contain less cholesterol (hence measured LDL is lower), but they easily penetrate the vascular endothelium, are easily oxidized, and are intensely atherogenic.^34–37 The low LDL level belies the importance of increased particle number, which is the parameter associated most strongly with vascular events.^31,38 Small HDL particles do not function well, leading to some loss of protective HDL function.^39–41 Because of small particle size, considerable HDL particles are lost via the kidney, resulting in reduced measured HDL levels.

Figure 1.

Physiology of visceral obesity and insulin resistance

FFA–free fatty acids, HDL–high-density lipoprotein, LDL–low-density lipoprotein, TG–triglyceride, VLDL–very low–density lipoprotein.

The true marker of increased cardiometabolic risk then becomes the atherogenic dyslipidemia triad^42,43 of increased LDL particle number, low HDL level, and high TG level. Measured LDL might be low, however, leading to a missed appreciation of true risk. The LDL level simply reflects the amount of cholesterol in LDL particles, and it is not a reliable measure when these particles become small and more numerous, or when substantial cholesterol is carried in VLDL and remnant lipoproteins.⁴⁴

Among the alternatives to LDL measurement are the TC/HDL ratio and non-HDL cholesterol, which reflect all cholesterol contained in particles containing apolipoprotein B (Apo B) (LDL, VLDL, intermediate-density lipoproteins, and remnant lipoproteins). The best available estimation of particle number is Apo B, as it is a constituent of all atherogenic particles.^37,44

Office identification of atherogenic dyslipidemia

Low HDL and high TG levels suggest atherogenic dyslipidemia, and might indicate risk independent of LDL levels. Alternative estimations of atherogenic cholesterol or particle number can give more accurate information. Canadian guidelines endorse using the TC/HDL ratio or non-HDL cholesterol, which are cholesterol measurements, or Apo B, which is a measurement of particle number,^6,7 as alternatives to LDL measurement when TG levels are elevated. The US guidelines recommend non-HDL cholesterol (TC minus HDL).²⁸ European guidelines suggest that measurement of either Apo B or non-HDL is acceptable.²⁹ Measurement of Apo B, because it is actually a measure of particle number, is believed by many to be superior^{31,37,38,44–48} and is supported by Canadian guidelines. However, the forthcoming and highly anticipated Adult Treatment Panel (ATP) IV guidelines might endorse calculation of non-HDL cholesterol.^3,45 The ongoing lack of harmonization among guidelines in North America and Europe might perpetuate confusion, possibly leading to poor uptake of any new recommendations.^49,50 In an effort to avoid this, many authors argue that calculation of non-HDL is as sensitive as measurement of Apo B, with the advantages of requiring no additional tests, having well established treatment thresholds and goals, and being an adequate reflection of particle number.^3,51–53 All tests can be done without fasting, as, unlike with the LDL calculation, TG levels are not required (Table 3).^6,7,28,29

View this table:

Table 3.

Comparison of measurements for cardiometabolic risk

For those who prefer to follow guideline treatment thresholds and targets (Table 4),^6,7,28,29 non-HDL measurement might be the preferred test. It can be readily calculated from results of a nonfasting lipid panel, and thresholds and goals are simply 0.8 mmol/L higher than LDL goals.²⁹ While it is only an indirect measure of particle number,³¹ it does measure all of the cholesterol in particles containing Apo B. Non-HDL levels impart all the information contained in LDL measurement along with additional information on the presence of atherogenic dyslipidemia without the need to measure TG levels.⁵⁴

View this table:

Table 4.

Guideline comparisons for treatment thresholds and targets

Risk assignment and treatment thresholds

Conventional 10-year risk of CVD is calculated using the Framingham risk score. The Canadian Cardiovascular Society dyslipidemia guidelines^6,7 are the most evidence based,⁵⁵ and a calculator is now available for mobile devices.

A model relating the various risk factor characteristics in Table 2^6,7,17,18 to appropriate laboratory measurements is represented in Figure 2.^6,7,17,18 A desktop calculator for the Framingham score using Canadian guidelines and including optional support for this extended model is available online (www.palmedpage.com/Framingham/Framingham%20Risk%20Calculator.htm). This desktop tool will calculate non-HDL levels and TC/HDL ratio, estimate numbers needed to treat, and provide detection and decision support for atherogenic dyslipidemia.

Figure 2.

Risk factor characterization

ApoA1–apolipoprotein A1, ApoB–apolipoprotein B, HDL–high–density lipoprotein, LDL–low–density lipoprotein.

^*Risk type: Traditional risk factors are included in the Framingham risk calculation. Novel or emerging factors are components of the metabolic syndrome and factors identified in the INTERHEART study. There is some crossover of traditional and emerging factors.

^†Risk scope: Global includes both metabolic and cardiovascular disease.

Scope is otherwise primarily metabolic or cardiovascular.

^‡Risk duration: Short term is 10 years, as defined by Framingham score.

Long term or lifetime indicates emerging risk factors affecting risk of events over the entire lifespan.

^§Risk relevance: Absolute is defined as a primary source of risk as defined in current guidelines.

Relative adds or subtracts an increment to primary risk.

^||Risk identification: Usefulness of laboratory tests in the detection of lipid abnormalities resulting from contributing risk factors.

Data from Genest et al,⁶ Alberti et al,¹⁶ and Yusuf et al.¹⁷

In order to take into account the increased relative influence of emerging risk factors, 4 possible courses of action exist. Best evidence for each approach is evaluated in Table 5.^{16,53,56–63}

View this table:

Table 5.

Comparing level and quality of best evidence for lipid markers in making treatment decisions

Calculate the conventional risk score, and if metabolic syndrome is present increase this by a multiple of 1.5 for men and 2.0 for women. This multiple comes from a meta-analysis of prospective cohort studies¹⁶ and its use is endorsed by the Canadian guidelines. The presence of metabolic syndrome will usually place the patient at high risk.
Use the TC/HDL ratio for calculation of treatment thresholds and targets in place of LDL values. This is supported by Canadian guidelines, and there is good support in the literature.^55,64–67
Calculate non-HDL cholesterol from the lipid panel results, and decide on treatment thresholds by adding 0.8 mmol/L to levels given for LDL. This has good support in the literature and is likely to be recommended in the new ATP IV guidelines.
Order measurement of Apo B levels if the patient has multiple emerging risk factors or low HDL or high TG levels. A single treatment threshold and a single target are given in the Canadian guidelines for all levels of risk. Coverage of the cost of this test is inconsistent.

With the exception of option 1, these approaches require no fasting and are valid in place of LDL measurement for all patients at all risk levels. Simple calculation of non-HDL level and TC/HDL ratio could easily be done for all fasting and nonfasting lipid panels. It remains uncertain whether the ATP IV guidelines will move to use of non-HDL level as a standard.

Treatment decision

Once risk has been calculated and a treatment threshold has been generated, it is important to reach a shared, informed decision with the patient. Understanding the numbers needed to treat might be helpful, especially as statins offer benefit at all levels of risk,⁶⁸ although benefits become vanishingly small when risk is low, especially when balanced against adverse effects and numbers needed to harm (Table 6).^69–80 While some high-risk patients with low LDL levels might become candidates for lipid-lowering therapy using this strategy, some patients might conversely avoid drug treatment despite higher LDL levels because of elevated HDL levels acquired through inheritance or exercise. The presence of a number of emerging risk factors, especially abdominal obesity and glucose intolerance, might add considerably to lifetime risk and should be considered as well.

View this table:

Table 6.

Adverse effects of statins in primary prevention

Aggressive statin therapy seems to have the strongest evidence for improvement of atherogenic dyslipidemia.⁸¹ There has been evidence for some time from high-dose statin trials^20,82–86 and meta-analyses^83,87–91 that cholesterol lowering in patients with “normal” levels of LDL results in further CVD mortality reduction in both primary and secondary prevention. There also exists a residual 20% incidence of repeat cardiovascular events in patients who have had initial events, even though lipid levels and risk factors were thought to be controlled.⁸⁴ These findings imply that there is potential for further cardiovascular mortality improvement from statin therapy even when LDL levels are at goal levels according to current guidelines. Some of this benefit might be a result of the reduction of unrecognized risk from atherogenic dyslipidemia. There is ample evidence from large trials that patients with metabolic syndrome derive greater absolute benefit from use of statins,^92–96 perhaps in part because their initial risk of CVD events is higher.

An option for simplifying statin administration is to place less importance on targets. Statin trials have been randomized to treatment or to dose, but never to LDL targets.^87,97 Recognizing this, the main priority is to ensure that the patient is actually taking the drug,⁵⁵ as two-thirds of the benefit from statin use occurs with administration of the initial dose.⁹⁸ Once adequate compliance has been achieved, the dose can be gradually titrated to a level determined by patient tolerance⁹⁹ rather than to a treatment target.

Additions to statin therapy

Addition of a second drug to a statin might improve the lipid profile, but with one exception there is no good evidence that this improves hard outcomes. There is currently evidence supporting use of fenofibrate along with statins for reduction in cardiovascular events or mortality, but only in patients with low HDL and high TG levels.^100–103 Drug interaction with statins seems to be minimal for fenofibrate.^81,104,105 Recent combination studies with niacin, omega-3 fatty acids, ezetimibe, and cholesterol ester transfer protein inhibitors have either shown no benefit or were stopped early owing to futility (Table 7).^{93,100,101,103,104,106–119} No combination trials have been done using resins.¹¹⁹ Thus, the only evidence for reduced risk of death or CVD resulting from combination therapy with optimized statin treatment at present is for fenofibrate, and only in those with the specific mixed dyslipidemic profile.¹⁰²

View this table:

Table 7.

Best evidence for drugs used alone or in combination with statins

Intolerance to statin therapy

Statins confer such overwhelming benefit to high-risk patients that in patients who cannot tolerate statin therapy it is important to try changes in dosage levels and timing, and to consider alternate statins, before switching to alternative drugs. A 3-fold rise in liver enzymes can be tolerated, and in the event of high enzymes caused by hepatic steatosis, improvement can be expected with continued statin use.¹²⁰ In the absence of symptoms of myopathy, a rise of less than 10-fold in creatine kinase level can simply be followed.⁶⁹

In the event of absolute intolerance to statins there is solid evidence from older studies of considerable benefit for both niacin and fibrates used alone. This benefit is seen for both CVD events and mortality in all patients meeting treatment criteria (Table 7).^{93,100,101,103,104,106–119} Evidence for benefit of fish oils has come from older observational and cohort studies, but recent meta-analyses^115–117 have not been able to demonstrate improvement in outcomes. Similarly, the evidence for benefit with use of resins is weak.¹¹⁹ Ezetimibe has not been studied as a single agent, nor has it been evaluated without a combined statin. All trials suggesting benefit have referenced lipid levels or other surrogate outcomes.¹²¹ Cholesterol ester transfer protein inhibitor trials, despite remarkable elevations in HDL levels, have thus far shown no benefit in outcomes.¹²²

Case revisited

J.E.’s Framingham risk score is 15.6% over 10 years according to the Canadian guideline calculator. His LDL level is 3.17 mmol/L, which is below the treatment threshold of greater than 3.5 mmol/L. He has abdominal obesity and low HDL and high TG levels, constituting metabolic syndrome and, therefore, has increased relative cardiometabolic risk. His calculated non-HDL cholesterol is 4.44 mmol/L (5.19 − 0.75 = 4.44 mmol/L). This is higher than the calculated treatment threshold for non-HDL (3.50 + 0.80 = 4.30 mmol/L). His TC/HDL ratio is 6.8, which exceeds the treatment threshold of 5 mmol/L. By either of these calculations, all cholesterol hiding in Apo B particles outside of LDL is accounted for, and treatment would be indicated even if LDL levels were normal. A decision could have been made without a fasting TG measurement.

The patient has consulted a dietitian and has begun a program under the supervision of a certified exercise trainer for the past 2 weeks. His weight is unchanged, but his waist circumference is down to 98 cm. He is informed of his moderate 10-year risk together with the relative increased longer-term risk imparted by metabolic syndrome, which places him at high 10-year and long-term risk. He agrees to a statin trial and is able to tolerate 80 mg of atorvastatin daily.

One year after the intervention he is compliant with exercise recommendations, but less so with diet. Weight and blood pressure are unchanged, but waist circumference is down to 94 cm. Laboratory results are as follows: TC, 3.5 mmol/L; HDL, 0.95 mmol/L; non-HDL, 2.55 mmol/L; TC/HDL ratio, 3.6 (nonfasting). There has been no change in liver enzymes. These values meet treatment goals provided he can remain compliant with diet and exercise. He is encouraged to continue taking his statin and to follow up with the dietitian. He might consider dropping to a moderate 40-mg dose of statin if he can improve his dietary compliance.

Treatment recommendations are summarized in Box 1.^{6,7,17,18,28,29,109,123}

Box 1.

Treatment recommendations

Consider the following treatment recommendations:

Optimize behaviour change such as smoking cessation and moderate exercise for at least 150 min/wk. Dietary changes should aim to reduce caloric load, simple carbohydrates, and saturated fats with a goal of cardiometabolic fitness rather than weight loss. The Mediterranean diet has the best evidence for mortality reduction.¹²³
Consider testing with a nonfasting lipid panel for patient convenience. Calculate non-HDL, and if this is high, optionally obtain a fasting TG level. Non-HDL treatment thresholds and goals are valid for all patients. Dyslipidemic patients with normal LDL levels will then not be missed. High TG and low HDL levels suggest atherogenic dyslipidemia even at normal LDL levels.
Canadian guidelines can be followed, substituting non-HDL for LDL treatment thresholds and targets. These are calculated by adding 0.8 to the LDL value (Table 4).^6,7,28,29
TC/HDL ratio can be used in place of non-HDL in this protocol with equal confidence¹⁰⁹ using Canadian guideline treatment thresholds and targets (Table 4). ^6,7,28,29
In addition to treatment of traditional risk factors, consider treatment for patients with metabolic syndrome or those with multiple emerging risk factors (Table 2),^6,7,17,18 especially if these include high TG and low HDL levels. Their additional risk is usually reflected in the non-HDL calculation or TC/HDL ratio.
Younger patients with multiple emerging risk factors might be at high lifetime risk despite low levels of non-HDL. Repeated emphasis on behaviour change is important, along with periodic follow-up of lipid profiles.
Once a patient with atherogenic dyslipidemia is identified and behaviour is optimized, treat with a high-potency statin and work up to the maximally tolerated dose if the patient concurs. No treatment target is necessary. Alternatively, treatment to non-HDL or TC/HDL ratio targets is supported in guidelines, but not by evidence.
If problems arise with tolerance or compliance, try to reach a consensus on a lower dose or a different statin.
If statin dose is maximized, but non-HDL levels remain above the goal, consider adding fenofibrate.
If the tolerated statin dose is low, consider adding fenofibrate.
If no statin is tolerated there is good evidence for use of niacin or fibrates alone. There is no information on combination of the 2.
Repeated reference to behaviour change is important in atherogenic dyslipidemia because risk can be substantially reduced with diet and activity modification, and present drug management outcomes are suboptimal.

HDL—high-density lipoprotein, LDL—low-density lipoprotein, TC—total cholesterol, TG—triglyceride.

Conclusion

Low-density lipoprotein levels have been beneficial in calculating Framingham risk, which is a short-term estimation, heavily influenced by age. Increasing incidence of obesity is accompanied by increasing glucose intolerance and metabolic syndrome leading to a more long-term cardiometabolic risk, which is poorly predicted by LDL levels. This resulting atherogenic dyslipidemia is characterized by novel risk factors, including the diagnostic features of metabolic syndrome, atherogenic diet, and lack of exercise. These factors combine over time to increase longer-term risk of CVD, and are particularly predictive in women and younger people. Non-HDL cholesterol level or TC/HDL ratio can be used in place of LDL measurement in establishing treatment thresholds and targets, are easily calculated from non-fasting serum, and should be routinely reported on lipid panels.

Atherogenic dyslipidemia, once identified, requires renewed attention to maladaptive dietary, exercise, and smoking habits, as changes in these habits will have a potent effect on risk reduction. Drug treatment involves optimization of compliance to a statin dosage based on drug tolerance, rather than lipid targets. Fenofibrate might provide further benefit if TG levels are high and HDL levels are low. Fibrates or niacin alone have shown benefit in the event of absolute intolerance to statins.

Notes

EDITOR’S KEY POINTS

Cardiovascular mortality rates have fallen almost 40% in the past several decades; however, the increasing prevalence of obesity, leading to atherogenic dyslipidemia, has begun to offset these improvements.
In adults, half of cardiovascular events occur in patients with no conventional risk factors. Conventional short-term measures of risk are influenced overwhelmingly by fixed factors such as age and sex, and so are less predictive of events particularly in young people and in women. Patient risk can be further clarified by considering the emerging concept of the long-term risk of developing cardiovascular events.
Ways of evaluating atherogenic dyslipidemia leading to long-term risk include modifying conventional risk scores in the context of metabolic syndrome (by a multiple of 1.5 for men and 2.0 for women); using the total cholesterol–high-density lipoprotein (HDL) ratio for calculation of treatment thresholds and targets; calculating non-HDL cholesterol from lipid panel results, and determining treatment thresholds by adding 0.8 mmol/L to levels given for low-density lipoprotein; or measuring apolipoprotein B levels if the patient has multiple emerging risk factors or low HDL or high triglyceride levels.

Footnotes

This article is eligible for Mainpro-M1 credits. To earn credits, go to www.cfp.ca and click on the Mainpro link.
This article has been peer reviewed.
La traduction en français de cet article se trouve à www.cfp.ca dans la table des matières du numéro de novembre 2013 à la page e479.
Competing interests

None declared

References

1.↵
1. Grundy SM
. Small LDL, atherogenic dyslipidemia and the metabolic syndrome. Circulation 1997;95(1):1-4.
OpenUrl FREE Full Text
2.↵
1. Assmann G,
2. Cullen P,
3. Schulte H
. Non-LDL-related dyslipidaemia and coronary risk: a case control study. Diab Vasc Dis Res 2010;7(3):204-12.
OpenUrl Abstract/FREE Full Text
3.↵
1. Ramjee V,
2. Sperling LS,
3. Jacobson TA
. Non-high-density lipoprotein cholesterol versus apolipoprotein B in cardiovascular risk stratification. J Am Coll Cardiol 2011;58(5):457-63.
OpenUrl CrossRef PubMed
4.↵
1. Fruchart JC,
2. Sacks FM,
3. Hermans MP,
4. Assmann G,
5. Brown WV,
6. Chapman MJ,
7. et al
. The residual risk initiative: a call to action to reduce vascular risk in dyslipidaemic patients. Diab Vasc Dis Res 2008;5(4):319-35.
OpenUrl Abstract/FREE Full Text
5.↵
1. Taslim S,
2. Tai ES
. The relevance of metabolic syndrome. Ann Acad Med Singapore 2009;38(1):29-5.
OpenUrl PubMed
6.↵
1. Genest J,
2. McPherson R,
3. Frohlich J,
4. Anderson T,
5. Campbell N,
6. Carpentier A,
7. et al
. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult—2009 recommendations. Can J Cardiol 2009;25(10):567-79.
OpenUrl CrossRef PubMed
7.↵
1. Anderson TJ,
2. Gregoire J,
3. Hegele RA,
4. Couture P,
5. Mancini GBJ,
6. McPherson R,
7. et al
. 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol 2013;29(2):151-67.
OpenUrl CrossRef PubMed
8.↵
1. Hunink MG,
2. Goldman L,
3. Tosteson AN,
4. Mittleman MA,
5. Goldman PA,
6. Williams LW,
7. et al
. The recent decline in mortality from coronary heart disease 1980–1990: the effect of secular trends in risk factors and treatment. JAMA 1997;277(7):535-42.
OpenUrl CrossRef PubMed
9.↵
1. Ford ES,
2. Capewell S
. Coronary heart disease mortality among young adults in the U.S. from 1980 through 2002: concealed leveling of mortality rates. J Am Coll Cardiol 2007;50(22):2128-32.
OpenUrl CrossRef PubMed
10.↵
1. Allender S,
2. Scarborough P,
3. O’Flaherty M,
4. Capewell S
. Patterns of coronary heart disease over the 20th century in England and Wales: possible plateaus in the rate of decline. BMC Public Health 2008;8:141. Available from: www.biomedcentral.com/1471-2458/8/148. Accessed 2012 Dec 19.
OpenUrl PubMed
11.↵
1. O’Flaherty M,
2. Allender S,
3. Taylor R,
4. Stevenson C,
5. Peeters A,
6. Capewell S
. The decline in coronary heart disease is slowing in young adults (Australia 1976–2006): a time trend analysis. Int J Cardiol 2012;158(2):193-8.
OpenUrl CrossRef PubMed
12.↵
1. Greenland P
. Time to end the mixed—and often incorrect—messages about prevention and treatment of atherosclerotic cardiovascular disease. J Am Coll Cardiol 2007;50(22):2133-5.
OpenUrl CrossRef PubMed
13.↵
1. Orpana HM,
2. Tremblay MS,
3. Fines P
. Trends in weight change among Canadian adults: evidence from the 1996/1997 to 2004/2005 National Population Health Survey. Ottawa, ON: Statistics Canada; 2006. Available from: www.statcan.gc.ca/pub/82-618-m/82-618-m2006005-eng.htm. Accessed 2011 Nov 3.
14.↵
1. Ford ES,
2. Li C,
3. Zhao G
. Prevalence and correlates of metabolic syndrome based on a harmonious definition among adults in the U.S. J Diabetes 2010;2(3):180-93.
OpenUrl CrossRef PubMed
15.↵
1. Reidiger ND
. Prevalence of metabolic syndrome in the Canadian adult population. CMAJ 2011;183(15):e1127-34. Available from: www.ecmaj.ca/content/early/2011/09/12/cmaj.110070.full.pdf+html. Accessed 2012 Nov 16.
OpenUrl PubMed
16.↵
1. Galassi A,
2. Reynolds K,
3. He J
. Metabolic syndrome and risk of cardiovascular disease: a meta-analysis. Am J Med 2006;119(10):812-9.
OpenUrl CrossRef PubMed
17.↵
1. Alberti KG,
2. Eckel RH,
3. Grundy SM,
4. Zimmet PZ,
5. Cleeman JI,
6. Donato KA,
7. et al
. Harmonizing the metabolic syndrome. Circulation 2009;120(16):1640-5.
OpenUrl Abstract/FREE Full Text
18.↵
1. Yusuf S,
2. Hawken S,
3. Ôunpuu S,
4. Dans T,
5. Avezum A,
6. Lanas F,
7. et al
. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): a case-control study. Lancet 2004;364(9438):937-52.
OpenUrl CrossRef PubMed
19.↵
1. Marma AK,
2. Berry JD,
3. Ning H,
4. Persell SD,
5. Lloyd-Jones D
. Distribution of 10-year and lifetime predicted risks for cardiovascular disease in U.S. adults: findings from the National Health and Nutrition Examination Survey 2003 to 2006. Circ Cardiovasc Qual Outcomes 2010;3(1):8-14.
OpenUrl Abstract/FREE Full Text
20.↵
1. Ridker PM,
2. Danielson E,
3. Fonseca FA,
4. Genest J,
5. Gotto AM,
6. Kastelein JJ,
7. et al
. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359(21):2195-207.
OpenUrl CrossRef PubMed
21.↵
1. Kones R
. Primary prevention of coronary heart disease: integration of new data, evolving views, revised goals and role of rosuvastatin in management. A comprehensive survey. Drug Des Devel Ther 2011;5:325-80.
OpenUrl PubMed
22.↵
1. Lloyd-Jones DM,
2. Wilson PW,
3. Larson MG,
4. Beiser A,
5. Leip EP,
6. D’Agostino RB,
7. et al
. Framingham risk score and prediction of lifetime risk for coronary heart disease. Am J Cardiol 2004;94(1):20-4.
OpenUrl CrossRef PubMed
23.↵
1. Yan LL,
2. Daviglus ML,
3. Liu K,
4. Stamler J,
5. Wang R,
6. Pirzada A,
7. et al
. Midlife body mass index and hospitalization and mortality in older age. JAMA 2006;295(2):190-8.
OpenUrl CrossRef PubMed
24.
1. Lloyd-Jones DM,
2. Dyer AR,
3. Wang R,
4. Daviglus ML,
5. Greenland P
. Risk factor burden in middle age and lifetime risks for cardiovascular and non-cardiovascular death (Chicago Heart Association Detection Project in Industry). Am J Cardiol 2007;99(4):535-40.
OpenUrl CrossRef PubMed
25.↵
1. Berry JD,
2. Dyer A,
3. Cai X,
4. Garside DB,
5. Ning H,
6. Thomas A,
7. et al
. Lifetime risks of cardiovascular disease. N Engl J Med 2012;366(4):321-9.
OpenUrl CrossRef PubMed
26.↵
1. Cameron A
. The metabolic syndrome: validity and utility of clinical definitions for cardiovascular disease and diabetes risk prediction. Maturitas 2010;65(2):117-21.
OpenUrl CrossRef PubMed
27.↵
1. Sundström J,
2. Risérus U,
3. Byberg L,
4. Zethelius B,
5. Lithell H,
6. Lind L,
7. et al
. Clinical value of the metabolic syndrome for the long term prediction of total and cardiovascular mortality: prospective, population based cohort study. BMJ 2006;332(7546):878-82.
OpenUrl Abstract/FREE Full Text
28.↵
1. Grundy SM,
2. Cleeman JI,
3. Merz CN,
4. Brewer HB,
5. Clark LT,
6. Pasternak RC,
7. et al
. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110(2):227-39.
OpenUrl Abstract/FREE Full Text
29.↵
1. Reiner Ž,
2. Catapano AL,
3. De Baker G,
4. Graham I,
5. Taskinen MR,
6. Wiklund O,
7. et al
. The task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32(14):1769-818.
OpenUrl FREE Full Text
30.↵
1. Sacks FM,
2. Tonkin AM,
3. Craven T,
4. Pfeffer MA,
5. Shepherd J,
6. Keech A,
7. et al
. Coronary heart disease with low LDL-cholesterol: benefit of pravastatin in diabetics and enhanced role for HDL-cholesterol and triglycerides as risk factors. Circulation 2002;105(12):1424-8.
OpenUrl Abstract/FREE Full Text
31.↵
1. Sniderman A,
2. Williams K,
3. de Graaf J
. Non-HDL C equals apolipoprotein B: except when it does not! Curr Opin Lipidol 2010;21(6):518-24.
OpenUrl CrossRef PubMed
32.↵
1. Liu J,
2. Sempos CT,
3. Donahue RP,
4. Dorn J,
5. Trevisan M,
6. Grundy SM,
7. et al
. Non-high-density lipoprotein and very-high density lipoprotein cholesterol and their risk predictive values in coronary heart disease. Am J Cardiol 2006;98(10):1363-8.
OpenUrl CrossRef PubMed
33.↵
1. Mottillo S,
2. Filion KB,
3. Genest J,
4. Joseph L,
5. Pilote L,
6. Poirier P,
7. et al
. The metabolic syndrome and cardiovascular risk. J Am Coll Cardiol 2010;56(14):1113-32.
OpenUrl CrossRef PubMed
34.↵
1. Hodis HN
. Triglyceride-rich lipoprotein remnant particles and risk of atherosclerosis. Circulation 1999;99(22):2852-4.
OpenUrl FREE Full Text
35.
1. Gardner CD,
2. Fortmann SP,
3. Kraus RM
. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. JAMA 1996;276(11):875-81.
OpenUrl CrossRef PubMed
36.
1. Ginsberg HN
. New perspectives on atherogenesis: role of abnormal triglyceride-rich lipoprotein metabolism. Circulation 2002;106(16):2137-42.
OpenUrl FREE Full Text
37.↵
1. Carmena R,
2. Duriez P,
3. Fruchart JC
. Atherogenic lipoprotein particles in atherogenesis. Circulation 2004;109(Suppl III):III-2-7.
OpenUrl CrossRef PubMed
38.↵
1. Charlton-Menys V,
2. Betteridge DJ,
3. Colhoun H,
4. Fuller J,
5. France M,
6. Hitman GA,
7. et al
. Targets of statin therapy: LDL cholesterol, non-HDL cholesterol and apolipoprotein B in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS). Clin Chem 2009;55(3):473-80.
OpenUrl Abstract/FREE Full Text
39.↵
1. Brewer HB
. The evolving role of HDL in the treatment of high-risk patients with cardiovascular disease. J Clin Endocrinol Metab 2011;96(5):1246-57.
OpenUrl CrossRef PubMed
40.
1. Arsenault BJ,
2. Pibarot P,
3. Després JP
. The quest for the optimal assessment of global cardiovascular risk: are traditional risk factors and metabolic syndrome partners in crime? Cardiology 2009;113(1):35-49.
OpenUrl CrossRef PubMed
41.↵
1. Cornier MA,
2. Dabelea D,
3. Hernandez TL,
4. Lindstrom RC,
5. Steig AJ,
6. Stob NR,
7. et al
. The metabolic syndrome. Endocr Rev 2008;29(7):777-822.
OpenUrl CrossRef PubMed
42.↵
1. Chapman MJ,
2. Ginsberg HN,
3. Amarenco P,
4. Anderotti F,
5. Borén J,
6. Catapano AL,
7. et al
. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32(11):1345-61.
OpenUrl Abstract/FREE Full Text
43.↵
1. Tenenbaum A,
2. Fisman EZ
. “The metabolic syndrome…is dead”; these reports are an exaggeration”. Cardiovasc Diabetol 2011;10(1):11.
OpenUrl PubMed
44.↵
1. Pischon T,
2. Girman CJ,
3. Sacks FM,
4. Rifai N,
5. Stampfer MJ,
6. Rimm EB,
7. et al
. Non-high-density lipoprotein cholesterol and apolipoprotein B in the prediction of coronary heart disease in men. Circulation 2005;112(22):3375-83.
OpenUrl Abstract/FREE Full Text
45.↵
1. Jacobson TA
. Opening a new lipid “apo-thecary”; incorporating apolipoproteins as potential risk factors and treatment targets to reduce cardiovascular risk. Mayo Clin Proc 2011;86(8):762-80.
OpenUrl CrossRef PubMed
46.
1. Sniderman AD,
2. Bergeron J,
3. Frohlich J
. Apolipoprotein B versus lipoprotein lipids: vital lessons from the AFCAPS/TexCAPS trial. CMAJ 2001;164(1):44-7.
OpenUrl FREE Full Text
47.
1. Robinson JG,
2. Wang S,
3. Jacobson TA
. Meta-analysis of comparison of effectiveness of lowering apolipoproteins B versus low density lipoprotein cholesterol and non-high-density lipoprotein cholesterol for cardiovascular risk reduction in randomized trials. Am J Cardiol 2012;110(10):1468-76.
OpenUrl CrossRef PubMed
48.↵
1. Saenger A
. Cardiovascular risk assessment beyond LDL cholesterol: non-HDL cholesterol, LDL particle number and apolipoprotein B. Mayo Clinic Communiqué 2011;36(6):1-9.
OpenUrl
49.↵
1. Maki KC,
2. Davidson MH,
3. Dicklin MR
. A comparison of Canadian and American guidelines for lipid management using data from the National Cholesterol Education Program Evaluation Project Utilizing Novel E-technology (NEPTUNE) II survey. Can J Cardiol 2006;22(4):315-22.
OpenUrl PubMed
50.↵
1. Henkin Y
. Re-evaluating therapeutic target goals for statin-treated patients: time for revolutionary changes? J Am Coll Cardiol 2008;52(8):633-5.
OpenUrl CrossRef PubMed
51.↵
1. Ridker PM,
2. Rifai N,
3. Cook NR,
4. Bradwin G,
5. Buring JE
. Non-HDL cholesterol apolipoproteins A1 and B100, standard lipid measures, lipid ratios and CRP as risk factors for cardiovascular disease in women. JAMA 2005;294(3):226-333.
OpenUrl
52.
1. Hoenig MR
. Implications of the obesity epidemic for lipid-lowering therapy: non-HDL cholesterol should replace LDL cholesterol as the primary therapeutic target. Vasc Health Risk Manag 2008;4(1):143-56.
OpenUrl CrossRef PubMed
53.↵
1. Boekholdt SM,
2. Arsenault BJ,
3. Mora S,
4. Pedersen TR,
5. LaRosa JC,
6. Nestel PJ,
7. et al
. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins. JAMA 2012;12(12):1302-9.
OpenUrl
54.↵
1. The Emerging Risk Factors Collaboration
. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302(18):1993-2000.
OpenUrl CrossRef PubMed
55.↵
1. Ridker PM
. What works and in whom? A simple, easily applied, evidence-based approach to guidelines for statin therapy. Circ Cardiovasc Qual Outcomes 2012;5(4):592-3.
OpenUrl FREE Full Text
56.↵
1. Simes RJ,
2. Marschner RC,
3. Hunt D,
4. Colquhoun D,
5. Sullivan D,
6. Stewart RA,
7. et al
. Relationship between lipid levels and clinical outcomes in the long-term intervention with pravastatin in ischemic disease (LIPID) trial: to what extent is the reduction in coronary events with pravastatin explained by on-study lipid levels? Circulation 2002;105(10):1162-9.
OpenUrl Abstract/FREE Full Text
57.
1. Lewington S,
2. Whitlock G,
3. Clarke R,
4. Sherliker P,
5. Emberson J,
6. Halsey J,
7. et al
. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Prospective Studies Collaboration. Lancet 2007;370(9602):1829-39.
OpenUrl CrossRef PubMed
58.
1. Robinson JG,
2. Wang S,
3. Smith BJ,
4. Jacobson TA
. Meta-analysis of the relationship between non-high-density lipoprotein cholesterol and coronary heart disease risk. J Am Coll Cardiol 2009;53(4):316-22.
OpenUrl CrossRef PubMed
59.
1. Gotto AM,
2. Whitney E,
3. Stein EA,
4. Shapiro DR,
5. Clearfield M,
6. Weis S
. Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation 2000;101(5):477-84.
OpenUrl Abstract/FREE Full Text
60.
1. Pedersen TR,
2. Olsson AG,
3. Faergeman O,
4. Kjekshus J,
5. Wedel H,
6. Berg K,
7. et al
. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation 1998;97:1453-60.
OpenUrl Abstract/FREE Full Text
61.
1. Kastelein JJ,
2. van der Steeg WA,
3. Holme I,
4. Gaffney M,
5. Cater NB,
6. Barter P,
7. et al
. IDEAL Study Group. Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment. Circulation 2008;117(23):3002-9.
OpenUrl Abstract/FREE Full Text
62.
1. Sniderman AD,
2. Williams K,
3. Contois JH,
4. Monroe HM,
5. McQueen MJ,
6. deGraaf J,
7. et al
. A meta-analysis of low-density lipoprotein cholesterol, non-high-density cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes 2011;4(15):337-45.
OpenUrl Abstract/FREE Full Text
63.↵
1. Guyatt GH,
2. Oxman AD,
3. Vist GE,
4. Kunz R,
5. Falck-Ytter Y,
6. Alonso-Coello P,
7. et al.,
8. GRADE Working Group
. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336(7650):924-6.
OpenUrl FREE Full Text
64.↵
1. Kinosian B,
2. Glick H,
3. Garland G
. Cholesterol and coronary heart disease: predicting risks by levels and ratios. Ann Intern Med 1994;121(9):641-7.
OpenUrl CrossRef PubMed
65.
1. Ingelsson E,
2. Schaefer EJ,
3. Contois JH,
4. McNamara JR,
5. Sullivan L,
6. Keyes MJ,
7. et al
. Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA 2007;298(7):776-85.
OpenUrl CrossRef PubMed
66.
1. Holman RR,
2. Shine BS,
3. Coleman RL,
4. Stevens RJ
. Non-HDL cholesterol is less informative than total-to-HDL cholesterol ratio in predicting cardiovascular risk in type 2 diabetes. Diabetes Care 2005;28(7):1796-7.
OpenUrl FREE Full Text
67.↵
1. Lemieux I,
2. Lamarche B,
3. Couillard C,
4. Pascot A,
5. Cantin B,
6. Bergeron J,
7. et al
. Total cholesterol/HDL cholesterol ratio vs. LDL cholesterol/HDL cholesterol ratio as indices of ischemic heart disease in men: the Quebec Cardiovascular Study. Arch Intern Med 2001;161(22):2685-92.
OpenUrl CrossRef PubMed
68.↵
1. Cholesterol Treatment Trialists’ (CTT) Collaborators
. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomized trials. Lancet 2012;380(9841):581-90.
OpenUrl CrossRef PubMed
69.↵
1. Radcliffe KA,
2. Campbell WW
. Statin myopathy. Curr Neurol Neurosci Rep 2008;8(1):66-72.
OpenUrl CrossRef PubMed
70.
1. Grable-Esposito P,
2. Katzberg HD,
3. Greenberg SA,
4. Srinivasan J,
5. Katz J,
6. Amato AA
. Immune-mediated necrotizing myopathy associated with statins. Muscle Nerve 2010;41(2):185-90.
OpenUrl PubMed
71.
1. Tolman KG
. The liver and lovastatin. Am J Cardiol 2002;89(12):1374-80.
OpenUrl CrossRef PubMed
72.
1. Heeschen C,
2. Hamm CW,
3. Laufs U,
4. Snapinn S,
5. Böhm M,
6. White HD
. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation 2002;105(12):1446-52.
OpenUrl Abstract/FREE Full Text
73.
1. Blanco M,
2. Nombela F,
3. Castellanos M,
4. Rodriguez-Yáñez M,
5. García-Gil M,
6. Leira R,
7. et al
. Statin treatment withdrawal in ischemic stroke: a controlled randomized study. Neurology 2007;69(9):904-10.
OpenUrl CrossRef
74.
1. Sattar N,
2. Preiss D,
3. Murray HM,
4. Welsh P,
5. Buckley BM,
6. de Craen AJ,
7. et al
. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375(9716):735-42.
OpenUrl CrossRef PubMed
75.
1. Preiss D,
2. Seshasai SR,
3. Welsh P,
4. Murphy SA,
5. Ho JE,
6. Waters DD,
7. et al
. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011;305(24):2556-64.
OpenUrl CrossRef PubMed
76.
1. Mascitelli L,
2. Pezzetta F
. Physical activity in statin-treated patients. Int J Cardiol 2009;134(1):136-7.
OpenUrl CrossRef PubMed
77.
1. Thompson PD,
2. Zmuda JM,
3. Domalik LJ,
4. Zimet RJ,
5. Staggers J,
6. Guyton JR
. Lovastatin increases exercise-induced skeletal muscle injury. Metabolism 1997;46(10):1206-10.
OpenUrl CrossRef PubMed
78.
1. Urso ML,
2. Clarkson PM,
3. Hittel D,
4. Hoffman EP,
5. Thompson PD
. Changes in ubiquitin proteasome pathway gene expression in skeletal muscle with exercise and statins. Arterioscler Thromb Vasc Biol 2005;25(12):2560-6.
OpenUrl Abstract/FREE Full Text
79.
1. Dormuth CR,
2. Hemmelgarn BR,
3. Paterson JM,
4. James MT,
5. Teare GF,
6. Raymond CB,
7. et al
. Use of high potency statins and rates of admission for acute kidney injury: multicenter, retrospective observational analysis of administrative databases. BMJ 2013;346:f880.
OpenUrl Abstract/FREE Full Text
80.↵
1. Hippisley-Cox J,
2. Coupland C
. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ 2010;340:c2197.
OpenUrl Abstract/FREE Full Text
81.↵
1. Rubenfire M,
2. Brook RD,
3. Rosenson RS
. Treating mixed hyperlipidemia and the atherogenic lipid phenotype for prevention of cardiovascular events. Am J Med 2010;123(10):892-8.
OpenUrl CrossRef PubMed
82.↵
1. Baigent C,
2. Keech A,
3. Kearney PM,
4. Blackwell L,
5. Buck G,
6. Pollicino C,
7. et al
. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90056 participants in 14 randomized trials of statins. Lancet 2005;366(9493):1267-78.
OpenUrl CrossRef PubMed
83.↵
1. Cholesterol Treatment Trialists’ (CTT) Collaborators
. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomized trials. Lancet 2010;376(9753):1670-81.
OpenUrl CrossRef PubMed
84.↵
1. Mora S,
2. Wenger NK,
3. DeMicco DA,
4. Breazna A,
5. Boekholdt M
. Determinants of residual risk in secondary prevention patients treated with high versus low-dose statin therapy: The Treating to New Targets (TNT) study. Circulation 2012;125(16):1979-87.
OpenUrl Abstract/FREE Full Text
85.
1. Miller M,
2. Cannon CP,
3. Murphy SA,
4. Qin J,
5. Ray KK,
6. Braunwald E
. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2008;51(7):724-30.
OpenUrl CrossRef PubMed
86.↵
1. Heart Protection Study Collaborative Group
. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomized placebo controlled trial. Lancet 2003;361(9374):2005-16.
OpenUrl CrossRef PubMed
87.↵
1. Josan K,
2. Majumdar SR,
3. McAlister FA
. The efficacy and safety of intensive statin therapy: a meta-analysis of randomized trials. CMAJ 2008;178(5):576-84.
OpenUrl Abstract/FREE Full Text
88.
1. Cannon CP,
2. Steinberg BA,
3. Murphy SA,
4. Mega JL,
5. Braunwald E
. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol 2006;48(3):438-45.
OpenUrl CrossRef PubMed
89.
1. Hulten E,
2. Jackson JL,
3. Douglas K,
4. George S,
5. Villines TC
. The effect of early intensive statin therapy on acute coronary syndrome: a meta-analysis of randomized controlled trials. Arch Intern Med 2006;166(17):1814-21.
OpenUrl CrossRef PubMed
90.
1. Afilalo J,
2. Majdan AA,
3. Eisenberg MJ
. Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative meta-analysis of randomized controlled trials. Heart 2007;93(8):914-21.
OpenUrl Abstract/FREE Full Text
91.↵
1. Mills EJ,
2. O’Regan C,
3. Eyawo O,
4. Wu P,
5. Mills F,
6. Berwanger O,
7. et al
. Intensive statin therapy compared with moderate dosing for prevention of cardiovascular events: a meta-analysis of > 40,000 patients. Eur Heart J 2011;32(11):1409-15.
OpenUrl Abstract/FREE Full Text
92.↵
1. Deedwania P,
2. Barter P,
3. Carmena R,
4. Fruchart JC,
5. Grundy SM,
6. Haffner S,
7. et al
. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study. Lancet 2006;368(9539):919-28.
OpenUrl CrossRef PubMed
93.↵
1. Pyörälä K,
2. Ballantyne CM,
3. Gumbiner B,
4. Lee MW,
5. Shah A,
6. Davies MJ,
7. et al
. Reduction of cardiovascular events by simvastatin in nondiabetic coronary heart disease patients with and without the metabolic syndrome. Diabetes Care 2004;27(7):1735-40.
OpenUrl Abstract/FREE Full Text
94.
1. Athyros VG,
2. Mikhailidis DP,
3. Liberopaulos EN,
4. Kakafika AI,
5. Karagiannis A,
6. Papageorgiou AA,
7. et al
. Effect of statin treatment on renal function and serum uric acid levels and their relation to vascular events in patients with coronary heart disease and metabolic syndrome: a subgroup analysis of the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) study. Nephrol Dial Transplant 2007;22(1):118-27.
OpenUrl Abstract/FREE Full Text
95.
1. Sattar N,
2. Gaw A,
3. Scherbakova O,
4. Ford I,
5. O’Reilly D,
6. Haffner SN,
7. et al
. Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation 2003;108(4):414-9.
OpenUrl Abstract/FREE Full Text
96.↵
1. Schwartz GG,
2. Olsson AG,
3. Szarek M,
4. Sasiela WJ
. Relation of characteristics of metabolic syndrome to short-term prognosis and effects of intensive statin therapy after acute coronary syndrome. Diabetes Care 2005;28(10):2508-13.
OpenUrl Abstract/FREE Full Text
97.↵
1. Hayward RA,
2. Krumholz HM
. Three reasons to abandon low-density lipoprotein targets: an open letter to the Adult Treatment Panel IV of the National Institutes of Health. Circ Cardiovasc Qual Outcomes 2012;5(1):2-5.
OpenUrl FREE Full Text
98.↵
1. Shepherd J
. Resource management in prevention of coronary heart disease: optimising prescription of lipid-lowering drugs. Lancet 2002;359(9225):2271-3.
OpenUrl CrossRef PubMed
99.↵
1. Allan GM,
2. Mannarino M
. Tools for Practice. How does high dose statin compare to low dose in people with heart disease? Edmonton AB: Alberta College of Family Physicians; 2012. Available from: www.acfp.ca/Portals/0/docs/TFP/20120522_090852.pdf. Accessed 2012 Nov 7.
100.↵
1. Bruckert E,
2. Labreuche J,
3. Deplanque D,
4. Touboul PJ,
5. Amarenco P
. Fibrates effect on cardiovascular risk is greater in patients with high triglyceride levels or atherogenic dyslipidemia profile: a systematic review and meta-analysis. J Cardiovasc Pharmacol 2011;57(2):267-72.
OpenUrl CrossRef PubMed
101.↵
1. Lee M,
2. Saver JL,
3. Towfighi A,
4. Chow J,
5. Ovbiageli B
. Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis. Atherosclerosis 2011;217(2):492-8.
OpenUrl CrossRef PubMed
102.↵
1. Tenenbaum A,
2. Medvedovsky D,
3. Fisman EZ,
4. Bubyr L,
5. Matetzky S,
6. Tanne D,
7. et al
. Cardiovascular events in patients received combined fibrate/statin treatment versus statin monotherapy: acute coronary syndrome Israeli surveys data. PLoS ONE 2012;7(4):e35298-7.
OpenUrl CrossRef PubMed
103.↵
1. Accord Study Group
. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362(17):1562-74.
OpenUrl
104.↵
1. Jacobson TA,
2. Zimmerman FH
. Fibrates in combination with statins in the management of dyslipidemia. J Clin Hypertens (Greenwich) 2006;8(1):35-41.
OpenUrl PubMed
105.↵
1. Guo J,
2. Menq F,
3. Ma N,
4. Li C,
5. Ding Z,
6. Wang H,
7. et al
. Meta-analysis of safety of co-administration of statin with fenofibrate in patients with combined hyperlipidemia. Am J Cardiol 2012;110(9):1296-301.
OpenUrl CrossRef PubMed
106.↵
1. Canner PL,
2. Berge KG,
3. Wenger NK,
4. Stamler J,
5. Friedman L,
6. Prineas RJ,
7. et al
. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986;8(6):1245-55.
OpenUrl CrossRef PubMed
107.
1. Brown BG,
2. Zhao XQ,
3. Chait A,
4. Fisher LD,
5. Cheung MC,
6. Morse JS,
7. et al
. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345(22):1583-92.
OpenUrl CrossRef PubMed
108.
1. AIM-HIGH Investigators
. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365(24):2255-67.
OpenUrl CrossRef PubMed
109.↵
1. Bruckert E,
2. Labreuche J,
3. Amarenco P
. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis 2010;210(2):353-61.
OpenUrl CrossRef PubMed
110.
1. Duggal JK,
2. Singh M,
3. Attri N,
4. Singh PP,
5. Ahmed N,
6. Pahwa S,
7. et al
. Effect of niacin therapy on cardiovascular outcomes in patients with coronary artery disease. J Cardiovasc Pharmacol Ther 2010;15(2):158-66.
OpenUrl Abstract/FREE Full Text
111.
1. Tenkanen L,
2. Mänttäri M,
3. Manninen V
. Some coronary risk factors related to the insulin resistance syndrome and treatment with gemfibrozil: experience from the Helsinki Heart Study. Circulation 1995;92(7):1779-85.
OpenUrl Abstract/FREE Full Text
112.
1. The BIP Study Group
. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the benzafibrate infarction prevention (BIP) study. Circulation 2000;102(1):21-7.
OpenUrl Abstract/FREE Full Text
113.
1. Rubins HB,
2. Robins SJ,
3. Collins D,
4. Frye CL,
5. Anderson JW,
6. Elam MB,
7. et al
. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341(6):410-8.
OpenUrl CrossRef PubMed
114.
1. Hermans MP
. Impact of fenofibrate on type 2 diabetes patients with features of the metabolic syndrome: subgroup analysis from FIELD. Curr Cardiol Rev 2010;6(2):112-8.
OpenUrl CrossRef PubMed
115.↵
1. Kwak SM,
2. Myung SK,
3. Lee YJ,
4. Seo HG
. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med 2012;172(9):686-94.
OpenUrl CrossRef PubMed
116.
1. Delgado-Lista J,
2. Perez-Martinez P,
3. Lopez-Miranda J,
4. Perez-Jimenez F
. Long chain omega-3 fatty acids and cardiovascular disease: a systematic review. Br J Nutr 2012;107(Suppl 2):S201-13.
OpenUrl CrossRef PubMed
117.↵
1. Rizos EC,
2. Ntzani EE,
3. Bika E,
4. Kostapanos MS,
5. Elisaf MS
. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA 2012;308(10):1024-33.
OpenUrl CrossRef PubMed
118.
1. Lipid Research Clinics Program
. The Lipid Research Clinics coronary primary prevention trial results: II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984;251(3):365-74.
OpenUrl CrossRef PubMed
119.↵
1. Bucher HC,
2. Griffith LE,
3. Guyatt GH
. Systematic review on the risk and benefit of different cholesterol-lowering interventions. Arterioscler Thromb Vasc Biol 1999;19(2):187-95.
OpenUrl Abstract/FREE Full Text
120.↵
1. Athyros VG,
2. Tziomalos K,
3. Gossios TD,
4. Griva T,
5. Anagnostis P,
6. Kargiotis K,
7. et al
. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study: a post-hoc analysis. Lancet 2010;376(9756):1916-22.
OpenUrl CrossRef PubMed
121.↵
1. Allan MG,
2. Zarnke KB
. Tools for Practice. Ezetimibe: lowers LDL cholesterol, but what else? Edmonton AB: Alberta College of Family Physicians; 2010. Available from: www.acfp.ca/Portals/0/docs/TFP/20111028_105411.pdf. Accessed 2012 Jul 11.
122.↵
1. Briel M,
2. Ferreira-Gonzales I,
3. You JJ,
4. Karanikolas PJ,
5. Akl EA,
6. Wu P,
7. et al
. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ 2009;338:b92.
OpenUrl Abstract/FREE Full Text
123.↵
1. Estruch R,
2. Ros E,
3. Salas-Salvadó J,
4. Covas MI,
5. Corella D,
6. Arós F,
7. et al.,
8. PREDIMED Study Investigators
. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368(14):1279-90.
OpenUrl CrossRef PubMed

In this issue

Download PDF

Article Alerts

Email Article

Citation Tools

Respond to this article

Main menu

User menu

Search

Approach to identifying and managing atherogenic dyslipidemia

A metabolic consequence of obesity and diabetes

Abstract

Case description

Sources of information