Hyperlipidemia

First, it was saturated fat, then high total cholesterol, and then high LDL cholesterol that played the role of the villains in the story entitled, “The development of heart disease.” Unfortunately the evidence does not suggest such a simplistic story line (1, 11, 13, 16). In fact, since the creation of the diet-heart hypothesis the evidence did not exist for cholesterol as causal and now the MOST recent evidence suggests high cholesterol as we age is associated with lower death rates (4). The lipid hypothesis of atherogenesis suggests that those with the highest cholesterol levels, such as those with confirmed diagnosis of familial hypercholesterolemia (FH) should have the highest rate of death from cardiovascular disease and other causes. The problem for the lipid hypothesis is the evidence does not show this. Studies are now showing lipid lowering is not having the intended effect of decreasing death by cardiovascular disease (3, 4, 5, 16). Looking at those with the highest cholesterol levels, those with FH, lowering their LDL cholesterol with lipid-lowering medication is not what is providing them with protection. The evidence supports the idea that decrease in small dense LDL (sdLDL) that is improving outcomes (14). In fact, in their later years, over 70 years of age, those with FH actually seem to enjoy a protective effect of their higher LDL actually lowering all-cause mortality with statistical significance (4). So, while cholesterol may be involved in the atherogenic process it is a dysfunctional cholesterol system and other factors that effect the function of that system and the advancement of atherogenesis. A major component of this dysfunction prevents LDL from being taken back into the liver for reprocessing, allowing for the increase and accumulation of sdLDL in the blood, at the same time this dysfunction also decreases HDL and increases triglycerides. These three conditions can be considered the trifecta of CVD risk (14, 15, 19).

Regarding the Lipid Hypothesis, a very recent commentary was published in The American Journal of Medicine in which the author, Dr. Robert DuBroff, M.D., states …“Therefore, it stands to reason that lowering serum LDL-C should prevent cardiovascular disease. Three decades of RCT’s, however, have yielded inconsistent and contradictory results. We must acknowledge these anomalies and either modify or reject the lipid hypothesis” (16). Another physician, cardiovascular surgeon, possibly one of the more respected surgeons in the world, Dr. Micheal DeBakey, in 1987 was quoted by the New York Times as saying, “30 years of observation of more than 15,000 patients had led him to conclude that cholesterol was not the central cause of atherosclerosis, the artery-clogging condition that kills hundreds of thousands of Americans each year.” Dr. DeBakey received numerous awards for his professional accomplishments, including the Presidential Medal of Freedom, and was involved in innovations such as coronary bypass operations, artificial hearts and ventricular assist devices.

Cholesterol and its involvement in the heart disease story is complicated. Dyslipidemia, rather than simple hyperlipidemia, provides a much more complete and accurate picture of the disease process. Our cholesterol system is a part of a complex metabolic system. When we look at markers such has Total Cholesterol:HDL ratios, Triglycerides and abnormally low HDL levels the accuracy of predicting disease significantly increases. Other surrogate markers such as hyperinsulinemia and insulin resistance (hypertension, visceral adiposity, high fasting blood glucose) further enhance the clarity of a dangerous situation (17). In fact, the evidence suggests that people can be very healthy with higher levels of LDL cholesterol as long as their high LDL cholesterol is accompanied by high HDL (>60 mg/dL) and low triglycerides (<100 mg/dL) (19).

* To our knowledge there are ZERO large RCT studies in existence showing statistically significant higher rates of CVD in untreated individuals with high HDL, low triglycerides and high LDL. If anyone finds a peer-reviewed paper that does suggest otherwise please notify us as soon as possible as there is a $3,000 bounty for anyone that can produce such a peer-reviewed paper.

When the Total Chol:HDL ratio is low it is suggestive of a highly functioning, healthy energy and cholesterol system. This situation, accompanied by low fasting triglycerides provide a picture of a highly functional energy system despite LDL levels. The data clearly suggests that it is a high Total Chol:HDL ratio with high fasting triglycerides that providers should find alarming. These markers suggest an energy system with abnormalities and metabolic dysfunction and high CVD risk (6,14,15,17).

The cholesterol system is highly responsive to diet and lifestyle therapy (10). While statins are considered a safe, life extending pharmacological therapy their efficacy and safety have recently come into question (12). Considering the effectiveness of diet and lifestyle modification these treatments should be used as a first line therapy (7,8,16). Dr. DuBroff simply states to close his commentary… “Although changing our patients’ Lifestyle is more difficult than prescribing a pill, the benefits are far more robust” (16).

Providers that identify these risk factors (high Total:HDL ratio, low HDL, High trigs) should counsel patients on the need to change as soon as any of these conditions present. The Framingham Offspring study showed that in those with low-HDL risk of CVD increased 30% in those that also had high TG’s or high-LDL and increased 60% in those with both (19). Providers should know that patients will need to be supported during any lifestyle modification process. AACE and ACE encourages earliest intervention focusing on on-going and structured lifestyle change (17). Recent research clearly suggests, that when it comes to behavior modifications, a few words in clinic by the  provider with a handout or two will usually be unsuccessful in motivating or helping the patient be successful (18). Providers must make a strong statement regarding the need to change in an effort to fully inform them as to their current health trajectory (9) and refer to a SPECIFIC program that will support patients during the change process if reversal of these conditions is to be expected (9, 18).

Here at Restore Medical Fitness Center patients that have begun our structured intensive lifestyle modification program with total cholesterol above 240 and HDL cholesterol below 50 we have seen their Total Chol:HDL ratio drop from 8.8 to 4.8 in 12 weeks. This was also associated with a 39% drop in fasting triglyceride levels (from 254 to 161). n=34+ In these same patients their Trig to HDL ratio dropped from 7.0 down to 3.9. These ratio changes represent MAJOR risk reduction for CVD (-37% according to ASCVD risk estimator).

Insulin resistance – Restore feels it is critical to point out that High total cholesterol, low HDL and high triglycerides, and therefor a high Total Chol: HDL and Triglyceride:HDL ratios are also very good surrogate cardiometabolic markers of insulin resistance. We feel it is important to highlight this fact considering the implementation of our structured, on-going Lifestyle modification program clearly shows that these treatments greatly reduce cardiometabolic risk and reversal of insulin resistance. Currently, there are no pharmacological treatments that can compare in effectiveness especially when adverse effects and cost are factored in.

References:

1- Ramsden, et al., BMJ 2016; 353:i1246 – Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73) – 

Abstract

Objective To examine the traditional diet-heart hypothesis through recovery and analysis of previously unpublished data from the Minnesota Coronary Experiment (MCE) and to put findings in the context of existing diet-heart randomized controlled trials through a systematic review and meta-analysis.

Conclusions Available evidence from randomized controlled trials shows that replacement of saturated fat in the diet with linoleic acid effectively lowers serum cholesterol but does not support the hypothesis that this translates to a lower risk of death from coronary heart disease or all causes. Findings from the Minnesota Coronary Experiment add to growing evidence that incomplete publication has contributed to overestimation of the benefits of replacing saturated fat with vegetable oils rich in linoleic acid.

2 – Harcombe Z, Baker JS, Cooper SM, et al., Open Heart 2015;2:e000196. doi:10.1136/openhrt-2014- 000196, – Evidence from randomised controlled trials did not support the introduction of dietary fat guidelines in 1977 and 1983: a systematic review and meta-analysis

ABSTRACT
Objectives: National dietary guidelines were introduced in 1977 and 1983, by the US and UK governments, respectively, with the ambition of reducing coronary heart disease (CHD) by reducing fat intake. To date, no analysis of the evidence base for these recommendations has been undertaken. The present study examines the evidence from randomised controlled trials (RCTs) available to the US and UK regulatory committees at their respective points of implementation.
Methods: A systematic review and meta-analysis were undertaken of RCTs, published prior to 1983, which examined the relationship between dietary fat, serum cholesterol and the development of CHD.
Results: 2467 males participated in six dietary trials: five secondary prevention studies and one including healthy participants. There were 370 deaths from all- cause mortality in the intervention and control groups. The risk ratio (RR) from meta-analysis was 0.996 (95% CI 0.865 to 1.147). There were 207 and 216 deaths from CHD in the intervention and control groups, respectively. The RR was 0.989 (95% CI 0.784 to 1.247). There were no differences in all-cause mortality and non-significant differences in CHD mortality, resulting from the dietary interventions. The reductions in mean serum cholesterol levels were significantly higher in the intervention groups; this did not result in significant differences in CHD or all-cause mortality. Government dietary fat recommendations were untested in any trial prior to being introduced.
Conclusions: Dietary recommendations were introduced for 220 million US and 56 million UK citizens by 1983, in the absence of supporting evidence from RCTs.

3- Kristensen ML, Christensen PM, Hallas J., BMJ Open 2015;5:e007118. doi:10.1136/bmjopen-2014-007118, – The effect of statins on average survival in randomised trials, an analysis of end point postponement

ABSTRACT
Objective: To estimate the average postponement of death in statin trials.
Setting: A systematic literature review of all statin trials that presented all-cause survival curves for treated and untreated.
Intervention: Statin treatment compared to placebo. Primary outcome measures: The average postponement of death as represented by the area between the survival curves.
Results: 6 studies for primary prevention and 5 for secondary prevention with a follow-up between 2.0 and 6.1 years were identified. Death was postponed between −5 and 19 days in primary prevention trials and between −10 and 27 days in secondary prevention trials. The median postponement of death for primary and secondary prevention trials were 3.2 and 4.1 days, respectively.
Conclusions: Statin treatment results in a surprisingly small average gain in overall survival within the trials’ running time. For patients whose life expectancy is limited or who have adverse effects of treatment, withholding statin therapy should be considered.

4- Mundal et. al.,  J Am Heart Assoc. 2014;3:e001236 doi:10.1161/JAHA.114.001236, – Mortality Among Patients With Familial Hypercholesterolemia: A Registry-Based Study in Norway, 1992–2010

Background-—Untreated patients with familial hypercholesterolemia are at increased risk of premature cardiovascular death. The primary aim of this study was to investigate whether this is also the case in the statin era.
Methods and Results-—In this registry-based study, 4688 male and female patients from the Unit for Cardiac and Cardiovascular Genetics (UCCG) Registry with verified molecular genetic diagnosis of familial hypercholesterolemia in the period 1992–2010 were linked to the Norwegian Cause of Death Registry. Standardized mortality ratios and 95% CIs were estimated. There were 113 deaths. Mean age of death was 61.1 years. Cardiovascular disease was the most common cause of death (46.0%), followed by cancer (30.1%). Compared with the Norwegian population, cardiovascular disease mortality was significantly higher in the UCCG Registry in all age groups younger than 70 years (standardized mortality ratio 2.29, 95% CI 1.65 to 3.19 in men and women combined; standardized mortality ratio 2.00, 95% CI 1.32 to 3.04 in men; standardized mortality ratio 3.03, 95% CI 1.76 to 5.21 in women). No significant differences were found in all-cause mortality or cancer mortality.
Conclusions-—Despite prescription of lipid-lowering drugs, familial hypercholesterolemia patients still had significantly increased cardiovascular disease mortality compared with the general Norwegian population.

5- Ravnskov et. al. BMJ Open 2016;6:e010401.doi:10.1136/bmjopen-2015-010401, – Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review

ABSTRACT
Objective: It is well known that total cholesterol becomes less of a risk factor or not at all for all-cause and cardiovascular (CV) mortality with increasing age, but as little is known as to whether low-density lipoprotein cholesterol (LDL-C), one component of total cholesterol, is associated with mortality in the elderly, we decided to investigate this issue.

Setting, participants and outcome measures: We sought PubMed for cohort studies, where LDL-C had been investigated as a risk factor for all-cause and/or CV mortality in individuals ≥60 years from the general population.

Results: We identified 19 cohort studies including 30 cohorts with a total of 68 094 elderly people, where all-cause mortality was recorded in 28 cohorts and CV mortality in 9 cohorts. Inverse association between all- cause mortality and LDL-C was seen in 16 cohorts (in 14 with statistical significance) representing 92% of the number of participants, where this association was
recorded. In the rest, no association was found. In two cohorts, CV mortality was highest in the lowest LDL-C quartile and with statistical significance; in seven cohorts, no association was found.

Conclusions: High LDL-C is inversely associated with mortality in most people over 60 years. This finding is inconsistent with the cholesterol hypothesis (ie, that cholesterol, particularly LDL-C, is inherently atherogenic). Since elderly people with high LDL-C live as long or longer than those with low LDL-C, our analysis provides reason to question the validity of the cholesterol hypothesis. Moreover, our study provides the rationale for a re-evaluation of guidelines recommending pharmacological reduction of LDL-C in the elderly as a component of cardiovascular disease prevention strategies.

6- Siri-Tarino et. al. Annu. Rev. Nutr. 2015. 35:517–43 doi:10.1146/annurev-nutr-071714-034449, – Saturated Fats Versus Polyunsaturated Fats Versus Carbohydrates for Cardiovascular Disease Prevention and Treatment

Conclusions
Replacing SFAs with PUFAs has been associated with cardiovascular benefit in the majority of metabolic, epidemiological, and clinical trial data, but study design caveats including residual con-founding in epidemiological studies and changes in multiple dietary variables in RCTs should be considered when weighing the evidence for specific nutrient effects. Epidemiological studies support a beneficial association of ω-3 fatty acids with CVD; however, clinical trial studies to date have not consistently confirmed this. In contrast, the replacement of SFAs with TFAs has been associated with adverse CVD risk factors and outcomes, whereas the replacement of SFAs with CHOs has not been associated with benefit and may be associated with increased CVD risk. These effects are likely multifactorial, including effects on atherogenic lipoproteins, particularly remnants and sdLDL particles. A particular concern with regard to the growing population of individuals with excess adiposity and insulin resistance is that they may be particularly sensitive to the adverse lipoprotein effects of refined and processed CHOs while being concomitantly resistant to LDL-C-reducing effects of reduced SFAs. The effects of various SFA replacement scenarios on CVD risk factors other than lipids and lipoproteins are ambiguous, with the strongest evidence for proinflammatory effects derived from cellular and animal studies. Importantly, accumulating evidence indicates that food sources of SFAs can vary in their associations with CVD risk independent of their SFA content. This is likely due to components within foods other than SFAs that may singly or synergistically affect the development and progression of CVD. Therefore, the SFA content of foods is not necessarily a useful criterion on which to base food choices. Overall dietary patterns that emphasize vegetables, fish, nuts, and whole versus processed grains are the mainstays of heart-healthy eating. Whether SFAs need to be reduced in the context of such dietary patterns is not established.

7- Cederberg et. al. Diabetologia (2015) 58:1109–1117 DOI 10.1007/s00125-015-3528-5, – Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort

Results Participants on statin treatment (N=2,142) had a 46% increased risk of type 2 diabetes (adjusted HR 1.46 [95% CI 1.22, 1.74]). The risk was dose dependent for simvastatin and atorvastatin. Statin treatment significantly increased 2 h glucose (2hPG) and glucose AUC of an OGTT at follow-up, with a nominally significant increase in fasting plasma glucose (FPG). Insulin sensitivity was decreased by 24% and insulin secretion by 12% in individuals on statin treatment (at FPG and 2hPG <5.0 mmol/l) compared with individuals without statin treatment (p<0.01). Decreases in insulin sensitivity and insulin secretion were dose dependent for simvastatin and atorvastatin.

8- Alsheikh-Ali et. al. Journal of the American College of Cardiology – Vol. 50, No. 5, 2007, doi:10.1016/j.jacc.2007.02.073, – Effect of the Magnitude of Lipid Lowering on Risk of Elevated Liver Enzymes, Rhabdomyolysis, and Cancer – Insights From Large Randomized Statin Trials – 

Results In 23 statin treatment arms with 309,506 person-years of follow-up, there was no significant relationship between percent LDL-C lowering and rates of elevated liver enzymes (R2 0.001, p 0.91) or rhabdomyolysis (R2 0.05, p 0.16). Similar results were obtained when absolute LDL-C reduction or achieved LDL-C levels were considered. In contrast, for any 10% LDL-C reduction, rates of elevated liver enzymes increased significantly with higher statin doses. Additional analyses demonstrated a significant inverse association between cancer incidence and achieved LDL-C levels (R2 0.43, p 0.009), whereas no such association was demonstrated with percent LDL-C reduction (R2 0.09, p 0.92) or absolute LDL-C reduction (R2 0.05, p 0.23).

Conclusions Risk of statin-associated elevated liver enzymes or rhabdomyolysis is not related to the magnitude of LDL-C lowering. However, the risk of cancer is significantly associated with lower achieved LDL-C levels. These findings suggest that drug- and dose-specific effects are more important determinants of liver and muscle toxicity than magnitude of LDL-C lowering. Furthermore, the cardiovascular benefits of low achieved levels of LDL-C may in part be offset by an increased risk of cancer. (J Am Coll Cardiol 2007;50:409–18) © 2007 by the American College of Cardiology Foundation

9 – Washburn, P.J., International Journal of User-Driven Healthcare, 6, 1, 2016 – Health Ballistics: Multiple Reference Point Informed Probability Theory

Conclusion: If an individual is afflicted with a chronic disease and does not know the realistic end point of their current health trajectory, they will never be fully ready, willing, motivated or able to make an informed, reliable, accurate and precise healthy behavioral decision in their current state of partially health informed reality. Alteration of health reality is accomplished by health informing the individual about the negatives of unhealthy behavior and the positives of healthy behavior.

10 – Hallberg, S.J., et.al., Diabetes Therapy, https://doi.org/10.1007/s13300-018-0373-9, – Effectiveness and Safety of a Novel Care Model for the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non-Randomized, Controlled Study

Discussion: …Beyond achieving improved glycemic control concurrent with medication and weight reductions, the Continuous Care Intervention (CCI) had broad positive impact on blood pressure, liver enzymes, hsCRP, triglycerides, and HDL-C. Elevated ALT, AST, and ALP are associated with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis [37]; these enzymes were significantly reduced with intervention. Rapid reduction in triglycerides and gradual rise in HDL-C observed following CCI are consistent with previously studied carbohydrate-restricted interventions and carbohydrates are well known to increase triglycerides…

11 – Gershuni, V.M., Current Nutrition Reports, Aug 2018, pp1-12, Saturated Fat: Part of a Healthy Diet

Recent Findings: Advances in understanding the role of various lipoprotein particles and their atherogenic risk have been helpful for understanding how different dietary components may impact CVD risk. Numerous meta-analyses and systematic reviews of both the historical and current literature reveals that the diet-heart hypothesis was not, and still is not, supported by the evidence. There appears to be no consistent benefit to all-cause or CVD mortality from the reduction of dietary saturated fat. Further, saturated fat has been shown in some cases to have an inverse relationship with obesity-related type 2 diabetes.

Summary: Rather than focus on a single nutrient, the overall diet quality and elimination of processed foods, including simple carbohydrates, would likely do more to improve CVD and overall health. It is in the best interest of the American public to clarify dietary guidelines to recognize that dietary saturated fat is not the villain we once thought it was.

12 – Demasi, M, British Journal of Sports Medicine, Jan 2018, 10.1136/bjsports-2017-098497 – Statin Wars: have we been mislead about the evidence? A narrative review

Abstract: Statins are the most widely prescribed, cholesterol lowering drugs in the world. Despite the expiration of their patents, revenue for statins is expected to rise, with total sales on track to reach an estimated US$1 trillion by 2020. A bitter dispute has erupted among doctors over suggestions that statins should be prescribed to millions of healthy people at low risk of heart disease. There are concerns that the benefits have been exaggerated and the risks have been underplayed. Also, the raw data on the efficacy and safety of statins are being kept secret and have not been subjected to scrutiny by other scientists. This lack of transparency has led to an erosion of public confidence. Doctors and patients are being misled about the true benefits and harms of statins, and it is now a matter of urgency that the raw data from the clinical trials are released.

13 – Ravnskov et. al., Expert Review of Clinical Pharmacology, Sept 2018 – LDL-C Does Not Cause Cardiovascular Disease: a
comprehensive review of current literature

Conclusion – The idea that high cholesterol levels in the blood are the main cause of CVD is impossible because people with low levels become just as atherosclerotic as people with high levels and their risk of suffering from CVD is the same or higher. The cholesterol hypothesis has been kept alive for decades by reviewers who have used misleading statistics, excluded the results from unsuccessful trials and ignored numerous contradictory observations.

14- Dr. Ken Sikaris was Director of Chemical Pathology at St Vincent’s Hospital in Melbourne between 1993 and 1996. A NATA-accredited laboratory assessor, Dr Sikaris specializes in Prostate Specific Antigen, cholesterol and quality assurance and is currently chair of the International Federation of Clinical Chemistry Committee on Analytical Quality. His expertise is highly sought and he has presented extensively at national and international symposiums.

15- Dr. Ken Sikaris was Director of Chemical Pathology at St Vincent’s Hospital in Melbourne between 1993 and 1996. Making Sense of LDL.

16 – DuBroff, R. – The American Journal of Medicine, Sept 2018 – A Reappraisal of the Lipid Hypothesis

Final Thoughts – LDL-C is considered the primary constituent of atherosclerotic plaque. Therefore, it stands to reason that lowering serum LDL-C should prevent cardiovascular disease. Three decades of RCTs, however, have yielded inconsistent and contradictory results. We must acknowledge these anomalies and either modify or reject the lipid hypothesis. Clearly, some individuals do benefit from lipid-modifying therapy. I believe the real question is how to identify them. Our current approach of focusing almost exclusively on lowering LDL-C for everyone does not consistently work, may result in unnecessary treatment of some healthy individuals, and likely reflects the fact that the pathogenesis of atherosclerosis is far more complex than originally thought. Our LDLC-centric approach to cardiovascular disease prevention may have distracted us from investigating other pathophysiologic mechanisms and treatments. Last, we should not ignore the benefits of a healthy lifestyle. Although changing our patients’ lifestyle is more difficult than prescribing a pill, the benefits are far more robust.

17- Mechanick, J et. al., Endocrine Practice Vol 24 No. 11 November 2018 – Dysglycemia-Based Chronic Disease (DBCD): An American Association of Clinical Endocrinologists Position Statement

From the Abstract: …In this context, stage 1 represents “insulin resistance,” stage 2 prediabetes,” stage 3 “type 2 diabetes,” and stage 4 “vascular complications.” This model encourages earliest intervention focusing on structured lifestyle change. Further scientific research may eventually reclassify stage 2 DBCD prediabetes from a predisease to a true disease state. This position statement is consistent with a portfolio of AACE endocrine disease care models, including adiposity-based chronic disease, that prioritize patient-centered care, evidence-based medicine, complexity, multimorbid chronic disease, the current health care environment, and a societal mandate for a higher value attributed to good health. Ultimately, transformative changes in diagnostic coding and reimbursement structures for prediabetes and T2D can provide improvements in population-based endocrine health care.  (Endocr Pract. 2018;24:995-1011)

Conclusion: Recognizing and managing prediabetes is a necessary component for an effective personalized and population-based T2D care plan. In order to substantiate this position, AACE has formulated a DBCD multimorbidity care model consisting of four distinct stages in the general context of ABCD (adiposity based chronic disease) and cardiometabolic health and specific context along with insulin resistance-prediabetes-T2D spectrum that are actionable in a preventive care paradiagm.

18 – McVay, et. al., Journal of General Internal Medicine – March 2019 – Portions of this study were presented at the Annual Meeting of the Society for Behavioral Medicine 2017 – DOI: 10.1007/s11606-019-04944-5 – Provider Counseling and Weight Loss Outcomes in a Primary Care-Based Digital Obesity Treatment

In summary, participants in a primary care-based, digital health weight loss intervention whose primary care providers’ document intervention-specific counseling may be more successful at weight loss.

19 – Bartlett, et. al. Circ Cardiovasc Qual Outcomes – 2016 – Is Isolated low High-Density Lipoprotein Cholesterol a Cardiovascular Disease Risk Factor? New Insights from the Framingham Offspring Study 

Conclusions – In the Framingham Offspring Study, low and high HDL-C phenotypes are not uniformly predictive of CVD risk. TG and LDL-C represent important modifiers of incident CVD risk at both ends of the HDL-C spectrum.