2018 American College of Cardiology/American Heart Association Cholesterol Clinical Practice Guidelines

2018 American College of Cardiology/American Heart Association Cholesterol Clinical Practice Guidelines

2018 American College of Cardiology/American Heart Association Cholesterol Clinical Practice Guidelines

 By Heather Nelson Cortes, PhD, Mary R Dicklin, PhD and Kevin C Maki, PhD

 

The American College of Cardiology (ACC) and the American Heart Association (AHA) recently released their 2018 Guideline on the Management of Blood Cholesterol during the 2018 AHA meeting in Chicago, IL and simultaneously in Circulation1 and the Journal of the American College of Cardiology.1 The authors listed the top 10 take-home messages from the guidelines (see below, taken from the publication):

  1. In all individuals, emphasize a heart-healthy lifestyle across the life course.
  2. In patients with clinical atherosclerotic cardiovascular disease (ASCVD), reduce low-density lipoprotein cholesterol (LDL-C) with high-intensity statin therapy or maximally tolerated statin therapy.
  3. In very high-risk ASCVD, use a LDL-C threshold of 70 mg/dL (1.8mmol/L) to consider addition of non-statins to statin therapy.
  4. In patients with severe primary hypercholesterolemia (LDL-C level ≥190 mg/dL [≥4.9 mmol/L]), without calculating 10-year ASCVD risk, begin high-intensity statin therapy without calculating 10-year ASCVD risk.
  5. In patients 40 to 75 years of age with diabetes mellitus and LDL-C ≥70 mg/dL (≥1.8 mmol/L), start moderate-intensity statin therapy without calculating 10-year ASCVD risk.
  6. In adults 40 to 75 years of age evaluated for primary ASCVD, have a clinician-patient risk discussion before starting statin therapy.
  7. In adults 40 to 75 years of age without diabetes mellitus and with LDL-C ≥70 mg/dL (≥1.8 mmol/L), at a 10-year ASCVD risk of ≥7.5%, start a moderate-intensity statin if a discussion of treatment options favors statin therapy.
  8. In adults 40 to 75 years of age without diabetes mellitus and 10-year risk of 7.5% to 19.9% (intermediate risk), risk-enhancing factors favor initiation of statin therapy (see No. 7).
  9. In adults 40 to 75 years of age without diabetes mellitus and with LDL-C levels ≥70 mg/dL-189 mg/dL (≥1.8-4.9 mmol/L), at a 10-year ASCVD risk of ≥7.5% to 19.9%, if a decision about statin therapy is uncertain, consider measuring coronary artery calcium (CAC).
  10. Assess adherence and percentage response to LDL-C-lowering medications and lifestyle changes with repeat lipid measurement 4 to 12 weeks after statin initiations or dose adjustment, repeated every 3 to 12 months as needed.

 

Comment: The previous ACC/AHA guidelines released in 2013 sparked a considerable amount of debate.2,3  Major areas of controversy at that time included the use of a new risk calculator for assessing 10-year ASCVD, and, notably, abandoning the use of lipid goals.3 Those guidelines were exceedingly statin-centric, and did not provide guidance for managing cholesterol with non-statin lipid-altering drugs.  Another set of national recommendations released shortly after the 2013 ACC/AHA guidelines, the National Lipid Association (NLA) recommendations for the patient-centered management of dyslipidemia, employed a more traditional approach of titrating lipid-lowering therapy to achieve patient-specific LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) goals.4  The NLA also recommended combination of statin and non-statin drugs to achieve atherogenic cholesterol goals when maximum tolerated statin therapy was inadequate.  Both sets of recommendations emphasized lifestyle management, and the importance of patient-clinician discussions in managing elevated cholesterol.

 

Noteworthy changes in the new ACC/AHA guidelines include goals by using percentage reductions to monitor adequacy of response to LDL-C-lowering therapy.  They also lower the CAC score for enhanced risk, and include lipoprotein(a) as a risk-enhancing factor that can be considered when the decision to use statin therapy is otherwise uncertain.1  The new ACC/AHA guidelines recommend that a CAC score of 1-99 favors statin use (especially after age 55 years), and that a CAC score of 100+ and/or ≥75th percentile is an indication to initiate statin therapy.  If measured in selected individuals, a lipoprotein(a) level of >50 mg/dL or >125 nmol/L indicates enhanced risk.  The new guidelines also recommend using non-statin drugs, specifically ezetimibe or a proprotein convertase subtilisin kexin type 9 inhibitor, but suggest that their use is limited mainly to secondary prevention in patients at very high-risk of new ASCVD events.

 

The new ACC/AHA guidelines close much of the gap between the 2013 guidelines and the NLA recommendations on issues that previously were either handled differently or had been unaddressed by the ACC/AHA.  We expect that these new guidelines will be readily incorporated into clinical practice and improve patient outcomes.

 

References:

  1. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2018; Epub ahead of print and J Am Coll Cardiol. 2018; Epub ahead of print.
  2. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll Cardio. 2014;63 (Pt B):2889-2934.
  3. Phillips E, Sasseen JJ. Current controversies with recent cholesterol treatment guidelines. J Pharm Pract. 2016;29:15-25.
  4. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 – executive summary. J Clin Lipidol. 2014;8:473-488.

 

Closeup of medical drugs on stainless tray

Putting the FOURIER Findings in Perspective

FOURIER

Putting the FOURIER Findings in Perspective

By Kevin C Maki, PhD

Background and Methods
Earlier this year the results from the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial were published in the New England Journal of Medicine1 in conjunction with their presentation at the American College of Cardiology Scientific Sessions.  For the trial, 27,564 patients with atherosclerotic cardiovascular disease (ASCVD) and low-density lipoprotein cholesterol (LDL-C) at least 70 mg/dL while on statin therapy were randomly assigned to receive 140 mg of evolocumab or placebo by subcutaneous injection every 2 weeks.  Evolocumab is a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor that lowers LDL-C and cholesterol carried by other apolipoprotein B-containing lipoproteins by reducing the rate at which hepatic LDL receptors are catabolized.

The primary and key secondary composite outcomes were:

  • Primary: cardiovascular (CV) death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization;
  • Key secondary: CV death, myocardial infarction, stroke.

 

Results
The median baseline LDL-C level was 92 mg/dL, which was reduced by an average of 59% compared to placebo at 48 weeks to a median value of 30 mg/dL. Levels of non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B, were also reduced by 52% and 49%, respectively. 

The primary outcome was reduced by 15% (95% confidence interval [CI] 8 to 21%) and the key secondary endpoint was reduced by 20% (95% CI 12 to 27%) with evolocumab vs. placebo over an average follow-up period of 2.2 years.  In the placebo group, the primary and key secondary outcomes occurred in 11.3% and 7.4% of subjects, respectively.  Efficacy results were consistent across subgroups, including men and women and quartiles of baseline LDL-C.  The effect appeared to grow over time.  Beyond 12 months, the reduction in the key secondary outcome with evolocumab was 25%, compared to 16% during the first 12 months.  Other than injection site reactions (2.1% vs. 1.6%), no significant differences in adverse events were present between treatment groups.

 

Comment
The results from FOURIER bolster the case for the view that “lower is better” when it comes to LDL-C and related atherogenic lipoprotein variables such as non-HDL-C and apolipoprotein B.  The trial had a shorter follow-up time (2.2 years) than most statin trials, which have averaged roughly 5 years of treatment.  The event rate in FOURIER was relatively high (about 3-5% per year in the placebo group).

The reduction in LDL-C from a median baseline level of 92 to an on-treatment level of 30 mg/dL is a reduction of about 62 mg/dL (1.6 mmol/L). The results from the Cholesterol Treatment Trialists’ (CTT) analysis of data from statin trials2,3 would predict a reduction in risk of roughly 33% over five years for major vascular events [1 – (0.78^1.6) = 0.328], assuming a hazard ratio of 0.78 per 1.0 mmol/L reduction in LDL-C.  However, the follow-up period was shorter than 5 years, so we have to look at the CTT analysis for shorter timeframes for comparison.  The definition of major vascular event in the CTT analysis included the combined outcome of major coronary event, non-fatal or fatal stroke, or coronary revascularization.  This outcome has elements of both the primary and key secondary outcomes in FOURIER.  For simplicity, I will focus on the key secondary outcome in FOURIER of CV death, myocardial infarction or stroke for comparison to the CTT results with statin therapy.

During years 0-1, the hazard ratio in the CTT analysis was 0.90 per mmol/L of LDL-C reduction.2 The corresponding hazard ratios for years 1-2 and 2-3 were 0.78 and 0.74, respectively.2  I will use 0.78 in my calculations for simplicity, since this corresponds to the overall result from the CTT analysis.  For the first year, the predicted risk reduction in FOURIER based on the CTT values would be 15.5% [1 – (0.90^1.6) = 0.155].  This corresponds very closely to the 16% reduction in the key secondary outcome during the first 12 months.  Beyond 12 months, the effect in FOURIER was a 25% reduction in risk.  This is slightly below the predicted 32.8% reduction predicted by the CTT relationship, but certainly not far enough below the predicted value to conclude that the relationship is not similar.

In his presentation at the American College of Cardiology meeting, the Principal Investigator, Dr. Marc Sabatine, compared the results from year 2 of follow-up in FOURIER and the CTT analysis for the outcomes of major coronary events and stroke.3 They were very similar, as you can see by examining the hazard ratios and 95% CIs, which are shown below:

  • Major coronary events
    • CTT: 0.78 (0.70 to 0.86)
    • FOURIER: 0.80 (0.71 to 0.90)
  • Stroke
    • CTT: 0.77 (0.66 to 0.91)
    • FOURIER: 0.77 (0.63 to 0.94)

Thus, once the relatively short follow-up period is taken into account, the results from FOURIER are consistent with those from the CTT analysis, and are generally supportive of a linear relationship between LDL-C reduction and lower CV event risk, extending to lower levels than had previously been studied in large CV outcomes trials.

The findings from FOURIER are consistent with those from a pooled analysis of 10 trials in the development program for another PCSK9 inhibitor, alirocumab.4 In that analysis, a 39 mg/dL reduction in LDL-C (roughly 1 mmol/L) was associated with a hazard ratio of 0.76 (95% CI 0.63 to 0.91) compared with control for major adverse CV events.  Similar results were obtained for non-HDL-C and apolipoprotein B reductions.  When expressed per 50% reduction from baseline, the relative risk reductions for LDL-C, non-HDL-C and apolipoprotein B were 29%, 29% and 32%, respectively.

The results from FOURIER have generated confusion because the risk reduction reported was less than some had expected.  The CV benefits of LDL-C reduction take some time to become fully apparent.  Thus, after taking into account the comparatively short follow-up period of 2.2 years, it is clear that the FOURIER results are aligned with previous results from statin trials, as represented by the CTT analysis, as well as the findings from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), in which the small incremental reduction of about 0.4 mmol/L in LDL-C when ezetimibe was added to statin therapy translated into additional CV event risk reduction of 7-10%.5  Accordingly, the FOURIER results further strengthen the evidence that reducing LDL-C (and related variables such as non-HDL-C and apolipoprotein B) will reduce CV event risk in high-risk patients.

Additional evidence is expected to become available in 2018 from a trial with the other PCSK9 inhibitor currently cleared by the Food and Drug Administration, ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab.  Assuming that the results from that trial confirm those from FOURIER, the debate will continue to focus not on who might benefit from therapy, but rather for whom PCSK9 inhibitor therapy is justified, given the cost of approximately $14,000 per year.

References:
1.     Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-1722.

2.     The Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267-1278.

3.     The Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670-1681.

4.     Ray KK, Ginsberg HN, Davidson MH, et al. Reductions in atherogenic lipids and major cardiovascular events: a pooled analysis of 10 ODYSSEY trials comparing alirocumab with control. 2016;134:1931-1943.

5.     Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.

 

FOURIER

Changes in Diet Quality and Mortality

Changes in Diet Quality and Mortality

Changes in Diet Quality and Mortality

By Kevin C Maki, PhD

Background
Sotos-Prieto and colleagues from the Departments of Nutrition and Epidemiology at Harvard University published an analysis of the relationships between changes in diet quality scores and mortality [all-cause, cardiovascular (CV), and cancer] in a recent issue of the New England Journal of Medicine.1  These relationships were examined in two large cohorts of health professionals, the US Nurses’ Health Study (women) and the US Health Professionals Follow-up Study (men).

Previous studies have shown that higher diet quality scores are associated with lower mortality.  Of course, the potential problem with observational evidence is that it is difficult to know whether it is higher diet quality per se that is responsible for the relationship to lower mortality, or other differences between those with lower and higher diet quality scores.  People who consume diets that conform to recommendations from health authorities often have other characteristics that might contribute to better outcomes.  They tend to be more health conscious, have higher educational attainment, exercise more regularly, have lower body mass index, and be less likely to smoke, use illicit substances and consume alcohol to excess, just to name a few of the differences.

Epidemiologists attempt to adjust for these differences using statistical techniques to reduce the potential for bias and confounding by differences other than the exposure of interest; in this case diet quality score.  It is often impossible to identify and adjust for all of the variables that may be relevant.  The ultimate goal is to identify exposures that are causally related to disease status and modifiable, which can serve as the basis for public health actions, including recommendations for the characteristics of a healthy diet.

While far from perfect, it is useful to investigate the relationships between changes in exposure variables over time and disease risk.  For example, it bolstered the case for a causal relationship between cigarette smoking and risks for lung cancer and heart disease when it was shown that risks declined over time in those who quit smoking, but did not in those who continued to smoke.  Similarly, the Harvard group sought to assess whether changes in diet quality scores over time predicted risks for all-cause and cause-specific mortality.

Methods
In order to address this question, the researchers calculated changes over time in three scores:  the Alternative Healthy Eating Index (aHEI), the Alternative Mediterranean Diet (aMED) score, and the Dietary Approaches to Stop Hypertension (DASH) score.  Scores were calculated based on responses to the Willett Food Frequency Questionnaire that was administered every 4 years over long periods in both cohorts.  For the main analysis, changes in diet quality were calculated from 1986 to 1998 and follow-up was through 2010 (12 years).  The analysis included data from 73,739 participants (65% women).

The aHEI used scores from 0-10 for 11 food components selected on the basis of their relationships with chronic diseases.  Thus, the score could be from 0 to 110.  The aMED score included 9 components and were scored as 0 or 1 according to whether intake was above or below the cohort-specific median, allowing a score from 0 to 9.  The DASH score included 8 components, each scored 1-5, thus producing scores ranging from 8 to 40.  For all, a higher score indicated higher diet quality.

Results
Participants who increased their diet quality scores reported increased intakes of whole grains, vegetables and omega-3 fatty acids, as well as reduced intakes of sodium.  Compared to participants with relatively stable scores (middle quintile for change), those in the top 20% for increases (roughly 15-16 points for aHEI, 2-3 points for aMED, and 5-6 points for DASH), had 9-14% lower mortality risk, all p < 0.05 for the fifth vs. the third quintile in multivariable-adjusted models.  Similar results were obtained when a 20-percentile increase in score was modeled (8-17% lower risk for mortality).

Results were somewhat less consistent for deaths from CV causes and cancer.  A 20-percentile increase in aHEI was associated with 15% lower CV mortality (p < 0.05), while the same increase in aMED was associated with a 7% lower CV mortality (p < 0.05), and a 20-percentile increase in DASH score was associated with a non-significant 4% reduction in mortality.  For cancer mortality, a 20-percentile increase was associated with 6-9% lower mortality, which was only statistically significant (p < 0.05) for the DASH score (9%).

Having constant high diet quality score was associated with reductions of 9-14% in all-cause mortality over 12 years compared to those with constant low scores.  The investigators also looked at 8-year and 16-year changes.  In general, the effect became more pronounced with longer periods.  This was particularly evident for the aHEI, although that may be due to the greater range of values possible, which increases the variation in the populations studied.

Comment
This study adds support for the healthy eating patterns recommended in the Dietary Guidelines for Americans (2015-2020).2  Although confounding by unmeasured, or crudely measured, factors cannot be ruled out, the available data are consistent with a causal association between a healthy diet pattern and reduced risks for all-cause and CV mortality.  The evidence for a reduction in cancer mortality with a healthy dietary pattern is less convincing.  These results particularly support the recommendations for increased consumption of whole grains, fruits, vegetables, and fish/omega-3 fatty acids, compared with the average American diet, since these were the foods that were primarily responsible for changes in diet quality scores over time.

As I have stated repeatedly, public policy recommendations regarding diet often have to be based on evidence from observational studies assessing disease risk and intervention studies of biomarkers for disease risk, because few randomized, controlled dietary intervention studies have been completed to assess effects on disease incidence.  The strongest recommendations should be reserved for those areas where we have alignment between results from all three types of studies.

The results from the Prevención con Dieta Mediterránea (PREDIMED) study support health benefits, including reduced incidence of CV events (particularly stroke) and diabetes associated with advice to consume a Mediterranean diet pattern supplemented with nuts or olive oil, compared to low-fat diet advice.3 PREDIMED was not a perfect trial.  More randomized, controlled dietary intervention trials with outcomes of disease incidence are badly needed to answer questions about risks and benefits of various types of dietary advice.  PREDIMED demonstrates the feasibility of completing such studies.

For now, despite a number of caveats and uncertainties, the best available evidence suggests that the dietary patterns recommended in the Dietary Guidelines for Americans (healthy US diet, Mediterranean diet, DASH diet) are associated with a variety of favorable outcomes, including reduced total and CV mortality.

References:

  1. Sotos-Prieto M, Bhupathiraju SN, Mattei J, et al. Association of changes in diet quality with total and cause-specific mortality. N Engl J Med. 2017;377:143-153.
  2. US Department of Health and Human Services and US Department of Agriculture. Dietary Guidelines for Americans 2015-2020. 8th December 2016. Available at https://health.gov/dietaryguidelines/2015/resources/2015-2020_Dietary_Guidelines.pdf.
  3. Estruch R, Martínez-González MA, Corella D, et al.; PREDIMED Study Investigators. Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Intern Med. 2006;145:1-11.

 

 

Changes in Diet Quality and Mortality

Another CETP Inhibitor Fails to Show Cardiovascular Benefit, Despite Reducing LDL Cholesterol and Raising HDL Cholesterol: Implications of the ACCELERATE Trial

CETP Inhibitor

Another CETP Inhibitor Fails to Show Cardiovascular Benefit, Despite Reducing LDL Cholesterol and Raising HDL Cholesterol: Implications of the ACCELERATE Trial

  By Kevin C Maki, PhD

Cholesteryl ester transfer protein (CETP) is an enzyme that modulates the transfer of cholesterol esters from high-density lipoprotein (HDL) particles to apolipoprotein (apo)-B containing particles, including very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) particles.  CETP inhibitor drugs, by blocking this action, raise the level of HDL cholesterol (HDL-C) and lower the level of LDL cholesterol (LDL-C).

Previous outcomes trials with two CETP inhibitors, torcetrapib and dalcetrapib, failed to show cardiovascular disease (CVD) event risk reduction.1 Torcetrapib use was associated with increased CVD event risk, which was believed to be secondary to off-target effects, including raising blood pressure and aldosterone levels and lowering serum potassium concentration.  Whereas torcetrapib raised HDL-C by 70% and lowered LDL-C by 25%, dalcetrapib was a weak CETP inhibitor and raised HDL-C by only 30%, while having no effect on LDL-C.  A CVD outcomes trial with dalcetrapib was stopped for futility, showing no evidence of benefit or harm regarding CVD event risk.

The ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial evaluated the effects of evacetrapib 130 mg/d vs. placebo, when added to standard therapies in ~12,000 men and women with high CVD risk secondary to having clinical atherosclerotic CVD with a history of a recent acute coronary syndrome, cerebrovascular atherosclerosis, peripheral atherosclerosis, or diabetes mellitus with known coronary disease).2

After randomization, the effects of evacetrapib compared to placebo on mean or median changes from baseline to the 3-month timepoint in lipoprotein-related parameters were as follows (all p < 0.001):

  • HDL-C: +134.8%;
  • LDL-C: -37.1%;
  • Triglycerides (TG): -6.0%;
  • Apo B: -19.3%;
  • Lipoprotein (a): -22.3%.

There were also small changes (all p < 0.01), relative to placebo, in systolic/diastolic blood pressure (+1.2/+0.5 mm Hg) and C-reactive protein (8.6%).

Despite substantial changes in potentially favorable directions in lipoprotein-related variables, no difference was present for the primary efficacy outcome of the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina:  hazard ratio (HR) 1.01, 95% confidence interval (CI) 0.91 to 1.11, p = 0.91.  After an interim analysis with 82% of the final projected number of events, the trial was stopped early for futility.  No significant benefits were present for any of the individual components of the primary outcome, nor for a secondary composite that excluded hospitalization for unstable angina.

Comment.  The third failure of a CETP inhibitor to show CVD event risk reduction may sound the death knell for this class of lipid-altering agents.  The reasons for the lack of benefit in ACCELERATE are unclear.  Although HDL-C concentration is a strong inverse predictor for CVD event risk, the mechanisms responsible for this consistent finding are uncertain.   There are numerous ways that the HDL-C level can be raised, some of which could be beneficial, while others may be only cosmetic.

More disturbing than the lack of benefit associated with a rise in HDL-C, is the fact that LDL-C, TG, apo B and lipoprotein (a) were all lowered, yet this did not reduce CVD event risk.  Reduced CVD event risk has been observed with other agents that lower apo B-containing lipoproteins such statins, ezetimibe and proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors, so why did changes in these values with evacetrapib fail to lower risk?

Niacin lowers apo B-containing lipoproteins and lipoprotein (a), while also raising HDL-C, and it failed to demonstrate CVD event risk reduction in both the HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) study (co-administered with laropiprant) and in the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial .3  However, there were issues in both trials regarding whether the subjects enrolled were appropriate candidates for niacin therapy.3  For example, more than two-thirds of the subjects in HPS2-THRIVE had baseline non-HDL-C of less than 100 mg/dL.  Such individuals would not be likely to have been prescribed niacin in clinical practice.

Interventions that lower LDL-C and apo B-containing lipoproteins through mechanisms that involve inducing an upregulation in hepatic LDL receptor activity, including statins, ezetimibe and PCSK9 inhibitors have all been shown to reduce CVD event risk.  Lowering LDL-C and apo B-containing lipoproteins with evacetrapib had no effect on risk.  Should we infer from these results that lowering LDL-C and apo B-containing lipoproteins through mechanisms that do not upregulate hepatic LDL receptor activity will not reduce CVD risk?  Alternatively, is it the case that evacetrapib had some off-target effect(s) that offset the benefits of LDL-C and apo B-containing lipoprotein reduction, as has been hypothesized for torcetrapib?  Evacetrapib did produce modest increases in blood pressure and C-reactive protein.  These changes were small enough that they are unlikely to have been sufficient to directly offset the expected CVD benefits from reductions in LDL-C and apo B-containing lipoproteins.  However, they could be indicators of other adverse neuroendocrine and/or inflammatory effects.  At present, it is not possible to determine whether the explanation for the lack of benefit with evacetrapib was attributable to one of these, or perhaps some other explanation.

References:

  1. Barter PJ, Rye KA. Targeting high-density lipoproteins to reduce cardiovascular risk: what is the evidence? Clin Ther. 2015;37:2716-2731.
  2. Lincoff AM, Nicholls SJ, Riesmeyer JS, et al.; ACCELERATE Investigators. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med. 2017;376:1933-1942.
  3. Mani P, Rohatgi A. Niacin therapy, HDL cholesterol, and cardiovascular disease: is the HDL hypothesis defunct? Curr Atheroscler Rep. 2015;17:521.

 

 

CETP Inhibitor

Mendelian Randomization – Nature’s Clinical Trial – is Providing New Insights About the Causes and Potential Treatments for Cardiometabolic Diseases

Mendelian Randomization

Mendelian Randomization – Nature’s Clinical Trial – is Providing New Insights About the Causes and Potential Treatments for Cardiometabolic Diseases

By Kevin C. Maki, PhD

In a recent issue of JAMA Cardiology, Lyall and colleagues1 report that a score based on 97 genetic variants related to body mass index (BMI) was associated with increased risks for hypertension [odds ratio (OR) per 1-SD higher genetically-driven BMI of 1.64, 95% confidence interval (CI) 1.48-1.83], type 2 diabetes mellitus (OR 2.53; 95% CI 2.04-3.13) and coronary heart disease (CHD; OR 1.35; 95% CI 1.09-1.69).  Notably, the genetic BMI score was not associated with stroke risk.

Because the genetic score provides a measure of exposure over a lifetime to genetic variants that increase BMI, it is a relatively unconfounded marker that is less likely to be influenced by reverse causality than BMI itself.  Genotypes are assigned randomly when passed from parents to offspring during meiosis.2 The population genotype distribution should therefore be unrelated to the distribution of confounding variables.2  Accordingly, Mendelian randomization can be thought of as experiments of nature, similar to what is accomplished through randomization in a clinical trial.  The new results from Lyall et al.1 add evidence to support a causal relationship between increased BMI and cardiometabolic diseases.

Results reported in another recent paper by Dale and colleagues3 using Mendelian randomization also suggest causal roles for abdominal (waist-hip ratio adjusted for BMI; WHRadjBMI) and total adiposity (BMI) regarding risks for CHD and type 2 diabetes mellitus.  Each 1-SD higher WHRadjBMI (about 0.08 U) was associated with an excess risk of CHD (OR 1.48; 95% CI 1.28-1.71), similar to findings for BMI (SD about 4.6 kg/m2; OR 1.36; 95% CI, 1.22-1.52). WHRadjBMI, but not BMI, was associated with higher risk of ischemic stroke (OR 1.32; 95% CI, 1.03-1.70).  For type 2 diabetes mellitus, both variables had significant associations: OR 1.82 (95% CI 1.38-2.42) per 1-SD higher WHRadjBMI and OR 1.98 (95% CI 1.41-2.78) per 1-SD higher BMI.  These results are consistent with those reported by Lyall et al.1

Prior studies using Mendelian randomization have provided evidence for and against causality for several potentially modifiable risk factors for cardiometabolic diseases.  Evidence for causality has been provided for various lipoprotein-related variables and risks for atherosclerotic cardiovascular disease, including:4

  • Low-density lipoprotein cholesterol;
  • Triglycerides and triglyceride-rich lipoprotein cholesterol;
  • Lipoprotein (a).

Evidence against direct causality has been produced through Mendelian randomization for:4

  • High-density lipoprotein cholesterol;
  • C-reactive protein.

However, it should be noted that for high-density lipoprotein cholesterol and C-reactive protein, lack of association should not be interpreted to mean that these are not important risk indicators, only that the levels of these variables likely reflect other processes that are more directly involved in causal pathways.

The real promise of Mendelian randomization is to identify novel, modifiable targets for which new therapies can be developed.  This process was nicely illustrated by the identification of proprotein convertase subtilisin kexin type 9 (PCSK9) variants as predictors of CHD risk5, which ultimately led to the development of a new class of pharmaceuticals, the PCSK9 inhibitors.6

References:

  1. Lyall DM, Celis-Morales C, Ward J, et al. Association of body mass index with cardiometabolic disease in the UK Biobank: a Mendelian randomization study. JAMA Cardiol. July 5, 2017 [Epub ahead of print].
  2. Thanassoulis G, O’Donnell CJ. Mendelian randomization: nature’s randomized trial in the post-genome era. JAMA. 2009;301:2386-2387.
  3. Dale CE, Fatemifar G, Palmer TM, et al. Causal associations of adiposity and body fat distribution with coronary heart disease, stroke subtypes, and type 2 diabetes mellitus: a Mendelian randomization study. Circulation. 2017;135:2373-2388.
  4. Lacey B, Herrington WH, Preiss D, Lewington S, Armitage J. The role of emerging risk factors in cardiovascular outcomes. Curr Atheroscler Rep. 2017;19:28.
  5. Cohen JC, Boerwinkle E, Mosley TH, Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264-1272.
  6. Durairaj A, Sabates A, Nieves J, et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and its inhibitors: a review of physiology, biology, and clinical data. Curr Treat Options Cardio Med. 2017;19:58.
Mendelian Randomization

Replacing Refined Carbohydrates with Egg Protein and Unsaturated Fatty Acids Improves Insulin Sensitivity and the Cardiometabolic Profile

Replacing Refined Carbohydrates with Egg Protein

Replacing Refined Carbohydrates with Egg Protein and Unsaturated Fatty Acids Improves Insulin Sensitivity and the Cardiometabolic Profile

Replacing Refined Carbohydrates with Egg Protein and Unsaturated Fatty Acids Improves Insulin Sensitivity and the Cardiometabolic Profile

Consuming a healthful diet and participating in an adequate amount of physical activity are key tools for managing metabolic abnormalities that can increase risk for both cardiovascular disease and type 2 diabetes mellitus.  A growing body of evidence supports the view that a diet high in refined starches and added sugars exacerbates disturbances in carbohydrate (CHO) metabolism.  Replacement of these macronutrients with protein and/or unsaturated fatty acids (UFA) may help to improve the cardiometabolic risk factor profile.  The MB Clinical Research team conducted a trial to evaluate the effects of a combination of egg protein (Epro) and UFA, substituted for refined starches and added sugars, on insulin sensitivity and other cardiometabolic health markers in adults with elevated (≥150 mg/dL) triglycerides (TG).

Participants (11 men, 14 women) with elevated TG were randomly assigned to consume test foods prepared using Epro (~8% of energy) and UFA (~8% of energy) for the Epro/UFA condition, or using refined starch and sugar (~16% of energy) for the CHO condition.  Each diet was low in saturated fat and consumed for 3 weeks in a controlled feeding (all food provided) crossover trial, with a 2-week washout between diets.  Insulin sensitivity, assessed by the Matsuda insulin sensitivity index (MISI), increased 18.1 ± 8.7% from baseline during the Epro/UFA condition, compared to a change of -5.7 ± 6.2% during the CHO condition (p < 0.001). The disposition index, a measure of pancreatic beta-cell function, increased during the Epro/UFA condition compared to the CHO condition (net difference 40%, p = 0.042), and low-density lipoprotein (LDL) peak particle size increased during the Epro/UFA condition compared to the CHO condition (net difference 0.27 nm, p = 0.019).  TG and very low-density lipoprotein cholesterol (VLDL-C) levels were lowered more following the Epro/UFA (~16% differences, p < 0.002) versus the CHO diet condition.  LDL-C was lowered by 9-10% with both diets, compared with baseline, but the response did not differ between diets.

Comment:

Consumption of a low-saturated fat diet, where ~16% of energy from refined starches and added sugars was replaced with Epro and UFA, increased indices of insulin sensitivity and pancreatic beta-cell function, increased LDL peak particle size, and lowered fasting TG and VLDL-C levels in men and women with elevated TG.  The results of this study are consistent with a previous study by our group, where daily consumption of three servings of sugar-sweetened products reduced insulin sensitivity by 18% as assessed by HOMA2-%S compared to a habitual diet baseline, and three daily servings of dairy products produced no change.  Reductions in TG and VLDL-C may benefit cardiometabolic health, and are often accompanied by a shift toward larger, more buoyant LDL particles.  This shift, as observed in the current trial, may result in a less atherogenic LDL particle.  The findings from this trial support the Dietary Guidelines for Americans’ recommendations to limit intake of refined starches and added sugars, and to emphasize UFA intake as replacements for both dietary saturated fatty acids and refined CHO.

References:

Maki KC, Palacios OM, Lindner E, Nieman KM, Bell M, Sorce J. Replacement of refined starches and added sugars with egg protein and unsaturated fats increases insulin sensitivity and lowers triglycerides in overweight or obese adults with elevated triglycerides. J Nutr. 2017;May 17 [Epub ahead of print]

Maki KC, Nieman KM, Schild AL, Kaden VN, Lawless AL, Kelley KM, Rains TM. Sugar-sweetened product consumption alters glucose homeostasis compared with dairy product consumption in men and women at risk of type 2 diabetes mellitus. J Nutr. 2015; 145:459-466. Available at http://jn.nutrition.org/content/145/3/459.full.pdf+html.

U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015-2020 Dietary Guidelines for Americans 2015-2020. Eighth Edition. December 2015. Available at http://health.gov/dietaryguidelines/2015/guidelines/.

 

Replacing Refined Carbohydrates with Egg Protein