Use of Supplemental Long Chain Omega-3 Fatty Acids and Risk for Cardiac Death: An Updated Meta-Analysis and Review of Research Gaps

Use of Supplemental Long Chain Omega-3 Fatty Acids and Risk for Cardiac Death: An Updated Meta-Analysis and Review of Research Gaps

By Orsolya M. Palacios, RD, PhD and Kevin C. Maki, PhD

Randomized, controlled trials (RCTs) assessing the use of supplemental long chain omega-3 polyunsaturated fatty acids (LC-OM3), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on risk for various types of cardiovascular disease events have yielded mixed results.  Some studies have suggested a beneficial effect, while others shown a neutral effect.  The outcome for which both the observational evidence on LC-OM3 intake or status and RCTs of supplementation appears to show the most consistent association is cardiac death.  Therefore, this meta-analysis and review of research gaps was conducted with two aims: 1) to update and further explore the available RCT data regarding LC-OM3 supplementation and risk for cardiac death; and 2) to briefly review the evidence regarding the effects of LC-OM3 intake on cardiac event risk, and to propose testable hypotheses for the mixed results obtained in RCTs regarding supplemental LC-OM3 use and cardiac event risk.

A literature search was conducted using PubMed and Ovid/Medline to identify RCTs examining supplemental LC-OM3 use (as dietary supplements or pharmaceutical LC-OM3 concentrates) and the outcome of cardiac death.  An intervention period of at least one year was required to be included in the primary analysis.  Studies that provided LC-OM3 in a food vehicle and studies in which the subjects had implanted cardiac defibrillators were excluded from the primary analysis but included in the secondary analysis.  Meta-analysis was employed to compare cumulative frequencies of cardiac death events between the LC-OM3 and control groups, including sensitivity and subset analyses.  Fourteen RCTs were identified for the primary analysis (71,899 subjects).  In the LC-OM3 arms, 1613 cardiac deaths were recorded (4.48% of subjects), compared to 1746 cardiac deaths in the control groups (4.87% of subjects). The pooled relative risk estimate showed an 8.0% (95% confidence interval 1.6%, 13.9%, p = 0.015) lower risk in the LC-OM3 arms vs. controls. Subset analyses showed numerically larger effects (12.9% to 29.1% lower risks, all p < 0.05) in RCTs with EPA+DHA dosages >1 g/d and with higher risk groups (secondary prevention, baseline mean or median triglycerides (TG) ≥150 mg/dL or low-density lipoprotein cholesterol (LDL-C) ≥130 mg/dL, statin use <40% of subjects). Heterogeneity was low (I2 ≤ 15.5%, p > 0.05) for the primary and subset analyses.


The present meta-analysis of RCTs showed a modest, but statistically significant, benefit of LC-OM3 supplementation on risk for cardiac death (8.0% in the primary analysis). Subgroup analyses show numerically larger benefits (12.9% to 29.1%, all p < 0.05) in studies that used >1 g/d of EPA+DHA, and in higher risk groups, including those with greater mean or median levels of TGs (≥150 mg/dL) or LDL-C (≥130 mg/dL), secondary prevention study samples, and studies with lower baseline use of statins (which is also a proxy for use of other cardioprotective agents).  These results suggest that additional research is warranted to further evaluate the potential risk reduction with LC-OM3 supplementation at higher dosages, and in higher risk samples.  Future RCTs should include evaluation of biomarkers of omega-3 status at baseline and during treatment, and should be designed to test specific hypotheses about the mechanisms through which benefits might be produced.  Taken together, the results of this analysis support the recent Science Advisory from the American Heart Association that concluded LC-OM3 “treatment is reasonable” for: 1) secondary prevention of coronary heart disease (CHD) and sudden cardiac death among patients with prevalent CHD, and 2) secondary prevention of adverse outcomes in patients with heart failure.  Because of the low risk for adverse effects with LC-OM3 supplementation, even a modest benefit is clinically meaningful.

A podcast by the lead author discussing this study is posted at Consultant 360:


Photo by Caroline Attwood

Redefining a Healthful Diet: New Results from the Largest Observational Study Ever Conducted on Nutrition and Heart Health Challenge Current Advice

Redefining a Healthful Diet: New Results from the Largest Observational Study Ever Conducted on Nutrition and Heart Health Challenge Current Advice

By Orsolya M. Palacios, RD, PhD and Kevin C. Maki, PhD

Cardiovascular disease is a major cause of morbidity and mortality worldwide.  Its relationship to healthful diet and lifestyle practices has been an area of active research for decades since these represent modifiable behaviors that have the potential to affect cardiovascular disease risk and overall health.  Within dietary recommendations, health authorities advise reducing total and saturated dietary fats while increasing carbohydrates from whole grains, as well as intakes of fruits, vegetables, nuts, seeds and legumes (DGA, 2015). These recommendations are based on studies that have been mostly observational in nature and conducted in high-income countries such as the U.S. and those in Western Europe.  The advice to lower saturated fat intake and replace it with unsaturated fat sources stems largely from the linear relationship between saturated fat intake and a low-density lipoprotein cholesterol (LDL-C) level.  LDL-C is a risk factor for cardiovascular disease, and thus, the working concept is that reducing saturated fat intake reduces LDL-C levels which, in turn, reduce cardiovascular disease risk.  In conjunction with lowering saturated fat intake, health authorities recommend reducing intakes of animal products such as meat and dairy products to accommodate higher intake of plant foods.  However, the advice to increase fruit, vegetable and legume intake also stems from observational studies conducted mainly in high-income nations.  Research on the associations of fruit, vegetable and legume intakes with health outcomes in other nations is sparse and inconclusive.

The dietary habits of populations within wealthy countries are generally one of excess, which significantly differs from the dietary habits of populations in low- and middle-income countries, where intake of certain nutrients, including adequate intake of complete proteins, may be sub-optimal.  Furthermore, dietary habits are strongly rooted in cultural practices, which can also vary greatly among countries, regardless of income status.  Since cardiovascular disease is a leading cause of morbidity and mortality in low- and middle-income countries as well, understanding the link between currently recommended dietary patterns, cardiovascular disease events and/or mortality in more globally-represented populations is crucial in providing accurate and meaningful guidelines for healthful food consumption.

The Prospective Urban Rural Epidemiology (PURE) study was conducted to address this topic.  Researchers recruited individuals aged 35 to 70 years of age in 18 low-income, middle-income and high-income countries between January 1, 2003 and March 31, 2013 to participate in the PURE prospective cohort study to assess the association between total mortality and major cardiovascular events and diet choices.  Habitual dietary intake data was analyzed from 135,355 individuals using validated food frequency questionnaires, which documented energy intake from fat (including total, saturated, monounsaturated and polyunsaturated fat), carbohydrate and protein as well as daily intake of fruit, vegetable and legume servings.  Demographic information, socioeconomic status, lifestyle, physical activity, health history and medication use questionnaires were also distributed and assessed.  Trained physicians using standard definitions completed standardized case-report forms to report mortality and major cardiovascular events.  The primary outcomes in this study were total mortality and major cardiovascular events (fatal cardiovascular disease, non-fatal myocardial infarction, stroke and heart failure) and secondary outcomes were all myocardial infractions, stroke, cardiovascular disease mortality, and non-cardiovascular disease mortality.

To assess associations between macronutrient energy contribution and cardiovascular disease events and/or mortality, participants were categorized into quintiles based on the dietary percentage of energy from total fat, individual fats, carbohydrates and protein; hazard ratios (HRs) were calculated using a multivariable Cox frailty model.  To assess the associations between daily fruit, vegetable and legume servings and cardiovascular disease events and/or mortality, Cox frailty models with random effects were also employed and HRs calculated.

Median follow up of participants was 7.4 years during which time 5796 deaths and 4784 major cardiovascular disease events were recorded.  Regarding macronutrient intake, higher carbohydrate intake was associated with a significantly higher total mortality risk for the highest quintile versus the lowest quintile, but there was no significant association between carbohydrate intake and cardiovascular disease, myocardial infarction, stroke or cardiovascular disease mortality.

Results from this study indicate that total fat, as well as saturated, monounsaturated and polyunsaturated fats all were significantly associated with a lower risk of mortality for the highest quintile versus the lowest quintile of total and individual fat intake.  Specifically, the HR for the highest versus the lowest quintile of fat intake was 0.77 (95% confidence interval [CI] 0.67-0.87) for total fat, 0.86 (95% CI 0.76-0.99) for saturated fat, 0.81 (95% CI 0.71-0.92) for monounsaturated fat, and 0.80 (95% CI 0.71-0.89) for polyunsaturated fat.  For cardiovascular disease events, the highest quintile of saturated fat intake was associated with a significantly lower risk of stroke (HR 0.79, 95% CI 0.64-0.98) compared to the lowest quintile of saturated fat intake.  Neither total fat nor any of the individual fats were associated with myocardial infarction risk or cardiovascular disease mortality.

Like total fat, the highest quintile versus the lowest quintile of total protein intake was significantly and inversely associated with total mortality risk (HR 0.88, 95% CI0.77-1.00) and non-cardiovascular disease mortality (HR 0.85, 95% CI 0.73-0.99).  Animal protein intake was associated with a significantly lower risk of total mortality whereas plant protein intake had no significant association with total mortality.

Total Fat HR (5th Quintile vs. 1st Quintile) 95% CI P-trend
Total Mortality 0.77 0·67–0·87 <0.0001
CVD Mortality 0.92 0·72–1·16         0.50
Non-CVD Mortality 0.70 0·60–0·82       <0.0001
Major CVD Events 0.95 0·83–1·08         0.33
Saturated Fat HR (1st Quintile vs. 5th Quintile) 95% CI P-trend
Total Mortality 0.86 0·76–0·99 0.0088
CVD Mortality 0.83 0·65–1·07         0.20
Non-CVD Mortality 0.86 0·73–1·01 0.0108
Major CVD Events 0.95 0·83–1·10         0.49
Fruits, Vegetables & Legumes HR (< 1 serving/day vs. 3-4 servings/day) 95% CI P-trend
Total Mortality 0.78 0.69–0.88 0.0001
CVD Mortality 0.81 0.65–1.02 0.0568
Non-CVD Mortality 0.77 0.66–0.89 0.0038
Major CVD Events 1.06 0.92–1.22 0.1301

Abbreviations: CVD, cardiovascular disease; HR, hazard ratio

Adapted from: Ramsden et al. Lancet (2017) S0140 (17)32241-9; Toledo et al.  Lancet (2017) S0140-6736(17)32251-1.

The mean fruit, vegetable and legume intake was 3.91 (standard deviation 2.77) daily servings.  When the researchers assessed the links between fruit, vegetable and legume intakes and outcomes, they found that higher fruit, vegetable and legume intake was significantly inversely associated with major cardiovascular disease, myocardial infarction, cardiovascular mortality, non-cardiovascular mortality and total mortality after adjustments for age, sex and random effects.  However, these effects were diminished after multivariable adjustments.  The HR for total mortality was lowest for those consuming three to four daily servings of fruit, vegetables and legumes (HR 0.78, 95% CI 0.69-0.88) compared to the reference group, who consumed less than one serving of these foods per day.  Higher intakes of fruits, vegetables and legumes were not associated with further lowering of risk.  When assessed independently, fruit intake was associated with lower mortality, including total mortality, cardiovascular mortality and non-cardiovascular mortality.  Raw vegetables were strongly linked to lower mortality risk whereas cooked vegetables had a modest association with lower risk.  Legume intake was inversely associated with non-cardiovascular death and total mortality.


To date, the PURE study is the largest observational study to assess the link between nutrient intakes, food group intakes, cardiovascular disease events (including death) and overall mortality.  It encompassed data from over 135,000 participants in 18 countries across five continents from low-, mid- and high-income nations.  The results of this study align with some general recommendations (e.g,. emphasize consumption of fruits, vegetables and legumes) but are in conflict with some others.  For example, health authorities recommend increasing intakes of fruits, vegetables and legumes at the expense of animal foods (DGA, 2015).  However, the results of this study suggest that the association between increased fruit, vegetable and legume intake plateaus after three to four daily servings, and the median fruit, vegetable and legume intake among participants was already 3.9 daily servings.  Thus, as a whole, participants were theoretically obtaining the maximal benefit from intake of these foods and the incremental benefit beyond the median level of intake in the populations studied is uncertain.  The study’s finding that higher energy intake from animal protein is linked to reduced total mortality, while plant proteins, such as those found in legumes, showed no significant association, does not align with the some aspects of the current Dietary Guidelines for Americans (DGA, 2015).  Although it recommends an increase in seafood, The Dietary Guidelines for Americans also recommends strategies such as using legumes, nuts and seeds in place of meat and poultry in mixed dishes to attain protein needs and to increase vegetable intake while cutting back on foods such as some meats, poultry and cheeses to help lower saturated fat intake (DGA, 2015).

However, the PURE study results challenge the emphasis on reducing intake of saturated fat.  Higher energy intake from fat and each individual type of fat, including saturated fat, was associated with lower total mortality, as well as lower risk for some cardiovascular disease events.  Carbohydrate energy intake either showed no association on assessed outcomes or was associated with an increased risk for mortality.  However, it should be emphasized that intakes of saturated fats were generally low, with mean values ranging from 5.7% in China to 10.9% in Europe and North America.  Across countries, total and saturated fat intakes are positively associated with socioeconomic status.  Thus, in countries with higher intakes of total and saturated fat, and thus lower intakes of carbohydrate, higher socioeconomic status, with resulting access to higher quality healthcare, is a potential confounder.

Taken together, the results from PURE raise questions about current dietary guidance, which is largely based on results from observational studies completed in the U.S. and Europe.  Unfortunately, very few randomized, controlled trials have been completed to assess the influence of dietary guidance on long-term health and disease incidence.  While difficult and expensive, these are essential for fully evaluating the potential benefits and risks of dietary recommendations (Maki, 2014).  The strongest recommendations should be limited to those instances where results from randomized, controlled trials align with findings from observational studies.  While the results from PURE are at odds with some current dietary recommendations, they are consistent with the age-old adage “everything in moderation.”

 PURE Study References

Dehghan M, Mente A, Zhang X, et al. Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study.  Lancet. 2017; S0140-6736(17)32252-3.

Miller V, Mente A, Dehghan M, et al. Fruit, vegetable, and legume intake, and cardiovascular disease and deaths in 18 countries (PURE): a prospective cohort study.  Lancet. 2017; S0140-6736(17)32253-5.

Ramsden CE, Domenichiello AF. PURE study challenges the definition of a healthy diet: but key questions remain.  Lancet. 2017; S0140-6736(17)32241-9.

Toledo E, Martinez-Gonzalez MA. Fruits, vegetables, and legumes: sound prevention tools.  Lancet. 2017; S0140-6736(17)32251-1.

Additional References

Maki KC, Slavin JL, Rains TM, Kris-Etherton PM.  Limitations of observational evidence: implications for evidence-based dietary recommendations.  Adv Nutr. 2014;5(1)7-14.

U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015 – 2020 Dietary Guidelines for Americans. 8th Edition. December 2015. Available at

Photo by Eaters Collective

CVD-REAL Results Suggest that Cardiovascular Benefits of Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors are, Indeed, Real


CVD-REAL Results Suggest that Cardiovascular Benefits of Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors are, Indeed, Real

By Kevin C Maki, PhD


In 2015, the release of the Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial results generated significant surprise and controversy.1 The investigators randomly assigned 7,020 patients with type 2 diabetes mellitus (T2D) to receive 10 or 25 mg/d of empagliflozin or placebo.  Empagliflozin is a sodium-glucose cotransporter-2 inhibitor that reduces renal reabsorption of glucose and sodium, thus increasing urinary losses and reducing the plasma glucose concentration.  The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in the pooled empagliflozin group compared with the placebo group.

The EMPA-REG OUTCOME results showed a 14% reduction (p = 0.04) in the primary outcome in the empagliflozin group.  Despite significant reductions in blood pressure, glycated hemoglobin and body weight, there were no differences between the groups in myocardial infarction or stroke.  However, there were substantial reductions (p ≤ 0.002) in death from cardiovascular causes (38%) and hospitalization for heart failure (35%).

More recently, the results from the Canagliflozin Cardiovascular Assessment Study (CANVAS) program were released in which data were pooled from two placebo-controlled studies of another SGLT-2 inhibitor, canagliflozin, involving 10,142 patients with T2D at high cardiovascular risk.2  The outcome for the primary composite, which was the same as that in EMPA-REG OUTCOME, showed that canagliflozin treatment was associated with a significant 14% reduction, a result that was essentially identical to that in the EMPA-REG OUTCOME study overall.  However, there were some differences between the results for individual components of the composite.


Outcome EMPA-REG OUTCOME (empagliflozin) CANVAS


Hazard Ratio (95% Confidence Interval)
Primary Composite 0.86 (0.74-0.99) 0.86 (0.75-0.97)
Death from Cardiovascular Causes 0.62 (0.49-0.77) 0.87 (0.72-1.06)
Non-fatal Myocardial Infarction 0.87 (0.70-1.09) 0.85 (0.69-1.05)
Non-fatal Stroke 1.24 (0.92-1.67) 0.90 (0.71-1.15)
Hospitalization for Heart Failure 0.65 (0.50-0.85) 0.67 (0.52-0.87)
Death from Any Cause 0.68 (0.57-0.82) 0.87 (0.74-1.01)

The notable differences are for death from cardiovascular causes (38% reduction vs. non-significant 13% reduction) and death from any cause (32% reduction vs. non-significant 13% reduction), for which the results with empagliflozin appeared more favorable, and non-fatal stroke (non-significant 24% increase vs. non-significant 10% reduction), for which the results appeared more favorable for canagliflozin. Or course, such differences could easily be due to random variation, so additional studies are needed with these and other agents in the SGLT-2 inhibitor class.  Large-scale randomized, controlled clinical trials are expensive and time consuming, so it is useful to look at results in the real world for patients prescribed these medications in clinical practice.  Results from such investigations need to be viewed with caution because they are more susceptible to various types of bias and confounding than results from randomized trials.  Nevertheless, they can be useful for evaluating risks and benefits of drug therapies and to further evaluate hypotheses generated from clinical trial data, such as whether there are differences in cardiovascular outcomes between agents in the SGLT-2 inhibitor class.

Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL) Methods and Results3

Data were collected from medical claims in the US and several countries in the EU.  A propensity score was used to adjust for SGLT-2 inhibitor initiation.  Hazard ratios were calculated for hospitalization for heart failure, all-cause mortality, and incidence of either outcome among those taking SGLT-2 inhibitors compared with other glucose-lowering drugs (GLD).

Data were included for more than 300,000 patients, half of whom took an SGLT-2 inhibitor and half of whom took other GLDs.  Canagliflozin was the most commonly used SGLT-2 inhibitor (53% of exposure), followed by dapagliflozin (42% of exposure) and empagliflozin (5% of exposure).  Canagliflozin was the most commonly used SGLT-2 inhibitor in the US (76%), whereas dapagliflozin was the most commonly used in Europe (92%); 87% of subjects had no known cardiovascular disease at baseline.

Over 190,164 person-years of follow-up, hazard ratios for hospitalization for heart failure (0.61, 95% CI 0.51-0.73), death (0.49, 0.41-0.57) and either outcome (0.54, 0.48-0.60) were all significantly below the null, indicating that incidence rates for these outcomes were 39-51% lower for SGLT-2 inhibitors compared with other GLDs.  Sensitivity analyses were consistent with the main results, with no evidence of significant heterogeneity across type of SGLT-2 inhibitor or country.


The results of the CVD-REAL investigation support the hypothesis that use of the SGLT-2 inhibitor class reduces risks for heart failure and death in patients with T2D.  The mechanisms responsible for these benefits, which are generally confirmatory (significant reductions or trends) for those observed in the EMPA-REG OUTCOME and CANVAS trials, are not well understood.  The SGLT-2 inhibitor class does not differ markedly from other GLD classes regarding effects on glycemic control.  Additional research will be needed to elucidate mechanisms responsible, which may have implications for the application of this drug class to other high-risk groups who do not have T2D.


  1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.
  2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. 2017; Jun 12. [Epub ahead of print].
  3. Kosiborod M, Cavendar MA, Fu AZ, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation. 2017;136:249-259.





Putting the FOURIER Findings in Perspective


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.


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.


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.

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.



Changes in Diet Quality and Mortality

Changes in Diet Quality and Mortality

Changes in Diet Quality and Mortality

By Kevin C Maki, PhD

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.

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.

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.

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.


  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
  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.


  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

Debates Rage on About the Health Effects of Low-Calorie Sweeteners – Newly Published Study Shows No Effect of Sucralose on Carbohydrate Metabolism

Health Effects of Low-Calorie Sweeteners

Debates Rage on About the Health Effects of Low-Calorie Sweeteners – Newly Published Study Shows No Effect of Sucralose on Carbohydrate Metabolism

  By Kevin C Maki, PhD

A study published recently in the journal Regulatory Toxicology and Pharmacology by Grotz and colleagues investigated the effects of sucralose consumption on glucose homeostasis in healthy men and women.1  Sucralose is one of six high-intensity sweeteners approved by the United States’ Food and Drug Administration (FDA) as food additives.  The approved high-intensity (low-calorie) sweeteners include:  saccharinaspartame, acesulfame potassium (Ace-K), sucralose, neotame, and advantame.2  Sucralose is one of the largest selling of the high-intensity sweeteners on the market, although consumption in the US has declined in recent years along with sales of diet soda, which were more than 20% lower in 2016 than in 2009.

There has been significant controversy about effects of high-intensity sweeteners on health, which seems to have intensified lately.  One of the findings that has generated debate is the relatively recent discovery of gut receptors for sweet taste, which has triggered concern that high-intensity sweeteners might have previously unappreciated effects on metabolism through their interactions with these receptors.1,3  Researchers at Purdue University have also hypothesized that when people consume high-intensity sweeteners, the body produces physiologic responses in anticipation of the arrival of sugar and calories, which could increase appetite and partially or fully offset the reduction in energy consumption of substituting a high-intensity sweetener for calorie-containing sugars.4

The newly published study by Grotz et al.1 was conducted a number of years ago, and the data were submitted to the FDA as part of the food additive petition for sucralose in 1996, but had never appeared in the peer reviewed literature.  Given the recent concerns expressed regarding the potential for high-intensity sweeteners to influence glucose homeostasis through their effects on sweet taste receptors in the gut, the investigators felt it would be useful to publish the results to make them more readily available to the scientific community.

The study was a randomized, double-blind parallel trial in which 48 healthy, normoglycemic males were randomly assigned to receive capsules containing either a cellulose placebo or 333.3 mg of sucralose, three times daily with meals.  The intake of 1000 mg/d in the sucralose group (n = 25) far exceeds the expected consumption from foods and beverages.  For perspective, diet sodas sweetened with sucralose typically contain ≤40 mg per serving.  A packet of Splenda® contains 12 mg of sucralose, which is 300-1000 times as sweet as sucrose.

The subjects underwent assessments of serum chemistry, hematology and glycated hemoglobin (HbA1C) levels, as well as fasting and post-oral-glucose-load (75 g) concentrations of insulin, glucose and C-peptide at baseline (twice), weeks 7 and 12 during the treatment period, and again 4 weeks after the end of the 12-week treatment period.  There were no significant differences between the placebo and sucralose groups for changes from baseline in HbA1C, or in fasting and post-glucose-load levels of glucose, insulin or C-peptide.  No differences were observed in clinical chemistry or hematology values.

Comment.  Given the widespread consumption of high-intensity sweeteners by large segments of the United States’ population, it is important to understand their effects on physiologic processes with implications for human health.  The results from this study in healthy men suggest that even very large intakes have no influence on indicators of glucose homeostasis.  Similar results have been obtained in patients with obesity or type 2 diabetes mellitus.1  Furthermore, reviews of the effects of high-intensity sweeteners, including sucralose, on appetite, gut hormones and gut motility have concluded that there is no evidence for material effects in humans.3,5  It is important for research on the physiological and psychological effects of high-intensity sweeteners to continue.  However, the results of this study and others suggest that sucralose has no adverse effects on glucose homeostasis.  Given evidence that sugar-sweetened products appear to have adverse effects on glucose homeostasis,6 the use of products sweetened with sucralose (and other high-intensity sweeteners) may be an acceptable option for those who would like to limit their intakes of added sugars and calories.7


 Grotz VL, Pi-Sunyer X, Porte, Jr. D, et al. A 12-week randomized clinical trial investigating the potential for sucralose to affect glucose homeostasis. Regul Toxicol Pharmacol. 2017;88:22-33.

  1. S. Department of Health and Human Services. U.S. Food & Drug Administration. High-Intensity Sweeteners. Accessed at on 11 July 2017.
  2. Magnuson BA, Roberts A, Nestmann ER. Critical review of the current literature on the safety of sucralose. Food Chem Toxicol. 2017;106 (Part A):324-355.
  3. Swithers SE, Martin AA, Davidson TL. High-intensity sweeteners and energy balance. Physiol Behav. 2010;100:55-62.
  4. Bryant C, Mclaughlin J. Low calorie sweeteners: evidence remains lacking for effects on human gut function. Physiol Behav. 2016;164 (Pt B):482-485.
  5. Maki KC, Nieman KM, Schild AL, et al. 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;145:1-8.
  6. Peters JC, Wyatt HR, Foster GD, et al. The effects of water and non-nutritive sweetened beverages on weight loss during a 12-week weight loss treatment program. Obesity. 2014;22:1415-1421.
Health Effects of Low-Calorie Sweeteners

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


  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

Results From a Systematic Review and Network Meta-Analysis Suggest that Lower Systolic Blood Pressure Targets Are More Effective for Reducing Risks for Cardiovascular Disease Events and Mortality

Reducing Risks for Cardiovascular Disease Events

Results From a Systematic Review and Network Meta-Analysis Suggest that Lower Systolic Blood Pressure Targets Are More Effective for Reducing Risks for Cardiovascular Disease Events and Mortality

Clinical trials have documented that lowering blood pressure reduces cardiovascular disease (CVD) and early death.1 However, the optimal target(s) for reduction of systolic blood pressure (SBP) are uncertain.1-4 Scientists from Tulane University School of Public Health and Tropical Medicine and the School of Medicine, along with scientists from the Medical College of Soochow University, China, conducted a systematic review and meta-analysis to assess the association of mean achieved SBP levels with the risk of CVD and all-cause mortality in adults with hypertension treated with antihypertensive therapy.5 From a MEDLINE and EMBASE search of articles through December 2015, Dr. Joshua Bundy and his colleagues identified 42 clinical trials of 144,200 patients that met their pre-defined criteria of random allocation to an antihypertensive medication, control, or treatment target that reported a difference in mean achieved SBP of 5 mm Hg or more between the groups compared.  The results showed that there was a linear association between mean achieved SBP and risks of CVD and mortality.  An achieved SBP of 120-124 mm Hg had the lowest risk.  Subjects in this lowest category had a hazard ratio (HR) of 0.82 (95% confidence interval [CI] 0.67-0.97) compared to subjects with even slightly higher SBP of 125-129 mm Hg, and this continued linearly through all of the 5 mm SBP cutpoints up to the comparison with the highest level of SBP ≥160 mm Hg, for which the HR for SBP of 120-124 mm Hg was 0.36 (95% CI 0.26-0.51). Similarly, subjects with an achieved SBP of 120-124 mm Hg had a HR for all-cause mortality of 0.74 (95% CI 0.57-0.97) compared with subjects in the 125-129 mm Hg category, and the benefit to all-cause mortality continued to as much as 0.47 (95% CI 0.32-0.67) when compared to subjects with SBP ≥160 mm Hg.


The 2003 7th Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of Blood Pressure recommended SBP goals of <130 mm Hg for patients with type 2 diabetes or chronic kidney disease and <140 mm Hg for individuals at least 60 years of age.1  The 8th Report of the Joint Committee released in 2014, raised these treatment targets to <140 and <150 mm Hg, respectively.2  The investigators of the Systolic Blood Pressure Intervention Trial (SPRINT) examined the association with CVD and all-cause mortality risks of the more intensive treatment goal (SBP <120 mm Hg) compared to <140 mm Hg among men and women with hypertension and at high CVD risk (but without diabetes or stroke).3  The mean achieved SBP was 121.5 mm Hg in the intensive-treatment group and 134.6 mmHg in the standard-treatment group. During a median follow-up of 3.3 years, a 25% reduction in the primary composite outcome of CVD events (HR, 0.75; 95% CI, 0.64-0.89; P < .001) and a 27% reduction in all-cause mortality (HR, 0.73; 95% CI, 0.60-0.90; P = .003) were observed.  However, some were concerned that those results were not necessarily generalizable for a variety of reasons.

Current guidelines provide inconsistent recommendations regarding the optimal SBP target, particularly in older adults.  Earlier this year, the American College of Physicians and the American Academy of Family Physicians released their joint guideline with evidence-based  recommendations on the benefits and harms of higher (<150 mm Hg) versus lower (≤140 mm Hg) SBP targets for hypertension in adults at least 60 years of age.4  They reported that mortality, incidence of stroke, and cardiac events were all reduced with the lower SBP target, but that treating to a lower target did not further reduce mortality, quality of life, or functional status in the target patient population.  They also reported increased withdrawals due to adverse events, as well as increased cough, hypotension, and risk of syncope with treating to the lower vs. higher SBP targets.  A report from the panel appointed to the Eighth Joint National Committee, recommended a SBP treatment target of 150 mm Hg for adults aged 60 years or older.2

On the other hand, in an analysis6 of data from 2636 SPRINT participants who were ≥75 years of age (mean age, 79.9 years; 37.9% women), at a median follow-up of 3.1 years, there were significantly lower rates of the primary composite outcome, HR = 0.66 (95%CI, 0.51-0.85) and all-cause mortality HR = 0.67 (95%CI, 0.49-0.91). The overall rate of serious adverse events was not different between treatment groups (48.4% in the intensive treatment group vs 48.3% in the standard ≥treatment group.

The multiple sets of hypertension guidelines and recommendations create confusion about the most appropriate blood pressure targets for patients with hypertension.  The results from the meta-analysis by Bundy et al.5 support the interpretation of the SPRINT investigators that a lower target is associated with reduced CVD and mortality risk.  Results from the subgroup analysis from SPRINT of elderly participants with a mean age of nearly 80 years suggest that a lower SBP target may produce benefits without unacceptable adverse effects even at advanced ages.  These findings suggest that reassessment of the body of evidence for the currently recommended SBP targets may be warranted.



  1. Chobanian AV, Bakris GL, Black HR, et al. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206-1252.


  1. James PA, Oparil S, Carter BL, et al. 2014 Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-520.


  1. Wright JT, Jr., Williamson JD, Whelton PK, et al.; SPRINT Research Group. A randomized trial of intensive versus standardized blood-pressure control. N Engl J Med. 2015;373:2103-2116.


  1. Qaseem A, Wilt Tj, Rich R, et al.; Clinical Guidelines Committee of the American College of Physicians and the Commission on Health of the Public and Science of the American Academy of Family Physicians. Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: A clinical practice guidelines from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2017;166:430-437.


  1. Bundy JD, Li C, Stuchlik P, Bu X, et al. Systolic blood pressure reduction and risk of cardiovascular disease and mortality: a systematic review and network meta-analysis. JAMA Cardiol. 2017; May 31, 2017 [Epub ahead of print].


  1. Williamson JD; Supiano MA, Applegate WB et al. Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged ≥75 Years. A Randomized Clinical Trial. JAMA. 2016;315:2673-2682.



Reducing Risks for Cardiovascular Disease Events

Dr. Ralph Defronzo Interview

Dr. Ralph Defronzo Interview

Dr. Ralph Defronzo Interview

Dr. Ralph Defronzo Interview

Steve Freed, RPh, CDE from Diabetes in Control conducted a terrific interview with Ralph DeFronzo, MD, who is an endocrinologist and Deputy Director of the Texas Diabetes Institute.  Dr. DeFronzo has been a pioneer in conducting studies to elucidate the pathophysiology of type 2 diabetes mellitus, and in the evaluation of treatment strategies that address the underlying defects.  Dr. DeFronzo recently surpassed 750 publications and it is difficult to overstate his influence on the field of diabetology.  The full interview on video and a transcript may be obtained at and

Below is a summary of Dr. DeFronzo’s key points.

  1. Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are two subtypes of prediabetes with different pathophysiologies:
    • IFG is characterized by hepatic insulin resistance and impaired first-phase insulin secretion;
    • IGT is characterized by skeletal muscle insulin resistance and impairment of second-phase insulin secretion.
  2. Progressive loss of pancreatic beta-cell function is the hallmark of progression from prediabetes to type 2 diabetes mellitus (T2D), and then to more severe T2D. Impairment of beta-cell response is due to a combination of dysfunction (hibernation) and loss of beta-cell mass.  This process can be arrested or slowed by drug therapies that have direct or indirect effects.
    • Direct effects – thiazolidinediones and GLP-1 agonists appear to have direct effects on the pancreas that help to preserve beta-cell mass, in part through reducing apoptosis.
    • Indirect effects – other drugs that lower glucose will reduce glucose toxicity, which, in turn, will improve beta-cell function and insulin sensitivity. DeFronzo believes that sulfonylureas should rarely be used and favors metformin and SGLT-2 inhibitors over other classes of glucose-lowering drugs.
  3. Recently published data support effects of three classes of hypoglycemic agents to reduce cardiovascular risk.
    • Pioglitazone (a thiazolidinedione) – the IRIS trial
    • SGLT-2 inhibitors – EMPA-REG Outcome and CANVAS
    • GLP-1 agonists – SUSTAIN-6 and LEADER
  4. DeFronzo advocates triple-therapy from early in the disease process (which can be costly) to address the underlying insulin resistance and arrest the progression of beta-cell impairment. This involves use of:
    • Pioglitazone (a thiazolidinedione),
    • A GLP-1 agonist,
    • Metformin or an SGLT-2 inhibitor.

Abbreviations:  CANVAS, Canagliflozin Cardiovascular Assessment Study; EMPA-REG, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; GLP-1, glucagon-like peptide-1; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; IRIS, Insulin Resistance Intervention after Stroke; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; SGLT-2, sodium-glucose cotransporter-2; SUSTAIN-6, Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes; T2D, type 2 diabetes mellitus.

Relevant references

Abdul-Ghani M, Migahid O, Megahed A, Adams J, Triplitt C, DeFronzo RA, Zirie M, Jayyousi A. Combination therapy with exenatide plus pioglitazone versus basal/bolus insulin in patients with poorly controlled type 2 diabetes on sulfonylurea plus metformin: The QATAR Study. Diabetes Care. 2017;40:325-331. Erratum: 2017 June 14 [Epub ahead of print].

DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: A new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773-795.

Kaul S. Mitigating cardiovascular risk in type 2 diabetes with antidiabetes drugs: A review of principal cardiovascular outcome results of EMPA-REG OUTCOME, LEADER, and SUSTAIN-6 trials. Diabetes Care. 2017;40:821-831.

Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR, for the CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017 June 12 [Epub ahead of print].


Dr. Ralph Defronzo Interview