The Effects of Nutritional Supplements and Dietary Interventions on All-Cause Mortality and Cardiovascular Outcomes

The Effects of Nutritional Supplements and Dietary Interventions on All-Cause Mortality and Cardiovascular Outcomes

By Aly Becraft, MS and Kevin C Maki, PhD


Despite scientific uncertainty surrounding the benefits of dietary supplements, many U.S. adults use them, along with various dietary interventions, with the belief that they will improve their overall health (1).  Khan et al. (2) recently published a systematic review to assess the effect of various nutritional supplements and dietary interventions on cardiovascular outcomes.  The criteria for inclusion were randomized controlled trials (RCTs) and meta-analyses of RCTs that assessed the effect of nutritional supplements (vitamins, minerals, dietary supplements) or dietary interventions on all-cause mortality and cardiovascular outcomes in adults and written in English.  The main outcome of interest was all-cause mortality and secondary outcomes included cardiovascular mortality, myocardial infarction (MI), stroke, and coronary heart disease (CHD).  From these criteria, 942 articles were identified, and after initial title and abstract screening, 140 full-text articles remained to be reviewed for eligibility.  Ultimately, 9 systematic reviews and 4 new RCTs were included, comprising a total of 105 meta-analyses, 24 interventions (16 types of nutritional supplements and 8 dietary interventions), 277 RCTs and 922,129 participants.  A list of these interventions is shown in Table 1 and the significant findings from the present analysis are summarized in Table 2.


Table 1. List of interventions analyzed in Khan et al. (2)

Nutritional Supplements

Dietary Interventions


Mediterranean diet

Vitamin B6

Reduced dietary fat

Vitamin B3 or niacin

Modified dietary fat

Vitamin B complex

Reduced saturated fat


Reduced salt (hypertensive)


Reduced salt (normotensive)

Vitamin E

Increased omega-3 α-linolenic acid

Vitamin A

Increased omega-6 PUFA

Vitamin C


Vitamin D


Calcium and calcium plus vitamin D


Folic acid




Omega-3 long-chain PUFA




Abbreviation: PUFA, polyunsaturated fatty acids




Table 2. Summary of statistically significant findings from Khan et al. (2)



RR (95% CI)



All-cause mortality

Reduced salt intake in normotensive patients

0.90 (0.85 to 0.95)



Cardiovascular mortality

Reduced salt intake in hypertensive patients

0.67 (0.46 to 0.99)




Omega-3 LC-PUFA

0.92 (0.85 to 0.99)




Omega-3 LC-PUFA

0.93 (0.89 to 0.98)




Folic acid

0.80 (0.67 to 0.96)




Calcium plus vitamin D

1.17 (1.05 to 1.30)



Abbreviations: CHD, coronary heart disease; CI, confidence interval; LC-PUFA, long-chain polyunsaturated fatty acids; MI, myocardial infarction; RR, risk ratio


Comment.  Overall, the researchers found little evidence for nutritional supplements or dietary interventions to significantly reduce risk for all-cause mortality or cardiovascular outcomes, with some exceptions as outlined in Table 2.  Interventions associated with lower risks included reduced salt intake and lower total (normotensives) or cardiovascular mortality (hypertensives), omega-3 fatty acid supplementation and reduced risks for CHD and MI, and folic acid supplementation associated with lower risk for stroke. 


Of note, calcium plus vitamin D intake was associated with increased risk for stroke.  This finding could be related to hypercalcemia-mediated vascular calcification and/or effects on coagulation, although additional research is needed to more firmly establish causality and mechanistic explanations (3-5).


Certainty of evidence from this systematic review was low for most interventions due to low precision of estimates, qualitative and quantitative heterogeneity, and publication bias.  Regardless, these findings can be a useful resource for healthcare professionals who would like to recommend evidence-based nutritional interventions and provide a basis for future studies to explore the gaps in the currently available evidence base. 



  1. Gahche JJ, Bailey RL, Potischman N, et al. Dietary supplement use was very high among older adults in the United States in 2011-2014. J Nutr. 2017;147:1968-76.
  2. Khan SU, Khan MU, Riaz H, et al. Effects of nutritional supplements and dietary interventions on cardiovascular outcomes: an umbrella review and evidence map. Ann Intern. 2019;E-pub ahead of print
  3. Chin K, Appel LJ, Michos ED. Vitamin D, calcium, and cardiovascular disease: A”D”vantageous or “D”etrimental? An era of uncertainty. Curr Atheroscler Rep. 2017;19(1):5.
  4. Anderson JJ, Kruszka B, Delaney JA, et al. Calcium intake from diet and supplements and the risk of coronary artery calcification and its progression among older adults: 10-year follow-up of the Multi-Ethnic Study of Atherosclerosis (MESA). J Am Heart Assoc. 2016;5(10).
  5. Heaney RP, Kopecky S, Maki KC, Hathcock J, MacKay D, Wallace TC. A review of calcium supplements and cardiovascular disease risk. Adv Nutr. 2012;3:763-771.


Photo by Shanice Garcia

Mechanisms Responsible for the Benefit on Cardiovascular Risk in the REDUCE-IT Trial

Mechanisms Responsible for the Benefit on Cardiovascular Risk in the REDUCE-IT Trial

By Kevin C Maki, PhD


Recently, we learned of the impressive topline results from the Reduction of Cardiovascular Events with Eicosapentaenoic Acid (EPA) – Intervention Trial (REDUCE-IT), which showed that Vascepa® (icosapent ethyl or EPA ethyl esters) lowered major adverse cardiovascular events (MACE) by nearly 25% (p < 0.001) when added to statin therapy in patients with hypertriglyceridemia at high cardiovascular risk.1  This is great news, since residual hypertriglyceridemia is common in statin-treated patients.2  Moreover, other relatively inexpensive evidence-based therapies such as ezetimibe have been shown to have only a modest effect on MACE risk (~10%) when added to statin therapy, consistent with the anticipated effect based on the degree of low-density lipoprotein cholesterol (LDL-C) lowering.  Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors offer greater LDL-C reduction, but at a much higher cost.


The topline results from REDUCE-IT were a surprise to many who had concluded, based mainly on results from studies of omega-3 fatty acid interventions at low dosages in groups that did not have elevated average levels of triglycerides (TG), that omega-3 fatty acids were ineffective for lowering cardiovascular disease risk.3-7  I am looking forward to seeing the full set of results from REDUCE-IT, which will be presented at the 2018 American Heart Association Scientific Sessions and, hopefully, simultaneously published in a peer-reviewed journal.  These should provide more insight into the nature of the event reduction and possible lipid and non-lipid related drivers of the MACE reduction.


We know from the development program for Vascepa that it produces significant reductions in TG and TG-rich lipoprotein cholesterol levels.  In the ANCHOR trial, 4 g/d of Vascepa lowered the TG level by 21.5% relative to placebo in hypertriglyceridemic patients (median baseline TG 259 mg/dL) on statin therapy.8  In REDUCE-IT, the median baseline TG concentration was 216 mg/dL.  Therefore, if we assume a similar percentage reduction in TG, that would be 0.215 x 216 = 46.4 mg/dL.


There are several mechanisms through which long-chain omega-3 fatty acid interventions, (including EPA) may affect cardiovascular risk, of which TG lowering is only one.  Others include reducing myocardial fibrosis, lowering blood pressure and heart rate, reducing platelet activation and anti-inflammatory effects.9,10  Also, the physiologic effects of EPA, docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA; an intermediate in the conversion of EPA to DHA) are not identical, so we cannot assume that the effects will be identical for interventions that vary in the proportions of these fatty acids.  However, my view is that a large fraction of the benefit in REDUCE-IT is likely to be attributable to TG lowering based on two lines of evidence.


First, a meta-analysis conducted by my colleagues and I of the effects of TG-lowering drug therapies showed a modest effect overall (12% risk reduction in 10 trials), but larger effects in subgroups with TG ≥150 mg/dL (18% risk reduction), especially if accompanied by low high-density lipoprotein cholesterol (HDL-C; 29% risk reduction).11,12  The subjects in REDUCE-IT all had elevated TG and a large percentage likely also had low HDL-C.


Second, a meta-regression by Jun et al. showed that each 0.1 mmol/L (8.85 mg/dL) reduction in TG with fibrate therapy was associated with a reduction of 5% in MACE risk.13  The approximate reduction in TG relative to placebo of 46.4 mg/dL in REDUCE-IT would therefore be expected to produce 5.24 units (46.4/8.85 = 5.24) of 5% MACE reduction, i.e., 1 - 0.955.24= 0.236 or 23.6% MACE reduction.  The biologic plausibility of a benefit being attributable to TG reduction is supported not only by evidence from prior randomized, controlled trials of TG-lowering drug therapies (albeit in subgroups), but also by studies showing that genetic variants associated with reduced TG (and TG-rich lipoprotein cholesterol) are associated with lower cardiovascular risk. 


My colleagues and I view the results from REDUCE-IT as a major positive development for patient care.  We eagerly anticipate the full REDUCE-IT results, as well as those from additional studies that, we hope, will provide greater insight into the mechanisms responsible for reduced MACE risk in the REDUCE-IT trial.



  1. Amarin Corporation. REDUCE-IT cardiovascular outcomes study of VASCEPA® (icosapent ethyl) capsules met primary endpoint. September 24, 2018. Available at


  1. Fan W, Philip S, Granowitz C, et al. Prevalence and predictors of residual hypertriglyceridemia according to statin use in US adults. J Clin Lipidol. 2018;12:530-531.


  1. Maki KC, Dicklin MR. Omega-3 fatty acid supplementation and cardiovascular disease risk: glass half full or time to nail the coffin shut? Nutrients. 2018;10:864.


  1. Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: Meta-analysis of 10 trials involving 77,917 individuals. JAMA Cardiol. 2018;3:224-234.


  1. Alexander DD, Miller PE, Van Elswyk ME, et al. A meta-analysis of randomized controlled trials and prospective cohort studies of eicosapentaenoic and docosahexaenoic long-chain omega-3 fatty acids and coronary heart disease risk. Mayo Clin Proc. 2017;29:15-29.


  1. Abdelhamid AS, Brown TJ, Brainard JS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018;7:CD003177.


  1. The ASCEND Study Collaborative Group. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018 [Epub ahead of print].


  1. Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR 101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012;110:984-992.


  1. Mozaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol. 2011;58:2047-2067.


  1. Mozaffarian D, Prineas RJ, Stein PK, Siscovick DS. Dietary fish and n-3 fatty acid intake and cardiac electrocardiographic parameters in humans. J Am Coll Cardiol. 2006;38:478-484.


  1. Maki KC, Guyton JR, Orringer CE, et al. Triglyceride-lowering therapies reduce cardiovascular disease event risk in subjects with hypertriglyceridemia. J Clin Lipidol. 2016;10:905-914.


  1. Maki KC, Dicklin MR. Do triglyceride-lowering drugs decrease risk of cardiovascular disease? Curr Opin Lipidol. 2017;28:374-379.


  1. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet. 2010;375:1875-1884.




Photo by Vincent Botta

Topline Results from REDUCE-IT Show a Significant Reduction in Cardiovascular Outcomes with Omega-3 Fatty Acid

Topline Results from REDUCE-IT Show a Significant Reduction in Cardiovascular Outcomes with Omega-3 Fatty Acid

By Kevin C Maki, PhD and Mary R Dicklin, PhD


Exciting topline results from the Reduction of Cardiovascular Events with Eicosapentaenoic Acid (EPA) – Intervention Trial (REDUCE-IT) were recently announced by Amarin, the maker of Vascepa®.1 The full results are scheduled to be presented on November 10, 2018 at the American Heart Association’s (AHA) Scientific Sessions in Chicago, IL.  REDUCE-IT was a randomized, controlled trial that examined the effects of 4 g/d Vascepa vs. placebo on cardiovascular outcomes in statin-treated adults at elevated cardiovascular risk.2   Topline results indicated an ~25% relative risk reduction (p < 0.001) in the primary composite endpoint of the first occurrence of a major adverse cardiovascular event, including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization, after a median follow-up of 4.9 y.1


These results will take some by surprise, based on the abundance of unfavorable interpretations of the effects of omega-3 fatty acids on cardiovascular outcomes from other recently published trials and meta-analyses.3,4  However, as my colleagues and I previously speculated,5 a failure to show benefit in some of those other studies has likely been due, at least in part, to study design issues, including administration of low dosages and absence of a clear pathophysiologic target for the intervention.  Unlike previous studies, many of which gave 1 g/d Omacor®/Lovaza®, containing ~850 mg EPA + docosahexaenoic acid (DHA),6 in REDUCE-IT subjects received a high dosage of 4 g/d Vascepa (roughly 3,700 mg of EPA).Subjects in REDUCE-IT were also required to have elevated baseline triglycerides (TG) of ≥150 mg/dL and <500 mg/dL (lower limit later changed to ≥200 mg/dL), resulting in a median baseline TG level of 216 mg/dL.  Results from our meta-analysis suggested that medications which substantially lower TG reduce cardiovascular risk in those with elevated TG, especially if accompanied by low high-density-lipoprotein cholesterol.7  Thus, REDUCE-IT directly addressed the issue of TG-lowering as a target of therapy.


Our separate meta-analysis of 14 randomized controlled trials that investigated the effects of omega-3 fatty acids on cardiac death showed an 8% lower risk with omega-3 supplementation vs. controls, although the effect was much larger (29%) in studies where the dosage employed was >1 g/d of EPA + DHA.8  It is uncertain whether REDUCE-IT will have enough cardiac deaths to show a benefit for that outcome, although it should add a substantial number of events to the aggregate database of studies using higher dosages. 


Results from another large-scale clinical trial of omega-3 fatty acids, the Vitamin D and Omega-3 Trial (VITAL), are also scheduled to be presented at AHA.  In VITAL, subjects received 1 g/d of Omacor/Lovaza and were not required to have elevated TG levels at baseline.9  The results from VITAL and another recently reported trial (A Study of Cardiovascular Events in Diabetes; ASCEND)4 will facilitate a more complete assessment of the effects of low-dosage EPA + DHA on the risk of cardiac death, which has important public health implications.


The Outcomes Study to Assess Statin Residual Risk Reduction with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia (STRENGTH) is another high-dosage study (4 g/d) of the carboxylic acids (free fatty acids) form of EPA + DHA, and the last of the large-scale omega-3 trials underway.  Subjects in STRENGTH were required to not only have elevated TG (≥180 mg/dL and <500 mg/dL), but also to have low levels of high-density lipoprotein cholesterol (<47 mg/dL for women and <42 mg/dL for men).10  STRENGTH is scheduled to complete in the fall of 2019.



  1. Amarin Corporation. REDUCE-IT cardiovascular outcomes study of VASCEPA® (icosapent ethyl) capsules met primary endpoint. September 24, 2018. Available at


  1. Bhatt DL, Steg PG, Brinton EA, et al. Rationale and design of REDUCE-IT: reduction of cardiovascular events with icosapent ethyl-intervention trial. Clin Cardiol. 2017;40:138-148.


  1. Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol. 2018;3:225-234.


  1. ASCEND Study Collaborative Group. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018; Epub ahead of print.


  1. Maki KC, Dicklin MR. Omega-3 fatty acid supplementation and cardiovascular disease risk: glass half full or time to nail the coffin shut? Nutrients. 2018;10(7).


  1. Abdelhamid AS, Brown TJ, Brainard JS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018;7:CD003177.


  1. Maki JC, Guyton JR, Orringer CE, et al. Triglyceride-lowering therapies reduce cardiovascular disease event risk in subjects with hypertriglyceridemia. J Clin Lipidol. 2016;10:905-914.


  1. Maki KC, Palacios OM, Bell M, Toth PP. Use of supplemental long-chain omega-3 fatty acids and risk for cardiac death: an updated meta-analysis and review of research gaps. J Clin Lipidol. 2018;11:1152-1160.


  1. Manson JE, Bassuk SS, Lee IM, et al. The Vitamin D and Omega-3 Trial (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin trials. 2012;33:159-171.



  1. Nicholls SJ, Lincoff AM, Bash D, et al. Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: rationale and design of the STRENGTH trial. Clin Cardiol. 2018; Epub ahead of print.
Photo by i yunmai

Participants with Elevated Lp (a) Had Greater than Average Benefit from Evolocumab in FOURIER

Participants with Elevated Lp (a) Had Greater than Average Benefit from Evolocumab in FOURIER

Kevin C Maki, PhD, CLS, FNLA and Mary R Dicklin, PhD

It has been known for decades that an elevated level of lipoprotein (a) or Lp (a) is associated with increased cardiovascular disease (CVD) risk.  The Lp (a) particle consists of a low-density lipoprotein (LDL) particle that has an apoprotein (a) glycoprotein linked to the apolipoprotein B via a single disulfide bond.

Lp (a) is mainly genetically determined and shows a right skewed distribution in most populations, with approximately 80% having values below 50 mg/dL, when measured by mass, and 100 nmol/L, when measured by particle concentration.1,2  Some individuals have extremely elevated levels, as high as 300 mg/dL in mass in some instances.  Lp (a) shares homology with the plasminogen molecule, and may interfere with fibrinolysis.  It can also enter the arterial endothelial space and participate, like other LDL particles, in initiation and promotion of atherosclerotic plaques.  In addition, oxidized phospholipids appear to bind to Lp (a); levels of Lp (a) and oxidized phospholipids are highly correlated.  Both elevated oxidized phospholipid and Lp (a) concentrations are associated with increased CVD risk.2,3

Mendelian randomization studies have shown that genetic variants associated with Lp (a) level are associated with CVD risk.  Smaller apolipoprotein (a) isoforms are associated with higher levels of Lp (a) in circulation, and both Lp (a) level (mass or particle concentration) and genetic variants associated with smaller isoforms have been associated with higher CVD risk in a dose-dependent manner (i.e., more alleles associated with higher CVD risk).  Thus, both traditional observational studies and studies of genetic variants that affect Lp (a) levels have been associated with CVD risk, which provides strong support for a causal relationship between Lp (a) level and CVD risk.

Statin therapy has little effect on the Lp (a) concentration.4  However, several interventions are known to affect the circulating Lp (a) concentration, but evidence has been lacking for a benefit of lowering Lp (a) level per se as an intervention to reduce CVD risk.  Among the interventions known to lower Lp (a) are niacin, estrogen, LDL apheresis, cholesterol ester transfer protein inhibition, and two drugs used to treat familial hypercholesterolemia (mipomersen and lomitapide).4  In addition, the proprotein convertase subtilisin kexin type 9 (PCKS9) inhibitor class of lipid-altering medications is known to lower Lp (a) by 25% or more.5-7

Because of the ability of PCSK9 inhibitors to lower Lp (a) mass and particle concentration, as well as LDL cholesterol and LDL particle concentration, it would be expected that if Lp (a) lowering produced CVD benefit, that the risk reduction associated with PCSK9 inhibitor therapy would be expected to be greater among those with elevated Lp (a) concentrations.

The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) was a CVD outcomes trial that tested the effects of treatment with maximally tolerated statin therapy plus the PCSK9 inhibitor evolocumab or placebo on CVD event risk in patients with stable atherosclerotic CVD at the time of randomization.  The main results showed a 15% reduction in the primary composite event outcome and a 20% reduction in a key secondary composite measure over a median treatment period of 22 months.8

A pre-planned subgroup analysis was presented at the 86th Annual Congress of the European Atherosclerosis Society in Lisbon, Spain in early May 2018.  At baseline, the median Lp (a) level was 37 nmol/L and the 25th and 75th percentiles were 13 and 165 nmol/L, respectively.  A higher baseline Lp (a) particle concentration was associated with greater risk for a CVD event in the placebo group, with the fourth quartile having 26% higher (95% confidence interval 2% to 56%) risk of coronary heart disease death or myocardial infarction compared with the first quartile.9

Evolocumab treatment lowered the Lp (a) concentration and the degree of lowering was related to the baseline level.  Median absolute (nmol/L) changes in Lp (a) were -1, -9, -24 and -36 nmol/L in the first through fourth quartiles, respectively.  An analysis of the results for those with baseline Lp (a) above and below the median baseline level showed a larger risk reduction in those with values above the median than below (24% vs. 15%) for the outcome of CV death, myocardial infarction or stroke.  The number needed to treat (NNT) to prevent one event was lower in those with Lp (a) above the median (NNT = 36) than those below the median (NNT = 79).  In addition, cumulative CVD event incidence was lowest in those who achieved both Lp (a) and LDL cholesterol levels at or below the median (6.57%), was intermediate in those who achieved only one value at or below the median (7.88-8.45%) and was highest in those who had both levels above the median value (9.43%).9,10

These findings add to the body of evidence supporting a causal role for Lp (a) in CVD risk.  They also provide support for the view that lowering Lp (a) reduces CVD event risk, and therefore is a promising therapeutic target.  Thus, PCSK9 inhibitor therapy may be a reasonable consideration for high risk patients who have elevated Lp (a).  These results also confer enhanced optimism regarding the potential efficacy of therapies in development that target Lp (a), such as monoclonal antibodies and an antisense oligonucleotide for apolipoprotein (a).11


  1. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein (a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31:2844-2853.
  2. Kronenberg F. Human genetics and the causal role of lipoprotein(a) for various diseases. Cardiovasc Drugs Ther. 2016;30:87-100.
  3. Tsimikas S, Witztum JL. The role of oxidized phospholipids in mediating lipoprotein(a) atherogenicity. Curr Opin Lipidol. 2008;19:369-377.
  4. Van Capelleveen JC, van der Valk FM, Stroes ESG. Current therapies for lowering lipoprotein (a). J Lipid Res. 2016;57:1612-1618.
  5. Raal F, Giugliano RP, Sabatine MS, et al. Reduction in Lp(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol. 2014;63:1278-1288.
  6. Raal FJ, Giugliano RP, Sabatine MS, et al. PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the LDL receptor’s role. J Lipid Res. 2016;57:1086-1096.
  7. Gaudet D, Watts GF, Robinson JG, et al. Effect of alirocumab on lipoprotein(a) over ≥1.5 years (from the phase 3 ODYSSEY program). Am J Cardiol. 2017;119:40-46.
  8. 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.
  9. Davenport L. Lp(a) levels may modulate CV benefits of evolocumab: FOURIER – Medscape – May 09, 2018. Accessed at file:///Users/Mary/Downloads/FOURIER%20Lp(a)%20Level%20Influences%20Benefit%20from%20Evolocumab%2010May18.pdf.
  10. Maxwell YL. Unlocking Lp(a): baseline levels matter, but so too does absolute reduction. tctMD/the heart beat. May 08, 2018. Accessed at

    11.  Vuorio A, Watts GF, Kovanen PT. Depicting new pharmacological strategies for familial hypercholesterolaemia involving lipoprotein(a). Eur

Photo by Joel Filipe

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.





MB Clinical Academy Releases its First Two Educational Programs

MB Clinical Academy

MB Clinical Academy Releases its First Two Educational Programs

MB Clinical Academy produces educational materials to help clinicians, clinical research professionals and students more effectively manage the cardiometabolic health of their patients/clients, and to understand the strengths and limitations of the available evidence, including gaps that can be filled with future studies.

We have just completed two new programs, which will be available for purchase and download during the week of July 10, 2017.

Short Course

Diet and Prevention of Type 2 Diabetes Mellitus:  Beyond Weight Loss and Exercise

This short course will review the evidence for dietary factors in the prevention of type 2 diabetes mellitus (T2D).  It contains three modules that will cover:

  • Module 1: Epidemiology and pathophysiology of T2D
  • Module 2: Predictors of T2D risk and effects of interventions on incidence
  • Module 3: Summary of the associations and mechanisms through which diet may affect T2D risk, with an emphasis on insulin sensitivity and glycemic load

Short Course

Interpreting Efficacy Results from Cardiovascular Outcomes Trials

Cardiovascular outcomes trials are integral to evidence-based medicine, and they are the most effective means for demonstrating that an intervention reduces major adverse cardiovascular events.  A sound understanding of the fundamentals of clinical study design and statistical methodology is essential for the interpretation of efficacy results from cardiovascular outcomes trials.  However, most clinicians have not had extensive training on how to interpret measures of association and statistical procedures used to assess the efficacy of interventions intended to reduce cardiovascular event risk.  This course will review of the following concepts and their use in cardiovascular outcomes studies:

  • Measures of cardiovascular event incidence
    1. Relative risk
    2. Hazard ratio
    3. Odds ratio
  • Comparing event rates and treatment effects
    1. Relative risk reduction
    2. Absolute risk reduction
    3. Number needed to treat (or harm)
  • Pitfalls when making comparisons between cardiovascular outcomes trials, including the three most important questions
    1. Who was studied (risk profile)?
    2. What outcomes were assessed?
    3. Over what time period?
  • Additional factors to consider in the interpretation of findings from cardiovascular outcomes trials
    1. Evaluating the roles of chance, bias and confounding
    2. Factors affecting validity and generalizability
    3. Assessing the potential for type I and type II statistical errors

We expect that those who purchase these programs will find them informative and practical.  If you have suggestions for future programs, don’t hesitate to send us an email:


MB Clinical Academy