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

Serum Markers of Oxidative Stress to Assess Mortality Risk in Patients with Type 2 Diabetes

Serum Markers of Oxidative Stress to Assess Mortality Risk in Patients with Type 2 Diabetes

By Aly Becraft, MS and Kevin C Maki, PhD

Hyperglycemia is thought to result in increased reactive oxygen species (ROS) production and weakened antioxidant capacity,1 which can make patients with type 2 diabetes (T2D) susceptible to elevated oxidative stress. Current research relating diabetes complications and oxidative stress is lacking because ROS are difficult to measure directly;2 however, methods that indirectly quantify oxidative stress by measuring derivatives of reactive oxygen metabolites (d-ROMs) as a proxy for ROS production3 and total thiol levels (TTLs) as a proxy for reduction-oxidation (redox) status of blood4 are also available.

Xuan et al. recently published pooled results from two cohort studies in a meta-analysis to investigate the association of these oxidative stress biomarkers with incident major cardiovascular events, total cancer incidence, and cause-specific and all-cause mortality in patients with T2D.5 Diabetes sub-cohorts of the ESTHER and DIANA studies, conducted in Germany, were included. In the ongoing ESTHER cohort, to date, patient follow up visits have been conducted after 2, 5, 8, 11 and 14 years. Follow up in the DIANA study occurred after 4 and 7 years. For this meta-analysis, the 8-year follow-up data from the ESTHER cohort was used as baseline and the 11-year follow-up for repeated biomarker measurements. For the DIANA study, baseline and the 4-year follow-up data were used. Biomarker measurements were conducted on 1029 patients from the ESTHER cohort, of which 720 had repeated measurements. In the DIANA study, measurements of both biomarkers were performed for 1096 baseline study participants, and repeated measurement of d-ROMs was done for 738 participants.

In both cohorts, significantly increased d-ROMs levels were observed in females, current smokers, patients with T2D who had body mass index (BMI) ≥40 kg/m2, those not taking any antidiabetic medication, with insulin therapy, without lipid-lowering medication, with high total cholesterol levels, or with high C-reactive protein (CRP) levels. In addition, significantly lower TTLs in both cohorts were observed in females, alcohol abstainers, and patients with T2DM with BMI ≥40 kg/m2, without any antidiabetic medication, with insulin therapy, with antihypertensive therapy, with anticoagulant medication, with high CRP levels, with estimated glomerular filtration rate (eGFR), or with a history of myocardial infarction, heart failure, or hypertension. Both biomarkers were significantly associated with all-cause mortality in each of the cohorts; however, the associations with cancer mortality and major cardiovascular events were not statistically significant. Adjustment for disease and CRP concentration attenuated observed effect estimates. Subgroup analysis of all-cause mortality demonstrated strong associations with d-ROM levels among males and among patients with T2D with glycated hemoglobin <7%, age <70 years, BMI <30 kg/m2, and a history of coronary heart disease.


The results of this study support the notion that an imbalanced redox system may play a role in increasing premature mortality in patients with T2D. Other evidence supports such a role for oxidative stress,6-8 but it remains to be determined if oxidative stress is also involved in the development of cardiovascular disease and cancer in patients with T2D. Although this study was observational, and thus, the possibility of residual confounding cannot be disregarded, the results demonstrate the potential need for oxidative stress interventions in patients with T2D and illustrate the usefulness of using d-ROMs and TTLs as biomarkers to identify individuals with T2D who may be at increased risk for premature death.




  1. Dincer A, Onal S, Timur S, et al. Differentially displayed proteins as a tool for the development of type 2 diabetes. Ann Clin Biochem. 2009;46:306–310.


  1. Stephens JW, Khanolkar MP, Bain SC. The biological relevance and measurement of plasma markers of oxidative stress in diabetes and cardiovascular disease. Atherosclerosis. 2009;202:321–329.


  1. Kotani K, Sakane N. C-reactive protein and reactive oxygen metabolites in subjects with metabolic syndrome. J Int Med Res. 2012;40:1074–1081.


  1. Marrocco I, Altieri F, Peluso I. Measurement and clinical significance of biomarkers of oxidative stress in humans. Oxid Med Cell Longev. 2017;2017:6501046.


  1. Xuan Y, Gào X, Anusruti A, Holleczek B, Jansen EH, Muhlack DC, Brenner H, Schöttker B. Association of serum markers of oxidative stress with incident major cardiovascular events, cancer incidence and all-Cause mortality in type 2 diabetes patients: pooled results from two cohort studies. Diabetes Care. 2019;Epub ahead of print.


  1. Broedbaek K, Siersma V, Henriksen T, et al. Urinary markers of nucleic acid oxidation and long-term mortality of newly diagnosed type 2 diabetic patients. Diabetes Care. 2011;34:2594– 2596.


  1. Kjaer LK, Oellgaard J, Henriksen T, et al. Indicator of RNA oxidation in urine for the prediction of mortality in patients with type 2 diabetes and microalbuminuria: a post-hoc analysis of the Steno-2 trial. Free Radic Biol Med. 2018;129:247–255.


  1. Kjær LK, Cejvanovic V, Henriksen T, et al. Cardiovascular and all-cause mortality risk associated with urinary excretion of 8-oxoGuo, a biomarker for RNA oxidation, in patients with type 2 diabetes: a prospective cohort study. Diabetes Care. 2017;40:1771–1778.



Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

By Aly Becraft, MS and Kevin C Maki, PhD

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial was designed to assess the effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor, canagliflozin, on renal outcomes in patients with type 2 diabetes (T2D) and chronic kidney disease.1,2 This randomized, double-blind, placebo-controlled, multicenter clinical trial included patients of at least 30 years of age with an estimated glomerular filtration rate of 30 to <90 mL per minute per 1.73 m2 of body-surface area, albuminuria, and a glycated hemoglobin level of 6.5 to 12.0%. Patients were randomized to receive a 100 mg daily dose of canagliflozin or placebo added to renin-angiotensin-aldosterone blockade. The primary outcome was a composite of end stage renal disease (ESRD), doubling of the serum creatinine level for at least 30 days, or death from renal or cardiovascular (CV) disease. Secondary outcomes were tested hierarchically in the following order:

  1. composite of CV death or hospitalization for heart failure (HF)
  2. composite of CV death, myocardial infarction (MI) or stroke
  3. hospitalization for HF
  4. composite of ESRD, doubling of the serum creatinine level or renal death
  5. CV death
  6. death from any cause
  7. composite of CV death, MI, stroke, or hospitalization for HF or for unstable angina (UA)


The trial design was event driven; after a planned interim analysis, the trial was stopped early due to the requisite number of primary outcome events having been achieved. The final analysis included 4401 randomized patients and a median follow up time of 2.62 years. The results for the outcomes, including the hazard ratios (HR) and 95% confidence intervals (CI), are shown in the table below.





(n = 2202)


(n = 2199)


(95% CI)



Events/1000 patient-years


Primary composite outcome




(0.59, 0.82)


Secondary outcomes

  CV death or hospitalization for HF




(0.57, 0.83)


  CV death, MI or stroke




(0.67, 0.95)


  Hospitalization for HF




(0.47, 0.80)


  ESRD, doubling of serum creatinine level or renal death




(0.53, 0.81)


  CV death




(0.61, 1.00)




*No significant between-group difference in the risk of CV death was observed, so the differences in all subsequent outcomes in the hierarchical testing sequence were not formally tested.


Conclusion: Compared to placebo, canagliflozin lowered risk of kidney failure and CV events after a median follow-up of 2.62 years, supporting efficacy as a treatment option for renal and CV protection in patients with T2D and chronic kidney disease.


  1. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019; Epub ahead of print.
  2. Ingelfinger JR, Rosen CJ. Clinical credence – SGLT2 inhibitors, diabetes, and chronic kidney disease. N Engl J Med. 2019; Epub ahead of print.



Photo by Akash Deep

Oral Semaglutide versus Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes

Oral Semaglutide versus Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes

By Aly Becraft, MS and Kevin C Maki, PhD


The PIONEER3 trial was designed to compare the efficacy, long-term adverse event profile, and tolerability of an orally administered formulation of the glucagon-like peptide 1 receptor agonist (GLP-1RA), semaglutide, with the widely-used dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin, as an add on to metformin, with or without sulfonylurea, in patients with type 2 diabetes (T2D).1,2 This 78-week, phase 3a, randomized, double-blind, active-controlled, parallel-group trial included a total of 1864 patients with T2D and glycated hemoglobin (HbA1c) levels of 7.0% to 10.5%. Patients were randomized to receive either 3 mg/d (n = 466), 7 mg/d (n = 466), or 14 mg/d (n = 465) of semaglutide, or 100-mg/d sitagliptin (n = 467). The primary endpoint was change in HbA1c from baseline to week 26. The key secondary endpoint was change in body weight from baseline to week 26. Additional secondary endpoints included changes in HbA1c and body weight from baseline to weeks 52 and 78. The analysis evaluated both intention-to-treat and per-protocol samples.

Semaglutide at doses of 7 and 14 mg/d was found to be superior to sitagliptin for reducing HbA1c and body weight (see table, intention-to-treat results at week 26). Neither superiority nor non-inferiority with 3-mg/d semaglutide was demonstrated.


Estimated mean changes from baseline and estimated mean

(95% confidence interval) differences

from sitagliptin at week 26





100 mg/d

3 mg/d

7 mg/d

14 mg/d

 HbA1c, %





 Difference from sitagliptin

0.2 (0.0, 0.3)

-0.3 (-0.4, -0.1)

-0.5 (-0.6, -0.4)

 Body Weight, kg





 Difference from sitagliptin

-0.6 (-1.1, -0.1)

-1.6 (-2.0, -1.1)

-2.5 (-3.0, -2.0)


At week 78, significantly (p<0.05) greater reductions in HbA1c were observed with the semaglutide dosage of 14 mg/d versus sitagliptin in both intention-to-treat and per protocol samples (-0.4% and -0.7%, respectively), but semaglutide 7 mg/d was greater only in the per protocol sample (-0.3%). Significantly (p<0.05) greater body weight reductions were observed with all three dosages of semaglutide versus sitagliptin at week 78 (estimated mean differences of -0.8, -1.7 and -2.1 kg for 3, 7 and 14 mg/d of semaglutide). In addition, significant reductions in fasting plasma glucose and mean self-measured whole-blood glucose were greatest in the the14-mg/d semaglutide group at weeks 26 and 78 compared with sitagliptin.

The overall proportions of patients with at least one adverse event were similar across all treatment groups. However, a greater incidence of discontinuation due to adverse events was reported with 14 mg/d of semaglutide (11.6%), while 3- and 7-mg/d dosages (5.6% and 5.8%, respectively) had comparable incidences of discontinuation to sitagliptin (5.2%).  The primary cause of discontinuation in all treatment groups was gastrointestinal adverse events; for a substantial proportion of patients in the 7- and 14-mg/d semaglutide groups, the onset of the event leading to discontinuation occurred during the dose escalation period.

Conclusion: Compared to sitagliptin, oral semaglutide at 7 and 14 mg/d further reduced HbA1c and body weight over 26 weeks.


  1. Rosenstock J, Allison D, Birkenfeld AL, et al. Effect of additional oral semaglutide vs sitagliptin on glycated hemoglobin in adults with type 2 diabetes uncontrolled with metformin alone or with sulfonylurea: The PIONEER 3 randomized clinical trial. JAMA. 2019; Epub ahead of print.
  2. Hirsch IB. The future of the GLP-1 receptor agonists. JAMA. 2019;321:1457-1458.


Photo by David Clode

Effects of pioglitazone on risks for cardiovascular events and diabetes in patients with prediabetes and a history of stroke or transient ischemic attack

Effects of pioglitazone on risks for cardiovascular events and diabetes in patients with prediabetes and a history of stroke or transient ischemic attack

By Aly Becraft, MS and Kevin C Maki, PhD


Insulin resistance is an established risk factor for stroke and other adverse cardiovascular events.1,2 As many as 50% of patients with stroke or transient ischemic attack have insulin resistance without being classified as having diabetes.3 Furthermore, insulin resistance is associated with cardiovascular risk factors such as increased blood pressure, elevated levels of triglycerides and inflammatory markers and reduced high-density lipoprotein concentration.4 Pioglitazone is an insulin-sensitizing medication that works to lower insulin resistance by activating peroxisome proliferator-activated receptors (PPAR)-γ, and slightly activating PPAR-α, which have potential cardioprotective effects by promoting fatty acid uptake and oxidation.5-9 In the Insulin Resistance Intervention After Stroke (IRIS) trial, pioglitazone was shown to reduce the risk of stroke or myocardial infarction (MI) by 24% compared to placebo in patients with insulin resistance and a history of stroke or transient ischemic attack.10 Treatment with pioglitazone also reduced new-onset diabetes by half.10

Spence and colleagues published a post-hoc analysis of the IRIS trial to investigate the effect of pioglitazone in those patients with good adherence (taking ≥80% of the protocol dose over the duration of the study) and with prediabetes defined using the American Diabetes Association (ADA) definition.11 In the IRIS trial, patients were enrolled based on their homeostasis model assessment of insulin resistance (HOMA-IR) score,10 which is not routinely measured in clinical practice, whereas the ADA definition considers patients to have prediabetes if their glycated hemoglobin (HbA1c) level is 5.7-6.4% or fasting plasma glucose level is 100-125 mg/dL.  The primary outcome was recurrent fatal or nonfatal stroke or myocardial infarction. Secondary outcomes included stroke; acute coronary syndrome; the composite of stroke, MI, hospitalization for heart failure; and the progression to diabetes.

In the IRIS trial, patients were randomized to receive either 15 mg/d pioglitazone titrated up to a maximum dose of 45 mg/d, or a matched placebo. In this analysis, 2885 of the 3876 participants enrolled in the IRIS trial were classified as have prediabetes; 1456 were in the pioglitazone group and 1429 in the placebo group. Among these, 1454 were also classified as having good adherence; 644 were in the pioglitazone group and 810 were in the placebo group. Median follow-up time was 4.8 years.

In those patients with ADA-defined prediabetes and good adherence, the relative risk reductions (RRR) with pioglitazone vs. placebo were 40% for stroke + MI, 33% for stroke, 52% for acute coronary syndrome, and 38% for stroke + MI + hospitalization for heart failure. The relative risk for new-onset diabetes was also reduced by 80% for pioglitazone vs. placebo. Adverse events in the pioglitazone group included weight gain of ≥10% of body weight (29.8% vs. 12% in placebo group; p < 0.001), edema (29.2% vs. 21.6% in placebo group; p < 0.001), and serious bone fractures (3.6% vs. 2.8% in placebo group; p = 0.08). These adverse effects were also observed in the full IRIS trial analysis.12


Comment: An initial requirement of enrollment in the IRIS trial was HOMA-IR score ≥3; therefore, the findings from this trial can only be extended to patients with prediabetes that meet this criterion. That said, this post-hoc analysis provides evidence that patients with prediabetes and established stroke or transient ischemic attack have improved clinical outcomes when treated early, particularly when adherence to treatment is high. Edema was a large contributor to weight gain observed with pioglitazone treatment, which may be less with lower dosages than were used in this trial. For instance, a dose of 7.5 mg/d has been associated with low incidence of weight gain and edema.12 The IRIS investigators conclude that the benefit of pioglitazone treatment demonstrated in this and in the original analysis10 appear to outweigh the observed risks. Additional research is warranted to assess the effects of lower dosage pioglitazone therapy for cardiovascular risk reduction in a wider range of patients than were studied in IRIS.



  1. Kernan WN, Inzucchi SE, Viscoli CM, et al. Insulin resistance and risk for stroke. Neurology. 2002;59:809-815.
  2. Burchfiel CM, Curb JD, Rodriguez BL, Abbott RD, Chiu D, Yano K. Glucose intolerance and 22-year stroke incidence. The Honolulu Heart Program. Stroke. 1994;25:951-957
  3. Kernan WN, Inzucchi SE, Viscoli CM, et al. Impaired insulin sensitivity among nondiabetic patients with a recent TIA or ischemic stroke. Neurology. 2003;60:1447-1451.
  4. Semenkovich CF. Insulin resistance and atherosclerosis. J Clin Invest. 2006;116:1813-1822.
  5. Lee M, Saver JL, Liao HW, Lin CH, Ovbiagele B. Pioglitazone for secondary stroke prevention: a systematic review and meta-analysis. Stroke. 2017;48:388-393.
  6. Yki-Järvinen H. Thiazolidinediones. N Engl J Med. 2004;351:1106-1118.
  7. Spencer M, Yang L, Adu A, et al. Pioglitazone treatment reduces adipose tissue inflammation through reduction of mast cell and macrophage number and by improving vascularity. PLoS One. 2014;9:e102190.
  8. Zhang MD, Zhao XC, Zhang YH, et al. Plaque thrombosis is reduced by attenuating plaque inflammation with pioglitazone and is evaluated by fluorodeoxyglucose positron emission tomography. Cardiovasc Ther. 2015;33:118-126.
  9. Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med. 2002;53:409-435.
  10. Kernan WN, Viscoli CM, Furie KL, et al; IRIS Trial Investigators. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374:1321-1331.
  11. Spence JD, Viscoli CM, Inzucchi SE, Dearborn-Tomazos J, Ford GA, Gorman M, Furie KL, Lovejoy AM, Young LH, Kernan WN. Pioglitazone therapy in patients with stroke and prediabetes: a post hoc analysis of the IRIS randomized clinical trial. JAMA Neurol. 2019; Epub ahead of print.
  12. Adachi H, Katsuyama H, Yanai H. The low dose (7.5 mg/day) pioglitazone is beneficial to the improvement in metabolic parameters without weight gain and an increase of risk for heart failure. Int J Cardiol. 2017;227:247-248.
Photo by Louis Reed

Bempedoic acid in conjunction with statin therapy for dyslipidemia management

Bempedoic acid in conjunction with statin therapy for dyslipidemia management

By Aly Becraft, MS; Kevin C. Maki, PhD

Use of statins to reduce risk of cardiovascular disease is an effective treatment strategy,1 but the statin doses required to adequately reduce low density lipoprotein cholesterol (LDL-C) and non-high-density-lipoprotein cholesterol (non-HDL-C) levels and achieve optimal cardiovascular disease risk reduction are not well tolerated by some patients, and even maximal statin therapy may be inadequate to achieve sufficient cholesterol-lowering in some patients.2-8  Bempedoic acid is a promising prodrug that may be useful as an adjunct therapy to stains for lowering LDL-C. Its activation is reliant on very-long-chain acyl-CoA synthetase 1, which is present in the liver, but absent from most other tissues.8 Once activated, it is thought to act via the same cholesterol biosynthesis pathway as statins; however, its target, ATP citrate lyase (ACL), is further upstream in the pathway than the target for statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase.8 The liver specific activation of bempedoic acid differentiates it from statins. Because muscle cells do not express the activating enzyme for bempedoic acid, it is less likely to have skeletal muscle-related side effects.  This makes it an attractive adjunct therapy to statins since the most commonly reported side effects with statins include myalgias and other muscle-related complaints.8 Bempedoic acid has also been studied in combination with ezetimibe in patients with and without statin intolerance.9,10 It was shown to reduce LDL-C more than ezetimibe alone, and to have a similar tolerability profile. In a trial of patients with a history of statin intolerance and LDL-C ≥100 mg/dL, bempedoic acid added to background lipid-modifying therapy that included ezetimibe reduced LDL-C by 28.5% more than the addition of placebo (p < 0.001).10 Until recently, the efficacy and safety of bempedoic acid had been evaluated in relatively small groups and in trials of short duration.9-13

Ray et al.14 published results from the Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Harmony trial. This 52-week, randomized, double-blind, placebo-controlled trial evaluated the safety and efficacy of bempedoic acid for reducing LDL-C. In this phase 3, parallel group trial, a total of 2230 patients were enrolled; 1488 were assigned to receive bempedoic acid and 742 received a placebo. Patients qualified for the study if they had either atherosclerotic cardiovascular disease (97.6% of subjects) or heterozygous familial hypercholesterolemia (3.5% of subjects), were taking stable doses of maximally tolerated statin therapy, and had fasting LDL-C levels of at least 70 mg/dL (mean ± standard deviation 103.2 ± 29.4 mg/dL) . The primary end points were safety-related, including incidence of adverse events and changes in laboratory variables. Secondary end points included changes from baseline to 12 weeks in LDL-C, non-HDL-C, total cholesterol, apolipoprotein B and high-sensitivity C-reactive protein.

Of the enrolled patients, 78.1% completed the intervention and 94.6% continued the trial through week 52, providing a total of 1248 patient-years of exposure to bempedoic acid. Adverse events were reported in approximately 79% of both treatment groups, with a majority of events (>80%) graded as mild to moderate in severity. Common adverse event incidence and major adverse events occurred with similar frequency in both groups; however, the number of patients who discontinued treatment due to adverse events was higher in the bempedoic acid group compared to the placebo group (10.9% vs 7.1%; p = 0.005). Incidence of gout in the bempedoic acid group was modestly increased compared to placebo (1.3% vs 0.3%; p = 0.03). Interestingly, the incidence of new-onset diabetes or worsening diabetes was lower among subjects receiving bempedoic acid compared to placebo (3.3% vs. 5.4%; p = 0.02), although the total number of events was low.

Treatment with bempedoic acid significantly (p < 0.001) reduced LDL-C levels compared to placebo at week 12 (18.1% from baseline) and week 24 (16.1% from baseline). All other measured cardiometabolic risk factors were also significantly reduced (p < 0.001 for all comparisons) from baseline at week 12 with bempedoic acid compared to placebo. The effects of bempedoic acid were sustained with minimal attenuation through the end of the trial (week 52). Efficacy was observed to be greater among women than men (p = 0.03) but was not significantly different across other subgroups, including type or intensity of background lipid-lowering therapy.

Comment: The present trial provides evidence for the safe and efficacious longer term (1-year) , use of bempedoic acid as an adjunct therapy to statins. Although discontinuation of the trial was higher among subjects in the bempedoic acid group, adverse events appeared to occur at similar frequency in both groups. Increased gout occurrence with the bempedoic acid treatment may be related to metabolite competition with uric acid for renal transporters involved in their excretion14 and the incidence of gout in this trial was modest.

Compared to placebo, use of bempedoic acid in conjunction with statin therapy modestly reduced the levels of LDL-C and other lipoprotein lipid and biomarker levels from baseline to week 12 and throughout the remainder of the 52-week trial. Bempedoic acid works via the same cholesterol synthesis pathway as statins;8 however, doubling statin dosage reduces LDL-C levels by ~6%,15 less than half of the reported effect from the present trial. Furthermore, bempedoic acid treatment did not appear to cause or exacerbate skeletal muscle-related side effects associated with statin use, further signifying its efficacy and tolerability as a prospective statin adjunct. Of note, the trial population was predominantly white (~96%), and more racial diversity is needed in future evaluations of bempedoic acid safety and efficacy. In addition, 73% of patients were male; therefore, the present findings of greater treatment efficacy in women should also be explored in future studies with a greater proportion of women subjects.

In February 2019, the manufacturer, Esperion Therapeutics, Inc. (Ann Arbor, MI), submitted two New Drug Applications to the US Food and Drug Administration for approval of bempedoic acid and a bempedoic acid/ezetimibe combination tablet as once daily oral therapies for the treatment of patients with elevated LDL-C who need additional LDL-C lowering despite the use of currently accessible therapies. Esperion expects to receive notification on whether the submissions have been accepted for review in May of 2019.


  1. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980–2000. N Engl J Med. 2007;356:2388-98.
  2. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504.
  3. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res. 2016;118:547–563.
  4. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:Suppl 2:S1-S45.
  5. Jacobson TA, Ito MK, Maki KC, et al. National lipid association recommendations for patient-centered management of dyslipidemia: full report. J Clin Lipidol. 2015;9:129-69.
  6. Danese MD, Gleeson M, Kutikova L, et al. Management of lipid-lowering therapy in patients with cardiovascular events in the UK: a retrospective cohort study. BMJ Open. 2017;7:e013851.
  7. Steen DL, Khan I, Ansell D, Sanchez RJ, Ray KK. Retrospective examination of lipid-lowering treatment patterns in a real world high-risk cohort in the UK in 2014: comparison with the National Institute for Health and Care Excellence (NICE) 2014 lipid modification guidelines. BMJ Open. 2017;7:e013255.
  8. Pinkosky SL, Newton RS, Day EA, et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun. 2016;7:13457.
  9. Thompson PD, MacDougall DE, Newton RS, et al. Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance. J Clin Lipidol. 2016;10:556-67.
  10. Ballantyne CM, Banach M, Mancini GBJ, et al. Efficacy and safety of bempedoic acid added to ezetimibe in statin intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study. Atherosclerosis. 2018;277:195-203.
  11. Ballantyne CM, Davidson MH, Macdougall DE, et al. Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. J Am Coll Cardiol. 2013;62:1154-62.
  12. Thompson PD, Rubino J, Janik MJ, et al. Use of ETC-1002 to treat hypercholesterolemia in patients with statin intolerance. J Clin Lipidol. 2015;9:295-304.
  13. Ballantyne CM, McKenney JM, MacDougall DE, et al. Effect of ETC-1002 on serum low-density lipoprotein cholesterol in hypercholesterolemic patients receiving statin therapy. Am J Cardiol. 2016;117:1928-33.
  14. Ray KK, Bays HE, Catapano AL, Lalwani ND, Bloedon LT, Sterling LR, Robinson PL, Ballantyne CM. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med. 2019;380:1022-32.
  15. Nicholls SJ, Brandrup-Wognsen G, Palmer M, Barter PJ. Meta-analysis of comparative efficacy of increasing dose of atorvastatin versus rosuvastatin versus simvastatin on lowering levels of atherogenic lipids (from VOYAGER). Am J Cardiol. 2010;105:69-76.
Photo by Louis Reed

The Effects of Icosapent Ethyl on Total Ischemic Events: An Analysis from REDUCE-IT

The Effects of Icosapent Ethyl on Total Ischemic Events: An Analysis from REDUCE-IT

By Aly Becraft, MS and Kevin C Maki, PhD


Statin therapy is highly effective for lowering low-density lipoprotein cholesterol (LDL-C), but many patients remain at risk for ischemic events, despite statin therapy.1 Elevated levels of triglycerides (TG) and TG-rich lipoproteins are independent risk factors for cardiovascular events and may play a casual role in the development of cardiovascular disease.2


Icosapent ethyl (VascepaÒ) is a highly purified derivative of EPA that is currently approved by the Food and Drug Administration for use as an adjunctive therapy in the treatment of hypertriglyceridemia in patients with TG levels ≥500 mg/dL.3 It has been shown to lower TG levels without raising LDL-C4,5 and may have anti-inflammatory, antioxidative, plaque-stabilizing, and membrane-stabilizing properties.6-9


Earlier this year, Bhatt et al. published results from the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) indicating that icosapent ethyl reduced risk for the first occurrence of the primary endpoint (composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization or hospitalization for unstable angina) by 25% in patients with elevated TG levels (≥500 mg/dL) receiving statin therapy during a median follow-up of 4.9 y.3 In this randomized, double-blind, placebo-controlled trial, a total of 8,179 statin-treated patients were given 4 g/day icosapent ethyl or a mineral oil-based placebo with meals. At baseline, patients had a median TG level of 216 mg/dL and a median LDL-C of 75 mg/dL. Seventy-nine percent of patients had history of atherosclerosis and 29% had a history of diabetes.


Recently, the REDUCE-IT investigators sought to determine the effect of icosapent ethyl on total ischemic events in the trial.10 For this analysis, the primary outcome was the total of first plus subsequent ischemic events (defined the same as for the primary outcome in the main analysis).  There were 1,606 first primary endpoint events and 1,303 additional primary endpoint events (727 second events, 272 third events, and 269 fourth or more events). Total ischemic event rate for the primary outcome was reduced by 30% with icosapent ethyl compared to placebo (rate ratio [RR] 0.70, 95% confidence interval [CI] 0.62-0.78, P < 0.0001). First events were reduced by 25%, second events by 32%, third events by 31%, and fourth or more events by 48%. The key secondary endpoint, defined for this analysis as hard major adverse cardiac outcome (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke), was also significantly reduced with icosapent ethyl compared to placebo (RR 0.72, 95% CI 0.63-0.82, P < 0.0001). Several statistical models were used, and each demonstrated consistent effects of icosapent ethyl for reducing total ischemic events.


Comment: The results from this analysis demonstrate the benefit of icosapent ethyl as a therapy for the reduction of first and subsequent ischemic events in statin-treated patients. The present analysis of REDUCE-IT included patients from 11 different countries, yielding more conclusive outcomes for cardiovascular benefit than for interventions conducted in single countries.11-13


The efficacy of icosapent ethyl was numerically larger for second and higher events, which illustrates two important points.  First, those who have had a recent cardiovascular event are at high risk for subsequent events.  Second, the traditional analysis method of focusing only on first events markedly underestimates the impact of cardiovascular disease and often the benefit of the therapy under study.  Related to the second point, cost effectiveness analyses generally only consider first event reduction and may therefore underestimate cost effectiveness. 


Future analyses of biomarkers collected from REDUCE-IT patients may provide further insight into the mechanisms of action of icosapent ethyl and help to better explain the mechanisms responsible for the effects and identify additional potential clinical applications for this new therapy.



  1. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504.
  2. Nordestgaard BG . Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res. 2016;118:547-63.
  3. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22.
  4. Bays HE, Ballantyne CM, Kastelein JJ, et al. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] trial). Am J Cardiol. 2011;108:682-90.
  5. Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012;110:984-92.
  6. Bays HE, Ballantyne CM, Braeckman RA, et al. Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies. Am J Cardiovasc Drugs. 2013;13:37-46.
  7. Nelson JR, Wani O, May HT, Budoff M. Potential benefits of eicosapentaenoic acid on atherosclerotic plaques. Vascul Pharmacol. 2017;91:1-9.
  8. Mason RP, Jacob RF, Shrivastava S, et al. Eicosapentaenoic acid reduces membrane fluidity, inhibits cholesterol domain formation, and normalizes bilayer width in atherosclerotic-like model membranes. Biochim Biophys Acta. 2016;1858:3131-40.
  9. Sherratt SCR, Mason RP. Eicosapentaenoic acid and docosahexaenoic acid have distinct membrane locations and lipid interactions as determined by X-ray diffraction. Chem Phys Lipids. 2018;212:73-9.
  10. Bhatt DL, Steg PG, Miller M, et al.; REDUCE-IT Investigators. Effects of icosapent ethyl on total ischemic events: from REDUCE-IT. J Am Coll Cardiol. 2019; Epub ahead of print.
  11. Yokoyama M, Origasa H, Matsuzaki M, et al.; JELIS Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis [published correction appears in Lancet. 2007;370:220]. Lancet. 2007;369:1090-8.
  12. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico [published corrections appear in Lancet. 2001;357:642 and 2007;369:106]. Lancet. 1999;354:447-55.
  13. Tavazzi L, Maggioni AP, Marchioli R, et al.; GISSI-HF Investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:1223-30.





Photo by Kendal James

C-Reactive Protein Levels and Cardiovascular Events after Acute Coronary Syndrome: Results from a Secondary Analysis of the VISTA-16 Trial

C-Reactive Protein Levels and Cardiovascular Events after Acute Coronary Syndrome: Results from a Secondary Analysis of the VISTA-16 Trial

By Aly Becraft, MS; Kevin C Maki, PhD


Each year approximately 29% of heart attack (myocardial infarction) events in the USA occur in people who have previously had a heart attack.1 Even with ideal medical interventions and treatments, there is high risk of subsequent cardiac events and death in people that have suffered an acute coronary syndrome (ACS).2,3 This elevated risk may be lowered if specific biomarkers associated with future adverse cardiac events can be identified and used in long-term management following ACS. Several biomarkers of cardiovascular disease (CVD) are currently being studied, including those related to inflammation, a major contributor to the development of atherothrombosis. Well-studied inflammatory biomarkers include fibrinogen, monocyte chemotactic protein-1, tumor necrosis factor-alpha, C-reactive protein (CRP), and others.4

High-sensitivity CRP (hsCRP) measurement has become a routine and effective method for predicting risk of CVD and is also used as a prognostic marker after ACS.5 Lowered hsCRP levels in patients with chronic CVD treated with anti-inflammatory and statin therapies has been shown to improve treatment outcomes and lower risk of adverse cardiovascular events.3,6 Furthermore, other studies have reported a correlation between CRP levels and the effectiveness of statin treatment7,8 and high-dose statins have been demonstrated to accelerate decreases in hsCRP levels after ACS.9,10 While there is a substantial body of research demonstrating these associations, in order to optimize clinical use, the applications for hsCRP levels in the treatment of CVD are still being investigated.


Mani et al. recently published a secondary analysis of the Vascular Inflammation Suppression to Treat Acute Coronary Syndromes for 16 Weeks (VISTA-16) trial to assess whether longitudinal changes in hsCRP levels were associated with residual risk of cardiovascular events or death following ACS.11 This randomized, double blind, multicenter trial tested treatment of ACS with the secretory phospholipase A2 inhibitor, varespladib, in 5145 patients. Treatment began within 96 hours of an ACS. Only patients with qualifying baseline and longitudinal hsCRP levels measured at weeks 1, 2, 4, 8, and 16 weeks of the trial were used in this secondary analysis (n = 4257). The primary end point of this analysis was the association between hsCRP and a major adverse cardiac event (MACE) defined as the composite of cardiovascular death, non-fatal myocardial infarction, stroke, or hospitalization for unstable angina at 16 weeks. Secondary end points included the associations between hsCRP and individual components of the primary composite end point.11 The trial treatment had no significant effects on hsCRP level.


Analyzed patients were overweight, had a mean age of 60.3 years and 74% were male.11 Approximately 77% of the patients had hypertension, 51% had hypercholesterolemia and 65% had metabolic syndrome. In addition, 30% of patients had experienced a previous myocardial infarction, 18% had undergone percutaneous coronary intervention, and 36% of patients were using lipid-modifying therapy prior to the trial.


Of the 247 events observed in the VISTA-16 trial, 145 were included in this analysis.11 Baseline hsCRP levels following ACS were associated with higher risk for future MACE and death, as had been shown previously. Longitudinal increases in hsCRP levels were associated with significantly higher incidence of MACE [hazard ratio (HR) per SD 1.16, P < 0.001], myocardial infarction (HR 1.16, P < 0.001), all-cause death (HR 1.25, P < 0.001), and cardiovascular death (HR 1.26, P < 0.001). These relationships were not attenuated in multivariate models that adjusted for several other predictive variables and treatment assignment.  Positive associations between changes in longitudinal hsCRP levels and age (P = 0.03), body mass index (P < 0.001), hypertension (P < 0.001), congestive heart failure (P < 0.001), and active smoking (P = 0.003) were reported. 


Comment: These results suggest that measuring longitudinal changes in hsCRP levels after ACS is useful for assessing residual cardiovascular risk.  Higher baseline hsCRP after ACS and persistent hsCRP elevation were both independently associated with increased risks for MACE and individual MACE components, as well as CVD and total mortality.  Each SD increase in hsCRP during follow-up was associated with an increase of 15% in MACE, 25% in total mortality and 26% in CVD mortality.


The present study adds to previous findings, such as those from the Canakinumab Antiinflammatory Thrombosis Outcome Study,12 which demonstrated similar associations between higher hsCRP levels and adverse cardiovascular outcomes and mortality and further showed that an anti-inflammatory intervention reduced MACE risk. Similarly, results from epidemiological studies have suggested that increases in serial measurement of CRP in relatively healthy populations are associated with adverse cardiovascular outcomes and increased mortality.13,14 Further study is needed to evaluate longer-term outcomes and to assess the efficacy of various treatment modalities to lower MACE and mortality incidence in those identified as having elevated residual risk after ACS due to persistent hsCRP elevation.



  1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131:e29-322
  2. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285(13):1711-1718.
  3. Cannon CP, Braunwald E, McCabe CH, et al. Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495-1504.
  4. Dhingra R, Vasan RS. Biomarkers in cardiovascular disease: statistical assessment and section on key novel heart failure biomarkers. Trends Cardiovasc Med. 2017;27(2):123-133.
  5. Ridker PM. Inflammation in atherothrombosis: how to use high-sensitivity C-reactive protein (hsCRP) in clinical practice. Am Heart Hosp J. 2004;2(4 Suppl 1):4-9.
  6. Ridker PM, Everett BM, Thuren T, et al. CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119-1131.
  7. Ridker PM, Rifai N, Clearfield M, et al. Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001;344(26):1959-1965.
  8. Ridker PM, Cannon CP, Morrow D, et al. Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352(1):20-28.
  9. Kinlay S, Schwartz GG, Olsson AG, et al. Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Study Investigators. High-dose atorvastatin enhances the decline ininflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation. 2003;108(13):1560-1566.
  1. Macin SM, Perna ER, Farías EF, et al. Atorvastatin has an important acute anti-inflammatory effect in patients with acute coronary syndrome: results of a randomized, double-blind, placebo-controlled study. Am Heart J. 2005;149(3):451-457.
  2. Mani P, Puri R, Schwartz GG, et al. Association of initial and serial C-reactive protein levels with adverse cardiovascular events and death after acute coronary syndrome: a secondary analysis of the VISTA-16 trial. JAMA Cardiol. 2019;Epub ahead of print.
  3. Ridker PM, MacFadyen JG, Everett BM, et al. CANTOS Trial Group. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet. 2018;391(10118):319-328.
  4. Currie CJ, Poole CD, Conway P. Evaluation of the association between the first observation and the longitudinal change in C-reactive protein, and all-cause mortality. Heart. 2008;94(4):457-462.
  5. Parrinello CM, Lutsey PL, Ballantyne CM, et al. Six-year change in high-sensitivity C-reactive protein and risk of diabetes, cardiovascular disease, and mortality. Am Heart J. 2015;170(2):380-389.


Photo by Lucas Vasques

New Trial Suggests Light Therapy may be a Promising Intervention for Treatment of Depression with Type 2 Diabetes

New Trial Suggests Light Therapy may be a Promising Intervention for Treatment of Depression with Type 2 Diabetes

By Aly Becraft, MS; Kevin C Maki, PhD

One in 11 adults have diabetes worldwide,1 with an estimated 25% of people with diabetes also suffering from depression.2 Co-occurrence of these diseases has been shown to increase risk for diabetes complications,3 potentially due to a lack of motivation to properly manage the disease.4,5 Therefore, people with diabetes and depression need effective therapies for both conditions in order to remain properly treated.

Often, depression simultaneously occurs with impaired sleep, leading to biological rhythm disturbances.6 While pharmacological interventions can be successful, some antidepressant drugs may have unfavorable effects on glycemic control in people with type 2 diabetes (T2D).7 Light therapy is an alternative or adjunctive treatment for depression with minimal side effects.8 It is thought to act by modifying the phase relationships between the biological clock and the light-dark cycle to restore appropriate sleep-wake cycles9 and has proven effective for treating seasonal depression (seasonal affective disorder) as well as some cases of non-seasonal depression.10-12 In 2017, an estimated 12% of global health expenditures were spent on diabetes,1 thus, if efficacy can demonstrated, light therapy would be a cost-effective treatment for T2D patients suffering from depression. In addition to altering mood states, sleep deficiency may also be related to changes in glucose metabolism and decreased insulin sensitivity.13 Previous studies have reported that partial sleep deprivation induced insulin resistance in healthy subjects and patients with type 1 diabetes.13-15 Therefore, the restoration of biological rhythmicity in individuals with impaired sleep may have the potential to improve glucose regulation.

Brouwer et al., (2019) report results from a randomized, double-blind, placebo-controlled trial which was published in Diabetes Care and investigated whether mood and insulin sensitivity could be improved via light therapy in clinically depressed patients with T2D.16 In this parallel-arm study, a total of 79 adults with depression and T2D were included in the outcome measures. Forty received light therapy (broad-spectrum, white-yellow light, 10,000 lux), while 39 received placebo therapy (monochromatic green light, 470 lux). Light therapy was provided in the homes of participants over 4 weeks for 30 minutes each morning. Participants were assessed for changes in depressive symptoms, and a subset of participants who agreed to hyperinsulinemic-euglycemic clamp (HEC) procedure were evaluated for insulin sensitivity. Both measures were assessed at baseline and after the 4-week intervention. Several secondary measures were also evaluated including anxiety symptoms, diabetes stress, self-reported insomnia, objective sleep duration, sleep efficiency, and mid-sleep time, as well as glycated hemoglobin (HbA1C) levels, fasting blood glucose, self-reported hypo-glycemic events and body weight.

After the intervention, light therapy did not significantly reduce depressive symptoms, and similarly, had no effect on insulin sensitivity in the primary analysis. However, per-protocol analyses were conducted to exclude 13 participants that changed glucose-lowering medication during the protocol, which resulted in 51 remaining participants.  In the per-protocol analysis, participants had a 26% greater reduction in depressive symptoms in response to light therapy (P=0.031). In addition, subgroup analysis suggested that patients with higher insulin resistance responded positively to light therapy (P=0.017), and there was a trend toward positive response in patients using insulin vs non-insulin glucose lowering medication (P=0.094). No significant differences in secondary measures were found between the treatment and placebo groups.

Comment.  Overall, the results of this study were inconclusive, but the per-protocol analysis was suggestive of improvements in depressive symptoms, which is a hypothesis-generating finding that should be investigated in additional research. Furthermore, the reduction in depressive symptoms observed in patients with higher insulin resistance may indicate greater efficacy of light therapy in this subset. A similar observation by Dimitrova et al., (2017) suggested that higher BMI, a factor strongly associated with insulin resistance, may be a baseline predictor for light therapy response in patients with seasonal depression.17 Although improvements in insulin sensitivity have been previously demonstrated in two case studies in response to light therapy,18,19 this effect was not established in the present study. This study shows potential for light therapy as a treatment for depression with T2D, but more research is needed with larger samples, longer duration of therapy and/or greater daily light exposure to more fully evaluate the effects of this therapy.



  1. Cho NH, Shaw JE, Karuranga S, et al. International Diabetes Federation (IDF) diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. DiabetesRes Clin Pract. 2018;138:271-281.
  2. Goldney RD, Phillips PJ, Fisher LJ, Wilson DH. Diabetes, depression, and quality of life: a population study. Diabetes Care. 2004;27(5):1066-1070.
  3. Petrak F, Baumeister H, Skinner TC, et al. Depression and diabetes: treatment and health-care delivery. Lancet Diabetes Endocrinol. 2015;3:472-485.
  4. Gonzalez JS, Peyrot M, McCarl LA, et al. Depression and diabetes treatment nonadherence: a meta-analysis. Diabetes Care. 2008;31:2398-2403.
  5. Lin EH, Katon W, Von Korff M, et al. Relationship of depression and diabetes self-care, medication adherence, and preventive care. Diabetes Care. 2004;27:2154-2160.
  6. van Mill JG, Hoogendijk WJ, Vogelzangs N, et al. Insomnia and sleep duration in a large cohort of patients with major depressive disorder and anxiety disorders. J Clin Psychiatry. 2010;71:239-246.
  7. Deuschle M. Effects of antidepressants on glucose metabolism and diabetes mellitus type 2 in adults. Curr Opin Psychiatry. 2013;26:60-65.
  8. Wirz-Justice A, Benedetti F, Terman M. Chronotherapeutics for affective disorders: a clinician's manual for light and wake therapy, 2nd. Karger Medical and Scientific Publishers. 2013.
  9. Wirz-Justice A. Biological rhythm disturbances in mood disorders. Int Clin 2006;21:S11-5.
  10. Tuunainen A, Kripke DF, Endo T. Light therapy for non-seasonal depression. Cochrane Database Syst Rev. 2004;(2):CD004050.
  11. Perera S, Eisen R, Bhatt M, et al. Light therapy for non-seasonal depression: systematic review and meta-analysis. BJPsych Open. 2016;2:116-126.
  12. Mårtensson B, Pettersson A, Berglund L, Ekselius L. Bright white light therapy in depression: a critical review of the evidence. J Affect Disord. 2015;182:1-7.
  13. Spiegel K, Tasali E, Leproult R, Van Cauter E. Effects of poor and short sleep on glucose metabolism and obesity risk. Nat Rev Endocrinol. 2009;5(5):253.
  14. Donga E, van Dijk M, van Dijk JG, et al. A single night of partial sleep deprivation induces insulin resistance in multiple metabolic pathways in healthy subjects. J Clin Endocrinol Metab. 2010;95(6):2963-2968.
  15. Donga E, van Dijk M, van Dijk JG, et al. Partial sleep restriction decreases insulin sensitivity in type 1 diabetes. Diabetes Care. 2010;33:1573-1577.
  16. Brouwer A, Nguyen HT, Rutters F, et al. Effects of light therapy on mood and insulin sensitivity in patients with type 2 diabetes and depression: results from a randomized placebo-controlled trial. Diabetes Care. 2019.
  17. Dimitrova TD, Reeves GM, Snitker S, et al. Prediction of outcome of bright light treatment in patients with seasonal affective disorder: discarding the early response, confirming a higher atypical balance, and uncovering a higher body mass index at baseline as predictors of endpoint outcome. J Affect Disord. 2017;222: 126-132.
  18. Nieuwenhuis RF, Spooren PF, Tilanus JJ. Less need for insulin, a surprising effect of phototherapy in insulin-dependent diabetes mellitus. Tijdschr Psychiatr. 2009;51:693-697.
  19. Allen NH, Kerr D, Smythe PJ, et al. Insulin sensitivity after phototherapy for seasonal affective disorder. Lancet. 1992;339:1065-1066.



Photo by Duy Hoang