Zolpidem increased cancer risk in patients with sleep disorder: A 3-year follow-up study


  Abstract

Background: Zolpidem has been increasingly used in patients with sleep disorder due to its minimal respiratory depressor effects and short half-life. Materials and Methods: Recent case reports indicate that zolpidem usage may be associated with increased cancer mortality. This study aimed to determine the impact of zolpidem usage on the risk of incident cancer events in sleep disorder patients over a 3-year follow-up. Of the 6924 subjects diagnosed with sleep disorder in 2004, 1728 had used zolpidem. A Cox proportional hazard model was performed to estimate 3-year cancer event-free survival rates for patients using zolpidem and those not using it, after adjusting for confounding and risk factors. Results: At the end of follow-up, 56 patients had incident cancers, 26 (1.5%) who used zolpidem, and 30 (0.6%) who did not. After adjustments for gender, age, comorbidities, and other medications, patients using zolpidem had a 1.75 times (95% confidence interval [CI], 1.02–3) greater risk of cancer events than those not using zolpidem during the 3-year follow-up. Greater mean daily dose and longer use were associated with increased risk. Among patients with sleep disorder, mean daily dose >10 mg and length of drug use >2 months was associated with 3.74 times greater risk (95% CI, 1.42–9.83; P = 0.008) of incident cancer events. Conclusions: In this study, zolpidem use increased cancer events risk in sleep disorder patients. Risks and benefits of chronic zolpidem usage should be explained to sleep disorder patients, and long-term use should be monitored.

Keywords: Cancer, hazard ratios, mean daily dose, sleep disorder, zolpidem

 

How to cite this article:
Lin SC, Su YC, Huang YS, Lee CC. Zolpidem increased cancer risk in patients with sleep disorder: A 3-year follow-up study. J Med Sci 2016;36:68-74

 

How to cite this URL:
Lin SC, Su YC, Huang YS, Lee CC. Zolpidem increased cancer risk in patients with sleep disorder: A 3-year follow-up study. J Med Sci [serial online] 2016 [cited 2018 Dec 15];36:68-74. Available from: http://www.jmedscindmc.com/text.asp?2016/36/2/68/181522

 

  Introduction Top

The clinical use of sedatives or hypnotics has increased gradually so that a 53% growth in prescriptions over 5 years was reported in 2006.[1] Some 6–10% of US adults have used hypnotics, and the percentage is higher in Europe.[2] The most commonly prescribed medications are benzodiazepines, nonbenzodiazepines, gamma-aminobutyric acid (GABA) agonists, melatonin receptor agonists, sedating antidepressants, antihistamines, and wake-promoting drugs.[3] However, the potential side effects of hypnotics, such as cancer risk, may be overlooked.

Zolpidem, an imidazopyridine in use since 1980, has been increasingly used in patients with sleep disorder due to its very few respiratory depressor effects and short half-life of 2.5 h.[4],[5] Of the 8607 patients who reported side effects of zolpidem on the eHealthMe website, which continuously monitor drug adverse effects, 71 (i.e. 0.82%) reported incident cancer.[6] Previous studies reported an association of hypnotics and cancer death.[7],[8],[9] However, in these studies, neither the specific hypnotic drug nor the quantity was provided. Furthermore, zolpidem was not included in these series. Recently, Kripke et al. conducted a matched cohort study and found that taking hypnotics, either zolpidem or temazepam, was associated with increased cancer risk in rural US patients.[10] The main limitation of this study was its stratification of hypnotic drug dosage in three equivalent groups to validate the dose-response relationship; however, such stratification is not practical in terms of clinical use.

The critical dosage and length of use at which zolpidem will affect the development of incident cancer events in patients with sleep disorder have not clearly explored. The goals of the current study are (1) to determine the relative risk of incident cancer events associated with zolpidem use in sleep disorder patients using a population-based dataset and (2) to provide the critical dosage and length of zolpidem usage associated with increased cancer risk.

  Materials and Methods Top

Ethics statement

This study was initiated after approval by the Institutional Review Board of Buddhist Dalin Tzu Chi General Hospital, Taiwan. Since all identifying personal information was stripped from the secondary files before analysis, the review board waived the requirement for written informed consent from the patients involved.

Database

The National Health Insurance Program, which provides compulsory universal health insurance, was implemented in Taiwan in 1995. It enrolls up to 99% of the Taiwanese population and contracts with 97% of all medical providers. The resulting database contains comprehensive information on insured subjects including dates of clinical visits, diagnostic codes, details of prescriptions, and expenditure amounts. This study used the Longitudinal Health Insurance Dataset for 2004–2006 released by the Taiwan Nation Health Research Institute. The patients studied did not differ statistically significantly from the general population in age, gender, or health care costs, as reported by the Taiwan National Health Research Institute (www. nhri.org.tw).

Study population

All patient records in the dataset between January 1, 2002, and December 31, 2002, with sleep disorder diagnostic codes (International Classification of Diseases, 9th revision-Clinical Modification [ICD-9-CM] 780.5x) from an urban area were included in the study.[11],[12] Excluded were those with any type of cancer (ICD-9-CM codes 140-208) diagnosed before or during the index ambulatory visit.

Identification of study cohort

A total of 6924 sleep disorder patients were identified. Each patient was tracked for 3 years from his or her index ambulatory visit in 2002 to identify outcomes, including any type of incident cancer (ICD-9-CM 140-208). To maximize case ascertainment, only patients verified by also being in cancer and catastrophic illness patient database were included in the study. These patients were then linked to the administrative data for the period 2002–2004 to calculate cancer disease-free survival time, with cases censored for patients who withdrew coverage from the National Health Insurance Program or were still robust without defined events at the end of follow-up.

Definition of exposure and covariate adjustment

The main exposure of interest was zolpidem. The dosage, date of prescription, supply days, and a total number of pills dispensed were obtained from the outpatient pharmacy prescription database. The mean daily dose was estimated by dividing the cumulative number of pills prescribed by the follow-up time from the date of initiating zolpidem treatment to the date of incident cancer, date of stopping medicine, or end of this follow-up study. The defined daily dose (DDD) was 10 mg for zolpidem. Other medications included in analysis were antihypertensives (i.e. propranolol, terazosin, doxazosin, prazosin, atenolol, furosemide, nifedipine, verapamil, diltiazem, isosorbide dinitrate, lisinopril, amitriptyline, chlorpromazine, or prochlorperazine), psychotropic agents (i.e. diazepam, alprazolam, or haloperidol), oral hypoglycemic agents, and insulin. Information on patients’ age, gender, comorbidities, and monthly income level as a proxy of socioeconomic status (SES) were collected. The comorbidities for each patient was based on the modified Charlson comorbidity index score, a widely used measure for risk adjustment in administrative claims data sets.[13]

Statistical analysis

The SAS statistical package, version 9.2 (SAS Institute, Inc., Cary, NC), and SPSS version 15 (SPSS Inc., Chicago, IL, USA) were used for data analysis. Pearson’s Chi-square test was used for categorical variables, demographic characteristics (age group and gender), comorbidities, and medications.

The 3-year cancer event-free survival rate was estimated using the Kaplan–Meier method. The cumulative risk of incident cancer event was estimated as a function of time from initial treatment. A Cox proportional hazard regression model was used to calculate the risk of cancer event in sleep disorder patients who used zolpidem versus those who did not, after adjustments for age, gender, comorbidities, SES and other medication usage. A P < 0.05 was considered statistically significant in the regression models.

  Results Top

The distribution of demographic characteristics for the two cohorts is shown in [Table 1]. Those taking zolpidem were significantly older and more likely to be female than those who did not take it. They were also more likely to have more comorbidities, low SES, and more frequently used antiglycemic drugs, psychotropic agents, and antihypertensive medications.

Table 1: Baseline characteristics (n=6924)

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At the end of follow-up, 56 patients had incident cancers, 26 (1.5%) in those using zolpidem, and 30 (0.6%) in those not using it. Patients using zolpidem had an increased risk of cancer events. [Table 2] shows the types of cancer events for the two cohorts stratified by gender. Increased mean daily dose and longer use were associated with increased cumulative risk of cancer events [Figure 1] and [Figure 2]. After adjustments for gender, age, comorbidities, and other medications, patients using zolpidem had a 1.75-times (95% CI, 1.02–3.02) higher risk of cancer events than those who did not use zolpidem during the 3-year follow-up period. [Figure 3] shows the combined effect of mean daily dose and length of zolpidem use on increased cancer risk. [Table 3] shows the adjusted ratios of cancer incidence with zolpidem usage after adjusting for gender, comorbidities, and other medications. Mean daily dose >1 DDD and usage >2 months was associated with 3.74 times (95% CI, 1.42–9.83; P = 0.008) higher risk of incident cancer events in a Cox regression model.

Table 2: Incident tumors in individuals with zolpidem usage and those without by stratification for gender

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Figure 1: Effect of zolpidem dose on cancer risk

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Figure 2: Effect of zolpidem duration on cancer risk

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Figure 3: Combined effect of zolpidem dose and duration on cancer risk

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Table 3: Adjusted hazard ratios for zolpidem in patients with sleep disturbance

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  Discussion Top

Our data showed that zolpidem usage was associated with increased incident cancer risk in patients with sleep disorder. Zolpidem usage >1 DDD for a period >2 months incurred a 3.7-fold higher risk of cancer events. Although zolpidem, the newer nonbenzodiazepine, has been shown to be safe and effective in patients with insomnia,[14] its chronic usage should be carefully restricted and monitored.

Our results suggest that zolpidem usage for more than 2 months increases cancer risk significantly in patients with sleep disorder. Comparing with previous studies, this series further provided a critical period (>2 months) and mean daily dose (>1 DDD) for elevated risk of incident cancer for clinical physicians and the general population.

Due to its short half-life and selective Type I GABAA receptor agonist, zolpidem is a widely used, standard treatment for patients with sleep disorder or insomnia.[3],[15] Of the 8607 patients who reported side effects with zolpidem use on the eHealthMe website, which continuously monitors drug adverse effects, 71 (i.e., 0.82%) reported an incident cancer.[6] In our study, 1.5% persons with zolpidem usage developed incident cancer within 3 years. Zolpidem use was associated with a 1.8-times higher risk of cancer events after adjusting for other medications and confounding factors. Our findings are consistent with Iqbal et al. that zolpidem usage was associated with a 1.13-times higher risk of cancer (95% CI, 1.09–1.17).[16] Higher doses and longer use were positively associated with cancer risk. This series revealed that a mean daily dose >1 DDD and drug usage >2 months was associated with 3.7 times risk (95% CI, 1.4–10) of incident cancer events in patients with sleep disorder.

The exact relationship between zolpidem and infection events remains unknown although several mechanisms are plausible. Benzodiazepines have been found to affect polymorphonuclear cell chemotaxis and phagocytosis.[17] Benzodiazepines in general suppress the immune response through peripheral and central benzodiazepine receptors.[18] The impairment of macrophage spreading could be attributed to the anti-inflammatory effect of the peripheral benzodiazepine receptor on blood cells through inhibition of the release of pro-inflammatory cytokines such as interleukin-6 and interleukin-13.[19] An uncontrolled small case series described carcinogenicity following the prescription of zopiclone or eszopiclone to HIV Type 1 infected individuals.[20] Eszopiclone and zolpidem use have been reported associated with increased risk of infection, raising the speculation that hypnotics impair immune surveillance.[21] A suppression of immune function may partly explain the increased risk of incident cancers. Sparse data on the new hypnotics (eszopiclone, zaleplon, zolpidem, and ramelteon) suggest an increased risk of cancer, which is supported by studies demonstrating a carcinogenic effect in rodents.[22]

Furthermore, hypnotics such as zolpidem can increase the incidence of sleep apnea and may suppress the respiratory drive. Zolpidem increased the apnea index and provoked greater oxygen desaturation than flurazepam and placebo in a controlled, double–blind, cross-over study. Such that 20 mg zolpidem failed to overcome the existing contraindications to administration of hypnotic drugs in patients with heavy snoring and obstructive sleep apnea syndrome.[23] Sleep apnea induced by medication may in turn induce early apoptosis of large granular lymphocytes which further compromises immunity and reduces immune surveillance.[24]

A greater incidence of depression with zolpidem use has been reported.[25] A decrease in the number of natural killer T-cells has also been reported in patients with major depressive disorder.[26] Depressed immunity to varicella zoster in older adults with major depressive disorder has been observed.[27] Compromised immunity may contribute to tumor formation.

Benzodiazepines can decrease lower esophageal sphincter tone, independently of the awareness or drowsiness of patients.[28] Zolpidem reduced the arousal response to nocturnal acid exposure and increased the duration of each esophageal acid reflux event.[29] Gastroesophageal reflux can lead to chronic sinusitis, recurrent croup, and laryngitis.[30] A recent meta-analysis reported an increased risk of infection with zolpidem use.[21] Infection may result from increased gastroesophageal regurgitation or from zolpidem usage and subsequent increased cancer development.[31] However, the exact relationship between zolpidem and cancer event remains unknown, and further research is needed to explore the possible mechanism.

This study has several limitations. First, the diagnosis of sleep disorder, incident cancer, and any other comorbid conditions are completely dependent on accurate recording of ICD-9-CM codes. However, the cancer events were further verified by their appearance in the registry for cancer and catastrophic illness patient database. Furthermore, the National Health Insurance Bureau of Taiwan randomly reviews charts and interviews patients to verify diagnosis accuracy. Hospitals with outlier charges or practice may undergo an audit, with subsequent heavy penalties for malpractice or discrepancies. Second, the database did not include detailed information on body mass index, smoking, or alcohol drinking. Further studies linking administrative data and primary surveys of health behaviors are warranted. Third, we did not control for depression, anxiety, and other emotional factors, which may have influenced these results. Fourth, the number of cases was small, warranting caution in interpreting the data. Finally, associations derived from epidemiological studies do not prove causality. It is hard to discern the correlation between the zolpidem usage and the sleep disorder in time sequence. We cannot exclude the possibility that zolpidem usage is a marker for other risk factors or cancer-related illness and acts a confounder in its association with cancer.

In summary, this study found that zolpidem use was associated with increased risk of cancer events in sleep disorder patients. For patients with sleep disorder who chronically use zolpidem, the likelihood of developing cancer events within 3 years is 1.7 times that of those who do not use zolpidem. Risks and benefits of chronic zolpidem usage should be explained to sleep disorder patients. Cognitive-behavioral therapy for patients with chronic insomnia may be more beneficial than use of hypnotics.[32]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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Iqbal U, Nguyen PA, Syed-Abdul S, Yang HC, Huang CW, Jian WS, et al. Is long-term use of benzodiazepine a risk for cancer? Medicine (Baltimore) 2015;94:e483.  Back to cited text no. 16
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A randomised trial of the effect of omega-3 polyunsaturated fatty acid supplements on the human intestinal microbiota


Abstract

Objective Omega-3 polyunsaturated fatty acids (PUFAs) have anticolorectal cancer (CRC) activity. The intestinal microbiota has been implicated in colorectal carcinogenesis. Dietary omega-3 PUFAs alter the mouse intestinal microbiome compatible with antineoplastic activity. Therefore, we investigated the effect of omega-3 PUFA supplements on the faecal microbiome in middle-aged, healthy volunteers (n=22).

Design A randomised, open-label, cross-over trial of 8 weeks’ treatment with 4 g mixed eicosapentaenoic acid/docosahexaenoic acid in two formulations (soft-gel capsules and Smartfish drinks), separated by a 12-week ‘washout’ period. Faecal samples were collected at five time-points for microbiome analysis by 16S ribosomal RNA PCR and Illumina MiSeq sequencing. Red blood cell (RBC) fatty acid analysis was performed by liquid chromatography tandem mass spectrometry.

 

Results Both omega-3 PUFA formulations induced similar changes in RBC fatty acid content, except that drinks were associated with a larger, and more prolonged, decrease in omega-6 PUFA arachidonic acid than the capsule intervention (p=0.02). There were no significant changes in α or β diversity, or phyla composition, associated with omega-3 PUFA supplementation. However, a reversible increased abundance of several genera, including Bifidobacterium, Roseburia and Lactobacillus was observed with one or both omega-3 PUFA interventions. Microbiome changes did not correlate with RBC omega-3 PUFA incorporation or development of omega-3 PUFA-induced diarrhoea. There were no treatment order effects.

 

Conclusion Omega-3 PUFA supplementation induces a reversible increase in several short-chain fatty acid-producing bacteria, independently of the method of administration. There is no simple relationship between the intestinal microbiome and systemic omega-3 PUFA exposure.

Efficacy and Safety of GIAPREZA™ (angiotensin II) in ATHOS-3 Trial



Distributive shock, characterized by low mean arterial pressure (MAP) and decreased tissue perfusion due to microcirculatory dysfunction, is associated with high morbidity and mortality.1 The Surviving Sepsis Campaign recommends an initial MAP of ≥65 mmHg.2 About 30% of patients in the intensive care unit who receive standard of care vasopressors (catecholamines) require high doses.3

GIAPREZA™ (angiotensin II) injection for IV infusion: A novel vasopressor to increase BP in adults with septic or other distributive shock

GIAPREZA™ (angiotensin II) is a vasoconstrictor that increases blood pressure in adults with septic or other distributive shock. It is the first and only FDA-approved synthetic human angiotensin II treatment that activates the renin-angiotensin-aldosterone system (RAAS) to increase MAP.4,5 GIAPREZA leverages a system that is currently not targeted by other therapies for hypotension in distributive shock.4-6

ATHOS-3 Trial Design

The Angiotensin II for the Treatment of High-Output Shock (ATHOS‑3) trial was an international, multicenter, randomized, double-blind, placebo-controlled study in which 344 adults with septic or other distributive shock who remained hypotensive despite fluid and vasopressor therapy were randomized 1:1 to GIAPREZA or placebo, and 321 of them received GIAPREZA or placebo.4,6,7

aGIAPREZA and placebo were studied in conjunction with norepinephrine, epinephrine, dopamine, phenylephrine, and vasopressin.4
bTreatment allowed up to day 7. Day 28 (+/- 2 days) follow-up determined safety events that occurred between day 7 and day 28.6,8

  • Doses of GIAPREZA or placebo were titrated to a target MAP of ≥75 mmHg during the first 3 hours of treatment while doses of other vasopressors were maintained4
  • From hour 3 to hour 48, GIAPREZA or placebo was titrated to maintain MAP between 65 and 70 mmHg, while reducing doses of other vasopressors4
  • The primary endpoint was the percentage of subjects who achieved either a MAP ≥75 mmHg or a ≥10 mmHg increase from baseline in MAP without an increase in baseline vasopressor therapy at 3 hours4

Efficacy in ATHOS-3

GIAPREZA increased MAP in critically ill, hypotensive patients with septic or other distributive shock4,6

At hour 3, significantly more patients treated with GIAPREZA achieved target MAP vs patients treated with placebo4

IMPORTANT SAFETY INFORMATION

Indication
GIAPREZA (angiotensin II) increases blood pressure in adults with septic or other distributive shock.

Contraindications
None.

Warnings and Precautions
The safety of GIAPREZA was evaluated in 321 adults with septic or other distributive shock in the randomized, double-blind, placebo-controlled ATHOS-3 study. There was a higher incidence of arterial and venous thrombotic and thromboembolic events in patients who received GIAPREZA compared to placebo treated patients in the ATHOS-3 study [13% (21/163 patients) vs. 5% (8/158 patients)]. The major imbalance was in deep venous thromboses. Use concurrent venous thromboembolism prophylaxis.

Adverse Reactions
The most common adverse reactions reported in greater than 10% of GIAPREZA-treated patients were thromboembolic events. Adverse reactions occurring in ≥4% of patients treated with GIAPREZA and ≥1.5% more often than placebo-treated patients in the ATHOS‑3 study were thromboembolic events (including deep vein thrombosis), thrombocytopenia, tachycardia, fungal infection, delirium, acidosis, hyperglycemia, and peripheral ischemia.

Drug Interactions
Angiotensin converting enzyme inhibitors may increase response to GIAPREZA.

Angiotensin II receptor blockers may reduce response to GIAPREZA.

To report SUSPECTED ADVERSE REACTIONS, contact La Jolla Pharmaceutical at 1-800-651-3861 or the FDA at 1- 800- FDA -1088 or www.fda.gov/medwatch.

Please see the full Prescribing Information at www.giapreza.com.

cModified intent-to-treat (mITT) population; patients randomized and treated with study drug in any quantity were included in the primary efficacy analysis.6

  • Target MAP defined as ≥75 mmHg or an increase from baseline of ≥10 mmHg without an increase in baseline vasopressor therapy4
  • In addition, GIAPREZA rapidly increased MAP, with a median response time of approximately 5 minutes for GIAPREZA responders, while some patients took longer.4,d The plasma half-life of GIAPREZA is less than 1 minute, which allows for individualized dose adjustment with titration every 5 to 15 minutes by increments up to 15 ng/kg/min4
  • Mortality through day 28 was 46% on GIAPREZA and 54% on placebo (hazard ratio 0.78; 95% confidence interval 0.57-1.07)4

dResponse was defined as achievement of target MAP ≥75 mmHg or an increase from baseline of ≥10 mmHg without an increase in baseline vasopressor therapy.4

Safety in ATHOS-3

87% of patients treated with GIAPREZA experienced at least one adverse event (AE) versus 92% of patients treated with placebo6,e

  • The most common adverse reactions reported in greater than 10% of GIAPREZA-treated patients were thromboembolic events: 12.9% for GIAPREZA versus 5.1% for placebo. Use concurrent venous thromboembolism prophylaxis in patients treated with GIAPREZA4
  • Adverse reactions occurring in ≥4% of patients treated with GIAPREZA and ≥1.5% more often than placebo-treated patients in the ATHOS‑3 study were thromboembolic events (including deep vein thrombosis), thrombocytopenia, tachycardia, fungal infection, delirium, acidosis, hyperglycemia, and peripheral ischemia4
  • 14.1% of patients discontinued GIAPREZA due to AEs versus 21.5% of patients who discontinued placebo due to AEs6,e

eNot statistically significant.6

fIncluded arterial and venous thrombotic events.4

In summary,

  • GIAPREZA is the first and only FDA-approved synthetic human angiotensin II treatment that activates RAAS to increase MAP4,6
  • 70% of patients treated with GIAPREZA achieved target MAP at hour 3 versus 23% of patients treated with placebo4,g,h,i
  • GIAPREZA also rapidly increased MAP, with a median response time of approximately 5 minutes for GIAPREZA responders, while some patients took longer4,d,i
  • Mortality through day 28 was 46% on GIAPREZA and 54% on placebo (hazard ratio 0.78; 95% CI, 0.57-1.07)4,i,j
  • More patients treated with GIAPREZA experienced thrombotic events compared with patients treated with placebo (12.9% versus 5.1%).4,j Use concurrent venous thromboembolism prophylaxis6

dResponse was defined as achievement of target MAP ≥75 mmHg or an increase from baseline of ≥10 mmHg without an increase in baseline vasopressor therapy.4
gTarget MAP defined as ≥75 mmHg or an increase from baseline of ≥10 mmHg without an increase in baseline vasopressor therapy.4
hGIAPREZA and placebo were studied in conjunction with norepinephrine, epinephrine, dopamine, phenylephrine, and vasopressin.4
iResults from ATHOS-3 trial.4
jNo significant difference.6

For additional Important Safety Information, please see the full Prescribing Information.

References:

  1. Vincent JL, De Backer D. Circulatory shock. N Engl J Med. 2013;369(18):1726-1734.
  2. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. March 2017;43(3): pp 304-377.
  3. Sviri S, Hashoul J, Stav I, van Heerden PV. Does high-dose vasopressor therapy in medical intensive care patients indicate what we already suspect? J Crit Care. 2014;29(1):157-160.
  4. GIAPREZA™ (angiotensin II) [package insert]. San Diego, CA: La Jolla Pharmaceutical Company; 2017.
  5. Trotter J. Catecholamine-resistant hypotension following induction for spinal exploration. AANA J. 2012;80(1):55-60.
  6. Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377(5):419-430. doi:10.1056/NEJMoa1704154.
  7. Chawla LS, Russell JA, Bagshaw SM, et al. Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS‑3): protocol for a phase III, double-blind, randomized controlled trial. Crit Care Resusc. 2017;19(1):43-49.
  8. Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock [trial protocol]. N Engl J Med. 2017;377(5):1-95. doi:10.1056/NEJMoa1704154.

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Evolocumab plus statin potentially reduces atherosclerosis progression in GLAGOV study


The addition of evolocumab to statin therapy in individuals with angiographic coronary disease appeared to encourage coronary atherosclerosis regression, as demonstrated in the GLAGOV* trial presented at the Scientific Sessions of the American Heart Association (AHA 2016) held in New Orleans, Louisiana, US.

In comparison with patients on statin alone who experienced a nonsignificant 0.05 percent increase in percent atheroma volume (PAV), those on combined therapy of statin and evolocumab had a 0.95 percent reduction in PAV (difference, -1.0 percent, 95 percent confidence interval [CI], -1.8 to -0.64 percent; p<0.001). Normalized total atheroma volume (TAV) decreased by 0.9 mm3 (nonsignificant) in those on statin alone compared with 5.8 mm3 in those on statin and evolocumab (difference, -4.9 mm3, 95 percent CI, -7.3 to -2.5; p<0.001). [AHA 2016, LBCT 03; JAMA 2016;doi:10.1001/jama.2016.16951]

Plaque regression occurred in a greater number of patients on evolocumab and statin compared with those on statin alone (64.3 percent vs 47.3 percent; difference, 17.0 percent, 95 percent CI, 10.4 to 23.6 percent; p<0.001 for PAV and 61.5 percent vs 48.9 percent; difference, 12.5 percent, 95 percent CI, 5.9 to 19.2 percent; p<0.001 for TAV).

“We are really reducing plaque burden in the coronaries if we can get [low-density lipoprotein cholesterol (LDL-C)] down to these very low levels,” said study chair Dr Steven Nissen from the Department of Cardiovascular Medicine at the Cleveland Clinic, Cleveland, Ohio, US, who presented the findings. “It turns out that a little bit of change in plaque volume translates into a very big change in plaque behaviour.”

“[These findings] suggest a new era in lipid management,” said discussant Dr Raul Santos from the University of São Paulo, Brazil.

Evolocumab appeared to be well tolerated with comparable incidences of injection site reactions (0.4 percent vs 0 percent), myalgia (7.0 percent vs 5.8 percent), neurocognitive events (1.4 percent vs 1.2 percent), and new onset diabetes (3.6 percent vs 3.7 percent) for evolocumab plus statin vs statin monotherapy, respectively.

In this double-blind, placebo-controlled, multicentre trial, participants (n=968, mean age 59.8 years; 72 percent male) with angiographic coronary disease, LDL-C levels ≥80 mg/dL or 60–80 mg/dL with additional high-risk features, and on stable statin therapy were randomized to receive monthly subcutaneous injections of the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor, evolocumab (420 mg) or placebo for 76 weeks. After angiography, participants underwent intravascular ultrasound (IVUS) of the same artery at baseline and at week 78.

“Both the primary and secondary IVUS efficacy measures showed atherosclerosis regression … in patients treated with the combination of evolocumab and statins and absence of regression in patients treated with a statin alone,” said study lead investigator Dr Steven Nicholls, also from the Cleveland Clinic. “These findings provide evidence that PCSK9 inhibition produces incremental benefits on coronary disease progression in statin-treated patients.”

“Over the last 4 decades, evidence has accumulated suggesting that optimal LDL levels for patients with coronary disease may be much lower than commonly achieved. While we await large outcome trials for PCSK9 inhibitors, the GLAGOV trial provides intriguing evidence that clinical benefits may extend to LDL-C levels as low as 20 mg/dL,” said Nissen, who acknowledged the limitations of the trial such as the small number of patients and short treatment period. “IVUS is a useful measure of disease activity, but the critical determination of benefit and risk will require completion of large outcome trials currently underway,” he said.

Other factors that could potentially influence disease progression in the setting of very low LDL-C levels also need to be investigated, said Nicholls.

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Dapagliflozin drives HbA1c, SBP, and weight down in DERIVE


Dr Siew-Pheng Chan.

The use of the sodium/glucose cotransporter 2 (SGLT-2) inhibitor dapagliflozin in patients with type 2 diabetes (T2D) and moderate renal impairment provides benefits beyond glucose lowering, with no new safety signals, in the phase III DERIVE* study.

At 6 months, the primary endpoint of mean reduction in HbA1c level was greater by 0.34 percent in patients treated with dapagliflozin vs placebo (p< 0.001). There were also greater reductions in systolic blood pressure (SBP, 3.1 mm Hg; p<0.05) and mean body weight (1.25 percent, p< 0.001) with dapagliflozin. (APSC 2018, abstract S105-01)

“Dapagliflozin induces glycosuria and lowers blood glucose. However, the glycaemic efficacy of dapagliflozin is attenuated in patients with moderate renal impairment, for example in stage 3 CKD, because less glucose is cleared in the kidney in this group,” said Dr Siew-Pheng Chan, consultant endocrinologist at Subang Jaya Medical Centre in Subang Jaya, Malaysia, who is unaffiliated with the study.

Researchers led by Dr Paola Fioretto of the University of Padova in Padua, Italy conducted the DERIVE study to compare the efficacy and safety of dapagliflozin vs placebo in 321 patients with T2D (HbA1c of 7 –11 percent) and moderate renal impairment (stage 3A chronic kidney disease (CKD), estimated glomerular filtration rate (eGFR), 45 to <60 mL/min/1.73m2). Patients were randomized to either dapagliflozin 10 mg (n=160) or placebo (n=161) over 6 months. Randomization was stratified by background glucose-lowering medication. Both groups had similar baseline characteristics.

At 6 months, treatment with dapagliflozin resulted in a significant reduction in mean HbA1c (-0.37 percent vs -0.03 percent for placebo) and mean body weight (-3.17 vs -1.92 kg, respectively) from baseline. The mean fasting plasma glucose was also significantly reduced with dapagliflozin (-21.46 vs -4.87 mg/dL for placebo) as was mean SBP (-4.8 vs -1.7 mm Hg, respectively) from baseline to 6 months.

In terms of safety, mean eGFR was reduced with dapagliflozin (-3.23 mL/min/1.73m2) vs placebo (-0.63 mL/min/1.73m2). Urinary tract infection and genital infection were the most common adverse events of interest reported. Overall, the safety profile of dapagliflozin was consistent with previous reports seen for T2D. No bone fractures or amputations were reported.

Dapagliflozin is currently indicated as an adjunct to diet and exercise to improve glycaemic control in adults with T2D. Dapagliflozin remains contraindicated in patients with an eGFR <30 mL/min/1.73 m².

 

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Low ankle-brachial index tied to cognitive decline


Even in the absence of peripheral arterial disease, a lower ankle-brachial index (ABI) is significantly associated with larger declines in cognitive function, according to a poster presented at the 2018 Congress of the Asian Pacific Society of Cardiology (APSC 2018) in Taipei, Taiwan.

“The present study aimed to investigate whether a graded association between ABI and cognitive function exists, and whether this association is independent of artery stiffness, which is a recognized predictor of cognitive impairment,” said researchers.

Categorizing 708 participants according to quartiles of ABI, researchers found that there was a significant and inverse correlation between ABI values and global cognitive function, represented as scores in the Mini-Mental Short Examination (MMSE; p=0.0011 for trend). [APSC 2018, abstract P006]

Specifically, mean MMSE scores were lowest in the first ABI quartile (27.4±3.1) and increased in the second (27.8±2.8), third (28.2±2.3) and fourth (28.4±2.0) quartiles.

The significant relationship between ABI and global cognitive function was confirmed in general linear (β, –0.137; p=0.0007) and fully adjusted multivariable logistic regression models (Q4 vs Q1: adjusted odds ratio [OR], 3.623; 95 percent CI, 1.096–11.972).

Researchers likewise found a significant and positive relationship between MMSE scores and carotid-femoral pulse wave velocity (CF-PWV; β, 0.114; p=0.0044).

Notably, using patients with both high ABI and low PWV as reference, the odds of cognitive function decline was elevated in those with high PWV only (OR, 2.34) and low ABI only (OR, 2.28). The effect was substantially more pronounced in those with both low ABI and high PWV (OR, 8.19).

ABI also showed a significant and inverse association with mean brachial pulse pressure (Q1: 58.3±11.8; Q2: 56.6±13.2; Q3: 54.7±10.6; Q4: 54.9±10.6 mm Hg; p=0.0094 for trend). There was a significantly higher proportion of male patients in the third (58.52 percent) and fourth (57.30 percent) ABI quartiles than in the first (35.16 percent) and second (42.42 percent; p<0.0001 for trend).

The findings of the present study show that a lower ABI value is significantly associated with a greater decline in global cognitive function, said researchers. In addition, the relationship was independent of and additive to the effect of arterial stiffness.

For the study, researchers recruited 708 adults without peripheral arterial disease (ABI >0.9; mean age 69.0±7.0 years; 48.35 percent male). Volume-plethysmographic apparatus was used to measure ABI, while CF-PWV was used as a measure of arterial stiffness.

Of the participants, 182 had ABI from 0.9–1.10 and were placed in the lowest quartile (mean age 69.3±7.1 years) while 165 had ABI from 1.10–1.14 and fell within the second quartile (mean age 69.1±6.9 years). The third (ABI 1.14–1.19; mean age 68.8±7.3 years) and fourth (ABI ≥1.19; mean age 68.9±6.6 years) quartiles included 176 and 185 participants, respectively.

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Lp(a) Levels May Modulate CV Benefits of Evolocumab: FOURIER


Patients treated with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab (Repatha, Amgen) may experience a greater reduction in cardiovascular events if they have higher baseline levels of lipoprotein(a) [Lp(a)], US investigators have shown.

The results are from a preplanned analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, published in March 2017 in the New England Journal of Medicine.

As reported by theheart.org | Medscape Cardiology at that time, main FOURIER results showed that evolocumab was associated with a 15% reduced risk for a composite of myocardial infarction (MI), stroke, cardiovascular disease (CVD), coronary revascularization, and unstable angina hospitalization at 22 months compared with placebo (P < .001).

Moreover, treatment was associated with a 20% reduction in a composite of CVD, MI, and stroke vs placebo (P < .001), which occurred in tandem with large reductions in low-density lipoprotein (LDL) cholesterol levels.

The current analysis, presented here at the European Atherosclerosis Society (EAS) 2018 meeting, shows evolocumab also achieves significant reductions in Lp(a) levels of more than 25%.

The researchers found that the greatest effect of the drug compared with placebo on the risk for cardiovascular death, MI, and stroke was in patients with higher baseline Lp(a) levels, at 24% vs 15% in those with lower levels, at a twofold increase in the absolute risk reduction.

Study presenter Michelle L. O’Donoghue, MD, Brigham and Women’s Hospital, Boston, Massachusetts, told theheart.org | Medscape Cardiology that whether or not the benefits offered by Lp(a) reduction are “above and beyond” the LDL reduction is an area of ongoing study.

“But I think it’s worthwhile that we were able to see that baseline Lp(a) concentration appears to help identify individuals who derive greater benefit from treatment with evolocumab,” she added.

“So if those individuals have a larger magnitude of benefit and a smaller number needed to treat, then that’s perfect, as we’re trying to think about different high-risk features that might help to identify individuals who get the greatest benefit from the drug in a cost-effective manner.”

For O’Donoghue, one of the key aspects of their results is that they suggest that evolocumab affects both Lp(a) and LDL separately to lower the risk for cardiovascular outcomes. This was underlined by data showing that the greatest benefit was seen in individuals who achieved both their Lp(a) and LDL cholesterol target.

“With a drug like evolocumab, you’ve got multiple effects, and it becomes almost like a pleiotropic effect, because you’ve got LDL lowering, which is obviously very compelling, in addition to the effects on Lp(a),” she said.

“I think there’s a lot of work to be done to figure out whether or not the Lp(a) reduction on its own offers as much, or greater, or less benefit than LDL reduction on its own,” she added. “It’s interesting to see, though, that those who achieved the dual targets of lower levels of both are those who do best.”

Evolocumab and Lp(a)

The FOURIER trial involved 27,564 patients with stable atherosclerotic CVD and LDL cholesterol levels of 1.8 mmol/L (70 mg/dL) or higher who were receiving statin therapy and were randomly assigned to evolocumab, 140-mg injections every other week or 420-mg injections monthly, or to placebo.

After a mean follow-up of 2.2 years, evolocumab treatment was associated with a 59% relative reduction (P < .00001), or a 56-mg/dL absolute reduction, in LDL levels down to a median of 30 mg/dL, alongside the observed clinical benefits.

Previous Mendelian randomization data suggested that Lp(a) plays a causal role in the risk for coronary heart disease (CHD), and PCSK9 inhibitors have been shown to significantly reduce Lp(a) levels, so the team examined the impact of evolocumab on Lp(a) in FOURIER.

As part of the trial, Lp(a) levels were measured at baseline and weeks 12 and 58, with results available for 25,096 participants. The median Lp(a) level was 37 nmol/L (interquartile range [IQR], 13 – 165 nmol/L).

Individuals in the highest quartile of Lp(a) levels were, compared with those in the lower quartiles, significantly less likely to be male, to have ischemic stroke and diabetes mellitus, and to currently use tobacco (P < .001 for trend).

In contrast, individuals in the highest quartile were significantly more likely to have had a MI, to have peripheral artery disease, and to have higher baseline LDL cholesterol levels than those in the lower quartiles (P < .001 for trend).

As expected, higher baseline Lp(a) levels were associated in the placebo group with a significantly higher risk for CHD death or MI, cardiovascular death, MI or stroke, and MI and coronary death individually on multivariate analyses taking into account a range of potential confounding factors.

For example, the adjusted hazard ratio of CHD death or MI in participants with an Lp(a) in quartile 4 vs those in quartile 1 was 1.26 (95% CI, 1.02 – 1.56).

Among 11,864 participants given evolocumab, treatment was associated with a mean absolute change in Lp(a) levels at week 48 of –11 nmol/L (IQR, –31 nmol/L to –1 nmol/L), or a median percentage change of –26.9% (IQR, –46.7% to –6.2%).

The correlation between percentage change in Lp(a) and change in LDL cholesterol at 48 weeks in treated patients was r = 0.37 (P < .001), while that for absolute change was r = 0.21.

When the team divided the patients into those whose baseline Lp(a) level was above the median and those whose level was at or below the median, they found a difference in the impact of evolocumab on cardiovascular outcomes vs placebo.

Specifically, patients with a baseline Lp(a) level above the median had a hazard ratio of cardiovascular death, MI, or stroke with evolocumab vs placebo of 0.76 (95% CI, 0.66 – 0.86), or an absolute risk reduction of 2.8% and a number needed to treat of 36.

This compares with a hazard ratio for evolocumab vs placebo among patients with a baseline Lp(a) level at or below the median of 0.85 (95% CI, 0.73 – 0.97), or an absolute risk reduction of 1.28% and a number needed to treat of 79.

Next, the team looked at Lp(a) and LDL cholesterol together in terms of the impact of evolocumab treatment on the risk for combined cardiovascular events after week 12.

The risk was lower in patients who achieved a reduction of Lp(a) and LDL cholesterol to at or below the median at baseline (6.57%) than in those who achieved that milestone only with Lp(a) (7.88%), those who got there only with LDL cholesterol (8.45%), and those who achieved that for neither measure (9.43%) (P < .001 overall).

Concluding her presentation, O’Donoghue said their findings show that evolocumab significantly reduces Lp(a) levels and that “patients starting with higher Lp(a) levels appear to derive greater absolute benefit.”

Moreover, individuals “who achieve lower levels of both LDL cholesterol and Lp(a) have the lowest subsequent risk of CV events.”

Speaking after the session in an interview, she said that this latter finding is particularly interesting when one thinks of the individuals who have a reduction in Lp(a) levels “but a rise in LDL cholesterol levels at the same time.”

“What are those genetic predictors that help to identify those individuals? It’s not completely clear,” she said.

Completely Different Story

Commenting on the findings, Alberico L. Catapano, MD, PhD, professor of pharmacology at the University of Milan, Italy, and past president of the EAS, told theheart.org | Medscape Cardiology that “it’s a completely different story” between Lp(a) and LDL cholesterol.

He explained that with LDL cholesterol, the greater the reduction in plasma levels, the greater the benefit, while with Lp(a), “there’s always been a struggle” to demonstrate a similar relationship.

“Lp(a) is related to cardiovascular disease, but the strongest relationship is with calcification of the aortic wall, or aortic stenosis,” he said.

However, Catapano noted that the “exact mechanism is still not completely clear,” unlike the situation with LDL.

“Of course, we’ll never know everything for sure but we have robust evidence with LDL,” he said. “With Lp(a), it’s not clear whether it’s coagulation, whether it’s atherosclerosis and the buildup of cholesterol, or both together.”

“Having said that,” he added, “there is clearly a relationship that is not linear but sort-of hyperbolic, so that above a certain level, the correlation gets stronger and the risk becomes higher.”

Catapano pointed out, however, that the median Lp(a) levels seen in the FOURIER trial were lower than those seen in the general population and lower than the 50 mg/dL that has been linked to a substantially increased cardiovascular risk, “so you would not expect a huge benefit” with Lp(a) reduction in this population.

“The second point is they saw a benefit that was larger in absolute terms according to the levels of Lp(a), [which] is entirely in line with what we know,” he said. “We know that Lp(a) contributes to the risk and we know that we have a higher risk if we have higher Lp(a), and that reducing LDL cholesterol for sure reduces the risk.”

“Whether the contribution of Lp(a) to that reduction of risk is important, we do not know; it would be almost impossible to disentangle from the data,” he said. “That’s my personal view.”

However, Catapano believes, these answers may be provided  with the results of ongoing studies into antisense nucleotides, which target Lp(a) specifically.

FOURIER was funded by Amgen. O’ Donoghue reports receiving research grant support from GlaxoSmithKline, Eisai, Merck & Co, Janssen, Amgen, The Medicines Company, and AstraZeneca. Catapano reports being a consultant for and receiving honoraria from Pfizer, Sanofi, Genzyme, Merck, Akcea, and Amgen; receiving honoraria from Kowa, Mediolanum, Farmaceuti, Menarini, Bayer, Eli Lilly, Recordati, and Genzyme; and receiving research grants from Pfizer, Merck, Sanofi, Menarini, Regeneron, Mediolanum, and Farmaceutici.

 

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First Trial of Three Aromatase Inhibitors: Similar Efficacy, Safety


The first-ever direct comparison of three adjuvant aromatase inhibitors for the treatment of postmenopausal hormone receptor–positive early breast cancer shows no significant differences in clinical efficacy or safety, according to an Italian research team.

In the randomized, open-label phase 3 FATA-GIM3 trial of almost 3700 women, the 5-year disease-free survival for patients treated with anastrozole (Arimidex, Novartis), exemestane (Aromasin, Pfizer), or letrozole (Femara, Novartis) was 90.0%, 88.0% and 89.4%, respectively.

There were no unexpected serious adverse reactions or treatment-related deaths, say Francesco Perrone, MD, of the Istituto Nazionale per lo Studio e la Cura dei Tumori, in Naples, Italy, and colleagues. No differences were observed between patient subgroups, even though more than 50% of patients were overweight or obese.

The study was published online February 23 in the Lancet Oncology.

This is also the first trial to compare an up-front treatment schedule with a switch schedule using anastrozole, the study authors note. The up-front schedule consisted of 5 years of treatment with aromatase inhibitors; the switch schedule consisted of 2 years of treatment with tamoxifen followed by 3 years of treatment with aromatase inhibitors.

The study shows that both treatment schedules were clinically relevant. There was only a 1.6% difference in disease-free survival after 2 years. After 5 years, the disease-free survival was 88.5% with the switch strategy and 89.8% with the up-front regimen (hazard ratio [HR], 0.89; P = .23).

“FATA-GIM3 is the only trial to compare upfront treatment with a switch strategy using anastrozole, and the first trial to directly compare the three aromatase inhibitors; thus, contributing to the knowledge base, which is currently limited to indirect comparisons of the EBCTCG [Early Breast Cancer Trialists’ Collaborative Group] meta-analysis and two head-to-head trials, one of which was limited to node-positive patients,” Perrone and colleagues write.

“The number of deaths and other breast-related events was too low to allow reliable conclusions to be drawn on endpoints other than disease-free survival,” the investigators add. The 5-year overall survival was 95.3% with the switch schedule and 96.8% with the up-front schedule (HR, 0.72; P = .052).

Tamoxifen vs AIs: Clear Differences

The researchers suggest that clinicians consider patient preferences, tolerability, and cost when determining the best treatment approach.

“Clinical benefits and tolerability are particularly important in the choice between aromatase inhibitors and tamoxifen,” Perrone told Medscape Medical News. The safety profile is “clearly different,” he added. He noted that musculoskeletal side effects are seen more frequently with aromatase inhibitors.

“We should still consider tamoxifen a good option,” Perrone emphasized.

Findings from the earlier ATAC study suggested that less costly switch therapy might be more effective than up-front therapy, state the investigators, who conducted a literature search through August 30, 2017. ATAC findings also indicated that longer exposure to aromatase inhibitors could be associated with a greater risk for cardiac and musculoskeletal toxicity.

When FATA-GIM3 was designed in 2006, the up-front aromatase inhibitor treatment strategy was about to become standard practice, the study authors say.

In an accompanying comment, Luc Y. Dirix, MD, of the University of Antwerp, Belgium, called the FATA-GIM3 trial “an important confirmatory study.

“These data are the first for the switch approach with anastrozole,” he confirmed. “Patients and clinicians can be confident that any aromatase inhibitor is acceptable in this treatment strategy.”

FATA-GIM3 reinforces results from the EBCTGC meta-analysis, which demonstrated a small absolute benefit with up-front therapy after 5 years of follow-up, Dirix notes. Two large international trials established the clinical relevance of the up-front and switch regimens while the FATA-GIM2 trial was still underway, he points out.

The BIG1-98 trial found that tamoxifen followed by letrozole was more effective then letrozole alone. Similarly, the TEAM trial showed that tamoxifen followed by exemestane was more effective than exemestane alone.

“The duration of adjuvant endocrine therapy is now considered a more crucial factor in treatment outcomes,” Dirix says.

The editorialist also says that “even if the upfront strategy is preferred, FATA-GIM3 confirms the absence of a relevant difference between the aromatase inhibitors (with only small differences in toxicities but not in efficacy), giving clinicians the freedom to exchange one aromatase inhibitor for another.”

For the study, 3697 postsurgical patients with invasive hormone receptor–positive breast cancer were enrolled from 76 Italian public healthcare institutions between March 9, 2007, and July 31, 2012. Participants were randomly assigned to one of six treatment groups.

A total of 1847 participants received up-front treatment. These patients took oral anastrozole 1 mg, exemestane 25 mg, or letrozole 2.5 mg once daily for 5 years. A total of 1850 patients were assigned to switch therapy. These patients received oral tamoxifen 20 mg once daily for 2 years followed by oral anastrozole 1 mg, exemestane 25 mg, or letrozole 2.5 mg once daily for 3 years.

The median time on tamoxifen was 24 months. The median time on the three aromatase inhibitors was 32 to 35 months in the switch group and 54 to 56 months in the up-front group.

Toxicity was the main reason for early treatment interruption. This was seen more frequently in patients treated with tamoxifen (11%) than in those treated with aromatase inhibitors (5% in the switch group and 7% in the up-front group).

Endometrial side effects were the most frequent reason for tamoxifen interruption (4%). Three percent of patients in the switch group and 4% in the up-front group experienced grade 3-4 musculoskeletal side effects.

A total of 85 patients were diagnosed with a second nonbreast cancer. Five patients were diagnosed after breast cancer recurrence.

There were 138 deaths, including 80 participants treated using the switch schedule and 58 patients treated using the up-front schedule. Breast cancer was the most frequent cause of death in both groups: 55 participants (3%) in the switch group, and 30 (2%) in the up-front group.

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Acne in Adolescents Linked With Dairy Intake–Again


The association between acne in adolescents and dairy consumption is supported by 2 recent studies, bringing renewed interest in the long-established hypothesis of this link.

The association between dairy intake and acne in teenagers has gained renewed interest with 2 new studies supporting the hypothesis that acne is linked with diet. Conflicting accounts exist about the significance of different types of milk as contributing factors, however, and the cause of acne is still unknown despite several studies.1,2 Dermatologists are still somewhat polarized in their opinion on the role of diet in acne, and it remains a controversial topic.3

A new study by Professor Maria Ulvestad and colleagues of Oslo University Hospital, Norway, published in the March 2017 issue of the Journal of the European Academy of Dermatology and Venereology, supports the argument for a connection between high consumption of milk and moderate-to-severe acne in adolescents.

According to the researchers, acne affects a significant percentage of adolescents. It leads to a reduced quality of life similar to chronic conditions like diabetes and arthritis, so it is of scientific and economic importance to understand the underlying cause.4

“Considering the extensiveness of acne, a great interest exists to reveal and comprehend its possible causative factors,” the authors point out. “Much is known about the pathophysiology of acne that eventually leads to a chronic inflammation in pilosebaceous units. What provokes these events to happen, however, is not fully understood. During the last decade, the acne-diet connection has been brought back to credibility, after being considered a myth for a long time. This hypothesis suggests that consumption of different foods influence the occurrence of acne.”4

In this latest study, adolescent participants were provided with a questionnaire for the self-assessment of their acne, and analyses of the results were done by separating the adolescents into 2 groups: those with no-to-little acne vs those with moderate-to-severe acne. The researchers then compared the level of dairy product consumption between the 2 groups, with further subgroup analyses differentiating the dairy consumed based on fat content, whether intake was low or high, as well as on gender.4

The investigators were unable to establish a link between low-fat or skim milk and acne, but instead, found that a correlation exists between high intakes of full-fat dairy products, defined as greater than or equal to 2 glasses per day, and moderate-to-severe acne.4

Low-fat dairy and acne

A slightly earlier study by Andrea Zaenglein, MD, and colleagues from the Pennsylvania State University College of Medicine, “Consumption of dairy in teenagers with and without acne,” was published in the August 2016 issue of the Journal of the American Academy of Dermatology. This study, which was supported by the American Acne and Rosacea Society, also showed a positive link with acne when including milk in the diet, but the association was only found with low-fat or skim milk, not full-fat milk or other dairy products.3 In this study, a dermatologist classified acne using the Global Acne Assessment Scale and, as with the 2017 study, self-reporting of dairy intake was included.3

“There are 4 main factors in the pathogenesis of acne: increased sebum (or oil) production from the glands in the skin, increased hyperkeratinization where the skin cells at the pores get sticky and build up blocking the pore outlet, an increase bacteria in the pore called Propionibacterium acnes, and inflammation. All of these factors are intertwined, each making the other worse. They are also influenced by such factors as diet and genetics,” Dr. Zaenglein told MedPage Today.

“The discussion was quiescent for years until a study found virtually no acne in select non-Westernized populations, leading researchers to infer that a Western diet may be to blame. Subsequent studies suggested an association between dairy, particularly skim milk and acne,” the authors also report.3

These contradictory findings in the literature may be a direct result of methodological limitations, and this should be given consideration when interpreting the results. However, whether full-fat or low-fat/fat-free dairy plays a significant role in the prevalence of acne in adolescents, both recent studies support the previous data linking milk intake with acne.1,5

“This is very controversial and the data is mixed to be sure. There are known differences in skim versus whole milk, however. Whole milk has natural Vitamin A and D. In skim milk, it is removed and replaced after the fat is skimmed off. So, absorption might be affected. Whole milk contains some additional beneficial components such as medium chain fatty acids that promote healthy metabolism and decrease insulin resistance, as well as conjugated linoleic acid and monounsaturated fatty acids,” said Dr. Zaenglein.

The more recent results from the 2017 study suggest there may be gender differences. Data indicate an association between acne and high total dairy consumption in female adolescents, compared with a greater magnitude of association between acne and high consumption of exclusively full-fat dairy in male adolescents. It is stated though, that any gender differences observed may be confounded by other gender-specific variables such as diet preferences or some behavioral or environmental factors like smoking or exercise.4

Data support dairy intake link with acne

It appears that the role of dairy in our overall health is a complex issue. Earlier studies report that milk causes an elevated insulinemic response and promotes an increase in insulin-like growth factor-1. It may be possible that this spike in insulin encourages phosphorylation of the transcription factor Foxhead box protein O1 (Fox01), thereby resulting in the activation of the mammalian target of rapamycin complex 1 (mTORC1) receptor and thus the stimulation of the sebaceous glands. These findings reveal a common mechanism of action for antiacne treatments and may provide a route to the development of new medication.3,6

“We have no explanation for why we solely found association with full-fat dairy products, and not with semi-skimmed or skimmed products. It has been proposed that different manufacturing processes of cow’s milk might alter the composition of other bioactive substances, as well as the intended change in fat content. Milk is a complex fluid, containing different proteins, carbohydrates and steroid hormones etc., which are likely to influence endogenic and possibly acne-promoting pathways. Lately, the ability of cow’s milk to increase IGF-1 and insulin levels in vivo has received much attention,” reported the authors of the 2017 study.

Although there were certain limitations of the 2017 study, the authors did highlight that their consistent results for full-fat dairy association support the hypothesis that dairy intake may be a relevant, contributing factor to acne.4

Future directions

The manufacturing process of skim milk where fat-soluble vitamins A and D are removed from full-fat milk and reintroduced later to the low-fat product may warrant further investigation to study the bioavailability and distribution of essential vitamins compared with full-fat milk.3

“Since I am a dermatologist and not a nutritionist, important next steps in research that need to be done before we make firm dietary recommendations to patients would be to see if switching from skim milk to whole milk actually makes a difference in acne,” Dr. Zaenglein concluded.

 

In Insane Coffee-Drinking Study, Coffee Appears to Be the Anti-Cannabis


Coffee has been the world’s favorite stimulant for hundreds of years, yet scientists are only now figuring out its impact on human health. In a new Journal of Internal Medicine study, scientists report that the addictive beverage has a unique impact on a person’s metabolism. In particular, coffee changes the metabolism of steroids and neurotransmitters that are usually associated with another of our favorite drugs — cannabis.

At the base level, the international team of researchers reported on Thursday, coffee shifts the levels of certain metabolites, which are chemicals in the blood that spike or drop after we eat or drink. Extremely heavy coffee drinking caused neurotransmitters related to the stress-regulating endocannabinoid system to decrease — which is the opposite of what happens after a person smokes marijuana. The researchers reasoned that the decrease in metabolites could be the body’s way of trying to get stress levels back to equilibrium after getting so hyped up on coffee.

“These are entirely new pathways by which coffee might affect health,” lead author Marilyn Cornelis, Ph.D., an assistant professor of preventative medicine at Northwestern University, explained in a statement released Thursday. “Now we want to delve deeper and study how these changes affect the body.”

Math explains how to make the perfect cup of coffee.
Scientists are still learning exactly how coffee impacts health.

For three months, the 47 study participants willingly let the scientists screw with their coffee schedule. In the first month, they didn’t drink any coffee; in the second month, they moved up to four cups a day; and in the third month, they slurped down eight cups a day (four more than what’s recommended as the healthy limit). Then, the scientists examined the hundreds of metabolites floating around in the blood samples collected after each stage of the study.

Heavy coffee drinking appeared to raise the number of metabolites linked to the androsteroid system, which helps the body get rid of steroid molecules. But the scientists also found that the blood metabolites related to the endocannabinoid system metabolic pathway decreased with coffee consumption, especially when participants were drinking eight cups of coffee a day. The endocannabinoid system regulates a wide range of functions in the body, including stress.

The body naturally produces endocannabinoids, which mimic the cannabinoid activity caused by chemicals in marijuana. But when a person smokes weed, endocannabinoid blood metabolites increase in the system — the opposite of what happens when you drink coffee.

What happens when you drink weed-infused coffee is a whole other question scientists have yet to figure out — and with the rapid legalization of marijuana, it may have to be a scientific puzzle they need to figure out soon.

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