Yftach Gepner, MPH (1); Rachel Golan, RD, PhD (1); Ilana Harman-Boehm, MD; Yaakov Henkin, MD; Dan Schwarzfuchs, MD; Ilan Shelef, MD; Ronen Durst, MD; Julia Kovsan, MSc; Arkady Bolotin, PhD; Eran Leitersdorf, MD; Shoshana Shpitzen, MA; Shai Balag, MD; Elad Shemesh, MD; Shula Witkow, RD, MPH; Osnat Tangi-Rosental, BA (2); Yoash Chassidim, PhD; Idit F. Liberty, MD; Benjamin Sarusi, MSc; Sivan Ben-Avraham, RD, MPH; Anders Helander, PhD; Uta Ceglarek, PhD; Michael Stumvoll, MD; Matthias Blüher, MD; Joachim Thiery, MD; Assaf Rudich, MD, PhD; Meir J. Stampfer, MD, DrPH; Iris Shai, RD, PhD
* Mr. Gepner and Dr. Golan contributed equally to this work.
This article was published online first at www.annals.org on 13 October 2015.
Acknowledgment: The authors thank the CASCADE participants for their consistent cooperation. They thank Harel Segal from Nuclear Research Center Negev; Dr. Lena Novak, Dr. Michael Friger, Dr. Arie Moran, Dr. Amos Katz, Noa Cohen, Michal Rein, Nitzan Bril, and Dana Serfaty from Ben-Gurion University of Negev; Dr. Tatiana Shuster, Sagit Saadon, Malka Kaminsky, Yasmin Asuly, Roman Tsirkin, and David Shushan from Soroka Medical Center; Eyal Goshen, Meir Aviv, Hassia Krakauer, Haim Strasler, Dr. Ziva Schwartz, Dr. Einat Sheiner, Dr. Dov Brickner, Dr. Rachel Marko, Esther Katorza, Ilanit Asulin, and Tzvika Tzur from Nuclear Research Center Negev; and Dr. Rosa M. Lamuela-Raventos, University of Barcelona.
Grant Support: By the European Foundation for the Study of Diabetes of the European Association for the Study of Diabetes.
Disclosures: The authors have no relationship with the companies that make products relevant to the manuscript. Drs. Shai and Bolotin had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Dr. Bluüher reports compensation as a board member of Novartis Pharmaceuticals, Boehringer Ingelheim, and Sanofi; compensation as a consultant for Novo Nordisk, Eli Lilly Pharmaceuticals, and AstraZeneca; and payment for lectures (including service on speakers bureaus) for Sanofi, Eli Lilly Pharmaceuticals, Novo Nordisk, Bayer HealthCare Pharmaceuticals, AstraZeneca, Novartis Pharmaceuticals, and Berlin-Chemie outside of the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-1650.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.
Reproducible Research Statement:Study protocol: Available from Dr. Shai (e-mail, firstname.lastname@example.org). Statistical code and data set: Not available.
Requests for Single Reprints: Iris Shai, RD, PhD, Department of Public Health, The S. Daniel Abraham International Center for Health and Nutrition, Ben-Gurion University of the Negev, PO Box 653, Beer Sheva, 8410501, Israel; e-mail, email@example.com.
Current Author Addresses: Drs. Golan, Bolotin, Rudich, and Shai; Mr. Gepner, Ms. Kovsan, Ms. Witkow, Ms. Tangi-Rosental, and Ms. Ben-Avraham: Department of Public Health, Ben-Gurion University of the Negev, PO Box 653, Beer Sheva, 8410501, Israel.
Drs. Harman-Boehm, Henkin, Shelef, Shemesh, Chassidim, and Liberty: Soroka Medical Center, Rager Boulevard, PO Box 151, Beer Sheva, 85025, Israel.
Dr. Schwarzfuchs and Mr. Sarusi: Nuclear Research Center Negev, 16th Beth Lethem Street, Dimona, 8477605, Israel.
Drs. Durst, Leitersdorf, Balag; and Ms. Spitzen: Hadassah Hebrew University Medical Center, Kiryat Hadassah, PO Box 12000, Jerusalem, 91120, Israel.
Dr. Helander: Department of Laboratory Medicine, H5, Division of Clinical Chemistry, CI:74, Karolinska Institute, Karolinska University Laboratory Hudding, Stockholm, SE-14186, Sweden.
Drs. Ceglarek, Stumvoll, Blüher, and Thiery: Department of Diagnostics, University of Leipzig, Paul List Street 13-15, 04103 Leipzig, Germany.
Dr. Stampfer: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard School of Public Health, 181 Longwood Avenue, Boston, MA 02115.
Author Contributions: Conception and design: Y. Gepner, I. Harman-Boehm, Y. Henkin, D. Schwarzfuchs, I. Shelef, R. Durst, E. Shemesh, S. Witkow, M. Stumvoll, A. Rudich, M.J. Stampfer, I. Shai.
Analysis and interpretation of the data: Y. Gepner, R. Golan, I. Harman-Boehm, I. Shelef, R. Durst, J. Kovsan, A. Bolotin, S. Shpitzen, E. Shemesh, Y. Chassidim, A. Helander, U. Ceglarek, M. Stumvoll, M. Bluüher, A. Rudich, M.J. Stampfer, I. Shai.
Drafting of the article: Y. Gepner, R. Golan, Y. Henkin, D. Schwarzfuchs, I. Shelef, R. Durst, J. Kovsan, A. Helander, U. Ceglarek, M. Stumvoll, A. Rudich, M.J. Stampfer, I. Shai.
Critical revision of the article for important intellectual content: Y. Gepner, I. Harman-Boehm, Y. Henkin, I. Shelef, R. Durst, J. Kovsan, E. Shemesh, A. Helander, M. Stumvoll, M. Bluüher, J. Thiery, A. Rudich, I. Shai.
Final approval of the article: Y. Gepner, R. Golan, I. Harman-Boehm, Y. Henkin, D. Schwarzfuchs, I. Shelef, R. Durst, J. Kovsan, A. Bolotin, E. Leitersdorf, E. Shemesh, I.F. Liberty, B. Sarusi, A. Helander, U. Ceglarek, M. Stumvoll, M. Bluüher, J. Thiery, A. Rudich, M.J. Stampfer, I. Shai.
Provision of study materials or patients: Y. Gepner, R. Golan, I. Harman-Boehm, Y. Henkin, D. Schwarzfuchs, R. Durst, S. Witkow, O. Tangi-Rosental, I.F. Liberty, I. Shai.
Statistical expertise: R. Golan, R. Durst, A. Bolotin.
Obtaining of funding: Y. Gepner, R. Durst, M. Stumvoll, I. Shai.
Administrative, technical, or logistic support: I. Shelef, J. Kovsan, E. Leitersdorf, S. Balag, E. Shemesh, O. Tangi-Rosental, B. Sarusi, M. Stumvoll.
Collection and assembly of data: Y. Gepner, R. Golan, Y. Henkin, D. Schwarzfuchs, I. Shelef, R. Durst, J. Kovsan, E. Shemesh, S. Witkow, O. Tangi-Rosental, I.F. Liberty, B. Sarusi, S. Ben-Avraham, M. Bluüher, A. Rudich, I. Shai.
Gepner Y., Golan R., Harman-Boehm I., Henkin Y., Schwarzfuchs D., Shelef I., Durst R., Kovsan J., Bolotin A., Leitersdorf E., Shpitzen S., Balag S., Shemesh E., Witkow S., Tangi-Rosental O., Chassidim Y., Liberty I., Sarusi B., Ben-Avraham S., Helander A., Ceglarek U., Stumvoll M., Blüher M., Thiery J., Rudich A., Stampfer M., Shai I.; Effects of Initiating Moderate Alcohol Intake on Cardiometabolic Risk in Adults With Type 2 Diabetes: A 2-Year Randomized, Controlled Trial. Ann Intern Med. 2015;163:569-579. doi: 10.7326/M14-1650
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Published: Ann Intern Med. 2015;163(8):569-579.
Published at www.annals.org on 13 October 2015
Recommendations for moderate alcohol consumption remain controversial, particularly in type 2 diabetes mellitus (T2DM). Long-term randomized, controlled trials (RCTs) are lacking.
To assess cardiometabolic effects of initiating moderate alcohol intake in persons with T2DM and whether the type of wine matters.
2-year RCT (CASCADE [CArdiovaSCulAr Diabetes & Ethanol] trial). (ClinicalTrials.gov: NCT00784433)
Ben-Gurion University of the Negev–Soroka Medical Center and Nuclear Research Center Negev, Israel.
Alcohol-abstaining adults with well-controlled T2DM.
Patients were randomly assigned to 150 mL of mineral water, white wine, or red wine with dinner for 2 years. Wines and mineral water were provided. All groups followed a Mediterranean diet without caloric restriction.
Primary outcomes were lipid and glycemic control profiles. Genetic measurements were done, and patients were followed for blood pressure, liver biomarkers, medication use, symptoms, and quality of life.
Of the 224 patients who were randomly assigned, 94% had follow-up data at 1 year and 87% at 2 years. In addition to the changes in the water group (Mediterranean diet only), red wine significantly increased high-density lipoprotein cholesterol (HDL-C) level by 0.05 mmol/L (2.0 mg/dL) (95% CI, 0.04 to 0.06 mmol/L [1.6 to 2.2 mg/dL]; P < 0.001) and apolipoprotein(a)1 level by 0.03 g/L (CI, 0.01 to 0.06 g/L; P = 0.05) and decreased the total cholesterol–HDL-C ratio by 0.27 (CI, −0.52 to −0.01; P = 0.039). Only slow ethanol metabolizers (alcohol dehydrogenase alleles [ADH1B*1] carriers) significantly benefited from the effect of both wines on glycemic control (fasting plasma glucose, homeostatic model assessment of insulin resistance, and hemoglobin A1c) compared with fast ethanol metabolizers (persons homozygous for ADH1B*2).
Across the 3 groups, no material differences were identified in blood pressure, adiposity, liver function, drug therapy, symptoms, or quality of life, except that sleep quality improved in both wine groups compared with the water group (P = 0.040). Overall, compared with the changes in the water group, red wine further reduced the number of components of the metabolic syndrome by 0.34 (CI, −0.68 to −0.001; P = 0.049).
Participants were not blinded to treatment allocation.
This long-term RCT suggests that initiating moderate wine intake, especially red wine, among well-controlled diabetics as part of a healthy diet is apparently safe and modestly decreases cardiometabolic risk. The genetic interactions suggest that ethanol plays an important role in glucose metabolism, and red wine's effects also involve nonalcoholic constituents.
European Foundation for the Study of Diabetes.
David Louis Keller, MD
October 13, 2015
Dilute wine, especially for diabetics
Epidemiologic evidence suggests that people with diabetes are at significantly higher risk for many forms of cancer . It has also been observed that cancer patients with pre-existing diabetes experience higher mortality than cancer patients without diabetes . The randomized controlled trial by Gepner and colleagues confirmed prior observations that moderate ethanol consumption is associated with improved cardiometabolic risk in diabetics and in other groups .A large observational study reported data on cancer and other harms among drinkers whose usual alcoholic beverage was wine, beer or spirits . A dose-response relationship was identified between the concentration of ethanol in the beverage of choice, and the incidence of cancers among those who consumed it . The risk of cancer for drinkers of beer (which contains about 5% ethanol), wine (12% ethanol) and distilled spirits (40% ethanol) were each divided by the cancer risk for teetotalers to yield respective cancer harm ratios (HRs) of 1.2, 1.38 and 1.69; note the dose-response relationship between the ethanol concentration in a beverage, and cancer rates for those who drink that beverage. The cancer HR for beer drinkers was not statistically significantly elevated above that for teetotalers, but its trend is consistent with the proposed dose-response relationship.Given the elevated risk of cancer in diabetics, and a risk of cancer in drinkers of alcoholic beverages which increases monotonically with the concentration of ethanol in the beverage, it seems prudent for diabetics who consume ethanol to dilute their beverage of choice to a concentration of 5% or less. Wine can be diluted to 4% ethanol by combining one part wine with two parts water or juice.References:1: Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA,Pollak M, Regensteiner JG, Yee D. Diabetes and cancer: a consensus report.Diabetes Care. 2010 Jul;33(7):1674-85. doi: 10.2337/dc10-0666. PubMed PMID:20587728; PubMed Central PMCID: PMC2890380.2: Ranc K, Jørgensen ME, Friis S, Carstensen B. Mortality after cancer amongpatients with diabetes mellitus: effect of diabetes duration and treatment.Diabetologia. 2014 May;57(5):927-34. doi: 10.1007/s00125-014-3186-z. Epub 2014Mar 15. PubMed PMID: 24633676.3: Gepner Y, Golan R, Harman-Boehm I, Henkin Y, Schwarzfuchs D, Shelef I, et al. Effects of Initiating Moderate Alcohol Intake on Cardiometabolic Risk in Adults With Type 2 Diabetes: A 2-Year Randomized, Controlled Trial. Ann Intern Med. [Epub ahead of print 13 October 2015] doi:10.7326/M14-16504: Smyth A, Teo KK, and the PURE Investigators. Alcohol consumption and cardiovasculardisease, cancer, injury, admission to hospital, and mortality: a prospective cohort study. Lancet. 2015 Sep 17. doi:10.1016/S0140-6736(15)00235-4. PubMed PMID: 26386538.5: Keller DL. Dose-response relationship observed between concentration of ingested alcohol and cancer rate. Comment on PMID 26386538. In: PubMed Commons [Internet]. National Library of Medicine; 2015 Sept 26 [cited 2015 Oct 12]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26386538#cm26386538_11980
Gianni Testino, Tiziana Fanucchi, Emanuele Scafato, Valentino Patussi, Paolo Borro
Centro Alcologico Regionale-Regione Liguria, World Health Organization, 4) National Institute for Health
October 21, 2015
Alcohol and cardiometabolic risk
The Authors suggest that initiating moderate wine intake among diabetics as part of a healthy diet is apparently safe and modestly decreases cardiometabolic risk. Wisely, they conclude that this benefit should be weighed against potential risks when translated into clinical practice.Alcohol and cardiovascular disease is controversial and difficult chapter to discuss even within the scientific community.Scientists are human and tend to defend their drinking and involuntarily remember the alleged positive effects of moderate consumption without reporting the negative ones. In fact all the descriptions that typically seek to define drinking (moderate, social, controlled) are in fact in its defense. The concept of moderate drinking has no meaning because so-called “moderate drinking” has not been scientifically defined and cannot be described either by frequency or amount. Everyone sees their own drinking as moderate. Higashiyama et al (2) evidenced how alcohol consumption is linearly related to increased blood pressure, arrhythmias (mainly atrial fibrillation) and haemorragic stroke.More recently the work of Whitman et al. (3) has confirmed these data. It sets the basis for a constructive discussion on the correlation of alcohol and health. It shows that in the cardio-vascular system with the same dose estimates alcohol increases the risk of mortality, hypertension and arrhythmia.In addition, recent evidence found with more sophisticated methods have strongly questioned the protective effect (4).To date, however, the scientific evidence has repeatedly stated that moderate doses reduce the risk of ischemic heart disease and diabetes mellitus type II (5), but the information is not provided in full (6):- the number of preventable deaths is much lower than the deaths caused;- with the same dose it favors cancer and many other different diseases.Scientific honesty in conjunction with a valid medical culture, however, requires the completion of this current truth with the same doses favoring cardiovascular diseases and cancer.This goes especially for cancers of the oral cavity, pharynx, larynx, esophagus and breast. For slightly higher dosages other tumors (intestine, liver, pancreas) are favored (7, 8, 9, 10).In fact, ethanol is not a nutrient, but a substance of nutritional interest as it provides 7 kilocalories per gram. This definition is found in the latest draft of the Assumption of Reference Levels of Nutrients and Energy for the Italian Population by the Italian National Institute of Research on Food and Nutrition (11). The doctor, therefore, as part of a cost-benefit assessment has a duty to properly inform his patient. Only in this way can it be a free choice. In fact, subjects with a moderate consumption who recognize a protective effect consume on average 50% more than those who do not recognize this property in alcohol (3).It is worth recalling that in reality consumption corresponding to a lower risk of death is as follows: 0 grams / day for subjects under 35 years old. 5 grams / day for middle-aged men and about 8 grams / day for those over 65 years old. For women: 0 grams / day for those between 35 and 64 years old and 5 grams / day for those over 65 years / old (12, 13).World Health Organization suggests that a greater reduction in death from ischaemic disease can be more effectively obtained by being physically active and eating a healthier diet than by drinking a low dose of alcohol (6, 14, 15)It is necessary, therefore, that physicians take on a leadership role in the area of alcohol-related problems, defend the public’s health without any ifs and buts, override “personal opinions” and ignore pressure from the media and advertising that encourages alcohol consumption even in the youngest of consumers.1) Gepner Y, Golan R, Harman-Boem I, Henkin Y, Schwarzfuchs D, Shelef I et al. Effects of initiating moderate alcohol intake on cardiometabolic risk in adults with type 2 diabetes. Ann Intern Med 2015; doi: 10.7326/M14-16502) Higashiyama A, Okamura T, Watanabe M et al. Alcohol consumption and cardiovascular disease incidence in men with and without hypertension: the Suita study. Hypertens Res 2013; 36: 58-643) Whitman IR, Pletcher MJ, Vittinghoff E et al. Perceptions, information sources, and behavior regarding alcohol and hearth health. Am J Cardiol 2015; http://dx.doi.org/10.1016/j.amjcard.2015.05.0294) Holmes MV, Dale CE, Zuccolo L et al. InterAct Consortium. Association between alcohol and cardiovascula disease: Mendelian randomization analysis on individual participant data. BMJ 2014; 349: g41645) Poli A, Marangoni F, Avogaro A et al. Moderate alcohol use and health: a consensus document. Nutrition, Metabolism and Cardiovascula Disease 2013; 23: 487-5046) Testino G, Borro P, Ancarani O, Sumberaz A. Cardiovascular disease and cancer. Alcohol Alcohol 2013; 48: 627-6287) IARC. A review of human carcinogens. IARC Monogr Eval Carcinog Risks Hum 2012; 100E: 377-478
Michelangela Barbieri, Maria Rosaria Rizzo, Giuseppe Paolisso, Raffaele Marfella
Second University of Naples
October 28, 2015
The carefully conducted study by Gepner Y and co-workers (1) reports that that initiating moderate wine intake, especially red wine, among well-controlled diabetics as part of a healthy diet is apparently safe and modestly decreases cardiometabolic risk in type 2 diabetic patients. About 10 years ago, we made the similar observations except for the fact that we have also highlighted, in type 2 diabetic patients after myocardial infarction (MI), the potential beneficial effects of moderate red wine intake on ischemic risk factors as well as on intermediate cardiac outcome. In our study, moderate consumption of red wine with meals was associated with a significant reductions in oxidative stress and inflammatory reaction and improvement of cardiac function in middle-aged diabetic survivors of a recent MI. Heart function, assessed by echocardiographic parameters of cardiac synchronization, improved significantly in the red wine group. In particular, moderate red wine intake resulted in significant improvement of dyssynchrony between right and left ventricular contraction and relaxation (2). Studies have identified dyssynchrony between right and left ventricular contraction and relaxation as an independent predictor of heart failure and cardiac mortality in patients with heart failure and cardiac ischemic diseases (3). Thus, the improvement of cardiac function suggests that moderate red wine intake may reduce cardiovascular complications after MI in subjects with diabetes. As background for this association, the reduction of both inflammatory cytokines and oxidative stress may explain the improved cardiac outcome in diabetic patients taking red wine after MI. It is now well recognized that a moderate alcohol intake has a favorable effect on cardiovascular disease in subjects with diabetes (4). However, it should be stressed that red wine consumption causes a decrease in oxidative stress and inflammatory cytokines independently of the alcohol content of the wine through polyphenols activities (5). Thus, moderate red wine intake may provide another safe method for down-regulating oxidative stress and inflammation in subjects with diabetes, and thus reduce cardiovascular complications after MI. References1. Gepner Y, Golan R, Harman-Boehm I, Henkin Y, Schwarzfuchs D, Shelef I, et al. Effects of Initiating Moderate Alcohol Intake on Cardiometabolic Risk in Adults With Type 2 Diabetes: A 2-Year Randomized, Controlled Trial. Ann Intern Med. 2015 Oct 13. doi: 10.7326/M14-1650.2. Marfella R, Cacciapuoti F, Siniscalchi M, Sasso FC, Marchese F, Cinone F, et al. Effect of moderate red wine intake on cardiac prognosis after recent acute myocardial infarction of subjects with Type 2 diabetes mellitus. Diabet Med. 2006;23:974-8188.3. Poulsen SH, Jensen SE, Tei C, Seward JB, Egstrup K. Value of the Doppler index of myocardial performance in the early phase of acute myocardial infarction. J Am Soc Echocardiogr 2000; 13: 723–730.4. Solomon CG, Hu FB, Stampfer MJ, Colditz GA, Speizer FE, Rimm EB et al. Moderate alcohol consumption and risk of coronary heart disease among women with type 2 diabetes mellitus. Circulation 2000; 102:494–499.5. Feng YH, Zou JP, Li XY. Effects of resveratrol and ethanol on production of pro-inflammatory factors from endotoxin-activated murine macrophages. Acta Pharmacol 2002; 23: 1002–1006..
Eirion Slade, Henry Drysdale, Ben Goldacre
COMPare project team, Centre for Evidence Based Medicine, Oxford University
November 9, 2015
Discrepancies between prespecified and reported outcomes in the trial “Effects of Initiating Moderate Alcohol Intake on Cardiometabolic Risk in Adults With Type 2 Diabetes: A 2-Year Randomized, Contro
Dear Editor,Your recent publication “Effects of Initiating Moderate Alcohol Intake on Cardiometabolic Risk in Adults With Type 2 Diabetes: A 2-Year Randomized, Controlled Trial”  reports outcomes that are different to those initially registered .There was 1 pre-specified primary outcome, which was reported incorrectly as a secondary outcome in the main paper. In addition, the paper reports 5 “primary outcomes” that were not pre-specified, without flagging them as such. There was also 1 pre-specified secondary outcome, which is not reported anywhere in the publication. In addition, the paper reports 9 new secondary outcomes, which were not pre-specified, without flagging them as such.Annals of Internal Medicine has endorsed the CONSORT guidelines  on best practice in trial reporting. In order to reduce the risk of selective outcome reporting, CONSORT includes a commitment that all pre-specified primary and secondary outcomes should be reported; and that, where new outcomes are reported, it should be made clear that these were added at a later date, with an explanation of when and for what reason.This letter has been sent as part of the COMPare project . We aim to review all trials published from now in a sample of top journals, including Annals of Internal Medicine. Where outcomes have been incorrectly reported we are writing letters to correct the record, and to audit the extent of this problem, in the hope that this will reduce its prevalence. We hope that you will publish our letter. Since this trial is now published and being used to inform decision making, and since this is a brief correction, on a matter of fact, from comparing two documents in the public domain, we also hope there will be no need for a lengthy review process or a publication delay awaiting an authors’ reply. We are maintaining a website at COMPare-Trials.org where we will be posting the submission date and publication date of this letter, alongside a summary of the data on each trial and journal.Many thanks,Eirion Slade, Henry Drysdale, Ben Goldacre on behalf of the COMPare project team. Gepner, Y., Golan, R., Harman-Boehm, I., Henkin, Y., Schwarzfuchs, D., Shelef, I., ... & Shai, I. (2015). Effects of Initiating Moderate Alcohol Intake on Cardiometabolic Risk in Adults With Type 2 Diabetes: A 2-Year Randomized, Controlled Trial. Annals of Internal Medicine, 163(8), 569-579. https://clinicaltrials.gov/ct2/show/NCT00784433 Moher D et al, CONSORT 2010 Explanation and Elaboration: updatedguidelines for reporting parallel group randomised trials, BMJ 2010; 340:c869. COMPare project website www.COMPare-Trials.org
November 6, 2015
CASCADE: from science news to sciensationalism
The alcohol industry has transformed an addictive carcinogen in a free lifestyle choice with massive marketing and advertising.($3.5 billion in 2011, according to the Federal Trade Commission, http://www.adweek.com/news/advertising-branding/ftc-study-revealshow-alcohol-advertisers-use-digital-marketing-156430) It does not seem necessary to promote it as healthy! The editors have overplayed scientific findings about incomplete and complex facts in their “summary for patients” about CASCADE: “This long-term trial showed that a healthy diet and moderate (no amount) alcohol intake, particularly red wine, were associated with better lipid and glucose control than water and had no significant harmful effects.”(1)This is even more surprising as Gepner et al clearly underlined limitations: a very specific population (well-controlled diabetics, alcohol abstainers, non-smokers), un-blinded study without placebo (eg. no grape juice), surrogate endpoints.(2) Gepner et al also cautiously concluded “MODESTLY decreases cardiometabolic risk” and was “APPARENTLY safe.” In summary, despite a 2 years of follow-up, which must be commended, this remains a kind of phase II study.The “French paradox”, from studies sponsored and publicized by the alcohol lobby, is not observed when avoiding selection bias (see in 3) and moderate alcohol consumption is not associated with reduced all-cause mortality.(4) Moreover, alcohol consumption causes a dose related increase in prevalence of oral cavity, pharynx, esophagus, breast cancers, beginning at the 1-2 drink/day level (the dose in CASCADE).(see in 3) Considering the two-fold increase in cancer risk in type 2 diabetes, this is a major issue. Last, the public health issue cannot be ignored. The one third of Health eHeart participants who believed alcohol to be heart healthy drank substantially more alcohol than the others and cited the lay press as the origin of that perception.(5) Hits from “diabetes wine” on Google news provide alarming results and the consequence of sciensationalism (sensationalism in science) cannot be ignored. The American Heart Association states “If you drink alcohol, do so in moderation. Drinking more alcohol increases such dangers as alcoholism, high blood pressure, obesity, stroke, breast cancer, suicide and accidents” and the College wisely comments: “as Saint Augustine put it, is that “complete abstinence is easier than perfect moderation.”(https://www.acc.org/latest-in-cardiology/articles/2015/01/05/13/06/alcohol-consumption-and-cvd-the-case-for-moderation?w_nav=LC)Last, could Gepner et al provide a) data about the socio-economic characteristics of their population; b) a rough estimate of the proportion of participants recruited among their cohort of patients with type 2 diabetes.1 Annals of Internal Medicine. Moderate wine intake in adults with type 2 diabetes. Ann Intern Med 2015;163:I-34.2 Gepner Y, Golan R, Harman-Boehm I , Henkin Y, Schwarzfuchs D, Shelef I et al. Effects of initiating moderate alcohol intake on cardiometabolic risk in adults with type 2 diabetes. A 2-Year randomized, rontrolled trial.” Ann Intern Med 2015;163:569-579. 3 Braillon A. No benefit to die from cancer with healthy coronary arteries, except in France. Am J Cardiol 2015;116:1646-164.4 Goulden R. Moderate alcohol consumption is not associated with reduced all-cause mortality. Am j Med 2015. Online 6 October. doi: 10.1016/j.amjmed.2015.10.013. 5 Whitman IR, Pletcher MJ, Vittinghoff E, Imburgia KE, Maguire C, Bettencourt L et al. Perceptions, information sources, and behavior regarding alcohol and heart health. Am J Cardiol 2015;11:642-6.
Douglas G Altman
Centre for Statistics in Medicine, University of Oxford, Oxford, UK
November 11, 2015
Misleading presentation and analysis of a randomized trial of wine versus water
In their most common form, randomized trials compare groups of individuals receiving different interventions studied simultaneously. Each participant receives one intervention selected at random at enrolment. Usually the probabilities of being allocated each treatment are equal (e.g. allocation ratio of 1:1). It is implicit that all participants have the same probability of receiving each of the treatments. That principle is violated if the allocation ratio is changed, for example from 1:1 to 1:2, part way through the trial. Although all participants are randomised to one of the same set of possible treatments, bias can arise because the sets of participants recruited in the two phases of the trial may differ – for example those recruited in the second part may be healthier than those in the first part. The correct approach here is to analyze separately the data for each part of the trial and then combine the results. A more extreme situation arises when, within a trial, there is variation in which interventions participants might receive. This is what happened in the recent trial of wine vs water among abstaining diabetic patients. In one center and for many participants in the other center participants were randomised in a 1:1 ratio to drink mineral water or red wine daily. But some participants in the second center were randomised to mineral water, red wine or white wine in ratio 1:1:3. The inclusion of the white wine group appears to have been an afterthought, with allocation ratios chosen to try to make the total numbers similar in the 3 groups. The comparison between water and red wine is entirely valid. But those allocated to white wine should only be compared to those in the other groups who were randomised in the same process, those in that part of one center where a 1:1:3 allocation ratio was used. It is wrong to analyze the complete data set as if this was a true 3-arm randomized trial.The table of baseline characteristics shows that the 3 groups were quite similar. However, the extreme variation in the distribution of genotypes is clearly a consequence of the fact that the white wine group were all from only one center. The text states explicitly that participants were randomized 1:1:1 between water, red wine or white wine. That statement is clearly untrue. Indeed not one participant was randomized in that way! This false idea is reinforced by the flow diagram and also the editors’ notes. 1. Armitage P, Borchgrevink CF. Prevention of recurrences of myocardial infarction. Comments on a previous article. Arch Intern Med 1966;118:270-4.2. Gepner Y, Golan R, Harman-Boem I, Henkin Y, Schwarzfuchs D, Shelef I et al. Effects of initiating moderate alcohol intake on cardiometabolic risk in adults with type 2 diabetes. Ann Intern Med 2015;163:569-579.
Ana Marina Moreira, Thizá M. Londero, Iuri M. Goemann, Beatriz D'Agord Schaan
Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
Cardiometabolic effects of CASCADE Trial explained by mediterranean diet
The CASCADE trial  is the first long-term randomized clinical trial that evaluated moderate wine consumption on glycaemia and lipid profile in an abstainer diabetic population. Patients were randomly assigned to regularly drink water, red wine or white wine on dinner and were also advised to follow a Mediterranean diet. They participated in group sessions guided by a clinical dietitian monthly for the first three months and quarterly thereafter, along 2 years. Some particularities of the study should be addressed. After the first 6 months of intervention all three groups showed an improvement in lipid profile, which was attenuated at the end of the study, suggesting an effect of diet intensification. Accordingly, a recent meta-analysis of controlled trials  showed that the Mediterranean diet is associated with improvement in glucose control (0.47% HbA1c reduction) and raised HDL cholesterol (mean difference: 1.54mg/dl) in diabetic patients, improving cardiovascular risk. Also, the reported difference in glucose control (decreased fasting plasma glucose) is not clinically relevant. Fasting plasma glucose is a transient parameter and this reduction might be explained by the ethanol-mediated acute hypoglycemic effect. Glycated hemoglobin (Hba1c), a more reliable measure of glucose control, was not different among groups at the end of the study. Indeed, fasting plasma glucose and HbA1c were evaluated in a 3-month trial  in which wine or non-alcoholic beverage at dinner and diet counseling were introduced into a population with similar characteristics of that of the CASCADE trial. While a reduction in fasting plasma glucose was found only in the wine group, HbA1c decreased in all groups, including placebo, suggesting an overall dietetic intervention benefit. Thus, the results reported in the CASCADE trial are, probably, mainly determined by the co-intervention (Mediterranean diet). There are no solid data to conclude that moderate alcohol intake would determine a real improvement on cardiometabolic risk in patients with diabetes.References Gepner Y, Golan R, Harman-Boehn I et al. Effects of Initiating Moderate Alcohol Intake on Cardiometabolic Risk in Adults With Type 2 Diabetes. Ann Intern Med 2015; 163: 569 – 579. Esposito K, Maiorino MI, Bellastella G, Chiodini P, Panagiotakos D, Giugliano D. A journey into a Mediterranean diet and type 2 diabetes: a systematic review with meta-analyses. BMJ Open 2015; 5: 1-10. Shai I, Wainstein J, Harman-Boehn I et al. Glycemic Effects of Moderate Alcohol Intake Among Patients with Type 2 Diabetes. Diabetes Care 2007; 30 (12): 3011-3016.
Richard Saitz, Timothy Naimi
Boston University School of Public Health, School of Medicine, and Boston Medical Center
November 10, 2015
Conflict of Interest:
No funding was received in support of this work.<br/>Dr. Naimi reports no conflicts.<br/>Dr. Saitz is and has been principal investigator of grants awarded to Boston Medical Center and Boston University from the National Institutes of Health (including NIAAA and NIDA, and the Substance Abuse and Mental Health Services Administration) to study the management of unhealthy substance use, including to test the accuracy of screening and the efficacy of screening, brief intervention and referral to treatment. He has been paid to speak or had travel reimbursed to speak at numerous professional and scientific organizations, all non-profit organizations for over a decade, such as the American Society of Addiction Medicine, the Research Society on Alcoholism, The BMJ, the Institute for Research and Training in the Addictions, the International Conference on Treatment of Addictive Behaviors, and the International Network on Brief Intervention for Alcohol and other drugs. I am an author and editor for Springer, UpToDate, the American Society of Addiction Medicine, the BMJ and the Massachusetts Medical Society (royalties and honoraria). Wolters Kluwer has supported conference travel to an editors’ meeting. In such roles, speaking and writing is often on or related to the topic of this letter. I have been paid to serve as an expert witness in malpractice cases related to the management of alcohol and other drug disorders. I am employed by Boston University School of Public Health.
Questionable conclusion of safety for a carcinogen that also increases risk for other acute and chronic diseases
We applaud Gepner et al. (1) for recognizing in doing a clinical trial that observational studies of purported health benefits of alcohol consumption are questionable. However, they report in both the abstract and similarly in their manuscript conclusions (where “wine” is replaced with “alcohol”), that “initiating moderate wine intake…is apparently safe.” They do also conclude there may be “potential risks” that should be weighed against benefits. Given that alcohol is a group 1 carcinogen (same category as plutonium and tobacco)(2) we do not find it appropriate to conclude safety from even a two year trial. In fact we wonder whether any other carcinogenic substance would be associated with a conclusion of safety based on clinical trial results. Furthermore, although not found in this trial, low amounts of alcohol consumption appear to be consistently associated with increased blood pressure, which would be particularly harmful to those with diabetes, and with injury, liver disease and violence (3,4). The Gepner et al. study conclusion appears to confirm the unusual status afforded to alcohol, which we speculate, among other reasons, relates to the fact that many people enjoy it and prefer to consider it as a nutritional component as opposed to a carcinogen and leading cause of preventable death in the world (5). As such any news of possible health benefit is welcome.1. Gepner Y, Golan R, Harman-Boehm I, Henkin Y, Schwarzfuchs D, Shelef I, et al. Effects of Initiating Moderate Alcohol Intake on Cardiometabolic Risk in Adults With Type 2 Diabetes: A 2-Year Randomized, Controlled Trial. Ann Intern Med. 2015;163:569-579.2. International Agency for Research on Cancer. Agents classified by the IARC monographs, vols 1–112. Available at:http://monographs.iarc.fr/ENG/Classification/index.php (accessed 8 November 2015).3. Chen L, Davey Smith G, Harbord RM, Lewis SJ (2008) Alcohol Intake and Blood Pressure: A Systematic Review Implementing a Mendelian Randomization Approach. PLoS Med 5(3): e52. doi:10.1371/journal.pmed.0050052 4. Corrao G, Bagnardi V, Zambon A, La Vecchia C: A meta-analysis of alcohol consumption and the risk of 15 diseases. Prev Med 2004, 38(5):613-619.5. Saitz, R. Alcohol: no ordinary health risk. Addiction 2015; 110, 1228–1229.
Annals of Internal Medicine
December 14, 2015
The COMPare Project (1) recently commented on 2 trials published in Annals of Internal Medicine (2, 3). This watchdog group aims to monitor the reporting of pre-specified outcomes in all clinical trials published in 5 top-tier medical journals, including Annals. Because these comments express concerns about “switched” or incompletely reported outcomes, we would like to describe our editorial process and potential reasons for the discrepancies noted by COMPare. We attempted to post a public comment on the COMPare website to express our concerns about their assessments, but there was no means for doing so.
We share COMPare’s overarching goals to assure the validity and reporting quality of biomedical studies, but we differ on how to best achieve those aims. We routinely ask authors of clinical trials to submit their protocols with their manuscripts, and we also examine trial registries for the initial and final information entered about trials. We review both because registries include only extracted information, do not routinely monitor whether the data in the registry match the protocol, and may not be updated when the protocol changes. We therefore rely primarily on the protocol for details about pre-specified primary and secondary outcomes, study interventions and procedures, and statistical analysis. Consistent with CONSORT recommendations, we ask authors to describe, either within the manuscript or in an appendix, any major differences between the trial registry and protocol, including changes to trial endpoints or procedures.
According to COMPare’s protocol (4), abstractors are to look first for a protocol that is published before the trial’s start date. If they find no such publication, they are supposed to review the initial trial registry data. Thus, COMPare’s review excludes most protocols published after the start of the trial, unpublished protocols or amendments, and ignores amendments or updates to the registry or protocols that occurred after the trial’s start date. The initial trial registry data, which often includes outdated, vague or erroneous entries, serves as COMPare’s “gold standard”.
Our review indicates problems with COMPare’s methods. For one trial (5) COMPare apparently considered the protocol (6) published well after data collection ended, but did not consider the protocol (7) published 2 years before MacPherson’s primary trial publication (3). The protocol (7) for MacPherson’s trial was more specific in describing the timing of the primary outcome (assessment of neck pain at 12 months) than the registry (assessment of neck pain at 3, 6 and 12 months). Yet, COMPare deemed the authors’ presentation of the 12 month assessment as primary within the trial publication to be “incorrect”. Similarly, COMPare’s assessment of the Gepner trial (2) included an erroneous assumption about one of the pre-specified primary outcomes, glycemic control, which the authors operationalized differently than the abstractors. Furthermore, the protocol for that trial clearly listed the secondary outcomes that COMPare deemed as being non-pre-specified.
Based on our long experience reviewing research articles, we have learned that pre-specified outcomes or analytic methods can be suboptimal or wrong. Regardless of pre-specification, we sometimes require that the published report improve upon the pre-specified methodology, or not emphasize an endpoint that misrepresents the health impact of an intervention. Although pre-specification is important in science, it is not an altar to be worshipped at. Pre-specification can be misused to sanctify inappropriate endpoints, such as biomarkers, when actual health outcomes are available, and methods that are demonstrably inferior.
COMPare’s assessments appear to be based on the premise that trials are or can be perfectly designed at the outset, that the initial trial registry provides a full representation of the critical aspects of trial conduct, that all primary and secondary endpoints be reported in a single trial publication, and that any changes investigators make to a trial protocol or analytic procedures after the trial start date indicate bad science. In reality, many changes to trial protocols or reports occur for justifiable reasons: institutional review board recommendations, advances in statistical methodology, low event or accrual rates, problems with data collection and changes requested during peer review. COMPare’s rigid evaluations and the labeling of any discrepancies as possible evidence of research misconduct may have the undesired effect of undermining the work of responsible investigators, peer reviewers and journal editors to improve both the conduct and reporting of science.
We have led or participated in many efforts to improve the transparency and accuracy of scientific reporting. We will continue to encourage authors of clinical trials to make their protocols available to others and to update their trial registry information. We respect COMPare’s effort to draw attention to the importance of accurate and complete public description of clinical trial procedures. But we don’t believe their approach that purports to draw a simple methodological line between “good” and “bad” reporting (or editing) serves our common cause well. Until the COMPare Project’s methodology is modified to provide a more accurate, complete and nuanced evaluation of published trial reports, we caution readers and the research community against considering COMPare’s assessments as an accurate reflection of the quality of the conduct or reporting of clinical trials. The Editors
1. The COMPare Project. Center for Evidence-based Medicine Outcomes Monitoring Project: Tracking Switched Outcomes in Clinical Trials. URL: http://compare-trials.org/ (accessed December 8, 2015)
2. Gepner Y, et al. Effects of initiating moderate alcohol intake on cardiometabolic risk in adults with Type 2 diabetes. Ann Intern Med 2015; 163: 569-572.
3. MacPherson H, et al. Alexander technique lessons or acupuncture sessions for person with chronic neck pain: A randomized controlled clinical trial. Ann Intern Med 2015; 163: 653-662.
4. http://compare-trials.org/downloads/protocol.pdf (accessed December 8, 2015)
5. Lind M et al, Liragutide in people treated for Type 2 diabetes with multiple daily insulin injections: randomised clinical trial (MDI Liraglutide trial). BMJ 2015; 351: h5364 (accessed December 8, 2015)
6. Lind M et al, Design and methods of a randomised double-blind trial of adding liraglutide to control HgA1c in patients with impaired glycaemic control treated with multiple daily insulin injections (MDI Liraglutide trial). Prim Care Diabetes 2015; 9: 15-22.
7. MacPherson H, et al. Alexander technique lessons, acupuncture sessions, or usual care for patients with chronic neck pain (ATLAS) study: study protocol for a randomised controlled trial. Trials 2013; 14: 209
Ben Goldacre, Henry Drysdale, Kamal Mahtani, Carl Heneghan on behalf of the COMPare-trials.org team
We have submitted a 1200 word reply to the Annals editors’ comment on COMPare. The Annals editors have declined to publish this, saying it exceeds their online comments word limit. We note the online
January 21, 2016
Concerning statements on outcome switching from Annals' Editors
We have submitted a 1200 word reply to the Annals editors’ comment on COMPare. The Annals editors have declined to publish this, saying it exceeds their online comments word limit. We note the online comment from the editors is over twice their word limit . It is impractical to cover all errors in their long comment without a similar word length. We hope the editors of Annals will want readers to have access to a clear response, especially when they have published their own concerning comment in the full edition of the journal. We will submit our full reply elsewhere, and have produced a longer post on COMPare-trials.org . We use this comment to signpost readers to our full reply which Annals have refused to publish. It says, in summary:The Annals editors argue that switching outcomes is acceptable if there's a good reason to do so. We agree, and so does CONSORT , but both we and CONSORT say you must tell the reader you've switched those outcomes. Throughout their comment the editors seem confused on this key issue. They argue that they should be entitled to permit undeclared outcome switching on the pages of Annals according to their own skilful judgement. This conflicts with their own prior commitment to good reporting standards, and with the standards readers will expect. They say registry information is often poor quality, with outcomes poorly pre-specified. We agree, but think inadequate pre-specification should be pointed out in a trial's results paper, not glossed over. Trialists should be reminded and motivated to maintain their registry entries, since registers were developed specifically to address selective outcome reporting.The Annals editors argue our coding is unfair because we ignore protocols that are either unpublished or published after a trial began. These protocols cannot be an adequate source of pre-specified outcomes. The editors repeatedly make arguments that rely on “pre-specified” outcomes being extracted from documents dated after the trial began. We are concerned and surprised that the Annals editors do not recognise and understand the importance of this.Further to their misunderstandings on timing of pre-specification, the editors claim to have found one small error in our coding: they apparently think the pre-specified primary outcome “glycaemic control”  can be reasonably reported as HOMA-IR . We are keen for feedback but explain why they are wrong in our full response.Lastly, their letter is anonymous. We find this concerning, especially since one deputy editor of Annals is current secretary of ICMJE and the figurehead for this sector’s approach to trial registration and selective reporting.We urge the editors to correct the record on trials they have misreported; clarify their support for CONSORT; and implement new processes to ensure that undeclared outcome switching does not persist in Annals at the current rate. Ben Goldacre, Henry Drysdale, Kamal Mahtani, Carl Heneghan on behalf of the COMPare-trials.org team Annals Editors, Discrepancies Between Prespecified and Reported Outcomes, Ann Intern Med. Published online 22 December 2015  COMPare blog post: http://compare-trials.org/blog/where-does-annals-of-internal-medicine-stand-on-outcome-switching-a-detailed-response/, last accessed 20/01/2016 Moher D et al, CONSORT 2010 Explanation and Elaboration: updated guidelines for reporting parallel group randomised trials, BMJ 2010; 340:c869. The Cardiovascular Diabetes and Ethanol (CASCADE) trial registry entry. ClinicalTrials.gov: NCT00784433: https://clinicaltrials.gov/ct2/show/NCT00784433, last accessed 19/01/2016 Gepner et al, Effects of Initiating Moderate Alcohol Intake on Cardiometabolic Risk in Adults With Type 2 Diabetes, Ann Intern Med. 2015;163(8):569-579.
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Cardiology, Endocrine and Metabolism, Diabetes, Dyslipidemia, Tobacco, Alcohol, and Other Substance Abuse.
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