Critique 136: Alcohol’s effects on cardiovascular risk among subjects with diabetes mellitus — 18 March 2014

Blomster JI, Zoungas S, Chalmers J, Li Q, Chow CK, Woodward M, Mancia G, Poulter N, Williams B, Harrap S, Neal B, Patel A, Hillis GS.  The relationship between alcohol consumption and vascular complications and mortality in individuals with type 2 diabetes mellitus.  Diabetes Care 2014; pre-publication: DOI: 10.2337/dc13-2727

Authors’ Abstract

OBJECTIVE  Moderate alcohol consumption has been associated with a reduced risk of mortality and coronary artery disease. The relationship between cardiovascular health and alcohol use in type 2 diabetes is less clear. The current study assesses the effects of alcohol use among participants in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) trial.

RESEARCH DESIGN AND METHODS  The effects of alcohol use were explored using Cox regression models, adjusted for potential confounders. The study end points were cardiovascular events (cardiovascular death, myocardial infarction, and stroke), microvascular complications (new or worsening nephropathy or retinopathy), and all-cause mortality.

RESULTS  During a median of 5 years of follow-up, 1,031 (9%) patients died, 1,147 (10%) experienced a cardiovascular event, and 1,136 (10%) experienced a microvascular complication. Compared with patients who reported no alcohol consumption, those who reported moderate consumption had fewer cardiovascular events (adjusted hazard ratio [aHR] 0.83; 95% CI 0.72–0.95; P = 0.008), less microvascular complications (aHR 0.85; 95% CI 0.73–0.99; P = 0.03), and lower all-cause mortality (aHR 0.87; 96% CI 0.75–1.00; P = 0.05). The benefits were particularly evident in participants who drank predominantly wine (cardiovascular events aHR 0.78, 95% CI 0.63–0.95, P = 0.01; all-cause mortality aHR 0.77, 95% CI 0.62–0.95, P = 0.02).  Compared with patients who reported no alcohol consumption, those who reported heavy consumption had dose-dependent higher risks of cardiovascular events and all-cause mortality.

CONCLUSION  In patients with type 2 diabetes, moderate alcohol use, particularly wine consumption, is associated with reduced risks of cardiovascular events and all-cause mortality.

Forum Comments

Background:  A U- or J-shaped curve for the relation of alcohol consumption to cardiovascular disease (CVD) among diabetics has been known for more than a decade.(1-3)  A variety of potential mechanisms have been described, including  beneficial effects of moderate drinking on lipids, inflammatory markers, and insulin resistance.   While some earlier studies show greater benefits for wine drinkers, others have demonstrated similar effects for all beverage types.

Forum member Skovenborg thought that “The authors seem to think that only 3 smaller studies have reported on association between alcohol consumption and reduced risk of non-fatal and fatal MI.  However, a very brief literature search found 8 studies on the subject and there may be more if you look carefully.  For example, Beylens et al (4) found that moderate alcohol consumption (1–2 drinks/day) is not only associated with a reduced risk of vascular and all-cause death in a high-risk patients with clinical manifestations of vascular disease, but also with reduced risks of non-fatal events like coronary artery disease,  stroke and possibly amputations.  Further, Diem et al,(5) reported that diabetic patients consuming 16 to 30 g per day had reduced mortality from coronary heart disease and from all causes. Alcohol intake above 30 g per day was associated with a tendency towards increased all-cause mortality.

“Many other papers showed that moderate drinking reduced all-cause mortality [e.g., Lin et al(6) [Nakamura et al(7)], peripheral vascular disease [e.g., Mingardi et al,(8)], coronary heart disease [Rajpathak et al,(9); Valmadrid(10)].  Sluik et al (11) reported that, compared with light alcohol consumption (<6 g/day, or an average of about 3.5 drinks/week), there was no relationship between subjects reporting consumption of greater amounts of alcohol and mortality [HR for ≥6-12 g/d was 0.89 (95% CI 0.61 – 1.30) in men and 0.86 (95% CI 0.46 – 1.60) in women].”

Comments on the present study:  The present study was based on more than 11,000 subjects with diabetes from 20 countries, including those in Eastern Europe, Asia, and established market economies in Western Europe, North America, and the Pacific region.  The outcomes over 5 years of follow up were CVD events (death from CVD, non-fatal myocardial infarction, non-fatal stroke), microvascular disease (renal disease, diabetic eye disease), and all-cause mortality.   

At baseline, only about 30% of subjects were alcohol consumers, so there was an adequate number of non-drinkers to serve as the referent group.  Approximately one-third of those drinking reported that more than one-half of their alcohol intake was from wine (median consumption 5 drinks/week) and two-thirds reported that more than one-half of their intake was from beer or spirits (median consumption 7 drinks/week).  Subjects who consumed alcohol were separated into categories of “moderate” (<21 drinks/week for men or <14 drinks/week for women), who made up 26.7% of total subjects, or “heavy” (exceeding these limits) based on their total alcohol consumption; the latter group made up less than 4% of total subjects. 

Overall, 9.8% of subjects in Asia, 23.7% in Eastern Europe, and 50.9% in established market countries reported drinking some alcohol.  There was high correlation between alcohol intake reported at baseline, the amount reported at 24 months, and that reported at the end of the study, as well as a high correlation between baseline and intake reported during the year prior to the diagnosis of diabetes.

Forum member Skovenborg commented:  “The present report by Blomster et al is a large study of diabetics at high-risk of CVD, a large number of events, a large number of participants with a modest and regular intake of alcohol, and also a large number of non-drinkers.  However, the adjustment for potential confounding factors did not include diet: a Mediterranean type of diet preference in wine drinkers might be a confounding factor in this study.(12) 

“In the present study, moderate drinking was defined as ≤ 21 drinks weekly for men and ≤ 14 drinks weekly for women.  In the previous studies from the U.S. moderate drinking was defined as 0.5 – 2 drinks/day for men and 0.5 – 1 drinks/day for women. This could explain why a protective effect of a higher alcohol intake was seen in the earlier studies: many American study participants with a ‘high intake’ of alcohol would have been moderate drinkers according to the definition used in the present study.

Key results of present study:  Over a median follow-up period of 5 years, more than 1,000 subjects (about 10%) had a major CVD event, with similar percentages experiencing a microvascular complication or dying.   The authors report that “Compared with abstainers, any alcohol use was associated with a 17% lower risk of cardiovascular events, a 15% lower risk of microvascular complications, and a 13% lower risk of all-cause mortality.”  While there were few heavy drinkers (<4%), their data suggested that there was no lowering of risk of the outcomes among such subjects. 

Do wine drinkers have extra protection?   The largest effect on CVD events and total mortality was among subjects reporting predominantly the consumption of wine, rather than beer and spirits.  Reviewer Estruch comments: “The results of two recent meta-analysis of twenty(13) and fifteen(14) cohort studies indicated that moderate alcohol consumption was inversely associated with diabetes risk, but no differences between the effects of the different types of alcoholic beverages were found.  However, Wannamethee et al(15) in 2003 reported that the reduction in the risk of incident diabetes was more apparent in those who reported wine or beer drinking.  The present study of Blomster and colleagues goes further and concludes that moderate drinkers with diabetes (especially wine drinkers) show a reduced risk of cardiovascular events and all-cause mortality.”

Reviewer Estruch continued: “Apart of the beneficial effect of wine on inflammatory markers, platelet aggregation and lipid profile (increase of HDL-cholesterol), its effects on glucose metabolism should also be taken into account.  In fact, the results of a recent randomized cross-over trial support the beneficial effect of the non-alcoholic fraction of red wine (mainly polyphenols) on insulin resistance, conferring a greater protective effects on cardiovascular disease.(16)”

Of the baseline characteristics reported in the present paper, most showed expected trends (e.g., more alcohol for subjects with higher education, smokers, etc.), but for unknown reasons there were no differences in the measured HDL-cholesterol levels according to reported alcohol intake.  The finding of less severe microvascular disease among consumers of alcohol is interesting, as some studies have found such protection from alcohol consumption while others have not.

Potential importance of moderate drinking among people with diabetes:  Reviewer Finkel considered the message from this paper to be of extreme relevance, as “The vascular ravages of diabetes are of monumental importance.  There are said to be more than 26 million diabetics in the US, even more in Europe.  There is also much misconception, even among physicians (who should know better), not to mention the media and the public, that adult-onset diabetics should eschew all alcohol-containing beverages, because ’they are loaded with carbohydrates!’  [I am embarrassed for our profession.]  It is just these vulnerable individuals who most sorely need the extra cardiovascular protection of moderate alcohol consumption.  My endocrinological colleagues and the American Diabetes Association agree that moderate alcohol consumption can be beneficial to diabetics, as long as they eat when they drink.  Thus, while not plowing new ground, this paper serves to further important truths.”

References for Forum critique:

1.  Solomon CG, Hu FB, Stampfer MJ, et al.  Moderate alcohol consumption and risk of coronary heart disease among women with type 2 diabetes mellitus. Circulation 2000;102:494–499

2.  Tanasescu M, Hu FB, Willett WC, Stampfer MJ, Rimm EB. Alcohol consumption and risk of coronary heart disease among men with type 2 diabetes mellitus. J Am Coll Cardiol 2001;38:1836–1842.

3.  Ajani UA, Gaziano JM, Lotufo PA, et al. Alcohol consumption and risk of coronary heart disease by diabetes status. Circulation 2000;102:500–505.

4.  Beylens JW, Algra A, et al. Alcohol consumption and risk of recurrent cardiovascular events and mortality in patients with clinically manifest vascular disease and diabetes mellitus: The Second Manifestations of ARTerial (SMART) disease study. Atherosclerosis 2010;212:281-286.

5.  Diem P, Deplazes M, Fajfr R, et al.  Effects of alcohol consumption on mortality in patients with Type 2 diabetes mellitus.  Diabetologia. 2003;46:1581-1585.

6.  Lin Y, Kikuchi S, Tamakoshi A, et al. Alcohol consumption and mortality among middle-aged and elderly Japanese men and women. Ann Epidemiol 2005;15:590-597.

7.  Nakamura Y, Ueshima H, Kadota A, et al.  Alcohol intake and 19-year mortality in diabetic men: NIPPON DATA80. Alcohol 2009;43:635-641.

8.  Mingardi R, et al.  Alcohol intake is associated with a lower prevalence of peripheral vascular disease in non-insulin dependent diabetic women.  Nutr Metab Cardiovasc Dis 1997;7:301-308.

9.  Rajpathak SN, Freiberg MS, Wang C, et al.  Alcohol consumption and the risk of coronary heart disease in postmenopausal women with diabetes: Women’s Health Initiative Observational Study.  Eur J Nutr 2010;49:211-218.

10.  Valmadrid CT, Klein R, Moss SE, et al.  Alcohol intake and the risk of coronary heart disease mortality in persons with older-onset diabetes mellitus. JAMA 1999;282:239-246.

11.  Sluik D, Boeing H, Bergmann MM, et al.  Alcohol consumption and mortality in individuals with diabetes mellitus. Br J Nutr 2012;108:1307-1315.

12.  Johansen D, Friis K, Skovenborg E, Grønbæk M.  Food buying habits of people who buy wine or beer: cross sectional study.  BMJ 2006;332:519-522.

13.  Baulinas DO, Taylor BJ, Irving H, Roerecke M, Patra J, Mohapatra S, Rehm J.  Alcohol as a risk factor for type 2 diabetes: A systematic review and meta-analysis.   Diabetes Care 2009;32:2123–2132.

14.  Koppes LLJ, Dekker JM, Hendriks HFJ, Bouter LM, Heine RJ.  Moderate alcohol consumption lowers the risk of type 2 diabetes: A meta-analysis of prospective observational studies.  Diabetes Care 2005;28:719–725.

15.  Wannamethee SG, Camargo CA Jr, Manson JE, Willett WC, Rimm EB.  Alcohol drinking patterns and risk of type 2 diabetes mellitus among younger women.  Arch Intern Med  2003;163:1329-1336.

16.  Chiva-Blanch G, Urpi-Sarda M, Ros E, Valderas-Martinez P, Rosa Casas R, Arranz S, Guillén M, Lamuela-Raventós RM, Llorach R, Andres-Lacueva C, Estruch R.  Effects of red wine polyphenols and alcohol on glucose metabolism and the lipid profile: A randomized clinical trial.  Clinical Nutrition 2013;32:200-206.

Forum Summary

A U- or J-shaped curve for the relation of alcohol consumption to cardiovascular disease (CVD) among diabetics has been shown in most prospective epidemiologic studies for many years, and CVD is the leading cause of death among diabetics.  A variety of potential mechanisms of protection against CVD have been described, including beneficial effects of moderate drinking on lipids, inflammatory markers, and insulin resistance.   The current paper assesses the effects of alcohol use among participants in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) trial.  It was based on more than 11,000 subjects with diabetes from 20 countries, including those in Eastern Europe, Asia, and established market economies in Western Europe, North America, and the Pacific region.  The outcomes over 5 years of follow up were CVD events (death from CVD, non-fatal myocardial infarction, non-fatal stroke), microvascular disease (renal disease, diabetic eye disease), and all-cause mortality.  

Key results of the analyses showed that during follow up, more than 1,000 subjects (about 10%) had a major CVD, with similar percentages experiencing a microvascular complication or dying.   The authors report that “Compared with abstainers, any alcohol use was associated with a 17% lower risk of cardiovascular events, a 15% lower risk of microvascular complications, and a 13% lower risk of all-cause mortality.”  While there were few heavy drinkers (<4% of subjects), their data indicated that there was no significant lowering of risk of the outcomes among such subjects.  Subjects who consumed wine had lower estimates of cardiovascular disease outcomes and mortality than consumers of other beverages.

Forum reviewers considered this to be a well-done analysis based on a large cohort of subjects with diabetes mellitus, with an adequate number of non-drinkers to serve as a referent group.  The results strongly support previous studies that have shown a lower risk of cardiovascular events and total mortality among diabetic subjects who consume moderate alcohol.  The study also showed that the risks of microvascular complications (diabetic kidney disease, diabetic eye disease) were lower among moderate drinkers.

The Forum considers this to be an important message (to physicians and the public), as the vascular ravages of diabetes are very serious, and diabetes is such a common disease that is increasing throughout the world.  Diabetic patients without contraindications to alcohol sorely need to know of the potential cardiovascular protection of moderate alcohol consumption.      

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Comments on this critique by the International Scientific Forum on Alcohol Research were provided by the following members:

Ramon Estruch, MD, PhD, Department of Medicine, University of Barcelona, Spain

R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA

Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark

Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA

Dominique Lanzmann-Petithory,MD, PhD, Nutrition/Cardiology, Praticien Hospitalier Hôpital Emile Roux, Paris, France