By Dr. Geoffrey Modest
An Israeli study was just published in which adults with type 2 diabetes were randomized to drinking wine vs water, and an array of cardiometabolic parameters were assessed (see Ann Intern Med. 2015;163:569-579) — the CASCADE trial: CArdiovaSCulAr Diabetes & Ethanol trial, which just goes to show you that you can develop an acronym pretty easily for just about anything.
- 224 patients (baseline: mean age 60, 69% men, BMI 30.0, HDL 1.12 mmol/L or 43.5 mg/dL, LDL 2.41 mmol/L or 93.0 mg/dL, cholesterol/HDL ratio 4.1, fasting plasma glucose 150.4 mg/dL or 8.3 mmol/L, HgbA1C=6.9%, BP 137/78, waist circumference 105 cm, and mean positive metabolic syndrome criteria was 3.1 of 5) were randomly assigned to 150ml of mineral water, white wine or red wine with dinner daily for 2 years. Previously, these subjects had drunk no more than 1 drink of alcohol/week (mean 2.3 g/d)
- All followed a Mediterranean diet without calorie restriction
- They also looked at alcohol metabolism/ ADH1B polymorphism, where 36% were CC, 38% were CT and 26% were TT (the TT polymorphism of ADH1B is also called ADH1B*2 rs1229984, and is associated with much faster hepatic clearance of alcohol); and assessed the homeostatic model assessment of insulin resistance score (HOMA-IR, a measure of insulin resistance), which was 5.0 at baseline
- Those on red wine vs water had: increased HDL [0.05 mmol/L (0.04=0.06), or 2.0 mg/dl (1.6-2.2), p<0.001] and apolipoprotein A1 [0.03 g/L (0.01-0.06),p=0.05], and decreased total cholesterol/HDL ratio by 0.27 [(-0.52 to -0.01), p=0.039]. Those drinking white wine were not significantly different from water in terms of lipid changes (except that, interestingly, both the red and white wine drinkers did have decreases in triglycerides by .09 mmol/L or 7.9 mg/dL with white wine and -0.1 mmol/L and 12.0 mg/dL with red wine). White wine, but not red wine, was associated with significant decreases in fasting plasma glucose levels (decreased 1.0 mmol/L, or 17.2 mg/dL) and HOMA-IR scores.
- Only when looking at the slow alcohol metabolizers (ADH1B*1 carriers), both red and white wine had better fasting plasma glucose, HOMA-IR, and hemoglobin A1C levels similarly
- And, sleep quality improved in those drinking wine (p=0.040)
- But no difference in blood pressure, adiposity, liver function, drug therapy, symptoms, or quality of life
- Overall, red wine led to decrease in number of components of the metabolic syndrome by 0.34 [(-0.68 to -0.001), p=0.049], not with white wine
So, there are a few issues here
- There have been many studies and meta-analyses from observational trials suggesting that moderate amounts of alcohol ingestion are cardioprotective, largely attributed to the alcohol content itself. For more discussion of this, see http://blogs.bmj.com/ebm/category/alcohol/ for blogs on alcohol, and http://blogs.bmj.com/ebm/2015/02/20/primary-care-corner-with-geoffrey-modest-md-moderate-alcohol-and-cardioprotection/ which argues that the attributable benefits from even small amounts of alcohol consumption are likely related to inherent biases in the observational data collection.
- This study is the first I’ve seen where there is an actual intervention done. Of course, the intervention is not really through a randomized controlled trial since I suspect that those drinking wine were in fact aware that it was not mineral water. And, one wonders if there might have been other changes in the diet related to drinking wine with the meal, though all were instructed in Mediterranean diet guidelines – i.e., they did not monitor the actual dietary composition, and the glass of wine could have altered the choices or quantities of foods consumed.
- As noted in prior blogs, not all HDL is the same, and there are nonfunctional and even pro-inflammatory variants (see http://blogs.bmj.com/ebm/2014/11/24/primary-care-corner-with-geoffrey-modest-md-hdl-a-negative-risk-factor-or-cholesterol-efflux/ , and will append an older blog on pro-inflammatory HDL at the bottom). So, looking at HDL numbers may not necessarily translate to cardioprotection.
- If the findings of the study are indeed valid, they suggest that the effect of wine on diabetic markers is basically through the alcohol itself (since both red and white wine improve the diabetes markers especially in the slow metabolizers who have more sustained blood alcohol levels), while the lipid effects were more evident with red wine, suggesting that its particular components may be protective (perhaps the phenolic compounds: resveratrol and quercetin), perhaps through their antioxidant, endothelial or antiplatelet actions (though in general it is felt that the quantity of these in red wine is insufficient to achieve therapeutic effects)
- So, interesting study, though I don’t think it provides definitive answers to the question. I.e., I’m not ready to suggest alcohol to patients yet… (and, per the 5/14/12 blog, the real answer will come from looking at real clinical events and not the surrogate markers of changes in cholesterol, since alcohol also increases the proinflammatory variant).
Here is blog from 5/14/12
Although the vast majority of epidemiologic studies have found HDL to be cardioprotective, there have always been some concerns. HDL is comprised of a diverse group of lipoproteins with significant metabolic heterogeneity. There were a few older studies finding a “pro-inflammatory HDL”, which predisposed people to heart disease. The clinical trial of Torcetrapib, a cholesterol ester transfer protein inhibitor, dramatically increased HDL but was not cardioprotective. The researchers suggested that the HDL was somehow deformed. (This large torcetrapib trial overwhelmed a meta-analysis last year in BMJ, suggesting no benefit to raising HDL). In any event, there is a likely very illuminating article from Harvard school public health (see doi:10.1161/JAHA.111.000232). They had found before that there was occasionally a small apolipoprotein (apo C-III) on some lipoproteins causing a pro-inflammatory and atherogenic response. On LDL particles, this apo C-III caused increased coronary atherosclerosis independent of the LDL itself. They looked at the data from 2 large epidemiologic studies — Nurses health study (NHS, 121K female nurses) and the health professionals follow-up study (HPFS, 52K males), looked at stored serum and assessed the HDL C-III relation to cardiac events.
- 14% of women in NHS had HDL with apo C-III; 11% of men in HPFS had apo C-III
- Overall, each standard deviation increase in HDL was assoc with a 21% dec in cardiac events; but for patients without apo C-III, there was a 34% decrease in events and for those with apo C-III there was a statistically significant 18%
- Looking at the effect of apo C-III in multivariate analysis of other risk factors (all of below statistic signif):
- Compared to pts with normal wt, overweight and obesity were associated with 7% and 12% lower levels of HDL without apo C-III – i.e., overwt/obesity with lower of the good HDL.
- Alcohol was assoc with 3% higher levels of both HDL types
- Smokers had 1% higher levels of HDL with apo C-III (the bad one)
- Premenopausal women had 9% higher levels of HDL without apo C-III, as did postmenop women on estrogen replacement therapy, vs other postmenop women
- Per SD increase in triglycerides, 8% lower HDL without apo C-III and 15% increase in HDL with apo C-III
- Per SD increase in A1C, 4% increase in HDL with apo C-III
(i.e., several of these risk factors which change HDL also lead to more HDL with apo C-III)