PREDIMED Study – Traditional Mediterranean Diet (TMD)
The PREDIMED Study evaluated the Traditional Mediterranean Diet (TMD) for the prevention of Cardiovascular Disease. The Traditional Mediterranean Diet has been a favorite for health advocates for years. Multiple observational and secondary prevention trials showed improvement in risk for Cardiovascular Disease so the authors of the PREDIMED Study conducted a randomized trial to confirm (or debunk) these observations.
The PREDIMED Study was conducted in multiple locations (centers) in Spain. The participants were considered to be at ‘High cardiovascular disease risk’ but had no cardiovascular disease at enrollment. High risk of cardiovascular disease meant that participants were either Type 2 diabetic or at least 3 of the following: smoking, hypertension, elevated LDL, low HDL, overweight/obese, or family history of premature cardiovascular disease.
Mediterranean diet supplemented with mixed nuts (walnuts, almonds, and hazelnuts)
Control diet – they were advised to reduce dietary fat
All participants received educational sessions (individual and group) every quarter. Depending on the group, they were given free extra-virgin olive oil (~1 liter per week), mixed nuts (30 grams per day), or small nonfood gifts. They did not control or adjust caloric intake and there was no promotion of exercise or physical activity.
Mediterranean Diet
Recommended Foods
Olive Oil: >4 tablespoons per day. The amount of olive oil includes oil used for cooking and salads and oil consumed in meals eaten outside the home. In the Mediterranean Diet Olive Oil group, the goal was to consume 50 grams (approximately 4 tablespoons) or more per day of the polyphenol-rich olive oil supplied to them as opposed to the ordinary refined variety, which is low in polyphenols.
Tree nuts and peanuts: > 3 servings per week
Fresh fruits: > 3 servings per day
Vegetables: > 2 servings per day
Fish (especially fatty fish) & Seafood: > 3 servings per week
Legumes: > 3 servings per week
Sofrito: > 2 servings per week. Sofrito is a sauce made with tomato and onion, often including garlic and aromatic herbs, and slowly simmered with olive oil.
White meat: instead of red meat
Wine with meals (optional, only for those already drinking alcohol): > 7 glasses per week
Discouraged Foods
Sodas (soft drinks): < 1 per day
Commercial baked good, sweets, & pastries: <3 servings per day
Spread fats: <1 serving per day
Red and processed meats: < 1 serving per day
Control Diet (low fat)
Recommended Foods
Low-fat dairy products: > 3 servings per day
Bread, potatoes, pasta, rice: > 3 servings per day
Fresh fruits: > 3 servings per day
Vegetables: > 2 servings per day
Lean fish & seafood: > 3 servings per week
Discouraged Foods
Vegetable oils (including olive oil): < 2 tablespoons per day
Fatty fish, seafood canned in oil: < 1 serving per week
Sofrito: < 2 servings per week
Compliance
Compliance with all of the diet groups was good. Biomarkers (hydroxytyrosol for olive oil group & ALA level for mixed nuts group) were measured to confirm compliance.
Participants were followed for 4.8 years. 209 participants (2.8%) opted to not attend subsequent visits. Dropouts were higher in the Control Diet (11.3%) than in the Mediterranean Diet (4.9%).
Increased benefit was noted in the group with dyslipidemia and hypertension in regards to the primary end-point.
Conclusions:
The primary end points (for what they were looking to see if the diet helped) were major cardiovascular disease events (myocardial infarction, stroke, or death from cardiovascular disease causes). The study was conducted for 4.8 years. The study was funded by the Spanish Government (Instituto de Salud Carlos III and others).
There were a total of 7447 participants, 55-80 years of age. The primary end-point (myocardial infarction, stroke, or death from cardiovascular disease causes) occurred in a total of 288 of the participants.
Mediterranean diet with extra-virgin olive oil – 96 events, 30% reduced risk (hazard ratio 0.70)
Mediterranean diet with mixed nuts – 83 events, 28% reduced risk (hazard ratio 0.72)
Control diet – 109 events
The author’s conclusion: “In this study involving persons at high cardiovascular risk, the incidence of major cardiovascular events was lower among those assigned to a Mediterranean diet supplemented with extra-virgin olive oil or nuts than among those assigned to a reduced-fat diet.”
Four years after the DASH Diet was published in the New England Journal of Medicine, the DASH-2 Diet (DASH-II) study was published. The DASH Diet showed good improvement in blood pressure. However, the study authors wanted to further evaluate the effects of sodium combined with a DASH Diet.
So many patients at our Tulsa Integrative Medicine preventive cardiology clinic want to avoid or reduce their medications yet want to maximize their health and reduce their risk of cardiovascular disease. The DASH-2 diet is an excellent tool to help achieve this goal.
The DASH-2 study sought to evaluate the effect of different levels of sodium intake in conjunction with the DASH Diet. 412 participants were randomly assigned to eat either a Standard American Diet or the DASH Diet (combined diet in the DASH Diet Study). Within the DASH Diet, participants were assigned three different levels of sodium intake for 30 consecutive days and in random order.
Participants were adults with a blood pressure of 120-159 over 80-95.
The 3 sodium levels were:
High: 150 mmol per day (3.45 grams sodium)
Intermediate: 100 mmol per day (2.3 grams sodium)
Low: 50 mmol per day (1.15 grams sodium)
However, the total daily sodium intake was proportionate to their overall caloric intake – bigger or more active people got more.
There was a 2 week run-in period where participants ate a high-sodium control diet. After the run-in period they were randomized to either the control diet or the DASH Diet. Each group ate their diet at one of the 3 sodium levels for 30 consecutive days. Their sodium levels were randomly reassigned every 30 days in a Crossover design.
Inclusion and exclusion criteria were similar to the DASH Diet except they were aiming for 50% blacks and 50% women in this trial. 95% of the DASH-Diet group and 94% of the control-diet group completed the study.
If any patient had a blood pressure more than 170 over 105 it necessitated a repeat reading. If it remained elevated then they were referred to their doctor for management.
Results
Blood pressure (both systolic and diastolic) significantly decreased in a stepwise fashion based on sodium intake. Low sodium intake had a greater effect on lowering blood pressure in the control group than in the DASH-Diet group. Blood pressure lowering based on sodium intake was greater in hypertensive participants than in those without hypertension.
The combination of the DASH-Diet and low sodium group had the most profound effect on reducing blood pressure. It decreased systolic blood pressure 11.5 mmHg (in hypertensive patients) and 7.1 mmHg (in normotensive patients) (p<0.001 in all groups).
Of note, there were 36 participants in the control-diet group but only 7 in the DASH-Diet group who had blood pressures of 170 over 105 or more. 18 were in the high sodium group (combined control group and DASH-diet group, 22 in the intermediate group, and 3 during the low sodium group. None of these occurred in the DASH-Diet low sodium group.
DASH-2 Diet Conclusions
In patients who were not hypertensive, systolic blood pressure was 7.1 mmHg in the low sodium DASH Diet (DASH-2 Diet). However, if you were hypertensive, the response was even greater with decrease of 11.5 mmHg.
Basically, the DASH-2 Diet does an excellent job of reducing blood pressure as a stand alone intervention and should be foundational in any hypertension campaign.
Lp(a) is a real problem! In fact, Bob Harper (Biggest Loser trainer) attributes his “widow maker” heart attack to Lp(a). If you have elevated levels then you have a significantly increased risk of having a heart attack.
Part of the problem is that most doctors aren’t even measuring it. But, if they do measure it then very few know how to address it.
Lp(a) is largely genetic and probably not due to anything you are doing (or not doing). It is also very difficult to lower. So what do you do about it?
Lifestyle Recommendations
Exercise: Gradual increase over 2 months to 60 minutes 6 d/wk. 40 minutes resistance and 20 minutes interval aerobics. Use the Revolution Exercise Plan as your foundation.
Ideal body weight and composition: Men 16% body fat or less. Women 22 % body fat or less. BMI between 18.5 and 24.9. Waist circumference: Men < 36 inches. Women < 30 inches.
Avoid all tobacco products. Limit alcohol (1-2 servings/day for men, 1 for women)
Mediation prayer, religion, spirituality and faith.
Caffeine: If you are a slow metabolizer, then avoid it completely. If you are fast metabolizer, it is OK to drink. You’ll learn if you are a fast or slow metabolizer on the CardiaX test. I believe that EVERYONE should have this test done. It is a one time since since your genetics will never change!
Avoid all artificial sweeteners. Use only Erythrytol (Swerve), Allulose, or Stevia.
Water: 50% of body weight (pounds) in ounces of filtered or distilled water per day. If you weigh 150 pounds that is 75 ounces of water, herbal teas, broths daily. No plastic.
Tea: 16 ounces of decaffeinated green tea per day and 8 oz of white tea per day
Pomegranate: ¼ cup of pomegranate seeds or 6 oz of pomegranate juice per day
Detox + elimination diet, then anti-inflammatory, blood sugar regulating protocol with high-fiber foods and cruciferous vegetables: broccoli, cauliflower, Brussels sprouts, and cabbage
How to Improve Lp(a)
There are no level 1 evidence trials which demonstrate that lowering Lp(a) will reduce cardiovascular events. Reduction of LDL to 30 mg/dl did not reduce risk from Lp(a).
Niacin – the effect is dose related. Niacin (Sustained Release) 500 mg tab once daily. Over time, work up to 2 grams per day (21%-40% decrease).
NAC (N-acetyl cysteine) 500-1000 mg twice daily
Aronia (Chokeberry) 900 mg twice daily and possibly elderberry. Order from Amazon or get at health food store.
Vitamin C 10 grams per day Buffered powder (27% decrease) (Designs for Health)
Proline (500 mg) with L-Lysine (1000 mg) + Vitamin C 10,000 mg.
Berberine: Berberine is a natural PCSK9 inhibitor with benefits on blood sugar, lipids (cholesterol), as well as gastrointestinal health. Take 500 mg bid and possibly curcumin, quercetin and Citrus Bergamot. Berbemycin 2 capsules twice daily.
Aspirin 81 mg (81% decrease), reduce IL-6 and inflammation.
Sex hormones: estrogen and testosterone. Postmenopausal women have 30 % increase Lp(a)
Thyromimetics and thyroid hormone
Antisense Oligonucleotides
Apheresis in a Russian study reduced coronary atheroma volume over 20 % compared to control
Even aggressive reduction of LDL to very low levels below 50 mg/dL in Jupiter trial with statins still left residual CHD risk due to Lp(a). Risk was 89% higher in those in the 4th vs 1st quartile.
Bioidentical hormone replacement therapy (BHRT) has absolutely revolutionized the health of many of my patients at Revolution Health in Tulsa. I see the benefits on a daily basis. Some patients come back (for follow up) in tears and can’t believe they feel so good after feeling so bad. They often tell me they feel as though they’ve gotten a second chance at life or that they have their life back.
Second only to Prolotherapy, which is probably the single most effective thing I do in my clinic, bioidentical hormone replacement therapy is one of the most effective interventions we offer.
I recall a former nurse of mine who went to see her OB/GYN. She saw a prescription to a local compounding pharmacy and asked the medical assistant what the doctor thought about bioidentical hormone replacement (BHRT). The assistant stated “she thinks its a scam but the patient wanted it.”
A scam.
This concept is simply beyond me. Why on earth would she think it is a scam?!?
I supposed it is because some major medical societies are opposed to bioidentical hormone replacement therapy (BHRT). At first pass this doesn’t make much sense either until you understand what bioidentical hormone replacement therapy (BHRT) is, how it is done, and why they are opposed to it.
What is Bioidentical Hormone Replacement Therapy (BHRT)?
Simply, it is the use of hormones which are bioidentical to human hormones and at doses which are generally customized to each individual patient.
Bioidentical hormones can be fashioned for oral (pills, troches, liquid), transdermal (creams, gels), injectable, and percutaneous (pellet) use. Doses can be individualized for a custom approach for each patient.
The only way to get this level of customizability is to compound these medications at a compounding pharmacy.
By the way, compounded medications are not FDA approved and that is one of the major hang ups these medical societies (ACOG, Endocrine Society, etc) have with bioidentical hormone replacement therapy (BHRT).
Some bioidentical hormone replacement therapy (BHRT) prescribers use a customized approach based on patient symptoms. Some use blood testing. Others use saliva testing or urine testing to tailor the dose to the specific patient.
What exactly does FDA approval mean?
The FDA approves certain medications. Basically, the drug manufacturer performs studies on safety and effectiveness and presents the data to the FDA. The FDA will review the data and either approve or reject it.
It is important to understand that FDA approval means that the company presented data on a specific drug and a specific dose or doses. For example, Testopel (testosterone pellets) are FDA approved in doses ranging from 150-450mg. [1] That is 2-6 pellets. So, technically speaking, 1 single pellet (75mg) is not FDA approved. Additionally, 525mg (7 pellets) is not FDA approved either. Neither of these doses appear to have been studied by the manufacturer so there was no data submitted to the FDA for approval so the FDA obviously couldn’t approve it.
Clearly a 75mg dose wouldn’t be harmful but it may be insufficient to achieve desired results. But, again, it virtually couldn’t be harmful or detrimental. It is also unlikely that the 7th pellet is harmful though I guess it is possible. In any case, use of Testopel at any dose other than 150-450mg is not FDA approved and considered “off label” use.
Physicians do have the authority to use medications “off label” and have done so for years. There are a number of medications that are being used off label.
Clonidine – a blood pressure medication used for ADHD
Namenda – approved for Alzheimer’s disease but used for Obsessive-Compulsive Disorder (OCD)
Propranolol – approved for hypertension but used for performance anxiety
Viagra – approved for male erectile dysfunction being used for female sexual dysfunction
I make no argument against these medications being used off label. In fact, they may be very beneficial in some cases. These are common uses which are generally accepted in the medical community. Additionally, the FDA merely governs drug approval not drug prescribing and physicians are free to prescribe a drug for any reason they believe is medically appropriate.
Non-bioidentical Hormones
Now that we understand a little about how medications are FDA approved we can dig a little deeper into the typical prescribing of hormones. There are FDA approved bioidentical hormones for estrogen, progesterone, and testosterone. However, many hormone prescriptions are for non-bioidentical hormones such as Premarin.
Most traditional physicians prescribing hormones are not customizing the dose to the individual patient. That is another component setting bioidentical hormone replacement (BHRT) apart from non-bioidentical hormone replacement.
Premarin is a great example of a non-bioidentical hormone replacement therapy option. Premarin is available as an oral tablet in 5 doses (0.3, 0.45, 0.625, 0.9, and 1.25 mg). Obviously there is a level of customization available but only in those options. In practice, it has been my experience that many doctors will simply prescribe one dose for most patients. Kind of a “one size fits all” approach. I think it is because they don’t understand how to properly manage the dose and tailor it for the patient.
The Women’s Health Initiative (WHI) study details some of the risks and benefits of using some of the non-bioidentical hormones for post-menopausal women.
The argument against bioidentical hormone replacement therapy
As stated earlier, many doctors and many medical societies are opposed to bioidentical hormone replacement therapy (BHRT).
The American College of Obstetricians and Gynocologists (ACOG) Position Statement on bioidentical hormone replacement states “Evidence is lacking to support superiority claims of compounded bioidentical hormones over conventional menopausal hormone therapy.” [2]
The Endocrine Society stated “‘Bioidentical hormones,’particularly estrogen and progesterone, have been promoted as safer and more effective alternatives to more traditional hormone therapies, often by people outside of the medical community. In fact, little or no scientific and medical evidence exists to support such claims about ‘bioidentical hormones.’ Additionally, many ‘bioidentical hormone’ formulations are not subject to FDA oversight and can be inconsistent in dose and purity.” [3]
I understand that there is not good ‘evidence’ to support a customize approach to hormone therapy but I believe it is very important to ask WHY there isn’t good evidence. What is the typical source of this evidence? The bottom line is that the source is research studies and if you can get randomized, placebo-controlled, double-blinded studies then you have the cream of the crop.
But these studies are very expensive and someone has to pay for them. The only ones, typically, willing to spend the money are those with something to gain. And it needs to be a LOT to gain! Estimated costs to get a prescription drug FDA approval range from $161 million to $1.8 billion dollars. That is a staggering amount of money! Additionally, the data submitted to the FDA have to cover the range and combination of medications seeking approval. Costs will go up exponentially.
Basically, you just have to follow the money to understand how these medications get support.
But let’s talk about compounding for just a minute.
Compounding medications
It is frustrating that the Endocrine Society said that these formulations “are not subject to FDA oversight…” [3] That is simply NOT the case!
The FDA absolutely has oversight over these medications. FDA Regulations 503a & 503b govern compounding pharmacies. Additionally, the state board of pharmacy also behaves as an agent of the FDA, DEA, and the State Board of Pharmacy. In fact, the FDA can walk into any compounding pharmacy at any time and ask to inspect the facility.
With that being said, there is a huge potential for quality concerns with compounding pharmacies. A great example of a poor compounding pharmacy was the New England Compounding Center (NECC). You may recall that several people died several years ago due to infections caused by medications from this pharmacy. I have had experiences with more than one compounding pharmacy illustrating these quality concerns.
One of my staff members was on progesterone when the compounding pharmacy we typically used was bought by another pharmacy. Her next refill after the transfer of ownership didn’t go well. She told me that she felt as though she wasn’t even taking progesterone anymore. Her night sweats returned as well as her other symptoms. She was very frustrated.
We called the pharmacy and they told us they had made some changes and would send another prescription which seemed to fix the problem. However, she got another prescription at a later date and had the same problem. It seemed that every time she got her medication filled at that compounding pharmacy there was a problem but when she got it somewhere else it was fine. That is obviously concerning.
On the other hand, I have used another compounding pharmacy for several years and never had a single problem. I have toured their facility and I know their quality control measures. I know how they seek the highest level of quality and what steps they take to ensure it. There are many pharmacies with the same level of quality and we have had good success with those as well.
If you are wanting compounded medications it is essential that you have a relationship with the pharmacy and know their history OR you know a reputable doctor who knows which pharmacy to use. I have talked with several compounding pharmacists asking them how the average patient knows which pharmacies are good and the bottom line is that you can’t. It is all about the relationship based on history.
The argument about quality variance is the cornerstone to the ACOG’s and Endocrine Society’s statements. Dr Santoro added “The biggest issue is the lack of evidence for safety or efficacy. The available evidence suggests that overdosage and underdosage can be common because of lack of standards in the bioidentical industry.” [4]
Their argument is valid. However, the risks can be easily circumvented when you find a good compounding pharmacy and there is tremendous value added. Unfortunately, these societies are throwing the baby out with the bathwater and ignoring a tremendous benefit. It is a true shame. The FDA has stated that “…compounded drugs can serve an important medical need for some patients…” [6] I believe that this is definitely one of the times when compounded drugs can make a big difference.
Customized Approach
The other reason ACOG and the Endocrine Society are opposed to bioidentical hormone replacement therapy is that they feel there is no evidence to support a customized approach for each individual patient. I can tell you they are wrong.
Their position is that there are no STUDIES proving that a customized approach is more beneficial. However, you will likely never see any studies proving this information. Why?
First, reference my discussion above about following the money trail. These studies are launched by people who have something to gain by funding a study. No money, no study.
The second reason you won’t see studies validating a customized approach is that you can’t standardize the approach. It is very difficult to ensure that all patients get the same level of therapy but still have a standardized approach. One way to do this would be to treat to a certain ‘level.’ Yet there is no consensus regarding treatment levels making this a very difficult concept to achieve.
Also, many of my patients had been on hormone replacement when they came to me. Countless women had been on different forms or doses of estrogens, progesterone (or progestins), and/or testosterone. Yet many of these patients were still having symptoms and didn’t feel well. Once we switched them over to bioidentical hormone replacement therapy (BHRT) they nearly instantly felt better.
How can we, in good conscience, tell patients that, despite the fact that they feel better, there is no evidence to support continuing their therapy? It just doesn’t make sense to me. Additionally, there is absolutely no evidence of harm. No study shows harm with the use of bioidentical hormone replacement therapy (BHRT).
No evidence of harm. Evidence showing benefit.
Bioidentical Hormone Replacement Therapy (BHRT) is Beneficial!
Bioidentical hormone replacement therapy (BHRT) is a valid, safe, and effective therapy that can help a lot of people!
As stated previously, the ACOG and Endocrine Society (among others) state that there is no evidence of benefit. Stated again, the Endocrine Society said that bioidentical hormones “have been promoted as safer and more effective alternatives to more traditional hormone therapies, often by people outside of the medical community. In fact, little or no scientific and medical evidence exists to support such claims about ‘bioidentical hormones.’ [3]
However, there IS evidence showing superiority and safety!
Risks associated with estrogen (Premarin) alone include stroke and blood clots. The combination hormone therapy (PremPro) risks include cardiovascular disease, stroke, breast cancer, and pulmonary embolism.
Another study showed a negligible risk of blood clots when non-oral estrogens are compared to oral estrogens. Non-oral estrogens also appear to be beneficial for blood pressure. [7]
They went on to say that “growing literature suggests that the progestins used in association with estrogens may not be equivalent.” [7] “Compelling indications also exist that differences might also be present for the risk of developing breast cancer, with recent trials indicating that the association of natural progesterone with estrogens confers less or even no risk of breast cancer as opposed to the use of other synthetic progestins.” [7]
A study by Simon showed no increased risk of VTE or stroke. He demonstrated that progesterone has no increased risk of VTE or breast cancer. He went on to say “the use of transdermal estradiol and micronized progesterone could reduce or possibly even negate the excess risk of VTE, stroke, cholecystitis, and possibly even breast cancer associated with oral HRT use.” [8]
A study performed in France, called the ESTHER trial, showed that “oral but not transdermal estrogen is associated with an increased VTE risk.” [9] They also noted that synthetic progestins (norpregnane derivatives) may increase blood clots but this risk was not noted with micronized progesterone and pregnane derivatives. [9]
Multiple studies demonstrate superior safety with bioidentical hormone replacement therapy (BHRT) compared to traditional hormone replacement. BHRT is an invaluable tool and it can be life changing for many women.
L’hermite M, Simoncini T, Fuller S, Genazzani AR. Could transdermal estradiol + progesterone be a safter postmenopausal HRT? A review. Maturitas. 2008 Jul-Aug;60(3-4):185-201. doi:10.1016/j.maturitas.2008.07.007. Epub 2008 Sep 5.
Simon JA. What’s new in hormone replacement therapy: focus on transdermal estradiol and micronized progesterone. Climacteric. 2012. Apr,15 Suppl 1:3-10. Doi: 10.3109/13697137.2012.66932.
Canonico M, et al. Hormone therapy and venous thromboembolism among postmenopausal women. Impact of the rout of estrogen administration and progestogens: the ESTHER study. Circulation. 2007;115;840-845.
PREDIMED Study – Traditional Mediterranean Diet (TMD)
