David Baxter PhD
Late Founder
VITAL News About Vitamin D and Omega-3s
Berkeley Wellness
December 11, 2018
Vitamin D and omega-3 (fish oil) capsules, two of the best-sellingdietary supplements, have been the focus of countless studies in recent years, the great majority of them observational. The results, unfortunately, have been confusing, conflicting, or inconclusive. One reason why it’s hard to evaluate these and other dietary supplements is the sparsity of large, well-designed, independently sponsored, placebo-controlled clinical trials, which are expensive to do.
So it’s no wonder that one such “gold standard” clinical trial, the NIH-funded VITAL study, has been so eagerly awaited. For more than five years it has been testing both supplemental vitamin D and omega-3s for their potentially protective effects against a wide array of diseases, and its first results finally appeared in the New England Journal of Medicine in November 2018.
These initial VITAL findings, published in two studies, focused on the biggest questions: Can vitamin D help prevent cardiovascular disease or cancer in healthy people? Can omega-3 capsules help prevent them? Overall, the answers were no, but there may be some positive news, especially for supplemental omega-3s.
A landmark study
The Harvard researchers randomly assigned a nationally representative sample of 25,871 people (men ages 50 and older, women 55 and older) to one of four groups:
After an average of 5.3 years, neither supplement reduced the overall incidence of major cardiovascular events (a composite of heart attacks, strokes, and cardiovasculardeaths) or cancer. Those were the primary endpoints, meaning that the studies were designed to evaluate them, so those negative findings rightfully made headlines. There were no serious adverse effects at these doses.
Slicing and dicing the data
The VITAL researchers also looked at a variety of so-called secondary endpoints, including subgroup analyses, and found the following:
Secondary endpoints and subgroup analyses are less reliable and harder to interpret than primary endpoints. A study can have dozens of secondary endpoints, and focusing on just a few of them can at least appear to be cherry-picking the data for something significant to report. Thus, the VITAL researchers noted that these positive findings could be due to chance and “should be considered hypothesis-generating, in the context of the negative findings for the primary outcome measures.”
As the accompanying editorial put it, “These ‘positive’ results need to be interpreted with caution. . . . The medical literature is replete with exciting secondary endpoints that have failed when they were subsequently formally tested as primary endpoints in adequately powered randomized trials.”
Bottom line: The primary findings of VITAL should slow the vitamin D and omega-3 bandwagons, though fans and marketers of dietary supplements will likely take the findings for a few secondary endpoints out of context to promote the supplements. These results are hardly the last word,however. The supplements may indeed still have benefits in higher-risk groups and for other medical conditions. Notably, many (though not all) studies suggest that vitamin D, working with calcium, can help maintain bone health and reduce fracture risk, at least in high-risk populations, such as those with low blood levels of D or osteoporosis. Supplemental omega-3s may help certain groups of people at high cardiovascular risk—for instance, those with high blood levels of triglycerides (see inset below).
Other important clinical trials on vitamin D or omega-3s are still underway. And the VITAL researchers are continuing to follow the participants’ incidence of cardiovascular disease and cancer. Also in progress are additional VITAL analyses looking at a long list of other primary endpoints, such as diabetes, cognition, bone health, depression, asthma, infections, and autoimmune disorders. So we’ll be hearing a lot more VITAL news about vitamin D and omega-3s in the next few years.
Big News About Prescription Omega-3s
People with high levels of triglycerides (fats in the blood) are at elevated risk for cardiovascular disease. High doses of long-chain omega-3 fatty acids (EPA and DHA) can lower elevated triglycerides by 50 percent or more; thus the FDA has approved several prescription drugs containing purified omega-3s for the treatment of triglyceride levels above 500 mg/dL. Now a major clinical trial, published in the New England Journal of Medicine in November 2018, has shown that one of these omega-3 drugs, called Vascepa and containing only concentrated EPA, can actually reduce the risk of heart attacks, strokes, and other cardiovascular events in people at high risk.
The study, called REDUCE-IT, involved 8,179 people, average age 64, who had high triglycerides (average 216 mg/dL; an ideal level is less than 100) and either established cardiovascular disease or else diabetes plus at least one other cardiovascular risk factor. At the start, they had low LDL (“bad”) cholesterol levels (average 75 mg/dL) as a result of statin treatment. Half took Vascepa (4 grams a day) plus their statin, the other half a placebo plus statin.
After five years, the Vascepa group had 25 percent fewer major cardiovascular events than the placebo group. That worked out to about one less event per 20 people. The observed benefit was seen regardless of the participants’ triglyceride levels (at baseline or after treatment), suggesting that other mechanisms besides triglyceride lowering, such as anti-inflammatory effects, could have contributed to the benefit. The Vascepa group had slightly more hospitalizations for atrial fibrillation.
Because Vascepa is the only drug containing just EPA (no DHA), it is not known if other omega-3 drugs would have the same benefits. As of late 2018, the FDA had not yet reviewed data from the study or approved Vascepa for use in this high-risk population, though doctors may prescribe it for them off-label.
One lingering question about the study was its use of mineral oil in the placebo capsules, which may have reduced statin absorption in some participants, thus raising average LDL cholesterol slightly — though the small difference in LDL levels between the groups would be un**likely to explain an observed benefit of this magnitude, the researchers noted.
Also see Vitamin D: A Research Roundup.
Berkeley Wellness
December 11, 2018
Vitamin D and omega-3 (fish oil) capsules, two of the best-sellingdietary supplements, have been the focus of countless studies in recent years, the great majority of them observational. The results, unfortunately, have been confusing, conflicting, or inconclusive. One reason why it’s hard to evaluate these and other dietary supplements is the sparsity of large, well-designed, independently sponsored, placebo-controlled clinical trials, which are expensive to do.
So it’s no wonder that one such “gold standard” clinical trial, the NIH-funded VITAL study, has been so eagerly awaited. For more than five years it has been testing both supplemental vitamin D and omega-3s for their potentially protective effects against a wide array of diseases, and its first results finally appeared in the New England Journal of Medicine in November 2018.
These initial VITAL findings, published in two studies, focused on the biggest questions: Can vitamin D help prevent cardiovascular disease or cancer in healthy people? Can omega-3 capsules help prevent them? Overall, the answers were no, but there may be some positive news, especially for supplemental omega-3s.
A landmark study
The Harvard researchers randomly assigned a nationally representative sample of 25,871 people (men ages 50 and older, women 55 and older) to one of four groups:
- Omega-3 capsule (1 gram a day) plus a placebo. The pharmaceutical-grade omega-3 capsules were highly purified and concentrated, supplying 840 milligrams ofthe fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid). That istwo to three times more EPA and DHA than is found in many standard 1-gram omega-3 capsules, though some “triple-strength” supplements have the higher dose.
- Vitamin D capsule (2,000 IU a day) plus a placebo.
- Both supplements.
- Two placebo capsules.
After an average of 5.3 years, neither supplement reduced the overall incidence of major cardiovascular events (a composite of heart attacks, strokes, and cardiovasculardeaths) or cancer. Those were the primary endpoints, meaning that the studies were designed to evaluate them, so those negative findings rightfully made headlines. There were no serious adverse effects at these doses.
Slicing and dicing the data
The VITAL researchers also looked at a variety of so-called secondary endpoints, including subgroup analyses, and found the following:
- When separating out different types of cardiovascular events, the researchers found that people taking omega-3s had 28 percent fewer heart attacks, including a 50 percent reduction in fatal heart attacks, than those taking the placebo. Based on the study findings, 246 people would need to be treated for five years to prevent one heart attack. There was no reduction in strokes or cardiovascular mortality rates.
- African-Americans taking omega-3s had a remarkable 77 percent reduction in heart attacks compared to the placebo. That means that 90 African-Americans would need to be treated for five years to prevent one heart attack.
- Among people taking omega-3s, those reporting below-average baseline intakes of fish (averaging less than 1½ servings a week) had a 40 percent reduction in heart attacks.
- When researchers looked at specific cancers, they found no reduction in breast, prostate, or colorectal cancers in people taking either supplement. However, the vitamin D group had a 25 percent lower rate of total cancer deaths compared to the placebo—but only starting after the first two years.
- In the vitamin D group, normal-weight participants had reductions in cancer incidence compared to the placebo, but overweight and obese participants did not.It’s possible that because of their larger bodies, overweight and obese people may need higher doses of vitamin D to derive benefits, the researchers speculated.
- Treatment effects did not vary by baseline blood levels of vitamin D. One shortcoming of many studies on vitamin D is that they do not report on baseline blood levels (supplements would be less likely to benefit people who already have adequate blood levels). VITAL included baseline blood levels of D and found that even people with low levels did not benefit from supplementation. Most participants had adequate D levels to start; only 1 in 8 had inadequate levels (less than 20 ng/mL).
Secondary endpoints and subgroup analyses are less reliable and harder to interpret than primary endpoints. A study can have dozens of secondary endpoints, and focusing on just a few of them can at least appear to be cherry-picking the data for something significant to report. Thus, the VITAL researchers noted that these positive findings could be due to chance and “should be considered hypothesis-generating, in the context of the negative findings for the primary outcome measures.”
As the accompanying editorial put it, “These ‘positive’ results need to be interpreted with caution. . . . The medical literature is replete with exciting secondary endpoints that have failed when they were subsequently formally tested as primary endpoints in adequately powered randomized trials.”
Bottom line: The primary findings of VITAL should slow the vitamin D and omega-3 bandwagons, though fans and marketers of dietary supplements will likely take the findings for a few secondary endpoints out of context to promote the supplements. These results are hardly the last word,however. The supplements may indeed still have benefits in higher-risk groups and for other medical conditions. Notably, many (though not all) studies suggest that vitamin D, working with calcium, can help maintain bone health and reduce fracture risk, at least in high-risk populations, such as those with low blood levels of D or osteoporosis. Supplemental omega-3s may help certain groups of people at high cardiovascular risk—for instance, those with high blood levels of triglycerides (see inset below).
Other important clinical trials on vitamin D or omega-3s are still underway. And the VITAL researchers are continuing to follow the participants’ incidence of cardiovascular disease and cancer. Also in progress are additional VITAL analyses looking at a long list of other primary endpoints, such as diabetes, cognition, bone health, depression, asthma, infections, and autoimmune disorders. So we’ll be hearing a lot more VITAL news about vitamin D and omega-3s in the next few years.
Big News About Prescription Omega-3s
People with high levels of triglycerides (fats in the blood) are at elevated risk for cardiovascular disease. High doses of long-chain omega-3 fatty acids (EPA and DHA) can lower elevated triglycerides by 50 percent or more; thus the FDA has approved several prescription drugs containing purified omega-3s for the treatment of triglyceride levels above 500 mg/dL. Now a major clinical trial, published in the New England Journal of Medicine in November 2018, has shown that one of these omega-3 drugs, called Vascepa and containing only concentrated EPA, can actually reduce the risk of heart attacks, strokes, and other cardiovascular events in people at high risk.
The study, called REDUCE-IT, involved 8,179 people, average age 64, who had high triglycerides (average 216 mg/dL; an ideal level is less than 100) and either established cardiovascular disease or else diabetes plus at least one other cardiovascular risk factor. At the start, they had low LDL (“bad”) cholesterol levels (average 75 mg/dL) as a result of statin treatment. Half took Vascepa (4 grams a day) plus their statin, the other half a placebo plus statin.
After five years, the Vascepa group had 25 percent fewer major cardiovascular events than the placebo group. That worked out to about one less event per 20 people. The observed benefit was seen regardless of the participants’ triglyceride levels (at baseline or after treatment), suggesting that other mechanisms besides triglyceride lowering, such as anti-inflammatory effects, could have contributed to the benefit. The Vascepa group had slightly more hospitalizations for atrial fibrillation.
Because Vascepa is the only drug containing just EPA (no DHA), it is not known if other omega-3 drugs would have the same benefits. As of late 2018, the FDA had not yet reviewed data from the study or approved Vascepa for use in this high-risk population, though doctors may prescribe it for them off-label.
One lingering question about the study was its use of mineral oil in the placebo capsules, which may have reduced statin absorption in some participants, thus raising average LDL cholesterol slightly — though the small difference in LDL levels between the groups would be un**likely to explain an observed benefit of this magnitude, the researchers noted.
Also see Vitamin D: A Research Roundup.
