Recently there was an electronic pre-publication ahead of print by Lancet, the British medical magazine. The article (and the accompanying editorial) discussed the result of a meta-analysis (and see my prior blogs for the errors inherent in meta-analyses) of 639 randomized trials of Cox-inhibitors (such as Celebrex) and NSAIDs (ibuprofen or Motrin/Advil, naproxen or Aleve, and diclofenac or Voltaren) to see if their use (a) caused increased upper GI bleeding and/or (b) increased vascular events (heart attack, heart failure, stroke). You may recall that Vioxx, a cox-inhibitor, was taken off the market because of an increased incidence of cardiac events.
The results were first announced as an increase in relative risk, which always looks worse than the increase in absolute risk. The studies looked at the effect of either a standard dose of a coxib, or a high dose (150mg diclofenac, 2400mg ibuprofen, 1000mg naproxen). The studies looked at major vascular events (heart attack or stroke), heart failure, overall mortality, and upper GI complications.
There was an increase in major vascular events of 33% with the use of Celebrex and Voltaren. There was also an increased risk with Motrin, but it did not reach clinical significance. There was no increased risk with Aleve. OTOH, the use of Aleve was associated with the greatest risk of upper GI bleeding compared with the other three drugs. And only coxibs showed a statistically significant rise in all-cause mortality.
In the case of vascular events and upper GI bleeding, the greatest risk factors were age, and conditions (diabetes, hypertension, GERD) that pre-dispose to a problem.
Now for the absolute numbers, which illustrate the real risk. Using a coxib or diclofenac was associated with 3 additional vascular events per 1,000 person years, one of which was fatal. If a patient had a 2% annual risk of a vascular event, then a coxib would add 7 additional events per 1000 patient years (2 of which would be fatal), Voltaren would add 8 (2 fatal), and Advil would add 9 (3 fatal).
In patients with a 0.5% annual risk of upper GI complications, coxibs and diclofenac would add 4 more events per 1000 patient years, ibuprofen 15 more events, and naproxen 16 more.
All four drugs showed a statistically significant increase in hospitalizations due to heart failure.
Once again, we see that the absolute risk seems less serious than the relative risk, as is almost always the case. Also, no studies were done at a lower dose of the drugs, and no studies were done to see if the addition of a PPI or other acid inhibitor lessened the risk of upper GI complications.
The data thus shows a small but statistically significant risk with some of these drugs to cause problems.
These problems occurred more frequently in high risk groups, and you should discuss with your doctor which group you fall into. To my mind, the data is barely significant, and the use of these drugs is a judgment call, and one has to compare quality of life to statistical risk.
Wednesday, June 19, 2013
Sunday, June 9, 2013
Coenzyme Q-10
After I mentioned the effect of statins on muscles and referred to coenzyme Q-10, I have received a number of questions about this ubiquitous molecule, so I thought I would answer a few of them here.
Coenzyme Q-10 is contained in animal foods that we eat, but over 90% of this molecule is synthesized in the body. Curiously enough, it shares a common molecule with the synthetic process for cholesterol. The subscript "10" refers to the number of side chains. This is important, because lab rats synthesize and use Co-Q-9, which is chemically different, so the results with lab rats should not be extrapolated to human use. Your tissue level of CoQ decreases with age, chronic heart failure, diabetes, some cancers, and HIV, but adding CoQ to the diet has not been shown to benefit any of these conditions. It will, however, help protect the heart from the side effects of doxorubicin, an anti-cancer drug, and does help the immune system of lab rats.
As I mentioned in my earlier blog, CoQ is a vital molecule for the electron transport chain that lets the cell generate aerobic (requiring oxygen) energy, which accounts for over 90% of the body's requirement. No other molecule in the body can do this job.The molecule was discovered in 1957, and is found in the membranes of many cell organelles, especially in mitochondria, the energy factories of the body. The molecule is fat-soluble, and also has anti-oxidant properties as well as the ability to regenerate other antioxidants such as Vitamin E.
Because the molecule is fat soluble, absorption is best when taken with food. A typical dose is 150 to 300 mg/day. It was found that it may help some migraneurs, and when taken with magnesium citrate and Vitamin B2 (riboflavin) help prevent migraine attacks in some patients. Because it shares a common molecule with the synthesis of cholesterol, statins, which reduce the level of cholesterol, also reduce the level of CoQ. Oddly enough, some beta-blockers also reduce the tissue level of CoQ.
There are few studies that show any unequivocal benefit from taking CoQ-10. It does improve the immune system of lab rats, but not of humans. It also seems to protect lab rats from the damages of external radiation.The two interventional studies, one on patients with heart failure and one on patients with breast cancer failed to show a significant benefit. Studies to see if CoQ supplementation increased the lifetime of lab rats led to contradictory results.
However, a meta-analysis (and see my previous blog for my critique of such studies) did show that Co-Q-10 lowered the blood pressure in humans, by as much as 15mm systolic and 10 mm diastolic, which is a very powerful result. No study has shown that Co-Q supplementation reverses the decrease of CoQ caused by statins.
In summary, coenzyme Q-10 is a vital molecule for energy generation, and we are busily looking for a clinical use for supplemental doses. I am looking forward to a double-blind study to validate its benefit in patients with hypertension, as well as to see if it can prevent the muscle aches and muscle breakdown that can develop with the use of statins.
Coenzyme Q-10 is contained in animal foods that we eat, but over 90% of this molecule is synthesized in the body. Curiously enough, it shares a common molecule with the synthetic process for cholesterol. The subscript "10" refers to the number of side chains. This is important, because lab rats synthesize and use Co-Q-9, which is chemically different, so the results with lab rats should not be extrapolated to human use. Your tissue level of CoQ decreases with age, chronic heart failure, diabetes, some cancers, and HIV, but adding CoQ to the diet has not been shown to benefit any of these conditions. It will, however, help protect the heart from the side effects of doxorubicin, an anti-cancer drug, and does help the immune system of lab rats.
As I mentioned in my earlier blog, CoQ is a vital molecule for the electron transport chain that lets the cell generate aerobic (requiring oxygen) energy, which accounts for over 90% of the body's requirement. No other molecule in the body can do this job.The molecule was discovered in 1957, and is found in the membranes of many cell organelles, especially in mitochondria, the energy factories of the body. The molecule is fat-soluble, and also has anti-oxidant properties as well as the ability to regenerate other antioxidants such as Vitamin E.
Because the molecule is fat soluble, absorption is best when taken with food. A typical dose is 150 to 300 mg/day. It was found that it may help some migraneurs, and when taken with magnesium citrate and Vitamin B2 (riboflavin) help prevent migraine attacks in some patients. Because it shares a common molecule with the synthesis of cholesterol, statins, which reduce the level of cholesterol, also reduce the level of CoQ. Oddly enough, some beta-blockers also reduce the tissue level of CoQ.
There are few studies that show any unequivocal benefit from taking CoQ-10. It does improve the immune system of lab rats, but not of humans. It also seems to protect lab rats from the damages of external radiation.The two interventional studies, one on patients with heart failure and one on patients with breast cancer failed to show a significant benefit. Studies to see if CoQ supplementation increased the lifetime of lab rats led to contradictory results.
However, a meta-analysis (and see my previous blog for my critique of such studies) did show that Co-Q-10 lowered the blood pressure in humans, by as much as 15mm systolic and 10 mm diastolic, which is a very powerful result. No study has shown that Co-Q supplementation reverses the decrease of CoQ caused by statins.
In summary, coenzyme Q-10 is a vital molecule for energy generation, and we are busily looking for a clinical use for supplemental doses. I am looking forward to a double-blind study to validate its benefit in patients with hypertension, as well as to see if it can prevent the muscle aches and muscle breakdown that can develop with the use of statins.
Wednesday, June 5, 2013
Pancreatic Cancer, Pancreatitis, and Diabetes.
There was an article last week (Friday, May 31) on the front page of the business section of the NY Times quoting an interview with a doctor who claims that he has evidence that a diabetes drug, Januvia, can predispose the users to pancreatic cancer, based on animal studies.
First, let me say a few words about all drug/animal studies. Animals have very different biochemical milieus than do humans, and the results of animal studies may not apply to humans. As an example of the difference, every animal but man and the guinea pig have the necessary enzymes to synthesize ascorbic acid, or Vitamin C. So already their chemistry is different. It is not automatic that a drug that has effect A on animals will have effect A on humans, and vice versa.
Several decades ago, Congress passed a law with the Delaney clause, saying that any food additive that caused tumors in animals could not be added to food for humans. Shortly thereafter it was found that saccharine caused tumors in mouse bladders. Since saccharine was the only synthetic sweetener then available, Congress immediately passed a law exempting saccharine. So even the lawmakers don't believe the animal-human link.
The changes that Dr. Peter Butler found were "pre-cancerous" lesions in rats, and no one knows how many precancerous lesions progress or what the time frame is. Post-marketing surveys have found no increased incidence of pancreatic cancers in users of Januvia, but there is argument as to whether or not there is an increased incidence of pancreatitis. As I have said before, if you have to argue about the significance of data, it almost certainly is not significant.
What are the risk factors for pancreatic cancer? Age, obesity, chronic pancreatitis, and diabetes. The link with diabetes is tricky, because often pancreatic cancer first makes its presence known by causing diabetes. No one has shown that alcohol consumption is a risk factor for pancreatic cancer, even though it is a risk factor for chronic pancreatitis, and chronic pancreatitis is "linked" to pancreatic cancer, but not shown to cause it if you parse the observational data. OTOH extrapolating from diet studies, the Mediterranean diet should be protective.
In summary, since diabetes itself is a risk factor for pancreatic cancer, the proper study would be to compare two groups of diabetics, one of whom takes Januvia while the other does not. And these patients should have the same diet vis-a-vis red meat and vegetables. I wonder if chronic pancreatitis is a risk factor for pancreatic cancer in lab rats? If it is not, then such a result would invalidate the extrapolation from lab rats to humans.
In summary, since diabetes itself is a risk factor for pancreatic cancer, the proper study would be to compare two groups of diabetics, one of whom takes Januvia while the other does not. And these patients should have the same diet vis-a-vis red meat and vegetables. I wonder if chronic pancreatitis is a risk factor for pancreatic cancer in lab rats? If it is not, then such a result would invalidate the extrapolation from lab rats to humans.
Tuesday, May 28, 2013
Statins and Muscles
A number of readers have asked me about the recent article in the NY Times which quoted an online article in the Journal of the American College of Cardiology which discussed the adverse effects of statin use on skeletal muscle.
To begin with, there is a molecule called Co-enzyme Q (or Q-10) which lines the inside of the membrane of mitochondria. A mitochondrion is an organelle inside a cell where ATP, the source of the cell's energy is generated. There are many mitochondria in muscle cells, for obvious reasons. The electron chain to create ATP must pass through Co-Q, so that in the absence of Co-Q the cell can generate no energy. Finally, one side effect of the use of statins is the reduction of the amount of Co-Q in the body. Another side effect of statins is muscle aches and occasionally elevation of CPK, which indicates muscle damage.
The study involved a study of overweight men and women, who did no exercise, and satisfied the criteria for the metabolic syndrome. They first did a stress test and underwent a muscle biopsy. Then one-half of the subjects were given a daily dose of a statin, and both groups underwent supervised exercise for 45 minutes five times a week. After 12 weeks, repeat stress testing and muscle biopsies were done.
Now we already have evidence that exercise and statins lower cholesterol, and lower the death rate in patients with dyslipidemia. There also was an article in this year's Lancet (Feb. 2, p. 394) that showed that in veterans with dyslipidemia both exercise and statins lower cholesterol levels and reduce mortality, and the effect of exercise plus statin was greater than either modality alone.
After the 12 weeks, the non-medicated group had increased their physical fitness, but the medicated group did not. The energy enzyme levels in muscle mitochondria increased in the non-drug group and decreased in the drug group.
What does this all mean? Since we do not know the precise mechanism(s) by which exercise lowers the death rate, the study cannot be interpreted. One would have to look at the death rate or heart attack rate of both groups, and since this is a group with no history of a heart attack, we would probably have to wait five years to detect a possible difference in outcomes. In other words, we know that exercise is beneficial for cardiac health, and the fact that statin use apparently prevents an increase in aerobic fitness does not mean that exercise plus statin use is no better than either treatment alone.
Just as lack of exercise and elevated cholesterol are separate risk factors for heart attacks, and together they are synergistic in increasing one's risk, so are statin use and exercise synergistic in preventing such an event.
To begin with, there is a molecule called Co-enzyme Q (or Q-10) which lines the inside of the membrane of mitochondria. A mitochondrion is an organelle inside a cell where ATP, the source of the cell's energy is generated. There are many mitochondria in muscle cells, for obvious reasons. The electron chain to create ATP must pass through Co-Q, so that in the absence of Co-Q the cell can generate no energy. Finally, one side effect of the use of statins is the reduction of the amount of Co-Q in the body. Another side effect of statins is muscle aches and occasionally elevation of CPK, which indicates muscle damage.
The study involved a study of overweight men and women, who did no exercise, and satisfied the criteria for the metabolic syndrome. They first did a stress test and underwent a muscle biopsy. Then one-half of the subjects were given a daily dose of a statin, and both groups underwent supervised exercise for 45 minutes five times a week. After 12 weeks, repeat stress testing and muscle biopsies were done.
Now we already have evidence that exercise and statins lower cholesterol, and lower the death rate in patients with dyslipidemia. There also was an article in this year's Lancet (Feb. 2, p. 394) that showed that in veterans with dyslipidemia both exercise and statins lower cholesterol levels and reduce mortality, and the effect of exercise plus statin was greater than either modality alone.
After the 12 weeks, the non-medicated group had increased their physical fitness, but the medicated group did not. The energy enzyme levels in muscle mitochondria increased in the non-drug group and decreased in the drug group.
What does this all mean? Since we do not know the precise mechanism(s) by which exercise lowers the death rate, the study cannot be interpreted. One would have to look at the death rate or heart attack rate of both groups, and since this is a group with no history of a heart attack, we would probably have to wait five years to detect a possible difference in outcomes. In other words, we know that exercise is beneficial for cardiac health, and the fact that statin use apparently prevents an increase in aerobic fitness does not mean that exercise plus statin use is no better than either treatment alone.
Just as lack of exercise and elevated cholesterol are separate risk factors for heart attacks, and together they are synergistic in increasing one's risk, so are statin use and exercise synergistic in preventing such an event.
Friday, May 17, 2013
Does Marijuana Prevent Diabetes?
An article in this month's (May 2013) American Journal of Medicine shows that current users of marijuana have better glucose control than do former users, who in turn have better glucose control than do abstainers. This study was a retrospective one, and needs to be validated by a forward study. This will probably never happen, for obvious reasons, much as retrospective studies showing that cigarette smokers have a lower incidence of Parkinson's disease were never followed up.
The use of marijuana was based on interviews with the 4657 members of the study; of this group 579 were current users and 1975 were prior users. Fasting glucose and insulin levels were measured, and the degree of insulin resistance was calculated. Diabetics and pre-diabetics both have insulin resistance.
This study was triggered by prior studies showing that marijuana users have a lower incidence of both obesity and diabetes, but there have been no similar studies of THC users. Current marijuana users in this study were seen to have lower levels of fasting insulin, and were less likely to be insulin resistant. They also had higher levels of HDL cholesterol and smaller waist sizes. Past users (more than 30 days before the study questionnaire) also had a lower incidence of insulin resistance than did non-users, but not as low as did current users.
The results of this study need to be followed up, but given the current federal law classifying marijuana as a Class I drug, meaning "no significant medical benefit", it is difficult to envision a prospective study being done. One possibility might be in the state of Washington or Colorado, where marijuana was recently legalized. OTOH, perhaps the federal law could be changed to make it legal to treat diabetes and the metabolic syndrome with THC and to do a study of its effect.
The use of marijuana was based on interviews with the 4657 members of the study; of this group 579 were current users and 1975 were prior users. Fasting glucose and insulin levels were measured, and the degree of insulin resistance was calculated. Diabetics and pre-diabetics both have insulin resistance.
This study was triggered by prior studies showing that marijuana users have a lower incidence of both obesity and diabetes, but there have been no similar studies of THC users. Current marijuana users in this study were seen to have lower levels of fasting insulin, and were less likely to be insulin resistant. They also had higher levels of HDL cholesterol and smaller waist sizes. Past users (more than 30 days before the study questionnaire) also had a lower incidence of insulin resistance than did non-users, but not as low as did current users.
The results of this study need to be followed up, but given the current federal law classifying marijuana as a Class I drug, meaning "no significant medical benefit", it is difficult to envision a prospective study being done. One possibility might be in the state of Washington or Colorado, where marijuana was recently legalized. OTOH, perhaps the federal law could be changed to make it legal to treat diabetes and the metabolic syndrome with THC and to do a study of its effect.
Sunday, May 12, 2013
The New Arabian Coronavirus.
A new respiratory virus which has killed 18 of the 31 infected cases has arisen in Saudi Arabia, where teams of Arabian physicians, members of the World Health Organization, and infectious disease specialists from the United States are all investigating jointly. This virus is a coronavirus, the same type (but genetically different) of the virus that originated in Chinses poultry and became the SARS virus when it infected man. The disease has developed in clusters of people. In one Arabian cluster of 15 people infected with the virus, 9 died. The most recent infection detected was in a man in France who inhabited the same hospital room as a person who returned from Dubai to France and was found to have the virus.
The virus has a predilection for elderly people with underlying chronic medical conditions that might impair their ability to fight disease. There is some evidence for people-to-people transmission, but this connection is weak and not 100%. For instance, only one doctor taking care of a patient has developed the disease. But since there are 4 clusters of the disease, this is evidence for weak person-to-person transmission.
At this point, we do not know the (presumed) animal reservoir of the disease. This disease has the potential to mutate and become much more infective and transmissible, which could create a weak epidemic or a strong pandemic. There is no antiviral currently on the market that treats this
infection, and efforts are just starting to sequence its genome and to develop a vaccine. There is not much more to say, except to recommending avoiding travels to areas in the Middle East where this new coronavirus has been found, as well as avoiding travels to areas of China and Taiwan where the new bird flu, InfluenzaA-N7H9 has been detected.
I strongly recommend following ProMED,com, the daily e-mailing of the International Society of Infectious Disease (ISID) for up to date information on both viruses.
The virus has a predilection for elderly people with underlying chronic medical conditions that might impair their ability to fight disease. There is some evidence for people-to-people transmission, but this connection is weak and not 100%. For instance, only one doctor taking care of a patient has developed the disease. But since there are 4 clusters of the disease, this is evidence for weak person-to-person transmission.
At this point, we do not know the (presumed) animal reservoir of the disease. This disease has the potential to mutate and become much more infective and transmissible, which could create a weak epidemic or a strong pandemic. There is no antiviral currently on the market that treats this
infection, and efforts are just starting to sequence its genome and to develop a vaccine. There is not much more to say, except to recommending avoiding travels to areas in the Middle East where this new coronavirus has been found, as well as avoiding travels to areas of China and Taiwan where the new bird flu, InfluenzaA-N7H9 has been detected.
I strongly recommend following ProMED,com, the daily e-mailing of the International Society of Infectious Disease (ISID) for up to date information on both viruses.
Monday, May 6, 2013
The New Asian Bird Flu
I thought I would share some facts with you about the new strain of influenza A H7N9, that has arisen in China and probably comes from birds, although we are not 100% certain of that. There has, as yet, been no evidence of people-to-people transmission (unlike SARS which infected health care workers). Furthermore, although this flu strain is resistant to amantadine, it is susceptible to oral oseltamovir (Tamiflu).
As of the end of April, there have been 126 confirmed cases in China, and 24 or 19% died. Older people are more susceptible to both catching the flu and succumbing to it, especially if they have a chronic health problem. Cases have been found in eight contiguous provinces in eastern China as well as in Beijing, Shanghai and Taiwan. China is making prodigious efforts to learn all it can about the flu and the birds' contribution to it. The flu has been found in some chickens and ducks, but the flu virus is harmless to poultry, and birds who are infected with the virus show no signs of being ill.
Thankfully, in the over 1500 close contacts of sick patients there has been no evidence of the flu, so unless it mutates there is no risk of an epidemic or pandemic. Except for one pigeon, the virus has only been found in chickens and ducks for sale in marketplaces; farms seem to be exempt. Relatively few poultry are carrying the virus, and 20% of the people with the virus report no exposure to birds. Chinese physicians and technicians are making herculean efforts to track and to find the virus, as well as sequencing its genome, and are examining pigs as well as poultry.
China has invited members from the World Health Organization as well as from our own Center for Disease Control to come and assist in their work. In addition, the CDC is monitoring patients here in the US for cases of Influenza A/H7N9, but so far have found no cases. There is not even the suggestion of facts or cases being hidden by China, so whatever you read should be accepted.
In summary, the virus is mild and relatively rare in poultry, but has a case fatality rate of 20% in humans, and while we think that poultry is the reservoir, we are not yet sure.
As of the end of April, there have been 126 confirmed cases in China, and 24 or 19% died. Older people are more susceptible to both catching the flu and succumbing to it, especially if they have a chronic health problem. Cases have been found in eight contiguous provinces in eastern China as well as in Beijing, Shanghai and Taiwan. China is making prodigious efforts to learn all it can about the flu and the birds' contribution to it. The flu has been found in some chickens and ducks, but the flu virus is harmless to poultry, and birds who are infected with the virus show no signs of being ill.
Thankfully, in the over 1500 close contacts of sick patients there has been no evidence of the flu, so unless it mutates there is no risk of an epidemic or pandemic. Except for one pigeon, the virus has only been found in chickens and ducks for sale in marketplaces; farms seem to be exempt. Relatively few poultry are carrying the virus, and 20% of the people with the virus report no exposure to birds. Chinese physicians and technicians are making herculean efforts to track and to find the virus, as well as sequencing its genome, and are examining pigs as well as poultry.
China has invited members from the World Health Organization as well as from our own Center for Disease Control to come and assist in their work. In addition, the CDC is monitoring patients here in the US for cases of Influenza A/H7N9, but so far have found no cases. There is not even the suggestion of facts or cases being hidden by China, so whatever you read should be accepted.
In summary, the virus is mild and relatively rare in poultry, but has a case fatality rate of 20% in humans, and while we think that poultry is the reservoir, we are not yet sure.
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