Wednesday, February 6, 2008

ACCORD Study: Don't stop your diabetes medicines, Please!

Just recently announced was the discontinuation of a large, NIH run study in diabetics. The ACCORD study was designed to look at whether getting the sugar to as close to normal as possible would prevent heart attacks and deaths. In fact, patients in the intense treatment group did worse than patients with standard care, leading to 54 excess deaths, which is why the study was stopped early. This study has already been mentioned on some of the main media outlets (MSNBC, NY Times, and the Washington Post) and will likely make its way to the morning TV news.

Bottom Line: Trying to get the sugar too low in these patients may have been harmful. However, most physicians don't even try to come close to getting the sugar this low. If you are diabetic, keeping your sugar under control is still extremely important. Also, it was made clear that Avandia was not a factor in these deaths.

For those who want to know more: We have known for some time that there is more to diabetes treatment than just the sugar. People with Type 2 diabetes don't die for high sugar, but rather suffer from the complications caused by diabetes- heart attack, stroke, kidney failure, blindness. One of the largest diabetes trials done in Europe (UKPDS) showed us that by treating diabetes more agressively, these complications were reduced. Recommendations to keep the hemoglobin A1c (measure of overall sugar control) under 7.0% was based on this study. However, though heart attacks were reduced in the UKPDS, this difference was only 95% certain (most scientist say you need more that 95% certainty to prove something). Thus, when it comes to heart attacks, there is something more than the sugar. The ACCORD study tried to get patients to a hemoglobin A1c under 6.0% (or normal) believing that more agressive care would benefit patients. Surprisingly, there were more deaths. The full report has not yet been released, but in order to get patients this close to normal, insulin was likely neededin many cases. Insulin can drop the sugar too low and has also been associated with an increase in cardiac risk. Interestingly, guidelines from the ADA suggest preferably using insulin to get patients under control, rather than use other (newer) agents because they are more expensive and don't work as well as insulin. (Perhaps this may not be the best approach).
Also released today, was a study in the New England Journal of Medicine that had absolutely no press. This was another agressive management study, but rather than try to get the sugar as low as possible, this study tried not lonly to get patients to an A1c below 6.5% ( a more reasonable target), but also their cholesterol less than 175, and blood pressure less than 130/80. Patients were treated for over seven years and then followed for more that 5 years after treatment. After 13 years, patients in the intensive treatment group had the total death rate cut in half, with over 40% lower rates of cardiac death and heart attacks, and almost half as many patients treated for eye complications. In order to achieve these goals, the patients in the intense group needed more medicine, including insulin, but likely not as much as those in the ACCORD study.
The implication of these two studies are that:
1) Diabetics should try to keep the sugar under control for as long as possible, at an A1c less than 6.5%
2) Going below 6.5% is probably not necessary, and going below 6.0% may be harmful.
3) Diabetics must also control blood pressure and cholesterol. (All diabetics should take a statin medication, even if their cholesterol is normal!)


Dave said...

Why should all diabetics take statins, especially in light of the recent results about Vytorin?

Dr. Matthew Mintz said...

According to the American Diabetes Association's guidelines : "Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels, for diabetic patients with overt CVD or without CVD who are over the age of 40 and have one or more other CVD risk factors."
This is essentially all diabetics.
The rationale for this statement is based on studies like the Heart Protection Study which found a 24% relative reduction in heart attacks for diabetics, regardless of what there baseline cholesterol was, i.e. even diabetics with normal cholesterols had benefit from statins.
See my prior link about Vytorin, but essentially all the recent Enhance study showed was that Vytorin (zetia plus simvistatin) was no better than the statin alone, meaning that there is more to the story than ldl. This actually makes sense when considering the diabetes studies (like Heart Protection) that showed that patients had benefit regardless of their ldl. In other words, statins do something to protect patients from heart attacks that can not be simply measured by ldl cholesterol reduction. There are many theories (plaque stabilization, lowering blood pressure, decreasing inflamation), but no one is really sure.

prior link about

Dave said...

Hello Dr. Mintz. 24% doesn't strike me as a terribly impressive reduction in absolute risk, especially given the cost of statins and potential for side-effects. What's the NNT for statin treatment of diabetics?

Who funded the study you mentioned? Are there other studies showing different results?

Since statins seem to exert their benefit (at least in diabetics, and probably in general) independent of cholesterol-lowering, is there any alternative treatment that might have the same (or greater) benefit without the cost and potential side-effects? Indeed, I believe that one could make a strong case that the observed statin side-effects are caused by reduction in cholesterol.

For instance, we know that statins block HMG-CoA reductase, thus preventing the conversion of HMG-CoA to mevalonate. Mevalonate is not only the precursor to cholesterol, but also of geranylgeranyl pyrophosphate, which activates the pro-inflammatory molecule Rho. Since it is known that CVD has a strong inflammatory component, AND it is known that diabetes is a highly pro-inflammatory condition, it certainly seems extremely plausible that it is the anti-inflammatory action of statins causing the 24% reduction. I would guess that this anti-inflammatory effect could be achieved by treatments (drugs and dietary intervention) which are considerably less expensive, with less potential for adverse side-effects.

I would be very interested to know your opinions, and any associated research.

Dave said...

Another question: while there was a 24% reduction in heart attacks in diabetics taking statins, what is change in all-cause mortality?


Dr. Matthew Mintz said...

Dave, great questions.
here is a link to one of the study publications
The Heart Protection Study was sponsored by Merk, the makers of Zocor/simvistatin (which was used in the study) as well a Vytorin, which was not. For diabetics, those on statins had a total of 22% reduction in heart attacks and stroke. The absolute reduction was 5% and NNT of about 20. The absolute mortality reduction for the entire study was about 2%, and NNT of 55. Two percent reduction may sound low, but treating 55 people to prevent one death is pretty substantial.
You are correct that this is costly, but you need to look at the cost of a heart attack as well. Average cost for a hospitalized heart attack is $10,000. So you would need to treat 20 diabetics with a statin for 4 years to prevent (about $50,000 given discount insurance companies get for a statin). So it is still costing alot of money, but there is a productivity and quality of life issue to take into consideration.
You are correct that the statins have what are called pleotrophic effects (anti-inflammation, decreased blood pressure, plaque stabilization, etc.) which may explain why Vytorin did no better than simvistatin in the ENHANCE study.
Though cheaper and more "natural" methods would be ideal, none have shown the outcomes that statins have. There is one trial done in the VA on gemfibrozil, but this has worse side effects then statins and the results are not impressive. Vitamin E and C have actually been proven to be harmful. There is some data on fish oil which does seem to work. Diet and exercise do improve surrogate markers, but don't substantially improve outcomes.
Finally, there is no questions that statins cause side effects, but the most common one is muscle aches which occurs in only about 3% of patients, is usually mild and usually goes away. If a patient has side effects, you can always stop the statin.

Dave said...

Hi Dr. Mintz. So a 5% absolute risk reduction in diabetics over 5 years can be achieved at a net expected cost of $2000/patient ($2500/year for statins minus 5% of $10000).

Wasn't the HPS the most positive result to date for statin treatment? We shouldn't rely on a single study, especially if others exist. What sort of risk reductions and side-effects have been observed in other studies? Merck, who funded the HPS, sold $4.3 billion worth of simvastatin in 2005, corresponding to $21.5 billion over a five-year period, and thus has a clear conflict of interest, both in terms of pumping up the benefits and minimizing side-effects.

What about simply reducing carbohydrate intake? Isn't high blood sugar highly pro-inflammatory?