Should all patients with metabolic syndrome or elevated HgA1c take statins?

Metabolic syndrome is a constellation of factors (increased waist circumference, high blood pressure, elevated fasting glucose, high triglycerides, low hdl) that are associated with increased cardiovascular risk. Metabolic syndrome is often called pre-diabetes both because sugars are high and because metabolic syndrome is related to insulin resistance, the primary mechanism of type 2 diabetes. Diabetes has been generally defined as having a fasting blood sugar of greater than 126, so patients with sugars between 100-125 have also been called pre-diabetics. Like diabetes, we know that metabolic syndrome is associated with increased cardiovascular risk (increased risk for heart attack and stroke). Men with three or more components of metabolic syndrome have more than double the risk for cardiovascular disease, and women with three or more factors have almost six times the risk for cardiovascular disease.

Because diabetes is associated with such a high cardiovascular risk, and because lowering cholesterol with statins in diabetics has proven to reduce these events, current guidelines recommend that virtually all diabetics take a statin, even for those patients with normal cholesterol levels. One question which remains is whether the same should be done for patients with elevated fasting blood sugars and/or metabolic syndrome.

A recent study in the New England Journal called Glycated Hemoglobin, Diabetes, and Cardiovascular Risk in Nondiabetic Adults may give us more reason to consider thinking about using cholesterol lowering agents in patients with elevated blood sugars, even if the cholesterol is normal. The study looked at the relationship of hemoglobin A1c (HbA1c) to development of diabetes and cardiovascular risk. It was not surprising that even high end normal HbA1c's predicted development of diabetes, but what was surprising was that high normal HbA1c was strongly associated with risk for heart attack and stroke.

In the study, patients with an HbA1c of less than 5.0% had 4% relative decreased risk of cardiovascular disease compared to patients with and A1c of 5.0 to 5.5%. However, those with A1c's from 5.5 to 6.0% had a 23% increase, those with A1cs of 6.0 to 6.5% had a 78% increased risk, and those with 6.5% or greater had an almost double risk of cardiovascular disease. This suggest a strong correlation between elevated blood sugar (pre-diabetic patients) and cardiovascular risk.

In the most recent updates to the ADA guidlines published in the January 2010 edition of Diabetes Care, the ADA now defines diabetes as patients with an A1c of >6.5%, and those patients with A1c's between 5.7–6.4% have been included in a category of increased risk for future diabetes. Thus, the last group in the recent study would now be considered to already have diabetes.

This study also made me think of the JUPITER trial. The JUPITER trial is a controversial trial which I have blogged about before (see Jupiter is Out, and the News is Good! and Crestor: Get Ready to Ask Your Doctor for the CRP Test). It showed that patients with relatively normal cholesterol levels, but high levels of CRP benefited from taking 20mg of Crestor. Crestor now has an FDA indication for primary prevention of heart disease.

Interestingly in the JUPITER study, 41% of patients had the metabolic syndrome. The median A1c was 5.7 (interquartile range was 5.4-5.9). This means that about half the patients in the study had an extra 23% increase for cardiovascular disease based on A1c alone, and about 25% of patients had a 78% additional risk or higher (with the new ADA definition, there was probably not an insignificant number of patients in the JUPITER study that had an A1c above 6.5% that would now be considered to be diabetic and should have been on a statin). The reason I bring up JUPITER is because we now have a primary prevention trial in which a substantial number of patients had metabolic syndrome or elevated sugar, and this trial showed that statins were beneficial.

Thus, there are compelling arguments that can be made to suggest that patients with either metabolic syndrome or an elevated HgA1c should be on a statin (similar to diabetics) regardless of their cholesterol number.

However........
1. In order to definitively make this case, you would need a large, randomized clinical trial of patients with metabolic syndrome (or A1c's between 5.5 and 6.5) and normal cholesterol, randomized to statin or no statin. I am hopeful that the NIH or some drug company is planning on doing this.
2. In a subgroup analysis of the JUPITER trial, the investigators looked to see whether metabolic syndrome was a factor in those patients that benefited from Crestor and didn't find a statistically significant difference. It appears that CRP levels and not sugar levels is what made the difference.
3. Though the presence of metabolic syndrome does predict cardiovascular disease, it predicts diabetes much better, and the Framingham risk score is a much better predictor of cardiovascular disease (see Metabolic Syndrome vs Framingham Risk Score for Prediction of Coronary Heart Disease, Stroke, and Type 2 Diabetes Mellitus )

Bottom Line: Elevated HgA1c levels and metabolic syndrome substantially increase risk for cardiovascular disease, and there are compelling reasons to consider statin therapy in these patients, though conclusive data is lacking. As per the new ADA guidelines, patients at risk for diabetes should be screened with a HgA1c, and if it is greater than 6.5%, these patients are now considered diabetic and should receive a statin.

Since the Framingham risk calculation is still the best predictor for cardiovascular risk, a reasonable approach might be to adjust the Framingham score for patients with HgA1c's between 5.5% and 6.5%. Currently, patients with a Framingham risk of greater than 10% are considered for more aggressive LDL goals (which usually means they need a statin). Based on the numbers from the recent New England Journal study, for patients with A1c's from 5.5 to 6.0%, more aggressive goals should be considered when these patients have a Framingham score of 8% (instead of 10%), and for those with A1cs of 6.0 to 6.5%, more aggressive goals should be considered for a Framingham score above 6%.

Crestor: Get Ready to Ask Your Doctor for the CRP Test.

The Wall Street Journal is reporting that and FDA panel voted 12-4 in favor of expanding its indication for treating elevated CRP levels. The FDA doesn't always follow the panel's advice, but it usually does, and probably will in this instance.

What's this about?

The FDA is reviewing the results of the JUPITER trial. I blogged about the results of the Jupiter trial a year ago. Basically this study looked at over 17,000 patients with relatively normal cholesterol levels, but an elevated CRP, which is a marker of inflammation and has been associated with elevated risk for heart attack and stroke. The study was planned for 4 years, but stopped just short of 2 years because they found a substantial benefit for patients taking Crestor. Crestor reduced the risk of heart related deaths, heart attacks, and other serious cardiac complications by 44%. These results are pretty impressive.

What's the FDA have to do with this?
Why is the FDA weighing in on a year old study for a drug that is already on the market? Because Astra Zeneca, the maker of Crestor, is asking the FDA to give Crestor and indication to use Crestor in patients with normal LDL's but elevated CRP's. Currently, all statin medications are only indicated to treat high cholesterol in order to prevent heart attacks and strokes, not to actually prevent heart attacks and strokes irrespective of cholesterol.
I have previously discussed the meaning of "indication" in a post called "An indication for change." Basically, even though Crestor has been proven to prevent heart attacks in patients with elevated CRP and normal cholesterol, the company can not share this information with doctors or advertise this information with patients until it gets the indication. You may notice that a recent Crestor commercial shows a woman over time who states that while she was building a family/career, atherosclerotic plaques were building up in her arterties. The reason this is a focus of the commercial is because Crestor recently got an indication to prevent the progression of atherosclerosis. Since it is the only statin with this indication, the company likely wants to use this as a competitive edge over other statins. It it gets the CRP indication, it will likely use this in advertising messages to doctors and patients.

What does this mean for me?
Actually, the study results have been out for over a year, so this is not really anything new. However, if the FDA does go forward with the panel's recommendations, you will likely hear more about testing for CRP, and your doctor may even recommend this test.

Should I use a statin to treat an elevated CRP?
The jury is still out. This may change though, as the Adult Treatment Panel IV (ATP4), a NIH sponsored group, will soon make its new cholesterol treatment recommendations. They will have to address the CRP issue. The US Preventative Health Task Force (the same government group that recently told younger women to stop getting mammograms) recently stated that they felt there was insufficient evidence to recommend this. This is true, because though there are numerous studies associating CRP to cardiovascular risk, only the JUPITER study shows that treatment works. That being said, the JUPITER study is a very large, randomized trial with substantial differences between treatment and placebo groups, so it should not be ignored. If you don't want to wait until the APT4 weighs in, I would discuss this with your physician. If you are very worried about heart attacks and strokes (possibly a strong family history), but have a normal cholesterol, treating an elevated CRP might be a reasonable option for you.

What do the nay-sayers say?
There are many that will come out against this, regardless of what the ATP4 decides. In addition to stating that there isn't enough data they will say:

• "The patients in the JUPITER study taking Crestor developed diabetes". This is true, but most of the patients in the study were at risk of developing diabetes. Even though there were statistically a few more patients taking Crestor that developed diabetes, it is very unlikely that this was real, and other markers of diabetes were the same
• "You are taking medications that have side effects." It is true that any medication has side effects. However, one interesting thing that came out of the JUPITER study was that there were really no difference in side effects between the placebo group and Crestor group. Given that the 20mg dose used in the study was a relatively high dose, this is pretty impressive. Groups like Public Citizen warned of the dangers of Crestor, but this drug has proven to be quite safe.
• "The patients in JUPITER did not exactly have normal cholesterol levels, and their risk was high." This is a valid criticism. In order to really prove that treating elevated CRP levels with a statin prevents heart attacks, you would need to find patients with an otherwise low risk for heart disease (i.e. not pre-diabetic) and an ldl cholesterol below 100. However, the patients in JUPITER were very representative of the normal population of patients (60% of the country is overweight or obese and many a pre-diabetic) that would not usually get a statin medication.

Do I have to take Crestor to treat an elevated CRP?

This is actually a very important question. Currently, simivastatin is a generic cholesterol medicine and much cheaper then Crestor. Though simvastatin has not shown it can reduce heart attacks by lowering CRP, many physicians will assume a "class effect" and believe that all statins will do this. The problem is that a dose of 20mg of Crestor was used in the JUPITER study, and no amount of simvastatin will lower CRP or LDL by that much. In most studies that have measured CRP lowering with statins, it is the very potent statins that seem to work. In addition, though all statins have shown prevention of heart attacks and strokes, only the more potent statins (Lipitor and Crestor) at high doses have shown to prevent the progresssion and even shown reversal of plaque build up. This will become an even more important issue when Lipitor goes generic.

Bottom Line:
The FDA will very likely approve Crestor for treating elevated CRP levels, and you will hear about this in the media and in advertisements. Though based on one study, the results are compelling enough to discuss this with your doctor and consider CRP testing.