Blogs - Thomas Dayspring MD, FACP, FNLA, NCMP / Uncategorized - Posts
The ACCORD Trial (also go to my Lipidaholics Group and see case 254 looking at an acutal patient) It is not arguable that elevated TG and increased TG-rich lipoproteins significantly increase CV risk. Often the high TG is associated with reductions in HDL-C (TG/HDL axis disorders) and of course since VLDL-C (TG/5) is always elevated, non-HDL-C is usually high. Indeed it is the ultimate NCEP ATP-III goal of therapy in patients with TG > 200 mg/dL. Fibrates have a long history of monotherapy success in improving CVD outcomes. Please see the following for a very thorough discussion of the trials (Fibrate Therapy in Patients with Metabolic Syndrome and Diabetes Mellitus by myself and Gregory Pokrywka. Current Atherosclerosis Reports 2006, 8:356–364. What we needed is data on how would fenofibrate perform when added to a statin. That is what the Action to Control Cardiovascular Risk in Diabetes (ACCORD) is all about. (NEJM 2010) On face value (main conclusion) the trial seems to be null on the ability of fenofibrate to improve outcomes above what a statin can do in T2DM patients. We do have previous data with fibrates in diabetics or TG/HDL axis disorders. The DAIS (Diabetes Atherosclerosis Intervention Study Investigators) data (a very successful angiographic trial used fenofibrate monotherapy (with zero statin contamination) vs. placebo - Lancet 2001;357: 905–10) was the first trial to show that fenofibrate delayed the onset or caused a disappearance of microalbuminuria (a microvascular endpoint). Of course since then we have had The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study trial theoretically looking at fenofibrate vs. placebo in T2DM patients (of course lots of statin drop ins occurred in the higher risk folks with abnormal lipids) and despite the overall null outcome, we got evidence that in metabolic syndrome patients with TG/HDL axis disorders (like the patient at hand) there was very significant benefit in those using fenofibrate (Diabetes Care 32:493–498, 2009). Although very few still use gemfibrozil (because of medicolegal reasons in a polypharmacy world) and no one in the US uses bezafibrate we know from the primary prevention trial Helsinki (gemfibrozil), and the BIP trial (bezafibrate) that the those fibrates were most successful in patients with elevated TG and low HDL-C. Glance at the following table from the ACCORD trial supplement data published in N Engl J Med 2010. DOI: 10.1056/NEJMoa1001282 (make no conclusions on ACCORD until you read the supplement). The table shows that in patients with high TG and low HDL-C fibrates perform remarkably well in reducing clinical events- data from Helsinki, BIP Field and ACCORD are amazingly consistent is supporting that conclusion. See ACCORD slides in the NLA slide URL. Despite the overall null finding, it sure looks like Fenofibrate duplicated the benefit seen in all of the other fibrate trials in patients with elevated TG and low HDL-C. I do not know of any other drugs, other than statins that have such an impressive record of helping our patients with TG/HDL-C axis disorders reduce adverse outcomes. Niacin would come closest using angiographic but no outcome data. So what do I now advise, after ACCORD Lipid about future use of fenofibrate? In actuality, the trial actually reinforced a lot of what we previously knew and I believe supports continued aggressive care of high risk patients (with T2DM and/or metabolic syndromes) who have TG/HDL axis disorders (with a TG > 200 mg/dl) with statin/TG synthesis inhibitor use. TG synthesis inhibitor is a term I use to include fibrates/fibric acids, higher dose niacin (Niaspan) and very high dose N-3 fatty acid (Lovaza) therapy (all of those drugs do reduce TG beyond inhibiting FA and TG synthesis, but I find it a convenient description). If microalbuminuria is present then fenofibrate/fenofibric acid is the reasonable drug of choice to add on to the statin or statin/ezetimibe. As we all know in FIELD, there was also significantly less need for laser photocoagulation therapy of the retina and a significant reduction in neuropathic-related amputations of feet and toes (an off label use of fenofibrate that must be considered in real world lipid management). Let’s look at the ACCORD Lipid trial in depth: 5518 patients with T2DM with TG< 700 or on-treatment TG < 400 and an abnormal HgbA1c (>7.5%)LDL-C < 180 mg/dL HDL-C < 55 for blacks and women < 50 for all othersMean Follow-Up: 4.7 years Mean Patient Age: 62 years % Female: 31%Age: 40-79 years with clinical cardiovascular disease or age 55-79 years with subclinical cardiovascular disease or at least two additional cardiovascular risk factors Endpoints:Combination of the primary outcome plus revascularization or hospitalization for heart failure Combination of a fatal coronary event, nonfatal myocardial infarction, or unstable angina Nonfatal myocardial infarction Nonfatal strokeAll cause deathCardiovascular deathHospitalization due to CHFThere were also prespecified subgroup endpoints including looking at those with the highest TG/HDL axis Baseline data in both treatment and placebo arms: BMI ~32 Normotensive TG ~ 162 (interquartile range 113-229) HDL-C ~ 38 LDL-C ~ 100 Females 1/3 of cohort Blacks 15% Hispanics 7% No lipoprotein concentration or non-HDL-C data released (mindboggling) 2765 assigned to receive fenofibrate plus simvastatin and 2753 assigned to receive placebo plus simvastatin (20-40 mg as need to normalize HDL-C). In some patients other drugs were needed to achieve LDL-C goal (6%) likely with ezetimibe. The average simvastatin dose was only 22 mg. There was ~ 80% compliance rate with study drugs and placebo Mean LDL-C fell from 100.0 to 81.1 in the fenofibrate group & from 101.1 to 80.0 in placebo group
Mean HDL-C increased from 38.0 to 41.2 mg per deciliter in the fenofibrate group & from
38.2 to 40.5 mg per deciliter in the placebo group. Median TG decreased from 189.0 to 147.0 in the fenofibrate group & from 186.2 to 170.0 in placebo group. Main Outcome: The annual rate of the primary outcome was 2.2% in the fenofibrate group, as compared with 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% CI 0.79 to 1.08; P = 0.32) Hazard ratios for the secondary outcomes, including the individual components of the primary outcome, ranged from 0.82 to 1.17 (P≥0.10 for all comparisons)
Annual rates of death from all causes were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P = 0.33 Finally we have a fibrate trial where no one can conjecture about increasing overall or CV mortality (even though such data was always null in all previous trials) In patients who had a TG level in the highest third (≥204) and an HDL-C level in the lowest third (≤34) were compared with all the other patients (P = 0.057 for interaction). In patients with high TG levels and low HDL-C levels, the primary outcome rate was 12.4% in the fenofibrate group, versus 17.3% in the placebo group, whereas such rates were 10.1% in both study groups for all other patients. The authors note: "Our subgroup results and those of these previous trials support the view that the addition of fenofibrate to a statin may benefit patients with type 2 diabetes who have substantial dyslipidemia. The use of combination fibrate–statin therapy in such patients is consistent with current guidelines that recommend treatment for patients with hypertriglyceridemia and low HDL cholesterol levels that persist despite statin therapy." So why the heck did they even study folks with TG < 200 mg/dL? There was indeed no lower limit for TG which would make a person ineligible for trial entry. The authors point out (in the supplemental paper available on line) that in reality only 15-20% of diabetics have TG > 200 mg/dL and finding > 5000 such patients would have been impossible. They correctly mention if they would have excluded patients with TG < 200 mg, we would have had a trial that only enlightened us on 20% of the diabetic population (that have TG > 200 mg/dL). We really needed to know what statin/feno would offer all T2 diabetics. The authors thought that the first trial looking at combination therapy had to look at the entire T2DM population. No one can argue with that. As a result of ACCORD, we now are a lot smarter. We now pretty much know with as much certainty as we will ever have, that in T2DM patients without elevated TG there is no clear indication to add a fibrate to a statin to reduce events. We can still add colesevelam, ezetimibe or Niaspan to get to goal in those patients with TG < 200. However, we now have additional data (supporting the findings of Helsinki, BIP and FIELD) that fenofibrate works best in those with TG > 200 mg/dL (see table above). If you did lipoprotein evaluations of those patients you would almost certainly find large VLDLs, VLDL remnants, CE-poor TG-rich large LDLs and lots of CE-poor small LDLs (all atherogenic particles contributing to apoB that usually do not respond well to statin monotherapy). Since the NCEP goal of therapy for patients with high TG is non-HDL-C, I wish they had analyzed that. There is no NMR analysis I am aware of from the study. It would be really interesting to see what happened to total HDL-P and HDL subspecies, which seemed to be so important in explaining the benefit of gemfibrozil in the VA-HIT trial. World class experts (Frank Sachs, JC Fruchart, etc.) of the Residual Risk Reduction Initiative faculty (www.r3i.org web site) state the following (and if you are not regularly viewing this web site, please do so): "The benefit of fenofibrate was only seen in the group of patients with atherogenic dyslipidemia, and none of the primary or secondary endpoints were statistically significant in the total study population which included many patients with LDL-C at goal and without combined atherogenic dyslipidemia. There is a risk that the positive and clinically important results seen in ACCORD Lipid will be lost in the context of ACCORD being seen as a ‘negative’ study. ----- ACCORD-Lipid shows that residual vascular risk can be safely and effectively addressed in patients with type 2 diabetes and atherogenic dyslipidemia. It is up to all of us to ensure that this message is communicated as effectively as possible to fellow physicians across the world as soon as possible." I also believe we got lots of other great info from this trial. There was more data on how safe fenofibrate and statin are. Virtually no toxicity. No venous thromboses or PE whatsoever as was seen in FIELD. No myositis over statin/placebo. No liver toxicity. No pancreatitis. No gallbladder toxicity, no cancers, etc. For whatever reason (and I offer no explanation) there seemed to be worse results in women (not adjusted for lipid quartiles). This is bizarre because In FIELD there was actually a trend towards more benefit in women than men. This is likely one of those unexplainable findings that occasionally show up when lots of data is analyzed. So the Dayspring take home from ACCORD is: In patients with cardiometabolic risk (high TG low HDL-C), especially those with T2DM the risk is high because of too many atherogenic lipoproteins (almost all explained by TG). Statin monotherapy helps, but residual risk remains unacceptable (the PROVE-IT trial showed if statins in ACS patients have the LDL-C < 70 but TG remains > 150, the residual risk is high). If on the statin or statin/ezetimibe (LDL receptor therapy) therapy the non-HDL-C remains high because the VLDL-C is high (remember VLDL-C is TG/5) then a fibrate add-on makes sense - so does high dose Niaspan or very high dose Lovaza (N-3 FA) but in diabetics the ACCORD results and the microalbumin benefit makes the fenofibrate an attractive as well as logical choice.
Mean HDL-C increased from 38.0 to 41.2 mg per deciliter in the fenofibrate group & from
38.2 to 40.5 mg per deciliter in the placebo group. Median TG decreased from 189.0 to 147.0 in the fenofibrate group & from 186.2 to 170.0 in placebo group. Main Outcome: The annual rate of the primary outcome was 2.2% in the fenofibrate group, as compared with 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% CI 0.79 to 1.08; P = 0.32) Hazard ratios for the secondary outcomes, including the individual components of the primary outcome, ranged from 0.82 to 1.17 (P≥0.10 for all comparisons)
Annual rates of death from all causes were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P = 0.33 Finally we have a fibrate trial where no one can conjecture about increasing overall or CV mortality (even though such data was always null in all previous trials) In patients who had a TG level in the highest third (≥204) and an HDL-C level in the lowest third (≤34) were compared with all the other patients (P = 0.057 for interaction). In patients with high TG levels and low HDL-C levels, the primary outcome rate was 12.4% in the fenofibrate group, versus 17.3% in the placebo group, whereas such rates were 10.1% in both study groups for all other patients. The authors note: "Our subgroup results and those of these previous trials support the view that the addition of fenofibrate to a statin may benefit patients with type 2 diabetes who have substantial dyslipidemia. The use of combination fibrate–statin therapy in such patients is consistent with current guidelines that recommend treatment for patients with hypertriglyceridemia and low HDL cholesterol levels that persist despite statin therapy." So why the heck did they even study folks with TG < 200 mg/dL? There was indeed no lower limit for TG which would make a person ineligible for trial entry. The authors point out (in the supplemental paper available on line) that in reality only 15-20% of diabetics have TG > 200 mg/dL and finding > 5000 such patients would have been impossible. They correctly mention if they would have excluded patients with TG < 200 mg, we would have had a trial that only enlightened us on 20% of the diabetic population (that have TG > 200 mg/dL). We really needed to know what statin/feno would offer all T2 diabetics. The authors thought that the first trial looking at combination therapy had to look at the entire T2DM population. No one can argue with that. As a result of ACCORD, we now are a lot smarter. We now pretty much know with as much certainty as we will ever have, that in T2DM patients without elevated TG there is no clear indication to add a fibrate to a statin to reduce events. We can still add colesevelam, ezetimibe or Niaspan to get to goal in those patients with TG < 200. However, we now have additional data (supporting the findings of Helsinki, BIP and FIELD) that fenofibrate works best in those with TG > 200 mg/dL (see table above). If you did lipoprotein evaluations of those patients you would almost certainly find large VLDLs, VLDL remnants, CE-poor TG-rich large LDLs and lots of CE-poor small LDLs (all atherogenic particles contributing to apoB that usually do not respond well to statin monotherapy). Since the NCEP goal of therapy for patients with high TG is non-HDL-C, I wish they had analyzed that. There is no NMR analysis I am aware of from the study. It would be really interesting to see what happened to total HDL-P and HDL subspecies, which seemed to be so important in explaining the benefit of gemfibrozil in the VA-HIT trial. World class experts (Frank Sachs, JC Fruchart, etc.) of the Residual Risk Reduction Initiative faculty (www.r3i.org web site) state the following (and if you are not regularly viewing this web site, please do so): "The benefit of fenofibrate was only seen in the group of patients with atherogenic dyslipidemia, and none of the primary or secondary endpoints were statistically significant in the total study population which included many patients with LDL-C at goal and without combined atherogenic dyslipidemia. There is a risk that the positive and clinically important results seen in ACCORD Lipid will be lost in the context of ACCORD being seen as a ‘negative’ study. ----- ACCORD-Lipid shows that residual vascular risk can be safely and effectively addressed in patients with type 2 diabetes and atherogenic dyslipidemia. It is up to all of us to ensure that this message is communicated as effectively as possible to fellow physicians across the world as soon as possible." I also believe we got lots of other great info from this trial. There was more data on how safe fenofibrate and statin are. Virtually no toxicity. No venous thromboses or PE whatsoever as was seen in FIELD. No myositis over statin/placebo. No liver toxicity. No pancreatitis. No gallbladder toxicity, no cancers, etc. For whatever reason (and I offer no explanation) there seemed to be worse results in women (not adjusted for lipid quartiles). This is bizarre because In FIELD there was actually a trend towards more benefit in women than men. This is likely one of those unexplainable findings that occasionally show up when lots of data is analyzed. So the Dayspring take home from ACCORD is: In patients with cardiometabolic risk (high TG low HDL-C), especially those with T2DM the risk is high because of too many atherogenic lipoproteins (almost all explained by TG). Statin monotherapy helps, but residual risk remains unacceptable (the PROVE-IT trial showed if statins in ACS patients have the LDL-C < 70 but TG remains > 150, the residual risk is high). If on the statin or statin/ezetimibe (LDL receptor therapy) therapy the non-HDL-C remains high because the VLDL-C is high (remember VLDL-C is TG/5) then a fibrate add-on makes sense - so does high dose Niaspan or very high dose Lovaza (N-3 FA) but in diabetics the ACCORD results and the microalbumin benefit makes the fenofibrate an attractive as well as logical choice.
The data on President Obama was just forwarded to me by an NLA member. What would your advice, as a lipidologist, be to the President and his physician? Here are the specifics:
2010 data: TG 46 HDL-C 62 LDL-C 138
CAC "negative"
Glucose normal
In 2007: TG 44 HDL-C 68 LDL-C 96 BP 105/62
Does the rise in LDL-C concern you?
For my thoughts please go over to Groups: Lipid Geeks and see my posted reply. Please join our lipid geeks group and please post coments.
Go over to the Groups Section and click on Lipidaholics and check out the new case discussion which illustrates some very important concepts, specifically understanding the core composition of LDL particles.
NLA members are frequently asked what the heck is a lipidologist. Please check out this web site which discusses this question and ask your patients to also check it out.
TD
Tags: lipidology
There is a lot of anecdotal buzz in lipiology circles that Vitamin D is a cure all for statin-associated myopathy. Well we finally have data from a clinical trial looking at this controversy. Low serum 25 (OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients. Ahmed W, et al. Translational Research 2009;153:11–16.
Go over to the groups page, and click on Lipidaholics and then Lipid Geeks to seek a discussion of this study.
Happy Lipiding, TD
Lipidaholics: Please go over to the Groups page and click on lipidaholics group to read the latest case discussion which gets into the importance of HDL particle size as both a risk factor and goal of therapy. Most of all please post any comments. I believe there is a lot of misinformation out there on HDL sizes, especially by labs offering such tests - what they mean and what to do about them.
Happy Lipiding, TD
Friends: Go over to my Lipidaholic group and check out Lipidaholics ANonymous Case # 250. Please post comments.
Tom D
The most recent Lipidaholics Anonymous Case has been posted under Groups: Lipidaholics. I pose the following question: Please surprise me with the correct answer: Who said and when did they say: "In a desire to use more specific terminology, certain durable nouns from the lipid era should not be discarded." The nouns being referred to are hypercholesterolemia and hypertriglyceridemia. Next question - if that is true, when did the lipid era end and what followed it? Third and final question: how many practicing physicians and lipidologists even know the lipid era has ended?
For the answer you have to read the case - Trust me you will be rewarded and perhaps very surprised.
Happy New Year, Tom Dayspring
Tags: lipoproteins
There is a new posting at my Lipid Geeks group: read the case and see if you would prescribe a statin or not to a patient with a normal LDL-P. Please feel free to post comments.
Ever dealt with a TG > 20,000. Can you figure out the underlying lipoprotein abnormality? How would you treat? The case is posted at the group page under the lipidaholics group. Please join my group and leave your comments.
Tom Dayspring
Results per page:
Author Information
Posts: 26
Comments: 8
Job Title: Clinical Assistant Professor of Medicine; Director: North Jersey Institute of Menopausal Lipidology
Categories
Tags
triglycerides (4)
ldl-p (4)
hdls (3)
lipoproteins (3)
apob (2)
statins (2)
therapy (1)
familial (1)
fenofibrate (1)
testing (1)
diabetes (1)
combination (1)
hyperlipidemia (1)
vitamin (1)
myopathy (1)
lipidology (1)
size (1)
particle (1)
lipid (1)
hdl (1)