APPROACH: Rosiglitazone doesn't affect atherosclerosis progression in diabetics with CV disease
New Orleans, LA - Atherosclerosis progression as gauged by intravascular ultrasound (IVUS) was unaffected by a year and a half of treatment with
rosiglitazone (Avandia, GlaxoSmithKline), compared with more conventional treatment with the sulfonylurea
glipizide (Glucotrol, Pfizer) in diabetics with CV disease, reported investigators at the
American Heart Association 2008 Scientific Sessions [
1].
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Dr Richard W Nesto
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In their international trial, called Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Type 2 Diabetes Patients with Cardiovascular History (APPROACH), there were no suggestions of any of a host of potential clinical hazards and adverse effects that have been attributed to rosiglitazone over the past 18 months, as covered extensively by heartwire. In particular, the trial, with fewer than 700 patients, showed no significant differences between the two antidiabetic therapies with respect to risk of CV death, new MI, heart failure, peripheral edema, or bone fracture.
Despite the trial being negative for its primary end point, its investigators pointed to secondary suggestions that the controversial thiazolidinedione (TZD) may have had an antiatherosclerotic effect among the trial's CV patients with more established diabetes.
"I do think it's reassuring as far as the effect of the drug on the coronary arteries," APPROACH principal investigator Dr Richard W Nesto (Lahey Clinic Medical Center, Burlington, MA), who presented the trial at the meeting, said at a press conference. The data suggest that rosiglitazone is not proatherosclerotic, at least, "and I think the data suggest it could be antiatherosclerotic."
Also at the press briefing, Dr Beatriz Rodriguez (Pacific Health Research Institute, Honolulu, HI), the assigned discussant for Nesto's formal presentation, acknowledged the recent controversies about rosiglitazone, including suggestions in a controversial meta-analysis from 2007 that suggested the drug increases the risk of MI and CV death. APPROACH, on the other hand, "suggests that rosiglitazone may be associated with a reduction in the total atheroma volume," she said, referring to another secondary observation. "But we need to be cautious with this interpretation."
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Dr Beatriz Rodriguez
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APPROACH randomized 672 patients with type 2 diabetes and indications for coronary angiography or PCI, at least one clinically significant coronary lesion, and 10% to 50% narrowing of at least one untreated coronary artery. They could be on up to three antidiabetic agents and had to have an LVEF of at least 40% and be free of heart failure.
Among the 339 patients who received glipizide at 15 mg/day and the 333 who took rosiglitazone at up to 8 mg/day, 54% were on one and 28% were on two other antidiabetic agents. Other medication use by the end of the trial included aspirin in about 84%, beta blockers in 67%, ACE inhibitors or angiotensin-receptor blockers in about 74%, statins in about 80%, and metformin in about 66% of patients.
When atherosclerosis progression over 18 months was measured in terms of "percent atheroma volume" (PAV) in the study's primary analysis, there was no significant difference between the treatment groups.
Change in volumetric end points by IVUS in glipizide and rosiglitazone groups
End point
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Glipizide, n=339
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Rosiglitazone, n=333
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Difference
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p
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Change in PAV* (%)
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+0.43
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-0.21
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-0.64
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0.12
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Change in atheroma volume (mm3)
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+1.2
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-3.9a
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-5.2
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0.04
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Change in atheroma volume (at the most diseased 10-mm vessel segment) (mm3)
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-3.6b
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-5.3b
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-1.7
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0.13
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*Primary end point
PAV=percent atheroma volume
a. p=0.05 vs baseline
b. p<0.0001 vs baseline
There were no significant differences in a composite clinical end point that included death from any cause, nonfatal MI, or stroke, revascularization, or hospitalization for ischemia; a composite end point including CV death or nonfatal MI or stroke; death from any cause; or new congestive heart failure, Nesto reported.
Prespecified subgroup analyses suggested that any rosiglitazone antiatherosclerotic effect may be stronger in patients with longer-established diabetes, and there was a favorable trend in older patients.
Subgroups showing primary-end-point differences between rosiglitazone and glipizide groups
Subgroup
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Difference between treatments (mm3) (95% CI)
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p
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Age >60 y
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-1.39 (-2.54 to -0.25)
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0.07
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Diabetes duration longer than median of 4.9 y
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-1.83 (-2.98 to -0.69)
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0.005
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Neither APPROACH nor another study that used IVUS to assess disease progression in TZD-treated diabetics with CV disease, called PERISCOPE, were large enough to say much conclusively about the drugs' safety or efficacy in that population, Dr Mark A Creager (Brigham and Women's Hospital, Boston, MA), who wasn't part of either trial, told heartwire. Creager has been a member of the writing committees for a range of guidelines from the North American cardiology societies on the use of coronary interventions and the treatment of acute coronary syndromes and arrhythmic and valvular diseases.
As reported by heartwire, PERISCOPE tracked the same IVUS metric used in APPROACH in 543 patients treated with either pioglitazone (Actos, Takeda Pharmaceuticals) or the sulfonylurea glimepiride (Amaryl, Sanofi-Aventis). But unlike APPROACH, the trial showed a significant slowing of atherosclerosis progression compared to the more traditional drug.
Adverse effects in APPROACH
Adverse event
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Glipizide
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Rosiglitazone
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p
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Mean weight change vs baseline (kg)
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1.4
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2.6
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0.02
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Hemoglobin decrease >3 g/dL (%)
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3
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8
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0.01
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Hypoglycemia (%)
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28
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8
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<0.0001
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Peripheral edema (%)
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7
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9
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0.48
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Bone fracture (%)
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0.6
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2
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0.17
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To download tables as slides, click on slide logo above
Nesto reports being on the speakers' bureau for GlaxoSmithKline and Takeda and a consultant for GlaxoSmithKline. The APPROACH coauthors include at least two employees of GlaxoSmithKline. Rodriguez said she had no disclosures.
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Source
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Nesto RW. Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Type 2 Diabetes patients with Cardiovascular History (APPROACH). American Heart Association 2008 Scientific Sessions; November 12, 2008; New Orleans, LA. Late Breaking Clinical Trials Session 4.
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November 13, 2008 05:15 (EST)
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Very interesting indeed, no cardiac signal for risk
High risk DM population indicated for QCA or PCI:
From this article above "There were no significant differences in a composite clinical end point that included death from any cause, nonfatal MI, or stroke, revascularization, or hospitalization for ischemia; a composite end point including CV death or nonfatal MI or stroke; death from any cause; or new congestive heart failure, Nesto reported."
But Doctor Nissen told me last year we would see MI and increased trend to moratlity within six months using rosiglitazone. I'm glad the FDA and AACE looked at the evidence in an unbiased fashion as now APPROACH, RECORD, ACCORD, ADVANCE, ADOPT, VADT, DREAM controlled prospective studies in nearly 45K pts haven't confirmed his and his counterparts conclusions. But, he's still sticking with that message.
From AHA Webpage Peggy Peck report - "Steven Nissen, M.D., of the Cleveland Clinic and principal investigator of the PERISCOPE trial, said, "because the studies were similar, the failure of APPROACH suggests that there are important differences in the efficacy of these two drugs." (See: ACC: Pioglitazone (ACTOS) May Slow Atherosclerosis Progression)
Dr. Nissen, who also authored a meta-analysis of rosiglitazone studies that revealed an increased risk of myocardial infarction (See: Meta-Analysis Links Rosiglitazone (Avandia) to Risk of Myocardial Infarction), said the failure of the APPROACH trial provides one more reason to "use rosiglitazone with caution.""
Looking at PERISCOPE and APPROACH very interesting to see each have one statistical endpoint out of the primary and two secondaries:
PERISCOPE:
Percent Atheroma volume SU vs. Pio +0.73 vs. -0.16 p 0.002
Change Atheroma volume SU vs. Pio -1.5 vs. -5.5 NS
Change AV 10 mm most diseased segment -2.1 vs. -2.0 NS
APPROACH:
PAV change SU vs. Rosi +0.43 vs. -0.21 NS
Change Ather Vol +1.2 vs. -3.9 p 0.04
Change AV most diseased -3.6 vs. -5.3 NS |
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November 13, 2008 05:47 (EST)
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surrogate markers, short trials, small sample sizes
I would not expect this trial to give any information whatsoever on CV risk. Trials are powered for their primary endpoint and proceed thereby. This trial was neither large enough or long enough to say anything about the hard cardiovascular risk or benefit of rosiglitazone.
It is as though you found out that Barack Obama won in Pennsylvania on Nov 4. Wouldn't you want to know what happened in the other 49 states before you could say he was elected President? This is exactly analogous - we need much larger, longer, hard outcome powered trials to show what is going on with this drug.
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November 13, 2008 07:16 (EST)
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and we had just that
Dan, we had all of those larger and longer prospective studies as mentioned in the post.
ADOPT 5 years 5K pts, DREAM 5 years 5K pts. VADT 7 years 2K pts, ACCORD 5 years 10K pts, ADVANCE 5 years 5K pts, RECORD 3.75 years interim anaysis with 4.5K pts. So then perhaps one could say that BO won in florida, pennsylvania, california, oregon, nevada, etc... Or you could do the meta-analysis with several off label studies and studies in stage 3-4 chf and alzheimers and short term data and put them all together and 'speculate' that in the short term 6 month period this drug caused MI and perhaps death. And then you could force 1 million pts to stop their diabetes medications based on poor statistics and poor science. That's what I'm thinking about.
And of course I think that PROactive and CHICAGO and PERISCOPE are great studies also. I don't think the science supports a special interest message that one TZD is better or safer than another until THAT study is performed. And if Dr. N and Takeda really feel it is safer, why not do the study, put their money where their mouth is. I write both medications equally. |
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November 13, 2008 07:33 (EST)
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problems
DREAM - too low risk to say anything by itself about CV events; VADT/ACCORD/ADVANCE - patients were not randomized to rosiglitazone vs no rosiglitazone, so, as a recent editorial in JAMA pointed out, can't say anything about specific effects of rosiglitazone (lower risk patients could have gotten it - eg lower risk for CAD at baseline, no nitrates, no CHF, not on insulin).
+ increased fractures
+ increased rates of CHF
+ no demonstrable improvement in any clinical outcome other than HbA1c
+ statistically increased risk of MI and CV death
Why are we using this drug again? |
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November 13, 2008 07:34 (EST)
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PS it wasn't just S. Nissen's meta-analysis
Meta-analyses in the lancet and jama showed similar increases in risk. |
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November 13, 2008 08:00 (EST)
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PS PS
This lancet article?: The Lancet, Volume 370, Issue 9593, Pages 1129 - 1136, 29 September 2007 Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials.
My problem with the JAMA metanalysis JAMA. 2007;298(10):1189-1195 is this - they include 3 large outcome studies - ADOPT, DREAM and interim RECORD all of which are negative in 15K pts and one heart failure study which completely skews the other 3 with only 200 pts (5 MIs in the rosi group vs. 0 could be random in this population). Why would you include a 4th study the Dargie analysis that is comprised of all patients having heart failure. Both TZD's are contraindicated in that population and for several years now.
Very confusing to me that they would do this, again shows the poor science of small metas and also you can make a study show anything you wish when looking back retrospectively. |
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November 13, 2008 08:06 (EST)
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problems
The reason why we use any fda approved medication for glucose is to control the glucose. My grandma said she had a 'case of the sugars'. It was interesting how people said it was all about the lipids and the bp in people with dm. Then all of a sudden ukpds 10 year extension comes out and the intense controlled glucose groups (met or su or insulin) all show benefit over the 10 years and the BP groups don't differ at all - surprise on that one.
Why do we use any of these agents:
Insulin has been associated with wt gain, heart failure, severe life threatening hypo, etc..
Met has been associated with GI toxicity and rare cases of renal
SU's wt gain, severe hypo, black boxed for death
TZD's - wt gain, heart failure, bone
Incretin - GI, rare cases pancreatic
Alpha's GI toxicity
etc..
Dan, your just trying to get my goat..
Certainly if people don't believe that TZD offers any control benefit (short term or long term) then they shouldn't use them and if they can't screen for CHF or osteop again the same. |
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November 13, 2008 08:18 (EST)
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goats
Lancet. 2008 Nov 1;372(9649):1520.Related Articles, Links
Rosiglitazone no longer recommended.
[No authors listed]
Publication Types:
Editorial
MeSH Terms:
Diabetes Mellitus, Type 2/drug therapy*
Humans
Hypoglycemic Agents/adverse effects*
Thiazolidinediones/adverse effects*
Substances:
Hypoglycemic Agents
Thiazolidinediones
rosiglitazone
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November 13, 2008 11:13 (EST)
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goats are goats
I grew up in sheep country. Love the taste of cows. I've learned that 'expert' recommendations are, oh, how shall we say it, kind of like fannie and freddie mac. :o)
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November 14, 2008 12:25 (EST)
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the rest of the people are not voting that way
There's data to suggest that rosiglitazone sales are down and pioglitazone sales are up. People are voting with their prescription pads. I don't want to be on something that may increase my risk of an MI by 1.5-fold and risk of CHF by more than 2-fold (granted pioglitazone has been implicated in the latter, only the latter). The best data we have on glitazones in a high risk crowd is still PROACTIVE (pio), showing reductions in macrovascular events in patients with diabetes and established large vessel disease. Given that we cannot assume a class effect with these drugs, there should be no reason to write rosiglitazone scripts without writing pioglitazone instead, |
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November 14, 2008 01:05 (EST)
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Dan
Yup voting with their pads and sales up and down. The point is there has not been a head to head study stating one tzd is safer than the other. Until that is done I will not show preference. You read a lot of article and you must admit that kind of meta-analysis is not what you would do. It's like the Meta with resp agents and then spiriva shows the exact opposite. In our area rosi is less expensive and has better patient assitance. We DON'T feel we are giving up safety nor increasing harm with that agent. Both products are great for the right people. Writing both for nearly 10 years now. good luck. ps. 80 events vs. 90 events over 1-5 years in metas yes stats say 30% rise but I'll take 170 cardiac events in 17K DM pts anytime. talk about a low event rate |
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November 15, 2008 02:45 (EST)
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APPROACH and PERISCOPE very similar
The Heartwire headline is WRONG. Avandia halted progression, as did Actos in PERISCOPE. The only difference in the APPROACH and PERISCOPE primary endpoint results is the significant progression of the glimepiride group (which permitted the significant between-group difference in PERISCOPE, relative to the non- significant progression of the glipizide group in APPROACH. Avandia also significantly reduced Total Atheroma Volume (TAV) and also AV in "most diseased segment" (not achieved by Actos).
I agree with Michael Cobble MD regarding safety of Avandia; there is no evidence Actos is safer than Avandia. |
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November 16, 2008 10:14 (EST)
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disagree
1) There is absolutely no evidence that rosiglitazone decreases cardiovascular events, and some data suggests it increases them.
2) A large hard outcome trial in a high risk population flush with events strongly suggets pioglitazone reduces macrovascular events.
3) Clinicians should not have to order BMD and echo before prescribing these drugs as Mike suggests (screening for osteoporosis and heart failure); therefore they should not be considered first-line glucose-lowering agents.
4) Clinicians are voting with their pads:
Diabet Med. 2008 Jul;25(7):871-4.
New use of rosiglitazone decreased following publication of a meta-analysis suggesting harm.Shah BR, Juurlink DN, Austin PC, Mamdani MM.
Institute for Clinical Evaluative Sciences, Toronto, Canada.
AIMS: It is uncertain whether meta-analyses lead to changes in prescribing practices. We studied trends in the prescribing of glucose-lowering therapy before and after the publication of a meta-analysis suggesting harm from rosiglitazone. METHODS: We examined the prescription records of all residents of Ontario, Canada, aged > or = 66 years. For each week between January and December 2007, we identified new users of five categories of glucose-lowering medications: rosiglitazone, pioglitazone, metformin, glibenclamide (glyburide) and insulin. The effect of the meta-analysis was assessed using interventional autoregressive integrated moving-average models. RESULTS: Following the release of the meta-analysis, there was a sudden decline in new users of rosiglitazone (P = 0.01), mirrored by a nearly identical but transient increase in new users of pioglitazone (P < 0.001). There was also a net decline in new users of thiazolidinediones as a class (P < 0.001). The number of new users of other glucose-lowering medications did not change. CONCLUSIONS: A highly-publicized meta-analysis regarding rosiglitazone's potential harms led to an abrupt decline in new users of the drug, as well as a transient surge in new use of pioglitazone. |
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November 17, 2008 12:41 (EST)
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Dr. Hackam, I Agree to disagree
Your comments, heard before, are understandable and typical of the mass hysteria (you have described so well) generated by the metanalysis; a publication that the NEJM, or its authors, are unlikely to apologize for, let alone retract.
If you have not been brainwashed completely and assuming you are not a fundamentalist, you can examine just the article itself, to find out the purposeful manipulation of data and why it should never have been published. Look carefully at the numbers. There were several-fold more reasons for the illegitamacy of the article than even stated by the authors. See if you can find a scrap of evidence that it was a true 'cardiovascular' meta-analysis at all. Was there even a single study that remained in the analysis that was a randomized, controlled study of cardiovascular disease? Were the groups controlled for pre-existing CV disease? pre-existing or in-treatment CV drug use. Look at the numbers. Look at tthe raw data calculations that were left out. If one also examines just some of whatelse is out there, one could only conclude that we are just living in very strange times; pharmacuetical wars abound and strong biases exist, especially with the rewards, or lack thereof, of pharmaceutical research grants.
Given the proper length of a well-conceived, and 'disease-bed' randomized (see the 'REACH' trial), controlled trial, powered sufficiently, for the appropriate duration of trial, at least 5 or more years, TZDs (either pio or rosi) will ultimately be shown to be of considerable CV benefit.
Afterall, lipid modifying trials (the strongest player in CVD progression), with 10-20K participants, take 3-5 years to demonstarte CV benefit and glucose-lowering trials have, historically, taken greater than 10 yrs to show CV benefit (the real problem for the recent FDA mandate), then 5-10 years for insulin sensitizers (TZDs), that reduce greater than 30 different CVD risks, would not be unreasonable.
What we need is a truce in this pointless TZD war; that has only damaged patients, physicians and the Pharmaceutical companies and possibly the reputation of the Institution harboring the instigators.
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November 17, 2008 09:52 (EST)
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More Goat Cheese
Would you like 'candied' walnuts with your salad?
Dan
"3) Clinicians should not have to order BMD and echo before prescribing these drugs as Mike suggests (screening for osteoporosis and heart failure); therefore they should not be considered first-line glucose-lowering agents."
Dan, I don't think anyone is advocating them as first line agents but certainly reasonable as second line agents or for people who need more than 1-2% A1c reduction in combination with other therapies. I agree with the current guideline that advocates tlc and bigaunide first line and bi, su or tzd second line. I also agree with the FDA that current evidence does not warrant the removal of rosi, and since that hearing the data has become even stronger in support of that decision. that's all.
I know how passionate you are about studies and your patient population. I think this is one of those cases where people have painted a picture which has been highly misrepresentative based on politics and special interests. Unfortunately the patient has suffered and continues to do so as this misinformation based on poor science/statistics is propogated.
bon apetite and cheers. mc |
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November 18, 2008 01:18 (EST)
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interesting
I would like to know your quibbles with the data. If you have time.
I will re-review the paper and compare notes with you. It's been a long time since I read it.
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November 18, 2008 08:53 (EST)
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papers
Dan, I think including the Dargie CHF study in the JAMA 4 study meta was silly if not crazy as this is a contraindication and skews the results to make the result negative (I don't care how it is weighted). Even when Dr. N used the Takeda supplied data for 'his' meta of their data the one CHF study they included had complicated CV results. I think his analysis meta picking and choosing and the 'null' amounts and final cv/mi events were very small and although interesting not conclusive. If we can't say any macro benefit in 5 years how can we say macro harm in 6 months with his analysis? Especially with several long term prospective studies now published not corroborating his hypothesis?
The point I wished to make is simply that if a pt has CHF 3-4 or are unstable or quite elderly perhaps aggressive glucose mgmt is complicated at best with any agent including tzd (or su or insulin, biguanide, acarbose - my grandmother had emergency GB surgery after this was started, etc..).
We have not seen tzd's increase cv or death signal and don't agree with the information printed or speculated upon. With that being said we have found that any patient over 60 (we like to check (bnp, gfr and cbc) prior to starting metformin, glp1, dpp4 or tzd. If a1c drops below 7% we like to reduce su and insulin to avoid hypo and specifically severe hypo. If we choose an su our preference is glimep or glicla.
Keep up the great work, your patients are very lucky to have such a passionate, well read clinician and researcher as their advocate and caretaker. Nothing is absolute for sure and I am always questioning guidelines and data and care. |
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November 19, 2008 12:12 (EST)
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Ok, Ok, but what do you make of the following results from APPROACH
Composite of hard CV events
rosi 4.2%, glip 2.9% (p=.31)
Some individual endpoints:
CV death - 1.2% vs 0.9% (p=.50)
stroke - 1.5% vs 0.3% (p=.13)
CHF - 2.4% vs 0.9% (p=.14)
Clearly the study - and the investigators say this - was not powered for CV events (rather it was an imaging endpoint powered design). But I don't think it's right to tout in your first post that the drug is safe on the basis of APPROACH???
By the way, thanks for your kind comments, I have the same admiration for you! |
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November 19, 2008 01:53 (EST)
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Implication
Dan, In interpret the results as not being statistical for cv endpoints. I didn't intend to 'tout' in the first post the drug is safe based on APPROACH. The quotes are from Dr. Nesto, however as Dr. Rosenblit has pointed out and myself - I do think the drug is safe based on multiple other studies DREAM, ADOPT, RECORD, etc.. and the suggestion promoted last year that CV events and death would occur in a very short time period was incorrect. None of the studies Dr. N looked at were powered for CV events either with rosi or pio. PROactive as you know in a very important secondary was good. That was a very unique pt population as well and I think complementery for tzd's although my endo colleagues in the area were unimpressed unfortunately and now all rec sitagliptan. |
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December 3, 2008 06:20 (EST)
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"IF",... all things being equal,.. as an assumption,..
...and if lipid fractioning data were run serially,.. it would be clear there are distinct differences in the drugs. Much like the paradoxic drop in HDL with ROSI & FENO in combo. HDL3 increases on FENO & HDL2 drops. PIO does not have the same deficits in surrogate markers seen with ROSI. HDL2, adiponectin, pattern B shifts, etc. After substantial clinical experience using these drugs in combo AND baseline fractioning data with the same at follow up,.. it becomes clear that PIO has a LOT over ROSI. Most dramatic is when niacin is combined with PIO. Not the same when in combo with ROSI. This is analogous to why prava or simva are preferred in cases wher Lp(a) is elevated @ baseline: They are both documented as Lp(a)neutral. The remaining drugs in that 'class' are not. When 2 gms of niacin are titrated in those patients, and ALP`s are followed for 2-3 years, Lp(a) is almost ALWAYS lower when niacin is added to prava or simva. Ezet may 'blunt' niacin effect on Lp(a) as well. Rosuva would be a great choice when Lp(a) is NOT a 'player'. YES Lp(a) is important,.. as we are treating it whether we measure it or not: the calculated-LDL "sandwich" is (R)LDL, IDL &
Lp(a). Knowing what type of "sandwich" you have at baseline helps in statin selection. Any statin is adequate with the 'c'-LDL containing >40% IDL. You`ll never hit <70 with a statin alone. This is also known as "statin resistance" = elevated IDL, Lp(a) or BOTH. PIO with niacin works so well in the insulin resistant [IR] patient it is almost a go to combo. Sometimes a 'best' starting point,.. then titrating in a low-dose generic statin to finish the job. Elevated chylos, remnants, VLDL3, etc., 6-9 gms frozen Wal-Mart fish or,.. or the more "elegant" cousin, euphasia superba: NKO, krill oil. ROSI may have utility, but the IR needs to be treated & PIO is intuitively the best bet. |
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December 8, 2008 12:26 (EST)
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Class Effect ??
The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 5 1722-1729
Dissociation between the Insulin-Sensitizing Effect of Rosiglitazone and Its Effect on Hepatic and Intestinal Lipoprotein Production
Hélène Duez, Benoît Lamarche, Kristine D. Uffelman, René Valéro, Linda Szeto, Simone Lemieux, Jeffrey S. Cohn and Gary F. Lewis
Context: Despite its potent, well-documented insulin-sensitizing effects, rosiglitazone (RSG) does not effectively ameliorate the hypertriglyceridemia of insulin-resistant or diabetic individuals and has even been shown to slightly but significantly increase triglyceride-rich lipoproteins (TRL) in some studies. The mechanism of this effect is currently not known.
Objective: We investigated the effect of RSG treatment on TRL metabolism.
Design: This was a 12-wk, single-sequence, cross-over study of rosiglitazone vs. placebo for 6 wk.
Participants: Participants included 17 nondiabetic men with a broad range of insulin sensitivity.
Intervention: Intervention included rosiglitazone 8 mg/d vs. placebo for 6 wk.
Main Outcome Measure: TRL metabolism (concentration, production and catabolic rates) was assessed in a constant fed state with a 12-h primed constant infusion of [D3]L-leucine and multicompartmental modeling.
Results: RSG treatment resulted in significant insulin sensitization with no change in body weight. Fasting plasma triglyceride (TG) concentration, however, was higher with RSG vs. placebo (P = 0.0006), as were fasting and fed TRL-TG, TRL-apoB-48, and TRL-apoB-100 (fed TRL-apoB-48: 0.93 ± 0.08 vs. 0.76 ± 0.07 mg/dl, P =0.017, and fed TRL-apoB-100: 15.57 ± 0.90 vs. 13.71 ± 1.27 mg/dl, P = 0.029). This small but significant increase in plasma TRL concentration was explained by a tendency for RSG to increase TRL production and reduce particle clearance, as indicated by the significantly increased production to clearance ratios for both apoB-48-containing (0.43 ± 0.03 vs. 0.34 ± 0.03, P = 0.048) and apoB-100-containing (7.0 ± 0.4 vs. 6.2 ± 0.6, P = 0.029) TRL.
Conclusion: These data indicate dissociation between the insulin-sensitizing effects of RSG and absence of anticipated reductions in production rates of apoB-100- and apoB-48-containing-TRL particles, which may explain the absence of TG lowering seen in humans treated with this agent.
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December 8, 2008 01:38 (EST)
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reps
I've had certain reps tell me for years they have a tzd product that lowers trigs and raises hdl and is better on the lipid panel. We use both tzd's equally after both were approved.
These same reps told me if I changed the tzd I would see tg's drop. We had a recent pt study (of one, not the large study you have above with 17) who had her tg's go up to 400 on the competitive tzd and almost changed her to the agent being promoted 'off label' for lipid benefits. She came back and repeat here panel and her tg's were down to 143. Upon questioning she states she had bread and peanut butter prior to her first 'fasting' lab which she agree was fasting when drawn.
I guess the point is.... triglycerides change a lot on any moment. use glucose drugs for glucose, use lipid drugs for lipids, use bp drugs for bp, use lifestyle as a foundation.
when and if the tzd agents do a real FDA clinical study comparing themselves head to head for safety, events or lipids is performed - then we can really start talking.
Sorry if I sound a little frustrated about this continuing political or marketing message that one agent in the class has specific differences.
Until the evidence is in, in a real study - these smoke screens are confusing. WE have seen ADA abstract studies that show both TZD's preventing stenosis in people with diabetes, people with prediabete and people without diabetes. Yet these studies are all small and have not been performed with rigor in which the FDA will allow claims or comparisons to be made. |
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December 16, 2008 09:15 (EST)
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Michael, you rock!
Back to agreeing with you is a place where I am more comfortable.
Regarding your female patient with the non-fasting TG of 400 and a fasting of 143, you surely saw the study demonstrating no correlation of fasting triglycerides by tertile with coronary events however there was a strong correlation with non-fasting triglycerides by tertile and coronary events. Bansal S et al. JAMA 2007; 298:309-316. I hope you have her on high dose omega-3 for her "normal" fasting TGs
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December 17, 2008 12:02 (EST)
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Wiliam
Yes I did, I really liked this more recent article (supporting the first) which was impressive for age over 55 and under 55 in men and women.
Seems there is a lot to be said about considering targets of lowering postprandial lipemia and postprandial glycemia. That would seem to be very important to target both.
Happy Holidays.
Jacob J. Freiberg; Anne Tybjærg-Hansen; Jan Skov Jensen; Børge G. Nordestgaard
Nonfasting Triglycerides and Risk of Ischemic Stroke in the General Population
JAMA, November 12, 2008; 300: 2142 - 2152 |
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