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'Heart Failure Is Killing Your Diabetes Patients,' Experts Warn at EASDShel ey Wood BARCELONA, SPAIN — Cardiologists speaking here at the European Association for the Study of Diabetes
(EASD) 2013 Meeting
are urging diabetologists to sit up and take notice: heart failure is kil ing their patients and is
not getting the attention it deserves.
Not only is heart failure one of the most lethal—if not the most lethal—complications of diabetes, its role in diabetesis being routinely overlooked by physicians, by journals publishing diabetes research, and perhaps worst of al , byregulators tasked with tel ing companies what's important for trials of new diabetes drugs.
Heart Failure in the Hot Seat
Their pleas come at a time when heart failure has vaulted once again onto the radar of physicians studying and
treating diabetes, this time after a signal of increased heart failure was seen in the SAVOR TIMI 53 trial. The
results were presented at the recent European Society of Cardiology (ESC) 2013 Congress meeting and
published simultaneously in the New England Journal of Medicine.
As reported by heartwire , patients randomized to the dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin had
a 27% increased risk of hospitalizations for HF as compared with placebo-treated patients. EXAMINE , a
second cardiovascular-outcomes study of another DPP-4 inhibitor, alogliptin, also presented and published
during the ESC meeting, did not include heart failure as a prespecified end point. A post hoc analysis presented
for the first time here today indicated that HF hospitalizations were numerical y higher in the alogliptin group
than in the placebo-treated group, but the difference was not statistical y significant.
Just how a clinical trial could travel from conception to publication without including heart failure as a stand-aloneend point, given the lethal nature of this complication in diabetic patients, was a key talking point in an EASDsession devoted to heart failure and diabetes.
"Not only do diabetologists, along with cardiologists, need to take heart failure seriously in patients with diabetes,
but the regulators do as wel ," Dr John J McMurray (University of Glasgow, Scotland) urged the audience. "We
need to make heart failure a much more prominent component of our clinical trials, and we must not see major
journals publishing major CV-outcomes trials in diabetes and not even mentioning one of the most important — if
not the most important — cardiovascular complication of diabetes, which is heart failure."
Heart Failure, Mortality, and Diabetes
For his presentation, McMurray reviewed the largest cardiovascular-outcome trials that included a predefined subsetof diabetic patients, as wel as the major diabetes trials that included cardiovascular outcomes. Only seven of 12major CV-outcomes trials actual y reported heart failure as an outcome, and worse stil , of the 24 major diabetes-outcome trials, only 10 reported heart-failure outcomes.
In slide after slide, McMurray showed data from clinical trials that, for years, were household names for cardiologists 2013-10-12 5:13 PM and endocrinologists alike, among them VALUE , LIFE , RENAAL , HOPE , LOOK Ahead , ADVANCE , and
ACCORD . In al of them, he pointed out, the likelihood of developing or being hospitalized for heart failure among
people with diabetes was as high as and in many cases higher than the risk for MI and universal y higher than the
risk for stroke or CV death.
"The story gets even more interesting when you look at patients who develop diabetic nephropathy," McMurray
continued, showing a comparison of HF hospitalizations in diabetic patients in LIFE and RENAAL. Both of those
trials evaluated losartan (vs placebo or atenolol ), and both excluded patients with heart failure at baseline. The
key point, however, was that regardless of treatment assignment, rates of HF hospitalizations were two to three
times higher among patients with diabetic nephropathy than in diabetics with no nephropathy. Similarly, in the
RENAAL, IDNT , and ALTITUDE trials, the most common CV outcome in patients with both diabetes and
nephropathy was heart failure, which, again, was sometimes twice as common as MI.

I would like to show you . . that heart failure is actually the most deadly of the cardiovascular
complications.

"You might be saying to yourselves, wel , that's al very wel , so heart failure is quite common: big deal, so what,"McMurray chided the audience. "What I would like to show you is that heart failure is actual y the most deadly of thecardiovascular complications." Looking again at data from LIFE and RENAAL, McMurray showed that deaths over the several years of fol ow-upwere at least twice as common in diabetic patients with heart failure than in diabetic patients without heart failure. InALTITUDE, a more contemporary trial, deaths were markedly higher among patients who required HFhospitalizations than they were for patients hospitalized for death, stroke, or end-stage renal disease.
"And this doesn't speak to disability," McMurray added, noting that there is a wealth of evidence showing that HF "isa much more disabling CV disorder than MI and even stroke." McMurray said he often hears from col eagues focused on diabetes who refer to heart failure as "just a bit of ankleswel ing" or "a bit of fluid retention." "I hope with the data I've showed you . . that you [no longer] think that's the case." History Repeating Itself?
Heart failure first emerged as an issue in the early glitazone trials but was ultimately eclipsed by concerns over MI, a
possibility that made headlines worldwide in the now-infamous Nissen/Wolski rosiglitazone meta-analysis. Asked
why MI concerns had held sway over HF risk, McMurray quipped: You'l have to ask Steve Nissen that question. He
was focused on a signal of what he thought was MI, and sometimes when you focus on one thing, you don't see the
bigger picture."
The rosiglitazone saga resulted in new FDA requirements for CV-outcomes trials with new diabetes drugs; SAVOR
TIMI 53 and EXAMINE were the first two studies designed with these new criteria at their core.
Regrettably, said McMurray, the FDA opted not to include heart failure as one of the end points required bycompanies designing CV-outcome trials, opting instead for major adverse cardiac events, typical y a combination ofMI, stroke, and CV death.
"The FDA guidance says you can also consider unstable angina and revascularizations and does, as a throw-away 2013-10-12 5:13 PM comment, say 'possibly look at other CV outcomes.' But that guidance clearly misses the elephant in the room,which is heart failure. I can hardly believe that it [instead] mentions things like coronary revascularization, which is arelatively soft, practice-driven end point and not one that reflects the development of CV disease." The ESC guidance for trialists is slightly better, he continued. While stil focused on "the same atherosclerosis-drivenend points, it at least does mention that HF should be considered." An alarming outgrowth of the FDA's current advice to companies, however, is that of 16 cardiovascular-outcomestrials for diabetes drugs either in development or already under way—enrol ing almost 150 000 patients in total—nota single one of them wil report heart failure as part of the primary outcome, McMurray noted.
Given the heart-failure signal recently seen in with the newer DPP-4 inhibitors, McMurray says he has graveconcerns about what this might mean once many more patients are exposed to the drugs. "Unless something isvery different in this trial [SAVOR-TIMI 53], this wil be a very deadly event," he warns.
Diabetes Drug Safety in HF Patients
Dr Barrie (Miles) Fisher (Glasgow Royal Infirmary, Scotland), another speaker in today's special session, tackled
the question of what diabetes therapies are actual y safe, from a heart-failure standpoint, in treating dysglycemia.
"I'm afraid I haven't got that much definitive to say," Fisher lamented. Reviewing the scant evidence, Fisher
concluded that metformin is "probably" safe; sulfonylureas, "we're not sure"; glitazones, "no"; DPP-4 inhibitors,
"possibly not, but we need more data"; and for the glucagonlike peptide-1 (GLP-1) receptor agonists, "we just don't
know."
Acknowledging that the heart-failure signal in SAVOR-TIMI 53 has been a major talking point at this meeting,alongside the numeric increase in HF events now reported for EXAMINE, Fisher predicts that other drugs in thisclass wil face new scrutiny.

Is this an effect with one drug or is it a class effect, and is it only in certain groups of patients with HF, or
will it become a clinical problem?

He pointed to VIVIDD , a study of another agent in this class, vildagliptin, which showed no differences in left
ventricular ejection fraction out to 52 weeks. There was, however, a statistical y significant difference in LV
end-diastolic and LV end-systolic volume between the placebo- and vildagliptin-treated patients.
A change in volume "is not a good thing if you have heart failure. So this might start to hint at mechanisms." As wel , Fisher continued, DPP-4 plays a role in the degradation of a range of peptides. "I think we have to askourselves, could the increase in hospitalizations for HF with saxagliptin be explained by the accumulation of one ormore of these peptides, or even a peptide that we haven't yet characterized? And that leads us to further questions:is this an effect with one drug or is it a class effect, and is it only in certain groups of patients with HF, or wil itbecome a clinical problem? As further CV-outcomes studies come out for this class, we wil be looking very closelyat their results." Turning to the GLP-1 agonists, Fisher noted that these agents have a known risk of volume depletion in "vulnerablepatients," particularly the elderly. "In heart failure, you want to get fluid volumes down, but not excessively. So itmight be that these drugs give some additional benefit in HF patients, but it might be that they give some additionalharm. It's real y too soon to say." 2013-10-12 5:13 PM For Cardiologists: Test for Diabetes, Watch for HF
In the third presentation of the dedicated session, Dr Darren McGuire (University of Texas Southwestern Medical
School, Dal as), a cardiologist, reviewed evidence-based medications that are proven to reduce the risk of heart
failure both in diabetic and nondiabetic patients. Efficacy is similar in both groups, he noted, but given the higher
risks associated with heart failure in diabetic patients, the benefits of control ing risk factors in these patients would
likely be amplified.
A key issue, noted McGuire, is the large proportion of patients with unrecognized diabetes, even those in the care ofcardiologists. Citing four cardiovascular-disease cohorts, McGuire pointed out that "new diabetes" diagnoses at thetime of a particular CV procedure ranged from 15% to more than 30%. Combined with previously diagnoseddisease, diabetic patients made up half of the patients across the four cohorts.

We need to get across that if you develop HF . . no matter what has happened to you to get there, you are
on a completely different prognostic trajectory, where you are going to do very badly indeed.

As a side note, McGuire also offered himself up as a prime example of someone who has failed to ful y appreciatethe impact of heart failure in diabetic subjects.
"I've been interested in diabetes for about 15 years now as an exclusive focus both clinical y and as an investigator,but I haven't paid much attention to heart failure until I got invited to this talk," he admitted. "So I've had the . .
myopic focus on atherosclerosis for far too long." To heartwire , McMurray reiterated his cal to al doctors treating patients with diabetes to watch out for heart failure
and treat it aggressively and to consider what diabetes drugs they use in this group.
"It's not just fluid retention; these people die," McMurray stressed. "When you talk to endocrinologists, that's exactlythe kind of comment you hear. We need to get across that if you develop HF it doesn't matter if it is on rosiglitazone,it's not just that you've retained some fluid, no matter what has happened to you to get there, you are on acompletely different prognostic trajectory, where you are going to do very badly indeed." Fisher disclosed advisory payments from AstraZeneca/Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly,GlaxoSmithKline, Janssen, MSD, Novartis, Novo Nordisk, Sanofi, and Takeda. McGuire disclosed consulting forGenentech, F Hoffman LaRoche, Takeda, Janssen, Sanofi, Boehringer Ingelheim, Merck, and Bristol-Myers Squibband research support from Genentech, F Hoffman LaRoche, Takeda, Boehringer Ingelheim, Merck, Dai chi Sankyo,Orexigen Therapeutics, Eli Lil y, Bristol-Myers Squibb, AstraZeneca, and GlaxoSmithKline. McMurray has previouslydisclosed consulting for Bristol-Myers Squibb, Guidant Europe, and Cardiokinetix. Heartwire 2013 Cite this article: 'Heart Failure Is Kil ing Your Diabetes Patients,' Experts Warn at EASD. Medscape. Sep 26, 2013.
2013-10-12 5:13 PM

Source: http://shelleywood.ca/wp-content/uploads/2013/10/HeartFailureIsKillingYourPatients.pdf

Doi:10.1016/j.ejca.2005.06.006

EuropeanJournal ofCancer European Journal of Cancer xxx (2005) xxx–xxx How good are rodent models of carcinogenesis in predicting efficacy in humans? A systematic review and meta-analysis of colon chemoprevention in rats, mice and men Denis E. Corpet *, Fabrice Pierre UMR Xenobiotiques, Institut National Recherche Agronomique, Ecole Nationale Veterinaire Toulouse, BP-87614, 23 Capelles, 31076 Toulouse, France

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