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SITAGLAPTIN USE AND HEART FAILURE RISK

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Signals of a possible heart-failure (HF) hazard from second-line treatment with dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes seen in recent randomized and observational studies have risen a few decibels[1]. An analysis of patient-level data from nationwide US insurance records saw initiation of sitagliptin (Januvia, Merck), one the most commonly used DPP-4 inhibitors, pose an 84% increased risk (p=0.01) of new HF hospitalization among diabetic patients initially with HF who had been treated withmetformin or a sulfonylurea. The more than 7600 patients in the cohort had been followed a median of 1.4 years.
Sitagliptin therapy showed no sign of increasing risk for all-cause hospitalization or death, which was the primary end point of the study, published July 2, 2014 in Circulation: Heart Failureby first author Daniala L Weir (University of Alberta, Edmonton) and colleagues.
As in prior analyses hinting at similar risks from DPP-4 inhibitors, in which only some diabetic patients already had HF when the drugs were started, HF hospitalization was a secondary end point while primary-end=point outcomes for DPP-4 inhibition were, in contrast, often favorable or neutral.
The increased HF risk in the current analysis "is likely clinically relevant," according to the authors, with an observed number needed to harm of 29, "and may have implications for choice of add-on therapy for patients with HF and diabetes poorly controlled with other agents."
They continue, "Although our results are intriguing, it is clear that additional studies are required, specifically in patients with HF, to solidify the risk/benefit picture," especially given "inconsistent" evidence from clinical trials regarding any HF risk from DPP-4 inhibitors.
Recent Causes for Concern
The randomized SAVOR-TIMI 53 trial of saxagliptin (Onglyza, Bristol-Myers Squibb/AstraZeneca) showed a significant 27% increased risk of HF hospitalization in 16 492 diabetic patients with a CV history or otherwise at elevated CV risk. That was despite saxagliptin noninferiority for the primary end point of CV death, nonfatal MI, or nonfatal ischemic stroke vs placebo.
And the 5380-patient Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE) trial ofalogliptin (Nesina, Takeda Pharmaceuticals) showed a nonsignificant trend suggesting more HF in diabetic patients taking the DPP-4 inhibitor. Both studies had been reported by heartwire .
On the other hand, a recent unpublished post hoc analysis of the much smaller Vildagliptin in Ventricular Dysfunction Diabetes Trial (VIVIDD), which focused on echocardiographic rather than clinical end points, found no elevated risk of HF hospitalizations or other HF events in diabetic patients with HF who received vildagliptin (Galvus, Novartis).
Two observational studies presented recently at the International Society of Endocrinology and the Endocrine Society joint scientific sessions, and covered by Medscape Medical News, gave somewhat conflicting results regarding DPP-4-inhibitor use and HF outcomes. One retrospective study of 13 185 outpatients with diabetes on metformin showed a significantly elevated HF risk over four years among those also taking a DPP-4 inhibitor compared with a different second-tier antidiabetic agent. And in the other study, a cohort of 32 419 matched pairs of patients with diabetes taking or not taking a DPP-4 inhibitor, DPP-4 inhibitors were not associated with an increased risk of CV events and may have even improved HF overall.Data from Diabetic Patients Initially With HF
The analysis of 7620 diabetic patients and HF (58% male) treated with metformin or a sulfonylurea but not a thiazolidinedione included 887 patients who started on sitagliptin sometime after their HF diagnosis.
In an adjusted analysis, there were no differences between sitagliptin users and nonusers for the primary end point of all-cause hospitalization or death, the secondary end point of HF hospitalization or death from any cause, or all-cause death or all-cause hospitalization by themselves. However, HF admissions went up significantly with sitagliptin.
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"Before recent studies, there was little evidence, either clinical or basic science, to suggest DPP-4 inhibition would increase the risk of heart failure," write Drs Deepak L Bhatt and Matthew A Cavender (Brigham and Women's Hospital, Boston, MA) in an accompanying editorial[2].
"In contrast, basic science data largely suggested that DPP-4 inhibition should improve cardiovascular events, including ventricular function," they continue, noting the confusing state of the evidence so far.
"The findings of this analysis, as well as other recent studies, highlight the need for well-designed trials that rigorously assess for HF in patients with diabetes. The ongoing . . .  Trial Evaluating Cardiovascular Outcomes with Sitagliptin [TECOS] has randomized approximately 14 000 patients with type 2 diabetes [and preexisting CVD] to sitagliptin or placebo, and it may help establish whether the class of DPP-4 inhibitors does indeed cause HF."
Adjusted* Odds Ratio (95% CI), Exposure vs No Exposure to Sitagliptin and Metformin in Diabetic Patients With HF
End pointsSitagliptin OR (95% CI), pMetformin OR (95% CI), p
All-cause death or hospitalization0.84 (0.69–1.03), 0.100.78 (0.71–0.85), <0 .001="" td="">
All-cause death1.16 (0.68–1.97), 0.590.52 (0.37–0.71), <0 .001="" td="">
All-cause hospitalization0.93 (0.76–1.14), 0.460.79 (0.71–0.87), <0 .001="" td="">
HF-related hospitalization or death1.34 (0.93–1.92), 0.120.70 (0.57–0.86), 0.001
HF-related hospitalization1.84 (1.16–2.92), 0.010.87 (0.66–1.12), 0.28
*Adjusted for age and sex; type of medical insurance; household income; recent glycosylated hemoglobin, low- and high-density lipoprotein cholesterol, triglycerides, and estimated glomerular filtration rate; history of CVD; antidiabetic drug therapies; CV drug therapies
CI=confidence interval
OR=odds ratio
The trial's primary end point is "time to first confirmed CV event (a composite defined as CV-related death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization)." Time to congestive HF is a TECOS secondary end point.
According to Weir et al, although the ongoing DPP-4 inhibitor trial as well as the earlier ones "enrolled patients with established cardiovascular disease or risk factors, none specifically identified individuals with established heart failure. Therefore, it is unlikely the upcoming results of the TECOS trial will provide evidence for the safety of sitagliptin therapy in those with preexisting HF, unless evaluated as a subgroup."

GENOMICS OF LUNG CANCER

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Researchers from Dana-Farber Cancer Institute, the Broad Institute of MIT and Harvard, and other centers have identified novel mutations in a well-known cancer-causing pathway in lung adenocarcinoma, the most common subtype of lung cancer. Knowledge of these mutations could potentially identify a greater number of patients with treatable mutations because many potent cancer drugs that target these mutations already exist. In addition, these findings, published online in Naturemay expand the number of possible new therapeutic targets for this disease.
Study Details
In this new study researchers from the Cancer Genome Atlas (TCGA) Research Network, led by Dana-Farber scientist Matthew Meyerson, MD, PhD, examined the genomes, RNA, and protein from 230 lung adenocarcinoma samples. In three-quarters of the samples, the scientists ultimately identified mutations that put a cell-signaling pathway known as the RTK/RAS/RAF pathway into overdrive.
“Lung adenocarcinoma is the leading cause of human cancer death. This is because there are so many ways to develop the disease, and many different pathways are altered in this cancer,” said Dr. Meyerson. “In recent years, we have made enormous progress in lung adenocarcinoma treatment by targeting EGFR, ALK, and other mutated proteins. Through this study, we are able to add to the range of such alterations and therefore gain potential new therapeutic targets.”
Mutations affecting the RTK/RAS/RAF pathway can cause it to become stuck in the “on” state. As a result, signals that promote cancer cell proliferation and survival are produced continuously. However, drugs are currently available that curb aberrant activity of this pathway and prompt therapeutic responses in patients.
“About 10% of patients have tumors with EGFR mutations, and these patients uniquely benefit from anti-EGFR therapy,” said Alice Berger, PhD, a postdoctoral fellow in the Meyerson lab and coauthor of the study. “We were motivated to find genetic aberrations in patients that lack EGFR mutations and that might be similarly suitable for therapeutic targeting. Ultimately, we want to be able to provide every patient with an effective drug for their specific cancer.”
Oncogene Mutations Identified
In the group’s initial scan of the tumor samples, researchers identified oncogene mutations that would increase RTK/RAS/RAF pathway activity in 62% of the samples; these tumor samples were classified as oncogene-positive. To identify additional alterations, the investigators looked at DNA copy number changes, or changes in gene number resulting from the deletion or amplification of sections of DNA in the genome. In doing so, they detected amplification of two oncogenes, ERBB2 and MET, which are part of the RTK/RAS/RAF pathway in the oncogene-negative cancers. Gene amplification usually leads to increased expression of the encoded protein in cells.
Now that these amplifications have been identified in cancers without other activity of the RTK/RAS/RAF pathway, clinicians may be able to treat patients whose tumors have specific gene changes with drugs that are either currently available or under development.
“It is quite striking that we have now identified an actionable mutation in over 75% of patients with lung adenocarcinoma, a significant improvement from a decade ago,” said Dr. Meyerson.
Additional analysis identified other genes that may play important roles in lung cancer development. Mutations in one of these genes, NF1—a known tumor suppressor gene that regulates the RTK/RAS/RAF pathway—had previously been reported in lung cancer. Mutations of NF1 also put that pathway into overdrive. Another mutated gene, RIT1, is also part of the RTK/RAS/RAF pathway, and this is the first study to associate mutation of this gene with lung cancer.
“This is one of the most comprehensive studies of lung adenocarcinoma to date,” said coauthorJoshua Campbell, PhD, a postdoctoral fellow in the Meyerson lab. “The TCGA data enabled us to profile and analyze DNA, RNA, and methylation from over 200 tumors, and it made the discovery of these rare alterations possible.”

ANTIOXIDANTS PROBABLY HARMFUL IN CANCER

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While alternative health gurus often encourage increasing antioxidants in the diet and the taking of antioxidant nutritional supplements such as beta-carotene, vitamins A, C, and E, and selenium, new research findings suggest that antioxidants could do more harm than good, especially in cancer patients.
The idea is discussed in a perspective article on the promise and perils of antioxidants for cancer patients in the July 10 issue of the New England Journal of Medicine.
Coauthor David Tuveson, MD, PhD, professor and deputy director of the Cold Spring Harbor Laboratory Cancer Center in New York, explained in an interview with Medscape Medical News that the idea that antioxidants could be useful in cancer goes back to Linus Pauling, and is based on observations that oxidation within cells is needed for cell growth. "As cancer cells growth rapidly, a cancer cell would have more oxidation within it than a normal cell," he added, and the hope was that antioxidants would interfere with these cellular oxidative processes and would suppress the growth.
"Although some early preclinical studies supported this concept," the authors write, there have now been several clinical trials that have shown no effect of antioxidants on reducing the incidence of cancer, and there have even been suggestions of harm in persons who are at risk for cancer.
Dr. Tuveson noted a clinical trial from Scandinavia in the early 1990s, which found that high doses of antioxidants, particularly beta-carotene, were associated with more lung cancer rather than less as had been hoped for.
There was a similar finding from the Selenium and Vitamin E Cancer Prevention Trial (SELECT), which found that the antioxidants did not reduce the risk for prostate cancer, as had been hoped, and in fact increased the risk in some men.
Dose-dependent Harmful Effect
The perspectives article was prompted by new findings reported earlier this year, he said. An animal study carried out by Swedish researchers showed that the harm from antioxidants was dose-dependent (Sci Transl Med2014;6:221ra15). The study was conducted in a genetically engineered mouse model that mimics early human non-small-cell lung cancer. The researchers studied N-acetylcysteine (which is used in patients with chronic obstructive pulmonary disease) and also derivatives of vitamin E, and they found that these antioxidants "actually increased cancer burden and mortality in a dose-dependent manner."
"The mice got lung cancer faster and they died more quickly of the disease," Dr. Tuveson said.
In their perspective article, Dr. Tuveson and coauthor Navdeep Chandel, PhD, from Northwestern University in Chicago, address the question of why.
It turns out that all cells have not only oxidative mechanisms producing reactive oxygen species, they also have a mechanism by which they produce antioxidants, and so there is a balance between the 2 in each cell. "And cancer cells, because they make more oxidants, also make more antioxidants," Dr. Tuveson explained.
"So when adding an antioxidant as a supplement, all you are doing is increasing a pool of what is already there," he said. "But you are not actually stopping the oxidative mechanisms, and you are not stopping the production of oxidants in the first place, and the pathways that are fuelling cell growth," he added."All you are doing is helping the cancer cell deal with the toxic effects of the oxidants, and by doing so you may be actually making the cancer cell even stronger," Dr. Tuveson said."The antioxidants that we take as a supplement or in our diet don't go after the root cause of how oxidants promote cancer cell biology,...and our suggestion is that we need to look much more carefully at these mechanisms if we are to truly develop strategies to prevent cancer," he said.
In their article, the authors propose 2 strategies for further research — the development of antioxidants that target specific intracellular sites of oxidant production, and also a synthetic lethal strategy directed at antioxidants produced within the cell. Both of these strategies are currently at the research stage, with work focused on developing compounds that could be tested in humans.
As for the clinical implications of the research so far, Dr. Tuveson said: "We don't firmly say that taking antioxidants is dangerous for cancer patients...but I do believe that our article will cause those discussions to begin."
However, others have already warned cancer patients not to take antioxidants; for instance, prostate cancer patients have been warned against taking selenium, as previously reported by Medscape Medical News.
In addition, there is a question of whether antioxidants may interfere with common cancer treatments, such as chemotherapy and radiotherapy, as these work by increasing oxidation within cancer cells, Dr. Tuveson commented. This is an area that needs to be studied more, he said.
This issue of antioxidants being harmful to cancer patients was raised last year by Nobel laureate James Watson, PhD, who is chancellor emeritus at the Cold Spring Harbor Laboratory. He described a new hypothesis on reactive oxygen species that he considers is "among my most important work since the double helix."
Dr. Watson proposed that antioxidant levels within cancer cells are a problem and are responsible for resistance to treatment, and that the untreatability of late-stage cancer might be the result of "its possession of too many antioxidants."
"The time has come to seriously ask whether antioxidant use more likely causes than prevents cancer," Dr. Watson said. Nutritional intervention trials have shown no obvious effectiveness in preventing cancer or in lengthening mortality, and, "in fact, they seem to slightly shorten the lives of those who take them."

HIGH CHOLESTEROL MAY INCREASE BREAST CANCER RISK

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A link has been found between high blood cholesterol and breast cancer risk in a large retrospective cross-sectional study,according to research presented at Frontiers in CardioVascular Biology 2014 in Barcelona, Spain.
However, the lead investigator cautioned that this is a preliminary finding, and experts have noted that the study did not control for obesity, which is known to be associated with breast cancer.
The study "only suggests an association between high cholesterol and breast cancer," said presenter Rahul Potluri, MD, from the Aston University School of Medical Sciences in Birmingham, United Kingdom.
He warned against overstating the findings. "Further research is required before anything can be confirmed. However, 10 to 15 years down the line, if further prospective studies confirm these findings, there is the possibility for a clinical trial on the use of statins in the prevention of breast cancer," he told Medscape Medical News.
Retrospective Analysis
Dr. Potluri said the team was prompted to study the possible link after research in mice suggested that lowering circulating cholesterol or interfering with its metabolism could be used to prevent or treat breast cancer (Science2013;342:1094-1098).
"We wanted to see if there were any associations between high cholesterol and breast cancer in a large sample," he explained.
He and his team conducted a retrospective analysis of a large clinical database of patient records from 2000 to 2013 in the United Kingdom.
Of the 664,159 women identified, 22,938 (3.5%) had high cholesterol and 9312 had breast cancer.
More women with high cholesterol than with normal cholesterol developed breast cancer (2.3% vs 1.4%)
In fact, having hyperlipidemia increased the risk for breast cancer by 1.64 times (95% confidence interval, 1.50 - 1.79).
"Further research is required to confirm this link before it can have any significance for patients," Dr. Potluri noted. "However, this provides a starting point."
Link Between Hypercholesterolemia and Breast Cancer No Surprise
"We have known for some time that obesity is associated with increased risk of breast cancer, especially in postmenopausal women," said Gabriel N. Hortobagyi, MD, professor of medicine in the Department of Breast Medical Oncology at the University of Texas M.D. Anderson Cancer Center in Houston, who was not involved in the study.
"There is also a large body of work that suggests that overweight or obese women with breast cancer have a higher risk of recurrence and death, despite receiving state-of-the-art treatment," he toldMedscape Medical News.
"There is also work that suggests that obesity and inflammation are linked and, of course, there is ample evidence that inflammation, obesity, and cardiovascular disease are linked. Obesity and the metabolic syndrome are also linked, so finding that hyperlipidemia and risk of breast cancer are associated is no surprise," he explained.
Dr. Hortobagyi also noted that data "suggest that patients with diabetes and breast cancer have a higher risk of recurrence, and that treatment of diabetes with metformin might be associated with reduced risk of recurrence of breast cancer."
On the basis of such data, Dr. Hortobagyi and his group are participating in a large adjuvant trial, led by the National Cancer Institute of Canada, looking at the addition of metformin to standard adjuvant therapy in primary breast cancer.
"That study has accrued more than 3500 patients but is not mature enough for analysis. This is an evolving story, and it is increasingly complex," he said.

CHOLESTEROL GUIDELINES

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Coupled with the guideline changes—the most surprising of which was abandoning LDL-cholesterol targets in favor of identifying four specific groups of patients who benefit from moderate- or high-dose statin therapy—the cholesterol scene is made complicated because other clinical guidelines, including those from Europe and Canada, also offer advice on treating patients at risk for atherosclerotic cardiovascular disease (ASCVD).
Given the confusion and controversyDr Pamela Morris(Medical University of South Carolina, Charleston) and colleagues published a state-of-the-art review of the clinical practice guidelines for the management of LDL-related risk in the July 15, 2014 issue of the Journal of the American College of Cardiology [1].
In it, they summarize the existing clinical guidelines of the ACC/AHA, the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS), the Canadian Cardiovascular Society (CCS), and the International Atherosclerosis Society (IAS), as well as clinical guidelines for the management of lipids in women, children, adolescents, and those with diabetes or chronic kidney disease (CKD). In doing so, they attempt to provide a clear picture of the guidelines' differences and similarities.
"It can be very confusing for healthcare providers," said Morris. "When I have a patient in my office, and it's a Hispanic woman who might have a little bit of renal insufficiency, what do I do? Do I follow the AHA guidelines for women, do I look to the CKD guidelines, or do I go to the ACC/AHA guidelines? There is some confusion regarding the multitude of available guidelines, and this confusion can result in suboptimal care of LDL-related risk."
Speaking with heartwire , Morris said that when she is speaking with other clinicians about the old and new clinical guidelines, the myriad of recommendations leads many of them to simply stay the course.
"They're doing the exact same thing they've always been doing," she said. "It's a barrier to change. So, hopefully, an article like this will help them understand previous guidelines and why the new guidelines were formulated. It will also help them understand that there are some similarities with the new guidelines, as well as some differences. I think if we can put it all in context, it might help them begin to implement new recommendations into their practice."
ACC/AHA Guidelines Launched in November 2013Reported by heartwire when they were published and later criticized, the ACC/AHA cholesterol guidelines recommend physicians treat four major primary- and secondary-prevention patient groups with statins. These four groups were selected because randomized, controlled clinical trials showed that the benefit of treatment outweighed the risk of adverse events. The four groups include:
  • Individuals with clinical atherosclerotic cardiovascular disease.
  • Individuals with LDL-cholesterol levels >190 mg/dL, such as those with familial hypercholesterolemia.
  • Individuals with diabetes aged 40 to 75 years old with LDL-cholesterol levels between 70 and 189 mg/dL and without evidence of ASCVD.
  • Individuals without evidence of ASCVD or diabetes but who have LDL-cholesterol levels between 70 and 189 mg/dL and a 10-year risk of ASCVD >7.5%.
The guidelines also recommend either moderate- or high-dose statin therapy, depending on the patient's risk. Those with ASCVD, for example, should be treated with a high-dose statin, such as atorvastatin 80 mg or rosuvastatin (Crestor, AstraZeneca) 40 mg, to achieve a 50% reduction in LDL-cholesterol levels.
To heartwire , Morris noted that while the new ACC/AHA practice guidelines abandon specific treatment targets, LDL remains the target of therapy, something it has in common with the other clinical guidelines. The majority of other practice guidelines continue to treat to specific LDL-cholesterol targets depending on patient risk and utilize low-dose statin therapy in certain patients (the US guidelines recommend low-dose statins only in those with a high risk of statin-related adverse events).
"LDL is still the lipoprotein of interest," said Morris of the 2013 ACC/AHA practice guidelines. "There might be variations in how you measure it. The big difference now is that there are no longer goals for how low to get it. And this is really unique to two sets of guidelines. It's unique to the ACC/AHA guidelines, and interestingly it's also a part of the new CKD guidelines, the new [Kidney Disease: Improving Global Outcomes] KDIGO guidelines. Again, in those guidelines, you start statin therapy at a fixed dose and there is no LDL-cholesterol goal."
New Risk Assessment Tool
In addition to coming under fire from those who believed the new guidelines opened the floodgates to treating more and more individuals with statins, especially those without ASCVD, the ACC/AHA guidelines had a rocky launch when two independent researchers reported that the algorithm used to assess the 10-year risk of ASCVD overestimated risk by 75% to 150% in three cohorts. The new risk-assessment calculator departs from the Framingham Risk Score (FRS) and was developed by an ACC/AHA expert panel who authored the 2013 guidelines for the management of patient risk.
"I think this change is important, that we now have a brand-new risk assessment tool," said Morris. "For decades we've been using different iterations of the Framingham Risk Score, whether it's the 10-year risk or lifetime risk. The new risk-assessment tool does have some limitations in terms of ethnic groups. It applies only to non-Hispanic whites and non-Hispanic African-Americans."
On the whole, however, the use of different risk calculators across the different guidelines makes sense, said Morris. These calculators should be tested and validated in the group of patients to which they are being applied.
Other Forms of Dyslipidemia
To heartwire , Morris said the older ATP III guidelines addressed how to treat most forms of dyslipidemia, including patients who would require a statin plus another LDL-lowering agent, such as cholesterol absorption inhibitors, bile-acid sequestrants, LDL apheresis, or newer drug therapies. The 2013 ACC/AHA guidelines are simplified and focus entirely on managing ASCVD risk caused by LDL cholesterol. Morris said this is appropriate given that this is where researchers have accumulated the most evidence. For example, there is very limited evidence supporting raising HDL or lowering triglycerides alone for the reduction of cardiovascular outcomes, she said.
The American Association of Clinical Endocrinologists (AACE) and the National Lipid Association(NLA) do not support the ACC/AHA guidelines, instead recommending that their members follow their own clinical guidelines for the management of cholesterol and CVD risk.
While Morris said she couldn't speak to why these two societies chose not to endorse the 2013 ACC/AHA guidelines, she suspects they still believe that treating to lower and lower goals still offers meaningful clinical benefits to the patient. In contrast to the ACC/AHA guidelines, which focused on randomized, controlled clinical trials only to support the recommendations, clinical lipidologists will often cite the totality of evidence, including animal and pathophysiologic studies of atherosclerosis, supporting lower LDL-cholesterol targets to decrease the risk of cardiovascular events.